Reformulation of Tenofovir Vaginal Gel Safe for Rectal Use

via Eurekalert.org

A change in the formulation of tenofovir gel, an anti-HIV gel developed for vaginal use, may make it safer to use in the rectum, suggests a study published online this week in the Journal of Antimicrobial Chemotherapy. In laboratory tests of rectal tissue, researchers from the Microbicide Trials Network (MTN) found that the reformulated gel was less harmful to the lining of the rectum than the original vaginal formulation, and just as effective in protecting cells against HIV.

"The lining of the rectum is much more fragile than the vaginal epithelium, so we can't be certain a product like tenofovir gel that is safe for vaginal use will be completely safe to use in the rectum," said lead study author Charlene Dezzutti, Ph.D., associate professor of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh School of Medicine and principal investigator of the MTN Network Laboratory. "We are very encouraged by our laboratory data that suggest the reformulated gel could be safer for rectal use, and serve as a dual compartment gel for use in both the vagina and rectum."

Tenofovir gel has shown some promise in reducing HIV risk in women through vaginal sex. But because the rectal epithelium – the lining of the rectum that serves as the first line of defense against HIV – is much thinner than the vaginal lining, the gel may not be safe or effective to use rectally. Indeed, unprotected anal sex is 10 to 20 times more likely to result in HIV infection than unprotected vaginal intercourse. By its nature, tenofovir gel is hyperosmolar – contains a higher concentration of sugars and salts relative to cells. This quality could have a harmful effect on the rectal lining by causing epithelial cells to shrink as they purge water to achieve balance. Weakened in this manner, the rectal epithelium may be less able to protect against HIV.

To make tenofovir gel safe and more amenable to rectal use, researchers from CONRAD, a research organization which holds the rights to develop the gel, reformulated it with a reduced amount of glycerin, a common additive found in many gel-like products. In laboratory tests conducted by MTN researchers, the reformulated gel was three times less likely to cause cells in rectal tissue to release water, and equally effective against HIV as the vaginal formulation.

Data from an early phase clinical trial of the reduced glycerin gel presented in March 2012 at the 19th Conference on Retroviruses and Opportunistic Infections (CROI), suggested it was safe and acceptable in 65 HIV-negative men and women who used it rectally once a day for one week. Results from this study, called MTN-007, and future studies will have important implications for the development of a rectal microbicide that could help protect against HIV or other sexually transmitted infections during anal sex.


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Researchers Present the Impact of Serosorting as an HIV Prevention Strategy

via AidsMap.com, by Gus Cairns

An meta-analysis of HIV-negative gay men’s sexual behaviour and HIV incidence rate in four HIV prevention studies, presented earlier this month at the 19th Conference on Retroviruses and Opportunistic Infections (CROI), has found that attempting to ‘serosort’ by restricting unprotected sex to partners known to be HIV negative does have efficacy as an HIV prevention strategy, when compared with using no strategy at all.

Serosorting is, however, considerably less effective in reducing the chances of acquiring HIV than four other strategies: 100% condom use, monogamy, only having insertive sex, or ‘seropositioning’ (only taking the bottom role with partners known not to have HIV and being top with partners of positive or unknown status). Interestingly, 100% condom use was the least effective of these other four strategies.

‘Seroadaptive’ behaviours include any method of attempting to reduce the risk of HIV acquisition or transmission by altering one’s sexual behaviour according to the HIV status of partners. The term ‘serosorting’ has been used in various different ways. Most commonly, it means restricting unprotected anal sex to partners known to have the same HIV status as yourself. When unprotected sex between HIV-negative men is confined to a primary relationship, with condoms used in all other encounters, this has been called ‘negotiated safety’.

 

While some studies have found serosorting in HIV-negative men to be effective, others have not. Attempted serosorting by HIV-negative people has an inherent drawback that serosorting by HIV-positive people lacks: people can only be certain of their status up to the first time they risk exposure to HIV after their last negative HIV test. Research indicates that a large minority of people in high-risk communities who assume they are HIV negative in fact have HIV, and that a large proportion of men who ‘know’ their partner’s HIV status have, in fact, tried to guess it.

 

The meta-analysis

 

Nonetheless, though serosorting is fallible, a recent meta-analysis of studies presented at CROI found that serosorting halved the likelihood of acquiring HIV compared to having no strategy at all.

The study pooled behavioural data and HIV incidence rates from four different studies in gay men:

• The HIVNET 001 Vaccine Preparedness Study (VPS), an observational study that took place in eight cities in the US between 1995 and 1997. 
• VAX 004, the first phase III efficacy trial of a candidate HIV vaccine, which took place at 61 sites in the US, Canada and the Netherlands between 1998 and 2001.
• The EXPLORE study, a randomised controlled trial of a behavioural HIV-prevention intervention that took place in six US cities between 1999 and 2003. 
• The STEP study, a phase III trial of another candidate vaccine, which took place in North and South America and Australia between 2004 and 2007.

There were a total of 12,705 HIV-negative gay men from North America included in these trials, of whom 663 (5%) acquired HIV.

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[If an item is not written by an IRMA member, it should not be construed that IRMA has taken a position on the article's content, whether in support or in opposition.]

NYT: Setback on PrEP Results May Have Been Misunderstood

via The New York Times, by Donald G. McNeil Jr.

The failure of a daily pill to protect healthy African women against AIDS may not have been the pill’s fault but the women’s reluctance to take it, scientists at an important AIDS conference in Seattle were told this week.

Last April, a promising trial of “pre-exposure prophylaxis” — giving small protective doses of antiretroviral drugs to uninfected people — was stopped early because women were getting infected anyway. It was a discouraging setback.

But scientists at this week’s Conference on Retroviruses and Opportunistic Infections who analyzed blood samples taken from the women reported that only a quarter of those who got infected had any of the drug, Truvada, in their blood. That suggested they had not taken their pills.
Papers presented at the four-day conference offered findings both optimistic and scary. There were hints at a possible way to flush the virus out of its hiding places in cells, and at ways to let some patients safely take “vacations” from triple therapy.

It is not known why so few African women took their Truvada, but there is still an enormous stigma about AIDS in Africa, and a bottle of AIDS drugs in the home implies that someone there is sick, said Mitchell Warren, executive director of AVAC, a prevention advocacy group. Mr. Warren pointed out that Truvada had protected women in a different study that enrolled established couples in which only one partner was infected.

In a different study, researchers from the University of North Carolina at Chapel Hill showed that they had used a cancer drug, vorinostat, to purge the virus hiding in the CD4 cells of six men who were already doing well on triple-therapy cocktails.

Although the cocktails can make the virus vanish from the blood, it hides in different types of cells, ready to roar back if the patient stops taking the cocktails.

