Two European PrEP trials report high effectiveness
Two European studies of pre-exposure prophylaxis (PrEP) closed the randomised part of their trials after interim analyses showed that, in both cases, the effectiveness of PrEP was so high that it would be unethical to withhold it from participants not taking it. The PROUD and IPERGAY trials will continue, but with all participants taking Truvada (tenofovir/emtricitabine) as a prevention measure against HIV.
Full data are expected at the Conference on Retroviruses and Opportunistic Infections (CROI) in February, but the trials are expected to show the highest effectiveness levels yet seen in PrEP studies.
The PROUD trial in the UK offered 545 gay men at high risk of HIV a safer-sex support package and offered half the men immediate daily Truvada pills as PrEP, while in the other half the offer of PrEP was deferred for a year. The main object of the study was to see if participants’ HIV risk behaviour changed if they knew they were taking PrEP, but when an interim analysis by the trial’s independent data and safety monitoring board (IDMB) showed significantly fewer HIV infections in people receiving PrEP, the decision was taken to close the randomised phase of the study on 16 October.
In France and Canada meanwhile, the IPERGAY trial has been testing a novel intermittent-PrEP regimen with 400 gay men. Participants were asked to take a double dose of PrEP the day before they expected to have sex and then to take two doses in the two days after sex. They were randomised to take either Truvada or a placebo.
Prompted partly by the PROUD announcement, IPERGAY’s IDMB also did an interim analysis and found that the effectiveness of the trial regime was so high it would be unethical to keep trial participants on a placebo. So it was announced on 29 October that all participants would be offered Truvada.
Comment: It is important not to anticipate the final effectiveness figures for these studies, which will probably be presented at CROI in February, but it is already clear that this is a significant development in research into PrEP. Previous trials, while showing high efficacy in the subset of people who actually did take their PrEP regimen, have also reported low adherence, which impacted on overall effectiveness. These appear to be the first two trials to demonstrate high effectiveness generally, at least in gay men, and adherence must therefore have been high too in most participants. This suggests more strongly than before that PrEP could be a practical and effective prevention measure in people who are at high risk of HIV and who are motivated to take it.
The news has spurred a group of prevention organisations in the UK to issue a sign-on community statement demanding faster access to PrEP. See http://www.prepaccess.org.uk/ to sign on.
Progress on HIV vaccines: new human trials by 2016?
A study in which volunteers in South Africa were given RV144, the only vaccine regimen that has, so far, shown any efficacy in preventing HIV, found somewhat stronger immune responses in the South African volunteers than in the original study volunteers in Thailand. A new study, HVTN100, starting in January will give more South Africans a version of RV144 adapted specifically to the HIV subtypes most common in South Africa rather than Thailand. If this produces stronger immune responses, a large efficacy study is planned for 2016.
Investigation of the immune responses in participants in the Thai study given a booster dose of RV144 eight years after the original one showed that the antibody responses generated could ‘neutralise’ (i.e. prevent from infecting cells) only strains of HIV that have not developed resistance to attack by the human immune system. However, there were promising signs the boosters were ‘pushing’ some people’s immune systems in the direction of developing so-called broadly neutralising antibodies, which can disable most strains of HIV.
Another human study that could start in 2016 would be a smaller one, giving a vaccine that wraps up HIV antigens (signal proteins) in the shell of another virus, CMV (cytomegalovirus). This vaccine works not by preventing HIV infection but by containing infections so they are harmless and in most cases disappear from the body altogether. Sixty per cent of a group of monkeys given the virus and then infected with the monkey version of HIV (SIV) are now clear of infection three years later, and experiments this year will investigate whether the vaccine, when given to monkeys already infected with SIV, will work as a medicine and enable them to stay healthy without antiretroviral therapy (ART). If so, human trials could begin in 2016.
Comment: The slow pace of HIV vaccine development sometimes leads to doubt that one will ever be developed. The reason for the slow progress is that HIV, as a virus that has cleverly hijacked the normal immune response to viruses as its means of reproduction, is a far more subtle foe than ruthless but relatively crude viruses like Ebola. HIV vaccine development involves fundamentally new science and is comparable in its complexity to a major space project. Nonetheless, recent research continues to make progress, both by improving established approaches such as RV144 and via ‘wild card’ discoveries such as the CMV vaccine.
