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.

Subscribe to this list via RSS Blog posts tagged in HIV treatment intensification

Delinkage of the cost of research and development from drug prices

James Love, Director of Knowledge Ecology International

This was a fascinating talk that proposed an alternative model for R+D of new drugs that would reduce the cost of new drugs and improve access for all.

Love outlines how the current drug patent and monopoly for funding the R+D of new drugs has many challenges. Pharmaceutical companies invariably set prices for maximum profitability and costs have risen dramatically even over the past 10 years. The current trajectory means that high and middle-income countries will likely limit access and impose restrictions on those who receive these treatments, and resource-limited settings will face further inequities.

Love proposes an alternative model that funds R+D by “delinkage” of the cost or R+D of new drugs, from the final price of the product.  Alternative funding models for R+D have been proposed; drug research grants and contracts, R+D subsidies, incentives and innovation prize funds.

Some of the above initiatives already exist. There are NIH and EU framework grants, R+D subsidies such as the Orphan Drug tax-credits which are funds available for R+D on drugs for rare diseases (apparently 47% of new US drug approvals in 2015 fell under this model).

Love proposes expansion of current incentives, and progressively switching from the current system of monopolies to alternative models of funding. Progressive delinkage mechanisms could be introduced by governments over time that sequentially move prices closer to the marginal cost of production of the drug.

Love talked about the $15 billion spent on HIV drugs in the US annually with the return of on average one new HIV drug per year. Recently Bernie Sanders in his US election campaign proposed that $3 billion of this money be set aside to fund R+D for new HIV drugs and at the same time eliminate monopolies. He also advocated setting aside funds to reward scientists and researchers who contributed to the development of a drug via open source platforms. 

There seems to be growing support for Love’s model with many seeing the current system as unfair and ridiculously expensive. Apparently several members of the European parliament have expressed interest in the delinkage model, the Human Rights Council has asked states to support the principles of delinkage, India and the World Health Assembly have endorsed the model, the CEO of GSK has endorsed the delinkage model in the context of expensive drugs for rare diseases and several companies have endorsed it for the development of new antibiotics.

This issue has repercussions the world over, and is pertinent at a conference being hosted in sub-Saharan Africa that addresses the HIV and viral Hepatitis epidemics. While we come from a relatively privileged position in Australia, we do face shortages in provision of access to many of the new cancer medications, and one wonders how our health budget will fund the escalating pharmaceutical costs in the future.  This talk outlined an elegant alternative model of funding R+D that would be more equitable and allow universal access to new drugs for all.

Central Demand of "Access Equity/Rights Now" Vocalised on Opening Day of AIDS2016 Durban

The IAS AIDS2016 Conference in Durban, officially opened Monday night local time, however multiple pre-conference meetings had already taken place in the days running up that, including the first MSM Global Forum to be held in Africa; the 1st IAS HIV Cure Symposium, TB, HIV/HCV co-infection, paediatric HIV sessions as well as funder meetings, and political activism, along with cultural and community events in the Global Village. It is 16 years since the conference was held in South Africa, in Durban and the current meeting's theme is "Access Equity/Rights Now" – a central demand is the need for world leaders to meet global goals they need to continue to support HIV treatment and prevention and stick to their funding commitments and goals as well as a call  to combat inappropriate criminalisation of HIV transmission (and recognising the current evidence base of very low HIV transmission risks in a treatment era) – something ASHM is working on through a Consensus Statement with expert stakeholders nationally.

 

MSM Global Forum points out critical issues

Chris Beyrer, President of the IAS opened the MSM Global Forum pre-conference day meeting, pointing out that the recent UNAIDS High Level Meeting on HIV/AIDS struggled to keep key populations on the agenda including MSM, and stigma remains a critical issue intersecting with very low funding (2% of global funding which is out of proportion to the burden of new infections among MSM), violence and criminalisation. An interesting angle taken by the Forum was considering the national economic costs of homophobia, based on a premise that if political leaders and decision makers do not listen to rights based arguments then the ‘dollar value’ impact of the consequences of homophobia on their respective government wallets might work better. Legal reform indicators need also to be included in UNAIDS global indicators.

