A small study in Lima, Peru has found that giving the drug valaciclovir to women who are co-infected with HIV and genital herpes (HSV-2) significantly reduced the amount of HIV they had both in their blood and in their genital tract, as well as reducing the frequency and amount of HSV-2 virus shed.
The findings were presented this week at the Fifteenth Conference on Retroviruses and Opportunistic Infections in Boston.
Although this study only involved 20 women, it offers a welcome lifeline to researchers testing the theory that suppressing HSV-2 may reduce HIV transmission and/or acquisition, following the announcement of the failure of a large international trial that gave valaciclovir’s parent drug, aciclovir, to high-risk HIV-negative volunteers, to see if it reduced the rate of HIV acquisition. Valaciclovir is better absorbed and the timing of doses is not as crucial as it is for aciclovir.
The findings confirmed results from a randomised study carried out among HIV-positive women in Burkina Faso, reported in 2006, which demonstrated that valaciclovir reduced HIV levels significantly in the genital tract in women who were not taking antiretroviral therapy - and also in women who were taking antiretroviral therapy.
However the same researchers are still conducting a large trial, Partners in Prevention, which gives aciclovir to the HIV/HSV-2 coinfected partner in heterosexual serodiscordant relationships, to see if HSV-2 prophylaxis can reduce the rate of HIV transmission. Partners in Prevention has enrolled more than 3,400 couples from 14 sites in seven countries in eastern and southern Africa, and researchers expect to announce results in February 2009.
The study in Peru was a double-blinded randomised placebo-controlled crossover study. What this means is that the 20 women were divided into two groups of ten who, for the first eight weeks of the study, received either 500mg of valaciclovir twice-daily or a placebo. Women were then taken off the medication for two weeks, and then they restarted – but with those who had taken valaciclovir taking placebo, and those who had taken placebo now on valaciclovir.
The crossover design is a way of trying to eliminate the effect of differences in trial volunteers, as everyone ends up getting both drug and placebo.
The women were all over 18, with a CD4 count over 200 (median: 372) and ART-naïve, apart from nine who had taken short-course AZT for the prevention of mother-to-child HIV transmission.
During the study the women were taught how to take a daily self-collected anogenital swab for HSV-2; they took a three-time-a-week cervical swab for HIV viral load tests and had weekly blood samples taken for HIV too.
Adherence to the study drug was reported to be virtually perfect. Altogether 2240 anogenital, 933 cervical and 320 blood samples were taken. Six women took open-label valaciclovir for symptomatic herpes during the placebo period: this means that on 2.8% of placebo days, some women were taking valaciclovir.
The valaciclovir reduced the average HIV viral load in both blood and in cervical swabs. The average cervical viral load drop was -0.35 logs and the average blood viral load drop was -0.27 logs, meaning that the amount of HIV in the blood nearly halved and the amount in cervical secretions more than halved. HIV was detected in cervical swabs 71% of the time in placebo recipients and 54% of the time in valaciclovir recipients.
The absolute viral load drops were as follows: from 4.6 to 4.37 logs in blood (from about 40,000 to about 23,000) and from 3.31 to 2.93 logs in the cervix (from about 2,000 to about 850).
The valaciclovir also reduced HSV-2 shedding both in terms of frequency and viral load. Placebo patients shed HSV-2 22.1% of the time but valaciclovir recipients only 3.7% of the time. The average HSV-2 viral load in swabs was 4.8 logs and in valaciclovir recipients 3.94 logs (63,000 and 9,300). Women reported herpes ulcers on 4.6% of placebo days and 2.1% of valaciclovir days.
Herpes and HIV transmission in gay men
Although this study and Partners in Prevention involve heterosexual women and men, another poster at CROI suggested that herpes suppression in HIV/HSV-2 co-infected gay men might be worthwhile too: a study comparing HIV-positive gay men who did and did not transmit HIV in San Diego found that when the source (HIV-positive) partner had HSV-2 and the recipient (HIV-negative) did not, it made HIV transmission 16 times more likely.
David Butler from the University of California in San Diego traced the recent sex partners of a group of men being evaluated for possible acute (i.e. very recent) HIV infection. By performing phylogenetic analysis on blood and semen samples he determined which partners had transmitted HIV to his patients and which had not. Blood and seminal HIV viral loads were also taken and HSV-2 seropositivity of both source partners and infected partners. Source partners’ CD4 counts were also determined and they were tested for syphilis, gonorrhoea and chlamydia.
Butler traced 43 men who were sexual partners of his acutely-infected patients. Phylogenetic analysis showed that 15 of these had transmitted HIV to his patients and 32 had not.
Transmitting partners were similar to non-transmitting ones in terms of age and CD4 count and there was no significant difference in the proportions who were taking ARVs: one of 15 transmitting partners was on ARVs (6.7%) and five out of 31 non-transmitters (16%), but this was not a statistically significant difference.
Transmitters had higher median seminal viral loads than non-transmitting partners (4,300 versus 380 copies/ml) and higher blood viral loads (55,000 versus 12,000 copies/ml), though of interest was the fact that three of the transmitters, when measured at the time of the study, had seminal viral loads of below 110 copies/ml. Interestingly, blood plasma viral load was significantly associated with transmission (odds ratio, 3.84) but seminal viral load was not (OR, 0.99). However it should be pointed out that blood and seminal viral loads were of course not being measured at the actual time of transmission.
Contrary to what has been seen in other studies, fewer of the infecting partners were themselves recently infected (25%) than the non-infecting partners (60%) and this was statistically significant, though the researchers did not speculate as to why.
Infecting partners were more likely to have a bacterial STI at the time of testing (50% versus 7%, p=
If the source had HSV-2 and the recipient did not, however, transmission was 16 times more likely. A third of transmitters had HSV-2 when their recipient did not, but only 3.4% of non-transmitters and their partners were in this situation.
Taken together, after a series of disappointing results, both of these studies suggest that there is still mileage in the idea of HSV-2 prophylaxis in people with HIV to prevent them transmitting HIV.
Baeten J et al. Herpes simplex virus suppressive treatment decreases plasma and genital HIV-1 viral loads in HSV-2/HIV-1 co-infected women: a randomized, placebo-controlled, cross-over trial. Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston. Abstract 676. 2008.
Butler D et al. Correlates of HIV transmission among MSM. Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston. Abstract 701. 2008.