HIVR4P 2016: Vaginal and Rectal Bacteria May Influence HIV Transmission and Microbicide Efficacy

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A number of presentations at the HIV Research for Prevention Conference (HIVR4P 2016) this week in Chicago looked at the influence of vaginal bacteria on HIV susceptibility, with one study finding that vaginal bacteria may have profound effects on levels of certain drugs used as microbicides -- but not others. A poster at the conference also looked at bacteria in the rectum in gay men, finding a correlation between condomless anal sex and changes in the predominant bacterial species which may similarly increase susceptibility to HIV infection.

[Produced in collaboration with aidsmap.com]

Bacterial Vaginosis: How it Alters HIV Susceptibility and PrEP Efficacy

Bacterial vaginosis is a condition in which acid-loving aerobic (oxygen-using) bacteria such as Lactobacillus are largely replaced by species such as Gardnerella which are anaerobic. For a number of years it has been associated both with higher rates of HIV acquisition and transmission in women. Other studies have suggested that it is not so much that the anaerobic bacteria are inflammatory, but that Lactobacillus is protective.

Irene Xie from the Public Health Agency of Canada reported that there was considerably more bacterial vaginosis among women in surveys from Africa than from North America. In women at low risk of HIV from the U.S. and Canada, Lactobacillus species comprised two-thirds of vaginal flora. In surveys of women from Africa, however, they only comprised about one-third, with about two-thirds being various anaerobic species, specially Gardnerella and Prevotella. These are average proportions; in fact, women tended to fall into 2 distinct categories -- those without bacterial vaginosis and those with -- having quite separate bacterial populations, and no in-between states.

The anaerobic and aerobic bacteria in turn stimulated quite different sets of inflammatory and skin-regeneration genes in the vaginal mucosa (lining), which in turn means that whereas Lactobacillus species actually promote wound healing, lesions heal 25% more slowly when Gardnerella is the main species. This is why bacterial vaginosis is associated with higher HIV infection and transmission rates. Interestingly, some injectable contraceptives disrupt the healing of the mucosa through a similar mechanism.

As also reported at this year’s International AIDS Conference, vaginal bacteria can also have an effect on drug concentrations when they are used in microbicides. However, here it is women who do not have bacterial vaginosis who are in danger of low drug levels. The drugs tenofovir and dapivirine, used in gels and rings, are efficiently absorbed by Lactobacillus crispatus, the most common species, resulting in drug concentrations in vaginal tissues 10 times lower in women when this species predominates.

Although this problem can be overcome by ensuring high enough drug levels in the vagina itself, it could result in loss of efficacy -- and may explain some HIV infections -- in situations where microbicides are used intermittently. The pro-drugs of tenofovir which are taken orally, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF), are not absorbed, so should maybe be considered for use in microbicides too.

Condomless Receptive Anal Sex and Changes in Rectal Bacteria in Gay Men

If the bacterial populations in the vagina form an established though still-growing area of research, research into rectal bacteria and whether differences also change inflammation and susceptibility to HIV via anal sex is almost new territory.

One poster at HIVR4P looked at rectal bacteria in gay men. The study surveyed rectal bacteria from 41 gay men who had condomless anal sex and 21 men in a control group who had never had anal sex at all. In the case of the men who had anal sex, researchers took samples for analysis at 2 time points: one more than 3 days after the last anal sex, and then one within 4 hours of it.

The researchers found that men who had condomless receptive anal intercourse tended to have higher levels of one bacterium, Prevotella, that is also higher in women with bacterial vaginosis. Control men instead had other species such as Bacteroides.

Similarly to the picture in the vagina, Prevotella also up-regulates the activity of inflammatory genes in rectal tissue. The researchers hypothesize that the alkalinity of semen and micro-trauma caused by anal sex may both increase rectal inflammation directly and also cause inflammation via the overgrowth of anaerobic species such as Prevotella. The alkalinity of sperm also tips the environment against Lactobacillus in women.

It is important to emphasize, first, that other factors may also influence the vaginal and rectal flora. For instance, a western diet high in protein tends to be associated with a higher proportion of Bacteroides in the rectum while a diet high in carbohydrates and fiber, more typical of poorer countries, with more Prevotella. Also, the genetic probes used to find bacteria are relatively insensitive and may miss minority species, and the correlation of genetic fingerprinting techniques with the more traditional Nugent score, which counts bacterial species on slides, is poor.

Nonetheless, research into vaginal and rectal flora is a growing area of HIV and sexually transmitted infection prevention work, and one which may guide microbicide development and treatments in the future.

10/21/16

Sources

A Zevin, I Xie, K Birse, et al. Microbiome Composition and Function Drives Wound-healing Impairment in the Female Genital TractHIV Research for Prevention (HIVR4P 2016). Chicago, October 17-21, 2016. Abstract OA04.05.

E Taneva, S Cameron, N Cheshenko, et al. Modulation of Tenofovir (TFV) Pharmacokinetics (PK) and Antiviral Activity by Vaginal Microbiota: Implications for Topical Preexposure ProphylaxisHIV Research for Prevention (HIVR4P 2016). Chicago, October 17-21, 2016. Abstract OA04.02.

IA Zalenskaya, N Chandra, N Yousefieh, et al. Use of Injectable Depot Medroxyprogesterone Acetate (DMPA) Downregulates Vaginal Epithelial Barrier Genes - Similarly to Mucosal InflammationHIV Research for Prevention (HIVR4P) 2016 conference, Chicago, abstract OA04.04, 2016.

C Kelley, T de Man, J Ingersoll, et al. The Relationship of Condomless Receptive Anal Intercourse, Mucosal Injury, and the Rectal Microbiota in Men Who Have Sex with Men. HIV Research for Prevention (HIVR4P) 2016 conference, Chicago, abstract P18.10.