Antiretroviral therapy recommendations for the global community: aspiration versus reality
Phillips, Andrew N.a; Munderi, Paulab; Revill, Paul A.c; El-Sadr, Wafaa M.d; Lundgren, Jens D.e
aResearch Department of Infection & Population Health, University College London, London, UK
bMRC/UVRI Uganda Research Unit on AIDS, Uganda
cUniversity of York, York, UK
dIndustrial and Commercial Abatement Program, Colombia University, New York, New York, USA
eCHIP @ Department of Infectious Diseases (8632), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Corresponence to Andrew N. Phillips, University College London, London, UK. E-mail: firstname.lastname@example.org
Received 28 September, 2012
Revised 28 November, 2013
Accepted 28 November, 2013
Around 10 million people with HIV are on antiretroviral therapy (ART) and some countries in sub-Saharan Africa are now estimated to be treating 80% of those with CD4+ cell count below 350per μl [1,2], representing substantial progress since the beginning of the global ART scale-up. The 2013 WHO treatment guidelines continue to map out a bold strategy , recommending a number of measures, including expanding the scope of HIV testing, phasing out use of the drug stavudine, introducing viral load monitoring, making plans for a third-line regimen, and expanding the number of people in whom treatment is recommended, including for all pregnant HIV-infected women and most notably to include adults with CD4+ cell count in the 350–500 per μl range. The latter recommendations were in part influenced by the data in support of the efficacy of ART for prevention .
It is of particular note that ART is not unconditionally recommended for individuals in the 350–500 CD4+ stratum in other regions of the world, particularly in western Europe [5,6]. The reason for this discrepancy is partially due to different interpretation of the available evidence. Several experts have argued that the evidence in support of individual health benefit for ART initiation at a CD4+ cell count as high as 500 per μl remains limited . In presenting the case for earlier initiation of ART, the WHO Guidelines include citation of analyses comparing the rate of progression to AIDS and death according to the CD4+ cell count at ART initiation, which should not be interpreted to address the question of what are the relative risks and benefits of ART initiation at a given CD4+ cell count because the comparison made does not reflect the clinical question – namely whether to initiate or defer ART [7–10]. Furthermore, nonfatal adverse effects of ART are not recorded in most studies considered in the development of Guidelines. For these reasons, the question of whether ART initiation at CD4+ cell counts higher than 350 cells/μl leads to individual health benefit that outweigh the risks remains a question of active clinical research, and the need for on-going trials is fully acknowledged in the WHO guidelines.
There is a critical difference between the situation in resource-rich settings such as western Europe and that in many resource constrained settings. A well tolerated ART deferral strategy requires that a person is assessed for ART eligibility and having established that they are not yet eligible, monitored through clinical assessments and CD4+ measurement with the aim of deferring ART initiation until they reach a given threshold. Linking people to care after HIV diagnosis and retaining them in ongoing care while deferring ART has proved to be difficult in resource-limited settings and rates of loss to follow-up are substantial [11,12]. In settings without the ability to reliably implement such a deferral strategy, it seems prudent to initiate ART almost as soon as a person is first identified by the care services, to decrease the risks of late re-presentation with advanced HIV symptoms. For this reason, the WHO recommendation to initiate ART sooner rather than later for programmatic simplification in settings that cannot implement a safe deferral strategy seems prudent, at least for countries which currently have high levels of ART coverage. For countries with limited ART coverage based on 2010 WHO guidelines and/or with constraints of ART supply it would seem to be a priority to develop the ability to implement a deferral strategy through regular CD4+ cell count monitoring in order to allow prioritization of those in most urgent need, and this would be greatly facilitated by increased access to low-cost CD4+ testing as promoted by the treatment optimization strategies of the WHO http://www.who.int/hiv/topics/treatment2/en/(accessed 28 Sep 2013).
