Wednesday 23rd July 2014

After a long wait to see Bill Clinton address a packed audience to encourage us to continue to implement the goals of the WHO (and who addressed the gathering as a ‘movement’ rather than a conference), sitting in the special session on antiretroviral management in 2014—an interactive case-based discussion with several prominent HIV and hepatitis specialists—almost seemed ‘easy’ rather than trying to solve the complex public health problems of the developing world.

At the completion of the session, however, we were brought back to reality by a sobering statement from an African doctor who did ask that perhaps the next discussions could take into account the limited antiretroviral options in developing countries with likely scenarios from those regions, hitting home to me just how lucky we are in the Australian treatment environment to have so many choices.

It was also pleasing to see that when asked about simplification regimens for simplicity sake that several panelists were of the opinion that ‘if it isn’t broken, don’t fix it’ as we may switch patients to a less tolerable regimen with poorer adherence and without past records we may run the risk of archived resistance. The concepts of a ‘lateral switch’, where a patient has been naïve to treatment and there is minimal risk to switch versus a ‘vertical switch’ where we may not know of past suppression or resistance profiles was also discussed.

Links to the various guidelines can be found below:

1. ASHM 2014 Antiretroviral guidelines

2. US DHHS Adults and adolescents antiretroviral guidelines

3. American Society for the study of liver disease and the Infectious Diseases society of America: guidelines for hepatitis C treatment

Two very interesting studies from the Kirby were also presented this afternoon.

Firstly, Ben Bavington presented results from the Opposites Attract study looking at behavioural risk compensation amongst couples in the study. ‘Behavioural risk compensation’ being the concept where there may be reduction in condom use due to perceived protection from antiretroviral medications.

Approximately 77% of the HIV negative partners perceived their HIV positive partners viral load was undetectable, which was largely in accordance with pathology results. This did seem to correlate with engagement in condomless sex with approximately 73% HIV negative partners reporting condomless sex (CLS) when they perceived their partner’s viral load to be undetectable and thus demonstrating risk compensation within this group. Amongst the HIV positive partners, however, approximately 90% were taking antiretroviral therapy so perhaps this gave a protective effect.

In a separate session, Andrew Grulich presented on results of the SPANC study. This is an interesting area in that there is a 30-50% prevalence of high-grade anal lesions (HSIL) in gay men.

Treatment is difficult with recurrence rates of 50% at 1 year with grade 3-4 side effects. Progression to cancer is also 1/400 per year in HIV positive men and 1/4000 per year in HIV negative men. Of men recruited into the study they found that 1 in 6 men will develop HSIL per year (16/100 person years) with a clearance of 42/100 person years over 12 months.

HIV positive men were more likely to have HSIL but there was no correlation with age. HSIL was also very uncommon in men without chronic HPV infection. Pleasingly, with the high clearance rates, he concluded that if HSIL is identified that it does not necessarily require treatment and could be observed.

Tuesday 22nd July 

In a program mixed with sessions on searching for a cure or simply arguing for the right for marginalised groups in developing countries to receive treatment, the oral abstract session titled ‘Antiretroviral therapy: not all strategies are created equal’ presented several studies of novel antiretroviral treatment.

The first presentation was presented by Eric Le Fevre who discussed the results of the MODERN trial, which was a phase 3, randomised, double-blind trial that compared triple therapy (TDF/FTC+DRV800/RTV100mg) versus nucleoside/nucleotide sparring, dual therapy (Maraviroc 150mg QD+DRV800/RTV100mg) in HIV positive patients naive to antiretroviral therapy.

Sadly at week 48 the study was terminated early due to inferiority of the Maraviroc containing regimen with only 77.3% subjects reaching the primary endpoint of HIV viral load < 20 copies/ml versus 86.8% of subjects on triple therapy.

Response was actually worse in subjects with a viral load > 100,000 copies and also in subjects with lower CD4 counts at baseline (200-350 cells) but pleasingly there was no emergence of resistance to study drug. Therefore, it still seems that a 3 drug regimen is still the gold standard for HIV therapy with possibly a greater benefit of including N(t)RTIs in the combination when treating subjects with a lower CD4 count.

Marina Klein from Canada then presented data on switching from a first antiretroviral regimen while virologically suppressed showing that it can be associated with increased risk of virological failure.

In Canada’s largest HIV treatment cohort (CANOC), 36% subjects switched from their original HIV treatment regimen, although the reasons for switch were not clearly identified – presumed to be for toxicity, simplification, tolerability or drug-drug interactions. Switching actually seemed to occur on average quite early at 0.8 years and was more common in women and people who inject drugs (PWID).

Klein reported that switching was more likely to be related to treatment failure, as identified as HIV VL > 1000 copies/ml, although did not present what proportion of subjects actually failed treatment. This does highlight some concerns about switching treatment and more specific switch studies should be considered before initiating switches in our patients.

And finally, Mark Boyd from the Kirby Institute in Australia presented interesting data from the Second-line resistance substudy, which aimed to examine the contribution of baseline N(t)RTI-resistance as well as other potential predictive variables to virological failure (VF).

Interestingly, they found that virological failure was associated with self-reported non-adherence, a higher baseline global genotypic sensitivity score (which should actually have indicated a better result), a baseline viral load of greater than 100,000 copies/mL, and race. He concluded that investment in effective adherence interventions and support are still needed.