 

"Know your epidemic means know your HIVDR"

At a well-attended pre-conference meeting, a WHO organised session on HIV Drug Resistance found speakers addressing an inherent potential paradox of a universal access or ‘Treat All’ global response and indeed PrEP scale up and the increased risk therefore of HIV drug resistance (HIVDR).  This session therefore focused on how to prevent the emergence and transmission of HIV DR and consequent risk of treatment failure, increase in drug costs, higher treatment complexity and lowered durability of 1st line regimens (i.e. if people need to switch to more expensive 2nd or even 3rd line regimens due to DR). Fast tracking of global treatment goals need to include the issue of HIV DR risk and this should be an integral part of delivering quality HIV services and be part of routine program management in terms of VL suppression across all the UNAIDS 90-90-90 goals. Presentations focused on strengthening surveillance with the inclusion of a new zero draft WHO Global Action Plan on Early Warning Indicators (EWI) for HIV DR.  This plan is intended to complement national HIV DR surveillance through for example indicators of possible emergence of DR such as monitoring ART prescribing practices, loss to follow-up at 12 months, retention on ART at 12 months, on-time pill pick up, on time appointment keeping, drug stock outs and their relation to VL suppression. VL monitoring is obviously also critically needed (as a proxy for possible patient HIV DR) but still unavailable in too many country contexts. Clinic level data from  55 countries have indicated high levels of appropriate prescribing but sub-optimal levels of loss to follow-up at 12 months, retention at 12 months on time ARV drug pick up and ARV stock outs – which could indicate emergence of HIV DR.

 

WHO seeks online public consultation on Global Action Plan on HIV Drug Resistance

WHO is consulting with global and regional stakeholders to inform the Global Action Plan  on HIV DR – of note to the region is a WHO Western Pacific/South-east Asia regional consultation in Bangkok, August 8th – 12th, 2016 with a plan finalised by end 2016 and full launch in early 2017.

Combating HIV drug resistance

 

With the rapid scale up of access to ART and with countries working towards the 90-90-90 and 2030 targets, this session seemed very pertinent in addressing the final tier of the cascade – that 90% of those on treatment should have an undetectable viral load. Meg Doherty from WHO discussed that this is particularly important in settings where access to viral load and drug resistance testing is limited.

Several low and middle income countries have reported levels of HIVDR at or above 10% in ART naive patients and up to 37% in those restarting ART with prior exposure to ART. *

The WHO speaker cautioned that a “one size fits all approach” would be a mistake and this was certainly evidence by presentations from certain countries with varying resistance rates. However access to viral load, not to mind genotypic resistance testing is lacking in many low and middle income resource countries and each country needs to collect this data to guide and tailor its own response.

Modeling suggests that the cost of inaction is a costly price to pay with increased morbidity and mortality, increased transmitted resistance, increased program costs with second and third line ARVs and increases in new infection rates.

WHO recommends that each country should have a HIVDR surveillance strategy that is based on 1) Early Warning Indicators which essentially reflect the quality of care of the program and include data on prescribing practices, loss to follow-up, ARV supply continuity, viral load etc, 2) National surveys of pre-treatment resistance, 3) National surveys of acquired drug resistance, and 4) Nationally representative surveys that measure drug resistance in <18month olds.

Other interesting comments from panel members at the session emphasised the importance of monitoring drug resistance in pregnant women returning to care with PMTCT option B+ and also in children and adolescents who have lower viral load suppression rates than with adults.

The Global Fund panelist talked about the important implications of HIVDR rates in reaching other targets such as 90% of people who have need of PrEP having access to it, and HIVDR rates being important for effective PrEP.

Dr Anna Flavia presented some of the drug resistant data from Brazil where pre-treatment Efavirenz resistance rates are 7%. This has prompted discussions about whether the national program should recommend routine resistance testing prior to ART initiation, or whether the country simply switch to including Dolutegravir in the first line regimen. All cost benefit analyses favour the switch to Dolutegravir rather than performing resistance testing on all commencing treatment.

The take home message from this presentation was that drug resistance is rising and if the target of ending AIDS by 2030 is to be achieved, then monitoring and responding to HIVDR will be a critical element and that each country is called to act and collect more and better data in order to tailor their response in terms of thinking about switching ART regimens and quality improvements to their HIV programs.

*The WHO draft of the Global Action Plan on Drug Resistance (2017-2021)

A brief blog reviewing the Bernard Fields Lecture. Monday 22nd Feb.

T Cells Control of HIV: Implications for Vaccines and Cure.

Speaker: Dr Bruce D Walker (Harvard, MA, USA)

In summary CD8 T cell immunity is still undergoing vital research in assessing how it impacts on overall immunity specifically relating to HIV. Can it help us in a cure or vaccine development? 

Known that CD8 T Cells can kill infected cells before progeny virions are produced. Yang 1997 showed that In vitro CD8 cells can kill HIV infected cells.

In order to assess T Cell response in initial pre peak viremia infection they are studying HIV infected babies in Durban, South Africa. FRESH program was implemented. It was noted within these patients that the rate of increase in viral load was similar across all new infection babies, but the actual peak viral load number and time to reach that in an individual varied. http://ragoninstitute.org/international/fresh/

 From current findings they have found that CD8 cells increase their activity within the human body just after initial exposure to HIV, a substance known as PD-1 is expressed and the more of this that is expressed over time there appears to be some correlation with the immune system getting turned down in regards to response. This was apparently similar to what has been noticed with cancer modulating cells and immune response impact.

