Guidelines for the Clinical Management of HIV Infection in Adults and Adolescents

National AIDS-STD control programme Department of Health, Ministry of Health Myanmar

Second Edition July 2007

Table of Contents List of experts who developed the guidelines..............................................................................................3 List of abbreviations ......................................................................................................................................4 Introduction and Objectives .........................................................................................................................6 HIV testing......................................................................................................................................................8 Two test Strategy for use in the general population ....................................................................................8 Three test Strategy for use in Pregnant Women ..........................................................................................9 Voluntary confidential counselling and testing ........................................................................................10 Clinical Assessment .....................................................................................................................................11 WHO Clinical Staging of HIV Disease ......................................................................................................11 Medical History and symptom check list ...................................................................................................12 Physical examination checklist ..................................................................................................................13 Management and follow up plan based on WHO staging .........................................................................14 Visit schedule and follow up for patients commencing ART .....................................................................15 Assessment of Patients’ readiness for therapy...........................................................................................15 Initiating Antiretroviral Therapy ..............................................................................................................16 Goals of Antiretroviral therapy..................................................................................................................16 Mechanisms of action of antiretrovirals ....................................................................................................16 Classification of antiretrovirals by class ...................................................................................................16 When to start antiretroviral therapy in adults and adolescents ................................................................17 CD4 testing not available...........................................................................................................................17 CD4 testing available .................................................................................................................................17 Commencing ART in the presence of active opportunistic infections .......................................................17 Managing opportunistic infections before starting antiretroviral therapy...............................................18 Recommended first line antiretroviral regimens .......................................................................................19 Starting ARV – What to expect and what to do..........................................................................................20 Triple NRTI-based regimens ......................................................................................................................20 Use of protease inhibitors (PIs) in initial therapy.....................................................................................20 Starting and stopping NNRTIs ...................................................................................................................21 ARV combinations not recommended ........................................................................................................21 Immune reconstitution inflammatory syndrome (IRIS) .............................................................................21 Adherence ...................................................................................................................................................23 Clinical and laboratory monitoring prior to commencing and on first line ART.....................................25 Antiretroviral drug toxicities......................................................................................................................26 Class adverse drug reactions to nucleoside reverse transcriptase inhibitors ..........................................26 Class adverse drug reactions to non-nucleoside reverse transcriptase inhibitors...................................26 Class adverse drug reactions to protease inhibitors (PIs) ........................................................................26 Symptom directed toxicity management table............................................................................................28 Individual drug substitutions for toxicity and intolerance ........................................................................29 Notes on Stavudine (d4T) ...........................................................................................................................29 Considerations for specific patients...........................................................................................................31 ART for women of childbearing potential or who are pregnant ...............................................................31 Interaction between ART and hormonal contraceptives ...........................................................................32 Initiating ART in pregnant women.............................................................................................................32 ART in Tuberculosis/HIV co-infection.......................................................................................................33 Initiating ART in patients with active TB...................................................................................................33 Recommendations for patients on ART who develop active TB ................................................................33 Second line ART for patients with TB indicating first-line ART failure....................................................33 Antiretroviral therapy for IDUs .................................................................................................................35 Viral hepatitis and chronic liver disease ...................................................................................................36 Opiod substitution therapy .........................................................................................................................36 HIV and Hepatitis Co-infection..................................................................................................................38 Hepatitis B infection ...................................................................................................................................38 Hepatitis C infection...................................................................................................................................39 ART failure and when to switch therapy ..................................................................................................40 Defining failure...........................................................................................................................................40 Immunological criteria for failure .............................................................................................................41 Choice of second-line regimens for treatment failure ...............................................................................42 Boosted PI/NRTI combinations..................................................................................................................42 Symptom directed toxicity management table for SECOND line ARVs....................................................42 Prevention of Mother to Child Transmission...........................................................................................44 The comprehensive strategic approach .....................................................................................................44

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Counselling for PMCT ...............................................................................................................................45 ARV prophylaxis for PMCT .......................................................................................................................45 Nevirapine resistance and its prevention...................................................................................................46 Doses of antiretroviral prophylaxis drugs for PMCT ...............................................................................47 Post exposure prophylaxis ..........................................................................................................................50 Occupational and non-occupational exposure prophylaxis......................................................................50 Occupational post exposure prophylaxis...................................................................................................51 Components of occupational PEP .............................................................................................................51 Antiretrovirals for PEP ..............................................................................................................................54 Non-occupation post exposure prophylaxis (nPEP)..................................................................................54 Summary of recommendations for occupational and non-occupational PEP ..........................................56 Syndromic approach to the management of opportunistic infections...................................................57 Annexes .........................................................................................................................................................75 Annex 1 Criteria for HIV-Related Clinical Events in Adults and Adolescents .........................................75 Annex 2 Dosages of antiretroviral drugs for adults and adolescents .......................................................79 Annex 3 Storage of Antiretrovirals ............................................................................................................81 Annex 4 Drugs that interact with ART .......................................................................................................82 Annex 5 Clinical diagnosis and management of common opportunistic infections .................................86 References .....................................................................................................................................................89

List of experts who developed the guidelines 1. 2. 3. 4. 5. 6. 7.

Dr Min Thwe Dr Win Maung Dr Htin Aung Dr Aung San Dr Chit Htun Dr Htin Aung Saw Dr Khin Yi Oo

8. Dr Phyu Noe 9. Prof Rai Mra 10. Prof Samuel Kyaw Hla 11. Dr Win Myat Aye 12. Prof Khin May Ohn 13. Dr Riitta Dlodlo 14. Dr Yasuda Tadashi 15. Dr Angela Bailey 16. Dr Anorla Bailei 17. Dr Lianne Kuppens 18. Dr Ying Ru Lo 19. Mrs Phavady Bollen 20. Dr Oscar Barreneche 21. Dr Catrina Casalini 22. Dr Chris Duncombe

National AIDS programme manager National TB programme manager National AIDS programme C. S. Specialist Hospital, Waibargi, N Okkalapa, Yangon Lecturer/Consultant Physician C. S. Specialist Hospital, Waibargi, N Okkalapa, Yangon Head/Consultant Virologist, National Health Laboratory, Yangon National TB programme Yangon General Hospital Consultant Paediatrician, Thingangyun Hospital Consultant Paediatrician, Magway Head, Department of Medicine, Institute of Medicine 2 HIV programme coordinator, IUATLD UNICEF, Myanmar AZG, Myanmar (REPLACE) AZG, Myanmar WHO Myanmar WHO South EAST Asia Regional Office (SEARO) WHO Myanmar WHO Myanmar WHO TB group WHO Consultant (Editor)

Acknowledgement The authors wish to acknowledge the contribution of the WHO South EAST Asia Regional Office (SEARO) for the source material used in these guidelines: Management of HIV infection and antiretroviral therapy in adults and adolescents: A clinical Manual WHO South East Asia Regional Office (2006)

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List of abbreviations TC AB ABC AFB AIDS ALT ANC ART ARV AST ATS ATV AZT b.d. CD4 count CMV CNS CSF CTX CXR d4T ddI DOT EC EFV FBC FDA FDC FPV FTC GI HDL Hb HBV HCV hgc HIV HSV IDV INH IRIS LPV MTCT NFV NNRTI nPEP NRTI NVP OHL OST PCP PEP PGL

lamivudine antibody abacavir acid-fast bacilli acquired immunodeficiency syndrome alanine aminotransferase Absolute Neutrophil count antiretroviral therapy antiretroviral (drug) aspartate aminotransferase amphetamine type stimulants atazanavir zidovudine (also known as ZDV) twice daily CD4+ T-lymphocyte cytomegalovirus central nervous system cerebrospinal fluid co-trimoxazole chest X-ray stavudine didanosine directly observed therapy enteric-coated efavirenz full blood count Food and Drug Administration fixed-dose combination fos-amprenavir furthicitibine gastrointestinal high-density lipoprotein haemoglobin hepatitis B virus hepatitis C virus hard gel capsule human immunodeficiency virus herpes simplex virus indinavir isoniazid immune reconstitution inflammatory syndrome lopinavir mother-to-child transmission (of HIV) nelfinavir non-nucleoside reverse transcriptase inhibitor Non-occupational post exposure prophylaxis nucleoside reverse transcriptase inhibitor nevirapine oral hairy leukoplakia opioid substitution treatment Pneumocystis pneumonia Post exposure prophylaxis persistent generalized lymphadenopathy

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PI PK PML PMTCT PPE /r RBV RTI RTV SEARO SJS SDN SQV TB TDF TLC VL US WBC WHO

protease inhibitor pharmacokinetic progressive multifocal leukoencephalopathy prevention of mother-to-child transmission (of HIV) pruritic papular eruption low-dose ritonavir Ribavirin reverse transcriptase inhibitor ritonavir World Health Organization, South East Asia Regional Office Stevens-Johnson syndrome Single dose nevirapine saquinavir tuberculosis tenofovir disoproxil fumarate total lymphocyte count viral load United States of America white blood cell count World Health Organization

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Introduction and Objectives This is the second edition of the Guidelines for the Clinical Management of HIV Infection in Adults and Adolescents and is fully updated from the first edition published in 2004. It was developed by an expert writing committee in collaboration with the National AIDS-STD Control Programme (NAP), Department of Health, Ministry of Health, Myanmar, for use by health facilities at state-divisional, district and township levels as well as by the private medical sector in Myanmar. It reflects consensus obtained after a series of working meetings with NAP experts, medical and laboratory specialists, NGOs and the World Health Organization (WHO). It is the intention of the writing committee to produce a single guideline applicable for use by the public, private and NGOs sectors in Myanmar. The guidelines include flexibility in the recommendations to accommodate different treatment strategies depending on individual program resources and the capacity to deliver care. Material and recommendations contained in this second edition have undergone peer review by expert clinicians in Myanmar and by external reviewers. Antiretroviral therapy (ART) is now considered an integral part of the comprehensive response to HIV prevention, care and support. These guidelines employ a public health approach to the delivery of comprehensive HIV care, including ART, using standardized ARV regimens provided through a simplified approach and supported by clinical and basic laboratory monitoring. There are three broad sections to the guidelines: •

Initial Assessment and patient management planning

•

Using antiretroviral therapy

•

Prevention and treatment of opportunistic infections

In 2006, WHO (Head Quarters, Geneva) published Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-Limited Settings: Towards Universal Access: Recommendations for a Public Health Approach as part of a series of updates on HIV care for adults and children, new recommendations on the use of cotrimoxazole prophylaxis, HIV disease staging and the prevention of mother to child transmission. Revised guidlines for post exposure prophylaxis are in preparation. The WHO South East Asia Regional Office (SEARO) has also produced two new publications for use in the region. These are: Management of HIV infection and antiretroviral therapy in children: A clinical Manual Management of HIV infection and antiretroviral therapy in adults and adolescents: A clinical Manual These global and regional WHO publications and recommendations from expert physicians and program managers in Myanmar are the basis of information included in this second guideline edition.

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Key new recommendations are: •

Choices for first-line ARVs have been broadened

•

Dosing of stavudine (d4T) is changed following new WHO recommendations that 30mg BID should be given to all patients irrespective of body weight. The previous recommendation was 40 mg BID for those ≥ 60kg and 30mg BID for those< 60 kg1

•

Recognition and management of the toxicities of Stavudine (d4T)

•

Recognition and management of Immune Reconstitution Inflammatory Syndrome (IRIS)

•

Clear guidlines on how to safely stop NNRTIs in chronic HIV infection and in the setting of PMCT to limit the development of resistance

•

Earlier initiation of ART before CD4 count drops below less 200 cells/mm3

•

The use of cotrimoxazole prophylaxis to prevent bacterial infections and malaria in addition to the “classic” prevention of PCP and toxoplasmosis

•

Expanded PMCT interventions

•

Updated guidelines for occupational and non-occupation post exposure prophylaxis

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1

Chapter

HIV testing Two test Strategy for use in the general population PRE-TEST education and/or counseling Ensure Informed Consent First HIV test (screening)

Positive test result*

NEGATIVE test result: Counsel for negative

Second HIV test

POSITIVE test result: Counsel for positive result

Negative test result

INCONCLUSIVE result** Repeat HIV test in 6 weeks

Positive test result

NEGATIVE test result: Counsel for negative result

Second HIV test

POSITIVE test result: Counsel for positive result

Negative test result

Notes The second test should use a different principle. When the population tested has an HIV prevalence of less than 10% the WHO/UNAIDS advise a third confirmatory test to reduce the risk of false positives. In the context of late pregnancy or labour, it is advised to give a single dose of nevirapine on the basis of a single positive rapid test. Where a result is inconclusive, this should be reported to the person being tested. Post-test counselling should focus on the possibility of the test being performed during the “window period”, i.e., when antibodies have not yet formed after exposure to HIV.

Three test Strategy for use in Pregnant Women Pre-test education and/ or counseling and ensure informed consent

First HIV antibody test a

Negative test result Counsel for negative result

Positive test result

Second HIV antibody test a

Positive test result

Person has signs/symptoms consistent with HIV

In the setting of PMCT

Positive test result: Counsel for positive result

Confirm by third specific HIV test

Negative test result

Inconclusive result b Repeat HIV test in 6 weeks

Positive test result: Counsel for positive result

Negative

Follow assessment and management procedures after HIV diagnosis is confirmed

Indeterminate Recheck 6 weeks

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2

Chapter

Voluntary confidential counselling and testing VCCT is an integral part of HIV prevention and care for people who want to know their HIV status in order to make an informed decision to be tested for HIV Pre test counselling All clients who request HIV testing should receive information: • The risks for transmission and how HIV can be prevented. • The benefits and consequences of HIV testing • The testing process • Assurance about confidentiality • The meaning of the test results in understandable language

Post test counselling • Clients should be counselled for a positive or a negative result and have the result explained • Clients should be assured of confidentiality In case of positive results, the counsellor needs to: • Provide emotional support • Assess the individual’s ability to cope • Assess the social support available • Explain how to prevent HIV transmission to uninfected or untested partners • Encourage individuals to share their HIV status with their sexual partners • Refer the individual for clinical monitoring and follow up and to evaluate the need for ART In case of negative results, the counsellor needs to: • Encourage the HIV negative individual to adopt safe practices (condom use) • Explain that the individual has to be tested again in 6 to 8 weeks in case if the first test was performed during the “window period”. • Explain that a negative test performed during “window period” may not mean that the individual is definitively uninfected.

Clinical Assessment WHO Clinical Staging of HIV Disease The revised WHO clinical classification of HIV-associated disease is designed to be used in patients with confirmed HIV infection. Along with CD4 count testing, where available, the staging system is used to guide decisions on when to start opportunistic infection (OI) prophylaxis and when to start and switch ART.

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Chapter

Clinical stage 1 (Asymptomatic) Asymptomatic Persistent generalized lymphadenopathy Clinical stage 2 (Mild disease) Moderate unexplained weight loss (10% of presumed or measured body weight ) Unexplained chronic diarrhoea for longer than one month Unexplained persistent fever (intermittent or constant for longer than one month) Persistent oral candidiasis Oral hairy leukoplakia Pulmonary tuberculosis Severe bacterial infections (e.g. pneumonia, empyema, pyomyositis, bone or joint infection, meningitis, bacteraemia) Acute necrotizing ulcerative stomatitis, gingivitis or periodontitis Unexplained anaemia (10% of body weight • diarrhoea lasting of more than 2 weeks • oral thrush • persistent headache • persistent cough • mucocutaneous manifestations (seborrheic dermatitis, prurigo, recurrent oral ulceration) Symptom directed laboratory evaluation (if available) • Full blood count • ALT • Sputum smear for TB when productive cough • Total lymphocyte count or CD4 cell count Follow up STI management counselling as for stage 1 patients Cotrimoxazole prophylaxis Start prophylaxis in all patients with WHO stage 2, 3 and 4 disease If CD4 testing is available, start prophylaxis in patients with: • Any WHO clinical stage and CD4 < 200 cells/mm3 where the aim of cotrimoxazole prophylaxis is the prevention of PCP and toxoplasmosis. • Any WHO clinical stage CD4< 350 cells/mm3 where the aim of cotrimoxazole prophylaxis is the reduction of morbidity and mortality associated with malaria, bacterial diarrhoeal disease and bacterial pneumonias in addition to the prevention of PCP and toxoplasmosis Dose One double strength tablet or two single strength tablets once daily Total daily dose is 960 mg (800 mg SMZ + 160 mg TMP)

Frequency of follow up depends on the patient’s individual condition. Frequent visits are recommended at initiation of ART (1-2 weekly) then 1-3 monthly once the patient is stable on ART. The main objectives of examination are to detect signs and symptoms of Immune Inflammatory Reconstitution Syndrome (IRIS) and OIs including pulmonary or extra pulmonary tuberculosis. Symptom directed laboratory evaluation (if available) • Full blood count • ALT • Sputum smear for TB when productive cough • Total lymphocyte count or CD4 cell count Start opportunistic infections (OI) prophylaxis Start cotrimoxazole (sulfamethoxazole 800 mg and trimethoprim 160 mg) P0 daily if symptom of stage III or stage IV.