UNAIDS: We can end HIV, but only if we treat nearly everyone
The Joint United Nations Programme on HIV/AIDS, UNAIDS, has released a highly ambitious ‘Fast track’ plan for virtually ending the HIV epidemic by 2030. This strategy, first trailed this summer, requires that 90% of the world’s HIV-positive population is diagnosed, 90% of those diagnosed (81% of all) is put on treatment and 90% of those on treatment (72.9%) achieve an undetectable viral load. UNAIDS says that without a programme of this ambition, the number of people with HIV in the world will grow inexorably, simply because more people are living with the virus already. Only if treatment reaches near-saturation levels will the effect of supressing people’s viral load and rendering them non-infectious have significant public health effect, UNAIDS argues.
UNAIDS provides evidence that these seemingly ambitious targets are achievable. A few countries, both rich and poor, are already approaching this kind of level of coverage, ranging from Rwanda, where HIV incidence (the rate of new infections) has plummeted to a fraction of its previous rate, to Australia and the UK, where currently 62% of all people with HIV are on therapy and have a viral load below 50 copies/ml, according to two separate reports; 68% of UK gay men are virally suppressed, a figure approaching the UNAIDS target.
As the recent Public Health England (PHE) report shows, the factor holding back achievement of the UNAIDS target is that still not enough people at risk of HIV are coming forward for testing, including regular and frequent testing. The big problem in the UK lies in heterosexuals in high-prevalence populations, largely black African people, who are still tested less often and diagnosed later than gay men, sex workers, people who inject drugs and other risk groups. PHE notes that this is partly because heterosexual people are much less likely to attend the specialist sexual health clinics that most reliably test for HIV: in fact, they admit there is no way of establishing how many HIV tests the primary care physicians heterosexuals are more likely to consult perform, or how often.
Comment: This campaigning document replaced the normal wide-ranging overview of the global epidemic UNAIDS has traditionally released on World AIDS Day. It makes a convincing case that targets that at first sound near-impossible can be achieved in many places. However, it also admits that only 60% of the effect needed will come from widespread treatment and viral suppression: the rest will have to come from improved prevention measures. It also admits that in some parts of the world, such as Russia and eastern Europe, there is little chance the target can be achieved – typically, because the people most in need of HIV treatment are those most discriminated against by the healthcare system.
What could stop treatment working as prevention?
As mentioned in the previous report, giving as many people with HIV access to treatment as possible could make the largest contribution of any method to bringing down the rate of HIV infection (incidence) worldwide. While this appears to be already happening in some places and populations, in others HIV incidence is stable or increasing – such as among gay men in western Europe, heterosexuals in eastern Europe, and African-Americans in the US.
In other areas, there are signs of success. In a rural part of South Africa, HIV incidence – the rate of infection – has fallen in step with the introduction of HIV treatment. Increasing the proportion of people with HIV who are on antiretroviral therapy to 40% has resulted in a fall in HIV incidence of almost the same amount, even when only people with CD4 counts below 350 cells/mm3 are treated. A trial is now underway to see if giving treatment to every diagnosed person in an adjacent area will bring incidence down further.
One reason for treatment not suppressing the onward spread of HIV is that, in high-incidence populations where most diagnosed people are on treatment, most transmissions come from people who are undiagnosed and therefore more likely to be recently infected. Many will have a high viral load and be very infectious. One model showed that in a population where more than 50% of infections come from people who have themselves recently acquired HIV, the proportion of all people with HIV with undetectable viral loads might have to rise as high as 70% before a reduction in incidence is seen.
Another reason is that people simply don’t test often enough, or at all. In the UK, only 40% of gay men have an HIV test once a year or more: if 90% got tested annually, the number of new infections could fall, a model shows, from the current 4000 a year to 1000.
Several large randomised controlled trials are underway in south and east Africa, involving up to two million people, to see if offering HIV treatment to everyone diagnosed will bring down HIV incidence within the community.
Comment: As detailed in the full HIV Research for Prevention symposium report, the presenters also considered other factors such as HIV drug resistance and the stigma against HIV which makes it difficult for people with the virus to talk about their status. The large African trials are tests of what would actually happen if an intensified programme of HIV treatment and prevention, as recommended by UNAIDS, was put in place. These huge trials will report results between 2017 and 2019.
Europe “is falling behind” in its HIV response
HIV diagnoses have increased in the World Health Organization (WHO) European region (which includes the EU plus Russia, central Asia and other non-EU countries) by 80% since 2004 and in eastern Europe – essentially, the former Soviet Union – the rate per 100,000 people has more than doubled since that year. New diagnoses are now mainly among heterosexuals, indicating a spread of HIV into the general population. Meanwhile, in western Europe, it is gay men amongst whom HIV diagnoses are still increasing, with a 33% rise in EU countries since 2004.
