Tag Archives: Medical Research Council

Discovery of HIV ‘invisibility cloak’ reveals new treatment opportunities

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“Glass Microbiology” by Luke Jerram. (See: https://blog.lass.org.uk/2013/01/23/2393/) for artwork details. (Image unrelated to story).

Scientists have discovered a molecular invisibility cloak that enables HIV, the virus that causes AIDS, to hide inside cells of the body without triggering the body’s natural defence systems.

Their study shows how ‘uncloaking’ the virus using an experimental drug triggers an immune response that stops the virus from replicating in cells grown in the laboratory. The findings could lead to new treatments and help to improve existing therapies for HIV infection.

The innate immune system is the body’s first line of defence against infection and incorporates an alarm system present in all cells of the body that detects the presence of ‘foreign’ material from invading bacteria and viruses. When the alarm is tripped, the infected cell begins an antiviral programme and sends out warning signals to alert other cells that a virus is around.

HIV infects vital cells of the immune system, so its ability to replicate undetected without triggering this alarm system has puzzled scientists since the discovery of the virus.

The team identified two molecules inside host cells that are recruited by HIV after infection that stop the virus from reproducing its genetic material too early. The effect is to shield the virus from the alarm system and stop the innate immune system from kicking into action.

In the absence of these molecules, whether caused by depletion from infected cells or by blocking their recruitment using an experimental drug, HIV is exposed to the alarm system and an antivirus immune response is triggered. Targeting the cloaking molecules and not the virus itself makes it much more difficult for the virus to mutate and become resistant to this treatment approach, a significant problem with standard HIV therapies.

Professor Greg Towers, a Wellcome Trust Senior Research Fellow at UCL and lead author of the study, said: “HIV is extremely adept at hiding from our body’s natural defences, which is part of the reason the virus is so dangerous. Now we’ve identified the virus’ invisibility cloak, and how to expose it, we’ve uncovered a weakness that could be exploited for new HIV treatments.

“There’s a great deal more research needed, but the potential for this approach is huge – as a possible treatment in itself, but also as a complement to existing therapies. We’re also interested to see whether blocking these cloaking molecules can help to boost immune responses to experimental vaccines against HIV or be used to protect against HIV transmission.

“The hope is that one day we may be able develop a treatment that helps the body to clear the virus before the infection is able to take hold.”

The experimental drug used in the study is based on cyclosporine, a drug that is widely used to prevent organ rejection in transplant patients because of its ability to dampen the immune response. Cyclosporines have been shown to block the replication of HIV and other viruses but are not suitable for treating infected patients because of their negative effects on the immune system.

The team used a modified version of the drug, which blocks the effects of the two cloaking molecules without suppressing immune activity.

Dr Kevin Moses, Director of Science Funding at the Wellcome Trust, said: “In 2012, 2.3 million people were newly infected with HIV. While existing treatments are helping people with HIV to live longer and healthier lives, the challenge of adherence to treatment programmes means that drug resistance remains a threat and the virus continues to burden the world’s poorest communities. Understanding how HIV interacts with the body’s own defences might just be crucial for developing the best approaches to therapy.”

The study is published today in the journal ‘Nature’ and was funded by the Wellcome Trust, the Medical Research Council and the National Institute for Health Research University College London Hospitals Biomedical Research Centre.

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HIV incidence in gay men unchanged in England and Wales, despite more testing

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A paper in The Lancet Infectious Diseases by scientists from the UK’s Medical Research Council and the Health Protection Agency (HPA) has calculated that the number of gay men in England and Wales who become infected with HIV each year remained unchanged between 2001 and 2010. This is despite a considerable increase in testing and, they estimate, a 40% reduction in the proportion of gay men with HIV who are undiagnosed.

The paper concludes that, in England and Wales at least, the proportion of gay men with HIV who are on treatment and with undetectable viral loads is currently too low to bring about a decline in annual HIV incidence in this population. This is in contrast to declines in diagnosis, and claims of declines in incidence, seen in places such as San Francisco, the province of British Columbia in Canada, and some locales in South Africa.

As well as extending HIV testing to non-traditional settings and urging gay men to test more frequently, the authors conclude that “the initiation of treatment on diagnosis, regardless of CD4 count might well be necessary to achieve control of HIV transmission”, and welcome the new BHIVA treatment guidelines’recommendation “that clinicians discuss the benefits of early treatment uptake as a prophylaxis to protect sexual partners” as a step towards this.

Calculating incidence

The paper is a mathematical model. It uses available data on diagnoses, CD4 counts at diagnosis, and the proportion of people on antiretroviral therapy (ART) to make estimates of the true annual number of infections (annual incidence) in gay men, the number undiagnosed, average time gap between infection and diagnosis, the distribution of CD4 counts among diagnosed and undiagnosed men and the proportion who are on treatment and with an undetectable viral load.

