NATIONAL GUIDELINES FOR

ANTIRETROVIRAL (ARV) THERAPY

HIS MAJESTY'S GOVERNMENT

MINISTRY OF HEALTH

NATIONAL CENTER FOR AIDS & STD CONTROL KATHMANDU, NEPAL

2003

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Medical knowledge is constantly and rapidly changing, particularly in relation to HIV/AIDS. Thus, readers are strongly advised to confirm that information (especially with regards to drug usage) complies with the latest standards of practice.

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EDITORIAL BOARD • Dr. Bal Krishna Suvedi • Dr. Shyam Sundar Mishra • Dr. Laxmi Bikram Thapa • Dr. Madhur Dev Bhattarai • Dr. Sashi Sharma • Dr. Sushil Kumar Shakya

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TECHNICAL EXPERT GROUP • Dr. Bal Krishna Suvedi -

Director, National Center for AIDS and STD Control

• Dr. Shyam Sundar Mishra - Ex. Director, National Center for AIDS and STD Control • Dr. Laxmi Bikram Thapa - Senior Physician, Teku Hospital • Dr. Madhur Dev Bhattarai - Senior Consultant Physician, Bir Hospital • Dr. Sashi Sharma -

Associate Professor, TU Teaching Hospital

• Dr. Sushil Kumar Shakya - General Practice Specialist SMO, Teku Hospital. • Dr. Lata Bajracharya -

Senior Consultant Gynaecologist, Maternity Hospital.

• Dr. Bimala Malla -

Consultant Gynaecologist, Patan Hospital

• Dr. Pushpa Bhatt -

Swiss AIDS-INFO-DOCU/Nepal, Team Leader

• Dr. Dhruba Prasad Singh - General Practice Specialist SMO, National Center for AIDS & STD Control. • Dr. Pulkit Chaudhary -

Senior Medical Officer, National Center for AIDS & STD Control.

SUPPORT GROUP Mr. Rajan Kumar Bhattarai – National Center for AIDS and STD Control Mr. Binit Bikram Sijapati — National Center for AIDS and STD Control

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CONTENTS Titles

Page No.

Abbreviation Background

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Diagnosis of HIV State

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Principles of Antiretroviral Therapy

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Indication for Antiretroviral Therapy

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Antiretroviral Drugs and their interaction

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Choice of Antiretroviral Regimen

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Monitoring

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Changing Antiretroviral Therapy

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Post Exposure Prophylaxis (PEP) of HIV

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Mother-to-Child Transmission

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Antiretroviral Therapy in Children Appendix 1 Appendix 2 Appendix 3 Appendix 4 Appendix 5 References

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FOREWORD HIV/AIDS has become a concern for everyone now days. Continuum of prevention to care and support are the cornerstones of present day practice. Taking into consideration, the importance of care and support program, the National HIV/AIDS Strategy (2002-2006) stresses on the implementation of the activities in this line. The knowledge and practice in this area of care and support of HIV infected persons is rapidly changing the background we are bringing out the "National Guidelines on Anti Retroviral Therapy", which needs regular updating based on new knowledge, experiences and practices. We would welcome the expert feedback and comments from the users and experts in this respect. National Center for AIDS and STD Control would like to thank all those; we have contributed in the development of the National Guidelines on Anti-Retroviral Therapy.

Dr. B. K. Suvedi Director National Center for AIDS & STD Control

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ABBREVIATIONS 3TC ABC AIDS ALT APV ARV ART CBC CD CMV d4T ddC ddI DLV EFV ELISA HCW HIV IDV LPV MTCT NFC NNRTI NsRTI NtRTI NVP OI PEP PCP PCR PI PO RTV,r RTV-PI SGPT SQV RT STI TB TLC VCT VL WHO ZDV

Lamivudin Abacavir Acquired immune deficiency syndrome Alanine amonitransferase also known as SGPT Amprenavir Antiretroviral Antiretroviral Therapy Complete blood count Cluster of Differentiation. Cytomegalovirus Stavudine Zalcitabine Didanosine Delavirdine Efavirenz also abbreviated as EFZ Enzyme linked immunosorbent assay Health Care Worker Human immunodeficiency virus Indinavir Lopinavir Mother-to-child transmission of HIV Nelfinavir Non-nucleoside reverse transcriptase inhibitor Nucleoside analog reverse transcriptase inhibitor Nucleotide analog reverse transriptase inhibitor Nevirapine Opportunistic infection Post exposure prophylaxis Pneumocystis carinii pneumonia Polymerase chain reaction Protease Inhibitor Per OS Ritonavir Ritonavir boosted Protease Inhibitor Serum glutamic pyruvic transaminase, also known as ALT. Saquinavir Reverse transcriptase Sexually transmitted disease Tuberculosis Total leucocyte count HIV voluntary counseling and testing Viral load World Health Organization Zidovudine, also known as AZT

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I.

