Abstract

Biological strategies for interrupting transmission of human immunodeficiency virus (HIV) type 1 should be directed at reducing infectiousness of and susceptibility to HIV-1. Potential antiretroviral interventions include reducing the likelihood of transmission of HIV-1 by reducing HIV-1 load in the blood and genital tract of HIV-1–infected person, prophylaxis after high-risk exposure, and pre-exposure prophylaxis for very high risk populations. Antiviral treatment of herpes simplex virus (HSV) type 2, the most common cause of genital ulcers, should be evaluated as a strategy for HIV-1 infection prevention by reducing infectiousness of and susceptibility to HIV-1, on the basis of biological and epidemiological data indicating that HSV-2 facilitates transmission and acquisition of HIV-1. The rationale for antiretroviral and HSV-2–specific interventions and studies to test these strategies are described

Biology of Transmission of HIV-1

HIV-1 can be transmitted from blood and blood products, at mucosal surfaces through sexual transmission, and from mother to child [1]. Although extensively studied, the basic mechanisms of infection and their relationship to potential prevention strategies that are just beginning to be evaluated through clinical trials are still only partially understood. HIV-1 (either cell free or cell associated) must find a receptive cell with unique receptors on macrophages and lymphocytes, such as CD4, CCR5, CXCR4, and DC-SIGN (dendritic cell–specific intercellular adhesion molecule–3–grabbing nonintegrin) [2], to which the virus envelope can bind; then, the virus enters the target cell. Syncytium-inducing (SI) viral variants use CD4 and CXCR4 receptors preferentially, and such variants may be of greater importance in bloodborne transmission. Non-SI (NSI) variants that have an affinity for macrophage-like cells and for CD4, CCR5, and DC-SIGN receptors are likely to be important in sexual transmission at mucosal surfaces, since most isolates from persons with primary infection are found to be NSI strains [3–5]. Some studies have indicated greater heterogeneity of the initial virus quasi species among newly infected women, compared with that found among men, which may have implications for rates of CD4 decline and disease progression [6]

Not all hosts are equally susceptible to infection. For example, a 32-bp deletion in the CCR5 allele renders CCR5+ cells difficult to infect with HIV-1 in vitro [7], and the prevalence of the homozygous 32-bp deletion is higher among highly exposed, uninfected people than among low-risk populations or HIV-1–infected persons [8]. Other innate or acquired defenses also may reduce the probability of HIV-1 acquisition, including host factors such as polymorphisms in DC-SIGN and the virologic factors described below

Plasma HIV-1 Load As a Predictor of Vertical and Horizontal Transmission

Infectiousness of HIV-1 is related to the inoculum size [9], and maternal HIV-1 level during labor is strongly correlated with maternal-infant transmission [10]. In a study of retrospectively identified, monogamous, HIV-1–discordant couples from Rakai, Uganda, the probability of transmission of HIV-1 from index partners with a plasma virus load >50,000 HIV-1 RNA copies/mL was 12-fold higher than the probability of transmission from those with a plasma virus load <3500 HIV-1 RNA copies/mL [11]. This observation implies a particularly high risk of transmission during primary HIV-1 infection, when virus loads are often 105–106 HIV-1 RNA copies/mL, before a virus set point is achieved, and when individuals are often unaware of their HIV-1 infection [12]. Plasma HIV-1 load and, therefore, potential infectiousness is higher during late-stage HIV-1 disease [13]

Chakraborty et al. [9] developed a probabilistic model for the estimation of transmission of HIV-1, by estimating the transmission of HIV-1 from men to women on the basis of the actual concentration of HIV-1 in the genital tract. The results closely mimicked the actual findings for transmission per couple in Uganda. Men with <1000 HIV-1 RNA copies/mL in seminal plasma had a 1 in 10,000 chance, on average, of infecting their partners during each sexual contact, compared with a 1–2 in 1000 chance for men with ⩾50,000 HIV-1 RNA copies/mL (i.e., a 10–20-fold increase). The probability of transmission from men with high seminal virus load associated with primary HIV-1 infection may be higher [14]. Similarly, the effects of antiretroviral therapy (ART) can be modeled on the basis of average reductions in plasma and genital tract virus load

