SOURCE: Ahmed K, et al. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: A randomised, multicentre, open-label trial. Lancet 2019;394:303-313.

All people deserve satisfying and safe sexual lives free from coercion, bias, unwanted pregnancy, and the risks of sexually transmitted infection (STI). In our modern era, human immunodeficiency virus (HIV) represents the STI of greatest consequence if acquired. Therefore, clinicians, scientists, public health officials, and governments have exerted considerable effort to stem the HIV epidemic. Since most heterosexual acts occur in a setting where pregnancy is not desired, the question of whether contraceptive methods modify the risk of HIV transmission has become a major area of interest in the fields of infectious diseases and family planning. In this special feature, I will review the evidence for the effect of hormonal and nonhormonal methods on HIV risk.

What current contraceptive methods offer protection from HIV? Only male and female condoms are FDA-approved for the indication of prevention of STIs including HIV. The term “universal condom” has been advocated to replace female condom, as many couples use female condoms for anal sex. Both the FDA (https://www.fda.gov/patients/hiv-prevention/condoms-and-sexually-transmitted-diseases) and CDC (https://www.cdc.gov/condomeffectiveness/) present information of their web pages that include instructions for the use of both male and female condoms. Although condoms are not 100% effective, strong evidence supports their use for risk reduction.¹ Vaginal diaphragms and cervical caps have not been shown to reduce the risk of HIV transmission.

What are MPTs? The term multipurpose prevention technology (MPT) refers to a class of products with dual activity to prevent both pregnancy and STIs (including HIV). While several approaches are in clinical trials, none have received regulatory approval. The most promising methods in clinical trials use vaginal MPT rings that deliver an antiretroviral (ARV) and a progestin [tenofovir/levonorgestrel (CONRAD: ClinicalTrials.gov Identifier: NCT03762382); dapivirine/levonorgestrel (International Partnership for Microbicides, NCT02855346)].

Vaginal gels that rely on non-hormonal approaches are also in development, but seem less promising due to higher failure rates likely for both pregnancy and HIV prevention. The NICHD Contraceptive Clinical Trials Network evaluated the contraceptive activity of C31G gel, a surfactant comprised of myristamine oxide and cetyl betaine with potent antiretroviral properties in vitro, in a randomized blinded study using a standard 4% nonoxyl-9 (N-9) based gel as a comparator.² Although this study demonstrated non-inferiority of C31G to N-9 (12-month pregnancy probabilities of 20% and 14% respectively), this was not an improvement over the expected high pregnancy rate. Not surprising, a concurrent study evaluating use of C31G for HIV prevention in Africa found no benefit.³ Vaginal gels do not seem an effective answer for either pregnancy or HIV prevention.

Other concepts for MPTs that have not yet moved to clinical trials include oral pills, implants, and IUDs. Of these, the LARC methods hold promise, yet have many challenges. Implants have limited real estate to accommodate loading of sufficient drug to allow effective release levels of both contraceptive hormones and antiretroviral agents. While pairing a copper IUD with an ARV is an attractive idea, the amount of drug delivery space available on an IUD frame to permit multiyear use is even more limited. We recognize that failure rates for oral contraceptives in typical use (~8%) are much higher than in clinical trials (1-2%). However, combined pills actually work fairly well despite poor compliance, as a follicle must both develop and ovulate. How noncompliance would affect HIV risk would depend on the pharmacokinetics of the various ARVs.