While in the best-served European countries, between 50 and 62% of all people with HIV are on antiretroviral therapy (ART), in eastern Europe the rate is only 20-25%, though some central-European countries such as Romania have achieved rates comparable with the West.
The European Centre for Disease Prevention and Control (ECDC) released a report at the end of November. It says that “Despite significant efforts dedicated to the prevention and control of HIV, the rate of new HIV diagnoses has not declined in the EU/EEA and has increased substantially over the last decade in the European Region.” The ECDC’s Mark Sprenger told the meeting that strong political leadership and a commitment to large-scale financing was needed. Prevention needed to be targeted at the key affected populations, who should be offered harm reduction programmes rather than criminalised. Europe also needs more community-based and less medicalised testing, and to scale up HIV treatment in eastern Europe, and to undocumented migrants throughout Europe.
Comment: Europe as a region suffers because of the vast disparity between its HIV epidemics in west and east, but this has not been helped by weak leadership and lack of co-ordination between politicians, especially when it comes to devising HIV prevention programmes that cross the EU’s porous borders and, in eastern Europe, tackle entrenched attitudes in favour of criminalisation and abstinence as ways of tackling HIV.
Injectable PrEP drug might work better for men than women
A long-lasting, injectable formulation of the anti-HIV drug rilpivirine (Edurant, also in Eviplera/Complera) could work as pre-exposure prophylaxis (PrEP), delegates at this autumn’s HIV Research for Prevention (HIV R4P) conference in Cape Town heard. However, the researchers found, unexpectedly, that the drug reached higher concentrations in rectal rather than vaginal or cervical tissues.
Rectal tissue samples taken from people given the injections were resistant to infection more than two months after a single injection. This indicates that a monthly injection could provide protection from HIV transmission via anal sex. However, this was not the case with cervical or vaginal tissues, which were not protected against infection at all. This is surprising, as one would have expected some protection: it is possible that the drug may build up to protective levels in tissues only with repeat injections.
Studies of another drug formulated as a long-lasting injection, cabotegravir, found the opposite: levels in vaginal and cervical tissues were actually higher than in the rectum. The unexpected finding here was that the drug was eliminated three times faster from men than from women.
The slow elimination rate of these drugs – in some people, detectable levels of cabotegravir may persist for 6-9 months after one injection – brings one problem with it: how to manage the period when someone has some, but not enough, drug in their body. If that person is then exposed to HIV, not only could they be infected, but the lingering drug provides ideal conditions for the development of drug resistance. The conference heard about one case in which this happened: a woman in a safety trial of injectable rilpivirine, supposedly for low-risk volunteers, tested HIV positive 84 days after a single injection, and developed resistance to the class of drugs that includes rilpivirine.
Phase II clinical prevention trials of both drugs are due to start in 2015.
Comment: Long-lasting injectable drugs are already used as contraceptives and anti-psychotics, and there is considerable interest in their promise both as PrEP and as treatment, particularly in settings where people have challenges to daily adherence. These studies do not rule out such an idea, but remind us that promising drugs do not always produce the results expected in clinical trials. Even if one or both of these drugs proves to be effective and safe, it could be 4-5 years before they became clinically available, and the case of resistance shows that there are practical problems to be solved about their safe use.
Other recent news headlines
Positive response to 'gift tokens for undetectable viral load' trial
A US study presented at the recent HIV Research for Prevention conference found generally positive responses among a selection of participants and clinic staff to a trial that used $70 gift tokens as an incentive for people with HIV to maintain an undetectable viral load. However, the study found that only just under half of patients interviewed had an accurate understanding of what viral load was, that this did not improve during the study, and that having an accurate understanding was associated with a higher likelihood of viral suppression, at least in patients interviewed. This qualitative substudy, which looked at attitudes to the gift tokens, cannot predict whether the scheme increased the proportion of people with an undetectable viral load in the whole group: full results will be published next year.
HIV in the UK: 76% diagnosed, 90% on treatment, 90% undetectable
The UK’s annual epidemiological report shows that the country already provides HIV treatment to 90% of people attending clinical services and that 90% of those on treatment have an undetectable viral load. But the UK has a long way to go in ensuring that people with HIV are aware of their HIV status – only 76% of people living with HIV have been diagnosed. The problem is particularly acute in black African communities, as only 62% of African heterosexual men and 69% of African heterosexual women living with HIV have been diagnosed.
