To assess the independent effect of therapy on genital tract viral load and to assess for the effect of potential confounding variables, we conducted a regression analysis. The outcome variable was log transformed to approximate a normal distribution, and the regression model included random effects to account for the effects of repeated measures. Plasma viral load was the most significant predictor of genital tract viral load. However, the only other significant predictor of genital tract viral load in the model was trichomoniasis therapy. It remained significant even after controlling for the potential confounding variables, such as age, contraceptive use, and BV (Table 3). And, although follow-up after therapy was associated with a decrease in genital shedding of HIV, cure of trichomoniasis was not in this regression model.
We found that single-dose directly observed therapy with oral metronidazole for vaginal trichomoniasis at point-of-care decreases genital shedding of HIV-1 among South African women not taking ART. Plasma viral load was not affected by therapy, as anticipated because metronidazole has no known activity against HIV-1. This finding supports the theory that trichomoniasis causes an inflammatory state, predisposing to the increased genital shedding of HIV-1. The trichomoniasis cure rate at 1 month was >80% even in the absence of partner therapy or known reliable condom use. The reason that cure of trichomoniasis was not associated with decrease in HIV shedding is unknown. This may be related to small cell sizes in the regression model but could also indicate that metronidazole decreases genital shedding by some other mechanism than eradication of trichomonads. The anti-inflammatory properties of metronidazole could play a role. The implications for the results of this study are that there is a potential for a screening and treatment program to decrease HIV transmission. It will be important for trials of screening and treatment to not only document change in shedding of virus but also show how that translates into transmission risk.
There have been recent disappointing findings from large trials aimed at decreasing risk of HIV transmission by treating genital herpes after much promise from early studies. Nagot et al reported a randomized controlled trial aimed at reducing both plasma and genital HIV-1 viral load.26 The study showed a promising decrease in both genital and plasma viral load, and thus trials aimed at decreasing HIV acquisition and transmission were undertaken. Unfortunately, the subsequent high-quality randomized trial of HSV suppression therapy by infected partners did not reduce the risk of transmission to uninfected partners.27 Genital herpes and its therapy may not be comparable with trichomoniasis for a number of reasons. Of most concern for therapy, herpes is not something that can be cured. It requires twice-daily therapy in a patient that is likely to be asymptomatic. Trichomoniasis can be treated with a single dose of a medication that is inexpensive. Further, the genital tract viral load decrease that is required to decrease transmission is not clearly known. Female-to-male transmission increases with a hazard ratio of 2.38 (95% CI, 1.13–4.78), with each log10 increase of endocervical HIV-1 viral load.23 It may be that the 0.29 log10 decrease seen with herpes suppression26 reported in the Nagot et al study was not adequate to decrease transmission risk.
Those trials that have included therapy for trichomoniasis have been predominantly syndromic therapy or aimed at multiple sexually transmitted infections.28 Similar to the herpes trials, these may have resulted in inadequate improvement in genital viral shedding. Alternatively, they may have included sexually transmitted infections that do not respond to therapy by diminished shedding.
Our study has several limitations. It was a single-arm treatment trial in which each subject served as her own control without a separate control group. Because of the relatively small sample size, we used genital tract shedding as a surrogate marker for transmission risk. We cannot draw any causal relationship between therapy for vaginal trichomoniasis and risk of HIV transmission. Because of the local social environment, we were not permitted to provide therapy for partners, but only partner letters or measure partner uptake of therapy. Therefore, we had to rely on the subjects to both give the letters to their partners and abstain from intercourse or use condoms until their partner was treated. This may have lead to a number of reinfections.
Strengths of the study include its prospective nature and the use of directly observed therapy in an HIV treatment government clinic, eradicating any concern about compliance with medication that is problematic in many studies. Because there is no medication to take home and because the therapy was taken at the time of the study visit, compliance was 100%. Thus, we can exclude noncompliance as a reason for not seeing a larger decrease in genital shedding. As has been seen in other studies examining HIV-infected women, the prevalence of BV was high at 43%. Another strength of the study was our ability to control for BV, which has been previously shown to increase shedding of HIV.29–33
Point-of-care testing for vaginal trichomoniasis is currently somewhat expensive, but uptake of therapy was good in this general HIV clinic, with a prevalence that was about what was expected even with the use of self-collected samples. Directly observed therapy with metronidazole is both convenient and inexpensive. If future studies are able to demonstrate efficacy in decreasing HIV transmission risk with therapy for trichomoniasis, an approach using point-of-care testing and directly observed therapy should be considered.
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