Do spermicides increase the risk of HIV or other STI acquisition? Wilkinson and colleagues completed a systematic review of randomized trials that evaluated the effectiveness of vaginally administered nonoxynol-9 (N-9) for the prevention of HIV and other sexually transmitted infections (STIs) in women.⁴ They found no statistically significant reduction in risk of HIV (relative risk [RR], 1.1; 95% confidence interval [CI], 0.88-1.42), gonorrhea (RR, 0.91; CI, 0.67-1.24), chlamydia (RR, 0.88; CI, 0.77-1.01), cervical infection (RR, 1·01; CI, 0.84-1.22), trichomoniasis (RR, 0.84; CI, 0.69-1.02), bacterial vaginosis (RR, 0.88; CI, 0.74-1.04), or candidiasis (RR, 0.97; CI, 0.84-1.12) comparing N-9 to placebo or no treatment groups. While N-9 use resulted in a significantly higher risk of genital lesions (RR, 1.18; CI, 1.02-1.36), the magnitude of this difference is very small. Nonetheless, the significance of genital lesions in increasing HIV acquisition has been documented in other studies, with herpes lesions and the presence of bacterial vaginosis large contributors to risk.^5,6 In 2007, the U.S. FDA issued a statement requiring labeling for all N-9 products warning consumers that they do not protect against HIV or STDs, and that N-9 can irritate the vagina and rectum and may increase the risk of HIV acquisition (https://www.federalregister.gov/d/07-6111/p-3).

In anticipation of future regulatory action that might lead to the withdrawal of N-9 from the market, other spermicides are in development. N-9 is a detergent-based surfactant, so the epithelial damage is not surprising. In contrast, products such as Acidform (Amphora, Evofem, San Diego), an acid-buffering gel that acts by creating an acidic vaginal environment hostile to viruses, bacteria, and to sperm, has been shown to have less vaginal irritation compared to N-9.⁷ A phase III RCT comparing N-9 and Acidform has been completed, but results have not been published (NCT01306331). In a separate RCT, Evofem is evaluating Amphora™ to reduce risk of chlamydia acquisition (NCT03107377). This product has not been evaluated for HIV risk reduction.

Does hormonal contraception increase the risk of HIV acquisition? For several years, the question of whether hormonal contraception increases the risk of HIV acquisition has been a hot topic in the family planning and public health communities. Most of the concern has focused on the use of injectable depot intramuscular medroxyprogesterone acetate (DMPA-IM), one of the most popular modern methods in Africa, a region with a high burden of HIV and unintended pregnancy. Observational studies support an increased risk with DMPA use compared to other hormonal methods including other injectables.⁸ However, a number of methodologic limitations and confounders, principally decreased condom use among women not using hormonal contraception,⁹ limit interpretation of these observational studies.

What is the latest data on DMPA-IM and HIV risk? The overall importance of this topic ultimately pushed leading international investigators and funders to organize the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium to conduct a multicenter randomized, open label trial at freestanding research centers, university-affiliated research centers, and clinical sites providing reproductive health services in Eswatini (Swaziland), Kenya, South Africa, and Zambia. The investigators recruited sexually active, non-pregnant, HIV-seronegative women aged 16 to 35 years (with no medical contraindications to study medications) who desired effective contraception, reported not having used injectable, intrauterine, or implantable contraception for the previous six months, agreed to randomization to a study medication, and to use the assigned method for 18 months. At enrollment, women were randomized to receive either an intramuscular injection of DMPA 150 mg (DMPA-IM group), or placement of a CuT380Ag (copper IUD group) or the levonorgestrel 2 rod implant (LNG implant). Women returned for scheduled follow-up visits at one month (to assess initial contraceptive side-effects) and then every three months for a planned duration of 18 months. At each visit, participants underwent testing for HIV and other STIs, and pregnancy was assessed at the final visit. Enrollment began on Dec. 14, 2015 and follow-up concluded on Oct. 31, 2018.

The primary endpoint was incident HIV infection. To ensure accuracy, they assessed plasma samples from the enrollment visit for detectable HIV RNA, and excluded those with a baseline positive result from the analysis (modified intention-to-treat (ITT) population). Secondary outcomes included pregnancy, serious adverse events, adverse events resulting in method discontinuation, and method continuation. The sample size of 7,800 was selected to provide 80% power to detect a 50% increase in the hazard of HIV for each contraceptive method compared with each of the others (i.e., DMPA-IM vs. copper IUD, DMPA-IM vs. LNG implant, and copper IUD vs. LNG implant). They selected a 50% increase in HIV risk as a meaningful difference that would inform policy change. They assumed an underlying HIV incidence of 3.5/100 woman-years, and a minimum of 250 HIV acquisition events per pairwise comparison. For the primary outcome, they used a significance level of 0.04 (96% confidence intervals).

