XVIII International AIDS Conference

Safety and effectiveness of 1% Tenofovir Vaginal Microbicide Gel in South African Women: Results of the CAPRISA 004 Trial TUSS05

Type:
Special Session Back
Location: SR 6
Schedule: 13:00 - 14:00, 20.07.2010
Code: TUSS05
Chairs: Tim Farley, Switzerland
Gita Ramjee, South Africa
Webcast provided by The Kaiser Family Foundation

An update of current state of microbicide development will be provided. Speakers will provide a state of microbicide development update, safety and efficacy data from CAPRISA 004 and implications of the CAPRISA 004 trial results for the microbicide and PrEP field.




Presentations in this session:

13:00
TUSS0501
Slides with audio
Introduction
Presented by Gita Ramjee, South Africa
Tim Farley, Switzerland



13:04
TUSS0502
Abstract
Slides with audio
Effectiveness of 1% Tenofovir Vaginal Microbicide Gel in South African Women: Results of the CAPRISA 004 Trial
Presented by Quarraisha Abdool Karim, South Africa

1UNC Chapel Hill, School of Pharmacy, Chapel Hill, United States, 2UNC Center for AIDS Research, Chapel Hill, United States, 3CAPRISA, Durban, South Africa, 4University of KwaZulu-Natal, Durban, South Africa

13:17
TUSS0503
Abstract
Slides with audio
Do systemic and genital tract tenofovir concentrations predict HIV seroconversion in the CAPRISA 004 tenofovir gel trial?
Presented by Angela DM Kashuba, United States
A.D. Kashuba1,2, S.S. Abdool Karim3,4, E. Kraft1,2, N. White1,2, S. Sibeko3,4, L. Werner3,4, L.E. Mansoor3,4, T. Gengiah3,4, S. Sidhoo3,4, Q. Abdool Karim3,4
1Family Health International, Behavioral and Biomedical Research, Durham, United States, 2CAPRISA, University of KwaZulu-Natal, Durban, South Africa, 3Mailman SPH, Columbia University, Epidemiology, New York, United States

13:30
TUSS0504
Abstract
Slides with audio
Safety of 1% tenofovir vaginal microbicide gel in South African women: results of the CAPRISA 004 trial
Presented by Salim Abdool Karim, South Africa
D. Sokal1, Q. Karim2,3, Z. Omar2, A. Grobler2, N. Yende2, S. Sibeko2, J. Frohlich2, L. Mansoor2, S. Abdool Karim2,3
1Family Health International, Behavioral and Biomedical Research, Durham, United States, 2CAPRISA, University of KwaZulu-Natal, Durban, South Africa, 3Mailman SPH, Columbia University, Epidemiology, New York, United States

13:43
TUSS0505
Slides with audio
Contextualising the CAPRISA 004 trial results in the HIV prevention field
Presented by Aaron Motsoaledi, South Africa



13:45

Slides with audio
The Caprisa 004 result in context
Presented by Sheena McCormack



13:56
TUSS0506
Slides with audio
Conclusion
Presented by Tim Farley, Switzerland







Rapporteur reports

Track C report by Anne BUVÉ


CAPRISA 004 was a Phase IIb, double-blind, randomized, placebo-controlled trial to test the effectiveness and safety of 1% tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women at increased risk of HIV. The study involved 889 women (ages 18-40 years) in urban and rural KwaZulu-Natal, South Africa who were randomised to receive tenofovir gel (N=445) or placebo gel (N=444). Each woman was asked to apply the first dose of the assigned study gel within 12 hours before anticipated sexual intercourse, and to insert the second dose as soon as possible after intercourse.  In the intent-to-treat analysis women in the tenofovir gel group had a 39% lower risk of becoming infected with HIV than women who used the placebo gel (P=0.017). Tenofovir gel was 54% effective among women who adhered to the dosing regimen at least 80% of the times, 38% effective among women who adhered to the regimen from 50-80% of the times, and 28% effective among women who adhered to the regimen less than 50% of the times. The effectiveness of the gel declined after the first 18 months in the study as the amount of gel being used by the participants decreased. Tenofovir gel also had a  51% protective effect against the acquisition of herpes simplex virus (HSV-2). Tenofovir gel was found to be safe and no drug resistance was found in women who acquired HIV infection during the study follow-up. As this trial was designed to be a proof of concept for effectiveness of microbicide gel, additional studies will be required to confirm and preferably improve the level of effectiveness observed in this trial. If this protective effect is confirmed, this gel could save millions of lives, especially in sub-Saharan Africa where women are most affected group.



