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MDP Statement on the discontinuation of tenofovir tablets in the VOICE trial

29th September 2011

The Microbicide Trials Network (MTN) and the US National Institutes of Health (NIH) today announced their decision to discontinue the oral tenofovir tablets arm, in VOICE, a major HIV prevention trial being conducted among women in South Africa, Uganda and Zimbabwe.

This decision follows a recommendation by the independent Data and Safety Monitoring Board after their routine review on the 16th September 2011 revealed that there was no possibility of demonstrating benefit from tenofovir tablets. More details are available on the MTN website http://www.mtnstopshiv.org/

The participants that have been allocated Truvada tablets and tenofovir vaginal gel, and both placebo groups, will continue to receive product. Women that were allocated tenofovir tablets will stop product, and exit the study in an orderly manner.

The final results will not be known until early 2013. They will provide important insight into the factors that underlie the effectiveness (or otherwise) of antiretrovirals in reducing HIV.

The MDP investigators are familiar with the challenges of discontinuing one product in an ongoing placebo-controlled trial. We sympathise with the VOICE investigators and wish them all the best for their important work in the remaining months of the trial.

Clinical trials, such as VOICE, are necessary because we need to rigorously evaluate the benefits of new interventions. While this interim result is disappointing, it is highly relevant to our understanding of HIV prevention.

MDP Statement on FEM-PrEP trial closure

18 April 2011

FHI today announced their decision not to complete the FEM-PrEP trial as planned in the protocol, following a scheduled interim review.

The Independent Data Monitoring Committee reviewed the available data which included 56 seroconversions. The committee concluded that the likelihood of showing protection against HIV was so remote, there was little point in continuing the trial until 72 HIV seroconversions had been observed, as planned. Consequently, FHI decided to proceed with an orderly closure of the study.

The study team plan to conduct at least three final follow-up visits for each participant over the next 3 to 4 months. They will complete further analyses to try and understand why there did not appear to be evidence of protection in this study population.

Truvada did not increase nor decrease the risk of HIV acquisition. It is particularly unexpected that oral Truvada did not show protection for women in light of the preceding trials that showed benefit to women with a vaginal application of tenofovir (CAPRISA 004), and to men who have sex with men with oral Truvada (iPrEx).

While the results are disappointing, they are of critical importance to HIV prevention. The very reason for conducting a clinical trial is because we are uncertain of the effect of a new product and this result highlights the importance of conducting multiple clinical trials in different population groups. The past, and ongoing, contributions of the women and communities in Kenya, South Africa and Tanzania that have engaged in FEM-PrEP, and the efforts of the study team, will advance the field and are accordingly of great value.

There are three ongoing trials assessing oral tenofovir based regimens for the prevention of HIV, in diverse populations, and these will provide further evidence in due course to help us understand the appropriate role of oral pre-exposure prophylaxis.

The FHI statement is available at: http://www.fhi.org/en/Research/Projects/FEM-PrEP.htm

iPrEx provides further evidence that the use of antiretrovirals prior to exposure can safely reduce the risk of HIV acquisition


29 November 2010

The MDP partners congratulate the iPrEx team and study participants for successfully completing a Phase III clinical trial designed to determine whether daily Truvada® (tenofovir/emtricitabine combination) can safely prevent HIV infection among men and transgender women who have sex with men (MSM).

The iPrEx study enrolled 2,499 MSM at higher risk of HIV infection in 11 centres in 6 countries. This was the first large scale clinical trial of Pre-Exposure Prophylaxis (PrEP) conducted amongst MSM. Participants allocated to daily Truvada® had 44% fewer infections compared to those allocated to placebo. The protection demonstrated adds to the evidence that anti-retrovirals used prior to exposure reduce the risk of HIV acquisition.

The iPrEx result follows on the success of the vaginal microbicide gel reported by the CAPRISA team in which women who received 1% tenofovir gel (used before and after sex) had a 39% lower risk of HIV infection compared to women receiving placebo gel.

In both trials the investigators collected self-reports of drug use and measured drug levels. Although self-reported adherence was high, drug levels suggest adherence was modest, and this seems to be the most likely explanation for effectiveness being lower than expected. One way to improve adherence, and therefore effectiveness, could be to simplify the regimen and reduce the dosing.