A total of 7,830 women enrolled, with 2,609 randomly assigned to the DMPA-IM group, 2,607 to the copper IUD group, and 2,613 to the LNG implant group with over 98% in all groups contributing to the primary analysis. More than 94% completed the full 18 months of follow-up, or were terminated early due to HIV acquisition. Most of the participants continued with use of the assigned method (DMPA-IM 93%, copper IUD 89%, LNG implant 94%).

Incident HIV infection occurred in 397 women (overall IR 3.81/100 woman-years met the pre-specified criteria), with no difference in the incidence rate between treatments: DMPA-IM 4.19/100 woman-years (3.54-4.94); Copper IUD 3.94 (3.31-4.66); LNG implant 3.31 (2.74-3.98). In the modified ITT population, the hazard ratios (HRs) for HIV acquisition were 1.04 (96% CI 0·82–1·33) comparing DMPA-IM with copper IUD, 1.23 (0.95-1.59) comparing DMPA-IM with LNG implant, and 1.18 (0.91-1.53) comparing copper IUD with LNG implant. As expected, the incidence of pregnancy was low; 0.61/100 woman-years in the DMPA-IM group, 1.11 in the copper IUD group, and 0.63 in the LNG implant group; the two hormonal methods had significantly lower pregnancy incidence than the copper IUD. Most (71%) of the pregnancies occurred after discontinuation of the randomly assigned method.

Evaluating ECHO and the risks of hormonal contraception. The ECHO study results were highly anticipated and attracted considerable attention when released on June 13, 2019. The study met the specified objective of ruling out a 50% increase risk of HIV acquisition in women using DMPA-IM, and the sample size provided sufficient power to exclude a 30% difference. Overall, these results provide reassuring news for clinicians, funders, governments, and most of all women using DMPA-IM in countries with a high prevalence of HIV.

The study does have important limitations. It did not evaluate the risk of using DMPA-IM to no contraception, to oral methods, or to other injectables. As pre-exposure prophylaxis regimens become more common, the results may have less relevance. Despite these limitations, the results provide good news of absence of an important impact of DMPA-IM on HIV acquisition risk. Research makes a difference in clinical practice, and in women’s lives!

REFERENCES

1. Holmes KK, et al. Effectiveness of condoms in preventing sexually transmitted infections. Bull World Health Organ 2004;82:454-461.
2. Burke AE, et al. Contraceptive efficacy, acceptability, and safety of C31G and nonoxynol-9 spermicidal gels: a randomized controlled trial. Obstet Gynecol 2010;116:1265-1273.
3. Feldblum PJ, et al. SAVVY vaginal gel (C31G) for prevention of HIV infection: A randomized controlled trial in Nigeria. PloS One 2008;3:e1474-e.
4. Wilkinson D, et al. Nonoxynol-9 spermicide for prevention of vaginally acquired HIV and other sexually transmitted infections: Systematic review and meta-analysis of randomised controlled trials including more than 5000 women. Lancet Infect Dis 2002;2:613-617.
5. Wall KM, et al. Risk of heterosexual HIV transmission attributable to sexually transmitted infections and non-specific genital inflammation in Zambian discordant couples, 1994-2012. Int J Epidemiol 2017;46:1593-1606.
6. Masese L, et al. Changes in the contribution of genital tract infections to HIV acquisition among Kenyan high-risk women from 1993 to 2012. AIDS 2015;29:1077-1085.
7. Bayer LL, Jensen JT. ACIDFORM: A review of the evidence. Contraception 2014;90:11-18.
8. Polis CB, et al. An updated systematic review of epidemiological evidence on hormonal contraceptive methods and HIV acquisition in women. AIDS 2016;30:2665-2683.
9. Heffron R, et al. Objective measurement of inaccurate condom use reporting among women using depot medroxyprogesterone acetate for contraception. AIDS Behav 2017;21:2173-2179.