Interpreting the results of HIV prevention trials (3) – So far so…

In the lats two years, the world had received the results of a
number of HIV prevention trials. Specifically, the following trials
have produced no evidence of effect, or a trend towards harm:

• CONRAD phase III study of cellulose sulphate (UsherCell)
microbicide halted after interim analysis showed higher rate of HIV
infection in UsherCell group (the Family Health International study
of cellulose sulphate, a trial also conducted in Nigeria – was also
halted not because there was harm but due to the fact that the
CONRAD study was stopped).

• MIRA female diaphragm and lubricant study completed, but no
evidence of protective effect.

•HSV-2 suppression therapy which were completed but no evidence of protective effect.

•Population Council phase III study of Carraguard microbicide
completed, but no evidence of protective effect.

•The 0.5% concentration PRO 2000 arm abandoned in the MDP
(Microbicides Development Program) phase III study due to futility

•STEP proof of concept study of Merck’s Ad5 HIV vaccine halted after
interim analysis showed lack of protective effect. There was a
tendency towards more harm

Although these studies have not provided a prevention technology for further development, they have demonstrated the ability of multiple sponsors to run large trials of prevention technologies, and
generated important information that will contribute to the design
of future studies.

The only positive results in the past two years from HIV prevention
phase III trials have come from adult male circumcision studies
which shows that circumcision reduces the rate of HIV infection IF
and WHEN the study site heals at least 6 weeks before commensing
sex. The need and importance of healing was evident from the results of a negative signal observed a study of male circumcision in HIV- positive men which showed a trend towards a higher rate of HIV
infection in sexual partners of circumcised men when compared to
partners of men who were not circumcised.

Has the field failed so far?
In the field of drug development, there are evidence to show that
when 10,000 potential drugs are found to possibly work in the
laboratory, it takes an average of 6.5years for ONLY 250 of these
compounds to show that it can actually do something in animals. Of
the 250 compunds, only 5 makes it through to phase III over a 7 year period. And of the five, only 1 makes it for drug approval after a 1.5year period. On the whole, it takes about 15 years to develop a
product even WHEN all the needed information is available.

The HIV prevention field has so far not deviated from the norm of
drug development even moreso in the light of the many unknown that plaques the research field. All trials have informed the planning
and implementation of the next trial in such a way as to improve the
care and protection of trial participants. The field is also more
responsive to community concern.

Has the field failed so far? The moderator lookd forward to your
sharing your views and perception on this. Happy discussion.

Could vaginal microbicides protect men more so than women?

In the July 15, 2008 issue of the Proceedings of the National Academy of Sciences (http://www.pnas.org), Dr. Sally Blower and her colleagues report that mathematical models of real-world use of ARV-based vaginal microbicides predict that men may actually derive greater long-term protection against HIV infection than women. There are a lot of assumptions and unknowns in these models, including questions of microbicide efficacy and adherence, condom use, and drug resistance. But even if ARV-based microbicides turn out to be only partially effective, these models predict that large numbers of at-risk men and women will be protected if these products are widely available and used.

One question that remains unanswered, however, is whether the widespread use of an ARV-based microbicide could select for drug resistant strains of HIV. The women enrolled in current or planned trials of ARV-based candidate microbicides likely are at low risk of developing drug resistance. Trial participants will be screened monthly for HIV infection, and will stop using a candidate microbicide immediately if they become infected. These women will be tested frequently to see if they develop drug-resistant virus, and arrangements will be made to ensure they have access to effective drugs. However, as the Blower model suggests, even if an ARV-based candidate microbicide does not seem to select for drug resistant virus during phase II and phase III safety and effectiveness trials, drug resistance could be a long-term problem once the product is widely available and used by women who undergo much more infrequent HIVcounselling and testing. Thus, it will be important to couple the widespread introduction of ARV-based microbicides with increased counselling, education, HIV testing, and drug resistance monitoring for at-risk individuals.

To learn more about ARV-based microbicides and HIV drug resistance, see the GCM fact sheets entitled “ARV-based Microbicides: The Promise and The Puzzle” and “Understanding HIV Drug Resistance.” These and other basic GCM fact sheets and materials are available for free download at http://www.global-campaign.org/download.htm.