To address this important question for microbicides, MDP partners in Mozambique, South Africa, Tanzania, Uganda and Zambia are seeking funding for a study designed to compare adherence to a single dose of 1% tenofovir used prior to sex to the ‘before and after’ dosing known as BAT24, and to assess the relative effectiveness of each regimen against placebo. This study, which will build on the successful MDP international collaboration, will also implement a visit schedule that is achievable for widespread implementation in resource limited settings.

MDP is delighted that the ANRS plans to start a trial evaluating the intermittent use of PrEp among MSM within 6 months. We also look forward to the results of the VOICE (Vagina and Oral Interventions to Control the Epidemic) trial which is evaluating daily 1% tenofovir vaginal gel against placebo, as well as tenofovir and Truvada® as oral prophylaxis. It will be especially interesting to know the relative effectiveness of vaginal application compared to oral dosing in the same study populations in VOICE. Vaginal application of antiretrovirals has the advantages of higher levels of drug in the genital tissue, and lower levels in the blood, which is assumed to reduce the risk of toxicity and emergent resistance in primary infections, particularly when detecting infection at an early stage remains a challenge.

The need for HIV prevention options for women and men is even more urgent as evidence is growing that services are struggling to deliver treatment. The iPrEx result is a step in the right direction and the MDP is ready to play its role in the future trials required. With a majority of the 1.8 million new HIV infections occurring amongst women in Sub-Saharan Africa in 2009, collecting reliable evidence of the effectiveness of a single dose of tenofovir vaginal gel applied prior to sex is an urgent necessity and a priority for the MDP.
 

CAPRISA provides ground-breaking evidence that the use of an antiretroviral drug (Tenofovir) in the form of a vaginal gel can prevent HIV infections in women

20 July 2010

London, July 20, 2009. The MDP partners congratulate the trial team and study participants on successfully completing the CAPRISA 004 trial of the 1% tenofovir microbicide gel, and are delighted to see proof for the concept of microbicides.

CAPRISA 004 was a phase IIb trial conducted in South Africa involving 889 HIV negative women. The trial assessed the effectiveness and safety of a vaginal gel containing the antiretroviral drug tenofovir, for the prevention of vaginally acquired HIV infection. The trial demonstrated that after 30 months of gel use, women who used 1% tenofovir gel had 39 percent fewer HIV infections compared to women who used the placebo gel during sex acts.

This is a major scientific breakthrough for microbicide research, and for antiretroviral prophylaxis. “Excited – yes! Ready to roll out – not quite” said Dr Sheena McCormack, MDP 301 Chief Investigator. Drug development is a long process and additional evidence from further trials in more diverse populations will be required to confirm the CAPRISA result before tenofovir gel could be made widely available as a HIV prevention option. “Caprisa 004 is a step in the right direction and MDP is ready to get on that path!'” added Dr McCormack.

The MDP looks forward to the results of the VOICE (Vagina and Oral Interventions to Control the Epidemic) trial which is evaluating the same candidate microbicide used every day, and the trials of oral antiretroviral prophylaxis such as iPrEx and FemPrep.

There continues to be an urgent need for additional HIV prevention options for women and men, and this exciting result will provide momentum to the search for safe, effective and acceptable microbicides. The MDP is ready to play its part in the future trials required.

For more information on the CAPRISA study visit www.caprisa.org


HIV ‘prevention’ gel PRO 2000 proven ineffective

14 December 2009

The largest international clinical trial to date into a preventative HIV gel has found no evidence that the vaginal microbicide, PRO 2000, reduces the risk of HIV infection in women, scientists announced today.

This placebo-controlled trial involved 9,385 women at six research centres in four African countries and found that the risk of HIV infection in women who were supplied with PRO 2000 gel was not significantly different than in women supplied with placebo gel. Although ineffective in providing protection, PRO 2000 gel itself was safe to use.

A vaginal microbicide is a product intended for use before sexual intercourse to help reduce HIV infection, as it is clear that condom promotion alone has not controlled the epidemic. The gel was given to participants together with a package of prevention against HIV infection that included free condoms, counselling for safer sex negotiation and sexual health throughout the trial.

