At the 15th Conference on
Retroviruses and Opportunistic Infections last week in Boston, conference
vice-chair John Mellors, MD, of the University of Pittsburgh called this "the
single most important finding in HIV prevention in the last decade, and arguably
in the entire epidemic."
Researchers with the Makerere University/Johns
Hopkins collaboration presented further good news about the beneficial effects
of circumcision for men, but some worrisome results for their female partners.
Genital
Infections in Men and Women
As
previously reported, nearly 5000 men in Rakai, Uganda, who expressed an interest
in circumcision were randomly assigned to undergo the procedure immediately or
after a 2-year delay.
In
the first analysis (abstract 28LB), investigators assessed whether circumcision
would help prevent infection with herpes simplex type 2 (HSV-2, the usual cause
of genital herpes) in men and vaginal infections in women. This analysis focused
on about 1400 men each in the immediate circumcision and the delayed control arm
who did not have HSV-2 at study entry. The men were followed for 24 months to
determine the rate of HSV-2 acquisition.
In addition, about 800 wives of
men in each group were followed for 12 months to assess the incidence of genitourinary
disease (GUD), bacterial vaginosis (BV), and trichomonas.
Results
•
Among the men, about 7% in the immediate circumcision
arm became infected with HSV-2, compared with 10% in the delayed control arm -
a reduction of 25%.
•
The relative risk of HSV-2 infection was lower
in the circumcision arm in all socio-demographic and behavioral subgroups.
•
PCR testing for HSV-1, HSV-2, Treponema pallidum
(which causes syphilis), and Haemophilus ducreyi (which causes chancroid) identified
a causal pathogen in more than one-third of genital ulcers, 90% of which was HSV-2.
•
Among the 62 men who acquired HIV during the
trial, about 60% had either prior HSV-2 infection or simultaneous HIV and HSV-2
seroconversion.
•
Among women, the rate of genital infections
was lower in the wives of men in the immediate circumcision arm compared with
the control arm:
•
Symptomatic GUD: 25% reduction;
•
Trichomonas: 50% reduction;
•
Bacterial vaginosis: 20% reduction;
•
Severe BV: 60% reduction.
•
Among women with normal vaginal flora at enrollment,
progression to BV was 20% less likely, and among women with BV at enrollment persistence
was reduced by a similar amount, in wives of men in the immediate circumcision
arm.
•
However, there were no differences in reported
symptoms of vaginal discharge or dysuria (difficult or painful urination) in the
2 study arms.
"Male
circumcision prevents HSV-2 acquisition in men and reduces rates of GUD, trichomonas,
and BV in their female partners," the researchers concluded. "These
effects of circumcision may influence the protective effect of circumcision on
HIV acquisition."
Raised
HIV Risk in Women?
Another
analysis suggested that men who are HIV positive at the time of circumcision may
be more likely to transmit HIV to their female partners if they resume sex before
the wound is fully healed.
In this study (abstract 33LB), researchers looked
at 1015 HIV positive men with a CD4 count above 350 cells/mm3 randomized to the
immediate circumcision or delayed control groups. The 770 married men were asked
to invite their spouses to participate; 566 did so, of whom 245 (43%) were HIV
negative. Men were seen post-operatively and at 1, 6, 12, and 24 months; women
were seen at 6, 12, and 24 months.
Results
•
In an intent-to-treat analysis that included
161 serodiscordant couples, the women's 24-month cumulative HIV incidence was
about 14 per 100 person-years in the immediate circumcision arm versus about 9
per 100 person-years in the control arm.
•
This difference did not reach statistical
significance (P = 0.42).
•
Women's incidence was highest in both arms
in the 0-6 month follow-up interval (27 vs 18 per 100 person-years), declining
during the following 6-24 months (6% vs 4% per 100 person-years).
•
In the immediate circumcision arm, the excess
cases of HIV transmission in months 0-6 occurred among couples who resumed sexual
intercourse more than 5 days prior to certified wound healing (29%) compared with
couples who waited longer (10%).
•
Rates of bacterial vaginosis, vaginal discharge,
dysuria, and genitourinary disease were comparable among wives in both study arms
during follow-up.
•
Circumcision reduced the rate of GUD in circumcised
compared with uncircumcised HIV positive men (about 10% vs about 16%).
•
The rate of circumcision-related moderate
adverse events in HIV positive men was equivalent to that of HIV negative men
in a parallel trial (about 3% in both).
•
There were no circumcision-related serious
adverse events seen in the in HIV positive men.
•
About 70% of HIV positive men had complete
wound healing by 30 days post-circumcision, compared with about 80% of HIV negative
men.
Male
circumcision was safe and reduced GUD in HIV positive men," the researchers
concluded. However, they added, "There were no direct HIV benefits to women
but, potentially, an increased risk of transmission with early resumption of sex."
Though
full healing after circumcision usually occurs by 1 month, co-investigator Maria
Wawer said men ideally should wait 6-8 weeks to be on the safe side, especially
given the evidence that healing may be slower in HIV positive men.
Much
remains to be learned about circumcision and HIV prevention. For example, it is
unclear why rates of genital infections decreased in wives of circumcised men
in the first of mostly HIV negative men but not the second study of HIV positive
men.
Women's risk of acquiring HIV would be reduced if female partners
of circumcised men have less genital ulcer disease, and if the overall proportion
of HIV positive men in a population goes down. But it remains to be seen how these
benefits would weigh against the potential higher risk of transmission due to
early sex after circumcision of HIV positive men.
For men, it is not yet
determined whether the reduced risk of acquiring HIV after circumcision is a direct
effect of removing susceptible foreskin tissue or an indirect effect of reducing
genital ulcer diseases such as herpes, which are known to facilitate HIV infection.
A
Tobian, D Serwadda, T Quinn, and others. Trial of Male Circumcision: Prevention
of HSV-2 in Men and Vaginal Infections in Female Partners, Rakai, Uganda. 15th
Conference on Retroviruses and Opportunistic Infections. Boston, MA. February
3-6, 2008. Abstract 28LB.
M Wawer, G Kigozi, D Serwadda, and others. Trial
of Male Circumcision in HIV+ Men, Rakai, Uganda: Effects in HIV+ Men and in Women
Partners. 15th Conference on Retroviruses and Opportunistic Infections. Boston,
MA. February 3-6, 2008. Abstract 33LB.
Circumcision
Lowers Risk of Genital Herpes in Men, but Has Mixed Effects for Female Partners
In
the first analysis (abstract 28LB), investigators assessed whether circumcision
would help prevent infection with herpes simplex type 2 (HSV-2, the usual cause
of genital herpes) in men and vaginal infections in women. This analysis focused
on about 1400 men each in the immediate circumcision and the delayed control arm
who did not have HSV-2 at study entry. The men were followed for 24 months to
determine the rate of HSV-2 acquisition.
Results