Background

The first case of AIDS was reported in 1981 in America. Since then, AIDS has become the most devastating and life threatening disease of the human beings. More than 60 million people are already infected and about 40 million people are estimated to be living with HIV, among which 1/3rd are aged between 15-24 years. Initially, the epidemic concentrated in African continent. But it is rapidly increasing in Asia, particularly in South Asia. In South Asia alone, there are more than 7.1 million people living with HIV/AIDS. In Nepal, the first case of HIV/AIDS was diagnosed in 1988. Number of cases is gradually increasing every year. The major mode of transmission is heterosexual. The available data show that there is high prevalence of HIV in high-risk group such as injecting drug users and sex workers. Currently, it is estimated that there are more than 60,000 people living with HIV/AIDS in Nepal, with an estimated 3,000 deaths (2002) annually. In 1986, first antiretroviral therapy was introduced and the first drug was Zidovudine (ZDV). Over the next few years, other antiretroviral drugs (NsRTIs, NNRTIs) and PIs were introduced. Initially, mono and dual therapies were used but there was problem of resistance. At present, 3 or more ARV drugs are recommended worldwide for the treatment of people with HIV infection. Since the use of combination therapy, this disease has been transformed into chronic condition. However, the use of antiretroviral therapy is not all in all solution in HIV/AIDS prevention and care program. The delivery of effective care and antiretroviral treatment for people living with HIV/AIDS in poorest countries is considered as an urgent priority and seems as a complement program to prevent HIV transmission. Initially, antiretroviral therapy was very expensive and unaffordable in most of developing countries. As drugs are increasingly available at affordable cost, the development of guidelines on the appropriate and rationale use of ART have been relevant in developing countries. The current guidelines are intended basically for use by medical doctors who use ARV therapy to the people infected with HIV/AIDS. Guidelines for the treatment and management of HIV infection have been produced in a number of countries in Europe, Australia, USA, India, Thailand, etc. and by WHO/UNAIDS. While the guidelines attempt to represent the current state of knowledge, it is inevitable that, as HIV/AIDS is a rapidly evolving medical field, new data will change therapeutic choices and preferences.

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II.

Diagnosis of HIV State

Diagnosis of HIV infection can be made if the HIV test is positive at least by two different methods. HIV testing of any person should encompass the 3 "C"s: • Counseling (Pre-and post-) • Confidentiality, and • Care (after care)

Counseling Counseling for an HIV test is not a form of psychotherapy and should be referred to as pretest discussion. The skills received are no different from those necessary in any clinical situation; namely awareness, sensitivity and good communication. Aims of Pre-test counseling • To provide information on the technical aspects of screening. • To provide information on the possible implications of being diagnosed positive or negative (e.g. medical, social and legal) • To educate on the risks of transmission and discuss behavior that might reduce these risks. Pre-test counseling check list • Assess risk factors • Explore level of knowledge on HIV/AIDS and its implications • Explain test procedures (a blood sample; confirmation of a positive result with a second test) • Discuss possible advantages including: o Early diagnosis and treatment o Reassurance, early treatment o Motivation for safer sex, safer drug use. • Discuss possible disadvantages including: o Life assurance o Social relationship prospects • Discuss coping with a negative or positive result; identify personal, social and medical support systems • Discuss how to protect sexual partner(s) in the meantime (safer sex and/or safer drug use) • If female, discuss pregnancy and fertility • Discuss whom to tell and who has been told Post test counseling: Telling patients they are HIV positive is not easy. It might be just like breaking any bad news in other day-to-day clinical medicine. It is best done by a person who counseled the person before test and recommended the test. Post-test counseling involves a discussion of both the results. If the test is positive, the person might ask

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with whom to share the information, regarding safer sex, injecting practices, treatment options and follow-up. In the case of a negative HIV test, there is an opportunity for reasserting safer sexual or injecting practices. The HIV testing strategy is described in Appendix I.

III. Principals of Antiretroviral Therapy Goals of Antiretroviral Therapy The goals of Antiretroviral (ARV) Therapy are: • Reduction of HIV-related morbidity and mortality. • Maximal and durable suppression of viral load. • Restoration and/or preservation of immunologic function. • Improvement of quality of life of those who are infected by HV.

Preconditions for starting Antiretroviral Therapy Following specific facilities and services are desirable to start Antiretroviral Therapy service:1. Availability of HIV voluntary counseling and testing (VCT) services along with follow up counseling services. 2. Medical services capable of managing common HIV-related infections including opportunistic infections and STIs. 3. Routine laboratory services, preferably with access to CD4+T lymphocyte count and PCR facility for viral load count. 4. Access to antiretroviral drugs and other drugs to treat OI and other diseases. Medical doctors who are trained in clinical management of HIV/AIDS should initiate and supervise antiretroviral therapy.