Mucosal Factors Affecting Infectiousness of and Susceptibility to HIV-1

The concentration of HIV-1 in the genital tract is correlated with blood plasma virus load but also may be modulated by inflammation and other factors that stimulate local replication of HIV-1 [15]. Genital tract inflammation greatly increases the concentration of HIV-1, most likely as a result of the release of local cytokines, as well as “leakage” of HIV-1 from the blood plasma pool. Viral diversity increases with genital tract inflammation [16]. Different factors may influence the concentration and infectiousness of HIV-1 in the oropharynx, including inhibition of HIV-1 in the presence of secretory leukocyte protease inhibitor and a high salt concentration [15]. Tonsillectomy also is associated with lower pharyngeal virus loads [17], perhaps owing to removal of a majority of the epithelial surface of the tonsils, which contains a rich lectin glycocalyx surface that may provide a location permissive to survival of cell-free HIV-1 [18]. However, even though orogenital sex is common and HIV-1 can be detected in specimens from tonsillar surfaces, very few cases of oral transmission of HIV-1 have been documented

Mucosal surfaces in uninfected subjects also are likely to be critical in affecting susceptibility to HIV-1. Acquisition of HIV-1 across the single-columnar epithelial layer in rectal mucosal surfaces or through the unkeratinized squamous epithelium of uncircumcised men may be enhanced by an increased number of receptive cells or increased trauma during anal sexual intercourse. In addition, there may be biological factors that provide innate resistance to HIV-1, such as histopathologic changes in the keratinized foreskin epithelium of circumcised males [19]. The vaginal ecosystem also may play a unique role: vaginal flora with low concentrations of hydrogen peroxide–producing lactobacilli, as occurs with bacterial vaginosis, seem to increase the risk of acquiring HIV-1 [20]

General Review of the Effect of Antiretroviral Agents in Reducing Infectiousness of and Susceptibility to HIV-1

A number of strategies for HIV-1 infection prevention that are based on ART have been proposed and are being studied (table 1). However, to date, ART for the prevention of maternal-infant transmission of HIV-1 is the only prevention strategy involving antiretroviral agents that has been proven to be effective. The effect of ART in reducing susceptibility to HIV-1, by means of postexposure prophylaxis (PEP) or pre-exposure prophylaxis (PREP), and in reducing the probability of transmission of HIV-1 from an infected person to his or her partner is being researched [21]

Table 1

Research initiatives to reduce acquisition and transmission of HIV-1 through the use of antiretroviral and herpes simplex virus (HSV) type 2 antiviral interventions

Table 1

Research initiatives to reduce acquisition and transmission of HIV-1 through the use of antiretroviral and herpes simplex virus (HSV) type 2 antiviral interventions

Extensive data from studies of animals have been used to examine PEP and PREP [22]. The available data strongly suggest that these methods may be effective in reducing the likelihood of acquiring HIV-1. PEP appears to work best in animals when drugs are administered early after exposure and continued for 28 days [23]. Studies have examined adherence to PEP among HIV-1–exposed humans; in general, the results support the feasibility of the approach [24]. In a small, nonrandomized study of PEP in Brazil, lower rates of HIV-1 infection were found among men who have sex with men (MSM), when PEP was used after potential exposure to HIV-1 during sexual intercourse [25]. More recently, studies of the pharmacology of antiviral agents in the genital tract support careful evaluation of the regimens recommended, to achieve the highest concentration of drug levels as soon as possible after exposure [26]. PREP requires identification of highly exposed populations, adherence to therapies, and application of the best agent(s). Clinical trials of the use of tenofovir by MSM and by commercial sex workers are planned (table 1). The long half-life, once-daily dosage, excellent safety profile, low potential for selection of resistant viruses, and high potency of tenofovir support study of this drug for PREP