They have been able to show that HIV some how activates CD8 activity –they hypothesize that perhaps active CD8 T cells are HIV specific. It was noted that an increased level of CD8 cell activated initial stages of infection was linked with a lower viral load set point.

Two other markers noted to be of relevant were, BCL-2 and perforin. As BCL-2 was activated CD8 cells underwent increased apoptosis, and similarly as there was a loss in perforin there was a progressive decline in CD8 functionality.

Overall early treatment does impact the overall quality of the immune response. To further hypothesis but if CD8 cell functions were maintained by commencing treatment in the pre-viremia stages of infection exposure could this help in the development of a cure and it’s effectiveness.

At the conclusion of the talk, despite being moderately confused with the biochem aspects, I got the impression that for now in order to help the development of future effectiveness of a potential cure we need to maintain baseline immunity of newly diagnosed HIV positive patients as much as possible, and prevent the exhaustion or destruction of CD8 cells after peak viremia.

I’m not sure if I would use this particular pitch to promote early commencement of ARVs in patients or for increased testing programs to detect earlier, but it’s food for thought as to why there is a possible other reason to suppress viral loads as early as possible.

 

This paper reviewed the increase in viral suppression and sustained viral suppression in USA adults on ART between 2009 and 2013.

Viral suppression increased in a linear fashion from 72 - 80% a significant 2% rise year on year. Sustained virological response followed a similar trajectory from 58% - 68% over the same time. This was not explained simply by an increase in number of people on therapy.

Women, 18-29 year old's, 30-39 year old's, African Americans all had a greater benefit than the overall. MSM were higher than the average at all time points.  There were two Guidelines introduced during the study period which actively promoted treatment and barriers and delays to accessing AIDS drugs. All suggesting that policy change is having impacts.

This is Oral paper number 53, in session O-5, if you want to have a look when the presentations go on-line. http://www.croiconference.org/

Sydney Rosen presented this SA randomised trial. Patients in South Africa were randomised to start ART on first visit or delay to standard guidelines (which require CD4 testing and behavioural visits, which can take up to 4-6 visits). Three quarters in the RapIT arm started on the first visit (TB was the main cause for delay in the RapIT arm). The RapIT arm had improved outcomes. It saw greater effect for young people, in primary care clinics and loss to follow up was very low.

The presentations should be on line shortly http://www.croiconference.org/ this one is #28 in Session Oral-2

What do we know that we do not know?

On Thursday afternoon, under Theme B: Antiretroviral Therapy, things moved up a gear, with back to back presentations touching almost every aspect of the ART and the long term complications. Dr David Nolan from Royal Perth Hospital gave a thoroughly captivating revision around HIV treatment. He gave a brief account of the pre, early and late HAART treatment options, how things have evolved in terms of the choices, co morbidities, tolerability and toxicity.

He reflected on the contemporary challenges around decision making in clinical practice, how we can factor in the newer therapies and novel diagnostic approaches in our existing treatment and screening paradigms.

What do we know that we do not know?

David argued that despite of having potent ARTs with superior virological efficacy, we don’t have enough evidence to guide us on how to screen, monitor, and subsequently manage the emerging associated co morbidities including HIV neurocognitive impairment, chronic immune activation, and increased risk of malignancies.

What don’t we know that we do not know?

David threw up some very topical questions with both ethical and public health implications. Does it matter that there are things we don’t know? Should we change ART regimen just because we have newer drugs? What if HIV patients with sustained viral suppression do not want to change their old medications?

These are very complicated and yet practical questions, and we still do not  seem to have a simple answer. With discovery of newer, safer and simpler ART regimen, we are likely to find ourselves in a situation where we might simply not have enough evidence to guide clinical choices when it comes to changing or switching regimen. In that case he concluded that we might simply accept the fact that there will always be unknown unknowns.

He also discussed the rationale of ART treatment intensification (using Maraviroc for example) and what should be realistically expected. He pointed out that current evidence indicate that treatment intensification makes little difference in some of the important prognostic clinical parameters like viral load and immune activation markers. It does not appear to impact on viral reservoirs and residual viremia which tend to be established early following primary HIV infection. He posited that, in absence of robust evidence for treatment intensification, the seemingly logical approach will be to start treatment early following seroconversion.

This was arguably one the most thought provoking presentation I have attended in this conference. It raises some of the difficult issues clouding the field of HIV and ART treatment and long term treatment outcome. Obviously, there are things that we do know, and things we have been doing well in improving our knowledge and understanding of how ART works.

Perhaps, It is time to start thinking about how do we integrate the use of monocyte activations markers like sCD14, in the standard of care for our patients.  For the next few years it will be pretty much about the known unknowns and the unknown unknowns that will really determine if we are going to win another important dimension of this epidemic when every HIV patient has undetectable viral load.