The Evolving Role of CD4 Cell Counts in HIV Care

REVIEW

CURRENT OPINION The evolving role of CD4 cell counts in HIV care

Nathan Forda, Graeme Meintjesb,c, Marco Vitoriaa, Greg Greened, and Tom Chillerd

Purpose of review The role of the CD4 cell count in the management of people living with HIV is once again changing, most notably with a shift away from using CD4 assays to decide when to start antiretroviral therapy (ART). This article reflects on the past, current and future role of CD4 cell count testing in HIV programmes, and the implications for clinicians, programme managers and diagnostics manufacturers. Recent findings Following the results of recent randomized trials demonstrating the clinical and public health benefits of starting ART as soon as possible after HIV diagnosis is confirmed, CD4 cell count is no longer recommended as a way to decide when to initiate ART. For patients stable on ART, CD4 cell counts are no longer needed to monitor the response to treatment where HIV viral load testing is available. Nevertheless CD4 remains the best measurement of a patient’s immune and clinical status, the risk of opportunistic infections, and supports diagnostic decision-making, particularly for patients with advanced HIV disease. Summary As countries revise guidelines to provide ART to all people living with HIV and continue to scale up access to viral load, strategic choices will need to be made regarding future investments in CD4 cell count and the appropriate use for clinical disease management. Keywords advanced HIV disease, antiretroviral therapy, CD4 cell count, treatment monitoring, viral load

INTRODUCTION The role of the CD4 cell count in the care of The CD4 cell count has been an essential com- persons with HIV/AIDS has evolved over the last 30 ponent of HIV treatment and care programmes since years. It began as and remains the best way to HIV was identified as a disease compromising the quantify the degree of immunosuppression and immune system. For healthcare providers, the CD4 associated risk of AIDS illnesses. However, it is likely cell count has guided key clinical decisions ranging best known for its role in guiding the initiation of from when to start antiretroviral therapy (ART) [1&&] ART in national treatment programs. The roots of to whether or not to screen for or provide prophy- using CD4 thresholds for ART initiation lie in the laxis against opportunistic infections [2,3]. CD4 early days of the ART era when drug toxicity, afford- testing has also provided valuable insight into pro- ability, and accessibility of paramount concern. gramme performance over time [4,5] and predicted CD4 subsequently developed into a measure for patient prognoses, with epidemiologists having identified associations between CD4 cell counts aDepartment of HIV and Global Hepatitis Programme, World Health and a risk of death [6], life expectancy [7] and treat- Organization, Geneva, Switzerland, bDivision of Infectious Diseases & ment adherence [8 ]. As a critical test for ART pro- and HIV Medicine, Department of Medicine, cClinical Infectious Diseases grammes, deployment of point-of-care (POC) CD4 Research Initiative, Institute of Infectious Disease and Molecular Medi- test devices has been used as a way to improve cine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa and dMycotic Diseases Branch, Centers for Disease Con- linkage to care and accelerate treatment initiation trol and Prevention, Atlanta, Georgia, USA [9]. Most importantly though, CD4 cell count pro- Correspondence to Nathan Ford, PhD, FRCPE, Department of HIV and vides the best direct measurement of a patient’s Global Hepatitis Programme, World Health Organization, 20 Avenue immune status and risk for opportunistic infections, Appia, 1211 Geneva 27,Switzerland. Tel: +41 22 791 19 49; fax: +41 22 and it remains an important test with regard to 791 21 11; e-mail: [email protected] diagnostic decision-making, particularly for patients Curr Opin HIV AIDS 2017, 12:123–128 with advanced HIV disease. DOI:10.1097/COH.0000000000000348