Truvada PrEP use rising in United States, especially among men
The number of people using Truvada for pre-exposure prophylaxis (PrEP) in the US is increasing and a growing proportion of users are men, according to an analysis of data from approximately half of American pharmacies presented last month at the HIV Drug Therapy Glasgow conference. The latest analysis showed that 1057 people were prescribed Truvada for PrEP in the first three quarters of 2013, with a further 880 prescriptions during the last quarter of 2013 and the first quarter of 2014. Overall, the analysis counted 3253 total unique PrEP users since January 2012.
Australia performs best in HIV treatment cascade – 62% with undetectable viral load
Australia and northern European countries are doing far better than North America at retaining people living with HIV in care and achieving viral suppression, according to a comprehensive survey of ‘treatment cascades’ in high-income countries presented at the HIV Drug Therapy Glasgow conference. The proportion of all people living with HIV who had an undetectable viral load ranged from 62% in Australia to a low of just 25% in the United States. Figures in the western European countries surveyed ranged from 52% in France to 59% in Denmark: the UK’s annual report (see above) estimates parity with Australia, at 62%.
Safer injecting practices would be better promoted by focusing on pleasure, not risk
Harm reduction interventions often fail to engage people who inject drugs because they over-emphasise infection and risk, Magdalena Harris of the London School of Hygiene and Tropical Medicine told the recent HIT Hot Topics conference in Liverpool. Her interviewees frequently adopted safer injecting practices, but were more motivated by a desire to have a quick, pleasurable hit than by concerns about blood-borne viruses. “Harm reduction needs to pay more attention to the pleasures and pragmatics of using drugs,” she said.
Editors' picks from other sources
San Francisco men shed condoms in favour of Gilead's HIV prevention pill
from San Francisco Business Insider
The good news: A pill from Gilead Sciences Inc. stops HIV infection among people at high risk of contracting HIV. The bad news: Men taking the drug to prevent HIV appear to be having more sex without a condom, putting them at risk of contracting other sexually transmitted diseases. In a subset of 90 men among the 500 prescribed PrEP by the Kaiser Permanente Foundation, there was a 45% drop in self-reported condom use.
Generations of HIV
from Huffington Post
“Young gay men are not complacent. Complacency is not driving the epidemic. For the post-AIDS generations, HIV is a constant in our lives and it's never far when we are having sex, or looking for sex, or thinking about sex. We have different relationships to the epidemic compared to those who came before. And for young gay men today, their world may look different, their choices around sex, condoms and PrEP may look different, and their activism may look different. But it's a profound misunderstanding of the experience of young gay men to call it complacency.”
Is HIV really weakening over time?
from Treatment Action Group
A little over nine years ago there was another widely publicised paper claiming that HIV had become less virulent. Although it's grim to be in the position of pouring cold water on optimistic-sounding scenarios, that paper was based on measuring HIV’s ability to replicate using a laboratory test, and other published data raised questions as to whether the test could actually predict differences in disease progression rates. Today, it’s déjà vu all over again because there has been an explosion of very similar media stories positing that HIV is evolving into a “milder form”. And once again, the study prompting the coverage relies primarily on laboratory measurements of HIV replication capacity, despite the fact that a prior publication – by several of the same authors – reports that results from this test do not predict the rate of CD4 cell decline over time.
Highest global rise in HIV and AIDS reported in Middle East
from Middle East Eye
Rates of new HIV infections and AIDS-related deaths are rising faster in the Middle East and North Africa (MENA) than anywhere else globally. There are 230,000 people living with HIV in the 21 countries that make up UNAIDS’s definition of the Middle East and North Africa. This is still a very low prevalence of 0.1%. But in 2013, the region lost 15,000 people to the disease, a 66% increase on 2005, and despite new infections declining globally by 38% since 2001, in MENA they have risen over the same period.
Circumcision guidelines target teenagers
from New York Times
Doctors should start telling sexually active teenage boys who aren’t circumcised that if they have the surgery, they can reduce their risk of contracting HIV and other sexually transmitted infections from their female partners, federal health officials propose. Similar counselling is urged for adult heterosexual men who remain uncircumcised and for expectant parents who will be making a decision about newborn circumcision if they have a boy, according to the new recommendations, proposed by the Centers for Disease Control and Prevention (CDC).