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Visit schedule and follow up for patients commencing ART Visit (any time if new problems occur)

First visit

Week 2

Week 4

Week 8

Follow-up

ART medically indicated CD4 count < 350 especially close to 200 CD4 250 If EFV is not available, option in patients receiving rifampicin are NVP, a PI based or a tripled nucleoside regimen. EFV may be used in women if they use consistent and reliable contraception EFV may be used on the second and third trimester of pregnancy d4T may continue to be used by many programs due to its availability and no requirements for laboratory monitoring. d4T has significant toxicities (lipoatrophy, lactic acidosis, peripheral neuropathy)

TDF* + 3TC + (NVP or EFV)

TDF is unavailable in many countries but this may change

Triple NRTI

Inferior virological response but keeps 2 classes to second line

Other options

Note * Preferred NRTIs ABC is not available in Myanmar and is not included in the first line recommendations

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Starting ARV – What to expect and what to do Drug Didanosine (ddI) Lamivudine (3TC)

What to expect

When

Hepatitis Pancreatitis Lactic acidosis Generally well tolerated Peripheral neuropathy

What to do

Anytime Anytime 3-12 months

Stop and change when stable

6-12 months

Stop, consider dose reduction Stop d4T before lipoatrophy is severe since it is usually not reversible Stop if acidosis

Lipoatrophy (fat loss) and progressive weight loss

6-24 months

Lactic acidosis

Anytime

Nausea, headache, fatigue

At commencement often resolves after 2 weeks

Anemia, neutropaenia

Anytime

Myopathy – muscle pain and muscle loss

6-24 months

Efavirenz (EFV)

Rash often self limiting

2-4 weeks

Try to treat through with antihistamines

Nevirapine (NVP)

Rash Hepatitis

At start of NVP or at time of dose escalation at 2 weeks

Stop if moderate -severe

Stavudine (d4T)

Zidovudine (AZT)

Take with food Paracetamol Check CBC 2-4 weeks after starting and regularly Stop AZT if severe

Note: Lead in NVP dosing at 200 mg once daily for the first 2 weeks produces adequate NVP drug levels. Due to enzyme auto induction, NVP levels decline over 2 weeks and dose escalation to 200 mg BID is required to maintain adequate levels. Starting NVP 200 mg BID without lead in dosing results in high serum concentrations of NVP and increased risk of rash and hepatoxicity. If nevirapine is restarted after more than 14 days of treatment interruption, lead-in dosing (200mg OD for 2 weeks, then200mg BID) is again necessary. Triple NRTI-based regimens Triple NRTI regimens are inferior to NRTI/NNRTI regimens.8 9 10 11 AZT+3TC+ABC may be considered in patients with intolerance or resistance to NNRTIs when PI-based regimens are unavailable, to preserve second-line options, for the treatment of HIV-2 infection and for the treatment of HIV/TB co-infected patients receiving rifampicin. Use of protease inhibitors (PIs) in initial therapy PIs are not recommended in first line regimens because the use of PIs in an initial treatment regimen essentially rules out second-line options in the setting of limited drug availability. PIs may be considered in first line regimens (with a standard dual NRTI backbone) for the treatment of HIV-2 infection, in women with CD4 count of 250-350 cells/mm3 who require ART and who cannot take efavirenz or in patients with NNRTI intolerance.

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Starting and stopping NNRTIs Starting Nevirapine AM Lead in NVP dose for the first 2 weeks

Escalate to full NVP dose after 2 weeks

PM

FDC (AZT or d4T + 3TC + NVP) One pill

(AZT or d4T) + 3TC One separate pill each OR FDC (AZT or d4T +3TC) One pill

FDC (AZT or d4T + 3TC + NVP) One pill

FDC (AZT or d4T + 3TC + NVP) One pill

Stopping either NVP or EFV Stop NVP or EFV Continue NRTI backbone (2 drugs only) for 7 days then stop all drugs. This is to cover the long half life of NNRTI decay and reduce the risk of NNRTI resistance

ARV combinations not recommended ARV combinations

Reason not to use

Monotherapy or dual therapy to treat chronic HIV infection d4T + AZT d4T + ddI

Rapid development of resistance Antagonism (reduced levels of both drugs) Overlapping toxicities (pancreatitis, hepatitis, lipoatrophy) Deaths reported in pregnant women Interchangeable, but should not be used together Select for K65R mutation and are associated with high incidence of early virological failure High incidence of early virological failure

3TC + FTC TDF + 3TC + ABC or TDF + 3TC + ddI TDF + ddI + any NNRTI

Immune reconstitution inflammatory syndrome (IRIS) Definition

Frequency Timing Signs and symptoms

A reaction against a foreign antigen (alive or dead) in patients who have started ART and have undergone a reconstitution of their immune responses against this antigen. MTB accounts for approximately 1/3 of all IRIS events 10% of all patients initiating ART Up to 25% among patients initiating ART with a CD4 cell count < 50 cells/mm3.12 13

Typically within 2-12 weeks of initiation of ART but may present later Unexpected deterioration of clinical status soon after commencing ART Unmasking of subclinical infections such as TB, which present as new active disease Worsening of co-existing infections such a flare of hepatitis B or C

Most common IRIS events

60% of IRIS events are M.Tuberculosis, MAC or cryptococcal disease 14

Management

IRIS may be mild and resolve without treatment. Continue ART if possible. Treat unmasked active OI, such as TB. This may mean temporary interruption of ART until the patient is stable on TB drugs, then reintroduction of ART. Corticosteroid treatment to suppress exaggerated inflammatory response may be indicated. For example, an acute hepatic flare where viral hepatitis coinfection is known or suspected. If the patient is taking nevirapine, clinical hepatitis and/or rising hepatic enzymes in association with rash and fever is more likely to be due to nevirapine than IRIS and switching to efavirenz is recommended. Prednisone 0.5mg/kg/day for 5-10 days is suggested in moderate to severe cases of IRIS.15

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Unexpected deterioration in clinical condition with signs and symptoms of inflammation/infection soon after commencing ART (Typically 2-12 weeks)

Suspect IRIS a

CNS symptoms

Reported IRIS Events Cryptococcal meningitis TB meningitis or abscess Toxoplasmosis PML CMV Lymphoma

Hepatobiliary symptoms

Reported IRIS Events Flare of hepatitis B or C Visceral leishmaniasis TB abscess

Fever without localizing signs

Reported IRIS Events Disseminated TB Invasive fungal disease MAC

a. A paradoxical reaction against a foreign antigen (alive or dead) in patients who have started ART and have undergone a reconstitution of their immune responses against this antigen. MTB accounts for approx. 1/3 of all IRIS events

Management Principles

CMV

Focal adenopathy

Reported IRIS Events Extra pulmonary TB MAC Kaposi’s sarcoma Histoplasmosis

Respiratory symptoms with worsening CXR changes

Reported IRIS Events Pulmonary TB Invasive fungal pneumonia PCP (if not on cotrimoxazole)

Mucocutaneous conditions

Auto immune diseases

Reported IRIS Events Herpes zoster and helped simplex HPV infection (warts) Molluscum contagiosum Kaposi’s sarcoma Psoriasis Eczema, folliculitis, PPE Leprosy Muco cutaneous leishmaniasis Reported IRIS Events Sarcoidosis Graves disease Guillain Barré Syndrome Reiter’s syndrome

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Continue ART if possible Diagnose and treat the specific pathogen in order to decrease the antigen load Consider corticosteroids in moderate to severe cases of IRIS (Prednisolone (or prednisone) at 0.5 mg/kg/ day orally or IV for five to ten days or longer depending on the severity of the inflammation Discontinue ART and prioritize treatment of the pathogen in patients who are severely unwell Aspiration and drainage of lymph nodes and abscesses (may need to be repeated several times) Emergency surgical decompression in cases of trachea or intestinal obstruction

Adherence The most common reason for ART failure is poor adherence. Adherence should be assessed and routinely reinforced at every clinic visit. A high degree of adherence to ARV drugs is necessary for optimal virological suppression. Studies indicate that 90-95% of the doses should be taken for optimal suppression and lesser degrees of adherence are more often associated with virological failure.16 Maintaining this level of adherence is difficult. Imperfect adherence is common and surveys indicate that onethird of patients missed doses within 3 days of survey.17 Factors that are associated with poor adherence include poor patient-clinician relationship, high pill burden, forgetfulness, mental depression, lack of patient education, inability of patients to identify their medications, drug toxicity and being too ill.18 Key Elements of treatment adherence counselling • Establishing trusting relationship with health workers • Providing necessary information and advice • Encouraging peer participation and help identify treatment support persons/organizations • Developing individual treatment plan fitting ART into patient’s lifestyle/daily events and identifying treatment reminders • Assessing readiness and commitment of patients for ART. Readiness to commence ART may be assessed by: − past ability to attend regular clinic visits and not miss appointments − past ability to take OI prophylaxis, such as cotrimoxazole − past ability to complete full course of TB therapy − adequate understanding • Treatment adherence should be strict and adherence to recommended regimens should be greater than 95% to avoid resistance. This means that missing more than 3 doses per month is associated with increased risk of drug resistance and failure • If regular dose are missed or lat, reinforce adherence counselling. Enlist community outreach teams and PLHA peer support groups as appropriate • Treatment has to be continued for life. • Timing of drug intake is critical (e.g. drugs taken twice daily must be taken every 12 hours+/- one hour). • Missed doses can be taken up to 6 hours in a BID regimen. If > 6 hours late, skip dose and take next normal dose • Some drugs are taken with food, some drugs are taken on an empty stomach, and some require an increase intake of water. • Drug side effects have to be understood and explained to the patient in advance of commencing ART • People on ART need to continue to use condoms regularly and practice safe injecting use. • Other medications, including herbal products, may interact with ART. Patients need careful counselling about which medications are allowed and which are not permitted with their ART • Regular clinic attendance for monitoring of efficacy and adherence is essential • If patient cannot make clinic appointment, they need to call or make home visit

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The treatment regimen should be simplified by reducing the number of pills, reducing the frequency of therapy such as twice daily dosing, and minimizing side effects. Simplified regimens improve adherence. Adherence may be measured by patient self-report, pill count, and the report of the primary care provider. The pre-enrolment information and counselling process The process of offering information, counselling and adherence support must be carried out by staff (counsellors and/or PLHA) who understands the problems in the lives of PLHA. There are 3 steps in this process. In some cases all 3 steps may be carried out during one session. Step 1 – Giving information Clients are given basic information enabling them to understand the need for a high level of commitment to treatment and adherence. Information can be provided to a group of PLHA if the facilitator has some understanding of group dynamics and is able to stimulate group discussion. Step 2 – Counselling – in one or more individual sessions Help the client explore his/her feelings. Many clients will be preoccupied with problems related to family, job, relationships etc, and cannot focus on strict adherence until they have released negative feelings about these problems Many will have no private place to store their medicines and will not be able to take them in secret. Not wanting others to know their HIV status is by far the commonest reason providers come across for poor adherence. The client needs to be realistic about who needs to know their HIV status and how to tell them. Step 3 – Solving practical problems and creating a treatment plan Where will the ARV drugs be stored? At what time will it be taken? Who will remind the clients to take it if he or she forgets? What will the client do if her or his normal routine is interrupted? A time should be arranged to meet or telephone the client within a few days in order to discuss any problems. Checklist to assess treatment adherence once ART is commenced • Number of doses missed in the last 3 days • Number of doses missed since last visit • If dose taken at correct time (if no, ask for delay in hours/days) • If correct dose taken • Specification of reasons for interruption or modification/failure to take doses • Estimated proportion of doses taken using visual analogue scale

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Clinical and laboratory monitoring prior to commencing and on first line ART Evaluation

Before or at ART start

W2

W4

W8

W 12

W 24

Every 6 Mnths

As needed

Clinical Clinical evaluation Weight Concomitant medications Check ART adherence Laboratory HIVAB test1 CD4 count Haemoglobin2 Pregnancy test3 VDRL/RPR Chemistry Serum lactate Viral Load4 1. Historical documented HIV antibody test is sufficient to commence ART. In the absence of documented, confirmed HIV antibody test, testing prior to commencing of ART is recommended 2. For patients receiving AZT; Haemoglobin monitoring prior to commencing AZT and at weeks 4, 8 and 12 and as required when taking AZT 3. Pregnancy testing for women initiating a first-line regimen containing EFV. Do not commence EFV if pregnancy test is positive and the woman is in the fist trimester 3. Pregnancy testing if pregnancy is suspected in women who are receiving an EFV-based regimen. Change to a non –EFV based regimen if the if the pregnancy test is positive and the woman is in the first trimester 4. chemistry includes liver and renal functions 5. HIV-RNA measurement is currently not recommended for decision-making on initiation or regular monitoring of ART in resource-limited settings. It may be considered to make the diagnosis of treatment failure earlier or to assess discordant clinical and CD4 findings in patients suspected of failing ART.

25

Antiretroviral drug toxicities Class adverse drug reactions to nucleoside reverse transcriptase inhibitors Acute lactic acidosis and severe hepatomegaly with steatosis during NsRTI use occur at a low frequency, but with a high risk of fatality. The incidence of lactic acidosis seems to be around 1%, while an increase in serum lactate levels can be found in as many as 5–21% of patients treated with NsRTI-containing regimens. While uncommon, lactic acidosis is associated with a high fatality rate (33–57%). The initial clinical manifestations of lactic acidosis are variable and may include non-specific gastrointestinal symptoms (weight loss, anorexia, nausea, vomiting, abdominal pain, diarrhoea) without dramatic increase of hepatic enzymes and, in some cases, dyspnoea and/or fatigue. Evaluation shows lactic acidosis with possibly elevated creatine phosphokinase (CPK), alanine transaminase (ALT), and/or lactate dehydrogenase (LDH), low bicarbonate and increased anion gap. All NsRTIs and tenofovir have been implicated but the syndrome is consistently reported at higher rates with the use of d4T or ddI. The combination of d4T and ddI is not recommended. The most important therapeutic intervention appears to be NsRTI withdrawal; the safety of substituting alternative drugs in this class is not known. This adverse event has been attributed to mitochondrial toxicity caused by NsRTIs. Other clinical expressions of mitochondrial toxicity include myopathy (AZT-related), dilated cardiomyopathy (AZT), peripheral neuropathy (d4T, ddI), pancreatitis (ddI, d4T, 3TC), bone marrow suppression (AZT) and/or lipoatrophy (d4T, AZT, ddI). Liver toxicity manifested as asymptomatic increases in liver transaminases, with normal bilirubinaemia, occurs in 5–15% of patients receiving NsRTIs. Class adverse drug reactions to non-nucleoside reverse transcriptase inhibitors Skin rash occurs most commonly with the NNRTI class of drugs. Most cases are mild-tomoderate in nature, occurring within the first few weeks of therapy. Management of NNRTIrelated skin rashes depends on the severity of the rash. In general, mild (grade1) and moderate (grade 2) rashes can be managed with symptomatic therapy (antihistamines) and careful monitoring (daily visits or daily telephone progress reports). If patients experience severe (grade 4) or life-threatening (grade 4) skin reactions, the drugs need to be stopped immediately. More serious cutaneous manifestations such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis should result in the prompt and permanent discontinuation of the NNRTI or other offending agents. Most cases of skin rash are confined to cutaneous reactions. However, a severe or even lifethreatening syndrome of drug rash with eosinophilia and systemic symptoms (DRESS) has also been described. The systemic symptoms may include fever, haematological abnormalities and multiple organ involvement. Among the NNRTIs, skin rash occurs more frequently and is greater in severity with NVP. Using a two-week lead-in dose escalation schedule when initiating NVP therapy may reduce the incidence of rash. Acute symptomatic hepatitis with jaundice, liver enlargement, gastrointestinal symptoms, fatigue and anorexia may occur. Hypersensitivity may manifest as rash, fever and other systemic symptoms, usually within 6–8 weeks of starting therapy. Lactic acidosis may occur. If adverse reactions occur, discontinue all ARVs until symptoms resolve. Transaminase and bilirubin levels should be monitored if possible. NVP should not be readministered in the future but ART should be restarted using alternative ARVs. Class adverse drug reactions to protease inhibitors (PIs) Hyperglycaemia New-onset diabetes mellitus, diabetic ketoacidosis, and exacerbation of existing diabetes mellitus, as well as hyperglycaemia, insulin resistance or glucose tolerance have all been reported in patients receiving PIs. Insulin resistance occurs in up to 40% of patients treated with PIs, while hyperglycaemia has been reported in 3–17% of patients receiving PIs with 1% of these patients develop clinical evidence of diabetes. The reversibility of these events is currently unknown, due to limited data and still limited follow up of patients. Some patients were able to continue PI therapy and initiated treatment with oral hypoglycaemic agents or insulin. 26

Fat redistribution Modifications in body fat distribution, lipodystrophy syndrome, fat redistribution syndrome are frequently (13–84%) observed in patients treated with PIs. These changes have also been described with NsRTI therapy (particularly with d4T-containing regimens). The most typical clinical findings include central obesity and peripheral fat wasting. The observed changes include visceral fat accumulation, dorsocervical fat accumulation (known as "buffalo hump"), extremity wasting with venous prominence, loss of buttock fat, facial thinning, breast enlargement and lipomatosis. Hyperlipidaemia Changes in blood levels of triglycerides and/or cholesterol have been observed very frequently, even in the absence of fat redistribution. Although all PIs have been implicated, RTV produces substantial increases in triglycerides and cholesterol most frequently, which reach higher blood levels than with other PIs. Monitoring serum triglycerides and cholesterol at regular intervals during treatment can be an option for the assessment of cardiovascular risk. However, a complete evaluation of all other independent cardiovascular risk factors (e.g. smoking, diet, weight, etc.) is necessary, and it should be suggested to patients to reduce these as much as possible. Intervention is usually recommended for triglyceride levels >750–1000 mg/dl and/or lowdensity lipoprotein (LDL) cholesterol levels >130 mg/dl (in individuals without known coronary disease and with two or more coronary risk factors) or >160 mg/dl (in individuals without known coronary disease and with fewer than two coronary risk factors). However, the effectiveness of dietary modifications and lipid-lowering drugs is not yet clear. In some cases, discontinuation of PIs was found to be beneficial; but such a decision requires a careful risk– benefit analysis. Time

Short term (the first few weeks)

Medium term (the first few months)

Long term (after 6-18 months)

Side Effects and Toxicities Gastrointestinal toxicities including nausea and vomiting, diarrhoea Rash Most rashes occur within the first 2-3 weeks Hepatoxicity More common in hepatitis B or C co-infection Drowsiness, dizziness, confusion, and vivid dreams are associated with the use of efavirenz. Normally self-resolving but can take weeks to months Anaemia and neutropaenia Sudden and acute AZT bone marrow suppression can occur within the first weeks of therapy or present as a slow onset of progressive anaemia over months Hyperpigmentation of skin, nails and mucous membranes Lactic acidosis can occur at any time More common after the first few months Most commonly associated with d4T Peripheral neuropathy can occur at any time More common after the first few months Pancreatitis can occur at any time Lipodystrophy and lipoatrophy

