Rationale and Evidence for Human Immunodeficiency Virus Treatment as Prevention at the Individual and Population Levels

Christopher J. Hoffmann, MD, MPHa and Joel E. Gallant, MD, MPHab*jgallant@southwestcare.org,     aDivision of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Room 226, Baltimore, MD 21205, USA; bDepartment of Specialty Services, Southwest CARE Center, 649 Harkle Road, Suite E, Sante Fe, NM 87505, USA

*Corresponding author. 649 Harkle Road, Suite E, Santa Fe, NM 87505.

Individual health benefits of antiretroviral therapy (ART) are becoming clearer. In resource-rich countries, side effects of current ART regimens are minimal. US guidelines recommend ART regardless of CD4 count or viral load. Maintaining an undetectable viral load with ART comes close to eliminating the risk of HIV transmission, leading the US guidelines to recommend universal ART to reduce HIV transmission. Achieving population-level control through treatment as prevention (TasP) may be feasible, but requires considerable investment of resources devoted to HIV testing, linkage to care, ART accessibility, and retention in care. Ongoing studies of TasP will provide insight into achieving meaningful ART coverage.

Keywords

HIV

Antiretroviral therapy

Prevention

TasP

Treatment as prevention

Adherence

HIV testing

Epidemic

Key points

 The risk of HIV transmission to a sexual partner is reduced 96% if the HIV-infected partner is on ART, and maybe close to 100% if the infected partner has achieved an undetectable viral load through the use of antiretroviral therapy.

 Initiation of HIV treatment with the safe and well-tolerated antiretroviral agents available in high-income countries is likely to benefit patients regardless of CD4 count.

 Scale-up of voluntary HIV screening followed by treatment of all HIV-infected individuals, along with other prevention methods, could have a significant public health impact, potentially slowing or stopping the HIV epidemic.

 Current levels of HIV testing and treatment are inadequate to achieve significant population-level prevention.

Introduction

Efforts to halt the human immunodeficiency virus (HIV) epidemic have failed on a population level. Despite attention and resources, the global HIV pandemic has been marked by an increasing number of people living with HIV.1 Overall an estimated 35 million individuals were living with HIV globally in 2012, an increase of 5 million from 10 years earlier. Although the global HIV prevalence is 0.8%, in some countries the prevalence is much higher. For example, in Swaziland 26% of the adult population is HIV infected.2

In both high- and low-prevalence countries, HIV distribution varies considerably by population group. For example, sex workers, men who have sex with men (MSM), and injection drug users (IDU) are consistently affected out of proportion to the background population. In the United States, nearly one quarter of black MSM are infected, and the overall prevalence among black men in Washington, DC, is 7%.3 In Africa, the HIV prevalence among MSM is often twice that of the non-MSM male population.4-6 Additional vulnerable groups, such as impoverished young women, are also at high risk for HIV infection. Among young women living in informal settlements in South Africa, the annual HIV incidence is between 5% and 15%.4,7

High HIV incidence has persisted despite substantial prevention efforts. The current situation reflects a failure to apply proven effective prevention approaches. The 3 notable exceptions have been the use of antiretrovirals for the prevention of mother-to-child transmission (PMTCT), condom promotion to reduce HIV infection among sex workers and their clients in Thailand,8 and needle exchange to reduce incidence among IDU in inner-city settings.9

PMTCT has parallels with treatment as prevention (TasP). PMTCT uses antiretrovirals during pregnancy and post partum to reduce the risk of MTCT. On a population level, implementation of PMTCT programs has reduced transmission from about 35% to 1% to 5%.10-12 The success of population-level implementation of PMTCT is a result of the intersection of global health funding that has made provision of services financially feasible and the time-limited intervention of PMTCT integrated within the medical management of pregnancy.

TasP has appeal with its parallels to PMTCT and its applicability to all types of epidemics, because it is presumed to interrupt heterosexual, MSM, IDU, and mother-to-child transmission. Evidence of the potential of ART to prevent HIV transmission has been present for at least a decade.13 More recently, clinical trial evidence, increased ART availability, and the development of better tolerated ART agents have coalesced to the point that TasP is a now considered to be a realistic approach to reversing the HIV epidemic. This article reviews the data supporting the use of TasP on an individual level and on a population level.

Theoretic basis: viral load and human immunodeficiency virus transmission observational studies

Untreated Individuals

The concentration of HIV in the blood correlates with the risk of both MTCT and sexual transmission.14 An early study of 415 HIV-discordant couples in Uganda, in which the seropositive partner was not receiving ART, found no transmissions when the infected partner had a plasma viral load of less than 1500 copies/mL.15 The rate of transmission increased progressively up to 23 per 100 person-years among partners of infected individuals with viral loads of greater than 50,000 copies/mL. A meta-analysis combining data from 10 serodiscordant partner studies reported a linear increase in transmission risk from 0.16 per 100 person-years for couples in which the infected partner had a viral load below 400 copies/mL to 9 per 100 person-years when the infected partner had a viral load of more than 50,000 copies/mL.16 These transmission risk studies were based on "stable" discordant relationships and may underestimate transmission risks during sex with new or casual partners.17

Treated Individuals

Several studies have prospectively followed heterosexual couples in which 1 member of the couple was HIV infected and received ART and the other was seronegative. Among 5 studies providing a combined 1000 person-years of follow-up and 5 incident infections, the calculated transmission rate with the use of ART was 0.5 per 100 person-years.16 This represents a markedly lower incidence than the 9 per 100 person-years that has been observed with partnerships in which the infected partner had a viral load of more than 50,000 copies/mL, but it still represents an important transmission risk.

What is unclear from these studies is whether the infected partner had a detectable viral load at the time of transmission; viral load data were not available in most of these studies. In addition, none of these studies confirmed that transmission occurred from within the partnership, because phylogenetic testing was not conducted. Thus, the estimate of 0.5 per 100 person-years may overestimate the risk for a stable, discordant couple if the infected partner is adherent to a suppressive ART regimen. Preliminary results from a European study of heterosexual and MSM couples suggest a very low risk of transmission when the HIV-infected partner is on ART with a viral load of <200 c/mL; no linked transmission events have been identified as of 2014.18 This study includes a substantial number of couples engaging in condomless sex (767); 30% of these couples are MSM within which 40% of the HIV-negative partners engaged in condomless receptive anal sex with ejaculation, which is associated with a higher risk of transmission than vaginal sex or insertive anal sex. The 95% confidence bound around the risk of transmission during receptive anal sex ranged from zero to 0.96 transmissions per 100 couple-years. If no transmission events are identified through the duration of the study (to be completed in 2017), the wide confidence interval will become narrower.

Plasma Versus Genital Fluid Human Immunodeficiency Virus Concentration and Transmission

One of the concerns regarding the transmission safety of unprotected sex despite an undetectable plasma viral load is the discrepancy between plasma and genital fluid HIV levels. In untreated infection, both plasma and genital HIV concentrations peak during acute infection, with genital levels remaining elevated for several months longer than plasma levels.19,20 Following the acute phase, genital fluid concentrations vary considerably more than plasma levels.19 Among individuals treated with ART and achieving an undetectable plasma viral load, genital HIV concentration tends to follow the plasma level, but the correlation is imperfect. Among men on ART with undetectable plasma HIV levels,...