Response to Lancaster et al. generalizability and scalability of HIV ‘treatment as prevention’

We appreciate the comments of Lancaster et al.[1], as they allow further discussion regarding the accumulated evidence in favor of the secondary preventive benefits of highly active antiretroviral therapy (HAART) on HIV transmission. First, the criticisms of the Bradford-Hill criteria or ‘viewpoints’ are well known; we apply these criteria to serve as a structured framework for synthesizing the accumulated evidence for the casual relationship of HAART on HIV transmission. It is in this context that the Bradford-Hill criteria continue to be influential today, nearly 50 years after they were first proposed [2]. Otherwise, the remainder of the critique results from a misunderstanding of the use of such criteria, and the synthesis of scientific evidence on the causal mechanism in question. Put simply, we view the body of literature reviewed in our article as investigations of the same fundamental, individual-level relationship between HAART and HIV transmission, as observed in a variety of different settings and study designs. We have emphasized that the evidence in support of this relationship is strengthened by its observation in different populations and using different study designs – experimental, observational and ecological. Each of the studies considered featured limitations in either internal or external validity or both; however, the consistency of the effect throughout these studies, and our ability to argue positively within each of the individual criteria, strengthens the argument considerably. The question about generalizability of the protective effect of HAART on HIV transmission to nonheterosexual, stable serodiscordant couples is raised in part because the HPTN 052 study predominantly enrolled this population; however, it should be noted that this was largely because few homosexual couples enrolled in the study, despite being eligible. Although it is true that HIV transmission is more efficient through unprotected anal intercourse or needle sharing than via vaginal intercourse, the evidence suggest that a protective effect of HAART is indeed present across all forms of transmission. The precise magnitude of the protective effect of HAART on HIV transmission is indeed incompletely characterized in the setting of unprotected anal intercourse or needle sharing. Of further relevance, however, it is clear that given the strength of the accumulated evidence, conducting a randomized trial of immediate versus deferred therapy among serodiscordant MSM couples or injection drug users (IDUs) to further characterize the HAART–HIV transmission relationship in these settings is no longer viewed as an acceptable proposition [3]. The question of ‘scalability’ is really a question of implementation – whether or not institutions and governing bodies can successfully expand HIV testing and treatment to the extent in which actual decreases in new case rates can be observed at the population-level. The experience in British Columbia, China, Taiwan and San Francisco, to name a few, already demonstrates that the HAART–HIV transmission relationship can be observed at the population-level. Further, the recent article by Tanser et al.[4] provides additional support for the causal mechanism at the population-level. In a large prospective cohort study of HIV-negative individuals (n =16 667) spanning 7 years of follow-up, the authors found the risk of individual HIV acquisition declined significantly with increasing ART coverage in the surrounding local community. Controlling for other factors, an HIV-uninfected individual living in a community with high ART coverage (30–40% of all HIV-infected individuals on ART) was 38% less likely to acquire HIV than one living in a community in which ART coverage was low (<10%). Crucially, this finding was demonstrated in a ‘real-world’ setting featuring considerable operational challenges to the successful and sustainable delivery of treatment and care to large numbers of patients. Further to the questions regarding the generalizability of the HAART–HIV transmission relationship, we note that the design of the study by Tanser et al.[4] was similar to that of Wood et al.[5], later confirmed in a different population by Kirk et al.[6], focusing on IDUs. Both studies featured individual-level outcome data, with ecological measures of HIV exposure, controlling for potential confounders, thus limiting potential biases. However, we readily accept that many challenges remain for the full and sustained optimal implementation of ‘HIV Treatment as Prevention’ initiatives globally. Lessons learnt in tuberculosis or sexually transmitted infections should alert us to the urgency of focusing on optimizing, supporting and sustaining such initiatives to be responsive to the needs of diverse populations and settings. As the recommendations of the 2013 WHO guidelines (to be released at the International AIDS Conference in Kuala Lumpur) are expected to expand HAART eligibility to about 80% of those infected with HIV worldwide, researchers should be encouraged to work with policymakers, implementing partners and communities to critically evaluate the implementation of this important scientific breakthrough [7]. Acknowledgements None. Conflicts of interest Dr Bohdan Nosyk has no conflicts of interest to declare. Dr Julio Montaner has received grants from Abbott, Biolytical, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck and ViiV Healthcare. He is also supported by the Ministry of Health, from the Province of British Columbia; through a Knowledge Translation Award from the Canadian Institutes of Health Research (CIHR); and through an Avant-Garde Award (No. 1DP1DA026182) from the National Institute of Drug Abuse, at the US National Institutes of Health. He has also received support from the International AIDS Society, United Nations AIDS Program, World Health Organization, National Institute on Drug Abuse, National Institutes of Health Research-Office of AIDS Research, National Institute of Allergy & Infectious Diseases, The United States President's Emergency Plan for AIDS Relief (PEPfAR), Bill & Melinda Gates Foundation, French National Agency for Research on AIDS & Viral Hepatitis (ANRS), Public Health Agency of Canada.

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