Common causes AZT, TDF, PIs NVP EFV Abacavir PIs (rarely) NVP, EFV PIs EFV

AZT AZT d4T, ddI, AZT d4T,ddI ddI d4T, ddI, AZT PIs

Dyslipidaemia

d4T,EFV,PIs

Diabetes

IDV PIs, especially IDV

Skin hair an nail abnormalities

27

Symptom directed toxicity management table Toxicity Causative ARVs Recommendations Acute pancreatitis d4T and ddI Discontinue ART. Supportive treatment and laboratory monitoring. Resume ART with an NRTI with low pancreatic toxicity risk. (AZT, ABC, TDF) Diarrhea ddI (buffered Usually self-limited, without need to discontinue formulation), NVF, ART. Symptomatic treatment should be offered. LPV/r SQV/r Drug eruptions (mild to NVP, EFV (rarely) In mild cases, antihistamines Moderate rash, non- progressing and without severe, including mucosal involvement or systemic signs, consider Stevens-Johnson a single NNRTI substitution (i.e., from NVP to syndrome or toxic EFV). In moderate and severe cases, discontinue epidermal necrolysis) ART and give supportive treatment. After resolution, resume ART with 3 NRTI or 2 NRTI + PI regimens. Dyslipidaemia, insulin PIs Consider replacing the suspected PI by drugs resistance and EFV with less risk of metabolic toxicity hyperglycemia GI intolerance All ARVs Usually self-limited, without need to discontinue ART. Symptomatic treatment should be offered. Hematological toxicities AZT If severe (Hg60 kg was recommended at 40 mg twice daily; dosing for patients 250) NVP is substituted for EFV with close monitoring in Women who are women with higher CD4 pregnant, are in the EFV should be discontinued and counts first trimester and are replaced with another drug Alternatively a PI-based or a taking EFV triple NRTI regimen could be substituted ART is recommended for postpartum breastfeeding women who meet the The preferred regimen is Women who are WHO criteria for initiation of therapy for AZT+3TC+NVP breast feeding their own health Women who have previously received SDN > 6 months single-dose NVP prophylaxis for NNRTI-based regimen prevention of MTCT should be Women who received SDN 350

Defer ART

CD4 not available

Recommend ART

Re-evaluate patient at 8 weeks and at the end of TB treatment 2-8 weeks

Choice of NRTI This is the same as for all HIV infected persons. Choice of NNRTI EFV is the preferred NNRTI. EFV blood levels are decreased in the presence of rifampicin. There is evidence standard EFV dosing of 600 mg/daily in patients with a weight 250 cells/mm3 in women and >400 cells/mm3 in men) are at higher risk for the development of symptomatic hepatic events, often associated with rash. The risk of symptomatic hepatic events regardless of severity is greatest in the first 6 weeks of therapy. However, hepatic events may occur at any time during treatment. In some cases, patients presented with nonspecific, prodromal signs or symptoms of fatigue, malaise, anorexia, nausea, jaundice, liver 35

tenderness or hepatomegaly, with or without initially abnormal serum transaminase levels Patients who have infection with hepatitis B or C and/or increased liver function tests at the start of therapy with NVP are at greater risk of later symptomatic events (6 weeks or more after starting NVP) and asymptomatic increases in AST or ALT. Serious psychiatric adverse experiences have been reported in patients treated with EFV. These include severe depression (2.4%, 0.9%), suicidal ideation, aggressive behavior, paranoid reactions and manic reactions. Viral hepatitis and chronic liver disease Co-infection with Hepatitis C is common in HIV infected IDUs. Chronic active infection with Hepatitis B and alcoholic liver disease are also common. Hepatotoxicity associated with these conditions complicates the choice of ART. The NRTIs with most hepatotoxicity are AZT, ddI or d4T. Both available NNRTIs can cause hepatotoxicity. NVP is more commonly associated with severe hepatotoxicity and should be avoided if possible in all patients with chronic liver disease.44 Efavirenz can be administered at full doses in patients with liver insufficiency. Protease inhibitors are also associated with hepatotoxicity. PI dosing is complex in patients with hepatic insufficiency 45. If drugs are available, the recommended treatment for HIV/HBV co-infection is TDF alone or in combination with 3TC or FTC as part of the ART regimen. 3TC should not be used alone due to rapid development of HBV resistance. Fatal cases of acute flare of HBV have been documented in HIV/HBV coinfected patients who discontinue 3TC monotherapy.46 47 Drugs for treating hepatitis C normally are not available in resource limited settings. Treatment is with pegylated interferon and ribavirin. There is no other treatment for hepatitis C. Patients should be stable on ART with CD4 >200 before pegylated interferon and ribavirin are commenced. AZT levels are increased by ribavirin and patients should be closely monitored for hepatic toxicity, neutropaenia, and anaemia. Other causes of hepatic dysfunction need to be considered in addition to viral hepatitis. Alcohol use/dependency has the same implication for treatment options and monitoring as does viral hepatitis. Where possible, the least hepatotoxic ARV should be used and hepatic enzymes monitored in all patients with hepatic dysfunction. Opiod substitution therapy OST is the most effective treatment for opioid dependence with substantially higher retention rates, suppression of drug use and improved psychosocial functioning. Its use in the context of HIV treatment has been associated with improved adherence and outcomes to treatment. Detoxification and abstinence based programs are unlikely to achieve similar levels of clinical effectiveness and may prove counterproductive in the context of ART. If possible, stabilization of substance use with substitution treatment is recommended prior to commencement of ART. Where substitution therapy is available, consideration should be given to offering HIV care and dispensing HIV medication at the same site where substitution therapy is delivered. This approach can achieve maximal levels of treatment supervision 36

which should enhance efficacy and reduce the risk of HIV drug resistance. In addition colocation of these services facilitates management of the drug-drug interactions between methadone and ART. Outcomes of OST in a structured program include: •

Decreased heroin use and reduced chaotic drug taking

•

Decreased needle sharing

•

Stabilization of client’s lives

•

Improved quality of life and the chance to lead a productive life in the community

•

Improved ability to commence and adhere to ART

37

HIV and Hepatitis Co-infection Hepatitis B infection Choice of ART Preferred first line ART Alternatives if TDF is unavailable

Drugs with anti-HBV therapy should be included in first line ART regimen for HIV-infected patients who are HBsAg+ (and HBeAg+ if known) TDF + (3TC or FTC) + EFV (AZT or d4T) + (3TC or FTC) + EFV (AZT or d4T) + (3TC or FTC) + NVP (See Choice of NNRTI below) In this case, 3TC (or FTC) will be the only drug with activity against hepatitis B • EFV is the preferred NNRTI option •

Choice of NNRTI

NVP should be used with care and regular monitoring in patients who have known HIV/HBV coinfection and grade 1, 2 or 3 elevation of ALT/AST

•

NVP is not recommended for patients with grade 4 or greater elevations of ALT/AST

Second line regimen

HBV Resistance

3TC be continued as part of second-line ART following initial ART failure, even if it was used in first-line regimen • Ideally, 3TC should be used either with TDF or not at all •

This may not be feasible in resource limited settings

•

HBV resistance to 3TC will develop in 50% of patients after two years and in 90% after four years of treatment if 3TC is the only active anti-hepatitis B drug in the ART regimen.

Therapy outcomes Hepatic flares

HBV seroconversion (loss of HBeAg and development of HBeAb) occurs in 11-22% of HBeAg-positive HIV-infected patients treated with 3TC for one year • Soon after initiation of ART as part of IRIS •

Discontinuation of 3TC also may result in hepatic flares

Hepatic flares Hepatic flares may occur •

Following initiation of ART as part of the immune reconstitution inflammatory syndrome (IRIS).

•

When ART is stopped

Flares typically present as unexpected increase in ALT/AST and symptoms of clinical hepatitis (fatigue, nausea, abdominal pain and jaundice) within 6-12 weeks of commencing ART. Flares may be difficult to distinguish from ART-induced hepatic toxicity. Drugs active against HBV should preferably be continued during a suspected flare. If it is not possible to distinguish a serious hepatitis B flare from grade 4 drug toxicity, all ART should be stopped until the patient stabilizes.

38

Hepatitis C infection HCV therapy

Therapy outcomes Side effects of interferon

Timing of HCV therapy

No ARVs are directly active against HCV. However, ART has been shown to delay progression of HCV liver disease in HCV/HIV coinfection The only effective treatment is pegylated interferon and ribavirin which are generally not available in resource limited settings48

Clinical trial outcomes •

HCV genotype 1: 15-28% sustained virological response rates

•

HCV genotype 2 and 3: 60-70% virological response rates

Up to 60% of individuals treated with IFN will experience mental health issues, mostly commonly depression. Monitor mental health closely. • Commence anti-HCV therapy before CD4 count drops to levels where ART is required •

If ART is required in HCV-positive patients, they should be stable on ART with a CD4 count >200 cells/mm3 before anti-HCV therapy is considered 40

Preferred first line ART

•

NRTI choice is the same as for HCV uninfected patients

•

EFV is the preferred NNRTI option

•

NVP should be used with care and regular monitoring in patients who have known HIV/HBV coinfection and grade 1, 2 or 3 elevation of ALT/AST

•

NVP is not recommended for patients with grade 4 or greater elevations of ALT/AST

•

Ribavirin and d4T/ddI - pancreatitis/lactic acidosis o

Drug interactions

•

Ribavirin and AZT - anaemia o

•

monitor closely

Interferon and EFV - depression o

Hepatic flares

do not co-administer

Monitor closely

Soon after initiation of ART as part of IRIS

39

7

Chapter

ART failure and when to switch therapy

Does the patient have good adherence to ART? [a]

No

Work with the patient to resolve issues causing nonadherence. Continue the same first line regimen, give OI prophylaxis of necessary and follow closely. Start second line therapy only after good adherence can be assured

Yes Signs or symptoms of IRIS or OI especially TB

Patient has been on ART for at least 6 months

Manage IRIS or OI Monitor response

Obtain CD4 count if possible before diagnosing failure

Patient improves after IRIS /OI management

Prepare the patient for second line regimen The regimen is like to be more complex Make sure the patient understands the new drugs, how to take them and possible side effects Reinforce adherence

No Diagnose treatment failure if OI present and on ART >6 months with good adherence

40

Yes

Continue first line ART

Defining failure Clinical failure Virological failure

New or recurrent WHO stage 4 condition after at least 6 months on ART Exceptions are TB, oesophageal candidiasis and severe bacterial infections which may not always represent ART failure Review response to therapy first and if response is good, do not switch Viral load >10,000 copies after at least 6 months on ART

Notes: ART failure cannot be diagnosed on clinical criteria grounds in the first 6 months on ART. Clinical events that occur before the first 6 months of therapy often represent IRIS and not failure. Immunological criteria for failure CD4 count

Pattern 3

Pattern 2

50 or 100

Pattern 1

12 months

6 months

Pattern 1 CD4 count < 100 cells/mm3 (some experts recommend 200 cells/mm3. Virological criteria for failure are included here as some countries in the region (such as India and Thailand) have increasing capacity to perform affordable viral load testing. Viral load remains the most sensitive indicator of ART failure. Recognizing early failure facilitates switching before multiple resistance mutations have developed to drugs in the first line regimen. The optimal viral load value at which ART should be switched has not been defined. 41

However, values of more than 5,000-10,000 copies/ml have been associated with subsequent clinical progression and appreciable CD4 cell count decline 49 50 51 52 53 Choice of second-line regimens for treatment failure Second Line Regimen First Line Regimen RTI Component*

PI Component

ddI + ABC or

Preferred regimens

AZT or d4T + 3TC +(NVP or EFV)

TDF + ABC or TDF + 3TC (± AZT)

PI/r

(or ddI + TDF ) (AZT or d4T) + 3TC EFV or NVP ± ddI Alternative regimen + (TDF or ABC) The entire treatment regimen needs be changed in the setting of treatment failure.

Boosted PI/NRTI combinations A ritonavir-boosted PI (PI/r) such as ATV/r, FPV/r, IDV/r, LPV/r or SQV/r is the backbone of all second line regimens. Unboosted PIs are not recommended with the exception of NFV if no ritonavir is available. Nelfinavir is less potent than a boosted PI. 54 55 Two unused NRTIs are added to the PI/r and ddI is a preferred NRTI.56 *If AZT or d4T are used in the first line regimen (as may be the case in many countries), TDF or ABC are included in all preferred second line regimens. If these drugs are not available, options are limited. ddI + 3TC (± AZT) may be the only option if ABC and TDF are not available. If preferred NRTIs are not available, some experts recommend supporting the

boosted PI component of the second line regimen with ddI plus retaining 3TC (+/-AZT), even though it was used in the first line.3TC reduces HIV fitness even if 3TC resistance is present. The combination of TDF and ddI plus and NNRTI is not recommended due to reports of early virological failure57, falling CD4 counts despite undetectable viral load58

59

and safety

concerns. TDF increases ddI exposure by 60% and intracellular ddI levels two fold60. There are also reports of renal and pancreatic toxicity. Although ddI and TDF are not recommended anymore, the combination is still mentioned as the drugs are still widely available in the public health sector. For those who received a triple NRTI first line regimen, the recommended combination is a boosted PI plus an NNRTI with the option to add ddI and/or 3TC to the boosted PI/NNRTI combination. 61 62 Symptom directed toxicity management table for SECOND line ARVs Toxicity Causative ARVs Recommendations Discontinue ART. Supportive treatment and Acute pancreatitis ddI laboratory monitoring. Start new regimen replacing ddI with ABC or TDF if available Usually self-limited, without need to discontinue NVF, ddI (buffered ART. Symptomatic treatment should be offered. formulation), LPV/r Diarrhea NFV is most commonly associated with SQV/r diarrhoea. Replace NFV with another PI 42

Dyslipidaemia

Insulin resistance and hyperglycemia Renal colic and calculi GI intolerance

PIs

Chol and TG elevations to grade 1or 2 Monitor, diet , exercise Chol and TG elevations to grade 3 or 4 Treat elevated TG with fibrates (fenofibate 600 mg 1-2 times per day Treat elevated chol with statins. Avoid simvastatin due to interactions with PIs (Annex 4)

Indinavir

Switch to a different PI

Indinavir

Drink 3l of fluid per day. Consider switching PIs Usually self-limited, without need to discontinue ART. Symptomatic treatment should be offered.

All ARVs

Hematological toxicities (particularly anemia and AZT leucopenia) LPV/r and other PIs Hepatitic dysfunction less commonly Hyperbilirubinaemia (indirect)

ATV, IDV

Hypersensitivity reaction

ABC

Lactic acidosis

All NRTIs (particularly d4T and ddI)

Lipoatrophy and lipodystrophy

All NRTIs (particularly d4T) and PIs

Renal toxicity ( renal tubular dysfunction)

TDF

Peripheral neuropathy

d4T and ddI

If severe (Hg5-fold the basal level, discontinue ART and monitor. After resolution, try a different PI Generally asymptomatic, but can cause scleral icterus (without ALT elevations). Replace ATV or IDV with another PI. Discontinue ABC and do not restart. Symptomatic treatment. Reexposure may lead to a severe and potentially life-threatening reaction. Discontinue ART and give supportive treatment. After clinical resolution, resume ART, replacing the offending ITRN. ABC, TDF and 3TC are less likely to cause this type of toxicity. Early replacement of the suspected ARV drug. Discontinue TDF and give supportive treatment. After clinical resolution, resume ART, replacing the offending drug. Consider replacement by an NRTI with minimal or no neurotoxicity (AZT, TDF or ABC). Symptomatic treatment should be considered.

43

8

Chapter

Prevention of Mother to Child Transmission Objective

Mother to child transmission is one of the important preventable causes of HIV infection. This guideline aims to provide guidance to assist the health workers in different settings including hospitals and primary health care facilities for the selection and provision of ARV for pregnant women, either for their own health or prophylaxis for the prevention of mother to child transmission (PMCT), taking into account the needs and constraints on health systems in various settings. The comprehensive strategic approach The comprehensive strategic approach to the prevention of HIV infection in infants and young children consists of four components: o primary prevention of HIV infection among women of reproductive age o prevention of unintended pregnancies among women living with HIV o prevention of HIV transmission from mothers living with HIV to their infants o care, treatment and support for mothers living with HIV, their children and families Although this document primarily describes the third component, it is always important to make sure the other components are appropriately addressed. Background Transmission Rate without intervention Most children living with HIV acquire the infection through mother-to-child transmission (MTCT), which can occur during pregnancy, labour and delivery or during breastfeeding. In the absence of any intervention the risk of such transmission is 15–30% in non-breastfeeding populations. Breastfeeding by an infected mother increases the risk by 5–20% to a total of 20– 45%. Transmission rate with intervention The risk of MTCT can be reduced by 50% with the administration of single dose Nevirapine to mother and baby. But this can be further reduced to below 2% by more potent antiretroviral (ARV) prophylaxis given to women during pregnancy and labour and to the infant in the first weeks of life followed by complete avoidance of breastfeeding. Risk Factors MTCT risk factors during pregnancy High maternal viral load (new or advanced HIV/AIDS) Viral, bacterial, and parasitic placental infection (especially malaria) Sexually transmitted infections Maternal malnutrition (indirectly) MTCT risk factors during labour and delivery High maternal viral load (new or advanced HIV/AIDS) Rupture of membranes for more than 4 hours before labour begins Invasive delivery procedures (vacuum, forceps, episiotomy) First infant in a multiple birth Chorioamnionitis (inflammation of the membranes covering the foetus) MTCT risk factors during breastfeeding High maternal viral load (new or advanced HIV/AIDS) Duration of breastfeeding Early mixed feeding of infant (breast milk with replacement feeding) Breast abscesses/inflammation or cracked nipples Maternal malnutrition 44

Infant oral disease (eg, thrush or mouth sores) Counselling for PMCT Counselling is an essential part of PMCT programs to provide informed choice so that pregnant women are able to decide on: o HIV testing o Choosing ART treatment or ARV prophylaxis, with commitment to good adherence o safe delivery options o appropriate infant feeding practice Another important aspect is that PMCT can be a useful means for HIV prevention as HIVnegative pregnant mothers can be thoroughly counseled to maintain their negative status, and their spouses will also be encouraged for testing. Safe delivery Interventions that reduce MTCT risk in labour and delivery include: o Universal precautions o Minimal use of cervical examinations o Avoidance of: Prolonged labour Routine rupture of membranes Unnecessary trauma such as episiotomies and foetal scalp monitoring o Minimise risk of postnatal haemorrhage o Safe transfusion practices Regarding mode of delivery, elective Cesarean section, when performed before the onset of labour or membrane rupture, has been associated with reduced MTCT. But it needs to be considered individually that the benefits and risks of vaginal delivery versus elective caesarean section, including the safety of the blood supply and the risk of complications from operation. ARV prophylaxis for PMCT Following are the potential case scenarios of HIV positive pregnant women : A. Women who become pregnant while receiving ARV treatment B. Pregnant women with indications for ARV treatment C. Pregnant women not yet indicated for ARV treatment [ARV prophylaxis for preventing HIV prevention in infants] D. Women living with HIV who are in labour and who have not received ARV prophylaxis E. Infants born to women living with HIV who have not received ARV drugs during pregnancy or labour A. Women who become pregnant while receiving ARV treatment For women who become pregnant while receiving antiretroviral therapy, the treatment should be continued. o However, if she is on an EFV-containing regimen and is in the first trimester of pregnancy, NVP should be substituted for EFV. Alternatively a triple NRTI- or PI-based regimen could be used. o Women who are receiving EFV and are in the second or third trimester of pregnancy can continue the current regimen. o Exposure to EFV during pregnancy is not an indication for abortion. Infants born to women who are receiving antiretroviral therapy should receive AZT for seven days. B. Pregnant women with indications for ARV treatment

