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microbicides

Failed PrEP trial (VOICE) participants give reasons for their poor adherence

13 Nov, 14 | by Leslie Goode, Blogmaster

Despite indications of the acceptability of Pre-Exposure Prophylaxis (PrEP) among certain populations (MSM in London (STI/Aghaizu & Nardone) 2013, and Australia (STI/Holt & De Wit) 2012), the extremely varied results that have emanated from large studies seeking to determine its efficacy and effectiveness as a preventative intervention remain a concern.  To name the most important examples, levels of risk-reduction were estimated as follows: CAPRISA 004 – 39%; iPrEX – 44%; CDC TDF2 – 62%; Partners-PrEP – 75%; FEM-PrEP – 0%; VOICE– 0%.  The reasons for this variation have been the topic of a number of contributions to this blog (especially: STI/blogs/Hendrix & Bumpus; STI/blogs/Haberer & Bangsberg), with consensus tending towards the poor adherence of study participants.

Last week in Cape Town results were briefly reported from a sub-study (VOICE D) of one of the less successful of these trials (VOICE). Microbicide Trials Network’s (MTN) VOICE study, discontinued in 2011, trialled daily tenofovir, in the form of vaginal gel or tablet, in 5,029 (mostly young) women from a representative range of sub-Saharan countries – S. Africa, Zimbabwe and Uganda. On the basis of self-reporting measures in the original VOICE trial, levels of adherence to the tenofovir regime had been estimated at 90%.  However, blood samples taken from participants found evidence of the drug in less of a third of the participants in the tablet arm, and less of a quarter of the participants in the gel arm, of the study.

After the closure of the VOICE study itself, the sub-study, VOICE D, engaged 127 former VOICE participants in in-depth interviews at which they were challenged with evidence of their poor adherence – with a view to stimulating frank discussion. When confronted with the evidence of blood tests, poor adherers initially expressed surprise and disbelief. Yet, according to the report, the aim of engaging frank discussion would seem to have been met.  The reason most frequently given was fear of the side effects of the drug, fuelled by peer participants and relatives and by the negative attitudes of community members.

Current trials of PrEP have re-evaluated and strengthened efforts to enhance adherence in the light of previous failures.  These include: the Follow-on African Consortium for Tenofovir Studies’ FACTS 001 (tenofovir gel before and after sex), the MTN’s ASPIRE and the International Microbial Partnership’s Ring Study (both the latter of vaginal ring releasing the ARV drug dapivirine) (MTN Trials). It is interesting that the Partners-PrEP study incorporated intensive “adherence interventions” for participants whose adherence levels fell below 80% (STI/blogs/Haberer & Bangsberg).

However, the VOICE D results may have implications for the usefulness of PrEP interventions more generally. At the very least, they discredit any idea that PrEP is able to offer a panacea. The value of PrEP, relative to other preventative interventions, is a contentious issue.  STI/Mukandavire & Vickerman (2013), for example, conclude that a scale-up of condom use is in most circumstances likely to be more effective than PrEP, but that PrEP could have a specific application in the case of female sex workers. STI/Verguet & Walsh (2012) see a future for PrEP in sub-Saharan countries with high HIV prevalence and without circumcision practice, such as S. Africa.  STI/Ying & Barnabas (2013) see targeted PrEP as a cost-effective addition to ARV.

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The dapivirine ring: success at last for a vaginal microbicide?

11 Jul, 12 | by Leslie Goode, Blogmaster

The International Partnership for Microbicides (IPM) has just announced the launch of a trial (IPM 027) to evaluate the effectiveness of the antiretroviral (ARV) drug dapivirine delivered by means of a monthly replaceable vaginal ring (http://www.ipmglobal.org/node/670).  The IPM study, which has enrolled 1,650 women at four sites in South Africa, is part of a broader licensing program which also includes the Microbicides Trial Network (MTN) study ASPIRE (MTN-020) due to commence in the coming months (http://www.mtnstopshiv.org/studies/3614).

The development of an effective vaginal microbicide would be a significant new weapon in the armoury of HIV prevention – not least because, for the first time, it would place a means of protection in the hands of women, who are often most at risk from the virus.  On the down side, there is the probable impact on condom use.  The potential contribution of microbicides has been the object of various modelling studies:  Foss & Watts (2009) predict a significant impact in contexts of low and high HIV prevalence with microbicides of even moderate efficacy (http://sti.bmj.com/content/85/4/276.abstract?sid=ec0fb4c2-06ee-4358-a8af-6e06c015bf05): while Cox and White ( 2011) argue that reductions of 30% in fifteen years could be achieved, if 49% levels of microbicide use were combined with 67% levels of male circumcision (http://sti.bmj.com/content/87/7/635.abstract?sid=ec0fb4c2-06ee-4358-a8af-6e06c015bf05).  As for cost-effectiveness, Verguet & Watts give positive results for high-prevalence contexts (>2.4%) even with a low efficacy microbicide (http://sti.bmj.com/content/86/3/212.abstract?sid=ec0fb4c2-06ee-4358-a8af-6e06c015bf05).

So far, unfortunately, the microbicides have not come up with the goods.  Some 23 products are currently in the course of development.  Microbicides act in different ways – some by creating a physical barrier, such as PRO2000, a trial of which is discussed by Kamali & Lacey (2009) (http://sti.bmj.com/content/86/3/222.abstract?sid=ec0fb4c2-06ee-4358-a8af-6e06c015bf05): others by enhancing vaginal defence mechanisms or by disabling the pathogens.  Trials of these microbicides having proved unsuccessful, the most promising candidates now seem to be ARV drugs which prevent replication of the virus inside the cell. Amongst the latter are Tenofovir gel, unsuccessfully trialled by the MTN VOICE trial (MTN 003), and now, most recently, the dapivirine ring, soon to be tested by IPM 027 and MTN ASPIRE (http://www.mtnstopshiv.org/node/82).

