The study genetically links HIV cases of serodiscordant couples where the uninfected partner became HIV-positive in the course of the HIV Prevention Trials Network 052 trial. The 052 trial provided early initiation of antiretroviral therapy to the HIV-positive individual in a serodiscordant couple to determine if treatment had a prevention benefit to the uninfected partner. Thirty-eight couples seroconverted during the course of the trial. Phylogenetic analysis of HIV pol sequences and Bayesian analysis of genetic distances between pol sequences were utilized to determine linkages between the two partners’ viral subtype. It was found that out of the 38 seroconversions, 29 (76.3 percent) were linked, 7 (18.4 percent) were not linked, and 2 (5.3 percent) could not be determined. The unlinked cases equates to a large minority acquiring HIV through someone other than the partner in the study. Linked cases were significantly associated with the HIV-positive partner being in the delayed treatment arm and were not receiving treatment at the time of transmission. In the unlinked cases, there was a significant association between having a higher number of sexual partners in the prior three months and HIV seroconversion. The authors underscore the importance of performing genetic linkage testing in similar trials.

The two-page article heralds the potential of antiretrovirals (ARVs) being utilized as an HIV prevention measure in a combination approach. The author cautions against wide-scale implementation of ARVs as an HIV prevention method until challenges and research questions can be adequately addressed. The challenges include identifying individuals most in need, missing individuals in the acute phase of disease, increasing adherence, reducing drug resistance and toxicity, and limiting risk compensation. Current ARV programs have difficulty meeting the existing needs of populations, and to expand ARV as a prevention approach may place untold stress on already existing programs. ARV programs should prioritize those who are positive but are untreated, HIV-positive pregnant mothers, as well as those at higher risk of acquisition and transmission of HIV such as sex workers and people who inject drugs. There are limited funds for HIV programs; therefore, an incremental and balanced prevention approach should be implemented.

The paper reviews the antiretroviral therapy (ART) as prevention for HIV and tuberculosis (TB) research literature to provide information for policies and future planning initiatives. The search included all research articles and current studies that evaluated or were evaluating how ART was used in prevention programs to impact HIV and TB morbidity, mortality, risk behaviors, and HIV incidence and transmission. A total of 50 studies covering 52 different countries were included in the review and geographical areas included North America (20), Africa (22), Asia (4), Europe (1), and studies having multiple country sites (3). Twenty-four studies were randomized controlled trials. It was found that there is considerable evidence to support ART as a prevention method. There are a number of current research studies being conducted as well as being planned in this area. The methodology, interventions, and geographical location across the studies vary greatly. The review found strong support for ART as a prevention method, but many unanswered questions remain such as when to start ART, the overall impact of ART on HIV and TB prevention at the population level, and how to improve coverage of ART.

This article reviews the evidence supporting antiretroviral therapy (ART) as an HIV prevention strategy while critically examining the public health implications of such a strategy. Data clearly show that current ART suppresses but does not eliminate shedding of HIV in genital secretions. As a result, the magnitude of HIV transmission during ART is impossible to estimate. Current evidence for using ART as prevention includes retrospective and prospective observational studies involving couples, ecologic community studies, and an ongoing randomized trial. Such studies have data collection limitations and several kinds of bias. Furthermore, studies assessing the impact of ART on sexual behavior find both increases and decreases in risky sexual behaviors. While mathematical models using optimistic inputs suggest this strategy can eradicate HIV, others conclude that this is not the case. Use of ART for prevention will require much wider use of drugs in much healthier individuals. Clinical and community randomized trials (CRTs) are needed to determine the feasibility and benefit of this approach.

This study broadly confirms that treatment has the potential to substantially reduce HIV transmission. However, how the treatment is best implemented and to what degree HIV infection is reduced depends on the epidemiological context. For instance, over 30 years, in populations with little variation in risk behavior and random mixing, HIV incidence can fall by 95 percent if 80 percent of the population is tested every three to four years. In other populations, testing once a year is most effective. Because ART as a treatment strategy depends crucially on the epidemiological context, it is likely that this approach is better suited to some populations than others. Although implementation of a test-and-treat strategy could reduce HIV incidence, failing to achieve sufficiently high coverage levels or failing to test frequently enough could lead to a dramatic spiraling of treatment costs. Furthermore, this model finds that the intervention does not interrupt HIV transmission, so the pool of those needing treatment would continue to grow. Failing to fully implement the test-and-treat strategy could lead to overall increased long-term ART costs.

