Antiretrovirals as Microbicides: Tenofovir (TFV)
Tenofovir (TFV) is a nucleotide reverse transcriptase inhibitor (NRTI) that prevents viral replication in susceptible cells. CONRAD, along with the International Partnership for Microbicides (IPM), has been granted a co-exclusive license by Gilead Sciences to develop, manufacture and, if proven effective, distribute TFV in developing countries.
Efficacy Studies of TFV 1% Gel
CAPRISA 004 - COMPLETED
CONRAD supervised the manufacture of clinical supplies of TFV 1% gel for CAPRISA 004, a Phase IIb clinical trial in South Africa that showed using TFV 1% gel before and after sex in the 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 and no more than two doses in a 24 hour period) reduced a woman’s risk of becoming infected with HIV by 39%. Women who were negative for herpes simplex virus-2 (HSV-2) at the beginning of the trial had a 51% reduced risk of acquiring HSV-2. Because HSV-2 facilitates HIV transmission, preventing HSV-2 infections further reduces a woman’s risk of HIV.
VOICE (MTN-003) - COMPLETED
CONRAD supplied TFV 1% gel for the VOICE trial (MTN-003), which was designed to compare the effectiveness of daily oral TFV, daily oral TFV and emtricitabine (FTC), and daily TFV 1% gel for the prevention of HIV. Results from VOICE showed that none of these methods were effective in preventing HIV. Analysis of drug levels in plasma samples showed that low adherence was behind these disappointing results.
FACTS 001 - COMPLETED
The FACTS 001 study was a double-blinded, randomized, placebo-controlled trial that tested whether tenofovir (TFV) 1% gel inserted vaginally before and after sex could prevent or reduce HIV and HSV (herpes) infections. The study was designed to replicate the CAPRISA 004 study on a larger scale. In both studies, women were asked to insert their assigned gel within 12 hours before sex and again up to 12 hours after sex, with no more than two gel doses in a 24-hour period.
Out of the 2059 enrolled participants, a total of 123 HIV infections occurred (HIV incidence: 4.0/100 women years), with 61 in the TFV arm and 62 in the placebo group. By intent-to-treat analysis, the gel was not proven to be effective and, therefore, FACTS 001 did not confirm the results of CAPRISA 004.
A trend toward TFV gel effectiveness was observed in a subgroup of women who used the product consistently (i.e., in greater than 72% of sex acts based on applicator return); however, this subgroup represented only 20% of the study participants, and an even smaller proportion of HIV infections.In a sub-group analysis consisting of 214 participants in the TFV-treated group, detection of TFV in genital fluids was associated with a 52% reduction in HIV acquisition. In this same sub-group, women who did not use the gel at all (no drug detected in genital samples) were 5 times more likely to become infected. These analyses were adjusted for baseline factors associated with HIV incidence such as being single, living with parents, HSV-2 status, etc. The protective effect of TFV gel seen in the high adherence group confirms previous findings in the CAPRISA 004 and VOICE studies. The magnitude of this effect, depending on study and measure of adherence, varies between 48-74% (Karim, 2011; Marrazzo, 2015; Rees; 2015).
Conclusion: While the gel was effective in women who used it consistently, consistent use in the overall study population was too low to confirm TFV gel effectiveness for the prevention of HIV acquisition in women in this trial.CONRAD Studies of TFV 1% Gel
Pharmacokinetic (PK) Study of TFV 1% Gel - COMPLETED
TFV works by inhibiting viral replication in the vagina, making levels of TFV in the vaginal tissue critical to its efficacy. At the same time, low levels of TFV in the blood are preferable to reduce the risk of developing resistance. This CONRAD safety and PK study of TFV 1% vaginal gel in women showed TFV concentrations to be low in blood plasma and high in genital fluids and tissues up to 24 hours following exposure.
Pharmacokinetic (PK)/Pharmacodynamic (PD) and Safety Study of TFV 1% Gel Used in Three Different Dosing Regimens - COMPLETED
This PK/PD and safety study is assessing the impact of different dosing regimens (modified BAT24 [1 hour before and 1 hour after sex], daily, precoital and postcoital) on TFV levels in the blood and genital tissue. After TFV 1% gel use, anti-HIV and anti-HSV activity will be assessed and the associations between tissue drug concentration and inhibition of HIV and HSV infections will be explored. The effects of TFV 1% gel on vaginal immunity will also be studied.
Influence of Hormonal Contraception and the Menstrual Cycle
on PK/PD and Microbicide Safety Endpoints in TFV 1% Gel Users - ONGOING
Alterations in cervicovaginal immunity (innate immunity, inflammation, epithelial integrity and microbiota) may affect the risk of HIV acquisition. Hormonal contraceptives, particularly long-lasting methods such as Depo-Provera®, are commonly used in the developing world where risk of HIV infection is greatest, but little is known about their effects on these immune markers. This study is enrolling HIV-negative women who wish to start hormonal contraception. The women will choose to use either Depo-Provera® or a combined oral contraceptive for 3 months and will also use TFV 1% gel 1 hour before sexual intercourse and 1 hour after. Samples from these participants will be used to assess the effects of these contraceptive methods and the menstrual cycle on the persistence of TFV within the mucosa and on changes in markers of mucosal safety.
PK Study of the Interaction of TFV 1% Gel and Three Commonly
Used Vaginal Products - PENDING
Commonly used vaginal products include antifungal creams (yeast infection treatment), antibacterial gels (bacterial vaginosis treatment) and the contraceptive ring (NuvaRing®). This study will determine how TFV 1% gel interacts with each of these products, assessing whether local release characteristics and systemic exposure for each product will differ when the products are used simultaneously.
CONRAD Studies of Other TFV Dosage Forms
PK/PD and Safety Study of TFV Intravaginal Ring
CONRAD’s product development team has developed an intravaginal ring (IVR) capable of releasing TFV at levels comparable to those seen with TFV 1% gel use. The first clinical study of this new 90-day ring is currently assessing safety, PK/PD, HIV-1 infectivity, changes in soluble markers, and acceptability in women using either the TFV IVR or a placebo IVR.
PK/PD and Safety Study of TFV and TFV/Emtricitabine (FTC) Vaginal Tablets
Fast-dissolve vaginal tablets with TFV alone and TFV combined with emtricitabine (FTC) are being tested in a clinical trial to assess vaginal and systemic safety, levels of drug in the vaginal tissue and plasma, anti-HIV activity, disintegration time, and acceptability. Women are being randomized to use 1 of 4 tablets: TFV, FTC, TFV/FTC, or placebo once a day for 14 days.