Circumcision trial shows how HIV and herpes amplify each other: circumcision protects against both

New findings from the South African randomised controlled trial (RCT) of circumcision have found that HIV and herpes simplex virus 2 (HSV-2) independently reinforce each others’ effects. People with one infection in the study were more likely to acquire the other infection. The study also found that circumcision protected men in the study against HSV-2 as well as HIV.

However it did not find that HSV-2 infection had any effect, positive or negative, on the anti-HIV protective effect of circumcision: men who were circumcised during the study had the same decrease in the risk of HIV infection regardless of HSV-2 status.

In a separate commentary on this study, Robert C Bailey, principal investigator of the RCT of circumcision in Kisumu, Kenya commented that this was possibly because herpes infection by antibody testing was monitored in this study but not herpes symptoms – outbreaks of lesions.

The new substudy examined 2974 young men (aged 18 to 24 at the time of trial enrolment) out of the 3274 who enrolled in the circumcision trial. It includes 122 men (5.6%) who already had HIV at the time of enrolment and were screened out of the circumcision trial.

This study looked at their HIV and HSV-2 status 21 months after they were randomised into an intervention arm (who were offered circumcision at the start of the study) and a control group (offered circumcision at its end). At this point 4.4% of the men had become HIV positive and 5.9% were HSV-2 positive.

Note that HSV-2 prevalence was in this study was lower than among the general population, largely due to the men’s age. Like HIV, HSV-2 rates rise rapidly during late adolescence and the early 20s when young men are at their most sexually active. HSV-2 prevalence among the general male population in the area was found to be 32% for all ages, rising from 1.8% in under-19s to 14% among men aged 20 to 24. HSV-2 prevalence in women was more than twice this, at 68% for all ages.

Having herpes had a highly significant effect on the chance of acquiring HIV. One point seven per cent of HSV-2 negative men acquired HIV during the study, 6.6% of men who were positive at enrolment, and 14.3% of men who acquired both HIV and HSV-2 during the study. This means that men already infected with HSV-2 were four times more likely to acquire HIV than HSV-2 negative men and men who acquired HSV-2 8.8 times more likely.

Men already infected with HIV were four times more likely to acquire HSV-2 than HSV-2 negative men and men who acquired HIV 7.7 times more likely.

Circumcision protected against HSV-2 as well as HIV, though the effect was not quite so strong. In an ‘intent to treat’ (ITT) analysis the annual incidence of HSV-2 among men randomised to the control arm was 3.54% and among men in the intervention arm 2.33%, meaning that men in the circumcision arm were one-third less likely to acquire HSV-2. This was not statistically significant (p=0.12).

There was however significant ‘crossover’ in the study, meaning that some men allotted to circumcision never got the operation, while some in the control arm decided to get circumcised before the end of the study. In the ‘as treated’ (AT) analysis, which looked not at which study arm men were in but whether they had actually been circumcised or not, the difference was statistically significant (p=0.028). Here HSV-2 annual incidence among men who remained uncircumcised was 3.8% and in circumcised men 2.1%. This was a 45% reduced risk.

Looking at the increased relative risk of HIV infection among HSV-2 study participants allowed the researchers to calculate that the proportion of HIV infections that were attributable to HSV-2 infection was 26%; in other words a perfect anti-HSV-2 prophylactic might be expected to reduce HIV infection by this amount.

Studies in Tanzania and in five other countries giving aciclovir as prophylaxis to HIV-negative women and gay men have not found that the drug had any effect on HIV infections, either due to poor adherence or because aciclovir does not completely suppress HSV-2 shedding. Results from a study giving aciclovir to HIV-positive people to find out if they transmit HIV less frequently are awaited.

In an accompanying commentary Robert C Bailey and Surpriya Mehta of the School of Public Health at the University of Illinois comment that considering the overall prevalence of herpes in this study was lower than in the general population, the finding that a quarter of infections were due to HSV-2 was a ‘remarkable’ finding. This ‘population-attributable fraction’ of HIV infections would be larger in populations that had more HSV-2.

They add that although herpes suppression has not worked in RCTs, the effect of herpes and HIV reductions amongst circumcised men might amplify each other over time, producing a ‘benign circle’ of reduced infection. They urge research into a vaccine against HSV-2.

HSV-2 infection did not appear to exert any effect on the protection circumcision offers against HIV infection. The protective effect of circumcision was 62, 63 and 55% among men who were HSV-negative throughout, HSV-positive throughout, and who acquired HSV-2 during the study in the ITT analysis. In the AT analysis the protective effect was 76, 80 and 72% respectively.

Bailey and Mehta comment that this lack of difference in circumcision efficacy may be due to the researchers only measuring HSV-2 infection by antibody testing, and not looking at asymptomatic herpes attacks by counting lesions. If HIV infectiousness in people with HSV-2 is substantially higher in people with symptomatic herpes, it may be possible to tell if circumcision had ‘added value’ in the case of people with HSV-2.