CROI CONFERENCE ON RETROVIRUSES AND OPPORTUNIST INFECTIONS

Friday 17 February 2017

Contents

Spanish vaccine induces viral control off ART in nearly 40% of recipients

A so-called ‘HIV Conserv’ vaccine has for the first time produced significant prolonged viral control in a large minority of recipients once they were taken off antiretroviral therapy (ART). So far, one participant has stayed off ART for seven months without having to resume it, the Conference on Retroviruses and Opportunistic Infections (CROI 2017) in Seattle heard yesterday.

Although a number of vaccine studies in monkeys have produced long-term viral suppression, this is the first human study to produce such an effect.

HIV Conserv vaccines contain selected antigens (immune-stimulating sequences of proteins or genes) from HIV that are highly conserved, hence the name. ‘Highly conserved’ means that they are the parts of HIV the virus can least afford to change, and which vary little from one virus to another.

The vaccine thus consists of sections of proteins from different strains of HIV stitched together that generate an immune response to HIV that the virus finds it hard to ‘escape’ from. It cannot afford to generate mutations that get round the body’s immune responses because to do so would weaken it.

What this means is that the vaccine ‘pushes’ the body’s anti-HIV CD8 T-cell response in the direction of becoming more potent and less wasteful, because the body does not generate responses that the virus can easily evade.

In the BCN02 study reported at the conference, 15 people received the vaccine at weeks zero and nine. They also received three doses of romidepsin, a drug which stimulates latently infected cells to produce HIV. It was hoped these bursts of virus production would strengthen the immune responses produced by the vaccine.

ART was stopped at week 17 in a so-called Monitored Antiretroviral Pause (MAP). ART was resumed if there was viral rebound. So far, 13 people have interrupted treatment.

Eight people experienced a rapid rebound in viral load, but five people have controlled HIV at very low levels for periods between 6 weeks and 28 weeks.

“This study is exciting because it is the first to demonstrate post-treatment control – that is, the virus is present but doesn’t rebound after stopping antiretroviral therapy,” said Sharon Lewin, Director of The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Australia. “However we also need to be cautious – there was no control group and we don’t know which part of the intervention was important.”

Unique case of PrEP failure without drug resistance

Elske Hoornenborg and Godelieve de Bree at CROI 2017. Photo by Gus Cairns, aidsmap.com

A man taking part in a pre-exposure prophylaxis (PrEP) demonstration project in Amsterdam has acquired HIV despite good adherence to PrEP and high drug levels. In unique contrast to the handful of previous case reports of PrEP failure, this case cannot be explained by starting PrEP during acute infection or by exposure to drug-resistant HIV.

Among the tens of thousands of cases of PrEP preventing HIV, there have been a few reports of people who acquired HIV. The most fully documented case was reported at last year’s CROI.

The new case concerns a man who tested HIV negative at months one, three and six after starting PrEP. Dried blood spot testing (which is a good guide to adherence in the past month) suggested excellent adherence.

Approximately eight months after starting PrEP, the trial participant came to the clinic complaining of fever, difficulty in urination and urethral inflammation. He tested HIV positive that day. Resistance testing showed that he had no drug resistance mutations at all, not even minority ones.

The clinicians involved say that this is the first case of infection with wild type HIV-1 in a person with documented intracellular levels of tenofovir diphosphate that would be considered to be protective. It is the first evidence that suggests that on rare occasions PrEP may not work against non-drug resistant HIV.

Some aspects of the case are intriguing. The man had an atypical pattern of seroconversion, potentially due to an aberrant immune response under PrEP. When he first tested positive to HIV antibodies, tests could not detect p24 antigen, cellular RNA or integrated DNA in blood cells or rectal tissues.

The man had a great deal of condomless sex, which could mean repeated exposure to HIV and mucosal damage. He had condomless sex, on average, 16 days per month with 3.7 partners on each of those days.

The researchers have a number of hypotheses about potential mechanisms for this extremely rare case of infection despite PrEP, but stress that any explanation at this time is speculative.