HSV-2 treatment does not reduce the risk of HIV infection

As we first reported in the April 18, 2008 issue of GC News, although number of studies have shown that herpes simplex virus type 2 (HSV-2) infection is associated with an increased likelihood of acquiring HIV, treating people who have HSV-2 doesn’t reduce their risk of HIV infection. In the June 21st issue of the Lancet, Dr. Connie Celum and her colleagues at the University of Washington present the results from the second large-scale clinical trial designed to test whether treating HSV-2 can help prevent HIV infection among high-risk individuals. They found no evidence of a protective effect.

In the accompanying editorial, Drs. Ronald Gray and Maria Wawer of Johns Hopkins University argue that these findings call into question current prevention policies that focus on control of sexually transmitted diseases to lower transmission of HIV, stating: “It is time to reassess [this] hypothesis and to adjust prevention policy accordingly.”

 

Identified risk factor for HIV infection in women

In a set of recently published articles, Depovera, a hormonal
contracepptive, has been found to increase the risk for HIV
infection in women in real life in women in Kenya, Lesotho, Malawi
an Zimbabwe. The study noted that injectable contraception was
associated with a minor increase in risk of HIV infection. The
reasons are yet to be defined.

The issue for the continued use of Depovera is and individual
woman’s issues: a woman has to be able to define her risk for
contracting HIV. If her partner is infected with HIV, she should be
using condoms. The use of hormonal contraception should be in
conjunction with the use of condom (dual protection).

Past studies have also indicated that hormonal contraceptives have
impact on the viral with the viral load being significantly higher
at the early infection period in persons who seroconvert and are
using hormonal contraceptives than those who have established HIV
infection and are using hormonal contraceptive.

Depovera is still legitimately recommended for use in women who are not exposed to HIV, and assuming that the injections used for giving the contraceptive are safe (clean and sterile). However, in
countries where the HIV incidence/prevalence is high, careful
considerations may need to be given to the use of Depovera (and
possibly other Hormonal contraceptives) as a contraception.

References

1. Hormonal contraeption and HIV prevalence in four African
countries: Pauline M. Leclerc, Nicolas Dubois-Colas, Michel Garenne.
Contraception 77 (2008) 371 -376

2. Natural History and Risk Factors Associated with Early and
Established HIV Type 1 Infection among Reproductive-Age Women in Malawi. Johnstone J. Kumwenda, Bonus Makanani, Frank Taulo, Chiwawa Nkhoma, George Kafulafula, Qing Li, Newton Kumwenda, and Taha E. Taha. HIV/AIDS CID 2008:46 (15 June) • 1913

When microbicide clinical trials end: lessons learnt and role of advocates

Recent experiences with clinical trials closures (either scheduled or unexpected, due to unforeseen circumstances) have elicited a broad range of reactions from civil society groups and the media. When negative, these reactions can have a damaging impact on the conduct of concurrent and future trials.

At a Microbicides 2008 workshop, participants examined recent trial closure experiences to determine what supports would help people understand trial closures and their significance at the community level more clearly. They also explored the roles that advocates can play in helping to prevent rumor and mis-communication about trial results and research findings.

The participants at the session agreed that closure of a microbicide trial ahead of schedule is not, in itself, a failure. All past trials had contributed immensely to progress in the field. A balanced public view of trial results can be facilitated by: increasing the sense of community ownership of a trial; highlighting the importance of thorough safety trials for all potential candidates; assuring early and frequent reviews of unblinded trial data by Data Safety and Monitoring Boards (DSMBs); developing effective mechanisms for disseminating the DSMB recommendations within communities; and cultivating transparent and effective stakeholder engagement in the research process. The need to develop a true universal placebo for microbicide trials was also discussed.

Advocates have played significant roles in helping to address issues as the trials close. The international, regional and national advocacy communities have helped to assure continued interest in microbicide research, despite setbacks and seemingly negative news from the field. However, their ability to play this role could be greatly strengthened by building advocates’ scientific literacy and capacity. This would better prepared them to: serve as effective CAB members; engage actively with protocol development; and make targeted inputs into decisions about secondary trial endpoints and the standard of care provided at trial sites. The need for a dedicated funding windows to give smaller NGOs much-needed access to funding for capacity-building and other relevant relevant community work was also discussed, as was the need for independent community-level monitors (distinct from DSMBs), to assure transparency.

Advocates agrred that they are well situated to identify the steps needed to prevent misinformation which can erode community trust in the research enterprise because they are part of the communities they serve. They can also help to build trust between researchers and civil society stakeholders. Microbicide clinical trials can harness this potential by engaging community advocates early in the various clinical trial design and implementation

Morenike Ukpong and Anna Forbes