This study examines the hypothesis that the provision of highly active ART (HAART) during a 15-year period (1996–2008) in the province of British Columbia, Canada, had a population-level effect on the transmission of HIV by means of reducing the CVL. Researchers looked at the association between newly diagnosed cases of HIV and the expansion of HAART and found that the data signaled three distinct periods: two periods when HAART uptake was high and new cases declined significantly (1996–1999 and 2004–2008), hyphenated by a period of relatively stable treatment levels and numbers of new cases (2000–2003). A number of competing reasons for the strong correlation between rates of treatment and new infections were considered (i.e., decreases in sexually transmitted infections [STI], extent of HIV testing), and none moderated the relationship. The authors conclude that, although cause and effect cannot be established, their model and convergent evidence from other sources strongly suggest that ART is an important factor in mitigating HIV incidence.

The authors of this commentary assert that the assumptions used in the Granich et al. (2009) model require validation. Retrospective analyses of existing data and designing and executing new studies are needed to inform the model’s inputs. Research gaps include the following: feasibility of universal testing, the relationship of the stage of HIV infection to the efficiency of transmission, the effectiveness of ART in preventing HIV transmission, drug resistance, behavioral disinhibition with ART-as-prevention, individual benefits of such treatment, and cost-effectiveness to society. The authors conclude that the mathematical model sets forth a testable strategy that potentially could curtail the global HIV pandemic. Evaluating the influence of each variable in this model can help prioritize the questions that must be answered to provide data needed to ultimately validate or refute this approach.

Current clinical guidelines recommend deferring initiation of ART until patients living with HIV reach certain immunologically or clinically defined stages of disease. The potential effect of ART on transmission of HIV is limited by the deferral of ART until later stages of disease, low coverage in many populations, and high viral loads during acute infection when individuals do not know they are infected. Moreover, the majority of individuals living with HIV in sub-Saharan Africa do not know they are infected and thus cannot receive ART. This mathematical modeling study attempted to define the optimal testing and treatment strategy if ART was to be used with the aim of eliminating HIV transmission. A strategy of yearly voluntary testing of all persons over 15 years of age combined with immediate ART initiation at the time of diagnosis could substantially decrease HIV transmission in sub-Saharan Africa and drive the epidemic into an elimination phase by 2020. Although the up-front costs would be substantial, cost-savings would be realized by 2050.

This commentary about Granich et al.’s (2009) findings suggests that researchers are “clutching at straws” when they consider whether providing treatment with ART to everyone with HIV can help eliminate the epidemic. In addition to some flaws in the assumptions used in the model, the author points to resource-rich countries where HIV infections began to rise among certain populations as ART became more widespread. The author asks: If more people are living with HIV and these people are having unprotected sex, that causes more HIV infections in places where the population is well informed, HIV testing is actively promoted, and treatment is free and universally available; how can researchers realistically expect a different outcome in the African context?

This presentation estimates of the net cost and cost-effectiveness of ART as a prevention strategy in sub-Saharan Africa. Cost data were obtained from current country health systems and services, and the models included HIV epidemics in different countries. Interventions modeled include current ART guidelines based on CD4 cell counts and universal ART. Using these data, the researchers estimated outcomes on HIV trends, deaths, disability-adjusted life years (DALY), cost, and cost-effectiveness of ART as a prevention strategy from 2010 to 2050. This model found that expanded ART for prevention yields considerable benefits for control of the HIV epidemic and health in South Africa and Kenya. Expanded ART in South Africa could sharply reduce the cost burden of HIV, with a break-even point occurring in 2024. In Kenya, universal ART has a lower cost per DALY averted when providing ART for those with CD4 cell counts less than 200, but did not reduce costs over the 40-year model due to lower averted hospital costs.

