A large study of daily tenofovir/FTC (Truvada)used as pre-exposure prophylaxis (PrEP) in women has closed less than halfway through after investigators concluded there was no chance of it being able to demonstrate any difference in the HIV infection rate between women taking Truvada and women taking a placebo.

This result comes as a major surprise after the international iPrEx study¹ in men who have sex with men reported that PrEP had an overall efficacy of 42%.

The FEM-PrEP study recruited 1951 HIV-negative women aged 18 to 35 at risk of HIV infection in South Africa, Kenya and Tanzania.

Last month the trial’s Data and Safety Monitoring Board found that, unexpectedly, there were exactly the same number of infections in women taking Truvada as in women taking placebo – 28 each.

It calculated that, even in the unlikely event that every single future infection was in women on placebo, the trial would be incapable of demonstrating a statistically significant advantage to Truvada.

Prevention advocates and experts were surprised at the lack of efficacy seen in the trial. “We really didn’t see this one coming,” said Mitchell Warren, Executive Director of the AIDS Vaccine Advocacy Coalition.

But, he added: “Even with this finding, there is still a strong rationale for continuing other trials, including those in women, in hopes of obtaining better results in the future.”

It is important to emphasise that, lacking a detailed explanation of the results, we are essentially in the same position as before; we do not know if PrEP will work for women.

The investigators will now concentrate on two linked areas: a detailed investigation of adherence, and of drug levels in women taking Truvada.

One thing the iPrEx study found was that self-report cannot be relied on as a measure of adherence: reported adherence was over 90%, but when researchers measured blood drug levels, they found that only 50 to 60% were taking the pills.

Monitoring will also discover whether blood drug levels are matched by levels in the vagina. Studies have found that oral tenofovir tends to reach higher levels in rectal tissues than in vaginal tissue and though a study presented at this year’s CROI found adequate levels in vaginal tissue, presenter Craig Hendrix warned that “what is ‘enough’ for prevention is yet to be defined”.²

There were significantly more pregnancies in women taking Truvada than placebo. This could explain the lack of efficacy. Pregnancy excluded women from the trial, which would mean women on Truvada spent more time not taking pills, on average, than women on placebo. Any protective effect of Truvada may be so attenuated that it was not demonstrably better than placebo.

The more troubling possibility is that Truvada had an unexpected drug interaction with the women’s contraception. If tenofovir or FTC altered levels of contraceptive, this could also alter the thickness of the vaginal mucous membrane and thus alter a woman’s vulnerability to HIV. However, no such interaction has been described.

The third possibility is that side-effects amongst women taking Truvada might have caused their adherence to be poorer than in women taking placebo; the iPrEx study found a higher rate of nausea in men taking Truvada in the first month.

The result indicates that antiretroviral drugs may show different levels of effective prevention according to population, locations in which they are studied and prevention method used: last year the CAPRISA 004 study found that tenofovir used as a vaginal gel was 39% effective at stopping HIV infection in South African women.

Two studies will continue to test the use of Truvada to prevent HIV infection in women: the Partners PrEP study is testing PrEP in 4700 serodiscordant heterosexual couples in Kenya and Uganda, and the VOICE study is comparing the effectiveness of oral tenofovir or oral Truvada to a vaginal gel containing tenofovir in 5000 heterosexual women in South Africa, Uganda and Zimbabwe. Both studies are expected to report results in 2013.

HIV testing guidelines developed by the British HIV Association (BHIVA) and others recommend that a wide range of non-HIV physicians should offer HIV testing, especially as a quarter of newly diagnosed people are thought to have had a ‘missed opportunity’ for an earlier diagnosis.³

However, these recommendations are not supported or are contradicted by a significant number of clinical guidelines developed by other professional bodies, Dr Martin Fisher, lead author of the testing guidelines, told the BHIVA conference last month.

In 2008, the guidelines, developed by BHIVA, the British Association for Sexual Health and HIV (BASHH) and the British Infection Society (BIS), urged healthcare workers of all specialities to consider HIV testing in a wide range of situations and settings, including GP surgeries and most hospital departments. More recently, the National Institute for Health and Clinical Excellence (NICE) issued recommendations endorsing most of the 2008 guidelines. But implementation outside of sexual health settings has been limited. Fisher’s investigation confirms previous findings that the most important barriers to implementation have not been with patients, but with healthcare staff.

One key aspect of the 2008 testing guidelines was the identification of a number of health conditions which may indicate underlying HIV infection.

Fisher did a survey of guidelines prepared by non-HIV specialist societies and other bodies describing the management of 13 ‘indicator’ diseases. In only four of the guideline documents is HIV testing considered or recommended.

For example, whereas BHIVA recommends an HIV test for some women with abnormal cervical screening results, recommendations from the UK National Screening Committee and the Royal College of Obstetricians and Gynaecologists specifically discourage the offer of an HIV test.

Fisher said it was “staggering” that the guideline on pulmonary tuberculosis developed by NICE and BTS (British Thoracic Society) suggests HIV testing should only be considered on a case-by-case basis. In BTS guidelines on bacterial pneumonia, its management in people with diagnosed HIV is excluded from scope, but the possibility of the condition being caused by undiagnosed HIV is not mentioned.

An audit of general practice showed that in only 16% of cases where a patient had a clinical indicator disease was HIV testing done or considered.⁴

Two studies presented at the BHIVA conference suggest that the proportion of people who have subtle brain impairment due to HIV may not be as high as previously thought.

About 16% of the general population has some degree of neurocognitive deficit. In 2010 the large CHARTER trial in the US caused concern when it found that 52% of 1526 people with HIV had evidence of neurocognitive impairment,⁵ including 28% with no disabling neurological symptoms and no HIV-related illness.

One of the studies presented last month, of 31 young people born with HIV and aged 16 to 25, found they had rates of neurocognitive impairment no higher than HIV-negative siblings, though it did find more memory problems reported. It also found changes in brain function in MRI scanning, of unknown significance.^6,7

The other study found a rate of asymptomatic neurocognitive impairment of only 19% in a group of older patients with suppressed viral loads (average age 55), very little in excess of the general population rate.

Researcher Dr Lucy Garvey explained: “This is one of the first studies to look at neurocognitive impairment only in stable HIV-asymptomatic patients on suppressive antiretroviral therapy.”

A vast array of hepatitis C antivirals currently in clinical trials is opening up new horizons for treatment of hepatitis C. At last month’s International Liver Congress in Berlin, agents from four new classes of drugs, as well as potential improvements to current therapy, were presented.⁸

The key issue is how to use telaprevir and boceprevir, the new hepatitis C protease inhibitors (PIs) available later this year – and who can afford them (see HTU 205).

For patients with previously untreated hepatitis C, new drugs will offer a substantially higher cure rate and possibly reduced treatment time.

However, the headline trial outcomes conceal several caveats. People who didn’t respond to standard therapy of pegylated interferon and ribavirin still have low response rates when the new PIs are added. Lower rates were also observed in patients with cirrhosis.

People with advanced liver disease will need to decide whether to attempt a cure now or wait for a greater choice of drugs. There are concerns that premature use of new agents in people with a poor chance of response could cause resistance that may reduce effectiveness of subsequent new treatments.

Other PIs being developed have improved results, such as TMC-235. In studies of this drug, 92 to 96% of people who had responded to interferon/ribavirin before but had not been cured were cured, as were 70 to 87% of people who had not previously responded at all.

Some studies have also produced cures in some patients (without HIV) without any need to take interferon or ribavirin.