Evidence of genital shedding of HIV during successful antiretroviral therapy in HIV/HSV-2-coinfected women

Antiretroviral therapy significantly reduces genital shedding of HIV in women infected with HIV and the genital herpes virus HSV-2, according to a study conducted in Burkina Faso and published in the online edition of Sexually Transmitted Infections.

The investigators believe that this could reduce the risk of HIV transmission to sexual partners, but note that almost half of women still had genital shedding of HIV even when they had an undetectable plasma viral load, showing the continued importance of safer sex and condom use for people taking antiretroviral therapy.

They speculate that one reason why some women continued to have genital shedding of HIV despite virologically suppressive anti-HIV therapy was herpes simplex virus-2 (HSV-2) coinfection, which has been shown to enhance genital shedding of HIV.

Potent antiretroviral therapy is becoming increasingly available in Africa. Levels of adherence to such therapy and immunological outcomes are just as good in patients Africa as in patients in industrialised countries.

As well as improving the health and prognosis of treated individuals, antiretroviral therapy, by reducing genital shedding of HIV, could be an important tool to reduce transmission of HIV. But there are limited data from Africa regarding this, and the studies that have been conducted have been cross-sectional, or ‘snap-shot,’ studies.

It is not possible to extrapolate findings from industrialised countries regarding genital shedding of HIV during potent antiretroviral therapy to African settings as there are key differences, such as the presence of genital tract infections, genital hygiene practices and prevalent HIV subtypes.

Furthermore, the variability of genital shedding of HIV means that cross-sectional studies may not be able to accurately determine the frequency of genital shedding of the virus. Therefore investigators conducted a longitudinal study (which looks at outcomes over a period of time) to asses the impact of antiretroviral therapy on genital shedding of HIV.

This analysis was a sub-study of a larger investigation into the effect of valaciclovir therapy on genital shedding of HIV in women coinfected with genital HSV-2.

A total of 39 women were recruited to the study, 19 of whom were sex workers, the other 20 being recruited from local HIV service organisations. All the women qualified for antiretroviral therapy under WHO guidelines (a CD4 cell count below 200 cells/mm³ or serious HIV-related illness) and were provided with therapy consisting of AZT (or d4T if there was a risk of anaemia), 3TC and efavirenz.

Blood tests and cervico-vaginal lavage samples were collected at baseline, and then 18 weeks after starting antiretroviral therapy, with further tests every two weeks until week 28.

The women had an average age of 35 years. At baseline, median CD4 cell count was 103 cells/mm³, median plasma viral load 100,000 copies/ml, and 72% of women had detectable HIV in their cerico-vaginal samples.

At the first follow-up visit, 18 weeks after starting therapy, only one woman had detectable plasma viral load (a highly significant change from baseline, p < 0.001), and two women had detectable HIV in their genital samples (once again, a significant change from baseline, p < 0.001). Median CD4 cell count had increased to 215 cells/mm³ (increase from baseline, p < 0.00.1).

At the final study visit, a median of 29 weeks after initiating antiretroviral therapy, five women (13%) had a detectable plasma viral load, and six women (15%) had detectable HIV in their genital secretions. The number of women with HIV present in their genital secretions at this time point was significantly lower than at baseline (p < 0.001), but not significantly different from week 18 (p = 0.79).

Overall, HIV was detected in 13% of cervico-vaginal lavage samples collected during the study. However almost half the women (19/39) had HIV present in such samples at some point during the study.

The investigators then restricted their analysis to the 34 women who had an undetectable plasma viral load throughout the study and found that 16 of these women (47%) had HIV present in their genital secretions at least once, and a per-visit analysis showed that genital HIV was detected in 10% of visits when plasma viral load was undetectable.

“Virological suppression at the systemic level was accompanied by a marked reduction in the frequency of HIV-1 genital shedding, and a near 7-fold decrease in quantity of HIV-1 RNA when genital shedding was measured”, write the investigators. They note that the shedding rate observed in their study was higher than that seen in studies undertaken in industrialised countries, and speculate that one reason could be that all the women in their study were coinfected with HSV-2 “which has been shown to enhance HIV-1 genital shedding. These results may therefore overestimate the genital shedding rates in a general population of HIV-1 infected women.”

The investigators continue, “our findings…suggest that the impact of HAART in the female genital tract is rapid, paralleling immunological recovery and virological decay, and that it can be sustained beyond the initial period of HAART.”

But they note that a significant number of women with undetectable viral load in their plasma had genital shedding of HIV. They speculate that this could be because efavirenz and d4T have poor penetration into the genital tract. Such poor penetration is not only inadequate for HIV suppression but could also allow drug-resistant strains of HIV to emerge which could be passed on to sexual partners or during labour.

The investigators believe that their findings have important implications for HIV transmission. They write, “successful antiretroviral therapy, through its impact on both systemic and genital HIV levels, probably leads to a substantial reduction in HIV transmissibility”. They add that they were unable to say if the quantity of HIV detected in the genital secretions of women taking antiretroviral therapy were infection, but they caution, “the risk of transmission does persist even during effective HAART.”

A separate study in Uganda found a 98% reduction in the risk of HIV transmission in serodiscordant couples when antiretroviral therapy was used. But the investigators note that the use of anti-HIV drugs was accompanied by rigorous HIV prevention efforts including condom provision and the counselling and testing of partners “which may all have contributed to the reduction of HIV transmission independently of HAART.”

They conclude, “our finding of frequent intermittent genital shedding of HIV among women on HAART with well-controlled systemic replication underscores the importance of continued education regarding safer sex messages and the use of condoms for patients taking HAART.”