Globally, an estimated 33 million people live with HIV, with nearly 3 million new infections occurring in 2007. Efforts to provide ART have reached over 4 million people in low- and middle-income countries in 2008, but many remain untreated. Treatment efforts have not been able to keep pace with infection and are not likely to unless a dramatic reduction in new HIV infections takes place. While current prevention approaches may reduce the number of new HIV infections, they are unlikely to eliminate the disease in settings with high prevalence. Thus, evaluating the role of ART for HIV prevention has emerged as a pressing issue. ART lowers the concentration of HIV in the bloodstream and in genital secretions. Because viral load is the single greatest risk factor for all modes of HIV transmission, ART use reduces the risk that HIV will be transmitted from one person to another. Currently, however, there is not enough evidence for the WHO to develop a policy or clinical guidance on the role of ART in HIV prevention.

In 2008, the Swiss Federal Commission for HIV/AIDS released a document stating that people living with HIV with undetectable plasma HIV RNA levels, who are on HAART, and have no other genital infections are not sexually infectious. This statement generated international controversy and concern about increases in risky sexual behaviors in response to the statement. This simulation study used a mathematical model to estimate the risk of HIV transmission from people living with HIV with undetectable viral loads over many sexual exposures. A key assumption of this model was that a person living with HIV could never be completely noninfectious, no matter how low his or her viral load. The model suggested that if condoms were completely abandoned by people with undetectable viral loads and who are on ART, the risk of HIV transmission would accumulate over time, and the population’s HIV incidence could increase four-fold.

This model assesses how ART can work as a treatment strategy using “best case” and “worst case” scenarios. Scenarios include treating all those infected and only those with AIDS. If only AIDS patients were treated, HIV prevalence would increase because of this population’s increase in life expectancy. If both AIDS and pre-AIDS cases were treated, the increase in prevalence would be initially counteracted by averting more infections. Over the long-term, however, these gains are negated by an increase in risk-taking behavior coupled with an increase in life expectancy. Treating both AIDS and pre-AIDS patients saves fewer life-years per year of treatment than only treating AIDS patients. Furthermore, the higher the ARV coverage, the more viral resistance occurs and the wider it spreads. The authors conclude that HIV epidemics in sub-Saharan Africa cannot be controlled through treatment, regardless to what degree ART is available. Thus, any ART strategies must be integrated with prevention efforts.

To help inform assumptions being used in mathematical models, this cross-sectional study randomly sampled the blood and urine of 1,000 people of reproductive age in South Africa. Researchers also obtained a questionnaire about participants’ sexual partnerships and condom use. HIV prevalence was found to be 21.8 percent. Using WHO guidelines for initiating ART, 9.5 percent of the subjects living with HIV (equaling 2.1 percent of people of reproductive age) needed to start ART immediately. Such treatment, they calculate, would reduce the risk of HIV infection annually by 11.9 percent. The U.S. Department of Health and Human Services has different guidelines on initiating ART. Using these guidelines on the same population, 56.3 percent of participants living with HIV would require immediate ART, resulting in an annual HIV transmission risk reduction of 71.8 percent. Thus, under WHO guidelines, HAART will not substantially reduce heterosexual spread of HIV in this population. The authors conclude that funding for treatment should not compete with funding for prevention.

A review of existing literature was conducted to explore the attrition rates in the continuum of care between when individuals test positive for HIV to linking to care and treatment services. People living with HIV (PLHIV) are lost at various points along this continuum and understanding the reasons behind this loss is vital in improving health outcomes of PLHIV. The systematic review included peer-reviewed literature as well as conference abstracts that studied patient retention between HIV testing and antiretroviral therapy (ART) initiation in sub-Saharan Africa. The authors defined three different stages: the first being from HIV testing to obtaining CD4 count results, the second from not eligible for ART to accessing pre-ART care until eligible, the third is ART eligible to initiating ART. Twenty-eight articles and abstracts were included in the review: twenty studied only one stage, six addressed two stages, and two addressed all three stages. The median proportion of patients retained in stage 1 was 59 percent (35 to 88 percent), stage 2 was 46 percent (31 to 95 percent), and stage three was 68 percent (14 to 86 percent). Therefore, based on this review, there are great challenges in following healthy PLHIV to ensure initiation to care and treatment services that could span a long period of time. A limitation to the review was the wide variation in how studies defined and measured entry points to care and treatment. It is recommended that researchers standardize language to allow the public health community to generalize across studies.