Another small trial, at the Wistar Institute in Philadelphia, gave patients synthetic interferon — a virus-blocker normally made by the human body — while they took “holidays” of up to six months from triple therapy. Nine of the 20 patients did not see their viruses rebound to dangerous levels. That result will not change clinical practice right away, said Dr. Luis J. Montaner, who led the study, but suggested an alternative to lifelong triple therapy, which can be debilitating.

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HIV/AIDS Treatments Compromised by Budget Cuts

via Nature News, by Erika Check Hayden

Preventing the spread of HIV used to mean testing people for infection and encouraging them to practise safe sex. Increasingly, it also means prescribing drugs, as studies show that giving infected people or their uninfected partners antiretroviral drugs as soon as an infection is diagnosed can help to check the spread of AIDS.

Yet at this week’s annual Conference on Retro­viruses and Opportunistic Infections in Seattle, Washington, there was growing concern that financial austerity in the United States and elsewhere is eating away at the funding needed for a worldwide prevention effort.

Many scientists and advocates agree that there is now an “awesome possibility to prevent the spread of HIV”, says Sharonann Lynch, HIV policy adviser for Médecins Sans Frontières (MSF, also known as Doctors Without Borders) in New York. “If we decrease the money invested in treatment now, we are squandering the best opportunity we’re going to have to get ahead of the wave of new infections.”

Last month, US President Barack Obama’s 2013 budget request proposed a 10.8% cut to direct international aid for HIV programmes under the President’s Emergency Plan for AIDS Relief (PEPFAR) which, together with previous cuts, would slice more than US$1 billion from the fund’s 2010 level (see ‘Sliding support’). And last November, the Global Fund to Fight AIDS, Tuberculosis and Malaria said that it would not hand out any more funds for scaling up AIDS treatments until 2014 because of tightening budgets in donor countries (see Nature 480,159–160; 2011).

The shortfalls come as a slew of results presented this week reinforce a growing consensus about the power of early treatment for HIV infections. The latest data are part of a trend that accelerated last May, when HPTN 052, a clinical trial run by the multinational HIV Prevention Trials Network, showed that giving antiretroviral drugs to people who are HIV-positive can stop them from passing the virus to their uninfected partners (M. S. Cohen et al. N. Engl. J. Med. 365, 493-505; 2011). In light of such results, the World Health Organization is expected to issue new guidelines for managing HIV in couples soon.

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[If an item is not written by an IRMA member, it should not be construed that IRMA has taken a position on the article's content, whether in support or in opposition.]

Researchers at CROI 2012 Share First Trial Results on Injectable HIV Drug Used as Prevention

via AidsMap.com, by Gus Cairns

The first trial in humans of an injectable, once-a-month formulation of an HIV drug has found that drug levels were maintained at a level that should in theory be high enough to protect recipients against infection, and that the drug has so far produced very few side effects. The research was presented at the 19th Conference on Opportunistic Infections (CROI), in Seattle.

The small trial at the St Stephen’s AIDS Trust (SSAT) at London’s Chelsea and Westminster Hospital gave 27 women and six men a single injection of the long-acting formulation of the drug rilpivirine, which was licensed as an oral HIV treatment last year as Edurant and is also in the tenofovir/FTC/rilpivirine pill Complera. Rilpivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) drug and is especially suitable to be turned into a long-lasting injectable form because the daily dose of it required to suppress HIV is very small.

No other HIV drugs are currently in a usable long-lasting injectable form, which will limit the use of long-acting rilpivirine (RPV-LA) in combination therapy, but it could conceivably make an ideal candidate as a prevention drug, as people would not need to remember to take it every day. Other preventative drugs already formulated as monthly injections include the injectable contraceptive Depo Provera and some anti-psychotic drugs.

SSAT recruited 27 HIV-negative women aged 18 to 50, more than 50% of them black African or Caribbean, for the trial and gave them one of three doses of RPV-LA as an intramuscular injection: 300, 600 or 1200mg (the oral dose of RPV is 25 mg/day). Drug levels were then measured over the course of the next twelve weeks in blood, vaginal fluid and in vaginal tissue samples. A substudy gave six men the 600mg dose and measured RPV-LA levels in blood, rectal fluid and rectal tissue samples.

Thirty days after injection, blood and vaginal fluid levels of rilpivirine were about 60 nanograms per millilitre (ng/ml) in both blood and vaginal fluid in women given the 600mg dose, and about 80 and 120ng/ml respectively in women given the 1200mg dose. Blood levels in men given the 600mg dose were about 70ng/ml at 30 days. For comparison, the trough levels of rilpivirine in people taking daily oral doses is about 140ng/ml; but the EC50 (the amount needed to reduce viral replication by 50%) in newly-infected T-cells is 27ng/ml. It is thought these levels should be adequate to prevent HIV infection.

Over the time period, levels of drug seen were about 80% higher in vaginal fluid than in blood in women taking the 300mg dose and about 20% higher in the other two doses: conversely, drug levels in vaginal tissue were about 25% lower than in blood, and 50% lower up to day 14 in the 300mg dose group.

Drug levels in rectal fluid were low but it is thought this was due to sample contamination: concentrations in rectal tissue were about the same as concentrations in blood.

The trial participants complained of very few side-effects apart from tenderness and some swelling at the injection site. There were no allergic reactions, psychological symptoms or effects on heart rate. Safety is of course a major consideration in a drug that remains in the body for up to twelve weeks.

Researcher Akil Jackson said, "There is an obvious need in HIV prevention and treatment for formulations that reduce the need for the user to depend on daily administration,” but added that these were very preliminary results and did not establish what dose would actually be protective. Further safety and drug-level studies in HIV-negative volunteers are to be conducted at the University of Pittsburgh, home of the Microbicide Trials Network, before the drug is given to volunteers with HIV.

 
[If an item is not written by an IRMA member, it should not be construed that IRMA has taken a position on the article's content, whether in support or in opposition.]

Two Studies Show the Importance of Adherence in PrEP at CROI 2012

via AidsMap.com, by Gus Cairnes

Adherence makes all the difference to the efficacy of pre-exposure prophylaxis (PrEP), the 19th Conference on Retroviruses and Opportunistic Infections (CROI) heard today.

Further data were presented from two trials of PrEP (giving anti-HIV drugs to HIV-negative people to prevent infection), which announced dramatically different results last year.

In April 2011, the FEM-PrEP study found that giving HIV-negative women tenofovir/FTC (Truvada) pills to prevent their acquiring HIV was totally ineffective: there was no difference in HIV incidence between women taking Truvada and women taking placebo.

In July 2011, however, the Partners PrEP study found that Truvada was 73% effective in preventing HIV transmission between heterosexual partners of different HIV status.