Although mathematical models are always estimates, in this case surveillance data from the UK are of good enough quality to make them quite robust, though because by definition fewer very recent infections are diagnosed, incidence estimates for the last two years are less certain than for previous years.

The incidence rate is not the same as the new diagnosis rate in HIV, because of the time lag between infection and diagnosis. If the number or frequency of HIV tests go up, the number of diagnoses will tend to go up, since more long-term undiagnosed infections will be identified. The researchers got round this problem by using CD4 count at diagnosis – available for the majority of diagnosed people in England and Wales – as a surrogate for the time delay between infection and diagnosis, given that CD4 counts in people with untreated HIV tend to decline at an even rate over time.

Results – diagnosed and undiagnosed

The number of diagnoses in gay men in England and Wales increased from about 1800 in 2001 to 2600 in 2010. However by adjusting this for CD4 count at diagnosis, the researchers estimated that the true annual total of HIV infections in gay men had remained virtually unchanged, from 2200 in 2001 to about 2300 in 2010. There was an increase in incidence to about 2700 a year in 2003-4, due to increased rates of sex without condoms in gay men, but this has reduced since.

This reduction is due, the researchers say, to more gay men taking tests and to a shorter period between HIV infection and diagnosis. The number of HIV tests taken by gay men in sexual health clinics has grown nearly fourfold, from 16,000 in 2001 to 59,300 in 2010. As a result, the estimated time between infection and diagnosis has shrunk from four years to 3.2 years during this time, and the proportion of gay men with HIV who are undiagnosed from 37 to 22%.

The reason it has not shrunk more, say the authors, is due to gay men not testing often enough. Last year, study co-author Valerie Delpech of the HPA told the IAPAC Prevention Summit that only an estimated 10 to 15% of gay men took an HIV test every year, and that two-thirds of gay men who had had a test at a clinic had, two years later, not returned to that clinic for another one.

Because there are (as of 2010) 3.2 years’ worth of undiagnosed infections in the population, the total number of gay men with HIV who are undiagnosed in England and Wales was estimated as 7690 in 2010. This was only a small increase from 7370 in 2001 and represents a 16% decline from 9140 in 2004-5, again due to more testing.

The proportion of gay men with HIV who are undiagnosed has gone down by 40% while the number has scarcely changed because total HIV prevalence and the number of UK gay men living with HIV has grown over the same period.

Results – implications for treatment

In 2001, at HIV diagnosis, about 65% of gay men had a CD4 count under 500 cells/mm3, 40% under 350 cells/mm3, and 18% under 200 cells/mm3. Ten years later, the proportion in these three categories had only fallen by about 5%. This means that less than 40% of gay men would currently be advised, under treatment guidelines, to begin taking antiretroviral therapy (ART) for treatment reasons as soon as they are diagnosed.

The researchers calculated that, because more undiagnosed infections are recent ones, only 20% ofundiagnosed gay men had a CD4 count under 350 cells/mm3 and only 45% under 500 cells/mm3. Further decreasing the proportion of gay men with HIV who are undiagnosed, and raising or abolishing the CD4 threshold for treatment initiation, would therefore have considerable cost implications for the National Health Service in England and Wales.

Conclusions

In many ways, the UK’s response to HIV has been excellent. The proportion of gay men with a CD4 count under 350 cells/mm3 who are on ART has increased from 75% in 2001 to 84% in 2010; 65% of all patients in care, including the untreated, have undetectable viral loads; and annual loss to follow-up of those attending care is under 5%.

In the US, in contrast, it is estimated that there are more gay men who are diagnosed but not taking ART than there are undiagnosed, and that only 28% of people with HIV are virally suppressed. But gay men in other countries test more frequently: as an accompanying editorial by Reuben Granich of UNAIDS points out, the 22% of gay men who remain undiagnosed in the UK is not as good as an estimated 14% in Vancouver and only 6% in San Francisco.

Because most of those with detectable viral loads in the UK are undiagnosed, it is estimated by the HPA that up to 50% of HIV infections in gay men here could be being transmitted by men in primary HIV infection and another 35% by undiagnosed men with long-term infection. The authors conclude that treatment initiation at diagnosis, earlier, more targeted testing, and better primary HIV prevention all need to be part of any national HIV prevention plan for England and Wales.

References

Birrell PJ et al. HIV incidence in men who have sex with men in England and Wales 2001-2010: a nationwide population study. The Lancet Infectious Diseases, early online edition:http://dx.doi.org/10.1016/S1473-3099(12)70341-9. See abstract here. 2013.

Granich R HIV in MSM in England and Wales: back to the drawing board? The Lancet, early online edition: http://dx.doi.org/10.1016/S1473-3099(13)70035-5. See first few lines here. 2013.