Hepatitis C ‘treatment as prevention’ cuts new infections by half

Victor Virlogeux and Bart Rijnders at CROI 2017. Photo by Liz Highleyman, hivandhepatitis.com

One year after the Netherlands instituted a policy allowing unrestricted access to direct-acting antivirals (DAAs) for the treatment of hepatitis C virus (HCV), there is already a dramatic decline in acute HCV infections in HIV-positive men who have sex with men.

The new DAAs make hepatitis C treatment faster, easier and much more effective. Promptly treating everyone with hepatitis C infection, especially those at greatest risk of passing the infection on, could cut transmission. But in many countries access to the new drugs has been limited due to their high cost.

From November 2015, all people with HIV and hepatitis C co-infection in the Netherlands could be prescribed DAAs, regardless of liver fibrosis stage. Uptake was swift, especially in people without severe liver disease who would previously have been denied treatment.

The study looked at 2422 participants in the Dutch ATHENA cohort of HIV-positive people who had hepatitis C co-infection.

As of January 2017, 82% had started treatment and 70% were either cured or still on therapy. Among people treated with DAAs, the sustained virologic response rate was very high, at 98%.

About three-quarters (76%) of gay men had been cured or were still on treatment, compared to 45% of other groups, including women and people who had formerly injected drugs. Gay men had been targeted for treatment in an effort to interrupt transmission networks and men were eager to be cured as soon as possible for this reason.

Within another cohort of HIV-positive men who have sex with men, there were 93 identified acute hepatitis C infections in 2014, but 49 infections in 2016. The annual incidence rate was 1.1% in 2014 and 0.5% in 2016, a highly significant 51% reduction.

This drop in hepatitis C incidence occurred at the same time as a substantial increase in syphilis infections and evidence of more sexualised drug use, suggesting that the drop in hepatitis infections is not attributable to changes in sexual risk behaviour.

France is another country offering unrestricted access to DAAs, although uptake is lower. A mathematical model presented to the conference looked at the potential impact of different levels of treatment coverage in France.

As of January 2016, around 7200 people living with HIV had active hepatitis C co-infection and were receiving care. Assuming hepatitis C treatment coverage is maintained at its current level of 30% per year, the model predicted that overall hepatitis C prevalence would drop from 5.1% to 1.1% in 2026, equivalent to around 2000 people. Increasing coverage to 70% would bring the number under 1000.

The decreases would be seen in most subgroups, including lower risk men who have sex with men. But given their higher rates of acute infection and reinfection, higher levels of treatment coverage would be needed for higher risk men who have sex with men. Behavioural interventions; regular screening, including in previously treated people; and reaching undiagnosed individuals for engagement in care would also be required to eradicate hepatitis C in this population.

American researchers called attention to the contrast between these European examples of falling incidence and the other countries where access to treatment is still heavily restricted and incidence is rising.

Smoking, cancer and heart attacks

Leah Shepherd at CROI 2017. Photo by Liz Highleyman, hivandhepatitis.com

Stopping smoking has profound benefits for people living with HIV, the conference heard. Just one year after quitting, the incidence of a range of smoking-related cancers falls significantly, although the risk of lung cancer persists. Moreover, smoking probably contributes far more to the risk of cardiovascular disease in people with HIV than viral load, antiretroviral drug choice or any factor linked to HIV.

Smoking is more common in people living with HIV than in the general population. Around 17% of the general population in the United States smoke, compared to 40% of people living with HIV. Comparative figures for the United Kingdom are 19% and 29% respectively, with people with HIV especially likely to be heavy smokers.

An analysis from the large D:A:D cohort included data on change in smoking behaviour with participants followed for a median of nine years. During this time, 1980 cancers were diagnosed among 35,424 participants, including 242 lung cancers and 487 other cancers recognised as smoking-related (such as head and neck, oesophageal, stomach, pancreatic, kidney and urinary, ovarian and liver cancer).

The incidence of smoking-related cancers – excluding lung cancer – fell substantially a year after quitting and thereafter it was comparable to the incidence in people who had never smoked.

