Co-Principal Investigators and Study Centers:

University of Washington, Global Health, International Clinical Research Center (ICRC); Kenya Medical Research Institute (KEMRI)/Centre for Clinical Research (CCR)

Nelly Mugo, MBChB, MMed, MPH

KEMRI/Center for Global Health Research (CGHR) Clinical Research Center, Kisumu (CRC)

Victor Mudhune, B Pharm, MPH

Study period (years): Approximately 1 year

• Approximately 12-18 months for study approval, training, and implementation; an additional 6-12 months for report preparation and dissemination of findings.

• Estimated date first study participant enrolled: Q3 2018
• Estimated date last study participant completed: Q2 2019

Rationale for Multipurpose Prevention Technology

The World Health Organization (WHO) estimated that 36.7 million people were living with HIV in 2015. Furthermore, despite the marked expansion of HIV prevention and treatment services over the last 15 years, in 2015, approximately 2.1 million new HIV infections occurred. Africa accounted for approximately two-thirds of the new HIV infections, with the greatest burden borne by women.¹

While gay and bisexual men account for the greatest number of people living with HIV (PLHIV) in the United States (US) and other economically developed settings, an estimated 19% of all new HIV infections in the US occurred among women in 2015, 86% of these attributed to heterosexual sex. Fully 62% of HIV infections among women in the US occurred among African-American women. The statistics emphasize the need for improved HIV prevention for women globally and in the US.

Among the more than 200 million pregnancies worldwide annually, almost half are unintended.² Despite the existence of a variety of effective contraceptives, weak health systems and multiple barriers to utilizing reproductive health services have resulted in an unacceptably high rate of unintended pregnancies. In Kenya, an estimated 43% of the pregnancies are unintended, according to the last national survey in 2012, with about 26% of married women, 30% of women aged 20-29 years and 22% of women aged 30-34 years indicating unmet contraceptive/family planning needs; the unmet need for family planning is highest among adolescents (aged 15-19 years).³ Although contraceptive vaginal rings are not yet available outside of research settings in Kenya, in a recently completed NuvaRing® acceptability and adherence study among women aged 18-34 years in Kisumu, Western Kenya, 91.0% and 9.0%, respectively, of study participants reported that they would recommend or highly recommend the IVR to other women (unpublished data). In the US from 2006-2010, an estimated 37% of pregnancies were determined to be unintended.⁴

Genital herpes is the most common sexually transmitted infection globally, and significantly increases the risk of HIV transmission and acquisition.^5,6 An estimated 417 million people worldwide were living with this chronic infection in 2012.⁵ Sub-Saharan Africa is the most severely affected region of the world with up to 80% of sexually active women infected with herpes simplex virus-2 (HSV-2).^7-10 The longitudinal Mombasa Cohort of high risk Kenyan women analysis showed a population attributable risk of prevalent HSV of around 50% at the time of HIV acquisition.¹¹

A significant number of women in most global regions, particularly resource-constrained settings such as Kenya, could benefit from combined protection against HIV and long-acting, highly effective contraceptive methods to prevent unintended pregnancy, but also concurrent protection against HSV. Market research among women in three sub-Saharan African countries found a preference for multipurpose prevention technology (MPT) that would confer protection against HIV and unintended pregnancies over separate methods for each indication.¹¹

CONRAD MPT IVR Platform

Tenofovir (TFV) is a nucleotide reverse transcriptase inhibitor with activity against HIV and other viruses, such as the herpes simplex virus (HSV).^12,13 Data shows that taking daily tenofovir disoproxil fumarate-containing oral pre-exposure prophylaxis (PrEP) [active ingredient TFV] is an effective HIV prevention tool for women; protection rates among discordant couples were 65-75% and among heterosexual men and women 62%.¹² However, uptake and use of oral PrEP, as well as long-term adherence, have been variable, reducing the efficacy and indicating a need for alternative delivery of TFV.^14,15

