Conference special – news from CROI 2015

Most of the stories in this bulletin are from presentations at the Conference on Retroviruses and Opportunistic Infections (CROI 2015) in Seattle last month. For Aidsmap’s full CROI 2015 conference coverage, see www.aidsmap.com/croi2015. The conference website is at www.croiconference.org.

Two European PrEP studies report very high effectiveness

Two separate European studies of pre-exposure prophylaxis (PrEP) were presented at the conference, demonstrating the highest effectiveness yet seen for this technique, in which HIV-negative people take anti-HIV drugs to prevent infection. By coincidence, both the English PROUD study and the French/Canadian Ipergay study reported exactly the same effectiveness – 86%. In other words, taking the two-drug combination of tenofovir and emtricitabine (Truvada) stopped more than 17 out of every 20 HIV infections that would otherwise have happened.

The 86% effectiveness was the difference in the HIV infection rate in people who were offered PrEP and people who were not. In fact, it is almost certain that none of the five people infected while allocated to PrEP – three in PROUD and two in Ipergay – were actually taking Truvada at the time they were infected. Four had stopped taking it and in one case it appears the participant was infected just before he started PrEP (he tested HIV-positive one month later).

These two PrEP trials were originally only intended as pilot trials for the much larger ones that it was thought would be necessary to demonstrate effectiveness. Both were ‘unrandomised’ and all participants offered PrEP last October when it became clear that they had worked far better than expected. The fact that they both demonstrated effectiveness early is due to there being very high annual rates of HIV infection in the men who did not take PrEP – 6.75% a year in Ipergay and 8.9% in PROUD.

One encouraging aspect of the two trials is that they used very different methods, yet came to the same result. In PROUD, the 545 men in the trial were allocated either to take PrEP immediately or to delay taking it for a year. The 86% is the difference in infections between men already taking PrEP and the men waiting for it. In Ipergay, a new PrEP regimen was followed – half of the 400 participants took Truvada, and half a placebo,only when they thought they were likely to have sex. They took two pills 2 to 24 hours before they expected sex and then if they actually had sex, took one pill on each of the next two days. Here the 86% is the difference in infections between men taking Truvada and men taking placebo.

Neither study reported any significant increases in HIV risk behaviour or in STI diagnoses during the study. About one in eight participants reported side-effects and some people stopped PrEP temporarily but only one person in Ipergay and two in PROUD permanently discontinued Truvada due to side-effects.

In PROUD, which was intended to mimic what a ‘real life’ sexual health service could provide, participants received their first PrEP dose at the same time as their first HIV test and six participants turned out to already be HIV positive the day they started PrEP. Of these, three acquired drug resistance to emtricitabine, as did two of the three who tested positive after being allocated to PrEP. However, none acquired resistance to tenofovir.

Comment: These two important studies show that PrEP can be a robust, flexible and reliable method of preventing HIV and should finally lay to rest fears that it will inevitably fail due to low adherence. The very high HIV incidence observed in both studies in those not on PrEP demonstrates that there are groups of gay men at imminent risk of HIV who could avoid it if given PrEP. In addition, one figure not reported in the Aidsmap report was that in PROUD one HIV infection would be prevented for every 13 men put on PrEP (every 18 in Ipergay). This so-called ‘number needed to treat’ is low enough to show that PrEP could be cost-effective, even at European drug prices. Drug companies and European regulators should be moving to licence PrEP in Europe as soon as possible.

Tenofovir microbicide gel fails in South African study

One disappointing result presented at CROI was that of the FACTS 001 study. This failed to prevent HIV infection in a group of 2029 women aged 18-30 in South Africa who used a microbicide gel containing the anti-HIV drug tenofovir before and after sex. The HIV infection rate – about 4% a year – was identical in women given the gel and women given a placebo gel.

The FACTS study was a follow-on study from the smaller CAPRISA 004 study, which demonstrated a moderate effectiveness of 39% for the same microbicide gel, back in 2010. Meanwhile the VOICE study – where women used the microbicide gel daily rather than just before and after sex – also failed to show any effect.

