How does the WHO clinical staging system for assessing ART eligibility compare with standard CD4 count cut offs in adults receiving care in routine HIV programme in sub-Saharan Africa? (Protocol)

By Chigomezgo Munthali (MBBS, MSc) Liverpool School of Tropical Medicine, United Kingdom Email: [email protected]

Collaborators Dr Peter MacPherson, Dr Miriam Taegtmeyer and Dr Paul Garner

BACKGROUND Description of the condition Human Immunodeficiency Virus (HIV) is a retrovirus that attacks the body’s immune system causing profound immunosuppression rending the body unable to fight diseases (Miedema F. 1992). The commonest mode of transmission of the HIV virus is through sexual intercourse. However, the virus can also be transmitted through sharing of contaminated needle, blood transfusion and can be passed from an infected mother to child during pregnancy, childbirth or breastfeeding. An infected individual may have no symptoms during the early stages of the disease but as time progresses and immune system weakens may develop advance stage of the disease AIDS. The time from being asymptomatic to developing AIDS varies considerably between individuals (Kassa, E. 1999) but on average may take 10 – 15 years. It is estimated that nearly 34 million people are infected with HIV in the world with two – thirds of all HIV patients living in sub Saharan Africa (UNAIDS, 2012). At present HIV has no cure however, significant breakthrough in the fight against HIV was made in 1990’s when Antiretroviral therapy (ART) were first discovered. ART has tremendously improved the prognosis of people living with HIV; this has resulted in a significant decline in the number of deaths due to HIV/AIDS (WHO, 2011). Based on evidence showing improved survival and reduce HIV transmission with earlier ART initiation, the current World Health Organization (WHO) guidelines recommend that HIVinfected adults in WHO clinical stage 3 and 4 or with a CD4 of less than 350 cell/ mm3 are started on ART (WHO 2009). These new guidelines are an upwards revision of the previously recommended CD4 count cut off value of 200 cell /mm3. HIV positive patients are required to complete a number of care- seeking steps, including assessment of eligibility for ART. The care pathway for an HIV patient is shown in figure 1 below, from time of diagnosis to initiation of ART. Figure 1: The HIV care pathway (Mcnairy Margaret L and El-safe Wafaa M. 2012)

HIV diagnosis

ART eligibility assessment (CD4/WHO stage)

Pre-ART care

ARV initiation & treatment

Index test The WHO clinical staging system is a staging and prognostic tool that was developed in 1990 out of original clinical case definitions for AIDS. Using the WHO clinical staging system, health workers classify HIV-infected patients into four stages, 1 through 4: from primary HIV infection to advance HIV disease or AIDS. It was initially developed as a highly specific method for diagnosing HIV infection before the availability of ELISA tests (WHO 2005). Since its development it has undergone modification and was last revised in 2009 (WHO 2009). The current WHO clinical staging system is given in annex 1. Although it was not originally designed for this purpose, the WHO clinical staging system has been adopted as a screening tool to evaluate whether HIV-infected individuals are eligible to start ART, with WHO recommending those individuals in stage 3 or 4 initiate treatment. The WHO clinical staging system is useful and easily accessible tool that helps to identify patient to be started on ART in resource poor setting and can be used by health care provider with less HIV expertise (WHO 2005; Idindili et al. 2011). Furthermore, evidence has shown that it is a good predictor of HIV disease progression and advanced WHO stage is associated with increased risk of death (Spacek et al. 2006). This helps to monitor HIV disease progression in low resource countries. However, it has been reported to be time consuming, difficult and frequently poorly performed, or not performed at all, in busy clinics (MacPherson et al. 2012).

Reference Test CD4+ T -Lymphocyte coordinates the response of immune system to infections. HIV virus attacks the CD4+ T Lymphocyte and depletion of these cells results in profound immunosuppression. CD4 count is measured by taking a venous blood sample which is conventionally analysed in the laboratory using BD FACSCalibur flow cytometer. However, in order to increase retention in care of HIV patients in ART clinics, new CD4 count machines have been developed to provide point of care CD4 counts. In the new technique; PIMA point-of-care (POC) CD4 test system (Alere, Waltham, MA) a drop of blood sample (capillary blood) is used and CD4 count results are available within 20 minutes (Mtapuri-Zinyowera, Chideme et al.) CD4 count is the gold standard test for identifying patients that are eligible to start ART. As a measure of immunosuppression CD4 count can predict the progress of disease and survival of an HIV patient (Johnson S. and Kuritzikes, D. 1997; Egger, M. 2002). Once ART is commenced measurements of CD4 counts can also help to monitor treatment response and identify those patients with treatment failure (Akinbami A., 2012). However, CD4 counts machines are expensive, technically difficult and reliant on laboratory services that are not yet widely available in resource-poor settings, where the majority of HIV care is delivered (Baveewo et al. 2011). For example, only 12 % of HIV clinics in Malawi had a CD4 count

machine installed on site at the start of 2012 (Government of Malawi Ministry of Health 2012).

Rationale In 2003, the WHO introduced a campaign to scale up the number of HIV patients accessing ART called ‘the 3 by 5 initiative’ with the aim of putting 3 million people on ART by 2005 (WHO, 2003). The WHO clinical staging system is an important tool that has played a significant role in the scale-up of ART uptake in resource poor settings. However, concerns have been raised regarding its discriminatory ability to identify patients eligible to start ART. No systematic review has yet examined its performance as a screening tool and there is no published review of the literature in this area. Aim To compare the sensitivity and specificity of the WHO clinical staging system for starting HIV treatment with CD4 count in studies by systematic review of relevant studies in Africa. Objectives 1. To identify and describe studies that report on the diagnostic accuracy of the WHO clinical staging system against CD4 count. 2. To summarize the sensitivity and specificity of the staging system against the standard CD4 count cut offs.

Inclusion criteria Type of studies 



Studies that measure concurrent WHO clinical staging and CD4 count data when assessing for ART eligibility. This includes o

Randomised controlled trials

o

Cohort studies

o

Cross sectional studies describing the set-up of an ART treatment programme

o

Analysis of routine collected data

Studies published in English language

Study location 

Studies conducted in sub- Saharan Africa

Type of participants Adult HIV positive patients (≥15 years) assessed for ART eligibility, including both naïve and retreatment patients. Index test The WHO clinical staging system used to assess patient’s eligibility for ART. The review will include all studies that used either the previous or the revised WHO clinical staging (see annexe 1). Comparator test Studies that performed in the same patient, a CD4 count before initiating on ART. Studies that evaluated the performance of WHO clinical staging against the standard CD4 count offs (< 200 cells/mm3,