Vaginal application of TFV gel is associated with cervicovaginal (CV) TFV concentrations that are up to 1000 times as high as those achieved with oral TFV, reaching levels well above the half-maximal effective concentration (EC50) for HSV-2. TFV gel applied before and after vaginal intercourse reduced HSV-2 acquisition by 51% among women in the CAPRISA 004 Study.¹⁶ The HSV-2 incidence rate among women who had been assigned to TFV gel was 10.2 cases per 100 person-years (95% CI, 6.8 to 14.7), as compared with 21.0 cases per 100 person-years (95% CI, 16.0 to 27.2) among women who had been assigned to placebo gel (incidence rate ratio [IRR], 0.49; 95% CI, 0.30 to 0.77; P=0.003).¹⁶ In an as-treated post hoc analysis based on gel use during the trial, TFV gel was associated with a 71% lower risk of HSV-2 acquisition (IRR, 0.29; 95% CI, 0.10 to 0.70) among women who used more than six gel applicators per month, a 52% lower risk (IRR, 0.48; 95% CI, 0.18 to 1.16) among women who used four to six applicators per month, and a 27% lower risk (IRR, 0.73; 95% CI, 0.34 to 1.55) among women who used fewer than four applicators per month.⁵ The efficacy of vaginal TFV 1% gel in preventing HSV-2 acquisition was also evaluated among women in the VOICE Study, a 5-arm, randomized, double-blind, placebo-controlled trial that studied daily use of oral and vaginal TFV for HIV-1 PrEP.¹⁷ Over follow-up of 513 PY, 92 incident HSV-2 cases occurred by enzyme immunoassay (EIA): 77 in women with no plasma TFV detected and 15 in those with plasma TFV (incidence 20.1 (95% CI 15.9-25.2) vs. 11.5 (6.4-18.9), respectively). Plasma TFV detection was associated with reduced risk of HSV-2 seroconversion (unadjusted IRR 0.57 (0.33-0.99; P=0.046); IRR adjusted for country, age, ≥2 sex partners, hormonal contraceptive use (injections and oral pills), anal sex, and HIV status, 0.55 (0.31-0.97; P=0.04).¹⁷

CONRAD has developed an intravaginal ring (IVR) which releases TFV in a controlled and sustained manner for at least 90 days and has completed pre-clinical product development and initiated clinical testing. The CONRAD IVR was designed to be similar in appearance to NuvaRing®. CONRAD 128, a phase I trial to study the safety, PK, PD, and acceptability of the TFV-alone IVR in women has completed (unpublished data). Conclusions include: no safety concerns, PK benchmarks met, TFV effect showing activity against HIV, ring performance within specifications, and high TFV-diphosphate (TFV-DP) levels supporting potential pharmacological forgiveness.¹⁸ Tissue levels of TFV-DP, the active metabolite of TFV, were similar to or exceeded those obtained with the gel after a BAT24 regimen (one dose of gel within 12 hours before sex and a second dose of gel as soon as possible within 12 hours after sex, with no more than two doses in a 24 hour period) identical to that tested in CAPRISA 004 or a daily regimen tested in VOICE. We, therefore, hypothesize that this TFV releasing ring will prevent both HIV and genital acquisition of HSV in women.

A variant of this ring releasing TFV and LNG a hormonal contraceptive, is also under development and was tested clinically in CONRAD 128, meeting both TFV and LNG benchmarks. Levels of TFV-DP remained high in tissues even after ring removal, providing the basis for a pharmacologically forgiving method. Given the continuous release of high amounts of TFV, the potential impact of bacterial vaginosis (BV) on the levels of TFV in CV fluid and tissue is low. The TFV/LNG ring is a stable product with more than 2 years of stability data.

Innovative female-initiated MPTs could both protect against HIV and HSV infections and allow women to better plan and space their children, reducing potentially negative consequences of unintended pregnancy, including maternal and infant mortality and morbidity. Individual interviews conducted with participants from microbicide studies in Malawi and Zimbabwe indicated strong interest in a vaginal HIV prevention product that could also prevent pregnancy.¹⁹ Reasons cited included convenience, reduction of stigma, problems with adverse effects with current contraceptive methods, concerns about long-term effects of contraceptives, and concerns about the health burdens of HIV infection during pregnancy. A quantitative market research survey of 1,722 women aged 15-35 years in high-HIV burden settings in sub-Saharan indicated near universal acceptance of the hypothetical concept of an MPT, which may prevent pregnancy and HIV.¹¹

This will be a first-in-Africa, randomized, placebo-controlled, FDA investigational new drug-enabling (IND) trial on the safety, pharmacokinetics, pharmacodynamics, tolerability, acceptability of, and adherence to a novel 90-day combination intravaginal ring (TFV/LNG) for HIV/HSV prevention and long-acting contraception, and a 90-day HIV/HSV-2 prevention IVR (TFV only) in preparation for the pivotal prevention trial.