February 2016

Tenofovir resistance may develop in more than half of patients failing HIV treatment in sub-Saharan Africa

More than half of people who experienced failure of a tenofovir-based antiretroviral regimen in sub-Saharan Africa had resistance to tenofovir, a meta-analysis of drug resistance studies published in The Lancet Infectious Diseases has shown.

The study found that the prevalence of tenofovir resistance after first-line HIV treatment failure ranged from 20% in Western Europe and North America to 56 to 60% in sub-Saharan Africa.

The authors say that their findings suggest that somewhere between 7.5 and 17.5% of people who start treatment in sub-Saharan Africa, with a regimen composed of tenofovir, efavirenz and either lamivudine or emtricitabine, will develop tenofovir resistance after one year, based on current rates of treatment failure. This projection assumes a treatment failure rate of between 15 and 35%, depending on how it is measured, and is in line with recent World Health Organization (WHO) estimates.

This study does not reflect the prevalence of HIV drug resistance in all people on treatment, nor the prevalence of drug resistance in people who have not yet started treatment, but only the prevalence of drug resistance in people who started specific drug regimens and subsequently experienced virological failure of that treatment regimen.

Comment: This study was inaccurately reported by the BBC and has caused considerable concern that if tenofovir resistance spreads it could lead to the drug becoming useless for treatment and PrEP (pre-exposure prophylaxis). So it’s important to re-iterate that this is a study of tenofovir resistance only in people experiencing treatment failure. A 2011 analysis, by the same research group, of patients not yet on HIV treatment in Africa found much lower levels of resistance. What this story is really about is unavailability of viral load monitoring for people in low-income settings, with the result that they stay on failing regimens far too long.

New PrEP studies will be a challenge, statisticians warn

While pre-exposure prophylaxis (PrEP) has been remarkably effective in preventing HIV, both in scientific trials and in public availability programmes in the US, there is a general consensus that alternatives to tenofovir + emtricitabine (Truvada) need to be found. But two statisticians involved in the PROUD and iPrEx trials of PrEP warn that future trials to test new PrEP drugs and formulations may be extremely difficult to design.

Directly comparing a new PrEP therapy with Truvada might require an unfeasibly large trial. In a ‘non-inferiority’ trial, the object is to find out whether the drugs are equivalent to each other in terms of effectiveness. If such a trial was conducted in a population with a fairly typical annual HIV incidence (infection rate) of 2.25%, then it would require a two-year trial with 19,000 participants to be able to rule out for sure that the new product was 25% more or less effective than Truvada. A smaller trial would be required if there were advance indications that the product was very much superior to Truvada or if HIV incidence in the trial population is considerably more than 2.25%.

However, they note, trials in the past have been very bad at predicting the background incidence in their population and it will not be an easy thing to establish if PrEP use becomes widespread. A variety of methods can be used: using historical data from the placebo arms of old trials, looking at HIV incidence in different populations attending clinics, and even in a high-incidence population by looking at the small but inevitable proportion of people in similar trials that turn out to have acute HIV infection.

Comment: We have reached a point, forecast twelve years ago, where a biomedical prevention method is so effective in ideal or even ordinary circumstances that it becomes difficult to design trials for the populations for whom it works less successfully – precisely because it’s unethical to withhold the standard-of-care intervention. There is a double irony of PrEP in that in some trials it would be unethical to withhold PrEP in a trial, even if it is not yet available in the trial location. Considerable ingenuity will be needed to devise trials that provide us with better PrEP alternatives – which clearly need to be available.

Model suggests HIV vaccine still has key role in ending AIDS

Even a modestly effective HIV vaccine would likely be cost-effective and could make a major contribution to a sustainable response to the global HIV and AIDS epidemic, especially in combination with the scale-up of other interventions, according to a report. Prevention approaches including condoms, antiretroviral treatment as prevention (TasP) and PrEP have already brought about substantial reductions in new HIV infections, but there are still too many people acquiring HIV worldwide to bring the epidemic to a halt.

According to the model, with current trends, incremental scale-up of existing interventions results in a flat trajectory of new infections in low- and middle-income countries, with around 1.6 million annually in 2070. However, if even 50% of the UNAIDS targets for scaling up treatment and prevention were achieved, then this would reduce the number of new annual HIV infections to approximately 1 million in 2070, or 550,000 if they were fully achieved.