Many studies have demonstrated the ability of ART to reduce, but not eliminate, HIV-1 from both the male and female genital tracts [27]. Most ART agents penetrate the genital tract, and nucleoside reverse-transcriptase inhibitors actually concentrate in the genital tract [28]. Conversely, drugs that achieve less concentration in the genital tract (e.g., some protease inhibitors) may be less effective in reducing the probability of transmission of HIV-1 and, in theory, could select for transmission of resistant HIV-1 variants. As a primary prevention approach, the effectiveness of ART in reducing infectiousness of or susceptibility to HIV-1 will need to be researched with regard to cost, adherence to therapy, and potential disinhibition with regard to high-risk sexual behaviors. In addition, ART will continue to be difficult to provide to people with primary HIV-1 infection, who may be among the most likely to transmit HIV-1. A study to examine the ability of ART to prevent transmission of HIV-1 in HIV-1–discordant couples (HIV Prevention Trials Network [HPTN] Protocol 052, Division of AIDS, National Institutes of Allergy and Infectious Diseases, National Institutes of Health) is planned and will be conducted primarily in international settings with high prevalences of HIV-1 infection and HIV-1–discordance in couples. Accordingly, this trial is based on World Health Organization (WHO) and in-country guidelines related to initiation of ART and incorporates the development of procedures for general counseling for couples and specific risk-reduction counseling for HIV-1–discordant couples

The use of ART for the prevention of transmission of HIV-1 by HIV-1–infected persons could have substantial public health importance. Although direct evidence of this prevention strategy has not yet been obtained, indirect evidence supports the plausibility of this strategy. First, the detection of ART-resistance mutations in people with primary HIV-1 infection demonstrates the selective pressure of ART, and recent findings that drug-resistance mutations are transmitted at a lower rate than has been predicted suggest that certain types of drug resistance may decrease the fitness and, thus, the infectiousness of HIV-1 [29]. Second, experience with other infectious diseases (especially tuberculosis and, more recently, suppression of herpes simplex virus [HSV] type 2 in HSV-2–discordant couples, as described below) suggests the potential importance of preventive and suppressive therapy in reducing transmission

Association of HSV-2 Infection with Amplification of Transmission of HIV-1

Over the past 2 decades, a number of observational studies have suggested that sexually transmitted infections (STIs) increase the probability of acquisition and/or transmission of HIV-1, by increasing susceptibility to and infectiousness of HIV-1, respectively. The mechanism of this interaction is likely to be related to increased numbers of activated target cells for HIV-1 (i.e., CD4+ lymphocytes and macrophages) in HIV-1–susceptible persons and of proinflammatory cytokines that lead to increased mucosal HIV-1 shedding from HIV-1–infected persons, as well as microulcerations caused by genital ulcer diseases (GUDs; syphilis, chancroid, and HSV-2 infection in particular). However, observational studies in which biological cofactors, such as STIs, and risk behaviors are assessed for their contribution to increasing the risk of acquisition and transmission of HIV-1 are limited by the difficulty in establishing a causal relationship and in controlling for potential confounding and misclassification in terms of exposure [30]

Most research in the area of STIs and transmission of HIV-1 has focused on bacterial STIs, which are prevalent in some populations at high risk for HIV-1 infection. Until more recently, the role of genital herpes was less actively researched, since management options were considered to be more challenging than those for bacterial STIs, which involve short courses of treatment. However, recent epidemiological and biological data supporting a consistent and strong association between genital herpes and acquisition and transmission of HIV-1 have been substantial; furthermore, the prevalence of HSV-2 infection is high worldwide, relative to other STIs. Thus, in this brief review, our focus is on the “epidemiological synergy” between HSV-2 infection and transmission of HIV-1 and the potential role of HSV-2 antiviral agents in reducing acquisition and transmission of HIV-1

