Genital herpes quadruples risk of HIV acquisition in high-risk women in Tanzania

Chronic or recent infection with the genital herpes virus (HSV-2) increases the risk of acquiring HIV more than four- and five-fold, respectively, according to research undertaken amongst high-risk women in Tanzania and published online ahead of print in the May 1^st issue of the Journal of Infectious Diseases. Although other sexually transmitted infections – including Chlaymdia trachomatis and bacterial vaginosis – were also associated with an increased risk of HIV infection, the investigators estimate that approximately 63% of HIV incidence in the study was attributable to HSV-2 infection, whether or not it caused symptomatic genital ulcer disease (GUD).

A number of studies have previously found that both chronic and recently-acquired HSV-2 infections are major factors, on both a population and individual basis, for increasing the risk of HIV acquisition. First reported amongst gay men and other men who have sex with men (MSM) in San Francisco in the early 1980s, more recent studies from South Africa and India have suggested that women in developing world settings are also at an increased risk.

Other studies have found similar risks for other sexually transmitted infections (STIs), including a recent report from Kenya on the role of Trichomonas vaginalis and a 2005 report from South Africa on the role of bacterial vaginosis (BV) .

Investigators from the United States and Tanzania had previously conducted a cross-sectional study to determine the behavioural and biological risk factors for HIV and other STIs amongst female bar and hotel workers in Moshi, a busy town nestled below Mount Kilimanjaro in Tanzania. However, accurate estimates of HIV incidence and the role of HSV-2 and other STIs were not obtained; consequently, the investigators conducted a prospective cohort study among female bar and hotel workers between December 2002 and November 2003.

HIV-1 incidence

Of the 1050 women enrolled, 1044 (99.4%) provided baseline blood samples for HIV antibody testing and 199 (19.1%) were found to be already HIV-positive. Of the 845 HIV-negative women at baseline, 156 did not return for any of their follow-up visits; consequently, the final sample for this analysis was 689. The 689 women were monitored every three months for a median of just over one year. During the follow-up period, there were 32 HIV seroconversions – an overall incidence rate of 4.6 per 100 person-years at risk (PYARs): 95% CI, 3.0-6.2/100 PYARs.

In unadjusted univariate analysis several demographic and/or behavioural factors – including no formal education and one previous pregnancy – increased the seroconversion risk. However age, marital status, alcohol use, duration of working in the bar/hotel was not associated with HIV infection. In addition, although, as one would expect, the risk of HIV acquisition was associated with a greater number of sexual partners at baseline and during follow-up, none of the above factors were found to be significant in multivariate analyses.

The role of STIs

The baseline prevalence of STIs amongst this group of high-risk women was very high. Over half of the women (51.2%) were HSV-2 infected; 28% had bacterial vaginosis (BV); 20% were diagnosed with candidiasis (“thrush”); 7.5% had trichomoniasis; 5.1% were infected with chlamydia; and 1% had active syphilis. Whilst BV prevalence remained steady during the follow-up period, rates of candidiasis and active syphilis increased, and those for trichomoniasis and chlamydia decreased.

In univariate analysis, a higher risk of HIV infection was seen among women with non-ulcerative BV and chlamydia at baseline, and amongst women with genital ulcer disease (GUD: notably the ulcerative STIs, HSV-2 and syphilis) during follow-up.

After adjusting for other risk factors in multivariate analysis, the greatest risk was seen in women with recent HSV-2 infection (Adjusted Hazard Ratio [HR] 5.5; 95% CI, 1.2-25.4); followed by women with chlamydia at baseline (HR 5.2; 95% CI, 1.9-14.4); women with HSV-2 at baseline (HR 4.3; 95% CI, 1.5-12.4); women with a history of GUD during follow-up (HR 2.7; 95% CI, 1.7-6.1); and women with BV or severe changes in vaginal flora at baseline (HR 2.1; 95% CI, 1.0-4.3).

The investigators note that “prevalence and incident HSV-2 infections were the strongest risk factors for HIV-1 acquisition. Women with prevalent HSV-2 infections had a 4-fold increased risk of HIV-1 acquisition, whereas the risk associated with incident infections was even higher. We estimate that ~63% of the HIV-1 incidence was attributable to prevalent HSV-2 infections.”

Effective interventions necessary but “proving difficult”

The study authors conclude by saying that that their data “confirms that female bar/hotel workers [in Tanzania] are at increased risk of HIV-1 and underscores the need for effective interventions in this population,” echoing calls earlier this year from French and UK researchers in the New England Journal of Medicine.

Lawrence Corey says that “the answer is simple – effective vaccines are needed for both HIV and HSV-2.” However, he concludes, ”defining the solution is easy; solving the scientific reality of these issues is, however, proving difficult.”

Overwhelming evidence

In an accompanying editorial, Lawrence Corey of the University of Washington, Seattle, argues that this study adds to the growing body of evidence suggesting an interaction between HSV-2 and HIV acquisition.

He points out that recent studies have helped us understand the “underlying biological mechanisms by which HSV-2 is a plausible factor for an increased risk of HIV-1 acquisition”. This includes understanding that “subclinical genital mucosal reactivations occur in ∼90% of HSV-2–seropositive women and 80% of seropositive men, that such reactivations are common (20% of days with daily sampling), and that these ‘shedding episodes’ are associated with microscopic ulcerations and the influx of activated CD4+ T cells to the ulcerative region.”

This study, which, he says, shows an “even higher risk between incident HSV-2 and HIV acquisition...can be explained by the even higher rates of subclinical reactivation (35%–40% of days) in early versus more chronic HSV-2 infection.”

Of great concern, he notes, “is the much higher prevalence of HSV-2” compared with other ulcerative STIs. This “high HSV-2 seroprevalence, coupled with the high frequency of reactivation in the HSV-2–seropositive person, creates frequent mucosal disruption that can influence the acquisition of a sexually transmitted disease (STD) such as HIV infection, even one that has relatively low rates of transmission on a per-sexual-contact basis.”