Adding a three-dose HIV vaccine with 70% efficacy, five years of protection and high coverage, introduced in 2027 along with the full scale-up scenario, would reduce annual infections by 44% over the first decade, by 65% over the first 25 years and by 78% (to around 122,000) in 2070. Adding PrEP, TasP and an HIV vaccine – individually or in combination – to the full UNAIDS scale-up scenario would reduce the annual number of new HIV infections in 2070 by 29%, 34%, 78% and 91%, respectively, with vaccination providing the strongest single benefit despite being introduced later.

Comment: It has always been a truism of HIV prevention that “we will need a vaccine to end the epidemic” but the emphasis on testing, treatment and PrEP recently has included models – see below for two examples – that attempt to show that an end to the epidemic could be achieved by these alone. This may be to do as much with impatience with progress towards a vaccine as the flowering of enthusiasm for treatment as prevention and PrEP recently. This model shows that even if we are still more than ten years away from an even moderately effective vaccine, it will swiftly become the foundation stone of a truly effective initiative to end the epidemic.

UK and Dutch studies show that PrEP is the most powerful single HIV prevention method we currently have

A new UK study finds that adding PrEP for gay men at high risk of HIV to relatively modest increases in HIV testing, and immediate treatment for those diagnosed, could substantially cut the number of gay men acquiring HIV by 2020. The researchers conclude that, without these interventions, the number of gay men acquiring HIV is unlikely to decrease by 2020, even if the UK achieves the ‘90-90-90’ target of 73% of all people with HIV virally suppressed by this time.

A Dutch study comes to very similar conclusions; both find that PrEP, in isolation, is the single most powerful HIV prevention method we currently have, but that in most realistic scenarios it would have to be combined with improved testing rates and immediate treatment for those diagnosed with HIV. 

The UK study found that if all HIV-negative gay men took PrEP, the proportion of men acquiring HIV between 2014 and 2020 would be reduced by 59%, and if only high-risk gay men took it – an estimated 294,100 men – it would be reduced by 51%. The only other intervention in which HIV infections would be cut by more than one-third was if all gay men tested for HIV twice a year (42% reduction) or all high-risk gay men (39%) did so. Reducing sexual partners by 50% in high-risk gay men would reduce it by 32.5%; testing once a year would reduce infections in all high-risk gay men by 30%; and decreasing condomless sex by 50% in all high-risk gay men would reduce infections by nearly 25%.

No intervention is going to be adopted by 100% of the men eligible for it, of course. In a probably achievable scenario, a combination of PrEP in 25% of 'high-risk' men, 25% uptake of annual HIV testing in the 75% who did not use PrEP, and 25% more men diagnosed with HIV starting treatment immediately reduced the number of infections acquired up to 2020 by 44%.

In the Dutch study, the researchers found that, in the Dutch population of men who have sex with men (MSM), even if only men under 30 were considered, immediate treatment of everyone diagnosed with HIV would have averted 19% of HIV infections. Combining immediate treatment and PrEP would have prevented 30% of infections. The greatest results would be seen by combining these with annual testing, averting 45% of infections. Expanding PrEP access to half of all gay men (rather than just those under the age of 30) would prevent 66% of infections.

In an accompanying editorial to the UK study, commentators ponder the challenges of implementing PrEP and predict that the public health system will need to strengthen ties between community-based organisations and sexual health clinics and providers, with a view to adopting ideas such as medical workers delivering PrEP in community settings, as has already been done to some extent with testing.

Comment: The full reports of these two studies, published on aidsmap.com, cover a range of scenarios explored in the studies. In the UK model, the contribution of PrEP to prevention is probably, if anything, underestimated because the modellers selected an effectiveness of 44% for PrEP, as seen in the iPrEx study. In reality, it is likely to be considerably larger than this, if the results of the PROUD study are anything to go by.

English sexual health clinics have started to support people buying PrEP online

Several large sexual health clinics in London and Brighton have responded to the growing numbers of people importing PrEP medications from overseas by offering free safety monitoring to PrEP users. This is in a context of increasing frustration with the slowness of the official NHS process to approve PrEP – no decision will be made until June.

Last August, the 56 Dean Street clinic in the heart of Soho, central London, announced that it could provide non-NHS prescriptions for PrEP and the necessary monitoring and clinical support that goes with it. However, a month’s supply of branded Truvada costs £400.

People have discovered a more affordable alternative – importing, for their personal use, generic PrEP medications. Tenvir EM, manufactured by the Indian pharmaceutical company Cipla, is available from several online pharmacies for around £45 a month. The active ingredients, tenofovir and emtricitabine, are identical to those in Truvada. A maximum of three months’ tablets at a time may be legally imported, for personal use only, into the UK.