In both cases, the explanation for the failure of the gel to prevent HIV was low adherence. In FACTS, the 20% of women with the highest adherence – who used the gel more than three-quarters of the time – had 57% fewer HIV infections than women using placebo, and in VOICE the HIV infection rate was reduced by 66% in the 25% of women with evidence from blood tests that they had used the gel.

In FACTS 001, the adherence rate was higher than in VOICE; 64% of blood samples taken indicated that women had used the gel in the last ten days (though this does not mean they were using it often enough) and only 13% never used the gel. However, only 22% of women had drug found in all of their samples.

Evidence from qualitative studies in VOICE suggested that women had not used the intervention offered because they did not trust it to be effective. However, the young women in FACTS 001 reported trying to use the gel but forgetting to take it with them or not being in a position to apply it.

Comment: As researcher Helen Rees told Aidsmap: “Most of the young women tried to use the gel…but it may be that this method of HIV prevention is just not suitable for young women” (the average age of FACTS 001 participants was 23). It is worth noting that young South Africans have greatly increased their use of condoms since 2002 but this is clearly not enough in this very high-prevalence country to reverse very high rates of new infection, especially in young women. It may be that measures like the vaginal rings being tested in the ASPIRE and RING studies, which only need to be inserted once a month, may suit young women’s lifestyles better.

PrEP use is becoming normalised in San Francisco

A survey at San Francisco’s main sexual health clinic has found that one in six HIV-negative gay men attending the clinic is now taking pre-exposure prophylaxis (PrEP) and that 60% wanted to take it. Other surveys from San Francisco have found similar usage rates for PREP.

A population survey of gay men in the city suggests that of the estimated 50,000 gay men in San Francisco, about 14,000 of the HIV-negative ones were at substantial risk of HIV infection, plus nearly 2000 transgender women and heterosexual women with bisexual HIV-positive partners. Of these highest-risk people, it was estimated that 31% were already using PrEP, and San Francisco’s continuing decline in HIV infections suggests that use amongst those most imminently at risk might be even higher.

Dr Bob Grant, lead investigator of the iPrEx study, told the conference that San Francisco had one of the highest rates of viral suppression in the HIV-positive population in the US (62%) but that, to reduce HIV infections by 70%, PrEP would have to be used by 95% of people at the highest risk of HIV. If the viral suppression rate in people living with HIV was also increased to 90%, then there could be as few as 50 new infections a year in a city that had 359 in 2013.

Comment: While this study was presented by Dr Grant as evidence that PrEP use had a long way to go before having a substantial public health impact, it is more likely to be received in the rest of the world as evidence that PrEP can be routinely adopted by the gay community and that other cities with large gay populations should be able to roll out PrEP to the same degree.

Mixing PrEP and treatment almost eliminates infections in African couples

A study in heterosexual couples in Kenya and Uganda combining pre-exposure prophylaxis (PrEP) for the HIV-negative partners with HIV treatment for the HIV-positive partners almost completely eliminated HIV infection in the negative partners.

The Partners PrEP demonstration project, a study by the same team that conducted the original Partners PrEP study, uses PrEP for the HIV-negative partner as a ‘bridge’ to protect them before the HIV-positive partner starts taking antiretroviral therapy (ART) and until they achieve an undetectable viral load. All partners are offered antiretrovirals (ARVs).

The study is still ongoing. Between November 2012 and August 2014, it enrolled 1013 couples (2026 participants) who were thought to be at especially high risk of HIV transmission within the couple. During this period, in 48% of couples the HIV-negative partner was taking PrEP, in 27% both partners were taking PrEP/ART, in 16% the HIV-positive partner was taking ART, and in 9% neither partner was on ARVs. It is expected that the proportion of HIV-positive partners on ART will rise as the study continues.

Adherence was 87% in the partners on PrEP and at least 90% in those on ART. By comparing with infections in the original Partners PrEP study, and adjusting for the characteristics of couples in the new study, it was estimated that 40 HIV transmissions would have occurred to HIV-negative partners during the period studied without ARVs being taken by either partner. Instead, there were two infections observed, equating to a 96% reduction in HIV infections. Both infections were in women who were not taking PrEP at the time. One came from an HIV-positive partner who had not started ART, and one from a new partner who was not in the study.

