Hormonal Contraception Does Not Increase HIV Risk

RESEARCH TRIANGLE PARK, N.C., Dec. 11 -- Major hormonal contraception methods appear to have little to no effect on HIV susceptibility for women at moderate risk, according to a study of more than 4,000 African women.

Although the study results, published online in the journal AIDS, were reasonably conclusive on speculations for the general population, they introduced an unexpected and strong association between genital herpes and HIV risk.

Previous studies had been inconclusive and typically had important methodological shortcomings, said the investigators. Also, most studies reporting increased HIV risk involved high-risk populations, such as sex workers or women attending sexually transmitted infection clinics.

So the National Institutes of Health commissioned Charles S. Morrison, Ph.D., of Family Health International here, and colleagues, to look at the risk in a population who more closely resemble the majority of women using hormonal contraception worldwide.

They recruited non-HIV infected women at family planning clinics in Uganda, Zimbabwe, and Thailand. About equal numbers used oral contraceptives containing estrogen and progestin, depot-medroxyprogesterone acetate (DMPA, an injected contraceptive containing progestin only), and no hormonal contraception.

During 15 to 24 months of follow-up, the investigators found no significant elevation in HIV infection risk for oral contraceptives (hazard ratio 0.99, 95% confidence interval 0.69 to 1.42) or DMPA (HR 1.25, 95% CI 0.89 to 1.78) compared with women not using hormonal contraceptives.

Women who were seronegative for herpes simplex virus type 2 (HSV-2) at baseline and using hormonal contraception had significantly higher HIV risk than those on no hormonal contraception. This was true for both oral contraceptive (HR 2.85, 95% CI 1.39 to 5.82) and DMPA (HR 3.97, 95% CI 1.98 to 8.00) users without HSV-2 at baseline.

Though this previously unreported finding for HSV-2 will need further study, the overall study results should be reassuring regarding this "critical public health issue," Dr. Morrison and colleagues said.

"This provides reassurance for women in a setting of moderate and high HIV prevalence who need effective contraception," they wrote, "that any increased overall risk associated with hormonal contraception is, at most, modest."

The study initially included 6,109 sexually active women (2,235 in Uganda, 2,296 in Zimbabwe, and 1,578 in Thailand) ages 18 to 35 who were tested for HIV every 12 weeks for up to two years. However, only four cases of HIV developed in the Thai cohort so it was dropped from the analysis.

Women were offered their choice of contraceptives and counseled on how to use them and reduce their risk of HIV infection. At baseline, 34.7% participants used combined oral contraceptives (low-dose pills containing 30 mg ethinylestradiol and 150 mg levonorgestrel) and 34.2% used DMPA (150 mg administered every 12 weeks). Among the remaining 31.1% who did not use hormonal contraceptives, 84% used condoms, 13% practiced withdrawal, 10% used the 'rhythm' method, 3% were sterilized, and 5% used another method.

Women using hormonal contraceptives were older, more frequently lived with a partner, and were more likely to have had at least two prior pregnancies compared with the non-hormonal contraception group. Women not taking a hormonal contraceptive reported more sexual risk factors but more consistent condom use (63% versus 5%, P<0.001) during the prior three months. There were no important differences in sexually transmitted infection prevalence at baseline between groups.

Among the African participants, HIV infection occurred in 213 for a rate of 2.75 per 100 person-years. The incidence was 2.59 per 100 person-years among women taking oral contraceptives, 3.11 per 100 woman-years for DMPA users, and 2.55 for those not on hormonal contraceptives.

In a multivariate model that controlled for the same full range of factors but including only sexually active participants reporting no condom use, hormonal contraception was still not significantly associated with HIV infection risk. For oral contraceptives, the hazard ratio was 1.47 (95% CI 0.78 to 2.80). For DMPA, it was 1.61 (95% CI 0.85 to 3.06).

There was also no difference in HIV infection risk between the two hormonal methods (covariate adjusted HR 1.26, 95% CI 0.92 to 1.74).

Neither vaginal (trichomonas, bacterial vaginosis, yeast) nor cervical (chlamydia, gonorrhea) infections affected the risk of HIV infection for women on hormonal contraception. However, HSV-2 infection status at baseline did have a significant effect on HIV acquisition (P=0.003). The findings were:

• HIV incidence was higher among HSV-2-positive participants (52%) than HSV-2-negative participants (48%) at enrolment,
• Among HSV-2-positive women, there was no association with elevated HIV risk for oral contraceptives (HR 0.71, 95% CI 0.47 to 1.08, P=0.108) or DMPA (HR 0.82, 95% CI 0.56 to 1.22, P=0.333) after adjusting for covariates,
• Among HSV-2-negative women, HIV risk was significantly higher for both oral contraceptives (HR 2.85, 95% CI 1.39 to 5.82, P=0.004) and DMPA (HR 3.97, 95% CI 1.98 to 8.00, P<0.001) compared with the non-hormonal contraceptive group, and
• Among women who were HSV-2-negative at baseline, there was no difference in the association between hormonal contraception and HIV whether a woman remained HSV negative or seroconverted during follow-up (P=0.335).

The researchers said this finding was largely unexpected, but may help explain inconsistent findings in other studies.

"Although we cannot rule out chance," they wrote, "this finding was strong, occurred with both [combined oral contraceptives] and DMPA use and was robust in all sensitivity analyses."

"Because HSV-2 infection has such an important impact on HIV acquisition risk, the effect of HSV-2 could overshadow any impact of hormonal contraception," they added. "Inconsistent results across studies might be explained by differences in study populations and their exposure to HIV and HSV-2 infections."

They concluded that their findings "should reinforce efforts to counsel all women at risk of HIV infection to use condoms consistently and correctly to prevent HIV acquisition."

Worldwide, more than 120 million women use hormonal contraception.

The study was funded by the National Institute of Child Health and Human Development of the National Institutes of Health through a contract with Family Health International.