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Posted: 24 Nov 2011
30 years in 30 weeks, 2010

In 2010, a microbicide gel was found to be effective against HIV infection in women when applied intravaginally before and after sex. Within two years, the HIV prevention field saw proofs of concept for two long-sought interventions – a vaccine and a microbicide. Interestingly, the active ingredient in the gel is an antiretroviral drug, which was originally developed to treat HIV infection. Thus, the fields of treatment and prevention have come together around this important breakthrough. Drs. Quarraisha Abdool Karim and Salim Abdool Karim discuss the results of the CAPRISA 004 trial.

Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women.
Science. 2010 Sep 3;329(5996):1168-74. Epub 2010 Jul 19.
Abdool Karim Q, Abdool Karim SS, Frohlich JA, Grobler AC, Baxter C, Mansoor LE, Kharsany AB, Sibeko S, Mlisana KP, Omar Z, Gengiah TN, Maarschalk S, Arulappan N, Mlotshwa M, Morris L, Taylor D; CAPRISA 004 Trial Group.

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Commentary by Drs. Quarraisha Abdool Karim and Salim Abdool Karim

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Drs. Karim
In July 2010 the results of the CAPRISA 004, a phase IIb, double blinded, randomized controlled trial testing the safety and effectiveness of 1% tenofovir gel for the prevention of HIV infection in women in South Africa, were presented at the International AIDS Conference in Vienna and were simultaneously published in the journal Science (1). This trial demonstrated that tenofovir gel, applied before and after sex, reduced HIV acquisition overall by 39%, and by 54% in women who used the gel consistently. The trial demonstrated that tenofovir gel is safe and that it reduces the risk of genital herpes (HSV-2 infection) acquisition by 51%.

After almost two decades of effort in the microbicide field, the CAPRISA 004 trial provided proof-of-concept that a topical antiretroviral can prevent HIV and HSV-2 infections in women. These findings were ranked among the top ten scientific breakthroughs for the year 2010 by the journal - Science.

Mathematical modelling data demonstrate that in South Africa alone over a million new HIV infections could be averted at current efficacy levels over the next 20 years (2). However, it remains a major challenge to transition from proof-of-concept to a licensed and accessible product that realises the true public health benefit of this new HIV prevention strategy. Within weeks of the results being released, WHO and UNAIDS hosted a large international consultation to define priority steps to advance licensure and access (3).

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Gel applicator
An important aspect of the CAPRISA 004 trial was the global precedent set by the award of a royalty-free voluntary license to a resource-constrained government for local manufacture and distribution of product. The South African government, in partnership with a private company, is currently planning to build a factory to manufacture tenofovir gel to ensure low cost access in Africa.

The impetus for this research emanated from epidemiological research undertaken in the 1990s in South Africa (4). The population-based survey demonstrated the age-sex differences in HIV acquisition, notably early acquisition of HIV infection in women compared to men with women acquiring HIV 5-7 years before men and a 3-6 fold greater burden of HIV infection in young women compared to young men – a distinctive characteristic of the HIV epidemic in sub-Saharan Africa.

These findings demonstrated the urgent need for a new HIV prevention technology for women. While recognising that women comprise about 60% of new HIV infections globally, with the majority occurring in southern Africa, the current “ABCC” HIV prevention strategy, comprising Abstinence, Be faithful, Condoms and Circumcision, is of little relevance to young women who are unable to negotiate condom use or mutual faithfulness with their husbands or male partners.

These early research data were the stimulus for our subsequent contributions to the newly emerging field of microbicides. In 1994, we undertook one of the earliest studies on microbicides – investigating the effects of nonoxynol-9 film on the vaginal epithelium and viral shedding in sex workers (5). Subsequent studies of three classes of candidate microbicides (surfactants, polyanions and vaginal defence enhancers) produced disappointing results, but each trial generated important lessons to inform the next trial. These lessons played an important role in informing the design of the CAPRISA 004 trial. We poured over large amounts of data and drew upon our past experience to make careful choices of the agent, the formulation, the dosing strategy and trial population in order to give the trial the best chance of success. However, anything that can go wrong in a clinical trial often does in microbicide trials. Product adherence remains an Achilles heel of microbicide trials and we were concerned about poor adherence leading to a negative result. Not only were we surprised by the positive results at the end of the trial in terms of preventing HIV infection, but we had the added bonus of preventing genital herpes.

The results heralded a new approach to deal with the single biggest challenge in our response to the HIV epidemic in the past three decades - reducing sexual acquisition of HIV in women. Until 2010, only 5 of 37 randomized controlled trials, which tested 39 HIV prevention strategies, demonstrated protection against sexual transmission of HIV infection (6). Tenofovir gel, as the first effective microbicide, gave hope to women that there finally was a tool to enable them to exercise their right to remain HIV uninfected. Given the impetus for women-initiated methods to prevent HIV infection we recognized that the trial was a significant breakthrough, but did not anticipate the full extent of its impact on the HIV prevention landscape.

