Research Article: Rapid antiretroviral therapy initiation in low- and middle-income countries: A resource-based approach

Date Published: January 15, 2019

Publisher: Public Library of Science

Author(s): Mark W. Tenforde, A. Sarah Walker, Diana M. Gibb, Yukari C. Manabe

Abstract: In an Essay, Mark Tenforde and colleagues advocate continued provision of baseline CD4 cell count testing in HIV care in low- and middle-income countries.

Partial Text: Antiretroviral therapy (ART) has substantially decreased HIV morbidity and mortality in high-income as well as low- and middle-income countries (LMICs). Several randomized trials have demonstrated benefits from starting ART regardless of CD4 count (Table 1) [1–3]; the World Health Organization (WHO) adopted a “treat all” strategy in 2015. Significant attention has been focused on rapidly initiating ART, reflected in the 2017 WHO guidelines, which recommend that ART be initiated within 7 days of HIV diagnosis and on the same day whenever possible [4–6]. Although considerable progress has been made, a significant proportion of patients starting ART in LMICs continue to present with severe immunosuppression, with recent laboratory-based surveillance showing that one-third of South African patients still enter care with advanced HIV infection (CD4 < 200 cells/μL) [7,8]. These late presenters have the highest risk for death, unmasking of opportunistic infections (OIs), and immune reconstitution inflammatory syndrome. The guidelines highlight these patients and state that “people with advanced HIV disease should be given priority for clinical assessment and treatment initiation” [6]. Paradoxically, difficulties in implementing guidance on screening for OIs may result in the greatest delays in ART initiation in this population who are at the most risk. In the “treat all” era, the challenge is targeting effective prophylaxis against the bacterial, mycobacterial, and fungal pathogens that are the major causes of death in these late presenters. Such prophylaxis saves lives (see below) but also costs money and raises the potential risk of antimicrobial resistance if used indiscriminately. Further, when prophylaxis is provided conditional on a diagnostic test result, unless truly point-of-care, there is the potential for delays in ART initiation, which may substantially increase mortality risk. Given the limited ability of clinical assessment alone to identify patients with advanced HIV disease and the evidence for mortality benefit of enhanced OI screening in patients with advanced disease (Table 1), we suggest that guidelines should take the availability of various point-of-need tests at sites into consideration in a resource-based approach (Fig 1). Baseline CD4 testing is still important to guide the diagnostic evaluation for common OIs and prophylaxis in patients newly diagnosed with HIV. Conventional laboratory-based CD4 testing using flow cytometry requires substantial infrastructure and technical expertise and may lead to significant delays in obtaining actionable results, with a systematic review estimating a mean time of 10.5 days from the time a CD4 test was conducted to the time the result was received, versus 0.1 days with point-of-care CD4 testing [40]. Several point-of-care CD4 assays are available but require specialized instruments [41]. Alere PIMA has been extensively validated and is most commonly used for rapid CD4 testing [42]. Assays are needed that, like the IMMY CrAg lateral flow assay, meet WHO ASSURED criteria (affordable, sensitive, specific, user-friendly, rapid and robust, equipment-free, and deliverable to end users). Several emerging CD4 assays are in development or undergoing validation [43]. Omega Diagnostics’ VISITECT CD4 Advanced Disease assay is an instrument-free point-of-care lateral flow assay that provides a semiquantitative result for a CD4 count above or below 200 cells/μL and is currently being evaluated in SSA and India. This test, if accurate, could potentially be combined with point-of-care CrAg testing of venous or capillary whole-blood and urinary LAM testing for those with low CD4 counts even in remote health centers. The United Nations Children’s Fund (UNICEF) and Rhodes University (Grahamstown, South Africa) have also collaborated on a colorimetric aptamer-based CD4 reader that uses a personal cell phone device and mobile application to deliver CD4 test results. Baseline CD4 is an essential part of HIV care, and implementation research is needed to better streamline this and other new point-of-care tests for OIs to make them practical to perform in underresourced centers. We present a resource-based public health approach according to diagnostic test availability that could decrease early mortality after ART initiation and would be practical to implement. Our approach does not allow “the best to be the enemy of the good.” Even the most resource-constrained settings can immediately implement interventions that have the potential to save thousands of lives, and further refinement can be offered in settings where rapid screening for common OIs is feasible. An optimal approach requires that pre-ART CD4 (preferably as a simple point-of-care threshold test) continues to be available. We believe this provides a pragmatic algorithm to avoid delaying ART for the most immunosuppressed patients who are at the highest risk of dying. Source:


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