HIV transmission remains a low probability but high consequence event, occurring in less than 1 in 100 contacts on average22-24
, but the global pandemic is potentiated by the frequency of humans having sexual intercourse and factors that amplify infectiousness and susceptibility in specific settings. The per contact calculation is based on composite data, and transmission probabilities vary considerably during the course of the disease, with higher transmission probability in the acute and late phases of HIV infection, as a reflection of plasma and genital HIV concentrations25-29
. The best empirical data related to our understanding of how viral suppression could lead to decreased HIV sexual transmission comes from the Rakai study conducted among Ugandan serodiscordant couples30
, though this study was completed before generic ART had become widely accessible in Uganda. HIV was not transmitted in discordant couples when the infected partner had a plasma HIV RNA level of less than 400 copies/ml30
. This association between viral load and the risk of HIV transmission among serodiscordant couples was confirmed in subsequent studies in Zambia and Thailand31, 32
in the pre-HAART era, and more recent data33
showed that HIV-infected partners in discordant relationships were substantially less likely to transmit HIV to their partners if they were on HAART.
However, other variables may affect genital tract HIV, besides systemic HIV burden. Mucosal HIV transmission is complex, since animal models suggest that either cell-free or cell-infected virus can replicate in a variety of host cells34-36
. The minimum inoculum of HIV that can cause human infection remains to be elucidated37
. Although some studies have documented HIV preferential binding to cervical and foreskin tissues through dendritic cells38, 39
, women who have undergone hysterectomy and circumcised men can also be HIV-infected12, 40
, so other urogenital cells can support HIV replication. The temporal window of opportunity for halting transmission through host defenses is very limited, as submucosal viral replication occurs within hours of exposure41
. In the first study examining the relationship between treatment and the detection of genital tract HIV, the virus was more readily cultured from seminal plasma and leukocytes in participants with leukocytospermia and/or advanced disease stage, and less likely to be detected in semen among men taking zidovudine (AZT)42
. Subsequent semen studies found that genital white blood cells were a significant source of viral burden43,44
. These data suggest that factors that increase genital tract inflammation may potentiate infectiousness, and ART could decrease infectiousness, presumably by decreasing viral burden.
Several groups have demonstrated that HAART suppresses viral replication not only in the blood and lymphoid tissues, but also in the male and female genital tract12, 13, 45, 46
. While treatment generally suppresses cell-free virus in the semen, many treated individuals can still harbor proviral CD4 cells in their semen44, 47
. A further complication is that not all drug combinations of HAART may be equally effective in the genital and systemic compartments12, 48
. Differential penetration of ART drugs in genital tissues may be a function of protein binding and other pharmacodynamic properties49
. Highly protein-bound drugs, like protease inhibitors, achieve lower concentrations in genital tract secretions compared to blood plasma14, 50
. Nucleoside analogues and non-nucleoside reverse transcriptase inhibitors achieve higher concentrations in genital tract secretions than blood plasma51-53
, which might make them particularly effective in decreasing sexual transmission of HIV.
Based on these findings, questions arise as to when would be the best time to initiate HAART if a primary goal is to decrease infectiousness among those who could transmit HIV to others. One key period for treatment could be the acute phase of HIV infection when patients have elevated viremia for about three weeks, until host defenses suppress replication, creating a “viral set point” 29, 54, 55
. When viral replication is unimpeded during acute HIV infection, individuals may have more than 1 million copies/ml of virus in their blood56
, and the potential to infect many individuals54, 57
. Studies from North America and Africa have shown between 40% and 50% of new transmissions were from recently infected patients54, 57
. Through employing discordant HIV rapid test results and RNA pooling, almost 2% of STI clinic patients in Malawi were identified with acute HIV infection58
. These findings suggest that promptly identifying “hot spot” microepidemics of newly infected persons may present an opportunity for early ART and behavioral interventions to slow the spread of HIV in high-risk settings59, 60
. Studies are underway to determine if early identification and treatment of acutely infected individuals can have a public health impact on local epidemics, but other questions will take more time to address, such as whether treatment can be discontinued without being detrimental to the patient if it is initiated in the setting of acute HIV infection. Public health challenges to identifying patients with acute infection include very short duration, frequent lack of clinical detection, and the expense of performing RNA-pooling in the era of constrained health resources.