How do we explain why giving HIV-negative women antiretroviral pills made no difference to the HIV infection rate in one trial, but prevented at least two in every three infections in the other? The difference, it appears, is that in the Partners PrEP trial, adherence to the study medication was very high, whereas in FEM-PrEP, despite counselling and support, less than half the women took their PrEP pills regularly.

The Partners PrEP study

The Partners PrEP study enrolled 4758 serodiscordant couples in Kenya and Uganda; the HIV-negative partner was female in 38% of couples. This study had three arms: a daily tenofovir pill, a daily Truvada pill, or placebo.

There were 17 infections in participants on tenofovir, 13 on Truvada and 52 on placebo. Efficacy overall was 75% in those assigned Truvada and 67% in those assigned tenofovir, though confidence intervals (44% to 81% in tenofovir and 55% to 87% for Truvada) overlapped, so the efficacy of the two regimens was the same statistically. The same was true of efficacy observed in women (65%) and men (70.5%).

Adherence according to pill counts of unused medication was 97%. A substudy (Donnell) compared tenofovir levels in the blood of 29 out of the 30 people who became infected in the two PrEP arms with levels in a random selection of 198 people who did not become infected.

Tenofovir was undetectable in the blood of 70% of the people who became infected but only 18% of the people who did not, indicating a ‘true’ adherence level of about 80% – and having a detectable level of tenofovir in the blood was associated with an 86% reduction in HIV risk in those taking tenofovir and a 90% reduction in those on Truvada.

The FEM-PrEP study

In the FEM-PrEP study, 2056 HIV-negative women in South Africa, Kenya and Tanzania were randomised to take a daily Truvada pill or a placebo. The trial was stopped when an interim analysis found near-identical HIV infection rates in both trial arms. There were 33 HIV infections in women taking Truvada and 35 in women taking placebo; this translates into annual incidence rates of 4.7% and 5.0% respectively. This 0.3% difference is no difference at all, statistically speaking (hazard ratio 0.94, 95% confidence interval 0.59 to 1.52, p = 0.81).

Participants in the study said they took their pills 95% of the time and adherence as measured by pill count was 85%. However when drug levels of tenofovir and FTC were measured in the blood of women assigned to Truvada, the investigators found that less than 50% of the women who should have been taking the drug had actually done so in the last 12 days, and less than 40% within the last 48 hours.

In infected participants, 26% had detectable levels of tenofovir in their blood in the last visit before they tested HIV positive, 21% at the visit they tested positive, and 15% at both visits; in non-infected participants whose samples were taken at the same visits they were 35%, 38% and 26% respectively.

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[If an item is not written by an IRMA member, it should not be construed that IRMA has taken a position on the article's content, whether in support or in opposition.]

CROI 2012: iPrEx Researchers Test Dosage of PrEP

via AidsMap.com, by Gus Cairns

Further testing of drug levels in the blood and immune cells of gay men participating in the iPrEx trial of tenofovir/FTC (Truvada) pre-exposure prophylaxis (PrEP) has found that HIV infection in men assigned to Truvada was associated with a lapse in taking the drug after initially adhering reasonably well, rather than never having taken it at all, which was what the researchers originally thought. The research was presented at the 19th Conference on Retroviruses and Opportunistic Infections (CROI), in Seattle.

The testing also found that only a minority of participants appeared to be taking their drugs as prescribed, seven days a week, but that protection levels were very high – in the order of 96% of infections prevented – as long as participants took four or more doses a week.

Drug levels plummet three months before infection

The results of iPrEx, a large multi-country study of PrEP in gay men, were announced in 2010 and showed an overall efficacy of 42% – in the trial subjects as a whole, four out of ten HIV infections that would otherwise have happened were prevented if subjects were given Truvada pills to take daily rather than placebo pills. When drug levels were tested in the 48 participants who became HIV-infected on Truvada, and a random sample of uninfected participants, it was found, perhaps not surprisingly, that drug was detectable in only 10% of the infected participants but also, perhaps more surprisingly, in only 50% of the uninfected ones.

New measurements have now looked back at drug levels in stored samples in the months prior to infection and compared with drug levels in the same time period in uninfected participants. In the uninfected participants, consistently 45% or so had detectable drug in their samples across the whole length of the study – confirming that at least half of the participants simply never took their pills. In the infected participants average adherence rates started off the same as in the uninfected. They showed a slight decline in the first year of the trial but then declined to 10% in the three months preceding infection. This suggests a role for quarterly adherence reinforcement.

What levels of tenofovir are protective?

The researchers also wished to find out what levels of tenofovir in the blood were associated with protection against HIV. They did this by comparing drug levels in iPrEx participants with drug levels in a small study called STRAND, presented at last year’s conference (Liu),which gave participants directly-observed doses of tenofovir twice, four time or seven times a week and then measured drug levels in their hair. By then comparing the levels of protection seen in participants with specific drug levels in iPrEx, the researchers were able to compute what drug level was protective.

In iPrEx the average drug levels seen in infected people were consistent with less than one dose of tenofovir a week, but drug levels in those who were not infected were consistent with only about three doses a week. Only 18% of iPrEx participants had drug levels consistent with taking seven doses a week. The investigators used very sensitive tests to look at levels of metabolised tenofovir inside cells and found that a reduction of 90% in the risk of HIV infection correlated with a drug level of 16 femtomols per mol (fm/M – 16 in every million billion molecules by weight). The average level associated with seven doses a week in STRAND was about 38 fm/M and with four doses a week about 32 fm/M.

This enabled them to calculate that the protection offered by taking four doses of tenofovir a week was high, and more or less the same as taking seven doses – that is, in the order of 96%, with a minimum likely protectiveness of 90%. They also calculated that absolutely perfect adherence would offer 99% protection. Taking two doses a week (consistently) would still offer 72% protection, though within wide confidence intervals (56% to 96%) while the 42% level of protection actually seen in iPrEx was consistent with participants taking, on average, one dose a week.

This study has important limitations. STRAND did not measure FTC levels so the iPrEx researchers could not calculate what extra protection was offered by that drug. They also could not measure drug levels at the actual moment of exposure – they were measured at anything between 15 and 90 days after infection. And of course the ‘number of doses a week’ measure is purely an average – most participants probably had much more irregular patterns of taking their pills, with (amongst the 50% who took it at all) periods of good adherence interspersed by periods off drug, maybe correlated with times on and off sex. But it does give a guide to the likely minimum levels of tenofovir that people need to maintain in order to be protected from HIV.



[If an item is not written by an IRMA member, it should not be construed that IRMA has taken a position on the article's content, whether in support or in opposition.]

