The Centre for the Aids Programme of Research in South Africa (CAPRISA) briefed the Committee on Science and Technology (the Committee) on the progress of the Tenofovir Gel Research trials. A total of seven studies since the CAPRISA 004 study had all systematically shown that across the board, those who used Tenofovir had the benefit of substantial levels of HIV protection.
In the CAPRISA 004 study, Tenofovir gel reduced the risk of HIV acquisition by an estimated 39% when used before and after sex and also reduced herpes simplex virus 2 infection by 51%. While it had been an excellent study, the population group was small and the effectiveness of the gel declined after 12 and 18 months. Also, it was conducted in KZN, which had the highest prevalence of HIV in the country. The Follow-On African Consortium for Tenofovir Studies: FACTS 001 targeted women in nine sites around the country. In addition to hoping to confirm the findings of the CAPRISA 004, which would lead to licensing of the product, the study also aimed to show that Tenofovir gel was effective in younger women and safe to use in women who were pregnant. In May 2013, an independent panel of scientists, the Data Safety Monitoring Board, without divulging the outcome of the study indicated that the study might continue. This meant that there were no current safety issues. A second take of results would be performed in October 2013.
CAPRISA 008 provided post-trial access of Tenofovir gel to HIV uninfected CAPRISA 004 study participants through family planning services. The first participant was enrolled in the trial on November 5, 2012. Since then, 425 participants had been screened and 359 enrolled.
CAPRISA 009 was for follow-up of HIV infected participants from CAPRISA 004 with both control & Tenofovir intervention therapy to be able to compare disease progression and therapeutic outcomes and to monitor drug resistance. The target population was the 119 sero-convertors at the end of CAPRISA 004, the 54 post-CAPRISA 004 sero-convertors and sero-convertors in CAPRISA 008.
The real challenge in all the studies was educating the participants that they had to use the product during the study. Telling a woman in the study that the product may not work and that they may receive the placebo was more challenging than telling her that the product was 50% effective and available at their family planning clinic.
Gilead Sciences had provided free Tenofovir gel to South Africa for the purpose of research. A feasibility study was underway for local production of the drug. All the research had been co-funded by the US and South African governments.
Members asked why Tenofovir was not 100%; if the tablet and gel were meant to achieve the same result; if there were any allergies or side effects of the drug; if there was any benefit to post-HIV infection use of Tenofovir; how long it would take before the gel would be available to the public; and how the volunteers were educated at the onset of the trial to ensure that they would use the product.
Since the Minister of the Department of Science & Technology (DST) had met with the Africa Institute of South Africa (AISA) Board on 10 May 2013, the Board felt assured that the move to the Human Sciences Research Council (HSRC) was in the best interest of the nation. A further meeting between the Minister, the Chair and CEO’s of the HSRC and AISA Boards, the DST Director-General and Deputy Director-General was that it was evident that there were no longer challenges expected ahead. The Incorporation Management Committee, consisting of HSRC, DST and AISA would ensure that the transition was as smooth as possible.
Since the AISA Act was being repealed, retention of the AISA brand would exist outside of this legislation. With the HSRC taking over administration of AISA, cost of administration would be reduced by 50%.
Two clauses were amended and a Member proposed that one clause should be deleted, since it referred to a Medium Term Expenditure Fframework budget that was pending. Members asked how the savings on the administration budget would be allocated after incorporated; how the ring-fenced funds would be spent; and for motivation as to why funds should be approved by the Committee for a period of three years and to a company that would be non-existent after repeal.
DST then briefly presented on the composition and status of the National Research Foundation Board and the candidates nominated to the Board. The member to be appointed would serve for the unexpired portion of the term (until 30 September 2014).
CAPRISA update on Tenofovir Gel Research
Professor Salim Abdool Karim, Director: CAPRISA said that since CAPRISA had last met with the Committee, substantial scientific progress on the use of ARV had been made. Among the ARV formulations tested, Tenofovir had been tested in all three formulations – tablet; in combination with emtricitabine in tablet form called Truvada, and as a gel. It had been tested in all populations and in people with differing sexual preferences, as well as in drug users. A total of seven studies since CAPRISA 004 had all systematically shown that across the board, that those who used Tenofovir had the benefit of substantial levels of HIV protection.