45

Recommended and alternative prophylactic ARV regimens for pregnant women who have indication for ART depends on the capacity of the staff, resources and facilities in addition to clinical criteria. If there is access to ARV treatment for pregnant women If she meets the criteria and conditions, initiate ARV using the same principles as in no pregnant women. Preferred regimen: AZT +3TC +NVP If there is no access to ARV treatment for pregnant women, Follow the recommendations in Scenario C. C. Pregnant women no indications for ARV treatment- ARV prophylaxis for preventing HIV transmission to the infants Single dose NVP is the simplest regimen to administer but less effective and at high risk of resistance to NVP. On the other hand, longer and more complex regimens are more effective and lower risk of NVP resistance but costly and more complex to deliver. The decision is based on the availability, capacity, resource as well as the informed choice of pregnant women. A new recommendation in this guideline is the AZT/3TC “tail”. This refers to the administration of AZT/3TC “tail” for seven days following single dose nevirapine given to the mother to reduce the development of resistance to NVP. Ranking

Pregnancy

Time Of Administration Labour

Recommended

AZT (>28 weeks gestation)

Sd-NVP a + AZT/3TC

Alternative

AZT (>28 weeks gestation)

Sd-NVP

Postpartum Mother: AZT/3TC × 7 days a Infant: Sd-NVP a + AZT × 7 days b Infant: Sd-NVP+ AZT × 7 days b

Mother: AZT/3TC × 7 days Infant: Sd-NVP Sd-NVP Minimum Infant: Sd-NVP a If the woman receives at least four weeks of AZT during pregnancy, omission of the NVP dose for mothers may be considered. In this case the NVP dose must be given to the infant immediately after birth, AZT is recommended for four weeks instead of one week, and the mother will not require 3TC during labour as well as AZT and 3TC postpartum. b If the mother receives less than four weeks of AZT during pregnancy, AZT is recommended for four weeks instead of one week. Sd-NVP + AZT/3TC

Minimum

Nevirapine resistance and its prevention NVP has a prolonged half-life, with detectable levels persisting in some women who have received Sd-NVP for up to 21 days postpartum. The prolonged half-life is beneficial in that, in addition to preventing intrapartum transmission, NVP can prevent MTCT occurring postnatally during the first few weeks of life. However, the woman is also exposed to a prolonged period of non-suppressive drug levels, promoting the development of resistance to NVP. Studies have shown that resistance to NVP may occur in as many as 60–89% of women given Sd-NVP. In addition, resistance to NVP usually confers cross-resistance to EFV. Viral resistance was also detected among 33–53% of infants with HIV when both they and their mothers were exposed to Sd-NVP. 46

The most important method of preventing resistance to NVP is to give combination therapy to those women who require it. However, accumulating data suggest that the incidence of resistance may be decreased if dual NRTI drugs are administered intrapartum and for a short period postnatally as a “tail” following Sd-NVP. By adding the “tail” with AZT and 3TC during labour and postpartum, the risk of developing resistance to NVP can be reduced from 60% to about 10%. Doses of antiretroviral prophylaxis drugs for PMCT All regimens are administered by mouth. Dosage is summarized in the below table. Paediatric formulations exist for the main drugs used in current prophylactic regimens to prevent MTCT (AZT, NVP and 3TC). For Mothers During pregnancy AZT 300 mg twice a day starting at 28 weeks or as soon as possible thereafter During labour Sd-NVP 200 mg at onset of labour AZT 600 mg at onset of labour OR 300 mg at onset of labour and every 3 hours until delivery 3TC 150 mg at onset of labour and every 12 hours until delivery. After delivery AZT 300 mg twice a day for 7 days 3TC 150 mg twice a day for 7 days For Infants Sd-NVP: 2 mg/kg oral suspension (or 6 mg) at once immediately after birth (within 72 hours) AZT 4 mg/kg twice a day for 7 days OR 4 weeks* 3TC 2 mg/kg twice a day for 7 days * If the mother receives less than four weeks of AZT during pregnancy, AZT is recommended for four weeks instead of one week.

D. Women living with HIV who are in labour and who have not received ARV prophylaxis If the pregnant women are in labour without receiving ARV prophylaxis, the recommended regimen is as shown below. If delivery is expected imminently, the NVP dose for the mother should be omitted and the same recommendations and considerations apply as for infants under scenario E. When delivery occurs within two hours of the woman taking NVP, the infant should receive Sd-NVP immediately after delivery and AZT for four weeks.

47

Selection of prophylactic ARV regimens depends on the capacity of the staff, resources, facilities as well as the informed choice of pregnant women. Time Of Administration Labour Postpartum Mother Sd-NVP + Recommended AZT/3TC × 7 days AZT/3TC Infant: Sd-NVP + AZT × 4 weeksa Mother AZT/3TC × 7 days Alternativeb AZT/3TC Infant AZT/3TC × 7 days Mother Sd-NVP + AZT/3TC × 7 days Minimum AZT/3TC Infant Sd-NVPa Minimum Infant Sd-NVP Sd-NVP a Data on added efficacy of four weeks of infant AZT in this situation are limited. b Equivalent efficacy to Sd-NVP alone intrapartum/postpartum and no risk of resistance to NVP in women or infants should they become infected Ranking

E. Infants born to women living with HIV who have not received ARV drugs during pregnancy or labour Sd-NVP immediately after delivery and AZT for four weeks are recommended for infants born to women living with HIV who do not receive any ARV prophylaxis, because this regimen results in a greater reduction in transmission than just Sd- NVP for the infant. ARV prophylaxis for infants should begin immediately after delivery or within 12 hours after delivery, if possible. Selection of prophylactic ARV regimens depends on the capacity of the staff, resources, facilities and well-informed choice of the mother. Time Of Administration Postpartum Infant: Sd-NVP immediately after birth + AZT × 4 weeksa Infant: Sd-NVP immediately after birth + AZT × 1 week Infant: Sd-NVP immediately after birth

Ranking Recommended Alternative Minimum a

NVP administered immediately after birth, if possible within 12 hours after delivery, is likely to result in a larger reduction in transmission than starting it later. Data on added efficacy of four weeks of AZT for infants in this situation are limited 2. Cotrimoxazole prophylaxis It is recommended for all HIV-exposed children born to mothers living with HIV, and pregnant women living with HIV who fulfil the criteria. For details please refer to OI prophylaxis for adult (Chap##) and children (Chap ##).

48

3. Diagnosis of HIV exposed babies Early diagnosis of exposed babies helps to guide the infant feeding option and OI prophylaxis, as well as introduction to ART. However, testing at young month does not provide reliable results due to the presence of maternal antibody in the infants. • Final confirmation should be made at 18 months by antibody test. • Negative result at 9 months by antibody test can confirm as negative, but positive result needs to be confirmed at 18 months. • Antigen testing by PCR after 6 weeks can provide more than 95% sensitivity and specificity. However, it has to be confirmed by antibody test at 18 months. 4. Referral for care and support The needs of HIV infected mother and their families are diverse and change over time. The need is not limited to medical. Health care staff should try to link with appropriate service available in the locality, either by public or private and continuously follow up with strict confidentiality.

49

9

Chapter

Post exposure prophylaxis

Occupational and non-occupational exposure prophylaxis What type of exposure has occurred?

Exposure with the potential for HIV transmissiona

≤ 72 hours since exposure

Exposures with no or negligible potential for HIV transmission

>72 hours since exposure

PEP not recommended

b

PEP recommended a. PEP should be provided following exposure of non-intact skin (through percutaneous sharps injury or other exposure) or mucous membranes (through sexual exposure or splashes to the eyes, nose, or oral cavity) to a potentially infected body fluid from an HIV positive or unknown HIV status source. Body fluids which may transmit HIV include blood, genital secretions, and cerebrospinal, amniotic, peritoneal or pleural fluids. b. While PEP will be less effective or ineffective if delayed > 72 hours, it may be considered in circumstances where a significant potential exposure has occurred

50

Occupational post exposure prophylaxis Prevention of occupational exposure in health facilities Since PEP is not 100% effective, the importance of primary prevention in all settings where HIV could be transmitted should be reinforced as part of all programs that provide PEP. Health facilities should implement and strengthen primary prevention measures including safety training the workplace and universal precautions for the prevention of exposure to potentially contaminated material. Universal precautions include: •

Training of all employees in handling and disposal of infectious material

•

Provision of guidelines for prevention and control of infections

•

Provision of equipment necessary for prevention and control of infections, such as, educational materials, disposable gloves, disposable syringes and needles and sharps bins

•

Monitoring mechanism to ensure implementation

Risk of Exposure The risk of occupational transmission of HIV varies with the type and severity of exposure.63 It is estimated that the transmission rate of HIV from an infected patient to an exposed person through significant needle stick accidents is approximately 0.3% (3 in a 1000) and approximately 0.09% in the case of mucous membrane exposure.64 Components of occupational PEP •

Treatment of exposure site

•

Assessment of risk and counseling of the exposed person

•

Discussion of PEP and provision based on informed consent (not necessarily written) and understanding of the benefits and possible side effects of ARVs

•

Provision of voluntary counselling and testing

•

Providing antiretrovirals if indicated

•

Follow up and documentation of the incident

Treatment of exposure site Skin Eyes Oral exposure

Wash skin with soap and water. Do not rub the exposed area Rinse eyes immediately with eye wash fluid Spit out immediately Rinse mouth immediately several times with clean water Do not use antiseptics

Assessment of risk If available, give PEP for deep skin injuries, large hollow-bore needle and blood visible on needle or sharp instrument if source patient is known to have HIV. Ascertain the HIV status of the patient and the injured health worker after providing appropriate counseling. Risk fluids and exposure 51

Deep skin injury (Needle stick, cut with sharp object) Contact with mucous membranes and non-intact skin Types of exposure (eyes, skin rash present, scratch, abrasion) with potentially infectious body fluid Blood is a high risk fluid Other high risk body fluids are semen vaginal secretions CSF, Risk fluids synovial, pleural, peritoneal pericardial amniotic fluids Saliva and urine are low risk fluids Contact with normal skin with no injury is not a risk for HIV transmission

Assessment of source patient If the status of source patient is unknown, provide counseling and encourage HIV testing if appropriate. If it is not possible to determine the HIV status of the source patient, PEP should be given if the exposure is assessed as a potential risk for HIV transmission If the source patient is HIV negative, no post-exposure prophylaxis is necessary for the exposed health worker. If the source patient is confirmed HIV positive, the risk of exposure to the HCW is higher if the source patient has advanced HIV disease, a known high viral load or is not on ART. If the source patient is on ART and known to be failing or has previously failed ART, the choice of PEP provided to the HCW will depend on a detailed ART history and review if the source patient’s medical record if available. In this scenario, as viral resistance is probably present, addition of a 3rd drug (a boosted PI) to the PEP regimen is recommended for the exposed person. Assessment of exposed person Baseline HIV testing should be performed on all persons seeking evaluation PEP. Rapid tests are recommended. If PEP is indicated, it should be commenced before test results for the exposed person or the source are available. The need to continue nPEP can be reviewed based in the test results. If the exposed person is HIV positive, no post-exposure prophylaxis is necessary but the person should be referred for further counseling and management on a long-term basis for his/her HIV infection. If the person is HIV negative and the source patient is HIV positive then continue antiretrovirals for a period of 28 days; repeat the person’s HIV tests at 3 months and at 6 months after the initial test. PEP, if indicted, should be commenced immediately and not delayed pending the result of the HIV status of the exposed person. If the HCW subsequently is found to be HIV positive, a 2 drug PEP regimen should be stopped and the person’s clinical and immunological (if available) status and the need to commence ART assessed. Two drug PEP should be stopped because resistance will rapidly develop if the HCW is already infected. A three drug PEP regimen may be continued if it is required for the medical needs of the person. If the person should seroconvert during this time then provide appropriate care and counseling and refer for expert opinion and management. 52

Counselling •

Give health care worker pre test counseling

•

Test the health care worker (baseline tests)

•

o

HIV

o

Hepatitis B and hepatitis C

Counsel HCW that they must not give blood and must practice safer sex and safer injecting practices until outcome is known

•

Review HCW (post test counseling) and give baseline results

•

Offer hepatitis B vaccination if HBsAg negative and HBsAg negative

•

Provide counselling on further HIV transmission including condom use, avoiding breast feeding and not donating blood until the person is tested HIV negative three moths after the exposure

Documentation of the incident •

Record date and time of exposure

•

Details of the event

•

Exposure source if known

•

Details of PEP treatment if given

•

Follow up

53

Antiretrovirals for PEP A limited number of studies have shown that immediate administration of antiretrovirals reduces the risk of transmission following exposure to HIV. ARVs should be started as soon possible and at the latest within 72 hours of the exposure. Persons presenting after 72 hours of exposure could also be considered for post exposure prophylaxis. ARV should be continued for one month.64 The drugs used in PEP should be aligned with the formulary adopted in the country. AZT, 3TC and boosted PIs are the most common ARV drugs used in these situations. Alternative NRTIs that can be considered are d4T and ddI. NRTIs (NVP and EFV) should not be used for PEP. Nevirapine is NOT recommended for PEP due to the risk of severe reactions reported in these situations. Efavirenz should be avoided due to CNS side effects and should not be given to pregnant women or women of child bearing potential. There is also no evidence that a three drug regimen is superior to a two drug regimen in the setting of PEP. 65 •

two drug regimen (for all potential exposures)

•

three or more drug regimen (for potential exposures where source is known or suspected to have ART resistance)

Non-occupation post exposure prophylaxis (nPEP) Situations where nPEP may be provided Unprotected sexual exposure including rape Needle sharing by IDUs Injuries from needles discarded in public places. 66 Human bite injuries Situations where nPEP should not be provided nPEP should not be provided in case of persistent potential exposure to HIV such as discordant sex partners who rarely use condoms, repeated unprotected sex with sex workers or other non regular partners or injection-drug users who often share injection equipment. Persons who engage in frequent, recurrent risk exposure behavior should be counseled and provided with appropriate risk-reduction interventions. Antiretrovirals for nPEP The choice is the same for occupational and non-occupation PEP Counselling •

Assess extent of risk exposure, frequency of exposure and timing

•

Try to ascertain the HIV status if the source (often unknown)

•

Evaluate for sexually transmitted infections

•

Assess the need for emergency contraception (“morning after pill”)

•

Give pre HIV test counseling 54

•

•

Test the individual (baseline tests) o

HIV

o

Hepatitis B and hepatitis C

o

Swabs and cultures for gonorrhea and Chlamydia if available

o

VDRL and TPHA

o

Pregnancy test (if available) following appropriate counselling

Counsel the individual that they must not give blood and must practice safer sex and safer injecting practices and not breast feed until outcome is known

•

Review and give baseline results

•

Offer hepatitis B vaccination if HBsAg negative and HBsAg negative

55

Summary of recommendations for occupational and non-occupational PEP As soon as possible after exposure and within one hour if possible Not more the 72 hours after exposure if possible Starting PEP Consider PEP > 72 hours after a high risk exposure 28 days Duration of PEP Which regimen to choose

2 NRTIs which are the same as the recommended NRTI backbone in the standard first line WHO ART in the country

Preferred two drug regimens

AZT 250mg or 300 mg BID or d4T 30/40mg BID Plus 3TC 150 mg BID

Alternative two drug regimens

TDF 300mg OD + (3TC 300mg OD or FTC 200mg OD) This ARVs can all be given once daily

Three drug regimens

Some counties have already implemented 3 drug PEP regimens. There are no prospective data regarding the relative efficacy of 2 or 3 drugs. The potential advantages of using 2 drugs include relative ease of administration potentially resulting in better adherence, fewer side effects, lower cost, and ease of procurement, storage and dispensing. In most cases where the source in unlikely to have ART-resistant HIV infection, 2 drugs are likely to be sufficiently potent to prevent HIV transmission with only incremental increase in potency with the addition of a third drug. In cases where the source is known or suspected to have ART resistance two NRTIs plus a protease inhibitor (PI) can be considered.

Preferred 3 drug regimens

2 NRTIs as listed above + Ritonavir boosted PI chosen according to availability OR Nelfinavir 1250 mg twice daily or IDV 800mg TID if RTV not available

NNRTIs in PEP

PEP in pregnant women

If a third drug is used, an NNRTI should NOT be used. Nevirapine is contraindicated for PEP due to risk of toxicities and the potential for development resistance. Efavirenz should not be used in women who are pregnant or are of child-bearing age. PEP should be provided if indicated. Pregnant women should not receive efavirenz, tenofovir or the combination of d4T + ddI The preferred PI in pregnancy is saquinavir/r.

56

Chapter

Syndromic approach to the management of opportunistic infections

10

Dysphagia [a]

Treat presumptively

for oesophageal candidiasis [b]

Improved after 7 days

Treat presumptively for HSV [c]

Improved after 7 days

No Yes

No

Esophagoscopy for diagnosis [c]

Yes

Continue fluconazole 14 days Recurrence is likely unless ART is commenced Consider prophylaxis with fluconazole 200mg twice weekly

Continue acyclovir 14 days Recurrence is likely unless ART is commenced Consider prophylaxis with acyclovir 400mg twice daily

Notes: a. Oesophageal candida Candidiasis may infect the oesophagus in immune compromised patients, causing difficulty and pain on swallowing. Diagnosis is based on clinical symptoms and response to systemic antifungal therapy. Endoscopy is not required unless the patient fails to respond to treatment. b. Systemic treatment Fluconazole 200 mg daily for 14 days or Itraconazole 200 mg daily for 14 days or Ketoconazole 200 mg daily for 14 days c. Acyclovir 400mg every 4 hours d. Failure of treatment Other causes of oesophagitis are cytomegalovirus (CMV), Kaposi’s sarcoma and lymphoma. Non –HIV related causes include acid reflux. Endoscopy is required for diagnosis

57

Lymphadenopathy [a]

Characteristics of the lymphadenopathy

Generalized nodes

Single node or asymmetrical nodes

HIV associated Persistent generalized lymphadenopathy (PGL) No specific treatment required Assess for clinical or CD4 count criteria for commencing ART

Lymph node biopsy available Yes

Treat according to biopsy results (tuberculosis or fungal or bacterial infection)

Yes

No

Clinical presentation suggestive of extra pulmonary TB

Treat for TB Notes: a. Persistent generalized lymphadenopathy is common in HIV-infected patients. In an asymptomatic patient no further investigation or treatment is required. However, in patients with recently symptomatic lymphadenopathy, rapidly enlarging nodes, marked nodal asymmetry, and constitutional symptoms, further evaluation and treatment is necessary. Causes of lymphadenopathy (other than HIV) include tuberculosis, cryptococcosis, histoplasmosis, lymphoma and Kaposi’s sarcoma. Extra pulmonary tuberculosis is common in HIV-infected patients. Clinical suspicion of tuberculosis is raised by the following signs and symptoms: fever, weight loss, unilateral nodes increasing in size, matted nodes, fluctuant nodes. Treat according to the national TB guidelines.