Both of the trials recently announced (IPM 027 and MTN 020) are phase III trials at the cutting edge of microbicide research.

 

Putting Rectal Microbicides “On the Map”

11 Jun, 12 | by Leslie Goode, Blogmaster

17th April saw the launch of the report: On the Map: Assuring Africa’s Place in Rectal Microbicide Research and Advocacy by the International Rectal Microbicide Advocates (IRMA) On the Map:  Ensuring Africa’s Place in Rectal Microbicide Research and Advocacy .  The report has been developed by African advocates and researchers on the basis of an IRMA consultation held in Addis Ababa in December 2011.  The report promotes initiatives to prepare for deployment of rectal microbicides (RM) in Africa, following successful completion of a Phase I trial of tenofovir-based RM in 2011 (MTN-007), and prior to the first Phase II trial (MTN-017), based in South African among other places.

In recent years a neglected epidemic among men who have sex with men (MSM) has been recognized in many low- and middle-resource settings where the predominant mode of transmission is heterosexual (J. Sanchez, STI 2011:87:Suppl.1). http://sti.bmj.com/content/87/Suppl_1/A7.2.abstract?sid=0dfd7f4e-457a-4935-ae85-9f1a939b9881  The activities envisaged by the IRMA report, including research, advocacy and communication, reflect the growing interest in the possibilities of RM as a means of HIV prevention.  M. Meyer, writing for STI journal (2011:87:Suppl.1) reviews the literature on the feasibility of RM and effectiveness.  http://sti.bmj.com/content/87/Suppl_1/A7.5.abstract?sid=0dfd7f4e-457a-4935-ae85-9f1a939b9881

The IRMA report also draws attention the need for further research on attitudes to anal sex in specifically African cultural settings, as well as to the acceptability of RM as a prevention tool, and the integration of anal sex and RM into health education programs.  STI journal has featured a number of studies seeking to remedy the paucity of data in this area, and determine risk factors for HIV transmission among MSM, and for their interaction with other populations.  These include studies conducted in regions that figure prominently in the IRMA report.

On Nigeria:

O. Busari, STI 2011:87:Suppl. 1 (Lagos: women and MSM sex workers (SW));

http://sti.bmj.com/content/87/Suppl_1/A126.3.abstract?sid=0dfd7f4e-457a-4935-ae85-9f1a939b9881

M. Merrigan, STI 2011:87:1 (Lagos, Kano, Cross River States: HIV and Syphilis among MSM);

http://sti.bmj.com/content/87/1/65.abstract?sid=0dfd7f4e-457a-4935-ae85-9f1a939b9881

On the region of southern Africa:

C. Beyrer, STI 2010:86:4 (Malawi, Namibia, Botswana: MSM and bisexual concurrency);

http://sti.bmj.com/content/86/4/323.abstract?sid=0dfd7f4e-457a-4935-ae85-9f1a939b9881

T.G.M. Sandfort, STI 2008:84:6 (South African: racial distribution of HIV amongst MSM).

http://sti.bmj.com/content/84/6/425.abstract?sid=92184215-ce7c-4f66-a691-163618765a8c

 

A biomarker for the efficacy of new antiretroviral microbicides?

4 May, 11 | by Leslie Goode, Blogmaster

A recent study claims to have proved the correlation between HIV-1 RNA in the genital secretions of infected individuals and HIV transmission (Spearman’s rank correlation coefficient ρ was 0.56 for endocervical samples, and 0.55 for semen).  Mechanisms of transmission of HIV transmission through genital mucosa are still not well understood.  But, prior to this study, there were important grounds for supposing that genital viral load would prove a reliable marker of HIV infectivity – possibly more reliable, where sexual transmission is concerned, than plasma viral load.  If definitive evidence has been long coming, this, according to the authors, is due to the logistical difficulties facing the organization of a longitudinal study in which HIV transmission takes place.

The study involved serological sampling from 2,521 heterosexual sero-discordant couples in six African countries, including endocervical swabs from 1805 infected women, of whom 46 were known to have transmitted HIV to their partners, and semen samples from 716 men, of whom 32 were known to have transmitted the disease.  Each 1.0 log10 increase in genital HIV-1 was associated with a 2.20-fold (endocervical samples) or a 1.79-fold (semen samples) increased risk of HIV transmission.

This study is in line with the recent research focus on transmission of HIV through genital mucosa and the development of new strategies for blocking HIV transmission through this path, such as topical ARV microbicides.  At the close of the discussion section of the paper, the authors draw attention to the potential role of genital sampling in quantifying the reduction in transmission risk from interventions directed at reducing infectiousness of persons with HIV.  Among such interventions the principal author mentions, in a recent interview (http://www.medicalnewstoday.com/articles/221595.php), reduction of an HIV person’s infectiveness through HIV treatment, treatment of patients’ other STIs, and microbicides inserted in the vagina.  In view of the current interest in the potential of topical antiretroviral microbicides inserted in the vagina, it would be interesting to consider the role that genital sampling of HIV-1 could play as a marker of efficacy in blocking virus transmission.

http://stm.sciencemag.org/

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