Track A report by Guido POLI


An exciting session was dedicated the latest development in the field of microbicides, entirely dedicated to the results of the CAPRISA 004 trial, based on a gel containing 1% Tenofovir (a nucleotide analog reverse transcriptase and hepatitis B virus polymerase inhibitor; NRTI) that was conducted in South Africa.

The first speaker of the session Dr. Quarraisha Abdool Karim (South Africa) discussed the effectiveness and safety of 1% Tenofovir vaginal microbicide gel for prevention of HIV infection in women. Earlier studies showed evidence that Tenofovir gel can be used as an effective therapeutic agent as it showed very good safety profile, prevents mother to child transmission, it is rapidly absorbed, has a long half life (ca. 2 days) and protects against non-human primates from sexual transmission of SIV. CAPRISA 004 trial assessed the safety and effectiveness of 1% Tenofovir gel. Effectiveness of Tenofovir in preventing HIV infection, impact of adherence and sensitivity analysis revealed statistical significant results. The study recommended to apply the gel not further 12 h before sex and a second time as soon as possible after sex (within 12 h). the study was designed as a double blinded, placebo controlled, randomized trial enrolling women with at least 2 sexual acts in the past 30 days. Two clinical sites, one rural and one urban, were selected. 2,160 women were screened, 1,085 were enrolled (those already HIV-1+ were excluded from the trial), and ultimately 889 were eligible. 445 received Tenofovir, and 444 placebo. Comparability in the selection for age, vaginal sex, anal sex (very infrequent) and coital frequency in the past month: average 8,6 times.

The results were clear-cut: 38 infection occurred in the Tenofovir arm vs. 60 in the placebo arm (Incidence ratio: 0.61, p=0.007). there was a decreased efficacy after 30 months (p=0.017) that was associated with a better adherence in those who remained HIV neg. (>80% adherence: 54% effect).

Although additional infections were seen after study completion, the statistics varied from 0.023 to 0.003. the application of Tenofovir gel did not have any impact on the viremia levels of the women who became HIV+. By mathematical models, it can be calculated that this gel could potentially prevent 1.3 ML infections and 800.000 deaths, or 100,000 women per year for the next 20 years, as discussed at a later session by the mathemathical modelist Brian Williams.

The same lecture further continued by next speaker Salim Abdool Karim (South Africa) highlighted impact of Tenofovir gel on Herpes Simplex Virus 2 (HSV-2) infection. According to UNAIDS report about 20% of sexually active adults have HSV-2 infection which is asymptomatic and no therapies are available against it. The small molecule drug HPMPA from Tenofovir group was tested in CAPRISA trial for its effectiveness in inhibiting  HSV-2 infection and results obtained showed that Tenofovir gel provided 51% protection against HSV II infection. Out of the cohort, 434 were at risk of acquiring HSV-2. 208 received Tenofovir, 226 placebo. A high number completed the study: 202 (T) vs. 224 (P). Again, the results were clear-cut: 29 cases in Tenofovir vs. 58 observed with placebo (IRR: 0.49, p=0.003). He finally summarized their safety findings in that women using Tenofovir gel showed no resistance, no increase in overall side effects, no safety concerns to be taken during pregnancy, no increase in HIV risk behavior while using gel and no liver side effects in people with HIV.

Finally, Angela DM Kashuba (South Africa) focused on the question on whether systemic and genital tract Tenofovir concentration could predict HIV seroconversion in the CAPRISA 004 Tenofovir gel trial? Her team quantified Tenofovir concentration in plasma and cervico-vaginal fluid (CVF) or tissue. Her finding showed that Tenofovir plasma concentrations were less then 1 ng/ml, Tenofovir CVF concentration ranged from 0-1.3 ng/ml or 1 ng/mg tissue, showing excellent correlations one another. She concluded that determination of CVF concentration is a promising marker for adherence. The proportion of women with detectable Tenofovir in plasma was 12 in those who seroconverted vs. 50% in those who did not. Similar findings were observed in the HSV-2 study, Kashuba concluded.