In considering the use of ART to prevent new infections, the proportion of people on ART who have suppressed viral replication is likely to increasingly depend more on coverage/frequency of HIV testing, linkage to care and adherence to, and retention on, ART than it does on whether the CD4+ cell count threshold for initiation is 350 or 500 cells/μl. In order to most cost effectively use ART as a prevention tool, as well as for maximizing its health benefits for those with HIV, a deeper understanding is needed within countries regarding these critical steps in the ‘cascade of care’ with attention to optimizing each step in this continuum .
Since their first iteration, WHO treatment guidelines have become increasingly aspirational, an approach that has been important for pushing funders and policy makers within countries for expansion of access to ART, advocating for higher quality HIV care. The list of recommended policy initiatives will, however, leave national health ministries with difficult decisions in terms of how to prioritize adoption of recommendations, given the many competing demands on limited resources. So, how will countries make specific decisions about HIV policy in the light of the new guidelines? Few countries will be able to immediately implement all the new recommendations – most of which require substantial additional resources. Indeed, many, with Nigeria, Angola and Russia being examples , are still far from providing ART for most of those with CD4+ cell count below 350, and many are also struggling to expand HIV testing programs, to link HIV-positive people to care and keep them in care to assess the need for ART, to fully provide CD4+ cell counts as necessary and to maintain an uninterrupted supply of ART and co-trimoxazole. The average CD4+ cell count at initiation of ART remains low in many countries . Clinicians and other health workers are the ones at the coal-face making difficult decisions in terms of prioritization of ART and other aspects of care, and expanding the eligibility for ART will not make this situation any easier. At worst, faced with aspirational guidelines, confusion may be the unfortunate consequence. There is urgent need for clear policy recommendations for countries based on their resource envelope and their current status in terms of maturity of their HIV response. The operational and programmatic guidance sections within the overall 2013 WHO guidelines document provide some helpful advice in this respect based on results of modelling research and pragmatic principles.
Modelling provides a useful framework within which all data on various aspects of a country's HIV epidemic and its programmatic response can be formally synthesized and used to predict outcomes of various alternative policies, including their cost effectiveness [15–20]. Although there are many similarities across countries in sub-Saharan Africa, there are also marked differences. Besides the differences in ART coverage mentioned above, there is variation in testing rates (high in Botswana, low in Malawi), prevalence (23% in Botswana, <3% in Rwanda), trends in prevalence (falling in Zimbabwe, static in Uganda), retention rates on ART (higher in Burundi than Kenya), availability of diagnostics (widespread real time viral load testing rarely done outside Botswana and South Africa), availability of CD4+ cell counts (not generally available in Malawi), and probably on other less well documented factors such as drug stock-outs and levels of adherence support http://www.unaids.org/en/regionscountries/countries/. In other regions, availability of opioid substitution therapy for persons with injection drug use, likely a critical requirement for adherence to ART and retention in care, varies substantially across countries (available in Kyrgyzstan, not in Russia). Country-specific models are increasingly being calibrated and utilized to tailor individual decisions that take into account many of these factors [16–19]. Such models, based to the extent possible on relevant country-specific data, can be a means of synthesizing and interpreting such data most effectively. There are limitations, however, partially exemplified by the fact that different models fitted to the epidemic in one country can produce somewhat inconsistent predictions, and modellers face the challenge of resolving any such differences. It is critical that empiric data continue to be generated from various countries in order to better calibrate models .
Modelling and cost-effectiveness analysis can inform the allocation of resources between HIV treatment and other health priorities. The value of an intervention, judged by its impact improving overall population health, is essentially determined by the amount of money spent for each healthy life year gained from applying the intervention compared with other relevant clinical alternatives. Broadly speaking, to maximize population health, countries should introduce all the health-related interventions they can afford, regardless of disease area, prioritizing those that offer healthy life years at lowest cost until their available health budgets are exhausted. Given disparities between countries in resources available for health, some interventions will make that cut in one country but not in another. Recommending interventions uniformly across countries therefore risks restricting or even displacing other interventions offering even greater health gains per dollar spent, particularly in settings with fewer resources available and other significant unmet health needs.