The trial, known as MDP 301, took place between September 2005 and September 2009 and was carried out by the Microbicides Development Programme (MDP), a not-for-profit partnership of 16 African and European research institutions. It was funded by the UK Department for International Development (DFID) and the UK Medical Research Council (MRC).

To date, no microbicide has been shown to be effective against HIV infection. This trial shows conclusively that PRO 2000 gel is of no added benefit, ending scientific speculation about its clinical importance.

MDP 301 Chief Investigator, Dr Sheena McCormack of the Medical Research Council said: "This result is disheartening; particularly in light of the results of a smaller trial sponsored by the US National Institutes of Health (NIH) which suggested that PRO 2000 could reduce the risk of HIV infection by 30 per cent. Nevertheless we know this is an important result and it shows clearly the need to undertake trials which are large enough to provide definitive evidence for whether or not a product works."

Professor Jonathan Weber, co-Chair of the MDP Programme Management Board from the Division of Medicine at Imperial College London, said: "This is a disappointing result for the product, as the trial shows that it is not effective. However, the trial itself was very well designed and undertaken, so we know that the results are definitive.

"It is unfortunate that this microbicide is ineffective at preventing HIV infection, but it’s still vital for us as scientists to continue to look for new ways of preventing HIV. There are many research groups exploring different avenues to tackle HIV; it is a slow process, but we are making progress. Now that we know this microbicide is not the answer, we can concentrate on other treatments that might be."


Dr Maureen Chisembele, Principal Investigator of the Zambian site, said: "In Sub-Saharan Africa, nearly 60 per cent of all people living with HIV/AIDS are women. Many are highly vulnerable to HIV despite the fact that they are faithful to their partners. The women will be disappointed by this result as they really liked the gel and hoped it would work."

A South African trial participant commented: "Even though the gel proved not to be effective, we played a role in the fight against HIV. We learnt a lot about caring for ourselves, such as using condoms. We also learnt to encourage others to test for HIV and we gained confidence in helping those who were already infected."

The trial participants are being informed of the trial outcome. The full results will be submitted for presentation at international conferences in 2010, as well as for publication in a peer-reviewed scientific journal.

The gel used in the study was provided by Endo Pharmaceuticals, a specialty pharmaceutical company with headquarters in Chadds Ford, Pennsylvania, USA.

ENDS


Downloadable documents

>  MDP 301 General Q&A (PDF)

>  MDP 301 Results Q&A (PDF)

>  MDP 301 Quick Facts (PDF)

>  MDP 301 Technical Fact Sheet (PDF)

>  Women’s Voice (PDF)


Notes for editors:

For media queries, please contact the MRC press office on 0207 637 6011 or press.office@headoffice.mrc.ac.uk