Evaluation Before Starting Antiretroviral Therapy A detailed evaluation is essential prior to initiating antiretroviral therapy and should aim to: Assess the clinical stage of HIV infection. Identify past HIV-related illnesses. Identify current HIV-related illnesses that will require treatment. Identify co-existing medical conditions and treatments that may influence the choice of therapy. Before initiating therapy, the following evaluations should be performed:• Complete history, with emphasis on OIs and other conditions. • Psychological and psychiatric history. Depression and other psychological problems are common and should be identified and treated as necessary. • Assessment of family and social support. • Continuation of safer sex practices, and detoxification for drug abusers. • Complete physical examination

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Physical examination before initiating ARV Therapy should include the following: • • • • • •

Body weight of the patient Skin: look for herpes zoster, Kaposi's sarcoma, and HIV dermatitis Lymphadenopathy. Oropharyngeal mucosa: look for candidiasis, Kaposi's sarcoma, and hairy leucoplakia. Examination of optic fundus: retinitis and papilloedema. Examination of abdomen, heart, lungs, neurological, musculoskeletal and genitourinary systems

Laboratory tests: • CBC and routine chemistry • X-ray chest • RPR, hepatitis B and C serologies • Cervical Pap smear, as indicated in female • CD4 cell count/total lymphocyte count (TLC) • Virologic load • Liver function test

IV. Indication For Antiretroviral Therapy (ART) Complete cure of HIV infection is not possible with presently available drugs. Therefore, the aim of the treatment is to prolong and improve the quality of life by suppressing viral replication as long as possible. Recommendations for initiating antiretroviral therapy in adults and adolescents with documented HIV infection are given in the box below. Start ART in the following instances If CD4 Testing is available: - WHO Stage IV disease irrespective of CD4 cell count. - WHO Stage I, II or III with CD4 cell counts < 200/mm3 If CD4 Testing is not available: - WHO Stage IV disease irrespective of total lymphocyte count. - WHO Stage II or III disease with a total lymphocyte count 10% of body weight. 2. Unexplained chronic diarrhoea, > 1 month. 3. Unexplained prolonged fever (intermittent or constant) > 1 month. 4. Oral candidiasis (thrush). 5. Oral hairy leukoplakia. 6. Pulmonary tuberculosis, within the past year. 7. Severe bacterial infections (e.g., pneumonia, pyomyositis). And/or Performance scale 3: bed-ridden < 50% of the day during the last month. Clinical Stage IV: 1. HIV wasting syndromea 2. Pneumocystis carinii pneumonia. 3. Toxoplasmosis of the brain. 4. Cryptosporidiosis with diarrhoea > 1 month. 5. Cryptosporidiosis, extrapulmonary. 6. Cytomegalovirus (CMV) disease of an organ other than liver, spleen or lymph nodes. 7. Herpes simplex virus (HSV) infection, mucocutaneous > 1 month, or visceral any duration. 8. Progressive multifocal leukoencephalopathy (PML) 9. Any disseminated endemic mycosis (e.g., histoplasmosis, coccidioidomycosis). 10. Candidiasis of the oesophagus, trachea, bronchi or lungs. 11. Atypical mycobacteriosis disseminated. 12. Non-typhoid Salmonella septicaemia. 13. Extrapulmonary tuberculosis. 14. Lymphoma. 15. Kaposi's sarcoma (KS).

16. HIV encephalopathyb. Performance scale 4: bed-ridden, > 50% of the day during the last month.

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HIV wasting syndrome: Weight loss of >10% of body weight, plus either unexplained chronic diarrhea (> 1 month), or chronic weakness and unexplained prolonged fever (>1 month). b HIV encephalopathy: Clinical findings of disabling cognitive and/or motor dysfunction interfering with activities of daily living progressing over weeks to months, in the absence of a concurrent illness or condition other than HIV infection that could explain the findings.

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V.

Antiretroviral Drugs and their interaction ` Approved antiretroviral drugs are grouped into three categories: 1.

Nucleoside analog reverse transcriptase inhibitors (NsRTI) constrain HIV replication by incorporation into the elongating strand of DNA, causing chain termination, thereby blocking the reverse transcriptase enzyme.

2.

Non-nucleoside analog reverse transcriptase inhibitors (NNRTIs) inhibit HIV by binding noncompetitively to the reverse transcriptase enzyme.

3.

Protease inhibitors (PIs) are a very potent group of drugs that block the action of the viral protease required for protein processing late in the viral cycle.

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Table 1: Nucleoside Reverse Transcriptase Inhibitors (NsRTIs) Dose Food Effect Adverse effects

Generic Name

Abacavir (ABC)

300 mg twice daily

Take without regards to meal

Didanosine (ddI)

>60 kg: 200 mg twice daily or 400 mg once daily

Take in empty stomach (1/2 hour before or 2 hours after meal)