58

Chronic diarrhea [a]

Dehydrated [b]

Correct with oral fluids and rehydration salts or IV fluids and symptomatic antidiarrhoeal treatment [g]

Stool microscopy &

No

culture available [d]

Empirical treatment with quinolones (eg. norfloxacin) or TMPSMZ for 7 days [e]

Yes No improvement

Treat according to specific diagnosis [f]

Empirical treatment with metronidazole 400-500 mg TID for 7 days [g]

Notes: a. Definition of chronic diarrhea: liquid stool three or more times a day, continuously or episodically or for more than one month Cryptosporidiosis Isospora belli Giardia lamblia Salmonella spp Microsporidium Cytomegalovirus HIV (no other pathogens) b. Assessment of dehydration Causes:

Campylobacter spp Entamoeba histolytica Strongyloides stercoralis Shigella flexneri Mycobacterium avium complex Lymphoma

General appearance Restless, irritable Pulse Rapid Respiration Deep, may be rapid Skin elasticity Pinch retracts slowly Eyes Sunken Mucous membranes Dry Urine flow Reduced amount & dark c. In the case of moderate dehydration, correct with oral fluids and rehydration salts (ORS), prescribe intravenous fluids in the case of severe dehydration. 59

Supplemental feeding should be given slowly with multiple and divided feeding, and supplemented with intravenous fluids (minimum 1.5 liter of water a day) d. Multiple stool examinations (each day for 3 days) increases the diagnostic yield. e. Empirical treatment Norfloxacin (400mg BID) or ciprofloxacin (500mg BID) or cotrimoxazole (2 tablets BID) +/metronidazole 400mg TID for seven days. Relapse may be due to the short duration of initial treatment. One prolonged course of treatment, for 3 weeks, is justified. f. Specific treatments Salmonellosis and shigellosis: Ciprofloxacin 500 mg, 1 tablet bid for 7 days or Ofloxacine or Ceftriaxone 1g, IM or IV, 1 injection each day, for 5 days. Campylobacter spp: Erythromycin (tablet 500mg) 3 tablets daily for 5 days. Giardiasis: Metronidazole tablet 250 mg, 2 tablets tid for 5 days. Entamoeba histolytica: Metronidazole tablet 250mg, 2 tablets tid for 7-10 days. Isospora belli: TMP-SMX tablet 480 mg, 2 tablets 4 times daily for 7 days. Strongyloidiasis: Thiabendazole 25 mg/kg, 3 times daily for 3 days. Cryptosporidiosis: there is currently no established effective treatment. ART is the only effective treatment. Maintenance of fluid and electrolyte balance is of greatest importance, and constipating agents may also be useful. Mycobacterium avium complex infection: drugs to be given are Ethambutol (single daily dose of 15mg/kg/day) and Clarithromycin (500mg BID), or/and Azithromycin (500 mg fourth hourly). Salmonellosis, shigellosis, campylobacteriosis and isosporiasis in HIV-infected patients often relapse. If relapse occurs after an initial course of antimicrobial therapy, a 6-12 weeks course therapy should be administered g. Symptomatic treatment Loperamide, 4 mg initially, followed by further 2 mg after each unformed stool (maximal daily dosage 16 mg) Constipating agents should not be used in patients with bloody diarrhea, because of the risk of inducing toxic mega colon.

60

Respiratory Symptoms

Sputum microscopy & AFB stain Induced sputum examination is necessary for PCP diagnosis [c]

AFB positive

Yes

Treat TB according to National TB Guidelines Give cotrimoxazole PCP prophylaxis to all HIV positive patients diagnosed with TB

No

Chest X ray consistent with: TB [d] PCP [e] Bacterial pneumonia [f] Fungal pneumonia [g]

Clinical presentation suggestive of PCP [b]

Empirical treatment for PCP and bacterial pneumonia with cotrimoxazole

Successful treatment of PCP is followed by secondary cotrimoxazole prophylaxis

Notes: a. Respiratory symptoms which commonly present in patients with HIV infection and immunodeficiency are fever, dry cough (typical of PCP), productive cough with sputum and/or haemoptysis (typical of pneumonia and TB), shortness of breath and severe respiratory distress Causes of respiratory symptoms Infections: Mycobacterium tuberculosis (cough > 2-3 weeks) Pneumocystis jiroveci pneumonia (cough often 1-2 moths) Bacterial pneumonia Fungal infection (cryptococcus, histoplasmosis) Atypical mycobacteria (MAC) CMV pneumonitis Malignancies Lymphoma, Kaposi’s sarcoma Others Pleural effusion/empyema (tuberculosis, bacterial infection or malignancies) Pneumothorax (tuberculosis, or pneumocystis jiroveci pneumonia) Pericardial effusion (often associated with tuberculosis) b. PCP typically presents with slow onset over weeks to months of dry cough, fever and shortness of breath 61

c. Sputum examination for acid-fast bacteria (AFB) is indicted inpatients with cough for more than 2 weeks.Three separate sputums are recommended. For diagnosis of PCP, induced sputum examination is essential. Clinical diagnosis supported by CXR findings is preferred for the diagnosis of PCP. Cough and sputum production is induced by inhalation of normal saline by nebulizer. Training of staff in safe induced sputum collections is necessary. d Tuberculosis: No chest X-ray pattern is absolutely typical of pulmonary TB. The classical pattern is more common in HIV-negative patients; the atypical pattern is more common in HIV positive patients. Pleural effusion is a prominent feature. Pleural tap and microscopic examination of pleural fluid may be helpful for diagnosis. Treat according to national TB guidelines. Classical Pattern Atypical Pattern Upper lobe infiltrates Interstitial infiltrates (especially lower zones) Cavitation Bilateral infiltrates Pulmonary fibrosis No cavitation e. PCP: The chest X-ray is abnormal in more than 90% cases of pneumocystis jiroveci pneumonia, typically showing bilateral interstitial infiltrates. Typical clinical presentation is with non-productive cough, shortness of breath and fever for 1-2 months. PCP treatment: Trimethoprim-sulfamethoxazole, (Cotrimoxazole- TMP 15 mg plus SMZ 75 mg/kg) daily in 4 divided doses, orally or intravenously, for 21 days. Treatment should be IV in severally ill patients. Cotrimoxazole, 4 vials in 500 ml of Glucose 10% by slow IV infusion (over one hour) three times a day. Cotrimoxazole cannot be administrated IV directly. Patient can switch to oral Cotrimoxazole if clinically improved. Total course of cotrimoxazole is 21 days. Oral doses are: • TMP-SMZ 480 mg, 2 tablets 4 times daily (patient 40 kg)

Alternative treatment: Clindamycin 600mg IV or 450mg orally TID + primaquine 15mg orally OD for 21 days if allergy to sulphonamides. Prednisolone, 20 mg 4 times daily, reducing slowly over 7-10 days depending on response to therapy is recommended for severely ill patients. Prevention of relapse with cotrimoxazole 2 tablets daily should be given after the first phase of treatment and needs to be continued lifelong (secondary prophylaxis). Dapsone 100mg OD is an alternative for allergic patients. f. Bacterial pneumonia: Typical presentation is with productive cough, purulent sputum and fever for 1-2 weeks. PCP presents more slowly and there is normally no sputum. Typical CXR finding is lobar consolidation. Gram-positive pyogenic bacteria will be the most probable cause of bacterial pneumonia. Cotrimoxazole as above will successfully treat most community acquired bacteria and PCP. Amoxycillin/clavulanate, 625mg 3 times daily or Azithromycin 250 mg, 3 tablets 3 times daily, for 7 days are an alternative if the clinical presentation suggests bacterial pneumonia and not PCP. g. Fungal pneumonia: Amphotericin B 0.7 mg/kg daily by intravenous injection for 4-6 hours for 6 weeks. Alternative: Fluconazole 400 mg daily for 10 weeks.

62

Neurological signs and symptoms [a]

Focal neurological signs [b]

Clinical signs of meningeal irritation

No

Treat for Cryptococcal meningitis [d]

Yes Yes

CSF examination available

Cerebral CT available

Yes

Bacteria, WBC, AFBs, Indian-ink

No

Treat based on clinical examination and CT findings

Treat for cryptococcal meningitis, bacterial meningitis, [e] tuberculous meningitis, syphilitic meningitis

Treat for toxoplasmosis [c]

Notes: a. Causes of headache include cryptococcal meningitis, tuberculous meningitis, cerebral toxoplasmosis, chronic HIV meningitis, bacterial meningitis, and lymphoma • Causes of headache not related to HIV infection include migraine, syphilis, malaria, tension, sinusitis, refractive disorders, dental disease, anaemia, and hypertension. And other infectious diseases such as malaria, typhoid fever, dengue fever, and rickettsiosis. b. Neurological examination • Evidence of meningeal irritation (photophobia, neck stiffness) or raised intracranial pressure (high blood pressure, and show pulse in the presence of fever). • Changes in metal state • Focal neurological deficits including paresis, cranial nerve palsies, movement disorders ataxia, and aphasia. Seizures c. Toxoplasmosis Pyrimethamine loading dose 75-100 mg, then 25-50 mg daily plus Sulfadiazine, 4 g daily in 4 divided doses for 6 weeks followed by chronic suppressive therapy with Pyrimethamine, 25 mg daily plus Sulfadiazine, 2 g daily in 4 divided doses. Alternative therapy is pyrimethamine as above plus clindamycin 300mg four times per day for 6 weeks. d. Cryptococcal meningitis Primary treatment Maintenance treatment Amphotericin B 0.7-1 mg/kg/day, IV, for 14 days 1. Amphotericin B, 0.7-1 mg/kg /week followed by Itraconazole 200 mg 2 times daily Itraconazole 200 mg/day for 8 weeks, or Fluconazole 400 mg daily. or Fluconazole 200mg/day Fluconazole 400 mg daily for 8 to 12 weeks Fluconazole 200 mg/day 63

e. Bacterial meningitis Benzyl-penicillin 1.2-2.4 million IU daily be intravenous injection in divided doses every 4 hours. Treat for a minimum of 7 days or for 4-5 days after the patient becomes afebrile. If allergic with Penicillin, ampicillin or chloramphenicol or ceftriaxone can be used.

Skin conditions: Differential diagnosis table

☺ Clinical diagnosis preferred. Diagnostic test normally not required *Highly suggestive of HIV infection. HIV counseling and testing if HIV status unknown Skin Conditions 1. Pruritic (itchy) rashes Diagnosis

Clinical features in favour of diagnosis

Erythematous, pruritic, follicular papules/pustules on face, upper trunk, upper arms, intense itching Hyperpigmented, hyperkeratotic papules and Papular pruritic nodules which often appear symmetrically on eruptions* arms, legs, lower back, buttocks Rash and excoriations on torso; burrows in Scabies web space and wrist; face spared. Extensive crusting (psoriatic like lesions) with Norwegian Scabies thick, hyperkeratotic scales overlying the elbows, knees, palms, and soles. Eczema Wet, oozing sores or excoriated, thick patches. Dry and rough skin, sometimes with fine Xerosis cracks. 2. Erythematous rashes Limited to area in contact with problem substance Contact dermatitis Early: redness and blistering Later: thick, dry, scaly. Eosinophilic folliculitis

Primary HIV infection*

Generalized maculo- papular rash usually with fever and systemic symptoms

Generalized erythematous pruritic rash with or without fever and signs of hepatoxicity. Severe drug reactions (Stevens Johnson Syndrome) Drug reaction with dlisters of skin and/or mucous membranes Typically in the first days to weeks of commencing the new drug 3. Blisters, sores, nodules and pustules Typical painful blisters in clusters along dermatomes. Can involve the eye. HIV infection should be suspected if lesions are multidermatomal or episodes of H. Zoster are Herpes zoster* recurrent Pre-pressional symptoms include parasthesiae and/ or pain in the dermatome a few days before the rash appears. Fever, malaise, and headache may precede the outbreak of blisters Typical blisters, with pain and tingling, usually in genital area or face. Chronic HSV presents Herpes simplex as a progressive, shallow, clean-based ulcer on genitalia, perianal, perioral areas Impetigo and Red, tender, warm crusts or small lesions folliculitis

64

Diagnostic tests (if available) Clinical diagnosis Clinical diagnosis Microscopy of skin scrapings KOH or mineral oil preparations Clinical diagnosis Clinical diagnosis

Clinical diagnosis Serology for HIV-RNA or HIV-DNA May be negative in early primary HIV infection

Clinical diagnosis

Clinical diagnosis

Clinical diagnosis Microscopy Gram positive cocci

Diagnosis

Cryptococcus*

Penicilliosis*

Clinical features in favour of diagnosis

Diagnostic tests (if available)

Generalized papulo-necrotic skin lesions resembling molluscum contagiosum associated with fever and other symptoms of disseminated cryptococcosis such as meningitis, lung infection Papulo-necrotic skin lesions associated with systemic disease of fever, lung involvement, cough, weight loss, anaemia, hepatosplenomegaly and lymphadenopathy. 70% of patients with disseminated Penicillium marneffei infection will have skin lesions. It is endemic in Northern Thailand, Southern China, Vietnam, Indonesia, and Hong Kong

Microscopic of skin biopsy lymph node aspirate or CSF India Ink, Wright’s stain or Cotton blue stain Blood culture Chest x-ray

Histoplasmosis*

Pustules, nodules, ulcers and papules in a patient with systemic symptoms including lung, CNS, gastrointestinal and ocular involvement

Bacillary angiomatosis*

Papules or nodules resembling pyogenic granuloma, nodules or plaques resembling Kaposi sarcoma. Splenomegaly, anaemia

Mycobacterium avium complex (MAC) *

Papulo-pustular eruptions on trunk and extremities. Systemic symptoms including fever and pulmonary symptoms, lymphadenopathy, diarrhea, weight loss, night sweats

Primary syphilis

Painless indurated genital ulcer (chancre) with localized lymphadenopathy. Other locations for chancres include mouth and anus

Secondary syphilis

Macula, papular or pustular rash on entire body, especially on palms and soles 40 percent of these patients will have CNS involvement with headache and meningism

Leprosy

Hypopigmented macules with a raised border. Plaques are also common. Necrosis, neuropathies

Cytomegalovirus*

Cutaneous tuberculosis

Ulcerations of oral mucosa and anogenital area Signs and symptoms GI CMV disease include nausea, vomiting, dysphagia, epigastric pain, jaundice, and watery diarrhea. TB verrucosa cutis: Asymptomatic warty papules on hands or extremities often mistaken for verruca vulgaris. Lesions may evolve and persist for years. Disseminated tuberculosis presents as papulonecrotic lesions (indistinguishable from penicilliosis, histoplasmosis, cryptococcosis).

65

Tissue biopsy results Yeast forms on hematoxylin and eosin staining Blood or tissue culture Microscopy of Warthin-Starry silver or Grocott-silver methenamine stain Acid-fast bacilli on skin biopsy Blood culture Dark field microscopy or immunofluorescent staining RPR, VDRL not positive until 7-10 days after appearance of chancre RPR, VDRL, TPHA CSF examination shows increased protein and lymphocytic pleocytosis Tissue smear testing/slitskin smears Ziehl-Neelsen acid-fast stain Biopsy

Acid-fast bacilli stained tissue

in

4. Skin rashes with few or no symptoms Erythematous plaques with greasy scaling on Seborrhea Clinical diagnosis the scalp, face, post auricular area, and chest. Raised dome shaped pedunculated lesions Molluscum usually on face and neck and genital area and Clinical diagnosis contagiosum armpits Condyloma Multiple raised irregular lesions with a Clinical diagnosis accuminata cauliflower appearance typically in genital area Dermatophytosis Hyper- or hypopigmented patches that are ringworm, itchy, with or without a ring pattern and with Clinical diagnosis onychomycosis scaling Extensive plaques that have well-demarcated borders and are covered with thick silvery white scales. It is often mistaken for a fungal Psoriasis Clinical diagnosis skin infection. Lesions are often bilateral and favor the scalp, elbow, knees, hairline and intertriginous areas. HIV-associated Itchy generalized maculo-papular Clinical diagnosis skin rash 5. Severe soft tissue or muscle infection Pyomyositis and Abscess or affected area is fluctuant and warm. Gram stain or culture skin abscess There may be discharge

