ASHM Report Back

Clinical posts from members and guests of the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM) from various international medical and scientific conferences on HIV, AIDS, viral hepatitis, and sexual health.

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Attending my first CROI in Boston, I am amazed by two things. Firstly, how cold it is during the day. I'm sure my eyeballs were going to freeze walking to the conference venue. More of that to come - it's only reaching a maximum of 0 degrees Celsius all week. At least the locals are warm and friendly.

Secondly, the scale of CROI is enormous. Over 4000 delegates this year and the main auditorium is imposing for any speaker. Thankfully there are large screens and excellent amplification. You can still sit way down the back and still see/hear what's going on.

This evening, Dr Paul D. Bieniasz from the Aaron Diamond AIDS Research Center presented the Bernard Fields Lecture on "Making and Breaking Barriers to Cross-Species HIV-1 Transmission". 

The lecture centred on the role of intrinsic host cell factors that directly inhibit viral replication. They work through a diverse mechanism of actions on invariant or genetically fragile viral features. For HIV these defences are called restriction factors. A number of restriction factors have been studied as potential inhibitors of HIV replication. Tetherin was used as an example - the expression of which causes retention of mature, fully formed infectious HIV-1 on surface of infected cells. Tetherin works by inserting its c-terminal anchor into viral envelope, trapping nascent HIV-1 virions by a direct tethering mechanism, leading to endocytosis and signalling.

The Research Center had created an artificial tetherin that was structurally similar but not the same protein sequence as the human protein. Remarkably, this artificial tetherin had action (not as good as real tetherin) to trap virions on the cell surface, preventing release of the virus and further viral replication.

However, viruses have evolved defence mechanisms to counteract these restriction factors. HIV has the Vpu protein that binds tetherin to overcome the cell's defence mechanism. The HIV-1 Vpu protein specifically evolved to work against human tetherin.

These defences are largely species specific, making it difficult to use animal models to study the actual HIV-1 virus. Many Simian immunodeficiency viruses (SIVs) do not encode a Vpu protein, and evolved a different mechanism - the Nef protein which interacts with simian tetherin via the protein's cytoplasmic tail.

Another HIV-1 restriction factor discussed was APOBEC3. APOBEC3 is antagonised by HIV-1 Vif proteins, which also has species specific action like Vpu. The researchers developed an HIV-1 strain with SIV Vif inserted that allowed the virus to replicate in pig-tailed macaque lymphocytes. Infecting successive groups of macaques, the researchers generated a terminal AIDS defining illness in phase 4 animals, when they artificially caused CD8 depletion at the time of infection using anti-CD8 antibodies. The phase 4 macaques developed a B cell lymphoma which showed marked CD4 depletion.

Interestingly, the HIV-1 Vpu in this modified strain adapted to antagonise the pig-tailed macaque tetherin, at the expense of the ability to antagonise human tetherin, providing an insight into viral mutation and cross-species infectivity.

Although Dr Bieniasz was hopeful on the ability to develop more realistic animal models for HIV-1, he cautioned against the use of such models for more advanced research such as vaccine development. While this adapted HIV-1 strain can cause AIDS in a non-hominid species, the adaptation is incomplete. Notably, in this experiment the researches needed to induce CD8 depletion at the time of infection, as the animal quickly adapted and post-infection depletion of CD8 was ineffective at inducing an AIDS defining illness.

 

Tagged in: CROI2014 IAS2013

There has been a considerable level of optimism at the International Network of Hepatitis in Substance Users conference in Munich today. There is a blossoming of new drugs to treat hepatitis C and they appear very effective over shorter durations than conventional therapy. The new DAA, those currently listed and those on the horizon or still in trial are competing for >90% sustained virological responses with some claiming  up to 100% in one of more genotypes. A number of presentations demonstrated that with support substance users can manage and complete treatment.

But the undercurrent to this meeting has been the issue of cost. Europe is reeling from the financial crisis and austerity measures. The cost of these new compounds is seen as prohibitive in developed economies, let alone middle and developing country settings. We have seen this in Australia with the listing of the first two DAAs. How we approach this issue is not clear, but it is likely that patents, trade agreements and intellectual property issues are likely to come under increasing scrutiny.

Restricting access to HCV treatment in people who use drugs is not supported by the science presented at this meeting and treatment is effective and achievable at a similar rate to that among non-drug users. The concept of treatment as prevention was raised by Natasha Martin from the University of Bristol and even modest treatment uptake has prevention benefits in her modelling. Michel Kazatchkine, reviewed the findings of the Global Commission on Drug Policy which has highlighted the futility of the war on drugs and its negative effects on health. The Commission has recently recommended harm reduction and treatment and Michel called for investment in health rather than the war on drugs as we move toward the 2016 UNGASS.

Treatment as prevention in hepatitis C has not really received much consideration yet in Australia. It was debated here and is emerging as an important concept in durable HCV management. As in HIV, it seems we must be exploring the role that treatment will have in preventing new HCV transmission. The review of the hepatitis C strategy provides an opportunity for exploring this issue further and modelling of the prevention effects of treatment should be included in the new National Hepatitis C Strategy.

Tagged in: IAS2013 INHSU

Everyone is excited. The new Guidelines are here and they are ‘game changers’. There is not a single copy left in Kuala Lumpur- they were all taken on the first day when the Guidelines were announced. There is a lot of new material in these Guidelines- the CD4 count has been shifted to ≤ 500 and independent of CD4 count, treatment is recommended for sero-discordant couples, pregnant women and all positive children under 5 years of age. The guidelines are aspirational and provide individuals with a strong tool with which to approach their respective jurisdictions and insist from a policy level that changes be implemented. While I understand that these Guidelines have been developed for that purpose, I have some questions and concerns about how all of this will translate into practice and one concern is how it will directly affect positive women, particularly in resource poor settings.

The new Guidelines recommend that ALL pregnant women are initiated onto a specific ART regime and are maintained on this regime during the transmission risk window. The recommendations then go on to say that treatment should then be maintained over the lifetime of the individual with the question changing from ‘when to start’ to ‘whether to stop’. The paradigm was clearly one of a ‘National Program decision and not an individual decision’. I am concerned, not just because of the significant amount of data being presented here showing that adherence is a complex beast fed by a variety of factors we do not fully understand, I am concerned because I haven’t seen any work on post-birth adherence and strategies to improve this in different contexts which perhaps should have preceded this announcement. I am concerned because it does not discuss strategies for couples to negotiate the treatment differential where a pregnant partner is prioritized for treatment and maintained beyond the risk period when the non-pregnant partner misses out. I am also concerned by the gap in our knowledge around women and treatment more broadly. At a symposia session on women living with HIV last night it was discussed that women are significantly underrepresented in clinical trials and that when pooled, all RCTs received by the FDA between 2000-2008 only had 20% representation by women. We know that women are different. We have different metabolism, higher body fat percentages, different hormones and varying reproductive intentions just to flag a few. Clinicians need the freedom to allow treatment progression to take all of these factors into account at an individual level but for many clinicians, particularly those operating in resource poor settings where the capacity does not exist to look extensively beyond the guidelines into more detailed research or where policy decisions around types of treatment limit the options available, it is possible that these factors may not be taken into account.

The new Guidelines are exciting but there is still work which needs to be done to ensure that we all understand how to reach the aspirations within the Guidelines and that individuals are given appropriate and sustainable treatment options.

Tagged in: IAS2013

Please join us for a memorial event celebrating the life of one of Australia’s leading HIV advocates, Levinia Crook… https://t.co/N7dof5xaGa

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