The real challenge was getting people to use the product when they had not volunteered on their own will to do so. This was evident in two studies: the FEM-PreP Study and the Vaginal and Oral Interventions to Control the Epidemic (VOICE) study. The extent to which the product was used could be measured by analysing levels of the drug in the blood or vagina. Several studies had shown that levels of 90.5 to 93% protection were measured in men and women who used the product. In men and women who had used/not-used the product, efficacy of the product was 40 to 60 %. In two large studies with discordant couples, where there was high incentive to use the tablet, protection levels were in the range of 70%.
The US FDA had confirmed that Truvada, taken each day as a tablet, was effective in preventing HIV infection and in prolonging life. In South Africa, Tenofovir gel could not be licensed until two independent studies showed that Tenofovir was effective in targeting the CD 4 receptors. Therefore, the purpose of the FACTS 001 study (Follow-On African Consortium for Tenofovir Studies) for Medicine Control Council and the US Food and Drug Administration approval and licencing. Tenofovir gel targeted CD 4 receptors within 15 minutes of being inserted in the vagina and was active for 3 to 5 days, depending on its half-life, thus preventing the HIV virus from reaching the CD 4 receptors.
FACTS 001 Study
Professor Helen Rees, Protocol Chair: FACTS 001; Executive Director: Wits University Reproductive Health and HIV Institute said that it was exciting that CAPRISA had handed the mantle of expanding this type of research to a broad range of researchers in the country. Dr Glenda Gray and herself were co-chairing the FACTS study.
The CAPRISA 004 trial showed the first vaginal microbicide to be effective in preventing HIV infection. It was overall 39% effective, but in women who used the gel according to instruction, it was 54% effective. In the CAPRISA 004, the gel also reduced the rate of herpes 2 infection. While it had been an excellent study, the population group was small - therefore the estimate for the gel’s effectiveness was very broad, and the effectiveness of the gel declined after between 12 and 18 months. The second point was that CAPRISA was conducted in KZN, which had the highest prevalence of HIV in the country. Thus FACT 001 would target women in nine sites around the country and also show whether it was effective in younger women and safe to use in women who were pregnant.
The regimen for the FACTS 001 confirmatory study was the same as that of CAPRISA 004. Women were instructed to use the gel anytime within the 12-hour period prior to having sex and again within 12 hours after having sex. No more than two doses could be administered within a 24-hour period. In order to licence the product, findings of the first study had to be confirmed as true and real.
The FACTS 001 study also aimed to show that Tenofovir gel reduced herpes. Up to 50% of women in the general community had this virus, which increased the risk of HIV infection. FACTS 001 would also aim to show how effective different levels of the use of the gel and use of condoms was and what happened in terms of HIV infection when the gel was stopped.
For any women who may become infected with HIV during the course of the FACTS 001 trial, the study would examine the impact of using the Tenofovir and the resistance to it, measured against their Tenofovir dose. In CAPRISA 004, there had been no resistance to Tenofovir. FACTS 001 exploratory research would address all factors and outcomes.
The FACTS 001 study had 2900 women enrolled, age between 18-40 years old. Of that, 2600 women were in the 18-30 year old age group, in which rate of HIV infection was highest. Women with and without exposure to the herpes virus would be enrolled.
Each of the study sites would have a comprehensive team of researchers, scientists and clinicians. Prof Lees acknowledged Dr Leila Mansoor (PhD), Senior Scientist: CAPRISA 004 Tenofovir Gel Trial coordinator, and the CAPRISA team for their support of the FACTS team.
The very large VOICE study conducted in African countries to test two ARV tablets and Tenofovir gel had been a disappointment as the figures showed that none of the three products had effect. The problem with the study was that although women reported to have used the product, blood samples taken throughout the study showed that only ¼ women <25 years old were actually using the product and married women were less likely to use the product. The FACTS 001 trial would prioritise education of the participants and motivate why they needed to use the product during the trial. The study reached out to the community, beyond individual women, and offered free consultation, testing, contraception and treatment. Each site had a community advisory board and social worker to interact with the women.
Enrolment was on track and 90% were single women and 80% young women. In May 2013, an independent panel of scientists, the Data Safety Monitoring Board, had looked carefully at the results of the study without divulging the outcome and had indicated that the study may continue. This meant that there were no current safety issues. A second take of results would be performed in October 2013.
Prof Rees acknowledged the DST, which had offered much support for the trial and in particular, Ms Claudina Loots, Director: Health Innovation, DST, who had gone the extra mile in supporting the FACTS 001 trial.