  1. More information about the MDP 301 microbicides trial can be found at http://www.mdp.mrc.ac.uk/
  2. There were 130 HIV infections out of 3,156 women who were given 0.5% PRO 2000 gel, and 123 HIV infections out of 3,112 given the placebo gel in the main analysis. The rates of HIV infection were very similar in both groups: 4.5 per hundred women years in the 0.5% PRO 2000 group, and 4.3 in the placebo group. Thus 0.5% PRO 2000 gel did not reduce the risk of HIV infection, and this was confirmed in the statistical analysis. The measure ‘per hundred women years’ takes into account the varying periods of time the women participated in the trial as well as the number of women involved and is used to calculate the risk of becoming infected by HIV. This is also known as the incidence rate.
  3. Trial participants were randomly assigned to PRO 2000 gel or a placebo gel group. Women were asked to use the gel before each sex act and were also given condoms and counselled to use them together with gel. Women were followed up for 12 months (or up to 24 months in Uganda) and were evaluated regularly. All were provided with safe sex counselling, treatment for sexually transmitted infections and referral for other non trial-related medical conditions
  4. The trial also included a major social science component which has yielded important new information about sexual behaviour and adherence, as well as factors which encourage or inhibit condom use. The social science research was coordinated by the London School of Hygiene and Tropical Medicine and the Barcelona Centre for International Health Research.
  5. MDP 301 was conducted at the following research centres (principal investigators at each centre are named in parentheses): University Teaching Hospital, Lusaka, Zambia (Dr Maureen Chisembele); Medical Research Council Uganda Virus Research Institute, Entebbe (Dr Anatoli Kamali); African Medical and Research Foundation and National Institute for Medical Research, Mwanza, Tanzania (Prof Richard Hayes); the Africa Centre for Health and Population Studies, KwaZulu-Natal, South Africa (Mitzy Gafos); South African Medical Research Council, Durban, South Africa (Prof Gita Ramjee); and the Reproductive Health and HIV Research Unit, Department of Obstetrics and Gynaecology, University of Witwatersrand, Johannesburg, South Africa (Prof Helen Rees). Contract Laboratory Services of South Africa (Prof Wendy Stevens) served as a central reference laboratory for serology testing and confirmation and provided Good Clinical Laboratory Practice training to nearly 60 laboratory staff at the research centres. Feasibility studies for future trials have been carried out in Mozambique, at the Health Research Centre in Manhiça and at Mavalane Hospital in Maputo (Dr Sibone Mocumbi).
  6. A trial of this scale and complexity could not have been completed without the involvement of many people across Africa, Europe and the US. MDP thanks all the participants, staff and communities whose enthusiasm and commitment made this study possible. They also extend their thanks to their colleagues in the field of microbicides and HIV prevention whose work contributed to this study.
  7. Coordination of the trial was provided by the Clinical Trials Unit of the UK Medical Research Council and Imperial College London. Other European partners involved in MDP 301 included the London School of Hygiene and Tropical Medicine; St. George’s Hospital, London; and the Universities of York, Southampton and Barcelona.
  8. The MDP 301 trial leaves a strong legacy. New laboratories have been equipped and accredited. Research centre staff have gained experience and training in conducting clinical trials to the highest international standards. Many were supported to acquire degrees and diplomas which will advance their careers. Thousands of women have received counselling that will help them practise safer sex and lead healthier lives. The trial has helped many women to discuss HIV prevention with their partners.
  9. The Medical Research Council

    For almost 100 years the Medical Research Council has improved the health of people in the UK and around the world by supporting the highest quality science. The MRC invests in world-class scientists. It has produced 29 Nobel Prize winners and sustains a flourishing environment for internationally recognised research. The MRC focuses on making an impact and provides the financial muscle and scientific expertise behind medical breakthroughs, including the first antibiotic penicillin, the structure of DNA and the lethal link between smoking and cancer. Today MRC funded scientists tackle research into the major health challenges of the 21st century. www.mrc.ac.uk
  10. Imperial College London

    Consistently rated amongst the world's best universities, Imperial College London is a science-based institution with a reputation for excellence in teaching and research that attracts 14,000 students and 6,000 staff of the highest international quality.

    Innovative research at the College explores the interface between science, medicine, engineering and business, delivering practical solutions that improve quality of life and the environment - underpinned by a dynamic enterprise culture.

    Since its foundation in 1907, Imperial's contributions to society have included the discovery of penicillin, the development of holography and the foundations of fibre optics. This commitment to the application of research for the benefit of all continues today, with current focuses including interdisciplinary collaborations to improve health in the UK and globally, tackle climate change and develop clean and sustainable sources of energy. Website: www.imperial.ac.uk

Announcements

>  MDP partners congratulate CAPRISA trial team (PDF)

>  HIV ‘prevention’ gel PRO 2000 proven ineffective (PDF)

>  Microbicides Development Programme announces date of release of the main findings of the MDP 301 Phase III trial of PRO 2000 vaginal microbicide gel (PDF)

>  Microbicides Development Programme update on release of results of the MDP 301 Phase III trial of PRO 2000 microbicide gel (PDF)

>  MDP 301 Completion of follow up web announcement v1.5 (PDF)

>  MDP Announcement 10 February 2009 Statement and FAQs (PDF)

>  MDP Announcement 19 December 2008 Statement (PDF)

>  MDP Announcement 20 August 2008 Statement (PDF)

>  MDP Announcement 11 June 2008 Statement (PDF)

>  MDP Announcement 14th February 2008 Statement (PDF)

>  MDP Announcement 14th February 2008 Q&A (PDF)

 





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