Researcher Jared Baeten commented that some African governments were now ready to adopt combinations of PrEP and ART like this in order to bring down HIV infection rates.

Comment: Partners PrEP demonstrated the highest effectiveness seen in PrEP until PROUD and Ipergay came along – 75% in couples where the negative partner was offered Truvada. This study reinforces what the original one showed – that trust in couples really helps with adherence. Note that the 96% effectiveness included a near-elimination of infections acquired from ‘extramarital’ partners as well as the primary one. The ‘risk algorithm’ the researchers used to estimate which couples were more vulnerable to HIV transmission happening between them was also an innovation in this trial.

No transmissions from HIV-positive partner seen in Australian gay-couple study

A study of 152 male gay couples with opposite HIV status (serodiscordant or ‘magnetic’ couples) from Australia, Thailand and Brazil has so far failed to observe a single HIV transmission from one partner to another, during what was estimated to be nearly 6000 acts of condomless anal sex.

Fifty-eight per cent of the couples in the Opposites Attract study reported condomless anal sex, with the HIV-negative partner as ‘bottom’ on 40% of occasions. Most of the HIV-positive partners (84%) were on antiretroviral therapy (ART) and nearly all of those had an undetectable viral load. Only 4% of condomless sex acts involved an HIV-positive partner not taking treatment or who was not virally undetectable.

No transmissions does not mean no risk of transmission, and the researchers estimated that, given the relatively small number of men recruited so far, the maximum-likely probability of transmissions per sex act they could have missed might be 4% a year and as much as 7% a year when the negative partner is bottom. This is a statement of the statistical uncertainly of the study, not the actual chance of transmission. The larger PARTNER study reported at CROI 2014 that the maximum-likely probability of transmission observed was 1%, and 2.5% with the negative partner as bottom.

Comment: Both studies are ongoing and unless an unexpected transmission is observed, the estimated maximum likelihood of transmission from a virally suppressed HIV-positive partner will get closer to zero as more data points are accumulated. Leaving aside arguments about the absolute chance of getting infected, this study, like PARTNER, reinforces the message that wherever gay men are getting HIV from, it is not from diagnosed HIV-positive people on treatment.

Young people find it particularly hard to adhere to taking HIV drugs, whether as prevention – as seen in the FACTS 001 study above – or even as lifesaving treatment.

A study presented at CROI has found that an antiretroviral therapy (ART) regimen in which 100 HIV-positive children and young people, average age 14, took their drugs on a five-days-on, two-days-off basis (with the two days usually at the weekend) was at least as successful in maintaining an undetectable viral load as was standard daily therapy in 100 other young people. It was also very popular, with three-quarters of the young people saying it made life “a lot” easier.

After a year on the five-to-two regimen, 6% of young people on the weekend-off regimen experienced a rebound of their viral load versus 7% on daily ART. They were also less likely to change treatment regimen during the year.

These were all young people who had achieved at least a year of viral suppression on their first ART regimen. It is also important to emphasise that the ART chosen contained the NNRTI drug efavirenz, which has a particularly long half-life.

Comment: This is not the first time a weekend-off regimen has been shown to be viable: the first was the FOTO study back in 2004. But this is the first study to try the idea in adolescents, who may be particularly sensitive about taking ART in leisure time: the main improvement the 5/2 regimen enabled, according to the young people in this study was in “going out with friends”.

Other recent news headlines

PrEP for other STIs might work

A pilot study in which 15 HIV-positive gay men were given the antibiotic doxycycline as pre-exposure prophylaxis (PrEP) against bacterial sexually transmitted infections (STIs) found that their overall rate of STI infection was reduced by 70%, compared with 15 HIV-positive gay men given financial incentives to avoid STIs. The researchers comment that because of the risk of antibiotic resistance, PrEP for STIs would not be an appropriate prevention tool in most gay men but that “for a small yet epidemiologically important population…its use may outweigh theoretical resistance risks.”