CROI Reports Rectal Tenofovir Trial Results

via AidsMap.com, by Gus Cairns

A gel containing 1% tenofovir formulated specifically for rectal use was much better tolerated than gels used in previous rectal microbicide trials when used in a safety study in 65 HIV-negative men and women, the 19th Conference on Retroviruses and Opportunistic Infections (CROI) heard yesterday.

The gel was also compared with other gels for any irritant or inflammatory effect on tissues. These tests included an in-depth ‘microarray’ analysis of a large panel of different human genes and uncovered a previously unsuspected effect: the tenofovir in the gel appeared to modulate the activity of a large number of genes in rectal tissue cells, primarily in the direction of reducing their activity.

Whether these genetic changes will have a synergistic or antagonistic effect on the efficacy of a tenofovir-based rectal microbicide is completely unknown as yet but illustrates that nucleoside antiretroviral drugs in topical formulations may have unexpected side-effects, as they do when used as treatment.

Background

Last year a study presented at CROI (Anton) found that a 1% tenofovir microbicide gel formulated for vaginal use (similar to the one used in the CAPRISA 004 trial) inhibited HIV infection of rectal cells taken from people using the microbicide by 80%. However the microbicide was unpopular in users, with only 25% reporting liking it, the majority of people reporting side-effects like diarrhoea, cramps and discomfort, and two out of eighteen subjects reporting severe side-effects that necessitated stopping use of the gel.

These side-effects, it is thought, are due to the gel having a high osmolality. This means it contains more salts than body fluid and this causes it to draw water out of cells, resulting in diarrhoea and abdominal discomfort. The Microbicide Trials Network therefore devised a low-glycerine formulation gel with an osmolality of 800 compared with 3000 for the CAPRISA 004 gel; the osmolality of body fluids is 300. Hyper-osmolar gels also strip cells away from the rectal lining and may actually increase vulnerability to HIV and STIs when used during unprotected sex.

Acceptability

The new formulation of the gel was far more popular and easier to tolerate than the vaginal one. Acceptability was nearly 87% as opposed to 25% last year for the tenofovir-containing formulation, 93% for the HEC placebo and even 67% for the gel containing N-9. Amongst specific side-effects, 16% versus 50% last year said they had regular diarrhoea while none, as opposed to 42% last year, experienced the need to rush to the toilet as soon as they applied the gel.

Inflammation markers and genes

Samples were taken from rectal tissues 9 centimetres and 16 centimetres inside from the anal opening and various tests made on inflammatory indicators and gene expression. Not surprisingly, the N-9 gel had the most effect on inflammatory markers, raising some and suppressing others.

Samples were tested using a ‘microarray’, a testing plate that detects the effect of the gels on hundreds of individual human genes and whether they are ‘switched on’ or supressed.

The effect of the HEC gel was completely neutral on genes, with fewer activated or suppressed than in the 16 people not using gel (16 genes versus 23). The N-9 gel affected 116 genes, mostly in the direction of increasing their activity. But the tenofovir gel affected 533 different genes, mostly in the direction of decreasing their activity.

Implications


The clinical significance of this is unknown, and processing the consequence of such a large number of changes in gene activity will take a long time. But Ian McGowan told aidsmap that the results, though unexpected, were not inexplicable.

“Tenofovir is a DNA chain terminator,” he said. “This is how it stops HIV.” He pointed out that the NRTI (nucleoside) drugs were well known for side-effects which had genetic causes ranging from fat loss (caused by damage to mitochondrial genes) through bone synthesis to nerve damage.

Essentially what this study shows is that, once the ‘noise’ from direct inflammation is taken away, it can be seen that NRTI drugs have direct effects on DNA activity in cells when applied topically, just as they do when taken orally. Whether these effects have any clinical consequences remains to be seen.

The next step will be a study called MTN017 in which tenofovir gel will be administered for eight weeks.




[If an item is not written by an IRMA member, it should not be construed that IRMA has taken a position on the article's content, whether in support or in opposition.]

CROI 2012: Recent Results Presented by Partners PrEP Study

via MedPage Today, by Michael Smith

Giving anti-retroviral drugs to HIV-negative people can reduce their risk of acquiring the virus from an HIV-positive partner, a researcher said here.

In a large randomized controlled trial in Africa, this type of pre-exposure prophylaxis, or PrEP, cut the risk of infection by up to 75% compared with placebo, according to Jared Baeten, MD, of the University of Washington Seattle.

The so-called Partners PrEP study is "clearly proof of concept" that treating the uninfected partner in a heterosexual couple can be a good approach to prevention, Baeten told reporters at the annual Conference on Retroviruses and Opportunistic Infections.

The trial is a mirror image of the major study reported last year – the HPTN 052 trial – that found that treating the infected member of such couples reduces the risk of transmission by more than 90%.

Given those findings – and the increasing desire of physicians to treat HIV-positive people as early as possible – the results of Baeten's study may fall on stony ground.

But Baeten told MedPage Today he thinks there will be a place for treatment of the negative partner.

Taken together, the two studies show "a high degree of protection with the use of anti-retrovirals," he said.

But in the heterosexual epidemics in much of the developing world, he said, people face "difficult choices about individual treatment, individual risk, and risk decision making, often related to the desire for pregnancy."
When, for one reason or another, the HIV-positive partner can't start treatment or doesn't want to start, offering therapy to the other partner makes sense, he said.

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[If an item is not written by an IRMA member, it should not be construed that IRMA has taken a position on the article's content, whether in support or in opposition.]

Is treatment really reducing infections?

via Aidsmap, by Gus Cairns

Moupali Das of the San Francisco Department of Public Health presented evidence to show that the city’s intensive testing and treatment policy was beginning to result in a declining HIV infection rate there. Similar evidence was presented from the province of British Columbia in Canada.

The evidence presented still leaves some questions unanswered, however.

• Is the reduction in viral load in the HIV-positive population (the 'community viral load' or CVL) really the cause of the decreased level of diagnoses seen in San Francisco in the last few years, or is it due to the success of prevention campaigns and reductions in risky behaviour?
  
• Do reduced diagnoses really indicate reduced incidence of infection?
  
• Is reducing the average viral load of diagnosed people a good indicator of the average infectiousness of people with HIV in the community – or do high viral loads in the minority who remain undiagnosed make this an unreliable indicator?

The answers to these questions are crucial as the future direction of HIV prevention policy may depend on them, in particular whether to concentrate on suppressing viral load or on behaviour change as the mainspring of prevention.

Read the rest. 

[If an item is not written by an IRMA member, it should not be construed that IRMA has taken a position on the article's content, whether in support or in opposition.]