progression and death were low at a CD4 cell count KEY POINTS greater than 200 cells/mm3 [6], and any drug The role of the CD4 cell count in HIV management is exposure above this threshold could result in severe changing, with a shift away from using CD4 to decide and unnecessary side-effects or development of drug when to start ART or monitor treatment efficacy. resistance at a time when alternative treatment options were limited [1&&]. Nevertheless, CD4 remains the best measurement of a As treatment became more affordable and less patient’s immune and clinical status, the risk of opportunistic infections and diagnostic decision-making, toxic, evidence supporting the overall benefits of particularly for patients with advanced HIV disease. starting treatment at higher CD4 thresholds accu- mulated, and the threshold for starting treatment Strategic choices will need to be made regarding future was progressively raised in guidelines. This evol- investments in CD4 cell count and the appropriate use ution is reflected in the WHO guidelines over this for clinical disease management. period, during which the recommended CD4 cell count threshold for when to start ART rose from 200 cells/mm3 in 2002 to 350 cells/mm3 in 2010 and when it was worth the risks and expense to initiate again to 500 cells/mm3 in 2013 [15]. In 2015, just ART and was also used to prioritize treatment to prior to the WHO Guideline Development Group those with more advanced disease in settings where meeting for revision of global guidelines, two large resources were scarce. The role is again changing randomized trials were completed and results from [10&], most notably with a shift away from using both studies showed that, in terms of reduced mor- CD4 to decide when to start ART. Recent random- bidity and mortality as a combined endpoint, the ized trials have shown that ART should be started in benefit of starting ART at CD4 cell counts above 500 all HIV-infected patients, irrespective of CD4 cell outweighed the risks [11&&,12&&]. In light of these count [11&&,12&&], Responding to this evidence, trials, together with evidence that early ART with WHO guidelines have been revised to recommend virologic suppression reduces the risk of HIV trans- starting ART as soon as possible following a con- mission [16], WHO subsequently updated their firmed diagnosis of HIV infection [13], and many guidelines in September of the same year to strongly countries are in the process of revising their national recommend that all HIV-positive individuals should guidelines to reflect this shift in policy [14]. WHO start ART irrespective of CD4 cell count [17]. has also recommended a shift to HIV viral load Although the implementation of this recom- instead of CD4 cell count for monitoring ART mendation remains challenging in many resource- [13], though WHO continues to emphasize CD4 cell limited settings, the evidence supporting starting count’s important role in evaluating disease status at ART at any CD4 cell count is strong, and countries baseline and prioritizing appropriate care for are moving to revise their national guidelines in line patients found to have progressed to advanced with the evidence and WHO recommendation [14]. stages of HIV [10&]. In settings where access to ART may be limited, This article reflects on the past, current and WHO continues to recommend prioritizing those future role of CD4 cell count testing in HIV pro- patients with a CD4 cell count less than 350 cells/ grammes, and what this could mean for clinicians, mm3, highlighting that CD4 cell count continues to programme managers and the diagnostics industry. be the best predictor of those at highest risk of disease and death and that these priority patients stand to gain the most from treatment in the THE EVOLVING ROLE OF CD4 CELL COUNT short term. TESTING

When to start treatment How to monitor treatment Over the last 30 years, clinicians, researchers and In the early days of the HIV epidemic, the develop- policy makers have debated the ideal CD4 threshold ment of specific CD4þ T-cell antibodies paired with for starting ART. During the late 1990s, treatment the increasing availability of flow cytometry tech- was expensive and associated with significant drug nology in a variety of formats and platforms made toxicity. Most drug combinations were less robust, CD4 cell counting and thus monitoring of a carrying a higher risk of causing drug resistance, patient’s condition during treatment possible for there were fewer treatment options and the decision the first time. However, there has been considerable about when to start treatment needed to balance debate around the role of such laboratory monitor- benefits against the significant risks. The prevailing ing in HIV treatment programmes over the past view during this period was that rates of disease decade. Initially, there was concern that, without