As we reflect now on the challenges we faced in doing this study, the experience on the whole was both exciting and educational. We experienced two major challenges in conducting this study; vociferous peer-critique and a logistical problem of co-enrolment. While debate and differences of opinion are typical in the scientific community and of scientific endeavours, the intensity with which some of our peers criticised the trial took us by surprise (7). The discovery of participants, who were simultaneously enrolled in another microbicide trial, about a year into the trial was challenging for staff and the participants who were eligibly enrolled in the trial (8). The investigation of reasons for simultaneous enrolment of participants in two trials deepened our appreciation of research participant experiences and put into context the co-enrolled participants in relation to the rest of the trial volunteers and participants.

With this deeper appreciation of what it takes for women to participate in this study, we knew it was urgent to get the results out in the peer-reviewed literature. The paper was written within 10 days after the unblinding meeting – this meant that the key writing and data analysis team burned the midnight oil to ensure we met the deadline for submission. Critically, this meant that everyone, especially the 16 co-authors and the entire statistical team working on the manuscript, had to maintain confidentiality while reviewing and editing the text. Further, we were simultaneously preparing the slides for the Vienna presentation and key documents for the public and the media to explain the study and its outcome. Managing the versions of the various documents and passwords was quite a task.

It was all worth it at the end. The paper was peer-reviewed, edited, finalised and released online by Science as we went up to the podium to present the trial results in Vienna. Some indication of the impact of the trial on the field can be gleaned from the fact that although the CAPRISA 004 trial article was published less than a year ago, it has already been cited in scientific articles over 100 times and has been quoted or mentioned in public media over 10,000 times.

About the Authors:
Quarraisha Abdool Karim, PhD, is an Associate Professor in Clinical Medicine at Columbia University, Adjunct Professor in Public Health at the Nelson R Mandela School of Medicine at University of KwaZulu-Natal and Associate Scientific Director of CAPRISA. She is also the Co-Principal Investigator of the HIV Prevention Trials Network and Director of the Columbia University - Southern African Fogarty AIDS International Training and Research Program.
Salim S. Abdool Karim, MBChB, PhD, is Pro Vice-Chancellor (Research), University of KwaZulu-Natal and Director of CAPRISA - Centre for the AIDS Program of Research in South Africa. He is also Professor of Clinical Epidemiology at Columbia University and Adjunct Professor of Medicine at Cornell University, New York.


References

  1. Abdool Karim Q, Abdool Karim SS, Frohlich JA, Grobler AC, Baxter C, Mansoor LE, Kharsany ABM, Sibeko S, Mlisana KP, Omar Z, Gengiah TN, Maarschalk S, Arulappan N, Mlotshwa M, Morris L, Taylor D, on behalf of the CAPRISA 004 Trial Group. Effectiveness and Safety of Tenofovir Gel, an Antiretroviral Microbicide, for the Prevention of HIV Infection in Women. Science 2010; 329: 1168-1174
  2. Williams BG, Abdool Karim SS, Gouws E, Abdool Karim Q. Epidemiological impact of tenofovir gel on the HIV epidemic in South Africa. JAIDS 2011 10.1097/QAI.0b013e3182253c19
  3. WHO/UNAIDS. Next steps 1% Tenofovir Gel. 2011. Available from: http://www.who.int/reproductivehealth/topics/rtis/WHO_UNAIDS_Next_steps_... [accessed June 2011]
  4. Abdool Karim Q, Abdool Karim SS, Singh B, Short R, Ngxongo S. Seroprevalence of HIV infection in rural South Africa. AIDS 1992, 6: 1535-1539.
  5. Rustomjee R, Abdool Karim Q, Abdool Karim SS, Laga M, Stein Z. Phase I trial of nonoxynol-9 film among sex workers in South Africa. AIDS 1999; 13: 1511-1515.
  6. Padian NS, McCoy SI, Balkus JE, Wasserheit NJ. Weighing the gold in the gold standard: challenges in HIV prevention research. AIDS 2010, 24: 621-635.
  7. Check E. Doomed by design, say critics. Nature 2007;448:110-11.
  8. Abdool Karim Q, Kharsany ABM, Naidoo K, Yende N, Gengiah T, Omar Z, Arulappan N, Mlisana KP, Abdool Karim SS. Co-enrollment in multiple HIV prevention trials — Experiences from the CAPRISA 004 Tenofovir gel trial. Contemporary Clinical Trials 2011, doi:10.1016/j.cct.2011.01.005 [Epub ahead of print]

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