The afternoon oral abstract session on pre-exposure prophylaxis (PrEP) was extremely well attended, showing a great interest in this area. There were two thought-provoking presentations from an open label ‘extension study’ of the well-known iPrEX study with the catchy title of ‘OLE’.

The first presentation by Kimberly Koester was based on 60 in-depth interviews of OLE participants. Interestingly and pleasingly, subjects stated that PrEP did not, in most cases, actually lead to increased condomless sex and condom use actually increased in younger participants. A major feature of being on PrEP was a decrease in stress, fear and guilt associated with sex. It would therefore seem that PrEP is being used as a supplement to existing HIV prevention strategies.

Jean-Michel Molina from France then presented interesting data from the Ipergay study that looked at high risk MSM who were enrolled in an ongoing, randomised, double-blind, placebo-controlled trial of ‘on demand’ PrEP with oral TDF/FTC.

Subjects were instructed to take 2 pills of TDF/FTC or placebo before sex (2 to 24 hours before), and 2 pills after sex (1 pill every 24 hours). Between February 2012 to May 2013, 153 patients were randomised with a median age of 35 years and median number of 2 episodes of sexual intercourses/week. During their last sexual intercourse (n=543), according to computer-assisted self report, 53% subjects used PrEP as scheduled, 28% used PrEP but did not follow the treatment schedule, and 19% did not use PrEP.

In order to look for drug concentration they collected blood and hair samples but only 59 hair samples from 38 patients were available for analysis – apparently not enough subjects had hair! TFV and FTC were detected in 51% and 49% of subjects in the TDF/FTC arm, and 14% and 0% in the placebo arm, respectively. 548 plasma samples from the first 113 randomized subjects were analysed. TFV and FTC were detected in 86% and 82% (75-100%) of patients in the TDF/FTC arm, and 4% (0-6%) and 3% (0-6%) in the placebo arm, respectively.

So despite variable adherence rates, there were acceptable levels of drug in plasma.

More interestingly, Robert Grant presented more data from the OLE study, especially looking at Tenofovir diphosphate levels in dried blood spots of subjects continuing in the iPrEX extension study. Those subjects with higher drug concentration levels and who reported ≥ 4 days of medication showed a 100% risk reduction in HIV incidence compared with a risk reduction of 84% with 2-3 tablets per week. Results of this study were published online today (July 22) in Lancet Infectious Diseases.

 

 

 

In keeping with the main theme of the AIDS 2014 conference ‘Stepping up the pace’, the first day of plenaries, oral abstracts and symposia sessions (amongst many other activities) focused on the so-called ‘Holy Grail’ of HIV medicine – finding a cure!

This largely focused on how can we identify HIV viral reservoirs and how we can eradicate them. While much of the science presented seems well beyond the scope of primary care, I felt the theme underpins the current debate of whether commencing treatment sooner rather than later is of individual benefit.

The opening plenary by Salim S Abdool Karim (Director of the Centre for the AIDS program of Research in South Africa) summarised the global response to HIV/AIDS over the last 30 years and pleasingly showed a global decrease in the number of new HIV infections in adults and children since the early 2000s. Less pleasingly though was the noticeable decrease in condom use in MSM in Australia between 2007 and 2011.

He also did theorise that the concept of elimination and eradication is not readily applicable to AIDS with the millions of people living with HIV/AIDS and that there is no cure available and that the key to the end of AIDS is ‘epidemic control’.

Jintanat Ananworanich, a paediatrician, immunologist and HIV researcher and now the Associate Director of HIV Therapeutic Trials at the US Military HIV research program in Maryland, USA, then outlined where we are in terms of an HIV Cure and where are we going. She introduced us to the concepts of the persistence of HIV in latent reservoirs and the difficulties of monitoring the elimination of HIV due to the fact that we do not have biomarkers to determine HIV remission.

She suggested that success will likely require combination approaches including early antiretroviral treatment.

This theme was continued in a special session on ‘The Future of Science in the HIV Response’ by Dr Anthony Fauci, Director, National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethseda, USA, where he further outlined the complexity of the HIV reservoir in terms of having qualitative and quantitative characteristics. Qualitative components including the body (e.g. gut, peripheral lymphoid cells, brain), cell type (naiive and memory CD4 cells, monocytes, macrophages and follicular dendritic cells) and the status of the virus (defective or replication competent) and the quantitative aspect simply indicating the quantity of viral reservoir which increases after infection.

HIV viral latency is believed to form very early in HIV infection and the various methods to eradicate HIV include:

• ‘flush out’ the virus or the so called ‘shock and kill’ method (use of latency activator therapies such as Panobinastat)
• immunotoxic therapy
• stem cell transplant
• gene therapy to eliminate CCR5 (Zinc-finger-nuclease modification of CCR5)

Dr Fauci also emphasised that a combination approach would be needed to achieve sustained virologic remission; early treatment initiation would “stack the deck in favour of eradication” by limiting the seeding of the reservoir, while use of novel immunotherapies (including passive transfer of HIV specific antibodies or therapeutic vaccination) would help eliminate HIV and HIV-infected cells. In addition, he outlined that recent advances in our understanding of the ‘broadly neutralising antibody response’ as particularly important in controlling the virus.

These concepts were further discussed in an afternoon abstract session that will be covered in another post.