66

Details of selected common HIV-related skin conditions Pruritic rashes Eosinophilic folliculitis Cause The exact cause of eosinophilic folliculitis is not clear. It is most likely an autoimmune process.67 Physical Examination Areas of erythematous papules and pustules and involves the face in 85% of patients. Patients with HIV present with widespread urticarial lesions or large erythematous plaques with excoriations. Other conditions to consider Acne, eczema, other causes of folliculitis (bacterial, fungal, or dermatophytic), psoriasis scabies, reactions to bites and stings Treatment Treat mild disease with topical steroids and oral antihistamines.68 Treat moderate to severe disease with oral itraconazole, isotretinoin, or phototherapy. Papular pruritic eruptions Cause This condition is considered to be a hypersensitivity reaction to the bites of mosquitoes, fleas, bedbugs, and other insects. Physical examination Papules may occur on any body part, but they tend to be grouped on exposed areas, particularly the extensor surfaces of the extremities (legs). Scratching may produce erosions and ulcerations. Secondary bacterial infection is common. Other conditions to consider Impetigo, insect bites Treatment Treatment includes mild topical steroids and systemic antihistamines for relief of the itching that often accompanies this condition. If secondary impetigo occurs, topical or systemic antibiotics may be needed. The condition improves with immune recover on ART but scarring form old lesions may be permanent. Scabies Cause Sarcoptes scabiei mite Physical Examination Classic scabies presents with burrows in the skin, typically in the web spaces of the fingers, flexor aspects of the wrists, axilla, umbilicus, buttocks, and feet. In men, red papules or nodules on the penile glans, shaft, and scrotum are almost pathognomonic of scabies.69 Norwegian (or crusted) scabies presents with extensive, widespread, crusted lesions appear with thick, hyperkeratotic scales over the elbows, knees, palms, and soles. Secondary infection bacterial be present.70 The mite is same the same as “regular” scabies. The difference is the host, with those developing Norwegian scabies usually having a compromised immune system and a higher parasitic burden. The skin manifestations are much more severe, with thick, hyperkeratotic crusts that can occur on almost any area of the body. Clinically, Norwegian scabies differs from regular scabies in two ways: more severe skin manifestations and often not very pruritic. The decreased pruritis observed in Norwegian scabies is due host's compromised immune response. Treatment 1. Gammabenzene hexachloride once a week for 2-3 weeks or until lesions are cleared. 2. Permethrin cream 5% Apply from chin to toes and shower off 10-12 h later; repeat in 1 week 3. 25% benzylbenzoate solution71. Apply the lotion from head to toe. The application is left on the skin to dry and then repeated the next day. Treatment should be repeated weekly until all lesions are clear. Itching can be relieved by chlorpheniramine 4 mg, 3-4 tab/day. Clothes and beddings should also be washed and kept separately for 3 days to prevent reinfestation. Household contacts should be treated. After treatment, all the clothes and bed linen should be washed and dried. Household and other close contacts require the same 67

treatment. In severe cases, Ivermectin (if available), administered in a single oral dose of 200 micrograms per kilogram, may be considered 72 Xerosis Cause The cause is not known. Xerosos (dry skin) is common, with up to 75% of patients with HIV infection experiencing dry skin. 73 74 Physical examination Lesions consist of a diffuse, pruritic, scaly rash, involving mainly the limbs and the back. Other conditions to consider Scabies Treatment Treatment is with moisturising skin lotion and antihistamines for itch (chlorpheniramine 4 mg TID or hydoxyzine 10 mg BID). The condition improves with immune restoration or ART.75 Erythematous rashes Primary HIV infection Cause The acute retroviral syndrome typically occurs 2-4 weeks after primary infection with HIV Physical examination The rash is usually generalized erythematous and maculopapular with or without itch. Other symptoms are fever, arthralgia, lymphadenopathy, headache pharyngitis and oral candida. HIV antibody tests may still be negative. HIV-RNA or HIV DNA will be positive Treatment No specific treatment is indicated for the rash or for primary HIV infection. Patient counseling, education and behaviour modification are necessary. Bacillary angiomatosis Cause Bacillary angiomatosis (BA) is the vascular proliferative form of infection with Bartonella infection. Cats are the reservoirs of Bartonella henselae, which may be transmitted by cat bites or scratches. It is more common on patients with CD4 counts 100 cells/mm3) Notes on the use of amphotericin B Amphotericin B is given by slow IV infusion over 45 minutes 4 times per day. Patient needs careful observation, especially with initial doses as fever and chills can occur. The other main side effects of Amphotericin B are electrolyte disturbances (especially hypokalaemia) and hypoglycemia. Frequent monitoring of electrolytes and blood sugar are required, with 5% dextrose co- infusion and potassium supplements to maintain normal levels Penicilliosis Cause Penicillium marnefei - a fungus endemic in Northern Thailand, Southern China, Vietnam, Indonesia, and Hong Kong. Physical examination This disease presents as typical papulo-necrotic skin lesions and often as systemic disease with fever, lung involvement and cough, weight loss, anaemia, lymphadenopathy over 3-4 weeks. It usually presents with advanced HIV disease and a CD4 cell count < 100 cells/mm3 Other conditions to consider Molluscum contagiosum Treatment IV amphotericin B (0.7mg/kg daily) for 2 weeks then itraconazole 400 mg orally daily for 10 weeks In mild cases: Itraconazole 400 mg orally daily for 8 weeks. Secondary prophylaxis is with itraconazole 200mg per day for life or until immune recovery on ART. Histoplasmosis Cause Histoplasma capsulatum (fungus) Physical examination Cutaneous lesions are present in 10% of patients with disseminated Histoplasmosis. These are erythematous maculopapular lesions, with ulceration and purpura. Oropharyngeal lesions may also be present. Systemic manifestations include CNS mass lesions, encephalopathy, meningitis hepatosplenomegaly and lymphadenopathy Other conditions to consider Aspergillosis, Lymphoma, mycoplasma infections, PCP, other Pneumonias (bacterial, fungal, viral) Sarcoidosis Tuberculosis Treatment Amphotericin B (0.7mg/kg daily) minimum total dose should be 2 g.78 Secondary prophylaxis is with itraconazole 200mg per day for life or until immune recovery on ART. Primary and secondary syphilis Cause The spirochete Treponema pallidum Physical examination The chancre of primary syphilis usually is a single, painless papule that rapidly becomes eroded and indurated. Chancres usually are located on the genitals but may be found in the anal canal, mouth. The primary lesion usually is associated with regional lymphadenopathy Secondary syphilis may present in many different ways but usually includes a localized or diffuse mucocutaneous rash which may be macular, papular, pustular, or mixed and generalized non-tender Constitutional symptoms of secondary syphilis include malaise, sore throat, headache, fever and anorexia. Secondary syphilis presents years to decades after the initial infection Other conditions to consider Primary genital syphilitic lesion: Herpes simplex, chancroid, carcinoma, granuloma inguinale, lichen planus, psoriasis, fungal infection 70

Cutaneous eruption of secondary syphilis: Drug eruptions, pityriasis rosea, psoriasis, lichen planus, viral exanthem Treatment Primary, secondary, and early latent syphilis (1 y duration), syphilis of undetermined duration, and late syphilis Benzathine penicillin G, 2.4 million U IM once weekly for 3 consecutive weeks Alternative treatment - Doxycycline 100 mg PO bid or tetracycline 500 mg QID daily for 4 weeks Neurosyphilis Aqueous crystalline penicillin G, 2-4 million U IV q4h for 10-14 days Alternative treatment - Procaine penicillin, 2.4 million U IM OD, plus probenecid 500 mg QID for 10-14 days Cutaneous tuberculosis Cause Mycobacterium Tuberculosis Physical exam Asymptomatic warty papules on hands or extremities often mistaken for verruca vulgaris Lesions may evolve and persist for years. Treatment: Treatment should follow the national TB Guidelines Skin rashes with few or no symptoms Seborrhea Cause Seborrheic dermatitis occurs on the sebum-rich areas of the scalp, face, and trunk. In addition to sebum, this dermatitis is linked to the fungus Malassezia furfu. Physical examination Scalp appearance varies from mild, patchy scaling to widespread, thick, adherent crusts. From the scalp, seborrheic dermatitis can spread onto the forehead, eyebrows, naso-labial folds, the posterior part of the neck, and the postauricular skin. Skin lesions are greasy and scaling over red, inflamed skin. Other conditions to be considered Xerotic (dry skin) eczema, exfoliative dermatitis, scaling drug eruptions, psoriasis, staphylococcal blepharitis, tinea, Vitamin B and/or zinc deficiency Treatment In mild cases, use 1% hydrocortisone cream or 0.1% triamcinalone cream or similar topical steroid cream .This condition also responds to topical antifungals. Use 2% ketoconazole shampoo to wash hair and scalp and spread shampoo lather over face eyebrows etc. Leave on for 5 minutes and wash off. Repeat daily until cleared and once weekly to prevent recurrence. Ketoconazole cream can also be used on the face. Whitfield's ointment twice a day or gentian violet twice a day or miconazole 2% cream twice daily. For refractory cases oral ketoconazole 200 mg/day during 7-14 days can be used.

71

Molluscum contagiosum Cause A large DNA poxvirus Physical examination Firm, smooth, umbilicated papules, may be present in groups or widely disseminated on the skin and mucosal surfaces. Some lesions become confluent to form a plaque. Other conditions to be considered Histiocytoma, herpes zoster, cryptococcosis Treatment Removal by enucleation (with forceps) or cryotherpy, prick the centre and apply Phenol. Condyloma accuminata Cause Human papillomavirus (HPV) Physical examination Cauliflower-like lesions typically on genital and facial areas. HPV cause cervical and anal dysplasia and caner. Treatment Removal by cryotherapy, cauterization or application of podophylline 25% solution (2-3 times weekly). Annual pap smears as the risk of invasive cervical cancer is increased. Dermatophytosis (cutaneous ringworm, onychomycosis) Cause Microsporum spp, Trichophyton spp, Epidermophyton Physical examination Irregular plaques with spreading raised edge and central clearing. Nail infections Treatment Topical antifungal creams. For extensive, intractable and recurrent deep (nail bed) infections use terbinafine 250 mg/day 6 weeks for finger nails, 12 weeks for toe nails, Itraconazole 200 mg/day/3-5 months or 400 mg/day for one week per month for 3-4 consecutive months or fluconazole 150-300 mg/ wk until cure (6-12 months) or griseofulvin 500-1000 mg/day until cure (1218 months) HIV-associated skin rash Cause HIV, especially with advanced immunosuppression and low CD4 count Physical examination Itchy generalized maculo-papular skin rash; erythroderma A generalized pruritic maculopapular skin rash due to eosinophilic folliculitis is typical of HIV. Treatment No specific cause has been identified. Treatment is mainly symptomatic such as antihistamines and emollient creams The condition may improve with immune recovery on ART Severe soft tissue and muscle infection Causes Staphylococcal and streptococcal infections Physical examination Folliculitis and furunculosis present as painful, hot, fluctuant, sometimes discharging, lesions Pyomyositis, caused most commonly by Staphylococcus aureus, is a suppurative infection of striated muscle characterized by localized muscle pain, swelling, and tenderness. Cellulitis and erysipelas are streptococcal infections of the subcutaneous tissue, and are a result from contamination of minor wounds. Other conditions to be considered Pyomyositis may resemble muscle strain, contusion, cellulitis, hematoma, perinephric abscess, deep vein thrombophlebitis, osteomyelitis, synovitis, septic arthritis, or soft tissue sarcoma. Treatment Flucloxacillin 500 mg QID orally for 10 days or 1-2 g IV QID intravenously for10 days. In the case of pyomyositis surgical drainage may be necessary.

72

Herpes zoster Local lesion care, such as with gentian violet and chlorhexidine. If available and indicated, acyclovir 800 mg 5 times daily for 7 days. Famciclovir and valaciclovir are alternatives. Herpes simplex Local lesion care, such as Burow’s solution wet compression 15 minutes 4-5 times/day or gentian violet or chlorhexidine. If available, acyclovir 200-400 mg 5 times daily for 7 days. In cases of frequent recurrences, long-term suppressive therapy with acyclovir 400 mg bid may be necessary. Molluscum contagiosum Pick each lesion with a needle or sharpened orange stick and touch with phenol. Alternative treatments are electrocautery, application of liquid nitrogen or simple enucleation of the molluscum body with forceps. Human papilloma virus (warts) Treat with podophyllin 20% solution 1-2 times per week, until cleared or use electrocautery or application of liquid nitrogen. Oral Hairy Leucoplakia (OHL) OHL is caused by Epstein Barr Virus (EBV). It occurs on the side of the tongue, is usually asymptomatic and requires no treatment. If the tongue is painful, OHL responds to oral acyclovir 800 mg 5 times per day. Resolves with ART Candidiasis Local lesion care is with 1% aqueous solution of gentian violet or nystatin or clotrimazole 1% cream twice daily, until lesions are cleared. In severe cases, systemic therapy may be required. Preferred treatment is fluconazole, 200 mg once daily for 14 days. Alternative treatment is ketoconazole, 200 mg twice daily for 14 days. Ketoconazole should not be coadministered with nevirapine Dermatophytosis Treat with topical broad-spectrum antifungal cream such as 1% clotrimazole for 4-8 weeks. Widespread dermatophytosis may necessitate systemic treatment with griseofulvin, 500 mg to 1000 mg daily for 4 to 8 weeks. Alternatives are ketoconazole 200 mg daily for 14 days or itraconazole 400 mg daily for 3 months. Systemic mycoses Cutaneous lesions of systemic cryptococcosis or disseminated histoplasmosis are rare. Systemic cryptococcosis is treated with fluconazole 400 mg OD for 10-12 weeks, followed by maintenance therapy with fluconazole 200 mg OD. Histoplasmosis is treated with itraconazole 400 mg OD for 12 weeks in uncomplicated cases. Bacterial infections Local skin care with antiseptic solution, and cloxacillin or erythromycin tablet 250 mg, 2 tablets, 3 times daily, for 7 to 10 days. In severe cases, intravenous antibiotics may be required. In non-responding cases, choice of antibiotic should depend on culture and sensitivity results. Scabies 1. Gammabenzene hexachloride once a week for 2-3 weeks or until lesions are cleared. 2. 25% benzylbenzoate solution. Apply the lotion from head to toe. The application is left on the skin to dry and then repeated the next day. Treatment should be repeated weekly until all lesions are clear. Clothes and beddings should also be washed and kept separately for 3 days to prevent reinfestation. Household contacts should be treated. Drug eruptions Withdraw drug. Local lesion care with moisturizing cream. Symptomatic treatment with antihistamines to relieve itching. Short course systemic corticosteroids such as prednisolone 10 mg bid for 3 days and then 5 mg bid for 3 days should be given in severe cases. Malignancies Kaposi’s sarcoma may respond to local surgical excision or liquid nitrogen therapy. In severe cases and in the treatment of lymphoma, systemic chemotherapy is required. Pruritic papular eruptions This condition responds poorly to any treatment. High potency topical corticosteroids and oral anti-histamines are needed. Resolves with ART 73

Seborrhoeic dermatitis In mild cases, use 1% hydrocortisone cream or 0.1% triamcinalone cream or similar topical steroid cream . In severe cases with coexistent candidiasis, topical ketoconazole cream or shampoo is beneficial. Systemic ketoconazole 200 mg OD for 14 days is useful in severe and recurrent cases. Primary HIV Infection 50% to 90% of patients acutely infected with HIV will develop a “flu-like” illness typically within 1-3 weeks following initial infection. However, many patients acquire HIV infection “silently” without the typical syndrome. The syndrome can be difficult to diagnose due to the non-specific clinical picture and the difficulty of obtaining a laboratory diagnosis in resource limited countries. Treatment is symptomatic only Presentation of Acute Retroviral Syndrome • Generalized maculo- papular rash usually with fever and systemic symptoms • Lymphadenopathy • Pharyngitis • Erythematous maculopapular with lesions on face and trunk and sometimes extremities, including palms and soles. • Mucocutaneous ulceration involving mouth, esophagus or genitals • Myalgia or arthralgia • Diarrhea • Headache • Nausea and vomiting • Hepatosplenomegaly • Weight Loss ( • Thrush • Neurologic symptoms • Meningoencephalitis or aseptic meningitis • Peripheral neuropathy or radiculopathy • Facial palsy • Guillain-Barré syndrome • Brachial neuritis • Cognitive impairment or psychosis

74

Annexes Annex 1 Criteria for HIV-Related Clinical Events in Adults and Adolescents Clinical event Clinical diagnosis Definitive diagnosis Clinical Stage 1 Asymptomatic

No HIV related symptoms reported and no signs on examination.

Persistent generalized lymphadenopathy (PGL)

Painless enlarged lymph nodes >1 cm, in two or more non-contiguous sites (excluding inguinal), in absence of known cause & persisting for ≥3 months

Moderate unexplained weight loss (10% body weight), with obvious wasting or body mass index 37.6 oC or more with no other cause of disease, negative blood culture, negative malaria slide and normal or unchanged CXR. Cytology or immunofluorescent microscopy of induced sputum or bronchoalveolar lavage (BAL), or histology of lung tissue. Positive culture or antigen test of a compatible organism. Positive culture or DNA (by PCR) of HSV or compatible cytology/histology. Macroscopic appearance at endoscopy or bronchoscopy, or by microscopy/histology. M. tuberculosis isolation or compatible histology from appropriate site, together with compatible symptoms/signs (if culture/histology is from respiratory specimen then must other have evidence of extra pulmonary disease). Macroscopic appearance at endoscopy or bronchoscopy, or by histology. Positive serum toxoplasma antibody AND (if available)single/multiple intracranial mass lesion on neuro-imaging Diagnosis of exclusion: and (if available) neuroimaging (CT or MRI)

Clinical event

Clinical diagnosis

Definitive diagnosis

Extrapulmonary cryptococcosis (including meningitis)

Meningitis: usually sub acute, fever with increasing severe headache, meningism, confusion, behavioural changes that responds to cryptococcal therapy.

Disseminated nontuberculous mycobacteria infection

No presumptive clinical diagnosis.

Progressive multi focal leukoencephalopathy (PML) PML

No presumptive clinical diagnosis

Isolation of Cryptococcus neoformans from extrapulmonary site or positive cryptococcal antigen test (CRAG) on CSF/blood. Diagnosed by finding atypical mycobacterial species from stool, blood, body fluid or other body tissue, excluding lung. Progressive neurological disorder (cognitive dysfunction, gait/speech disorder, visual loss, limb weakness and cranial nerve palsies) together with hypodense white matter lesions on neuroimaging or positive

polyomavirus (JCV) Cryptosporidiosis (with diarrhoea lasting more than one month) Chronic isosporiasis Disseminated mycosis (coccidiomycosis, histoplasmosis) Recurrent non-typhoid salmonella bacteraemia Lymphoma (cerebral or B cell non-Hodgkin) or other solid HIV associated tumours. Invasive cervical carcinoma

No presumptive clinical diagnosis. No presumptive clinical diagnosis. No presumptive clinical diagnosis.

PCR on CSF. Cysts identified on modified ZN microscopic examination of unformed stool. Identification of Isospora Histology, antigen detection or culture from clinical specimen or blood culture.

No presumptive clinical diagnosis.

Blood culture.

No presumptive clinical diagnosis

Histology of relevant specimen or for CNS tumours neuroimaging

techniques No presumptive clinical diagnosis.

Histology or cytology. Diagnosed by histology (amastigotes visualized) or culture from any appropriate clinical specimen.

Visceral leishmaniasis

No presumptive clinical diagnosis.

HIV-associated nephropathy

No presumptive clinical diagnosis

Renal biopsy

No presumptive clinical diagnosis

Cardiomegaly and evidence of poor left ventricular function confirmed by echocardiography.