HSV infections, particularly infection by HSV-2, are the most common cause of GUD worldwide, accounting for >60% of GUD cases in many STI clinics in developing countries [31]. A substantial shift in the etiology of GUD toward HSV infection has been noted in many developing countries, especially those with explosive and mature HIV-1 epidemics [32–34]. This etiological shift is likely to primarily reflect relatively successful treatment of GUD caused by syphilis and chancroid, through the WHO syndromic management guidelines; increasing recognition of HSV-2 infection as a result of diagnostic advances such as the glycoprotein G–based antibody assays and HSV-specific polymerase chain reaction (PCR) tests [35–37]; and longer-lasting and more-extensive ulcerations in patients with progressive HIV-1–associated immunodeficiency

A systematic review of the literature, including 31 studies involving >25,000 people, assessed the contribution of HSV-2 infection to the risk of acquiring HIV-1 [38]. The risk estimate from the most methodologically rigorous cohort and nested case-control studies that have documented HSV-2 infection prior to HIV-1 infection was 2.1 (95% confidence interval [CI], 1.4–3.2). The most compelling observational data about the effect of HSV-2 seropositivity on acquisition of HIV-1 are from the community-level, mass STI-treatment trial in Rakai, Uganda [11, 39]. In the Rakai population, the prevalence of HSV-2 was 61% among 15–29-year-old women and 31% among 15–29-year-old men; HSV-2 was detected in 87% of ulcers with a confirmed etiology [40]. Risk factors for acquiring HIV-1 were analyzed among retrospectively identified, monogamous, HIV-1–discordant couples; whereas urethritis and laboratory-confirmed cases of STI did not increase the risk of acquiring HIV-1, HSV-2 infection increased the risk among HIV-1–negative partners by ∼70% (odds ratio, 1.7; 95% CI, 1.24–2.37) [41]

The biological basis for the plausibility of increased risk of acquiring HIV-1 is supported by frequent detection, by use of PCR, of HSV-2 on mucosal surfaces during periods of subclinical reactivation [42], in addition to clinically apparent lesions. Presumably, during these periods of subclinical reactivation, inflammatory cells and microulcerations may be present, which would provide an increased number of target cells and portals of entry for HIV-1. Further understanding of the mechanisms of HSV-2 infection that increase susceptibility to HIV-1 may assist in guiding potential prevention strategies

HSV-2 infection has a very high prevalence globally among HIV-1–infected persons, and HSV-2 infection may enhance transmission of HIV-1 and HSV-2 from persons with coinfection [43, 44]. The biological basis of the plausibility of the increased infectiousness of HIV-1 in persons with HIV-1/HSV-2 coinfection has been demonstrated in studies of HIV-1–positive men with symptomatic genital herpes, in the United States [45], India [46], and Africa [27]: in these studies, HIV-1 virions were detected in herpetic lesions, with reduced lesional HIV-1 shedding during episodic antiviral treatment for HSV infection [34, 47]. Increased cervical shedding of HIV-1 during subclinical reactivation of HSV-2 also has been documented among women with HIV-1/HSV-2 coinfection, in the United States and Africa [48–50]. In studies of women and men in the United States, most HSV-2 shedding in persons with HIV-1/HSV-2 coinfection was demonstrated to be subclinical and often in difficult-to-visualize anatomic locations (e.g., perianal or cervical) [51, 52]. The variability in rates of reactivation of HSV-2 is high at all levels of CD4 cell count. Many HIV-1–infected persons with CD4 cell counts >350 cells/mm3 have reactivation as frequently as those with CD4 cell counts <100 cells/mm3, especially among those not undergoing highly active ART (HAART) [51]