Original Article by Gus Cairns at aidsmap

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PrEP acceptable to UK gay men, studies find

Pre-exposure prophylaxis (PrEP) would be an acceptable HIV prevention strategy for large numbers of gay, bisexual and other men who have sex with men in major UK cities, according to two studies presented to the British HIV Association (BHIVA) conference in Birmingham this week.

The conference also heard details of a small pilot PrEP study, likely to start recruiting later this year.

A cross-sectional survey of 842 HIV-negative gay and bisexual men, recruited at bars, clubs and saunas in London, suggested that half the respondents would be interested in taking PrEP.

Respondents were given information about pre-exposure prophylaxis and asked: “If PrEP were available, how likely is it that you would take a pill (oral dose) on a daily basis to prevent HIV infection?”.

Half said yes, with 16% saying they were likely to take PrEP and 34% saying they were very likely to. Men interested in PrEP were slightly more likely to be under the age of 35 (AOR adjusted odds ratio 1.58), have attended a sexual health clinic in the past year (AOR 1.59) and to have previously taken post-exposure prophylaxis (PEP) (AOR 1.96). After statistical adjustment, various measures of risky sex were no longer associated with interest in PrEP.

In this survey, 17 men (2.1% of those answering the question) said that they had previously taken antiretroviral drugs to reduce their risk of HIV infection.

Secondly, clinicians at the Manchester Centre for Sexual Health surveyed HIV-negative men attending their service who reported unprotected receptive anal intercourse. Of the 121 men who responded, 36% said they would be “very willing” to take PrEP while only 14% said they would not take the treatment. Daily dosing was perceived as a better option by four fifths of respondents – just one fifth would prefer taking a dose before sexual activity.

These data confirm and reinforce findings from a study reported in November 2011, which found that half the gay men surveyed would consider taking PrEP. Once again, daily dosing was preferred to taking a dose before sex. In the qualitative data, men commented that sex is often spontaneous and that they felt daily dosing would facilitate adherence.

However these data are all based on giving men a few key facts about PrEP and presenting it as a hypothetical option. In real-life circumstances, where men think more seriously about PrEP as an option and hear friends’ experience of taking it, actual uptake and sustainability may be very different.

While the Manchester respondents largely assured the researchers that they would take all their doses of PrEP and wouldn’t have more risky sex, real-life experience needs to be tested in research.

To this end, the Medical Research Council are seeking funding for a 5000-participant, two-year study which would randomise HIV-negative gay men who report unprotected anal intercourse to either take PrEP (Truvada) and attend motivational interviewing (intervention group) or to be put on a one-year waiting list for PrEP and to have motivational interviewing in the meantime (control group).

For the researchers, it is crucial that this is an open label but randomised study, in which participants know whether they are receiving the actual drug. This unusual research design would, they argue, tell us more about the real-world effectiveness of PrEP than a blinded study as it would take into account the possible impact of participants taking more sexual risks because they felt that PrEP afforded some protection. (Researchers call this ‘risk compensation’ or ‘behavioural disinhibition’).

Rather than test efficacy in artificial conditions, the study would therefore test effectiveness in more realistic UK conditions.

So far, however, the potential funders of this costly study have not been persuaded by this argument and it is unclear whether the study will be able to go ahead.

What will, however, start recruiting later this year is a pilot version of the same study, aiming to include 500 men who attend one of around twelve sexual health clinics.

As well as allowing the researchers to have a dry run of the main trial and identify teething problems with its strategy, it should also provide valuable information on the number of men who actually follow through on a clinician’s offer of PrEP. Data on the characteristics of men who seek PrEP, drop-out rates and risk compensation will also be collected.

The researchers intend to take some of these data back to the main study’s potential funders, in order to support a revised application.

Acceptability of taking HIV treatment for prevention purposes

As well as asking people hypothetical questions about PrEP, researchers have also been asking people waiting for an HIV test result hypothetical questions about treatment as prevention.

Individuals from high-risk groups attending the Jefferiss Wing at St Mary’s Hospital for HIV testing were given an explanatory paragraph about treatment, infectiousness and safer sex. They were then asked: “If you were diagnosed with HIV would you consider taking treatment to reduce the risk of passing on infection (even if you did not need to take treatment for your own health)?”.

Four out of five respondents said ‘yes’. Encouragingly, gay men who reported unprotected anal intercourse in the past three months were more likely than others to be interested in the idea. Less encouragingly, people who had had a sexually transmitted infection or who had previously taken PEP were slightly less likely to say that they would take treatment for prevention.

The researchers suggested that the latter factor may be associated with PEP users’ experience of side-effects. It contrasts with the findings of the London PrEP attitudes study described above which found people who had previously taken PEP more likely to be interested in PrEP.

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