On the other hand, the incidence of lung cancer remained at least eight times higher in ex-smokers five years after giving up when compared to people who had never smoked. This finding is in contrast to studies in HIV-negative people, where a decline in the risk of lung cancer begins to become evident five years after quitting.

A second study analysed the contribution of various risk factors to heart attacks in people in the NA-ACCORD collection of North American cohorts. During a median of three and a half years, 347 heart attacks occurred in 29,515 people.

  • If everyone stopped smoking, 38% of all heart attacks would be avoided.
  • If everyone had normal cholesterol, 43% of heart attacks would be avoided.
  • If everyone had normal blood pressure, 41% of heart attacks would be avoided.

In comparison, changing risk factors associated with HIV – a low CD4 cell count, a lack of viral suppression, an AIDS diagnosis, or hepatitis C co-infection – would have a much smaller effect on the total number of heart attacks.

The studies suggest the need for a much greater emphasis on smoking cessation in people with HIV, as well as a greater emphasis on the management of cholesterol and high blood pressure. This will require greater input from primary care physicians and non-HIV health care services.

Good results for three-drug regimen against XDR-TB

Nix-TB patient in waiting area at Brooklyn Chest Hospital in Cape Town. Credit: John-Michael Maas for TB Alliance.

A regimen of three oral drugs given for six months was enough to clear extensively drug-resistant tuberculosis (XDR-TB) in 29 of the first 31 people to have completed the treatment course, CROI heard this week. If the results are replicated in a larger study, the findings could revolutionise the prospects for treating XDR-TB and severe cases of multidrug-resistant tuberculosis (MDR-TB).

XDR-TB is a growing problem in countries with a high burden of MDR-TB, such as South Africa. Current treatment for XDR-TB requires a six-drug regimen, including a six-month phase of treatment that includes injectable drugs, and a further 12-18 months of treatment with five drugs. Some of the drugs used have serious side-effects, and the cure rate is shockingly low: just 11% of South Africans are cured five years after beginning treatment, whereas 73% die.

The NIX-TB study is testing a three-drug regimen consisting of bedaquiline (Sirturo, the first new TB drug to be approved in 40 years), linezolid (a cheap antibiotic), and pretomanid (PA-824), an experimental TB drug being developed by TB Alliance.

Early results from the first participants were presented at CROI. Thirty-one people in South Africa have completed treatment and 6 months of post-treatment follow-up. The study’s primary endpoint is the incidence of bacteriologic failure, relapse, or clinical failure at this stage. This was only reached by two individuals – one person has been reinfected with drug-susceptible TB and one person appears to have suffered a relapse of XDR-TB.

A separate study used genetic analysis to show that migration and travel plays a big part in the spread of XDR-TB in South Africa’s most severely affected province, KwaZulu-Natal. It had been thought that the transmission of XDR-TB is concentrated in households, but the analysis found the median geographical distance between pairs of genetically-linked XDR-TB infections was 111km. Four in five people in genetically linked pairs lived in different districts of the province.

How should HIV self-testing services be provided?

Pitchaya Indravudh at CROI 2017. Photo credit: Robb Cohen Photography & Video.

The best way to implement HIV self-testing, the most appropriate form of self-testing services and the best ways to ensure linkage to care remain open questions, but the conference heard research from Malawi and the United States that addresses these issues.

In order to inform service design in Malawi, discrete choice experiments were used to determine the strength of user preferences for different aspects of service delivery. Provision of self-test kits by lay volunteers in people’s homes was preferred. Even a price as low as US$0.10 would deter people from testing. Participants expected more than a leaflet for post-test support and would like to be able to link to follow-on care at home.

There were problems with comprehension of the pictorial instructions provided with the self-test kits, but the researchers found that an in-person demonstration prior to testing was acceptable and allowed people to test accurately.

In New York City, the free distribution of self-testing kits to gay men using dating apps and websites was a feasible and acceptable way to reach a diverse range of participants, including many who had not tested recently. However, relatively few new cases of HIV were identified.

One US pilot study is trialling a test kit fitted with sensors that detect when the kit is opened. A telephone counsellor can then call the person to offer support and linkage to care.

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