Acute HIV infection is followed by a longer period of chronic viral homeostasis in which an infected person may be asymptomatic with good systemic virological control. This period can be interrupted by STI infections, which may override the suppressive effects of ART in the genital tract by causing inflammation, potentiating local HIV replication27
. Due to the relatively shorter periods of acute- and late-stage infection, the prolonged asymptomatic period, which may last more than a decade, may be the time in which substantial transmission events occur61-63
. An analysis from Sub-Saharan Africa suggests that acutely infected persons play a major role in HIV transmission during early highly concentrated epidemics, while the contribution of chronically infected persons becomes more prominent during advanced and stabilized epidemics61
. A recent projection suggested that annual HIV testing followed by immediate initiation of ART for all HIV-infected patients regardless of CD4 cell count could have a major impact by reducing the number of new HIV infections64
So, can HAART effectively suppress genital tract HIV over a sufficiently long period of time to stop HIV sexual transmission?65
. Studies from Taiwan and British Columbia, Canada have documented a greater than 50% reduction in anticipated number of incident HIV cases following the free provision of ART in 19979, 66
. A study among 393 couples in the pre- and post-HAART eras in Spain observed an 80% reduction in HIV transmission following the introduction of HAART67
. A recent observational study of discordant African couples showed substantially lower rates of HIV transmission among patients who were on HAART, but these individuals also tended to practice safer sex more than those who remained untreated33
. In order to better understand the preventive effects of therapy in discordant couples, the Health Prevention Trials Network of the National Institutes of Health is in the midst of a randomized controlled trial to assess the impact of HAART on transmission among 1750 discordant couples in eight countries (HPTN052)68
. HIV-infected partners in serodiscordant, monogamous relationships who have CD4 counts that would not warrant immediate initiation of HAART (ie >350 cells/ul) based on current guidelines are being randomized to either initiate HAART right away or are clinically monitored until their immunological or clinical status warrants treatment. This study will be fully enrolled in the coming year, and should provide important information shortly thereafter.
As more individuals live with HIV because of HAART, there is a larger pool of individuals who could transmit HIV, if HAART is not fully suppressive and they increase risk taking behavior. Studies on the impact of ART on sexual behavior among HIV-infected individuals have been inconsistent, and it is not clear whether the provision of ART may be associated with high risk sexual behavior in some subpopulations69, 70
. Though data from injecting drug users and men who have sex with men (MSM) in the developed world suggest that high risk behavior can increase with ART17, 71
, studies from resource-limited settings to date have not shown that the provision of ART does increase HIV risk taking behaviors72
Despite the increasing interest in the evaluation of “test and treat” strategies, other genital tract factors could mitigate the public health impact of early initiation of HAART. For example, concurrent STIs can increase HIV transmission probabilities73
, by attracting CD4 T-lymphocytes and releasing cytokines (TNF-alpha, IL-1) that enhance HIV transmission37
. Bacterial STIs can increase genital tract HIV concentrations74
, and interventions that provide treatment of these infections can decrease viral shedding27, 75-77
. In the Rakai study, HSV-2 antibody negative participants with viral loads >38500 copies/ml and HSV-2 antibody positive participants with viral loads <1700 copies/ml had a similar probability of transmitting HIV to the uninfected partner78
. Unfortunately, in many settings HSV-2 seroprevalence in young adult populations exceeds 50%79
, and 2 studies have documented that thymidine-kinase inhibitor chemoprophylaxis does not decrease HIV transmission to uninfected patients80, 81
. It is feasible that the removal of a pathogen that initiated a genitourinary inflammatory response may not be enough to restore the local cellular milieu.
Another concern about the wider use of ART for prevention has been the potential for the development and transmission of antiretroviral resistance if healthy individuals are expected to be fully adherent over many years. Multiple reports have now documented that resistant HIV has been sexually transmitted82
. Though ART resistance has been demonstrated with increased frequency in newly diagnosed and treatment-naïve patients over time83, 84
, recent findings suggest that ART-resistant HIV strains may have lower viral transmisability85
. Thus, public health systems around the world will need to track some of the potential unintended consequences of earlier initiation of antiretroviral therapy for prevention, including risk compensation, trends in STI co-epidemics, and the prevalence and incidence of transmitted ART-resistant HIV, in order to fully understand the costs, as well as the benefits of treatment as prevention.