Research Article: HIV Treatment-as-Prevention Research at a Crossroads

Date Published: June 3, 2014

Publisher: Public Library of Science

Author(s): Till Bärnighausen, Nir Eyal, Daniel Wikler

Abstract: In light of changing WHO guidelines for HIV treatment, Till Bärnighausen and colleagues consider how large-scale HIV treatment-as-prevention trials can be adapted so that they can remain viable.Please see later in the article for the Editors’ Summary

Partial Text: In June 2013, the WHO issued new guidelines for antiretroviral treatment (ART). The guidelines substantially expand eligibility for ART, recommending initiation at CD4 cell counts ≤500 cells/µl instead of at ≤350 cells/µl. For HIV-positive patients with active tuberculosis (TB) or hepatitis B, HIV-infected partners in serodiscordant couples, pregnant and breastfeeding women, and children younger than five years of age, ART is to begin immediately upon HIV diagnosis and irrespective of CD4 cell count or clinical stage [1].

In addition to male medical circumcision, prevention of mother-to-child transmission (PMTCT) and pre-exposure prophylaxis (PrEP) [4], recent optimism for an “AIDS-free generation” has rested in large parts on the promise of TasP [5]. In TasP, ART is provided to all HIV-infected individuals upon HIV diagnosis, irrespective of CD4 cell count or clinical stage. The hope is that the suppression of viral loads in nearly everybody who is infected will prevent most onward transmissions of HIV. It has been shown that TasP nearly eliminates HIV transmissions in one particular population: HIV-uninfected partners in stable HIV-serodiscordant couples who have disclosed their HIV status to each other and are willing to jointly participate in an individually randomized controlled clinical trial [6]. However, TasP’s potential for curbing the HIV epidemic in general populations with many different relationship types and different levels of care delivery and support remains an untested hypothesis, notwithstanding strong evidence on the preventive effect of ART under current guidelines from a population-based cohort study in rural South Africa [7] as well as results from several mathematical models predicting large TasP effects on HIV incidence [8],[ 9],[10].

If host countries adopt the new WHO threshold of CD4 cell count ≤500 cells/µl, current ethical standards will require that care given to patients enrolled as controls in the TasP trials be based on this threshold as well. For two decades, controversy has surrounded the standard of care offered to patients enrolled as controls in clinical trials in low-income countries. Opinions range from, at one extreme, the World Medical Association’s Declaration of Helsinki, according to which new interventions “…must be tested against those of the best current proven intervention…” (§32) to those who would require only that care for controls meet the standard prevailing at the test site [14]. None of the parties to the dispute, however, has defended provision of care inferior to the care available locally. That is what was offered to trial subjects in the infamous Tuskegee Syphilis study and is one basis for its odious reputation.

Policy makers, trialists, and members of the HIV community may wonder: Do we still need trials, now that ART initiation immediately after HIV diagnosis is considered so effective and safe for the individual patient’s health that, since 2012, it is the United States standard of care [20]? The purpose of the trials, however, is not to establish the effectiveness or safety of early ART for already infected individuals, but to determine whether comprehensive TasP will reduce HIV incidence at the population level. A positive trial result would justify large increases in ART investment and TasP implementation in the countries worst-affected by the HIV epidemic.

How can rigorous scientific evidence on TasP effectiveness be obtained even as sub-Saharan countries are adopting the new guidelines? We present four alternatives. The first two are clearly unsatisfactory, in our view. The last two are tentative proposals that might deserve consideration. Even if none is satisfactory, they may prompt other proposals and serve as a starting point for an important debate.

HIV TasP is one of our best current hopes for bringing the era of HIV to a close. Strong causal evidence that TasP works in general populations in sub-Saharan Africa, where the HIV epidemic is at its most severe, is still outstanding. This evidence, however, will be critical for ensuring that countries and donors will continue to provide the resources that are necessary to deliver near-universal ART coverage over the coming decades. Three large TasP trials that would generate this evidence are currently underway in sub-Saharan Africa. The adoption of the new WHO treatment guidelines, which recommend substantially expanded ART eligibility, would render the trials in their original designs unethical. Discussion is needed in order to allow some format of TasP trials to take place without delaying the adoption of the new WHO guidelines. We have mentioned several policy alternatives—some clearly unsatisfactory from an ethical or practical viewpoint, others more promising—in the hope of starting that discussion. More broadly, the case of the TasP trials and the WHO treatment guidelines is an example of the often difficult interaction between health policy and the scientific enterprise. Governments and international organizations demand strong evidence for policy formulation, but are commonly also compelled to act while evidence remains incomplete. As in the case of TasP, careful study design and well-coordinated policy implementation may allow major policy initiatives to go ahead without conclusive evidence, while preserving our ability to generate the evidence and, in doing so, ensuring the long-term success of the policies.