124 www.co-hivandaids.com Volume 12 Number 2 March 2017 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. The evolving role of CD4 cell counts in HIV care Ford et al. the capacity to undertake laboratory monitoring, complicated clinical management [27]. In 2013, low-income countries with a high burden of HIV WHO gave preference to efavirenz over nevirapine may be reluctant to offer ART. In response, the first in first-line ART [13], and there has been a rapid shift WHO guidelines for ART provision issued in 2002 away from nevirapine use by countries [14]. New stated that lack of laboratory testing should not be a drug options such as dolutegravir are even better barrier to ART [15]. From 2003 onward, WHO guide- tolerated, removing any prospect that CD4 cell lines stated that CD4 cell count testing was advis- count determination will be needed in the future able, but noted that access remained a barrier and to guide antiretroviral drug choice. that initiation of ART remained the priority. Viral load monitoring of ART was first described in 1991 [18] and has been recommended by WHO Availability of tests since 2006 as a more direct measure of response to Recent survey findings indicate that global capacity treatment, although initially the use was limited to of available CD4 instruments is sufficient to meet tertiary centers because of cost and technical con- the needs of all people living with HIV/AIDS, irre- straints [15,19]. The cost–effectiveness of viral load spective of treatment status [28]. However, CD4 monitoring has been debated. Some studies con- instruments are considerably underutilized, with ducted in Cameroon [20] and Uganda [21] found only 13.7% of existing CD4 capacity utilized in that viral load monitoring was not cost-effective 2013 across 50 countries reporting data. Key reasons when compared with alternative strategies of for nonutilization included noninstallation, break- clinical and immunological monitoring. However, down for CD4 conventional instruments with lim- other studies that assessed viral load to confirm ited or no maintenance contracts and lack of failure in Coˆte d’Ivoire [22], or to use viral load reagents for POC CD4 instruments [28]. instead of CD4 cell count in South Africa [23], found In contrast, viral load instrument capacity is not viral load to be cost effective. WHO and national adequate to meet the needs of all people living with guidelines have evolved toward recommending HIV/AIDS. In 2013, 28% of reporting countries did viral load as the preferred way to monitor treatment not have adequate viral load (VL) capacity to per- efficacy because of the poor accuracy of CD4 form at least one VL test per patient/year on ART. In monitoring in predicting viral suppression [24], addition, only 37% of theoretical instrument test and concern that delays in switching ART among capacity was actually being used, mainly because of people failing treatment could lead to an accumu- noninstallation and lack of reagents [28]. Many lation of drug resistance and increased risk of countries continue to rely substantially on donor mortality and morbidity [25]. The latest WHO funding to deliver viral load, which raises concerns guidelines recommend that, where viral load about long-term sustainability. monitoring is available and patients are stable on As viral load continues to be scaled up, countries ART, CD4 monitoring can be stopped. This is in will need to make strategic decisions regarding recognition of the fact that CD4 cell count offers relative investments in scale-up and placement of little added information in patients who are clin- CD4 and viral load technologies. ically well and virologically suppressed on ART [26&&], and that the cost of scaling up viral load can be partially offset by limiting CD4 testing to a FUTURE ROLE OF CD4 CELL COUNT single baseline or several early tests, where it is still TESTING necessary to assess the patient’s clinical status before WHO guidelines no longer recommend CD4 for ART safely initiating ART [23]. initiation or disease monitoring, though baseline CD4 is still recommended and plays a vital role in guiding clinical management of patients with Informing treatment choices advanced disease, a group that still makes up nearly Until 2013, nevirapine was among the most widely half of all people living with HIV starting/restarting used antiretroviral drugs, and was recommended by treatment [7]. WHO guidelines recommend that WHO as part of first-line ART. However, nevirapine ART can be started irrespective of CD4 cell count use has been associated with a heightened risk of and that CD4 cell count monitoring can be stopped hepatic and cutaneous adverse drug reactions in patients who are stable on ART and that ART particularly in women at higher CD4 cell counts, efficacy can thereafter be monitored with viral load. leading to recommendations against using nevira- These two recommendations in particular are likely pine in women with CD4 cell counts more than to result in fewer CD4 cell counts needed and thus 250 cells/mm3 and in men with CD4 cell counts fewer resources necessary to commit to CD4 testing more than 400 cells/mm3; this concern further in HIV programmes. For example, in Namibia,