CROI 2011: Rectal Microbicides to Prevent HIV Infection in Heterosexual Populations in High-prevalence Settings

Poster from CROI 2011

Dobromir Dimitrov*1, M-C Boily2, S Abdool Karim3, and B Mâsse1,4
Fred Hutchinson Cancer Res Ctr, Seattle, WA, US; 2Imperial Coll London, UK; 3Univ of KwaZulu-Natal, Durban, South Africa; and 4Univ of Montreal, Canada


Background:
The role of anal intercourse in the overall heterosexual HIV epidemic remains unclear. However, it may be an important risk factor because the considerably higher risk of HIV infection during unprotected receptive anal intercourse compared to vaginal intercourse. Anal intercourse is widely practiced by heterosexuals in many countries; in Tanzania, 6% of sexually active school pupils reported anal intercourse at their first sexual experience. In Cape Town, 10 to 14% of the study participants reported engaging in anal intercourse over the last 3 months. Different mathematical modeling studies have assessed the potential impact of a vaginal microbicide in heterosexual populations and of a rectal microbicide for homosexuals. However, none have assessed the potential impact of a rectal microbicide in heterosexual population. Our study aims to compare the potential impact of rectal, vaginal, and bi-compartment (i.e. applied vaginally and protective during vaginal and anal intercourse) microbicides to prevent HIV acquisition and transmission in heterosexual populations.

Methods:
Risk equations were used to determine under which conditions a rectal microbicide could be as useful as a vaginal microbicide. A transmission dynamic model was used to assess the population-level impact of the different microbicides in a variety of intervention scenarios and high HIV prevalence settings and to predict the fractions of new HIV infections prevented over fixed time periods.

Results:
Without anal intercourse, a 50% efficacious vaginal microbicide used by 100% of females prevents about 10% and 25% of all new male and female HIV infections over 10 years if adherence is 30% and 75%, respectively. These 10-year infection preventions are reduced by 32% in populations with 10% frequency of receptive anal intercourse, assuming 4-fold increase in transmission risk per receptive anal intercourse (RRRAI). A rectal microbicide could be as effective as a vaginal microbicide in populations with anal intercourse rates ranging from 5% to 20% across a range on RRRAI, assuming similar efficacy and frequency of use of both products. A rectal microbicide has less impact than a vaginal microbicide in populations with <5% anal intercourse, unless it is used more often or is more efficacious than a vaginal microbicide. The 10-year infections prevented of bi-compartment microbicide is 2-fold larger than vaginal microbicide in populations with 10% anal intercourse if RRRAI = 10- and ~6-fold larger than rectal microbicide, in populations with 5% anal intercourse if RRRAI = 4.

Conclusions:
Both rectal microbicide and bi-compartmental microbicide are necessary prevention tools for heterosexual populations engaging, relatively frequently (~10% of sex acts), in anal intercourse.


[If an item is not written by an IRMA member, it should not be construed that IRMA has taken a position on the article's content, whether in support or in opposition.]

Q and A: Moving PrEP from Promising Trial Result to Practical, Public Health Prevention Intervention?

by Julie Davids, AIDS Foundation of Chicago, HIV Prevention Justice Alliance and IRMA member

As noted in these pages and press reports worldwide, the iPrex trial found that daily use of truvada protected gay men, other MSM and trangender women from HIV infection.

Updated data presented at this week's Conference on Retroviruses and Opportunistic Infections (CROI) showed the trial results held true through 144 weeks - nearly three years - and that the key challenge seems to be adherence. Those who took the drug most or all of the time (about 1/2 of the people in the study) had high rates of protection - over 90%. But because the other half took little or no drug at all (as confirmed by blood tests), the overal efficacy rate among trial participants was 44%.

After a long day at the conference, an eager crew of conference-goers - including researchers, people with HIV, White House officials and press - joined local community members here in Boston on Tuesday night in the auditorium of Fenway Community Health for ARV-Based Prevention: A Community & Research Forum on Recent Results and What Happens Next, sponsored by AVAC and Fenway.

At the end of the formal presentations, I asked the panelists (on behalf of the HIV Prevention Justice Alliance)

"What are one to three next steps that are vital to making PrEP [pre-exposure prophylaxis] effective at the community or public health level, rather than just a boutique intervention for a few individuals?"

I captured the responses, which cover a wide range of issues and strategies, and wanted to share them with you. Panelists, in order of response, were:

- Morenike Ukpong, New HIV Vaccines and Microbicide Advocacy Society, Nigeria
- Kevin Cranston, Massachusetts Bureau of Infectious Disease
- Cate Hankins, UNAIDS
- Salim Abdool Karim, CAPRISA
- Jared Baeten, University of Washington and Partners PrEP
- Robert Grant, Gladstone Institute of Virology and Immunology
- Jim Rooney, Gilead Sciences
- Mark Hubbard, Tennessee Association of People With AIDS



Q and A: Moving PrEP from Promising Trial Result to Practical, Public Health Prevention Intervention? from HIV Prevention Justice Alliance on Vimeo.

High-Impact Prevention: New Approach to the Science and Practice of HIV Prevention in the United States?

by Julie Davids, AIDS Foundation of Chicago, HIV Prevention Justice Alliance and IRMA member

This week at the Conference on Retroviruses and Opportunistic Infections (CROI) in Boston, researchers and clinicians from around the world met to share and discuss HIV research.

The opening plenary on Monday was delivered by Jonathan Mermin, Director of the Division of HIV/AIDS (pictured). Titled The Science and Practice of HIV Prevention in the US, the 30 minute presentation outlined Mermin's vision of a new approach called high-impact prevention (HIP). I caught up with Mermin the following day, and asked him to talk about his speech, explaining what HIP is all about.

If this quick video grabs your interest, you can view Mermin's full presentations and slides right here - and you can look around that conference site for more webcasts of important sessions. I'll be blogging about other conference matters of interest to HIV prevention justice advocates in the coming days, including some thoughts on high-impact prevention, pre-exposure prophylaxis, racial disparities in infection, and other matters...



[If an item is not written by an IRMA member, it should not be construed that IRMA has taken a position on the article's content, whether in support or in opposition.]

PRESS RELEASE: Researchers Reformulate Tenofovir Vaginal Gel for Rectal Use

via Microbicide Trials Network

[The abstract, Tenofovir Gel Reformulation Results in Improved Product Safety for Rectal Application, was presented at a poster session from 2-4 p.m., Monday, Feb. 28. The results of RMP-02/MTN-006 were discussed at a CROI press conference from 7:30-8:30 a.m., Monday, Feb. 28]

‘New’ gel safe in laboratory studies




BOSTON, Feb. 28, 2011 – A change in the formulation of tenofovir gel, an anti-HIV gel developed for vaginal use, may make it safer to use in the rectum, suggests research presented today at the 18th Conference on Retroviruses and Opportunistic Infections (CROI). In laboratory tests of rectal tissue, researchers from the Microbicide Trials Network (MTN) found the reformulated gel was less harmful to the lining of the rectum than the original vaginal formulation, and just as effective in protecting cells against HIV.