National health policy-makers face enormous challenges as they consider the recommendations included in the 2013 WHO treatment guidelines in the context of other elements of their HIV response and in the context of other health priorities their countries are facing. Further modelling and implementation research is needed in order to obtain answers to critical questions that will enable decision-makers to effectively respond to the challenges they face and to ensure the most health gains from available resources.
Conflicts of interest
The authors have no conflicts of interest to declare.
1. UNAIDS Report on the global AIDS epidemic. 2013 unaids.org
2. UNAIDS Report on the global AIDS epidemic. 2012 unaids.org
3. WHO. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Recommendations for a public health approach. 2013.
4. Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, et al. Prevention of HIV-1 infection with early antiretroviral therapy
. N Engl J Med
5. Williams I, Churchill D, Anderson J, Boffito M, Bower M, Cairns G, et al. for the BHIVA Guidelines Writing GroupBritish HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012
. HIV Med
7. Sabin CA, Cooper DA, Collin SC, Schechter M. Rating evidence in treatment guidelines: a case example of when to initiate combination antiretroviral therapy (cART) in HIV-positive asymptomatic persons
8. When to Start ConsortiumTiming of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies
9. HIV-CAUSAL CollaborationWhen to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries: an observational study
. Ann Int Med
10. Phillips AN, Staszewski S, Weber R, Kirk O, Francioli P, Miller V, et al. for the Swiss HIV Cohort Study, the Frankfurt HIV Clinic Cohort and the EuroSIDA Study GroupHIV viral load response to antiretroviral therapy according to the baseline CD4 cell count and viral load
11. Rosen S, Fox MP. Retention in HIV care between testing and treatment in sub-Saharan Africa: a systematic review
. PLoS Med
12. Severe P, Jean Juste MA, Ambroise A, Eliacin L, Marchand C, Apollon S, et al. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti
. N Engl J Med
13. McNairy ML, El-Sadr WM. The HIV care continuum: no partial credit given
14. Yiannoutsos CT, Johnson KF, Boulle A, Musick BS, Gsponer T, Balestre E, et al. Estimated mortality of adult HIV-infected patientsstarting treatment with combination antiretroviral therapy
. Sex Transm Infect
2012; 88:i33–i43. doi:10.1136/sextrans-2012-050658
15. Walensky RP, Wood R, Ciaranello A, Paltiel AD, Lorenzana SB, Anglaret X, et al. CEPAC-Int InvestigatorsScaling up the 2010 World Health Organization HIV treatment guidelines in resource-limited settings: a model-based analysis
. PLoS Med
2010; 7:e1000382doi: 10.1371/journal.pmed.1000382
16. Eaton JW, et al. How should HIV programmes respond to evidence for the benefits of earlier treatment initiation? A combined analysis of 12 mathematical models
. Lancet Global Health
2014; (in press).
17. Keebler D, Revill P, Braithewaite S, Phillips AN, Blasér N, Borquez A, et al. How should HIV programmes monitor adults on ART? A combined analysis of three mathematical models
. Lancet Global Health
18. Cambiano V, Bertagnolio S, Jordan MR, Pillay D, Perriens JH, Venter F, et al. Predicted levels of HIV drug resistance: potential impact of expanding access to care and eligibility criteria for antiretroviral therapy initiation.
19. Konings E, Ambaw Y, Dilley K, Gichangi P, Arega T, Crandall B. Implications of adopting new WHO guidelines for antiretroviral therapy initiation in Ethiopia
. Bull World Health Organ
20. Siegel JE, Weinstein MC, Russell LB, Gold MR. Recommendations for reporting cost-effectiveness analyses
21. Amornkul PN, Karita E, Kamali A, Rida WN, Sanders EJ, Lakhi S, et al. Disease progression by infecting HIV-1 subtype in a seroconverter cohort in sub-Saharan Africa
antiretroviral therapy; CD4+ lymphocyte count; cost effectiveness; economic analysis; guidelines; health economics; HIV; implementation; mathematical models; models; resource limited settings; when to start
© 2014 Lippincott Williams & Wilkins, Inc.
Highlight selected keywords in the article text.