The last speaker of the session Sheena Mc Cormack (U.K.) concluded the session underscoring that CAPRISA adds to the list of “good news” in HIV prevention, including circumcision and the vaccine Thai Trial (RV144) showing even superior protection. In addition, the results are consistent with adherence, in situ concentrations of Tenofovir, proven protection in MTCT, HSV-2, and macaque challenge studies. Questions arise on whether it will be also effective in preventing rectal transmission and what are the right intervals for gel application. By focusing on certain aspects that are important in intervention like ARV as prophylaxis, we cannot ignore challenge of delivering effective treatment in resource limited settings, managing risk of resistance and consultation with communities, ethics and government will be critical to step.




Track B report by Annie LUETKEMEYER


TUSS05 Special session on CAPRISA 004

 

(NB : the CAPRISA 004 publication is available as a free full text publication at www.sciencemag.org )

 

TUSS05 - Safety and effectiveness of 1% Tenofovir Vaginal Microbicide Gel in South African Women: Results of the CAPRISA 004 Trial (Presenter: Querraisha Abdool Karim)

 889 HIV uninfected, sexually active South African women were randomized and eligible to receive 1% tenofovir vaginal gel versus blinded placebo. The gel was to be used within 12 hours of intercourse, followed by a second application within 12 hours.  HIV incidence was nearly halved in women randomized to tenofovir gel, with an incidence rate ratio of 0.61 (95% CI 0.40-0.94, p=0.017) over a 30 month study. Bolstering the evidence of tenofovir’s preventative efficacy was the association of high adherence (>80%) with a 54% reduction of HIV incidence compared to those with low adherence (<50%) who had a 28% HIV incidence reduction. Tenofovir’s preventative effect remained robust in multiple sensitivity analyses.

 

TUSS0504 Impact of tenofovir gel on HSV-2 infection (Presenter: SS Abdool Karim)

The CAPRISA 004 investigators hypothesized that vaginally applied tenofovir may have anti-HSV activity, as tenofovir is related to the anti-herpes virus drug cidofovir and leads  to high intragavaginal drug concentrations which may supercede the MIC of tenofovir for HSV. Of the 889 women enrolled, 434 were HSV-2 negative at study entry and had stored samples evaluated for HSV-2 conversion at study completion.  29 women in the tenofovir arm vs 58 women in the placebo arm converted to HSV antibody positive, for a statistically significant incidence rate ratio of 0.43.  Sensitivity analyses maintained the HSV-2 preventive effect with a 47-52%.  reduction in HSV seroconversion with tenofovir use. Tenofovir gel was not associated with increased adverse events other than mild diarrhea (17 vs 11%) nor  with acquisition of tenofovir resistance in those with HIV seroconversion.

 

TUSS0503 Do systemic and genital tract tenovofir concentrations predict HIV seroconversion? ( Presenter Angela Kashuba)

Kashuba and the CAPRISA 004 investigators quantitated the levels of tenofovir in vaginal and cervical tissues and found a predictable relationship between lower drug levels and HIV seroconversion.  Lower TFV genital tract levels were also correlated with HSV-2 seroconversion. TFV was detectable in the plasma at 4-6 days after gel use in 12% of HIV uninfected and 50% of HIV infected women assigned to active gel; all levels were <1 ng/ml. Tenofovir levels were linearly correlated the active intracellular phosphorylated metabolite TFV-DP.

 

TUSS05 The CAPRISA 004 trial results in context

(Presenter Sheena McCormack)

Tenofovir as a vaginal microbicide has now joined the ranks of the limited number of HIV interventions that have demonstrated efficacy in reducing HIV incidence.  The 004 study demonstrated proof of concept that HIV can be prevented with pre/post exposure prophylaxis and with a vaginal microbicidal agent, which up to now have been ineffective. Dr. McCormack stressed that tenofovir vaginal gel is not ready to roll out globally, both because data are limited to a single study and that the strength of evidence is limited by a confidence interval whose lower bound is 6%, suggesting a possibly limited effect.  Although it will be increasingly difficult to conduct placebo controlled microbicide trials given the promising finding of 004, these results must be confirmed by other studies, and tenofovir gel must be evaluated for optimal dosing, other routes of delivery, including rectal, and long  safety and efficacy.




   

    The organizers reserve the right to amend the programme.


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