In summary, HIV-1–related immunosuppression has a direct effect on the natural course of HSV-2 infection, magnifying both the frequency of reactivation and shedding of HSV-2 and the amount of virus present in genital secretions and supporting increased transmission of HSV-2 and possibly of HIV-1, from persons with HIV-1/HSV-2 coinfection. The combination of better serologic and DNA-amplification tools for the diagnosis of HSV-2 infection and improved control of bacterial STIs clearly indicates that, even though HSV-2 infection is more often subclinical, compared with many bacterial STIs, the high prevalence, frequency of reactivation, and ability to directly amplify replication of HIV-1 may make HSV-2 infection as important as or more important than bacterial STIs in promulgating the HIV-1 epidemic [44]. Thus, the above data indicate that treatment for HSV-2, particularly through suppression, may have a role in the prevention of HIV-1 infection. In general, current treatment and prevention guidelines for HIV-1 infection do not address the interactions between HSV-2 and HIV-1 and the potential public health implications

Strategies and Implications of Treatment for STIs and Genital Herpes, for the Prevention of Acquisition and Transmission of HIV-1

For bacterial STIs (e.g., chlamydia, gonorrhoea, chancroid, and syphilis), STI treatment is usually short (ranging from a single dose to several weeks) and is aimed at both reducing the severity and duration of symptoms (when present) and eliminating the etiological agent. For viral STIs, particularly HSV-2 infection, for which several safe and effective antiviral agents are available, treatment can be either short episodic therapy that will reduce the severity and duration of symptomatic recurrences or longer-term suppressive therapy that will reduce the number and severity of symptomatic episodes and asymptomatic shedding

If the presence of STIs (symptomatic or asymptomatic) enhances the probability of acquisition and/or transmission of HIV-1, then reducing population levels of STIs will reduce susceptibility to and infectiousness of HIV-1 and may serve to decrease the population spread of HIV-1 infection. The primary interventions for reducing population levels of STIs include increasing effective, consistent use of male condoms; reducing higher-risk sexual behaviors; and increasing the use of effective treatments for STI. The extent to which STI treatments may reduce population levels of STIs will depend on a number of factors, including the prevalence of bacterial and viral STIs; recognition of symptoms and inexpensive, sensitive screening tests that will enhance treatment-seeking behaviors; the efficacy of, access to, and cost of treatments; patient tolerance of and adherence to treatments; rates of reinfection; and treatment paradigms (e.g., syndromic rather than targeted, depending on confirmed etiology). The extent to which treatment for STIs may reduce transmission of HIV-1 depends not only on the factors that influence the prevalence of STIs but also on the stage of the HIV-1 epidemic, the per-contact–enhancing effects of different STIs on acquisition and transmission of HIV-1, behavior patterns, and sexual networks

During periods of no virus shedding, HSV-2 infection may have little enhancing effect on acquisition and transmission of HIV-1, whereas, during periods of subclinical and, in particular, clinical reactivation (e.g., GUD), the per-contact–enhancing effects of HSV-2 infection may be considerable. The combination of the lower enhancing effect for the majority of time during infection combined with the possibly high enhancing effect for relatively short periods translates to an average enhancing effect of ∼2-fold [38]. The proportion of cases of HIV-1 infection attributable to STIs will depend not only on the enhancing effects of STIs on transmission of HIV-1 but also on the prevalence of STIs. The proportion of cases of HIV-1 infection attributable to high-prevalence STIs with a relatively low average enhancing effect (e.g., HSV-2 infection) may be greater than that attributable to low-prevalence STIs with a higher average enhancing effect (e.g., syphilis). In a meta-analysis, Wald [38] used the risk estimate 2.1 to determine that the population attributable risk was 19% in populations with a prevalence of HSV-2 infection of 22% and that risk increased to 47% in populations with a prevalence of HSV-2 infection of 80%, as in many parts of sub-Saharan Africa