Bridging the gap between research, MCC approval and public access to Tenofovir Gel
Professor Quarraisha Abdool Karim, Principal Investigator of the CAPRISA 004 Proof of Concept Trial (that Tenofovir gel could prevent HIV infection) & Associate Scientific Director: CAPRISA said that after confirmation and licensing, the next step would be manufacture of the product, establish normative guidelines and making Tenofovir accessible to the public.
Ms Gethwana Mahlase, Director & Co-ordinator: Siyayifuna “We want it” Campaign, responsible for bridging the gap between science and community knowledge and fast-tracking the process of getting the gel to women in the rural communities, said that in CAPRISA 004, the main reason why women consented to the study and signed the informed consent was that if found to be effective, the product would be rolled-out to all women in the community. However, after the trial found the gel to be effective, the MCC had not made the gel available because it was not licenced. The women knew their rights and after 14 months, Ms Mahlase met with the MCC to get answers. After no response from the MCC, women took to the streets to put pressure on CAPRISA, the MCC, the premier and Minister of Health. About 27000 women signed a petition to have access to the gel.
Prof Q Abdool Karim said that the key goals of CAPRISA 008 were to provide post-trial accessibility of Tenofovir gel for HIV uninfected CAPRISA 004 study participants and community volunteers (in accordance with the UNAIDS Guidance point 19); to develop and assess an implementation model for Tenofovir gel provision through family planning services with a Quality Improvement Model to enhance and expand on family planning services and Comprehensive Sexual Reproductive Health services; and collect additional safety data on Tenofovir gel. Public Access preparation involved marketing issues, toolkit development for providers and community advocacy efforts.
In CAPRISA 008, nurses at family planning clinics and CAPRISA clinics provided the gel to women. The first participant was enrolled in the trial on November 5, 2012. Since then, 425 participants had been screened and 359 enrolled. 43% of women enrolled were CAPRISA 004 high adherers. Notably, 54 of the 516 women from CAPRISA 004 had become infected prior to initiation of CAPRISA 008. This translated into a 10.5% sero-conversion rate and incidence rate of 3.8/100 women years.
CAPRISA 009 was about treatment outcomes in women with HIV. The CAPRISA 009 trial was for follow-up of HIV infected participants from CAPRISA 004 with control & Tenofovir intervention therapy to compare disease progression and therapeutic outcomes and to monitor drug resistance. The target population was the 119 sero-convertors at the end of CAPRISA 004, the 54 post-CAPRISA 004 sero-convertors and sero-convertors in CAPRISA 008.
Prof S Abdool Karim added that Gilead Sciences' contribution to stemming the HIV epidemic was that it gave South Africa the licence to own the rights for Tenofovir gel, without paying royalties to Gilead. Gilead had also provided free Tenofovir gel to South Africa for the purpose of research. South African technicians had visited the US to learn the technology to ultimately manufacture Tenofovir (ProPreven) locally. A feasibility study was underway. All the research had been co-funded by the US and South African governments.
Prof S Abdool Karim thanked the DST for their vision and foresight, the researchers and the thousands of women who had volunteered to participate in the trials.
Mr P Smith (IFP) asked if the hiccup over US funding and South Africa’s commitment to the CAPRISA 008 trial had been resolved.
Prof S Abdool Karim replied that the issue had been well resolved and the DST and US provided 50/50 funding.
Mr Smith asked if the tablet and gel were meant to achieve the same result and whether there were social issues relating to acceptance of one form over another, which would perhaps make one form more efficacious than the other in mass rollout.
Prof S Abdool Karim replied that in short, although the vaginal gel provided 10 000 times higher level of drug than the tablet could provide in the vaginal compartment, they were equally effective.
Mr Smith asked why Tenofovir was not 100% effective and what efficacy rate would be expected if it had to be rolled out en mass.
Prof S Abdool Karim replied that while researchers were working towards 100% efficacy rate, in those who were compliant there was 39 to 50% efficacy. Laboratory testing on hysterectomy tissue grown in a test tube to mimic a vagina had shown that inflammation in the vagina affected the efficacy of the drug. The paper on the results of the study will be published in the near future.
Mr Smith asked how long it would take before the gel would be available to the public. The MCC had delayed the rollout for two years and even the FACTS 001 study did not appear to have a time line.