HIV-associated cardiomyopathy

Source: Revised WHO Clinical Staging and Immunological Classification of HIV and case definition of HIV for surveillance, May 2006

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Annex 2 Dosages of antiretroviral drugs for adults and adolescents Generic name Dose Nucleoside RTIs Abacavir (ABC) 300 mg twice daily or 600 mg once daily Zidovudine (AZT) 250 mg or 300 mg twice daily1 Emtricitabine (FTC) 200 mg once daily Didanosine (ddI)2 >60 kg: 400 mg once daily buffered tabs or enteric coated 60 kg, the recommended dose is 250 mg once daily. If weight 1 and < 5 y. old (15kg)

12

2

LAMIVUDINE (3TC) + STAVUDINE (d4T) + NEVIRAPINE (NVP) > 5 y. old (25kg)

20

LAMIVUDINE (3TC) + STAVUDINE (d4T) + NEVIRAPINE (NVP) < 1 y. old (10kg)

ZIDOVUDINE (AZT) + LAMIVUDINE (3TC) + NEVIRAPINE (NVP) < 1 y. old (10kg)

EFV 600 mg tablets

d4T 20mg tablets

NVP NVP 200mg d4T 30mg 50mg/5ml, oral tablets tablets solution

EFV 50 mg capsules

EFV 200 mg capsules

AZT AZT 100 mg AZT 300 mg 50mg/5ml capsules tablets oral solution

14 1 1

1

8

1 20

14

ZIDOVUDINE (AZT) + LAMIVUDINE (3TC) + NEVIRAPINE (NVP) > 1 and < 5 y. old (15kg)

12

1

ZIDOVUDINE (AZT) + LAMIVUDINE (3TC) + NEVIRAPINE (NVP) > 5 y. old (25kg)

20

1

1 2

1

2

1

LAMIVUDINE (3TC) + STAVUDINE (d4T) + EFAVIRENZ (EFV) < 1 y. old (10kg) (not recommended) LAMIVUDINE (3TC) + STAVUDINE (d4T) + EFAVIRENZ (EFV) > 1 and < 5 y. old (15kg)

12

LAMIVUDINE (3TC) + STAVUDINE (d4T) + EFAVIRENZ (EFV) > 5 y. old (25kg)

20

2 1

1

1

1

3

1

ZIDOVUDINE (AZT) + LAMIVUDINE (3TC) + EFAVIRENZ (EFV) < 1 y. old (10kg) (not recommended) ZIDOVUDINE (AZT) + LAMIVUDINE (3TC) + EFAVIRENZ (EFV) > 1 and < 5 y. old (15kg)

12

1

1

ZIDOVUDINE (AZT) + LAMIVUDINE (3TC) + EFAVIRENZ (EFV) > 5 y. old (25kg)

20

3

1

second line adults Tenofovir (TDF) 300 mg + Abacavir (ABC) 300mg + Lopinavir /Ritonavir (LP/r) 200/50 mg Tenofovir (TDF) 300 mg + Abacavir (ABC) 300mg + Saquionavir /Ritonavir (SQV/r) 200/100 mg Tenofovir (TDF) 300 mg + AZT 300 mg +3TC 150 mg + Lopinavir /Ritonavir (LP/r) 200/50 mg Tenofovir (TDF) 300 mg + AZT 300 mg +3TC 150 mg + Saquinavir /Ritonavir (SQV/r) 200/100 mg Tenofovir (TDF) 300mg + Didanosine (ddI) 125mg + Lopinavir/Ritonavir (LPV/r) 133.3/33.3 mg 60kg Tenofovir (TDF) 300mg + Didanosine (ddI) 125mg + Saquinavir/Ritonavir (SQV/r) 200/100mg 60kg

TDF 300 mg tablets

1 1 1 1 1 1 1 1

ddI 25 mg tablets

ddI 100 mg ddI 200 mg tablets tablets

1

1 1

1

1 1 2 1 2

Abacavir (ABC) 300mg + Didanosine (ddI) 400mg + Saquinavir/Ritonavir (SQV/r) 200/100mg >60kg

ABACAVIR (ABC) + DIDANOSINE (ddI) + NELFINAVIR (NFV) > 5 y. old (25kg)

4 2

10

2

10

2 2

9 9

9 9

2 2

9 9

9 9

6 6

1

Abacavir (ABC) 300mg + Didanosine (ddI) 250mg + Saquinavir/Ritonavir (SQV/r) 200/100mg 1 and < 5 y. old (15kg)

LPV/r AZT 300 mg 200/50 mg +3TC 150 capsules mg

4

Abacavir (ABC) 300mg + Didanosine (ddI) 400mg + Lopinavir/Ritonavir (LPV/r) 133.3/33.3 >60kg

ABACAVIR (ABC) + DIDANOSINE (ddI) + NELFINAVIR (NFV) < 1 year (10kg)

LPV/r ABC 300 mg RTV 100 mg SQV 200 mg 133.3/33.3 tablets capsules capsules mg capsules

2 2

Abacavir (ABC) 300mg + Didanosine (ddI) 250mg + Lopinavir/Ritonavir (LPV/r) 133.3/33.3 40 kg, > 5yr old (25 kg)

PMTCT (for Mother) ZIDOVUDINE (AZT) 300 mg (during pregnancy) ZIDOVUDINE (AZT) 300 mg + NEVIRAPINE (NVP) 200 mg (during labour) ZIDOVUDINE (AZT) 300 mg + NEVIRAPINE (NVP) 200 mg (after delivery)

PMTCT (for Infants)

6 10 10 10 10 AZT 300 mg tablets

1 1 1 1 1

5.5 7 8 9.5 10

NVP 200mg recommend tablets ed days

2 2 2

1 2

196 7 7

NVP AZT 3TC recommend 50mg/5ml, oral 50mg/5ml oral 50mg/5ml, ed days solution solution oral solution

ZIDOVUDINE (AZT) 50mg/5ml oral solution

0.2 0.8

1 7

ZIDOVUDINE (AZT) 50mg/5ml oral solution(during pregnancy receives < 28 days)

0.8

LAMIVUDINE (3TC) 50mg/5ml, oral solution

0.4

28 7

NEVIRAPINE (NVP) 50mg/5ml, oral solution

PEP

AZT 300 mg tablets

PEP (for pregnancy woman)

RTV 100 mg capsules

ZIDOVUDINE (AZT) 300 mg + STAVUDINE (d4T) 30mg

Saquinavir/Ritonavir (SQV/r) 200/100mg

ARVs_3DF_Aug 07.MM

2

d4T 30mg tablets

recommend ed days

2

28

SQV 200 mg recommend capsules ed days

2

Page 2 of 2

2

28

10/24/2007

Annex 3 Storage of Antiretrovirals

Generic name Nucleoside RTIs Abacavir (ABC) Zidovudine (AZT) Didanosine (ddI) Emtricatabine (FTC) Lamivudine (3TC) Stavudine (d4T) Stavudine (d4T)+Lamivudine (3TC) + Nevirapine (NVP) Zidovudine (AZT) + Lamivudine (3TC) + Abacavir (ABC) Zidovudine (AZT) + Lamivudine (3TC) + Nevirapine (NVP)

Storage requirements Room temperature Room temperature Room temperature for tablets and capsules. Reconstituted buffered powder should be refrigerated; oral solution for children is stable after reconstitution for 30 days if refrigerated. Room temperature Room temperature Room temperature. After reconstitution, oral solution should be kept refrigerated; if so, it is stable for 30 days. Room temperature Room temperature Room temperature

Nucleotide RTIs

Tenofovir (TDF)

Room temperature

Non-nucleoside RTIs

Efavirenz (EFV) Nevirapine (NVP)

Room temperature Room temperature

Proteases inhibitors

Atazanavir (ATV) Indinavir (IDV) Fos-amprenavir (FPV)

Room temperature Room temperature Room temperature Refrigerate for long term storage Lopinavir/Ritonavir (LPV/r) capsules At room temperature: stable for 30 days Lopinavir/Ritonavir (LPV/r) heat Room temperature stable tablets Nelfinavir (NFV) Room temperature Refrigerate capsules until dispensed; Stable at room temperature for 30 days Ritonavir (RTV) Room temperature for oral solution (do not refrigerate) Saquinavir – hard gel caps. (SQVhgc) Room temperature Room temperature is defined as 15-30 deg C. Refrigeration is defined as 2-8deg C

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Annex 4 Drugs that interact with ART ARV Antimycobacterium

Rifampicin

Rifabutin

Clarithromycin

NVP ↓NVP level by 20-58%. Virological consequences are uncertain; the potential of additive hepatotoxicity exists. Coadministration is recommended only be done with careful monitoring

Levels: NVP↓ 16%. No dose adjustment.*

none

EFV

LPV/r

↓EFV level by 25% Standard dosing of EFV recommended

↓LPV AUC by 75% Should not co-administer

Levels: EFV unchanged; Rifabutin ↓ 35% Dose: ↑ rifabutin dose to 450-600 mg Once daily or 600 mg 3x/week. EFV: Standard

Levels: Rifabutin AUC ↑ 3-fold. 25 Decrease rifabutin dose to 150 mg once daily or 3x/week LPV/r: Standard.

↓Clarithromycin by 39% Monitor for efficacy or use alternative drugs

↑Clarithromycin AUC by 75%, adjust clarithromycin dose if renal impairment

No significant changes in ketoconazole or EFV levels

↑LPV AUC ↑Ketoconazole level 3fold Do not exceed 200mg/day ketoconazole

NFV

SQV

↓NFV level by 82% Should not co-administer

↓SQV level by 84% Severe liver impairment with co-administer reported Should not co-administer

Levels: NFV ↓ 82%. Should not be coadministered.

Levels: SQV↓40%. Contraindicated unless SQV/RTV. Dose: Rifabutin 150 mg once daily or 3x/week

No data

Without RTV, ↑clarithromycin level by 45%, ↑SQV level 177% RTV can ↑Clarithromycin level by 75% No clarithromycin dose adjustment needed for unboosted SQV. For boosted SQV if renal impairment – no data

No dose adjustment necessary

↑SQV level by 3 fold No dose adjustment necessary if given unboosted. For RTV-boosted SQV – no data (RTV treatment

Antifungal

Ketoconazole

↑Ketoconazole level by 63% ↑NVP level by 15-30% Do not recommend coadminister

82

ARV

Fluconazole

Itraconazole

NVP ↑NVP Cmax, AUC, Cmin by 100% No change in fluconazole level Possible increase hepatotoxicity with coadminister requiring monitoring of NVP toxicity

EFV

No data

LPV/r

No data

NFV

SQV dose can increase ketoconazole level 3-fold)

No data

No data

No data

No data

↑Itraconazole level Do not exceed 200mg/day itraconazole

No data but potential for bidirectional inhibition, monitor toxicities

Bidirectional interaction has been observed. May need to decrease itraconazole dose. Consider monitor SQV level (especially if given unboosted with RTV)

↓Ethinyl oestradiol by 20%. Use alternative or additional methods

↑Ethinyl oestradiol by 37%. Use alternative or additional methods

↓Ethinyl oestradiol level by 42% Use alternative or additional methods

↓levels of norethindrone by 18% and ethinyl oestradiol by 47%

No data for unboosted SQV. RTV treatment dose can ↓level of ethinyl oestradiol by 41%

Unknown, but may decrease NFV levels substantially. Monitor anticonvulsant levels and virological response.

Unknown, but may markedly ↓ SQV levels. Monitor anticonvulsant levels and consider obtaining SQV level.

Oral contraceptives Ethinyl oestradiol

Anticonvulsants

Carbamazepine Phenytoin

Use with caution. One case report showed low EFV concentrations with phenytoin.

Unknown. Use with caution.

Many possible interactions: Carbamazepine ↑ levels when co-administered with RTV. Use with caution. Monitor anticonvulsant levels. Phenytoin: ↓levels of LPV, RTV, and↓ levels of phenytoin when

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ARV

NVP

EFV

Opiod Substitution Treatment (OST) Levels: NVP unchanged. methadone ↓ significantly. Opiate withdrawal common when this combination is Methadone used. Increased methadone dose often necessary. Titrate methadone dose to effect.

Levels: methadone ↓ 60%. Opiate withdrawal common, increase methadone dose often necessary. Titrate methadone dose to effect.

Buprenorphine

Buprenorphine levels ↓ 50% nut no withdrawals reported. No dose adjustment is recommended

Not studied

LPV/r administered together. Avoid concomitant use or monitor LPV level.

NFV

SQV

Methadone AUC ↓ 53%. Opiate withdrawal may occur. Monitor and titrate dose if needed. May require↑ methadone dose.

NFV may decrease methadone levels, but opiate withdrawal rarely occurs. Monitor and titrate dose if needed. May require ↑ methadone dose.

Methadone AUC ↓ 20%. When co-administered with SQV/RTV 400/400 mg BID. No adjustment for this PI regimen, but monitor and titrate to methadone response as necessary.

No significant interactions

No significant interactions

No significant interactions

Potential large ↑ statin level Avoid concomitant use

↑ Simvastatin AUC by 505% Potential large ↑ lovastatin AUC Avoid concomitant use

Potential large ↑ statin level Avoid concomitant use

↑Atorvastatin AUC 5.88 fold Use lowest possible starting dose with careful monitoring

↑Atorvastatin AUC 74% Use lowest possible starting dose with careful monitoring

↑ Atorvastatin level by 450% when use as SQV/RTV Use lowest possible starting dose with careful monitoring

Lipid lowering agents

Simvastatin, Lovastatin

Atorvastatin

No data

No data

↓ Simvastatin level by 58% EFV level unchanged Adjust simvastatin dose according to lipid response, not to exceed the maximum recommended dose ↓Atorvastatin AUC by 43% EFV level unchanged Adjust atorvastatin dose according to lipid response, not to exceed maximum recommended

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ARV

NVP

EFV

LPV/r

NFV

SQV

dose Pravastatin

No data

No data

↑Pravastatin AUC 33% No dose adjustment needed

No data

↓Pravastatin level by 50% No dose adjustment needed

Anticonvulsants ↑Carbamazepine from Unknown for unboosted Unknown but may RTV decrease NFV level SQV but may markedly ↓ Carbamazepine, Both phenytoin and substantially SQV level Phenobarbital, LPV/r levels ↓ Monitor Monitor phenytoin For all, avoid concomitant NFV/anticonvulsant SQV/anticonvulsant use or monitor levels levels LPV/anticonvulsant levels Proton pump inhibitors. All the PIs and EFV can ↑ levels of cisapride and non sedating antihistamines (aztemizole, terfenedine) which can cause cardiac toxicity. Co administration is not recommended Unknown. Use with caution Monitor anticonvulsant levels

Use with caution. One case report showed low EFV levels with phenytoin Monitor anticonvulsant and EFV levels

Abbreviations: AUC: area under the curve, Cmax: maximum concentration, Cmin: minimum concentration. Note: Concomitant use of fluticasone with RTV results in significant reduced serum cortisol concentrations. Coadministration of fluticasone with RTV or any RTV-boosted PI regimen is not recommended unless the potential benefit outweighs the risk of systemic corticosteroid side effects. (Adapted from the Guidelines for the use of antiretroviral agents in HIV infected Adults and Adolescents, May 4, 2006, www.aidsinfo.nih.gov.)

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Annex 5 Clinical diagnosis and management of common opportunistic infections Opportunistic Infection

Pneumocystis jiroveci (previously know as carinii)

Candida

Clinical Features

Dry cough Shortness of breath Fever Night sweats Subacute presentation over 1-2 months

Oral candida White mucosal plaques +/- erythema in oral cavity

Oesophageal Candida Dysphagia +/- retrosternal chest pain

Diagnosis

Treatment

Chest X-ray is abnormal in more than 90% cases of pneumocystis jiroveci pneumonia, typically showing bilateral interstitial infiltrates

Typical clinical appearance on physical examination Microscopic demonstration of psuedohyphae on potassium hydroxide preparation Typical clinical presentation and response to antifungal therapy Endoscopy if available

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Preferred treatment Cotrimoxazole (Trimethoprim-sulfamethoxazole, TMP 15 mg plus SMZ 75 mg/kg daily) in 4 divided doses, orally or intravenously, for 21 days. Treatment should be IV in severally ill patients. Patients can switch to oral cotrimoxazole if clinically improved. Oral doses are 480 mg, 2 tablets 4 times daily (patient 40 kg) Alternative treatment Clindamycin 600mg IV or 450mg orally TID + primaquine 15mg orally OD for 21 days if allergy to sulphonamides. Prednisolone, 20 mg 4 times daily, reducing slowly over 7-10 days depending on response to therapy is recommended for severely ill patients.

Clotrimazole or nystatin lozenges, to be sucked every 4 hours for 7 days or Nystatin oral suspension 100,000 IU, three times a day for 7 days

Fluconazole 200 mg daily for 14 days or Ketoconazole 200 mg daily for 14 days

Opportunistic Infection

Clinical Features

Diagnosis

Treatment

Cryptococcosis

Occipital headache meningeal irritation photophobia, neck stiffness or raised intracranial pressure Fever Changes in mental state Disseminated disease with papulonecrotic skin lesions resembling molluscum contagiosum associated with fever and pulmonary infiltrates

Elevated intracranial pressure CSF and protein on lumbar puncture Organism demonstrated from CSF or skin legions with India Ink stain and light microscopy

Preferred treatment IV Amphotericin B (0.7 mg/kg/day) for 2 weeks followed by Itraconazole 200 mg 2 times daily or fluconazole 400 mg daily for 8 weeks Alternative treatment Fluconazole 400 mg daily for 8 to 12 weeks Maintenance treatment Itraconazole 200 mg/day or Fluconazole 200mg/day

Penicilliosis

Papulo-necrotic skin lesions associated with systemic disease of fever, lung involvement, cough, weight loss, anaemia, and lymphadenopathy. 70% of patients with disseminated Penicillium marneffei infection will have skin lesions

Microscopy of skin biopsy or lymph node aspirate Organism demonstrated with Wright’s stain or Cotton blue stain

Preferred treatment IV amphotericin B (0.7mg/kg daily) for 2 weeks followed by itraconazole 400 mg orally daily for 8-10 weeks. Maintenance therapy Itraconazole 400 mg daily

Toxoplasmosis

Headache Drowsiness Fever Focal neurologic abnormality Seizures

Focal neurological signs Single or multiple ring-enhancing lesions on CT (if available) Response to presumptive treatment can be used to support the diagnosis

Preferred treatment Pyrimethamine loading dose 75-100 mg, then 25-50 mg daily plus Sulfadiazine, 4 g daily in 4 divided doses Folinic acid 10 mg per day if available Treat for 6 weeks Maintenance therapy Pyrimethamine, 25 mg daily plus Sulfadiazine, 2 g daily in 4 divided doses

Herpes simplex virus (HSV)

Clusters of typical blisters, usually in genital area or face Systemic involvement (such as HSV oesophagitis, encephalitis) is possible

Typical clinical appearance

Usually self-limiting and may not require treatment. Local lesion care, such as with gentian violet and chlorhexidine. If indicated, acyclovir 200-400 mg 5 times daily for 7 days.

