Can norethisterone enantate (NET-EN) reduce the risk of recurrent bacterial vaginosis in women at high risk for HIV infection?

Lead Research Organisation: London Sch of Hygiene and Trop Medicine
Department Name: Epidemiology and Population Health

Abstract

Bacterial vaginosis is a common condition in which the balance of bacteria inside the vagina becomes disrupted. Bacterial vaginosis can cause an abnormal discharge and unpleasant odour, and it is one of the most common reasons women seek reproductive health care, although many women have no symptoms. We do not understand the causes of bacterial vaginosis or how to control it long-term. Importantly, it is a risk factor for premature births, pelvic inflammatory disease, and sexually transmitted infections, including HIV. This is of particular concern among women at high risk for HIV infection where bacterial vaginosis is also highly prevalent. In a study among female sex workers in Kampala, Uganda, we found that 56% of the women had bacterial vaginosis, and after treatment, 72% of these women tested positive again within 3 months. Developing more robust treatment for bacterial vaginosis is important for HIV prevention in key populations at increased risk for HIV infection.
Several types of hormonal contraceptives have been shown to decrease a woman's risk of bacterial vaginosis, including an injectable progestin-only contraceptive called depot medroxyprogesterone acetate (DMPA). However, the use of DMPA to prevent bacterial vaginosis is problematic because there is evidence that DMPA also increases the risk of HIV infection. Thus, there is a paradox: both bacterial vaginosis and DMPA are risk factors for HIV infection, yet DMPA is protective against recurrent bacterial vaginosis. DMPA is the most popular form of hormonal contraceptive in East and Southern Africa. However, there is growing evidence that newer forms of progestin-only injectable contraceptives, such as norethisterone enantate (NET-EN) do not have a harmful effect on HIV risk. Newer contraceptives such as NET-EN may serve a dual purpose of preventing recurrent bacterial vaginosis and increasing options for safe, acceptable and reliable hormonal contraception among women at high risk for HIV. To date, no published studies have investigated the effect of NET-EN on vaginal bacteria. Safe and effective hormonal contraception may augment current or future treatment for women with recurrent bacterial vaginosis, but we need to know more about the effects of non-DMPA hormonal contraception on the vaginal bacteria and reproductive tract.
We work with a cohort of female sex workers in Kampala, Uganda. Approximately one quarter of women in this cohort use DMPA, and no women use NET-EN even though it is available from the clinic. We plan to carry out a study to investigate the effects of NET-EN and DMPA on a wide range of outcomes, including vaginal bacteria, in this cohort. We will invite women who are HIV negative and bacterial vaginosis positive to join our study. All women will be treated for bacterial vaginosis. Consenting women who are not currently using a type of reliable contraceptive will be allocated at random to receive either NET-EN plus condoms or condoms only. Consenting women already using DMPA will also be enrolled. Both groups will be followed 7 months to see the effects on the vaginal bacteria and reproductive tract. We will also interview women who have started NET-EN as a part of this study to find out their opinion about using NET-EN. Outcomes from this study will provide information for future treatment trials for both bacterial vaginosis and HIV prevention.

Technical Summary

Bacterial vaginosis (BV) is highly prevalent among women in Africa and is associated with HIV acquisition. BV has been described as a dysbiosis, or a microbial imbalance, and is treated with metronidazole; however, once treated, it often recurs rapidly. Developing robust treatment strategies to prevent recurrent BV is important for HIV prevention in key populations at high risk for HIV infection.
There is evidence that hormonal contraceptives, including depot medroxyprogesterone acetate (DMPA), decrease BV recurrence; however, there is also evidence that DMPA increases the risk of HIV infection. Encouraging women to start or switch to an alternative progestin injectable such as norethisterone enantate (NET-EN) may mitigate HIV risk whilst decreasing the risk of recurrent BV. To date, there are no published studies that have investigated the effect of NET-EN on vaginal microbiota.
The proposed study will investigate the effect of NET-EN and DMPA on recurrent BV, vaginal microbiota and inflammatory markers among women at high risk for HIV in the Good Health for Women Project in Kampala, Uganda. Consenting and eligible women will be treated for BV, and randomised to either NET-EN plus condoms or condoms only. Women currently using DMPA will be enrolled as an observational comparison group. All participants will be interviewed and examined; samples for vaginal microbiota, sexually transmitted infections, and inflammatory markers will be obtained. Women will be followed up after 1 week, and 1, 3, 5 and 7 months. The primary outcomes will be differences in vaginal microbiota community state types, time to recurrent BV, and inflammatory markers. Qualitative research will be carried out to assess the acceptability of, and adherence to, NET-EN.
Safe and effective hormonal contraception may augment current or future (e.g. probiotic) treatment for women with recurrent BV, and results from our study may inform future clinical trials investigating BV and HIV prevention.