Table 1. Past and future role of CD4 cell count testing prophylaxis to all HIV-infected adults with a CD4 cell count less than 350 cells/mm3, and discontinu- Role of CD4 testing in PLHIV Past Current ing once patients are stable on ART [2]. In settings Starting and stopping cotrimoxazole Yes Yes where malaria and/or severe bacterial infections are prophylaxis highly prevalent, cotrimoxazole prophylaxis should Cryptococcal antigen testing Yes Yes be initiated and continued regardless of CD4 cell TB diagnosis (urine LAM) No Yes count; cotrimoxazole prophylaxis should also be ART initiation Yes No administered to all HIV-infected people with active TB disease regardless of CD4 cell counts. ART monitoring Yes No Although the notion that advanced disease will ART drug choice (use of nevirapine) Yes No cease to pose a problem as ART programmes expand,

ART, antiretroviral therapy; LAM, lipoarabinomannan; PLHIV, people living trends in CD4 cell counts over the past decade with HIV; TB, tuberculosis. indicate the advanced disease is and will for the foreseeable future remain an issue for HIV pro- changing from CD4 to viral load monitoring and grammes. The average CD4 cell count at start of using CD4 only as a baseline test have resulted in ART has somewhat risen globally over the last decade, nearly a 90% decrease in CD4 cell counts being reflecting the evolution in treatment guidelines performed, which has helped to offset the increase toward recommending starting treatment at higher in costs for more viral load monitoring. Neverthe- CD4 cell counts [4,34]. However, the proportion of less, CD4 cell count testing still has an important patients presenting with advanced HIV disease has role to play as a way to assess clinical status of a remained relatively constant, with a 2015 meta- patient at first initiation of treatment, most notably analysis of CD4 trends estimating that over half of in the management of advanced HIV disease (Table patients have progressed to advanced disease by the 1). CD4 cell count will also be important in evaluat- time of ART initiation [4,35,36]. Tuberculosis, bac- ing patients who are failing ART and who come in terial infections, fungal infections and other AIDS- after being off treatment for some time. related infections continue to be leading causes of hospitalization and mortality among people living with HIV globally [37]. Although this persistence of Management of advanced disease advanced HIV disease partly reflects the fact that CD4 cell count testing is one of the most important people continue to be diagnosed late in their HIV tools for assisting clinical management decisions in infection – almost one-third of HIV-positive patients patients with advanced disease. In particular, a CD4 admitted to hospital are diagnosed at the time of cell count less than 200 cells/mm3 is considered a admission [37] – an important proportion of patients critical threshold for heightened risk of death [6,29] presenting with advanced disease is also represented and is used as the current WHO definition of by HIV-positive individuals who have already started advanced HIV disease [30]. Screening for cryptococ- ART but subsequently interrupted their treatment cal antigen (CrAg) is recommended for all patients [38,39]. Persons with HIV/AIDS who are defaulting with a CD4 cell count less than 100 cells/mm3[13], on therapy represent an ever increasing number of and several randomized trials have found a positive patients seen in clinics and admitted to hospital [38], benefit associated with a package of interventions with defaulters constituting over half of late present- aimed at reducing mortality among patients pre- ing patients (CD4 < 350 cells/ml) in some settings senting below this CD4 cell count threshold [40]. These challenges will be critical to address mov- [31,32]. WHO also recommends the use of the urine ing forward in the test and treat era. lateral flow-LAM assay to assist in the diagnosis of TB For these reasons, WHO recommends that HIV in a specific category of HIV-positive individuals programmes should retain the capacity to perform presenting with CD4 less than 100 cells/mm3; this CD4 cell count at baseline and during the case of threshold was chosen because of reduced diagnostic treatment failure, as this remains one of the best accuracy (in particular poor sensitivity) at higher predictors of general patient wellness, disease pro- CD4 cell counts [13,33]. Cotrimoxazole is a fixed- gression and mortality risk, and can guide further dose combination of two antimicrobial drugs (sul- diagnostic tests to address the causes of these famethoxazole and trimethoprim) that prevents mortality concerns [13]. morbidity and mortality from a variety of bacterial, fungal and protozoan infections. Provision of cotrimoxazole prophylaxis has been recommended Future research in CD4 testing by WHO since 2006. The latest guidelines, issued Much has been learned about CD4 testing over the in 2014, recommend giving cotrimoxazole past three decades and a couple of the major