People buying generic tablets online have turned to NHS sexual health clinics for support with PrEP. 56 Dean Street provides regular testing for HIV, sexually transmitted infections and kidney function and recommends a urine dipstick test to check for protein in the urine every three to four months. If necessary, this can be followed up with a blood or urine test for kidney function. Once a year, a blood test for kidney function will be provided.

The same services are also available at several other centres in London and one in Brighton so far, and in January, 56 Dean Street announced that they could also provide free therapeutic drug monitoring for people using PrEP to check that the drugs they have purchased are genuine.

Comment: This is a pragmatic response to the increasing phenomenon of online PrEP purchase. Sexual health clinicians – most of them already convinced of the effectiveness of PrEP – have felt they have little choice but to provide testing and monitoring services both to ensure people are not taking PrEP while unknowingly HIV positive, and also to monitor side-effects. It is important to note that importing PrEP (or other drugs) for personal use is not legal in most other EU countries, though German users have reportedly found a loophole that enables them to buy a month’s worth of Truvada for travel purposes. There are also reports that UK users are increasingly being charged VAT by customs. For up-to-date information, see www.iwantprepnow.co.uk or www.prepster.info. 

Two HIV infections on solo tenofovir pose significant research questions

A report, originally presented to the 2015 British HIV Association (BHIVA) conference, details two cases where therapeutic levels of solo tenofovir unequivocally failed to prevent HIV infection in gay men. In one case, despite the tenofovir apparently suppressing the man’s HIV viral load in his blood plasma, it failed to prevent HIV infecting the cells of his immune system. Solo tenofovir has been tested as PrEP in two major studies, Partners PrEP and the Bangkok Tenofovir Study, with moderate to good results, and it has been assumed that tenofovir may have the predominant preventive effect.

The men were not taking tenofovir specifically as PrEP, but instead were taking it as treatment for chronic hepatitis B infection. One had had persistent hepatitis B infection for six years and had been taking tenofovir for four years; the other had had hepatitis B for seven years and had been taking tenofovir for three years. In both cases, the date of HIV infection can be pinpointed fairly closely, one to within a 12-day period. Both men appeared to have excellent adherence to tenofovir based on pill counts, and tenofovir drug levels taken on the day they tested HIV positive were well in excess of what should have been an adequate level to suppress HIV replication.

The biggest difference between the two cases was that in patient A the tenofovir, despite not preventing HIV infection, did seem to be suppressing his HIV viral load in the blood. Although testing HIV-positive and having HIV integrated into his cells (see below), at no point did he have a viral load over 50 copies/ml. This ‘blunting’ of the HIV viral load has been seen before in cases of PrEP failure, notably in the animal studies that established its efficacy. This means his HIV could not be tested to see if it had acquired, or already had, drug resistance to tenofovir.

Comment: These are the first two cases ever reported on tenofovir and no unequivocal case of the failure of Truvada (tenofovir + emtricitabine) has yet been reported. However, the cases raise a number of interesting questions: whether the levels of tenofovir required to prevent infection need to be higher than those used for treatment; whether hepatitis B co-infection may have made HIV infection more likely; whether the men would have acquired HIV if they had been taking Truvada; and if not, what are the exact contributions to prevention of the two drugs.

Lessons learnt from the history of contraception are relevant for the implementation of PrEP

Achieving a widespread and appropriate use of PrEP will take several years and will require considerable attention to the shape and quality of health services, according to researchers who have looked at the way in which contraceptive methods have been introduced.

Prior to its introduction in the United States in 1960, many people doubted that large numbers of women would want to take a medication in order to prevent pregnancy and pharmaceutical companies did not believe the market had much potential. Scale-up was slowed by its high initial cost, equivalent to around $80 a month in today’s prices. This, together with a need for regular clinic visits, created economic and logistical hurdles that only more socially privileged women could overcome, say the writers.

After some years, subsidised programmes and government funding helped to narrow inequalities in access. Moreover, media coverage, word of mouth endorsement and promotion by pharmaceutical companies led to a swell of interest and acceptance. Women actively sought out ‘the pill’ from their doctors.

As with PrEP, there was concern about the potential side-effects of the contraceptive pill, as medications taken by healthy people are expected to be safer than those used to treat an illness. While the contraceptive pill’s short-term side-effects were understood, its long-term safety profile was initially unclear. Evidence of a raised risk of deep vein thrombosis only emerged after a few years and resulted in necessary changes in the way the pill was prescribed.