Researchers are now testing the reformulated gel in an early-phase clinical trial with men and women. Results from these and future studies will have important implications for the development of a rectal microbicide that could help protect against HIV or other sexually transmitted infections during anal sex.

Tenofovir gel has shown significant promise in reducing HIV risk in women through vaginal sex. But because the rectal epithelium – the lining of the rectum that serves as the first line of defense against HIV – is much thinner than the vaginal lining, the gel may not be safe or effective to use rectally. By its nature, tenofovir gel is hyperosmolar – contains a higher concentration of sugars and salts relative to cells. This quality could have a harmful effect on the rectal lining by causing epithelial cells to shrink as they purge water to achieve balance. Weakened in this manner, the rectal epithelium may be less able to protect against HIV.

To make tenofovir gel safe and more amenable to rectal use, researchers from CONRAD, a research organization which holds the rights to develop the gel, reformulated it with a reduced amount of glycerin, a common additive found in many gel-like products. In laboratory tests conducted by MTN researchers, the reformulated gel was three times less likely to cause cells in rectal tissue to release water, and equally effective against HIV as the vaginal formulation.

“The lining of the rectum is much more fragile than the vaginal epithelium, so we can’t be certain a product like tenofovir gel that is safe for vaginal use will be completely safe to use in the rectum,” said Charlene Dezzutti, Ph.D., associate professor of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh School of Medicine and principal investigator of the MTN Network Laboratory. “We are very encouraged by our laboratory data that suggest the reformulated gel could be safer for rectal use. These results provide an important bridge to clinical studies, and we have already begun testing it with men and women.”

The new formulation of tenofovir gel is being tested for safety and acceptability in a clinical trial called MTN-007, currently underway at three MTN-affiliated sites at the University of Pittsburgh,

RMP-02/MTN-006, the first-ever clinical study to test the safety of vaginal tenofovir gel in the rectum. These results, which were also presented at CROI, found the gel significantly inhibited HIV in tissue samples, but that men and women in the study did not particularly like it and some experienced uncomfortable gastrointestinal side effects. Researchers are hopeful the reformulated gel now being tested in MTN-007 will address these concerns.

In addition to Dr. Dezzutti, other authors of the study are Lisa Rohan, Ph.D., University of Pittsburgh; J.D. Lynam, Magee-Womens Research Institute; Lin Wang, M.D., Ph.D., Magee-Womens Research Institute; and David Friend, Ph.D., CONRAD, Arlington, Va.

Tenofovir gel contains the antiretroviral tenofovir, which is commonly used in the treatment of HIV. Both the oral and vaginal formulations of tenofovir were developed by Gilead Sciences, Inc., of Foster City, Calif. In 2006, Gilead Sciences assigned the rights for tenofovir gel to the International Partnership for Microbicides of Silver Spring, Md., and CONRAD, of Arlington, Va.

The study was conducted through the MTN, which is funded by the National Institute of Allergy and Infectious Diseases Division of AIDS with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

# # #

The abstract, Tenofovir Gel Reformulation Results in Improved Product Safety for Rectal Application, was presented at a poster session from 2-4 p.m., Monday, Feb. 28. The results of RMP-02/MTN-006 were discussed at a CROI press conference from 7:30-8:30 a.m., Monday, Feb. 28.

About the Microbicide Trials Network

The Microbicide Trials Network (MTN) is an HIV/AIDS clinical trials network established in 2006 by the National Institute of Allergy and Infectious Diseases with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health. Based at Magee-Womens Research Institute and the University of Pittsburgh, the MTN brings together international investigators and community and industry partners who are devoted to preventing or reducing the sexual transmission of HIV through the development and evaluation of products applied topically to mucosal surfaces or administered orally.


[If an item is not written by an IRMA member, it should not be construed that IRMA has taken a position on the article's content, whether in support or in opposition.]

PRESS RELEASE: Tenofovir Gel Provides High Level of Protection Against HIV in Rectal Tissue

via Microbicide Trials Network

[The abstract, RMP-02/MTN-006: A Phase I Placebo Controlled Trial of Rectally Applied 1% Vaginal Tenofovir Gel with Comparison to Oral Tenofovir Disoproxil Fumarate, is being presented at a scientific session at CROI 2011 TODAY from 10 a.m. - 12:15 p.m. ET.]



Strongest effect seen in tissue taken from participants after one week of use

BOSTON, Feb. 28, 2011 – A gel developed to protect against HIV during vaginal sex produced a strong antiviral effect when used in the rectum, according to an early-phase study presented today at the 18th Conference on Retroviruses and Opportunistic Infections (CROI). The results, based on rectal tissue biopsies sampled from HIV-negative men and women who used the product daily for one week, provide the first-ever evidence that tenofovir gel could help reduce the risk of HIV from anal sex, even though the vaginal gel formulation may not be optimal for rectal use.

Tenofovir gel was not especially well-liked by a majority of men and women in the study, yet most reported they would be likely to use the gel if it became available in the future as a method for preventing HIV. Although the study found use of the gel generally safe, side effects were problematic to a few study participants. In hopes of making tenofovir gel more acceptable for rectal use, researchers have since modified the gel and are now testing it in another study.

“We are very encouraged about these findings that indicate applying tenofovir gel topically to the rectum could be a promising approach to HIV prevention,” said Peter Anton, M.D., professor of medicine and director of the Center for Prevention Research at the University of California, Los Angeles (UCLA), who led the study with Ian McGowan, M.D., Ph.D., co-principal investigator of the Microbicide Trials Network (MTN) and professor of medicine at the University of Pittsburgh.

“These are early results, but help set the stage for current and future trials of rectal microbicides and the development of a rectal-specific formulation of tenofovir gel,” added Dr. McGowan, who is leading the second study of the new gel formulation.

Microbicides, products applied on the inside of the rectum or vagina, are being designed and tested to help prevent or reduce the sexual transmission of HIV or other sexually transmitted infections. The majority of microbicide research thus far has focused on products to prevent HIV during vaginal sex. Yet, the risk of becoming infected with HIV from unprotected anal sex may be at least 20 times greater than unprotected vaginal sex, in part because the rectal lining is only one-cell thick compared to the vagina’s multiple layers, making it easier for the virus to reach cells to infect.

The study, known as RMP-02/MTN-006, is the first clinical trial of tenofovir gel for rectal use. Last year, tenofovir gel was shown in a trial called CAPRISA 004 to reduce the risk of HIV infection in women who used it before and after vaginal sex.