Planned Impact

This project addresses pressing questions related to contraception and HIV risk. There is an urgent need for alternative contraceptive methods for women in Africa where HIV, sexually transmitted infections (STIs) and bacterial vaginosis (BV) are highly prevalent. Increased susceptibility to HIV is likely mediated by mucosal immune responses which have been shown to be induced by BV, depot medroxyprogesterone acetate (DMPA) and STIs. Our anticipated impact is to identify a safe alternative to DMPA that can prevent recurrent BV, increase options for safe, acceptable and reliable hormonal contraception, and reduce HIV incidence. Findings from this study will inform researchers from the public and private sectors to aid in the development of new treatment strategies to reduce BV prevalence, and ultimately, interventions to reduce HIV incidence. Several private/public partnerships are investigating potential new treatments for BV, such as probiotics, biofilm disrupters and high dose antibiotics for BV treatment. For women not wishing to be pregnant, a safe hormonal contraceptive may be a relatively simple addition to treatment that could further increase efficacy. Treatment strategies that robustly reduce the prevalence of BV, could reduce the risk of HIV infection and other STIs. However, it is not possible to move forward with a trial to treat BV for the prevention of HIV until such a treatment is found.
Findings from HCBV will also inform programme and policy makers working on the agenda for safe and effective contraception for women at high risk for HIV prevention. Unintended pregnancies lead to a number of adverse outcomes including maternal and infant deaths. Maternal mortality and unsafe abortion are one of the biggest threats to health in sub-Saharan Africa. Most countries in the region have limited or no access to safe abortion procedures. East Africa has highest estimated abortion rates of 38 per 1000 (https://www.guttmacher.org/pubs/IB_AWW-Africa.pdf). The WHO 2012 Technical Statement on Hormonal Contraception and HIV left many service and programme providers unclear about how to proceed in settings with high DMPA usage and high HIV prevalence. Our findings will provided information on NET-EN for global family planning organizations such as Mary Stopes International and International Planned Parenthood Federation who are on the forefront of providing reproductive services in resource limited settings. We will also feed our findings back to local policy makers in the Ugandan Ministry of Health, and globally through the WHO.
The population most likely to immediately benefit from our research are women at higher risk of HIV exposure living in sub-Saharan Africa. Women in the Good Health for Women Project (GHWP) are self-identified sex workers and/or involved in transactional sex work. Sex workers are a key population which have the highest risk of contracting and transmitting HIV. Women in GHWP are offered contraception at every visit, yet only 35% are on a reliable form on contraceptive; most of whom are on DMPA. The outcomes of this study may provide information on the alternative to DMPA that many increase the contraceptive methods mix, and improve vaginal health, without conferring a risk of HIV infection. Our results will also be of broad relevance to all women in countries with high DMPA usage, prevalent BV and/or high HIV prevalence. Our findings will contribute to an increased knowledge of safe contraceptive choices, and evidence needed to develop strategies for encouraging women to switch to, or start, a non-DMPA hormonal contraceptive.

Publications

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Description Imperial College (NIRG) 
Organisation Imperial College London
Department Department of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution I am the Principal Investigator
Collaborator Contribution Professor Robin Shattock, a Professor of Mucosal Infection and Immunity within the Department of Medicine at Imperial College, London, is an international expert on mucosal immunity in the female genital tract. Professor Shattock's laboratory will provide testing of inflammatory markers using Luminex multiplex testing.
Impact We are collecting data
Start Year 2017
 
Description MRC/UVRI and LSHTM 
Organisation MRC/UVRI Uganda Research Unit on AIDS
Country Uganda 
Sector Public 
PI Contribution I am the Principal Investigator
Collaborator Contribution Professor Janet Seeley, the Head of Social Science at MRC/UVRI Uganda Research Unit on AIDS, will be providing expertise in the conduct of qualitative research. Dr Anatoli Kamali, the Deputy Director of the MRC/UVRI and co-PI of GHWP, will be providing access to this cohort.
Impact We are collecting data
Start Year 2017
 
Description University of Liverpool (NIRG) 
Organisation University of Liverpool
Country United Kingdom 
Sector Academic/University 
PI Contribution I am the Principal Investigator.
Collaborator Contribution Professor Janneke van de Wijgert, a Professor of Infection and Global Health at the University of Liverpool, has developed a 16SrRNA pipeline for vaginal microbiome with assistance from US collaborators. Professor van de Wijgert's laboratory will carry out the 16SrRNA sequencing and train the LSHTM research fellow in the bioinformatics pipeline.
Impact We are collecting data
Start Year 2017