South Africa’s treatment goal in the national strategic plan is to provide antiretroviral therapy (ART) to at least 80 percent of treatment-eligible clients. It is necessary to understand the challenges in expanding treatment to those who are eligible, including those who refuse treatment, to reach this goal. Included in the study were adults who tested positive for HIV at the Perinatal HIV Research Unit in Soweto and were eligible for treatment based on CD4 counts. There were 7,287 clients who presented for voluntary counseling and testing, and 2,562 clients (35 percent) tested positive. Of those who tested positive, 743 (29 percent) were eligible to start treatment but 148 (20 percent) refused. It was found through multiple logistic regression that those who refused were more likely to be single and to have active tuberculosis compared to those who accepted treatment. Social workers recorded the reasons for refusal and the most sited “feeling healthy” followed by unable to disclose status, drug side effects, unable to adhere to drugs, cultural beliefs, and stigma. Increasing voluntary counseling and testing, drug availability, and reducing cost of drugs are not the only factors in expanding treatment. Promoting ART as a life-saving and safe method will be necessary to encourage all eligible individuals to accept treatment.

With no HIV prevention interventions producing dramatic declines to the HIV epidemic in sub-Saharan Africa, the authors wonder whether Granich et al.’s (2009) test-and-treat theoretic model provides a “ray of hope” in curbing the epidemic in this part of the world. As such, if proof of concept and validation studies find that this model is indeed plausible, the authors present four key operational challenges to universal testing and treatment in sub-Saharan Africa, and possible ways to address them. These include 1) community acceptability and protection of human rights—that is, weighing public health benefits versus health benefits to the individual; 2) availability of safe, effective, first-line ARV regimen for asymptomatic patients; 3) delivering ARV on a mass scale in sub-Saharan Africa; and 4) ensuring a viable, accurate monitoring and reporting system. Their insights include discussion of conceptual, financial, ethical, and programmatic issues related to a universal test-and-treat strategy.

This presentation outlines the PopART pilot study, which will assess whether a CRT of universal testing and treatment is feasible, practical, acceptable, and potentially effective in drastically reducing HIV transmission. Taking place in Uganda and Zambia from 2010–2013, this study will collect information on acceptability; refine and explore mathematical models that can inform the design of the CRT; undertake qualitative research on trust, barriers, and experiences in service delivery; and assess five components related to human rights and ethics. The study will also pilot test 100 individuals who are living with HIV with immediate treatment with ART. If results indicate that the intervention is safe, acceptable, and has a greater than 50 percent effect on HIV incidence, then the researchers will begin a large-scale CRT using a universal test-and-treat strategy.

After reviewing studies that find reduced HIV transmission among people using ART, this presentation reviews ways that studies could show the “proof of concept” for a universal test-and-treat strategy. It includes discussion of using a cluster of individuals (for example, an entire village) as the unit of randomization and two trials to assess whether a test-and-treat strategy can work.

Thirty representatives from human rights organizations in seven sub-Saharan African countries met to discuss the Granich et al. (2009) model and the practical application of this model to HIV programming. A two-page statement of opposition to the universal test-and-treat strategy outlined in the Granich et al. paper lays out their concerns, including flawed assumptions, human rights shortcomings, and a lack of attention to marginalized and/or vulnerable groups. They state that the model fails to adequately capture modes of transmission outside of heterosexual sex, barriers to testing and treatment among vulnerable groups in particular, and ideological opposition to many proven HIV prevention methods. They state, “The model is fundamentally at odds with a human rights based response to HIV.” The group recommends discussions, research, and analysis of a list of key issues before any action is taken to implementing such a universal test-and-treat model.