HIV testing continues to rise in UK gay men

A comparison of the last two Gay Men’s Sex Surveys in the UK has found that the proportion that had ever taken an HIV test rose from 72% in 2010 to 77% in 2014 and that the proportion who had tested for HIV in the past year jumped from 43% to 56%. Among those who had previously tested, the proportion who had done so in the past year increased from 66% to 75%.

We may need to combine many approaches to achieve a cure

A number of different presentations at the CROI conference covered approaches towards curing HIV, ranging from bone marrow transplants and gene therapy to a new class of drugs, PD-1 blockers. Many approaches however are at the test-tube or animal-model stage or may be difficult to use in most patients, delegates at the main conference and at a community cure workshop heard.

US abstinence funding had no impact on sexual behaviour in Africa

Nearly US$1.3 billion spent on US-funded programmes to promote abstinence and faithfulness had no significant impact in 14 countries in sub-Saharan Africa, an analysis of sexual behaviour data has shown.

Circumcision is reducing HIV incidence in Uganda

The growing uptake of medical male circumcision by men in the Rakai district of Uganda is leading to a substantial reduction in HIV incidence among men in one of the districts of the country worst affected by HIV. The study found that every 10% increase in circumcision coverage was associated with a 12% reduction in HIV incidence.

Financial incentives did not improve linkage to care in US study

A US study which offered patients gift cards to present themselves for HIV care after testing, and also to stay in care and maintain an undetectable viral load, did not succeed in its main aims and with most patients. Rates of linkage to care, retention in care and viral suppression were not significantly higher in centres where patients received gift cards than in ones where they did not. However, the study did produce some improvement in the proportion of people who remained in care. And it improved viral suppression rates in smaller and under-performing centres.

Europe needs the HIV prevention pill now

from EATG

The European AIDS Treatment Group (EATG), Europe’s network of HIV activists, and AIDES, a leading French NGO in the fight against AIDS and viral hepatitis, backed by 81 European HIV LGBT civil society organisations and concerned actors, has issued an urgent HIV Prevention Manifesto. It demands that pre-exposure prophylaxis for HIV (PrEP) is made available as soon as possible within the European Union, and that Gilead, the company that makes the PrEP medicine Truvada, submits an application to the European Medicines Agency (EMA) for a change of indication so that its use to prevent HIV can be approved.

Protection from HIV without a vaccine

from New York Times

Scientists at Scripps Research Institute announced last month that they had developed an artificial antibody that, once in the blood, grabbed hold of the virus and inactivated it. The molecule can eliminate HIV from infected monkeys and protect them from future infections. But this treatment is not a vaccine, not in any ordinary sense. By delivering synthetic genes into the muscles of the monkeys, the scientists are essentially re-engineering the animals to resist disease. Researchers are testing this novel approach not just against HIV, but also Ebola, malaria, influenza and hepatitis.

How we are failing a generation of young gay men

from NAT press release

New research in the UK has found three-quarters of young men who are sexually attracted to other men (young MSM) do not receive any information about same-sex relationships at school and athird do not receive any information on HIV transmission and safer sex. Over half of respondents in NAT’s Boys who Like Boys survey of 14-19 year olds had experienced bullying and discrimination because of their sexual orientation – 39% of them by teachers. Over a quarter (27%) did not know how HIV was passed on and almost a third didn’t know you can’t get HIV from kissing.

PrEP: so effective, it's unheard of

from The Body.com

In 2014, the Internet began to froth and boil with articles, websites and commentary about Truvada (tenofovir/emtricitabine) as pre-exposure prophylaxis (PrEP), the newest HIV prevention tool. The drug had been available for prescription to HIV-negative people in the US for two years, but only last year did it become possibly the biggest topic in the HIV prevention conversation. "How could we have a medical tool to end HIV transmissions, have support of legislators around the US, insurance coverage, support from the CDC, WHO, and HRC, front-page coverage on The New York Times and still people don't know about it?" That's the question posed by New York City psychotherapist and PrEP educator Damon L. Jacobs, administrator of the Facebook group "PrEP Facts: Rethinking HIV Prevention and Sex."