126 www.co-hivandaids.com Volume 12 Number 2 March 2017 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. The evolving role of CD4 cell counts in HIV care Ford et al. concerns remain to be addressed in the near future. variation over time can be independent predictors One major concern is the potential for delay in of cardiovascular disease (CVD) events in HIV- treatment initiation that could result from CD4 infected individuals [44]. Further studies to examine turnaround times and another is the cost of con- its role as clinical biomarker of CVD outcomes and tinuing to support a CD4 infrastructure based on immune senescence are needed in prospective stud- flow cytometry, especially as the bulk of testing ies and larger cohorts. Finally, the use of CD4 cell moves to viral load. More affordable and user- count reference curves to identify immune nonres- friendly POC testing platforms have offered a viable ponse among virally suppressed patients can be an alternative, although issues remain with quality additional tool for clinicians when evaluating assurance, testing volumes maintenance and supply response to ART [45]. chain management. Considerable progress has been made in the development of even more robust, simpler, faster and more affordable testing plat- Specifications for an ideal CD4 test forms, such as highly accurate microchip assays As we move into the era of test and treat, CD4 count and semiquantitative lateral flow assays (LFAs) that testing will be a critical component of clinical assess- would indicate whether or not a patient was above ment at baseline initiation of ART and to evaluate or below a certain CD4 cell count. Although much immune status after ART interruptions and noncom- of this work has fallen to the wayside in the wake of pliance. An ideal test would only need to be semi- WHO guidance to treat regardless of CD4 cell count, quantitative with cutoffs at either 100 or 200 cells this technology remains relevant in identifying mm3, or possibly both, and in a rapid diagnostic test patients with advanced disease and continued effort or POC format. This would ensure that testing could and investment remains important. Ideally, a simple be done easily and quickly during initiation of ART at semiquantitative CD4 LFA would provide a cheap baseline and in treatment failure situations, where and sustainable alternative to current CD4 testing in clinical status of the patient is a key to assess. the future. Such a test could be performed during a patient’s initial visit without the need to collect and send off specimens, and would allow clinicians to CONCLUSION determine if a patient has advanced disease (CD4 < 3 CD4 cell count testing has made a critical contri- 200 cells/mm ) and needs additional screening and bution to the management of people living with treatment/prophylaxis of opportunistic infections HIV over the past three decades. Increased access to necessary to safely initiate ART. Microchip technol- ART and viral load, and recent policy changes rec- ogy, while slightly more costly, has the added ommending ART start in all HIV-positive individ- benefit of multiplexing, allowing the consolidation uals irrespective of immune status have brought of CD4 with other tests, such as CrAg and syphilis. A into question the future role of CD4 cell count recent collaboration between UNICEF and South testing in the global HIV response. In light of this, Africa’s Rhodes University is working on offering the role of CD4 testing is likely to become more another alternative for rapid CD4 testing, using a restricted to baseline testing, returning to its original colorimetric aptamer-based test strip and a reader purpose as an essential tool in the assessment of that attaches to a cell phone camera to produce an disease progression in patients and, most impor- accurate quantitative CD4 result in less than 20 min. tantly, in the proper management of patients with Such innovation will be crucial to CD4 testing in the advanced HIV disease. As viral load continues to be future. The development of better POC testing plat- scaled up, countries will need to make strategic forms should be strongly encouraged and not aban- decisions regarding relative investments in further doned because of the elimination of CD4 thresholds scale up of CD4 and viral load technologies. We for treatment initiation. encourage test manufacturers to pursue CD4 tech- Another area of future research will be to explore nologies that will allow this important test to con- the role of CD4 cell count monitoring as a tool to tinue to be accessible in resource-limited settings as assist clinical decisions in current and future treat- this shift occurs. ment strategies beyond the management of advanced HIV disease. Several new experimental HIV cure strategies and structured treatment inter- Acknowledgements ruption protocols are using high CD4 thresholds as a None. criterion to start/stop therapy [41,42]. There are Disclaimer: The contents of this publication are solely the several safety and ethical concerns about this responsibility of the authors and do not necessarily approach that remain to be clarified [43]. A recent represent the official views of the Centers for Disease study suggested that CD4/CD8 ratio and its Control and Prevention or the World Health Organization.

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