The authors note that, as with initial contraceptive research, most participants in PrEP studies were located outside of the US. “While safety seems promising for emtricitabine-tenofovir, we should expect some surprises as use is scaled up to populations who were not included in the clinical trials,” they argue.

Most famously, the contraceptive pill was thought by some to promote promiscuity and to have caused a ‘sexual revolution’ in the 1960s and 1970s. Similarly, some predict that PrEP will result in reductions in condom use and increases in sexually transmitted infections.

However, the authors suggest that both claims ignore gradual, ongoing changes in sexual norms that had begun before the new medical technologies were introduced. “Changes in behaviour should not automatically be blamed on the new HIV prevention pill,” they say.

Comment: It’s probably best simply to leave the last word to the writers, who say that PrEP advocates can learn many lessons from contraception: “Perhaps the most important of these is that a narrow focus on a single technology alone is unlikely to solve health and social challenges associated with HIV. That, however, is no cause for inaction, but rather a call for innovation to expand the HIV prevention mix, to pay careful attention to access and service delivery issues and constraints, and to incorporate the views and perspectives of all stakeholders.”

Other recent news headlines

Long-term tenofovir treatment poses increased risk of serious liver disease

Long-term therapy with tenofovir increases the risk of end-stage liver disease and liver cancer, according to data from the D:A:D study. Five-year cumulative use of the drug, in people taking it for HIV treatment, increased the relative risk of serious liver disease by 46%.

HIV patients lost to follow-up come back to care through Los Angeles scheme

A programme in Los Angeles County successfully re-engaged and retained patients who dropped out of HIV care. Over 1000 patients lost to follow-up were identified, of which 36% were receiving care elsewhere and 29% could not be located. Of the remainder, 78 people (8%) were successfully enrolled in the programme and another 8% returned to the clinic independently.

Anal infection with high-risk HPV common in HIV-positive women in France

A large proportion of women living with HIV in a national study have an anal infection with types of human papillomavirus (HPV) associated with a high risk of cancer, French investigators report. Anal infection with a high-risk HPV type was detected in 48% of women, with only 26% having a high-risk cervical infection.

Young men with detectable viral loads more likely to engage in risky behaviour

From HIVPlusMag

A new study of gay men living with HIV reported that participants with detectable viral loads were more likely to have anal sex without condoms than those who had undetectable viral loads, and that condom use was closely related to substance abuse. The study examined participants aged 15-26 across the US from 2009 to 2012. Among those with detectable viral loads, 44% reported condomless sex, significantly more than the 25% of those who were virally suppressed who had condomless sex.

The Kremlin shows the world how to make an AIDS crisis worse

from Newsweek

New HIV infections have slowed dramatically throughout the world in recent years, including in much of sub-Saharan Africa – the region worst hit by HIV – but Russia is a deadly exception. Even the official figures, which most experts agree are a significant underestimation, are terrifying. Almost 1 million Russians are registered as having contracted HIV, out of a population of 143 million people, an almost twofold increase from 2010.

How the war in Ukraine is causing a rise in HIV infections

from VICE

Between January and November 2015, more than 13,000 cases of infection have been recorded in Ukraine. The uptick is connected to the failure of the health system, the destruction of medical buildings, and the shutting down of assistance programs for people living with HIV. On top of those factors, the deterioration of the economic situation in the country and the 300% devaluation of the Ukrainian currency, a fall of 25% has been registered in the purchase and distribution of condoms in 2014.

DIY healthcare: importing PrEP into the UK

from Prepster

“It’s been a lot of effort for something that shouldn’t be,” says John from Stockport. He’s educated himself about PrEP, chosen to import and pay for PrEP medicines himself, worked out which tests for side-effects he needs and battled with the NHS to get support. “None of this is really simple,” he says.

Short- or medium-term PrEP is safer than aspirin

from POZ

Truvada (tenofovir/emtricitabine) as PrEP against HIV has comparable safety to aspirin, at least for the short- and medium-term. Publishing their findings in Open Forum Infectious Diseases, researchers compared safety data from the five major PrEP studies to data from two major aspirin safety studies, looking at the relative numbers needed to harm.

I'm an HIV activist, and I support the FDA gay blood ban

from The Body

There's been a lot of talk about the US Food and Drug Administration (FDA) ban on gay blood, and it's time to set the record straight. The blood ban for sexually active gay men and other men who have sex with men (MSM) is necessary. It's not a question of discrimination; it's a question of public health.