Prof Lees said that they were anticipating results of the FACTS study in 2014 and they would then be analysed together with CAPRISA 004 results. The MCC would be requested to fast-track approval for this unique and potentially life-saving product. She predicted that without delays and backlogs, the product would be available in 2017.
Mr Smith said that he believed that the CAPRISA 008 trial was supposed to be a confirmatory study of CAPRISA 004, yet it was now altogether a different study.
Prof S Abdool Karim replied that CAPRISA 008 was always designed for post-trial access, with no placebo involved. CAPRISA’s ethical obligation was that everyone should get the gel and CAPRISA had requested to the MCC that the gel be extended to all districts. However, the gel could only be given to the women who were on the original CAPRISA trial.
Mr Smith asked if Gilead still owned the Intellectual Property while giving South Africa unlimited access to it.
Prof S Abdool Karim replied that the original formulation for Tenofovir was the Intellectual Property of Dr Eric DeClercq, the inventor. Gilead exploited his IP. South Africa had added its own IP, in terms of protection from herpes virus infection, which could be exploited at some point. However, the goal was to get it into the public domain on a non-profit basis.
Ms M Dunjwa (ANC) asked if there were any allergies or side effects of the drug.
Prof S Abdool Karim replied that there were no cases of sensitivity to the drug. However, there were cases of sensitivity to condom use.
Ms Dunjwa asked if in addition to rural areas, tertiary institutions in urban areas had been targeted for female volunteers.
Prof S Abdool Karim replied that although students at tertiary institutions were high-risk individuals, they were not able to be part of the long-term study, which extended past three years. They would, however, be a target for rollout of the drug when it was made available.
Ms J Kloppers-Lourens (DA) asked how the volunteers were educated at the onset of the trial to ensure that they would use the product.
Professor Glenda Gray, Co-Chair: FACTS 001, Director: Perinatal HIV Research Unit at Wits University, Office of the AIDS Research: MRC replied that there was a correlation between perception of risk and product use. In anticipation of issues such as denial, intimate partner violence, desire to take product but lack the freedom to do so freely and unpredictable daily activities, the women were counselled on planning and managing their lives together with the gel, on understand risks and how to take their medication.
Prof Lees added that taking medication for prevention of illness was more difficult than taking medication when one was sick. Telling a woman in the study that the product may not work and that they may receive the placebo was more challenging than telling her that the product was 50% effective and available at their family planning clinic.
Prof S Abdool Karim added that inserting gel for four days in a row meant that 16 ml of gel had to come out of the vagina and this led to challenges and embarrassment. If the women were asked to use the gel around the time of sex, they were much more likely to use it.
Dr Kathryn Mngadi, Project Director: CAPRISA said that at the beginning of the VOICE trial, women using the gel every day complained about wetness and having to wear sanitary pads. Part of the education in the trial was teaching them about risk behaviour and that sex was a risk. It did not make sense to many of them to insert the gel every day when they were not having sex every day, and generally when one could not follow the logic in what they were being asked to do, they were unlikely to follow the instruction.
Prof Lees added that in retrospect, many of those who had not taken the gel optimally had confessed that they did not understand fully that they had to take it and didn’t realise that they were damaging the trial. They believed that attending the clinic, being treated and receiving their money for the trial was adequate participation.
Ms P Mocumi (ANC) asked how use of the product after being infected benefited the women.
Prof S Abdool Karim said that gel itself would not benefit someone if they already had the HIV virus. Those who had been infected during the trials were enrolled into the randomized CAPRISA 009 study, where they received treatment of either Tenofovir-containing anti-retroviral combination or Tenofovir-sparing combination (no Tenofovir) to determine whether there was any problem using Tenofovir in women who had been infected while using the gel. So far, there had been no problem using Tenofovir in these participants, but these were long-term studies.
Committee Deliberations on the Africa Institute of South Africa Act Repeal Bill [B6-2013]
Dr Olive Shisane, Chief Executive Officer: Human Sciences Research Council said that the outcome of the consultation between the Minister of DST, the Chair and CEO’s of the two Boards, the Director-General and DDG of DST was that it was evident that there were no big challenges expected ahead. It had become clear that there was interest by both AISA and the HSRC to proceed with the incorporation. Ms Nombuyiselo Mokoena, Deputy Director-General: Corporate Services; DST was delegated to dedicate time to lead the Incorporation Management Committee (IMC), consisting of HSRC, DST and AISA to ensure that the transition was as smooth as possible.