This commentary proposes that the “positive prevention” approach to HIV prevention being used in industrialized nations—focusing preventive interventions only on those infected with HIV—be adopted in Africa and other high-prevalence regions. The authors propose 10 approaches for such a program in Africa and prioritize the interventions based on those with the greatest potential to reduce HIV transmission. These include disclosing HIV status to partners, partner testing, providing ART, preventing unintended pregnancies and maternal-to-child transmission of HIV, among others. Some of these approaches are proven and some have just been piloted, while others need exploration and the development of evidence-based policy.

According to the author, HIV testing must become the entry point for all individually focused HIV combination strategies. He advocates focusing on the psychosocial and structural drivers that impede HIV testing, such as lack of access to care if the diagnosis is positive. He identifies linkage and retention in care as imperative to move treatment as prevention from proof of concept in a clinical trial to a public health intervention. He points out that linkage to care continues to remain a challenge in many settings; for example, 50 percent of HIV-positive people in the United States are currently not receiving care services, including antiretroviral therapy (ART). He stresses that easy-to-use point-of-care testing kits administered by peer counselors may provide access to those hard-to-reach populations that may not otherwise seek care. He also stresses that linkage to care is not enough and that there must be a focus on retention, particularly following initiation of ART treatment. According to the author, other issues related to treatment as prevention include the effect of the route of exposure to HIV on the efficacy of ART as prevention, the most effective way to initiate early treatment, and a possible role for therapeutic vaccines and a functional cure. Other issues include how to sustain the prevention effect and how to improve viral load testing and HIV therapy. He also advocates for increasing implementation research on the factors that impede access to testing and care services.

The research presented in this article compared the costs and impact for South Africa of providing universal access to HIV treatment—antiretroviral therapy (ART) for those who test positive for HIV and have a CD4 count under a certain level—versus a “test and treat” (T&T) strategy where all individuals are tested in a certain area, and all who test positive receive treatment, regardless of CD4 count. This study followed an earlier World Health Organization (WHO) study that found that universal T&T would eliminate HIV in South Africa within 10 years and cost approximately U.S.$10 billion less than universal access to treatment over 40 years. Using the same mathematical model as the WHO study but with additional variables to reflect epidemiological realities, the authors got very different results: universal T&T would take 40 years to eliminate HIV in South Africa and cost about U.S.$12 billion more than universal access. The authors attribute the difference between these two sets of results to limitations in the earlier WHO mathematical model, which underestimated survival length and did not account for the development of resistance to HIV drugs. The authors predict that, after 20 years of universal T&T implementation, about 2 million individuals in South Africa would require expensive second-line ART, compared to about 1.5 million for a universal access strategy.

This introductory article provides a framework for a series of articles commissioned by the HIV Modelling Consortium on the future research agenda and implementation approaches of treatment as prevention (TASP). According to the authors, the role of antiretroviral therapy in reducing HIV incidence will be one of the most important tools in HIV prevention in the near future. They stress that implementation requires an interdisciplinary approach that involves epidemiology, economics, demography, statistics, biology, and mathematical modeling. Examining 12 mathematical models, the authors report that HIV incidence can be reduced by 35 to 54 percent after eight years if 80 percent of people living with HIV were treated when their CD4 count is 350 cells/µl. They report that once more years are added to these models, it becomes difficult to pinpoint which of many sexual risk behaviors lead to transmission. The series also examines how early infections before diagnosis—when viral concentration spikes and individuals are more infectious—may or may not lessen the impact of TASP programs and modeling estimates. Other topics included in this series include costs associated with TASP, the future direction and priorities of modeling, and best practices for model presentation and interpretation. A related presentation at the International AIDS Conference discussed the use of modeling to show efficacy of TASP for the South African epidemic.

This document briefly reviews seminal articles related to two emerging research areas: community-based HIV testing and treatment as prevention. The author presents strategies and evidence for voluntary community-based HIV testing and provider-initiated CT. The key knowledge gaps and research needs for the test-and-treat strategy are also reviewed. The author welcomes comments on the test-and-treat approach, particularly from individuals living with HIV.