Daily treatment with aciclovir to suppress HSV-2 reactivation reduced genital and plasma HIV-1 RNA levels in women co-infected with HIV-1 and HSV-2. In this proof-of-concept trial, women in the aciclovir arm had a lower rate of genital HIV-1 RNA detection after 3 months of treatment, although the evidence for impact at a single visit (M3) weak. Single measurements of genital HIV-1 RNA shedding are limited because HIV-1 genital shedding is subject to high within-person variability [18
]. This variability is related in part to variability in both genital sample collection and the accuracy of measurement within mucosal samples. The impact of anti-HSV-2 suppressive therapy on genital HIV-1 RNA transmissibility therefore is best observed when multiple measurement points are included in the analysis. In this trial, anti- HSV-2 suppressive therapy with aciclovir was associated with a significant reduction in the frequency of genital HIV-1 RNA detection. The finding that these effects are even stronger in the sub-group of women who shed high levels of HIV-1 RNA and HSV-2 DNA simultaneously, provides support for earlier observations that HSV-2 reactivation can enhance HIV-1 transmissibility by increasing HIV-1 mucosal replication either through transactivation of HIV-1 expression by HSV-2 proteins[19
]or stimulating the release of pro-inflammatory cytokines in addition to the recruitment of activated CD4+ cells to the genital mucosa and skin levels[22
]. Recent studies of the genital tract immune milieu have revealed that co-infection with HIV-1 results in depletion of the immune cells in the cervix responsible for the immune control of HSV-2 reactivation (DC-SIGN), confirming the biological synergy between these two viruses [24
]. Our findings are consistent with the results from smaller trials conducted among women in Burkina Faso and Thailand, and among homosexual men in Peru, which have also shown reductions in plasma and genital or rectal HIV-1 viral loads using valaciclovir[6
It remains unclear, however, what reductions in the frequency of genital HIV-1 RNA shedding are required to reduce sexual transmission of HIV-1. A direct assessment of whether daily suppressive therapy with aciclovir can prevent the sexual transmission of HIV-1 is currently underway in a large, multi-centre, randomised controlled trial of HIV-1 serodiscordant couples[26
]. While two recently published randomised controlled trials have shown that daily aciclovir does not reduce the risk of HIV-1 acquisition in HIV seronegative individuals, we need the results of ongoing trials to conclude about the value of daily aciclovir in reducing HIV infectiousness and transmission[27
]. Given that the biological mechanisms by which HSV-2 increases HIV-1 transmissibility are different, the results of our trial support the notion that that suppression of HSV-2 reactivation could prevent the sexual transmission of HIV-1.
A 0.34 log (46%) reduction in HIV-1 plasma viral load after three months of aciclovir was observed. Similar reductions of 0.33 and 0.53 log10
copies/mL in plasma HIV-1 RNA have been observed in the two smaller trials of valaciclovir suppression for 2 to 3 months in HSV-2 and HIV-1 co-infected men in Peru[7
] and women in Burkina Faso[6
]. Such impact may have important implications for HIV-1 transmission and disease progression. Plasma viral load remains one of the strongest predictors of HIV-1 transmission[29
] and interventions that reduce plasma HIV-1 viral load are likely to influence HIV-1 transmission.
Reductions in plasma HIV-1 viral load of similar magnitude have previously been seen to be clinically significant[30
]. Moreover, earlier studies showed a survival benefit for HIV-1 infected persons receiving aciclovir for treatment of cytomegalovirus (CMV)-associated conditions compared to untreated patients[31
]. A meta-analysis of AIDS mortality in eight subsequent trials concluded that treatment with high-dose aciclovir offered a significant survival benefit for HIV-1 infected persons[32
], despite the absence of a direct pharmacological activity of aciclovir against HIV-1[33
]. Instead, the effects of aciclovir on HIV-1 plasma viral load are believed to be mediated through the suppression of clinical and sub-clinical reactivations of HSV-2, which have been shown to be associated with increases in systemic HIV-1 viral loads[34
]. In addition, an indirect effect mediated by impact on other Herpesviridae
(HSV-1, Epstein-Barr virus, CMV, human herpesviruses −6 and −8) cannot be ruled out, although drugs and dosages used to control reactivation of these viruses might differ from the ones used to control HSV-2.
While we showed an impact of aciclovir on plasma HIV-1, we could not demonstrate any significant impact of aciclovir on CD4+ count. Trials of longer duration are required to confirm whether the observed reductions in HIV-1 plasma viral load would translate into immunological benefits in co-infected persons at high CD4+ count levels, potentially delaying the loss of CD4+ T-lymphocytes and prolonging the time before antiretroviral therapy initiation.
As anticipated, aciclovir significantly reduced both sub-clinical and clinical reactivations of HSV-2. Episodes of genital ulcerations were fairly frequent during the pre-randomisation visits of the trial (12%). While all episodes of GUD during the trial were treated with aciclovir irrespective of treatment arm, there was no evidence to suggest that this approach undermined our intent-to-treat analysis (data not shown). However, the most likely effect, if any, would have been to underestimate the impact of aciclovir on genital and plasma HIV-1 RNA.
In summary, this large proof-of-concept trial confirms the hypothesis that asymptomatic reactivation of HSV-2 leads to increased levels of genital and plasma HIV-1 RNA, and that HSV suppressive therapy can help reduce, but not eradicate, HIV-1 replication. The results from other ongoing or planned trials will provide further evidence of whether this translates into prevention of HIV-1 disease progression and transmission. Given the high prevalence of both HSV-2 and HIV-1 infections in Africa, HSV suppressive therapy in HIV-infected individuals offers a potential new HIV prevention tool which may also have individual clinical benefits for co-infected individuals.