Once the Bill was passed into law, it would be necessary to ensure that all AISA assets were safeguarded. Since the Act was being repealed, retention of the AISA brand would exist outside of this legislation. Weaknesses and strengths of AISA would be addressed comprehensively. With the HSRC taking over administration of AISA, cost of administration would be reduced by 50%.
Ms Phumelele Nzimande, Chair: HSRC Board said that the Board was very encouraged by the outcome of the meeting between the chair of AISA, acting CEO, herself and Chair of HSRC. Both sides had acknowledged that there would be no feeling of ‘junior/senior’ partner collaboration. The incorporation was seen as an important national project with overarching objectives to ensure that projects of the incorporation had meaningful impact on the people of Africa. Any issues with stakeholders on either side would be resolved internally within the structures available, particularly the IMC, rather than seeking outside advice.
Professor Phindile Lukhele-Olorunju, Interim CEO, AISA said that after Minister Hanekom met with the AISA Board on 10 May 2013, where he fully explained the benefits of the incorporation, the Board of AISA felt assured that the move was in the best interest of the nation. The content of the meeting between AISA, the HSRC and Minister the previous Friday, had been outlined by the previous presenters.
Mr Smith said that it appeared that issues were resolved and all that remained was the technical edits to the Bill.
Ms Mokoena added that ring fencing of AISA funds had been addressed with Treasury and the letter would be shared with the Committee for Members (sentence inaudible).
Mr Thulani Mavuso, Chief Operations Officer: DST said that the proposed amendments had been circulated to the Committee:
Clause 3 (5): the institution would be disestablished; the council would be dissolved (not disestablished); it would hereby be dissolved; with commencement of the Act (not from the date contemplated in section 5).
Clause 3 (6) would be problematic as the institution would be disestablished and therefore its operational activities could not be referred to. It was proposed that (6) be deleted and replaced with a new clause as below.
“Notwithstanding the AISA Repeal Bill section 4, the Institute’s parliamentary budget allocation for a period of three financial years from the date referred to in section 5 would be exclusively reserved for the operational activities which would have been performed by the former Institute”.
Mr Smith said that he still had concerns about the wording. It would be difficult for the Committee to approve money for three years in advance for a company that did not exist. He asked for clarity on how the ring-fenced funds would be spent, and how the savings on the administration budget would be allocated, as it would be half of the previous budget. He suggested that it should be ring-fenced for operational research.
Mr Herman Smuts, Principal State Law Adviser: Office of the Chief State Law Adviser said that the Member was correct in that as clause 6 was currently written, parliament was bound to approving three years of funding. According to the MTEF period, the money had been budgeted for. It did not appear to be unconstitutional, yet it was up to the Committee to adopt it or not.
Mr Smith said that the MTEF was indicative appropriation, but was not annual adjusted appropriation approved by parliament. It was thus still pending. While he understood the logic for doing it, he was not comfortable with the wording.
Mr Smuts affirmed that if the Committee adopted the Bill as it was, the Committee would be bound to the three-year period of funding. The intention was for the money to be available for at least two years for both the HSRC and the institute’s operations, to ensure smooth transition.
Mr Smith suggested that the wording be more specific. Budget allocation referred to the current budget allocation and anything in the future was indicative allocation.
Mr M Nonkonyana (ANC) said that he agreed with Hon Smith - that the Committee could not budget for a non-existent entity and that there should be a presentation on the basis for the clause to be written as such. The Committee needed to understand the motivation for it.
The Chairperson concluded that while parliament accepted the resolutions, reference to the MTEF cycle and appropriation of funds had to be clearly reflected in the Bill.
Mr Smith again asked why the whole administration budget would need to be ring-fenced. He also suggested that the HSRC Act have transitional provision rather than have a budget for a non-existent company.
Dr Shisane replied that savings in administration costs would be used to boost research funds. The transitional measures could be addressed through operations as it all fell under DST and would not be difficult to negotiate. The Minister of DST had to approve the strategic plan of the HSRC and could address transitional measures rather than bring it to parliament, in the form of regulations.
Mr Smith suggested that in that case the clause should be deleted completely.
The DST then presented the short-list of candidates for consideration for appointment to the Board of the National Research Foundation. (See the document attached).
The meeting was adjourned.
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