Since antiviral therapies can reduce virus shedding and virus load [21, 22], the possibility that they also may reduce transmission of HSV-2 and HIV-1 infections has been hypothesized. The first trial to assess the impact of antiviral therapy on the heterosexual transmission of a viral infection has been completed recently [53]. In a multicountry trial, monogamous, heterosexual, HSV-2–discordant couples were randomly assigned to a group receiving once-daily suppressive therapy, with 500 mg valacyclovir, or to a group receiving a matching placebo, for a period of 8 months [51]. Laboratory evidence of the incidence of HSV-2 infection among the HSV-2–susceptible partners in the couples with the HSV-2–seropositive partner randomly assigned to the group receiving valacyclovir was reduced by 48% (P=.04), and the high risk of acquiring symptoms of genital herpes was reduced by 75% (P=.01) [53]. These results might suggest that, at a population level, increasing suppressive therapy for HSV-2 infection could have a substantial impact on reducing the incidence and, in the longer term, the prevalence of HSV-2 infection. However, since the valacyclovir trial was conducted among monogamous, heterosexual, HSV-2–discordant couples, the extent to which inferences from the results may be applied to persons with multiple partners or to other populations is not clear. A modeling study has suggested that the benefit of increasing antiviral therapy associated with a decreasing incidence of HSV-2 infection is likely to far outweigh the risk of possible increases in HSV-2 resistance [54, 55]

Next Steps for Assessing the Effect of ART and HSV-2 Antiviral Therapy on Acquisition and Transmission of HIV-1

Researchers have been initiating studies to assess the effect of antiretroviral agents and treatment or suppression of HSV-2 infection on transmission of HIV-1 (table 1). Because HAART reduces HIV-1 load, an effect on infectivity, transmission, and spread of HIV-1 has been hypothesized, and models provide a tool to assess the likely effect of HAART at a population level, by using different assumptions regarding the population, the environment, and the effect of HAART on infectivity. The probability of transmission from men with the high HIV-1 levels associated with primary HIV-1 infection is likely to be much higher than that from men with established chronic HIV-1 infection [14]. In Africa, a substantial number of individuals with STIs also may have unrecognized primary HIV-1 infection [14], representing an important challenge for possible interventions, given our limited ability to detect acute HIV-1 infection and a lack of consensus about the utility of ART for recent HIV-1 infection

The possible role of treatment or suppression of HSV-2 infection on transmission of HIV-1 has become a major focus of research on prevention of HIV-1 infection, given the growing biological and epidemiological evidence of an interaction between HSV-2 and HIV-1. Several potential approaches to researching the interaction between HSV-2 infection and acquisition and transmission of HIV-1 ultimately may have public health applications, including the following: (1) preventing acquisition of HSV-2; (2) reducing the enhancing effect of HSV-2 on HIV-1, by episodic treatment of genital herpes in populations at high risk of transmission or acquisition of HIV-1; and (3) suppression of HSV-2, to reduce either susceptibility to HIV-1 among HIV-1–negative, HSV-2–seropositive persons or infectiousness of HIV-1 among persons with HIV-1/HSV-2 coinfection, in the absence or presence of ART. Acyclovir is a well tolerated, inexpensive, and safe medication that provides a unique tool for testing if the “synergy” between HSV-2 and HIV-1 can be interrupted and thus affect the HIV-1 epidemic. If effective, these findings may be relevant to once-daily regimens of HSV antiviral agents, such as valacyclovir, with which adherence may be higher but must be balanced by cost and access considerations