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Opportunistic Infection

Herpes zoster virus (HZV)

Clinical Features

Diagnosis

Treatment

Typical painful blisters in clusters along dermatomes. Can involve the eye

Clinical appearance

Local lesion care, such as with gentian violet and chlorhexidine. Acyclovir 800 mg 5 times daily orally for 7 days, commenced within 72 hours of onset of blisters. Famciclovir and valaciclovir are alternatives. Acyclovir ointment applied into eye every 4 hours for ophthalmic H. zoster

Pulmonary TB Cough, fever, weight loss, fatigue

Sputum examination for AFB Chest X-ray Classic chest X-ray pattern Upper lobe infiltrates Cavitation Atypical Pattern Bilateral Interstitial infiltrates Infiltrates, pleural effusion Pleural tap for AFBs

Mycobacterium tuberculosis

Extra pulmonary TB Enlarged lymph nodes or spleen CNS or gastro-intestinal symptoms

Treat according to national TB guidelines.

Unilateral nodes increasing in size, matted nodes, fluctuant nodes, fever, weight loss, splenomegaly Diarrhoea and abdominal pain

Mycobacterium Avium Complex (MAC)

Chronic or recurrent fever Weight loss Fatigue

Isolation of organism from blood or other sites Unexplained anaemia

Preferred therapy Azithromycin (500-600mg once a day) or clarithromycin (500mg twice a day) plus ethambutol (15mg/kg/day) plus rifabutin (300mg once a day) ART may resolve the condition Maintenance therapy Clarithromycin (500mg twice a day) or azithromycin (500mg once a day) plus ethambutol (15mg/kg once a day)

Cryptosporidium

Chronic diarrhea Cramps and vomiting Right upper quadrant pain

Modified AFB stain on stool specimen

ART is the preferred treatment

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References 1

2

Hill A, et al. Meta-analysis of efficacy and safety for clinical studies of d4T 40 mg versus 30 mg BID in 1008 patients. 16th World AIDS Conference, Toronto, August 2006

Egger M, May M, Chene G, et al. Prognosis of HIV1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet, 2002. 360(9327):119-29. 3 Gulick RM, Mellors JW, Havlir D, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunODeficiency virus infection and prior antiretroviral therapy. N Engl J Med, 1997. 337(11):734-9. 4 Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunODeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. N Engl J Med, 1997. 337(11):725-33. 5 Garcia F, De Lazzari E, Plana M, et al. Long-Term CD4+ T-Cell Response to Highly Active Antiretroviral Therapy According to Baseline CD4+ T-Cell Count. J Acquir Immune Defic Syndr, 2004. 36(2):702-13. 6 Teerawattananon Y, Hanshaoworakul W, Russell S, Tangcharoensathien V, Jiamton S. Targeting antiretroviral therapy: lessons from a longitudinal study of morbidity and treatment in relation to CD4 count in Thailand. Asia Pac J Public Health. 2006;18(1):39-48 7 WoOD E, Hogg RS, Harrigan PR, Montaner JSG. When to initiate antiretroviral therapy in HIV-1 infected adults: a review for clinicians and patients. Lancet Infect Dis 2005;5:407-14. 8 . Gulick R, Ribaudo H Ph.D. for the AIDS Clinical Trials Group Study A5095 Team Triple-Nucleoside Regimens versus Efavirenz-Containing Regimens for the Initial Treatment of HIV-1 Infection. New Eng J. Med. Volume 350:1850-1861 April 29, 2004 Number 18 9 DART Virology Group and Trial Team; Virological response to a triple nucleoside/nucleotide analogue regimen over 48 weeks in HIV-1-infected adults in Africa AIDS 2006, 20:1391–1399 10 Gallant JE, RODriguez AE, Winkler G et al and the ESSS3009 Study. Early virologic non-response to tenofovir, abacavir and lamivudine in HIV-infected antiretroviral -naive subjects. J Inf Dis 2005; 192(11):1921-30. 11 Jemsek J, Hutcherson P, Harper E. Poor virologic responses and early emergence of resistance in treatment naïve, HIV-infected patients receiving a once daily triple nucleoside regimen of didanosine, lamivudine, and tenofovir DF. 11th Conference on Retroviruses and Opportunistic Infections; Februrary 2004; San Francisco, CA. 12 French MA, Lenzo N, John M, et al. Immune restoration disease after the treatment of immunODeficient HIV-infected patients with highly active antiretroviral therapy. HIV Med 2000; 1:107–15. 13 Breen RAM, Smith CJ, Bettinson H, et al. Paradoxical reactions during tuberculosis treatment in patients with and without HIV co-infection. Thorax 2004; 59:704–707. 14 Lipman M, Breen R. Immune reconstitution inflammatory syndrome in HIV. Curr Opin Infect Dis 2006;19:20-5. 15 McComsey G, Whalen C, Mawhorter S, et al. Placebo-controlled trial of prednisone in advanced HIV-1 infection. AIDS 2001;15:321-7. 16 Paterson DL, Swindells S, Mohr J, et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med 2000;133:21-30. 17 Ickovics JR, Meisler AW. Adherence in AIDS clinical trials: a framework for clinical research and clinical care. J Clin Epidemiol 1997;50:385-91. 18 Chesney MA. Factors affecting adherence to antiretroviral therapy. Clin Infect Dis 2000;30 Suppl 2:S171-6. 19 Shibuyama S, Gevorkyan A, Yoo U et al. Understanding and avoiding antiretroviral adverse events. Curr Pharm Des 2006, 12(9): 1075-90. 20

21

Antiretroviral therapy for HIV infection in adults and adolescents in resource-limited settings: towards universal access. Recommendations for a public health approach. Geneva, World Health Organization, 2006. Hill A, et al. Meta-analysis of efficacy and safety for clinical studies of d4T 40 mg versus 30 mg BID in 1008 patients. 16th World AIDS Conference, Toronto, August 2006.

22

Sánchez-Conde M, Medoza C, Jímenez-Nacher I et al. Reductions in stavudine dose ameliorate mitochondrial -associated complications without compromising antiviral activity. HIV Clin Trials 2005 6(4):197-202. 23 Winston A, Boffito M. The management of HIV-1 protease inhibitor pharmacokinetic interactions. J Antimicrob Chemother 2005;56:1-5. 24 Back D, Gibbons S, Khoo S. Pharmacokinetic drug interactions with nevirapine. JAIDS 2003;34 (Suppl 1):S8-14. 89

25

Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-Limited Settings: Towards Universal Access. Recommendations for a public health approach; 2006 revision. World Health Organization 2006 26 Tarantal AF, Castillo A, Ekert JE, et al. Fetal and maternal outcome after administration of tenofovir to gravid rhesus monkeys (Macaca mulatta). JAIDS 2002;29:207-20. 27 Hazra R, Gafni R, Madlarelli F, et al. Safety, tolerability, and clinical responses to tenofovir DF in combination with other antiretrovirals in heavily-treatment-experienced HIV-infected children: data through 48 weeks. 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, February 8-11, 2004 (Abstract 928). 28 Almond L, Gibbons S, Davies G, Dack D, Khoo S. A retrospective survey of the Liverpool TDM Service: factors influencing efavirenz concentrations in patients taking rifampicin. 6th International Workshop on Clinical Pharmacology of HIV Therapy, Quebec, April 2005, poster 2.12. 29 Patel A, Patel K, Patel J et al. Safety and antiretroviral effectiveness of concomitant use of rifampicin and efavirenz for antiretroviral-naive patients in India who are coinfected with tuberculosis and HIV-1. J Acquir Immune Defic Syndr. 2004 Sep 1;37(1):1166-9. 30 Pedral-Sampaio D et al. Efficacy and Safety of Efavirenz in HIV Patients on Rifampin for Tuberculosis. The Brazilian Journal of Infectious Diseases 2004; 8(3):211-216 31 Manosuthi W et al. A randomized controlled trial of efavirenz 600 mg/day versus 800 mg/day in HIVinfected patients with tuberculosis to study plasma efavirenz level, virological and immunological outcomes: a preliminary result. In: XV International AIDS Conference, Bangkok, Thailand, July 2004 [Abstract MoOrB1013] 32 Sheehan NL, Richter C, Efavirenz 600 MG is not associated with Subtherapeutic Efavirenz Concentrations when given concomitantly with Rifampin. 6th International Workshop on Clinical Pharmacology of HIV therapy. 28-30 April 2005, Quebec City, Canada. 33 Autar RS et al. What is the clinical relevance of the drug interaction between nevirapine and rifampin? In: XV Int AIDS Conf., Bangkok, Thailand, July 2004 [Abstract B11784]. 34 Oliva J et al. Co-administration of rifampin and nevirapine in HIV-infected patients with tuberculosis. AIDS 2003, 17:637-642 35 Ribera E et al. Pharmacokinetic interaction between nevirapine and rifampin in HIV-infected patients with tuberculosis. J Acquir Immune Defic Syndr 2001, 28:450-453 36 Dean G L, Back D J, De Ruiter A. Effect of tuberculosis therapy on nevirapine trough plasma concentrations. AIDS 1999; 13: 2489-2490. 37 Van Cutsem G, Cohen K., Bedelu M., Sarunchuk P., Hilderbrand K., Coetsee D. Boulle A. TB/HIV coinfected patients on rifampicin containing treatment have equivalent ART treatment outcomes, and concurrent use of nevirapine is not associated with increased hepatotoxicity. WePp0303. 3th IAS Conference on HIV Pathogenesis and Treatment. 24-27 July 2005, Rio de Janeiro, Brazil. 38 Dean GL, Edwards SG, Ives NJ, et al. Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy. AIDS. 2002 Jan 4;16(1):75-83. 39 Justesen U.S, Andersen A.B., Klitgaard. Pharmacokinetic interaction between rifampicin and the combination of indinavir and low dose ritonavir in HIV infected patients. Clin Infect Dis. 2004 Feb 1;38(3):426-9. 40 HIV/AIDS Treatment and Care For Injecting Drug Users. Clinical Protocols for the WHO European Region. In press 41 Wood E, Hogg RS, Yip B, et al. Rates of antiretroviral resistance among HIV-infected patients with and without a history of injecting drug use. AIDS 2005;19:1189-95. 42 Wood E, Montaner JS, Yip B, et al. Adherence to antiretroviral therapy and CD4 T-Cell count responses among HIV-infected injection drug users. Antiviral Therapy 2004;9(2):229-35. 43 Altice, Frederick L.; Friedland, Gerald H.; Cooney, Elizabeth L Nevirapine induced opiate withdrawal among injection drug users with HIV infection receiving methadone. AIDS. 13(8):957-962, May 28, 1999. 44 British HIV Association guidelines for the treatment of HIV-infected adults with antiretroviral therapy 2005 45 HIV/AIDS Treatment and Care: WHO protocols for CIS countries. The Regional Office for Europe of the World Health Organization 2004 46 Bessesen M, Ives D, Condreay L, Lawrence S, Sherman KE. Chronic active hepatitis B exacerbations in human immunodeficiency virus-infected patients following development of resistance to or withdrawal of lamivudine Clin Infect Dis. 1999 May;28 (5):1032-5 47 Filippini P, Coppola N, Pisapia R, Scolastico C, Marrocco C, Zaccariello A, Nacca C, Sagnelli C, De Stefano G, Ferraro T, De Stefano C, Sagnelli E. Impact of occult hepatitis B virus infection in HIV patients naive for antiretroviral therapy AIDS. 2006 Jun 12;20 (9):1253-60. 90

48

Alberti A, Clumack N, et al Short statement on the first European Consensus Conference on the Treatment of Chronic Hepatic B and C in HIV Coinfected Patients. Journal of Hepatology 2005;42:615-24. 49 Ledergerber B, et al. Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes. Lancet 2004;364(9428):51-62; 50 Tomasoni LR et al. Predictors of long-term immunological outcome in rebounding patients on protease inhibitor-based HAART after initial successful virologic suppression: implications for timing to switch. HIV Clin Trials 2003;4(5):311-23; 51 Kousignian I et al. MODeling the time course of CD4 T-lymphocyte counts according to the level of virologic rebound in HIV-1-infected patients on highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2003;34(1):50-7; 52 Murri R et al. Is mODerate HIV viremia associated with a higher risk of clinical progression in HIVinfected people treated with highly active antiretroviral therapy: evidence from the Italian cohort of antiretroviral-naive patients study. J Acquir Immune Defic Syndr 2006;41(1):23-30.] 54

Walmsley S, Bernstein B, King M et al and the M98-863 Study Team. Lopinavir-ritonavir versus nelfinavir for initial treatment of HIV infection. N Engl J Med, 2002; 346(26):2039-46. 55 King MS, Brun AC; Kempf DJ. Relationship beetween adherence and teh development of resistance in antiretroviral-naive, HIV-infected patients receiving lopinavir/ritonavir or nelfinavir. J Infect Dis 2005; 191:2046-52 56 Molina J, Marcelin A et al Didanosine in HIV-1-Infected Patients Experiencing Failure of Antiretroviral Therapy: A Randomized Placebo-Controlled Trial. J Infect Dis. 2005 Mar 15;191(6) 57 Leon EA, Martinez E, Mallolas J et al: Early virological failure in treatment naïve HIV-infected adults receiving didanosine abd tenofovir plus efavirenz and nevirapine. AIDS; 2005; 19 (2) 213-215 58 Barrios A, Rendon A, Negredo E, et al: Paradoxical CD4+ T-cell decline in HIV-infected patients with complete virus suppression taking tenofovir and didanosine. AIDS. 2005 Mar 24;19(6):569-75. 59 Negredo E, Molto J, Burger D, et al: Unexpected CD4 cell count decline in patients receiving didanosine and tenofovir-based regimens despite undetectable viral load. AIDS. 2004 Feb 20;18(3):459-63 60 Ray AS, Olson L, Fridland A. Role of purine nucleoside phosphorylase in interactions between 2',3'dideoxyinosine and allopurinol, ganciclovir, or tenofovir. Antimicrob Agents Chemother. 2004 Apr; 48 (4):1089-95 61 Negredo E, Molto J et al; Lopinavir/ritonavir plus nevirapine as a nucleoside sparing approach in antiretroviral experienced patients (NEKA Study). JAIDS; volume 9, Jan.1, 2005 62 Boyd M, Siangphoe U, Ruxrungtham K, Duncombe C et al; Indinavir/ritonavir 800/100mg bid and efavirenz 600mg qd in patients failing treatment with combination nucleoside reverse transcriptase inhibitors: 96-week outcomes of HIV-NAT 009. HIV Medicine (2005), 6, 410–420 63 Bell DM. Occupational risk of human immunODeficiency virus infection in health-care workers: an overview. Am J Med 1997;102(5B):9–15. 64 Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HIV and Recommendations for Postexposure Prophylaxis. Department of Health and Human Services Morbidity and Mortality Weekly Report September 30, 2005 / Vol. 54 / No. RR-9 65 Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HIV and Recommendations for Post exposure Prophylaxis, Department of Health and Human Services (DHHS) (Morbidity and Mortality Weekly Report September 30, 2005) 66 Wahn V, Kramer HH, Voit T, Bruster HT, Scrampical B, Scheid A. A horizontal transmission of HIV infection between two siblings. Lancet 1986;2:694. 67 Brenner S, Wolf R, Ophir J: Eosinophilic pustular folliculitis: a sterile folliculitis of unknown cause?. J Am Acad Dermatol 1994 Aug; 31(2 Pt 1): 210-2 68 Ellis E, Scheinfeld N: Eosinophilic pustular folliculitis: a comprehensive review of treatment options. Am J Clin Dermatol 2004; 5(3) 69 Clinical AIDS care guidelines for resource poor settings. Médecins Sans Frontieres: Lut Lynen, author; Marc Biot, editor. 70 Brook I: Microbiology of secondary bacterial infection in scabies lesions. J Clin Microbiol 1995 Aug; 33(8): 2139-40 71 Chosidow O: Clinical practices. Scabies. N Engl J Med 2006 Apr 20; 354(16): 1718-27 72 Terri L. Meinking, David Taplin, Jorge L. Herminda, Rube Pardo, and Francisco A. Kerdel The Treatment of Scabies with Ivermectin NEJM, Volume 333:26-30 July 6, 1995 73 Dermatologic manifestations of HIV infection. Top HIV Med. 2005 Dec-2006 Jan;13(5):149-54. 74 Prevalence of dermatological disorders in Thai HIV-infected patients correlated with different CD4 lymphocyte count statuses: a note on 120 cases.Int J Dermatol. 2004 Apr;43(4):265-8. 91

75

HIV-associated pruritus: etiology and management. Am J Clin Dermatol. 2003;4(3):177-88 Gasquet S, Maurin M, Brouqui P, et al: Bacillary angiomatosis in immunocompromised patients. AIDS 1998 Oct 1; 12(14): 1793-803 77 Stevens-Johnson syndrome and toxic epidermal necrolysis: a review of the literature. Ann Allergy Asthma Immunol. 2005 Apr;94(4):419-36 78 Wheat LJ, Conces D, Allen SD, et al: Pulmonary histoplasmosis syndromes: recognition, diagnosis, and management. Semin Respir Crit Care Med 2004 Apr; 25(2): 129-44 79 Cressey T, Leenasirimakul P, Jourdain G et al: Intensive Pharmacokinetics of Zidovudine 200 mg Twice Daily in HIV-1-Infected Patients Weighing Less Than 60 kg on Highly Active Antiretroviral Therapy. JAIDS 2006;42(3):386-8 80 Pruvost A, Negredo E, et al. Measurement of Intracellular Didanosine and Tenofovir Phosphorylated Metabolites and Possible Interaction of the Two Drugs in Human ImmunODeficiency Virus-Infected Patients. Antimicrobial Agents and Chemotherapy, May 2005, p. 1907-1914, Vol. 49, No. 5 81 Cressey TR, Leenasirimakul P, Jourdain G, et al. Low-doses of indinavir boosted with ritonavir in HIVinfected Thai patients: pharmacokinetics, efficacy and tolerability. J Antimicrob Chemother. 2005 Jun;55 (6):1041-4. Epub 2005 May 9. Cressey TR, Leenasirimakul P, Jourdain G, TOD M, Sukrakanchana PO, Kunkeaw S, Puttimit C, Lallemant M. 82 Boyd M, Mootsikapun Petal; Pharmacokinetics of reduced-dose indinavir/ritonavir 400/100 mg twice daily in HIV-1-infected Thai patients. Antiviral Therapy 10:301–307. 76

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