Conducted at UCLA and the University of Pittsburgh, RMP-02/MTN-006 tested two products – tenofovir gel and oral tenofovir – in 18 sexually abstinent, HIV-negative men and women. Oral tenofovir, an antiretroviral (ARV) tablet commonly used to treat people with HIV in combination with other ARVs, is being explored as a means to prevent infection in people who are HIV-negative through an approach called pre-exposure prophylaxis, or PrEP.

The trial directly compared the anti-HIV activity of a single dose of oral tenofovir to a single dose of rectally-applied tenofovir gel. This was followed by six days of at-home dosing of tenofovir gel or a placebo gel, with the last and seventh dose given in the clinic. A novel approach was used to determine whether any actual protection was provided by the drug given in the different regimens – single oral, single gel and seven-day gel (or placebo) – in which small biopsies were taken from the rectal lining of the participants using a standard clinical procedure called sigmoidoscopy. The tissue samples were then sent directly to the laboratory where they were exposed to HIV to determine how well study products protected the tissue from infection.

The researchers found that HIV was significantly inhibited in tissue samples from participants who used tenofovir gel daily for one week compared to tissue from participants who used the placebo gel. While a slight anti-viral effect was noted in tissue from participants who received a single dose of tenofovir gel, the finding was not statistically significant. The single dose of oral tenofovir did not provide any protection against HIV in rectal tissue samples.

“These kinds of efforts early in the development phase of rectal microbicides can give us insight into a particular product’s potential efficacy, which enables us to better design and hasten the pace of future clinical trials,” said Dr. Anton.

According to self-reports, only 25 percent of men and women who had used the tenofovir gel said they liked it. However, when asked whether they would consider using the product in the future, 75 percent of these participants reported a high likelihood of future use. Two of the 12 participants who received tenofovir gel reported severe gastrointestinal side effects, including diarrhea and lower abdominal cramps.

“These results tell us that tenofovir gel was relatively safe to use in the rectum for most participants, but we need to address side effects to make it more acceptable to use,” said Dr. Anton, who reported the findings at CROI. “Even though three-quarters of the participants reported they didn’t like the gel, we are very encouraged that the majority would consider using such a product in the future.”

Another study, MTN-007, now underway is using a formulation of tenofovir gel with less glycerin, a common additive found in many gel-like products, in the hope that this will make it better tolerated when used in the rectum. Laboratory tests of the reformulated gel suggest it is just as effective as the original formulation but less irritating to the epithelium – the layer of cells that serves as a protective barrier inside the rectum. The study began in October 2010 and is enrolling 60 men and women at three sites – University of Pittsburgh, University of Alabama at Birmingham and Fenway Health in Boston.

In addition to Drs. Anton and McGowan, other authors of RMP-02/MTN-006 are Ross Cranston, M.D., University of Pittsburgh; Alex Carballo-Dieguez, Ph.D., Columbia University; Angela Kashuba, PharmD, University of North Carolina; Elena Khanukhova, UCLA; Julie Elliott, UCLA; Laura Janocko, Ph.D., MTN and Magee-Womens Research Institute; William Cumberland, Ph.D., UCLA; and Christine Mauck, M.D., M.P.H., CONRAD.

RMP-02/MTN-006 was a collaboration between the Microbicide Development Program at UCLA and the MTN. UCLA’s Microbicide Development Program is funded by the Division of AIDS Integrated Preclinical/Clinical Program for HIV Topical Microbicides at the National Institute of Allergy and Infectious Diseases. The study products were developed by Gilead Sciences, Inc., of Foster City, Calif., which assigned the rights for tenofovir gel to the International Partnership for Microbicides of Silver Spring, Md., and CONRAD, of Arlington, Va., in December 2006. Gilead Sciences and CONRAD provided the study products free of charge.

# # #

Additional information about the study and rectal microbicides is available here.

The Microbicide Trials Network (MTN) is an HIV/AIDS clinical trials network established in 2006 by the National Institute of Allergy and Infectious Diseases with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health. Based at Magee-Womens Research Institute and the University of Pittsburgh, the MTN brings together international investigators and community and industry partners who are devoted to preventing or reducing the sexual transmission of HIV through the development and evaluation of products applied topically to mucosal surfaces or administered orally.


[If an item is not written by an IRMA member, it should not be construed that IRMA has taken a position on the article's content, whether in support or in opposition.]

Maraviroc showing tantalising promise as (a rectal) microbicide in preclinical studies (CROI)

via Aidsmap, via Gus Cairns

Excerpt: 

n the other presentation, Kevin Brown of the University of North Carolina presented findings of maraviroc concentration in the semen and rectal tissue of male volunteers after oral dosing.

The study used twelve HIV-negative male volunteers, who took an eight-day course of maraviroc dosed at the treatment level of 300mg twice daily.

Blood and semen drug levels were measured five times in twelve hours after a single dose on days one, seven and eight of the study, and also once on days three to six. Rectal biopsy specimens were collected on days one, seven and eight.

After a single dose, semen and blood plasma levels were initially the same but after six hours semen levels fell off more quickly. Trough levels in semen were 70% of blood levels on days 7/8, and the area under the curve (AUC – total drug exposure) in semen was 60% of that in blood. Levels seen after multiple dosing were similar.

Concentrations in rectal tissue were much higher than in blood, with a mean trough level 91 times higher than in blood and the AUC 28 times higher.

Dr Brown said that the rectal tissue levels appeared promising for the use of maraviroc as a rectal microbicide. Levels might be higher because maraviroc was partially eliminated in the faeces.  

Read the whole thing.

CHAMP and AVAC Webinar Series on CROI --- Materials Available

This past February, scientists and clinicians convened at the Conference on Retroviruses and Opportunistic Infections (CROI) in Montréal to present, discuss and critique their research on the biology and epidemiology of HIV.

Envisioned as a "meeting of the minds" between laboratory and clinical science, the goal of this annual conference is to translate this research into progress against the AIDS epidemic. For the past several years, prevention has gained a place of prominence at the conference, which previously had focused on treatment issues.

Due to activist pressure during the conference's initial years, this meeting also includes AIDS activists and community press. Participation by community members adds a vital voice to the conference by asking critical questions that have broadened and sharpened the perspectives of researchers and other stakeholders attending this important meeting.

Unfortunately, participation remains out of reach to many due to the limited number of scholarship slots as well as financial constraints.

This year, CHAMP and AVAC worked with partners to bring the information and dialogue from the conference to a much broader audience through a Webinar Series (held in February and March) - materials of which are all available online.

In order to deepen community understanding and discussion of the prevention research issues discussed at CROI, the series featured four webinars that provided an overview of the scientific presentations.