Several proof-of-concept studies have been implemented to define the role of HSV-2 suppressive or episodic therapy in the prevention of acquisition of HIV-1 among heterosexual women in Africa and among MSM in Latin America and North America (e.g., HPTN 039), as well as the effect of suppression of HSV-2 on transmission of HIV-1 in HIV-discordant couples in Africa and India (table 1). Episodic treatment would be less expensive and easier to implement than suppressive therapy but may be of more limited impact, since most HSV-2–seropositive persons have mild and unrecognized clinical disease and episodic acyclovir therapy provides only a modest reduction in the duration of lesions [56]. This approach is particularly problematic for HIV-1–infected persons who have frequent and long durations of HSV-2 shedding and in whom genital ulcers are often subclinical, in part owing to the cervical or perianal location of the ulcers. A trial is under way to study the effect of suppression of HSV-2 on reducing transmission of HIV-1 in HIV-1–discordant couples among persons with HIV-1/HSV-2 coinfection, particularly those with CD4 cell counts >200 cells/mm3, those for whom antiretroviral agents are not usually recommended or prescribed, and those from whom the majority of cases of transmission of HIV-1 may occur (Partners in Prevention Trial [funded by the Bill and Melinda Gates Foundation]). In this trial of suppression of HSV-2, as well as in the trial of HAART among HIV-1–discordant couples (HPTN Protocol 052), the couples will be provided with extensive counseling about transmission of HIV-1, risk reduction, condoms, and bacterial STI treatment

Discussion and Conclusions

The biology of transmission of HIV-1 is now understood well enough to inform intervention strategies; biological interventions must reduce infectiousness of HIV-1 in the infected person or the susceptibility to HIV-1 of the uninfected person. Biological strategies that reduce infectiousness are particularly attractive because they target sexually active, HIV-1–infected persons, a smaller and easier-to-identify population than the susceptible population, although identification of those who are unaware of their HIV-1–infection status has challenges. The use of HAART to prevent HIV-1–infected persons from spreading infection also will enter clinical trials, both as PREP and through ART for monogamous HIV-1–discordant couples. These trials will measure directly the efficacy of strategies to reduce infectiousness of and susceptibility to HIV-1 in the context of risk-reduction counseling and bacterial STI treatment. However, modeling of epidemiological data from San Francisco did not support the idea that ART prevents transmission [57], possibly because of direct and indirect issues related to ART use outside clinical trials, including poor adherence to drug regimens, increased risky sexual behavior, and drug resistance. However, behavioral changes associated with a false sense of security arising from decreased virus load could offset reductions in per-contact infectiousness. Increased risky behavior in the context of virus suppression during HAART has been documented [58] and may partly explain recent increases in the incidence of HIV-1 infection in some communities [59]. Any biological intervention is unlikely to be so effective that it can offset the importance of safer sexual intercourse for HIV-1–infected individuals

Almost all STIs can be expected to increase transmission of HIV-1 on a per-contact basis. However, given limited resources, the high seroprevalence of HSV-2, and the long period of reactivation of HSV-2 among populations with emerging and mature HIV-1 epidemics, an emphasis is now on HSV-2 infection. Clinical trials using acyclovir to prevent acquisition of HIV-1 will address the hypothesis raised from the results of a large number of observational studies linking HSV-2 and HIV-1. If acyclovir provided to at-risk subjects prevents acquisition of HIV-1, a major shift in prevention and management practices for HSV infection may ensue. Development of an HSV-2 vaccine is ongoing, but few promising candidate vaccines are available for testing. If the intervention trials demonstrate an ability to reduce transmission of HIV-1 through suppression of HSV-2, the efforts to develop an HSV-2 vaccine will acquire an even greater urgency

Even if trials of ART or HSV-2 antiviral therapy are successful, prevention benefits may be difficult to translate to community benefits; in general, trials of ART and HSV-2 antiviral therapy must be viewed as proof-of-concept studies. Favorable results can lead to the development of agents more appropriate to prevention and to operational strategies required for optimal implementation. Even if successful, implementation of new strategies into existing prevention paradigms will be challenging, particularly in lower-income countries, many of which already bear the major burden of the HIV-1 pandemic. Given the limited number of strategies for prevention of HIV-1 infection that have proven efficacy, novel biological approaches to reducing susceptibility to and infectiousness of HIV-1 are critically needed

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