Biologic and epidemiologic studies have demonstrated strong synergy between HSV-2 and HIV.8-10,17-20
It is therefore plausible that therapy to suppress HSV might reduce HIV acquisition. However, we found no significant effect of twice-daily treatment with acyclovir on the incidence of HIV infection among the participants in our study.
Possible explanations for the lack of effect include chance, limited power to detect moderate effects, bias due to losses to follow-up, and suboptimal adherence to treatment, or the acyclovir regimen (400 mg twice daily) may not be potent enough to fully suppress HSV-2 at the cellular level, especially if any dose is delayed.
Participants lost to follow-up in both groups were more likely to be younger and to consume 10 or more alcoholic drinks per week. Both of these were independent risk factors for HIV infection during the trial (results not shown). It is therefore possible that the overall incidence of infection with HIV in the trial was underestimated and that this bias may have been slightly greater in the acyclovir group. In this case, the true rate ratio would be slightly higher and the main qualitative conclusions of the study would be unchanged.
This was a proof-of-concept trial, and we chose a standard suppressive acyclovir treatment regimen that has been shown to have an efficacy against HSV shedding similar to that of valacyclovir (500 mg twice daily).21
HSV-2 infection is characterized by frequent subclinical reactivations as well as clinical episodes,22
and recent evidence shows that it acts at the cellular level to potentiate HIV target cells.23
We considered it theoretically possible that partial suppression of HSV-2 might have an effect on the risk of HIV acquisition. However, the short half-life and poor absorption of acyclovir may mean that plasma levels are not sufficient or are not maintained at a level high enough to switch off this cellular trigger, especially if adherence is suboptimal. In contrast, oral valacyclovir is more readily absorbed, has higher trough plasma acyclovir levels, and leads to greater bioavailability of acyclovir, with a half-life of 2.62 to 3.13 hours.24,25
Several trials of suppressive therapy with valacyclovir (500 mg twice daily) found significant reductions in genital and plasma HIV over periods of up to 3 months.11-14
A trial of acyclovir (800 mg twice daily) in Thailand found a significant effect on genital HIV viral load,26
and there was a significant reduction in plasma HIV and frequency (but not quantity) of genital HIV in a trial of acyclovir (400 mg twice daily) in South Africa.12
In contrast, no effect was found for this dose of acyclovir among HIV-positive participants in our trial.27
These results suggest that valacyclovir (500 mg twice daily) or a higher dose of acyclovir may be necessary to reduce the replication of HSV-2 in populations in which adherence to treatment is suboptimal.
The median adherence according to counting of tablets was 90%. Adherence proved challenging to measure. The main limitation of counting was that if participants did not bring back their tablet boxes, or if they reported that tablets had been lost, stolen, or damaged, an accurate estimate of adherence was not possible. Even if participants did return their boxes, they could have discarded tablets before attending a visit. Because of these limitations, we also used a biologic marker of adherence by testing for the presence of acyclovir in urine samples from a sample of participants. A substantial proportion of participants in the acyclovir group did not have any acyclovir detectable, a finding that implies that it had been more than 12 hours since the participants had taken a dose. We also found evidence that a small number of participants in the placebo group had exchanged tablets with participants in the acyclovir group, and this was most apparent soon after the start of the trial. However, one or two tablets of acyclovir taken by a small number of participants in the placebo group are unlikely to have affected the overall outcome of the trial, given the drug's short duration of action.
Despite the limitations of the trial, it is unlikely that we have failed to detect a moderate or strong effect of acyclovir on HIV acquisition that would be important at the public health level. This trial underlines the challenges in asking asymptomatic individuals to take tablets to treat one virus (HSV-2) to prevent infection with or shedding of another virus (HIV). Improved adherence at a level that might be required to demonstrate an effect of acyclovir might be achieved by more frequent clinic visits, by the use of electronic monitoring devices that can record the time when a bottle of medication is opened,28,29
or by working with a study population with greater access to health care services and therefore a better understanding of the importance of adherence.
The proportion of participants shedding HSV-2 was low in both groups as compared with the proportions shedding in other recent studies in both HIV-negative and HIV-positive women in Africa.11,12,30,31
Recurrences of HSV-2 episodes are most frequent in the first months and years after primary infection.32,33
Many characteristics of our participants were similar to those of a Nairobi cohort in which HSV-2 was shown to be associated with increased numbers of genital mucosal target cells that may increase susceptibility to HIV infection.23
However, it is possible that our participants had acquired HSV-2 early and had reached a stage at which their HSV-2 infection was not active enough to contribute substantially to the risk of HIV acquisition. A recent meta-analysis demonstrated little overall association between HSV-2 and the acquisition of HIV in high-risk women,8
and it is conceivable that other risk factors outweigh the influence of HSV-2 on the risk of HIV acquisition in such groups. Our trial was carried out in a population at moderately high risk for acquiring HIV. Therefore, the results may not be applicable to women in the general population.
The results of this trial indicate that, despite good biologic plausibility, acyclovir at a dose of 400 mg twice daily is not a viable public health intervention for preventing infection with HIV. It is possible that the hypothesis that infection with HSV increases HIV acquisition is false, but this seems unlikely, given the strong biologic and epidemiologic evidence for a synergistic effect between HIV and HSV-2. The potential of HSV suppression in HIV-positive subjects for preventing transmission of HIV will be tested in an ongoing multicenter trial among HIV-serodiscordant couples that is scheduled for completion in 2009. The lack of effect of suppressive therapy on HIV acquisition suggests that renewed attention should be given to new strategies of HSV-2 prevention and control to prevent HIV infection.