Each webinar featured:

* An online slide show presented by key researchers and/or advocates
* Discussion on how each topic fits in a broader research advocacy agenda and opportunities for further engagement in advocacy

The distance-learning program is formatted in four 60- to 75-minute sessions, and is divided into the following topics:

Introduction: How to Read an Abstract and Understand Research Language

Pre-Exposure Prophylaxis and Other Topics in Biomedical Prevention Research

HIV Transmission: Characteristics and Prevention

HIV Prevention Research: Looking Back and Moving Forward

Click here to access all the materials, including recordings and slides.

Thanks to CHAMP and AVAC for this wonderful resource!

Scientists Debate HIV Prevention Products - NPR today

[NOTE - not a word on rectal microbicides, and a rather pessimistic take on microbidide development from the Gates Foundations's Tachi Yamada]

via Morning Edition, March 10, 2009

For years now, scientists have tried to find a product that would give women in developing countries more control in protecting themselves against sexually transmitted HIV. They have yet to find a universally effective and safe method.

A recent study presented at the Conference on Retroviruses and Opportunistic Infections in Montreal highlighted the dilemmas in this field — a gel to prevent HIV worked in 30 percent of the women who tried it. Many scientists have dismissed those results because there was a 1-in-10 chance that the effect was due to chance. Others who had great expectations riding on the findings were encouraged.

Still, Tachi Yamada (pictured), director of global health policy for the Bill and Melinda Gates Foundation, was concerned that the results were presented as promising.

"To me, it was very unfortunate," says Yamada. "In fact, there should be a little bit of concern that this is now the fifth or sixth trial that came out statistically insignificant."

Read the rest.

Listen Now [4 min 50 sec]

Rectal Microbicide Research at CROI 2009

The prevalence of receptive anal intercourse among men and women the world over requires the research and development of safe, effective and acceptable microbicides designed specifically for the rectum as well.

Today at CROI 2009, two interesting Poster Discussions were held of special interest to IRMA members.

You can access the abstracts and actual posters for each of these.

IRMA asked Drs. Peter Anton and Ian McGowan for their thoughts regarding these important findings. You can read their remarks below.






A Phase 1 Safety and Acceptability Study of the UC781 Microbicide Gel Applied Rectally in HIV Seronegative Adults: A First in Field

Peter Anton, A Adler, E Khanuknova, J Elliott, W Cumberland, Y Zhou, A Ventuneac, A Carballo-Dieguez, C Mauck, and I McGowan

Representing David Geffen Sch of Med, Univ of California, Los Angeles, US; Translational Sci Corp, Mill Valley, CA, US; Univ of California, Los Angeles Sch of Publ Hlth, US; HIV Ctr for Clinical and Behavioral Studies, New York, NY, US; CONRAD, Arlington, VA, US; and Magee-Womens Res Inst, Pittsburgh, PA, US

Click here for the abstract.

Click here for the PDF of the poster.



Strong Ex-Vivo Suppression of HIV-1 Infection of Colorectal Explants from In-Vivo Rectal Application of UC781 Gel: A Novel Endpoint In A Phase 1 Trial

Peter Anton, J Elliott, I McGowan, A Adler, K Tanner, EJ Johnson, T Saunders, C Siboliban, E Khanukova, Y.Zhou.

Representing David Geffen School of Medicine, Los Angeles, CA,
Magee-Women’s Research Institute, University of Pittsburgh Medical School, Pittsburgh, PA

Click here for the abstract.

Click here for the PDF of the poster.


Dr. Peter Anton – "The Phase I rectal safety trial of the vaginal gel formulation of UC781 was historic in that it was the first of its kind in the field. While we determined that the gel appeared safe, well tolerated and acceptable among trial participants, it is noteworthy that we also observed signs of efficacy. Namely, this type of test could be an important new protocol the entire microbicide field might adopt as a way to help evaluate which products move forward in the pipeline.

"This Phase 1 rectal safety study for microbicides, using CONRAD’s UC781 lays the foundation for the many necessary trials to follow. This study required close, active collaboration with CONRAD, NIH and the FDA, as well as the academic research institutions (UCLA, U Pittsburgh/McGee Women’s Hospital and Columbia University).

"So, the first point is that this study has forged new territory in beginning to define relevant procedures, definitions of risk and mucosal injury.

"Second, the study itself showed great results for Phase 1: the drug and formulation appears safe by all indices measured. This bodes well for its advancing and also assisting an FDA application for vaginal use (should that prove possible) by already having a rectal safety study completed.

"Thirdly, and of great interest for future trials, were the remarkable results from the novel “explant study”, which saw a strong suppression of HIV replication (HIV was applied to tissue biopsies in the laboratory) from study subjects who had received the study drug (in vivo) 30 minutes before biopsy.

"This is the closest we can come to testing real, human, sexually-exposed tissue, already treated with a microbicide to determine if it helps to resists HIV infection. In this study, it did….a remarkable result that even we did not anticipate to this degree.

"With limited resources and the clear necessity for both vaginal and rectal microbicides, we need sophisticated tools to make the best decisions earlier about the viability of any candidate microbicide and which ones to advance to more expensive, longer studies. This is not yet an actual early marker of eventual efficacy, but it is an exciting start."

Dr. Ian McGowan – “The results of the UC781 trial, in which we observed both safety and efficacy signals after testing the vaginal gel formulation of an NNRTI, are encouraging for the field of rectal microbicides.

"Later this year, the Microbicide Trials Network will launch a new Phase I safety trial to determine the safety and acceptability of Tenofovir vaginal gel applied rectally and will co-sponsor a parallel Phase 1 trial using tenofovir gel and oral formulations with NIH’s Integrated Preclinical-Clinical Program (IPCP) for microbicides.

"There is an associated 10-20 fold increased risk of HIV transmission during unprotected anal intercourse compared to unprotected vaginal intercourse. Anal intercourse among gay men, men who have sex with men, and between heterosexual men and women is common globally. We know that much of this behavior is unprotected.

"Therefore, we need two things. first, we must have rectal safety data on all vaginal microbicides in the pipeline, because we know they will be used vaginally and rectally.

"And secondly, the prevalence of receptive anal intercourse among men and women the world over requires the research and development of safe, effective and acceptable microbicides designed specifically for the rectum as well."

PrEP could work even if taken several days in advance

via Aidsmap

A study using tenofovir and FTC (Truvada) to prevent rectal HIV infection in monkeys – so-called pre-exposure prophylaxis (PrEP) - has shown that it is as effective to take the medication up to three days before exposure as it is to take it a day before. Even taking Truvada a full week before exposure resulted in a considerable reduction in the risk of infection.

In contrast, taking the medication only two hours before exposure resulted in a smaller protective effect, possibly because intracellular concentrations of the drugs had not reached high enough levels.

Read the rest.