In the Resistance and Topism session, Prof Jonathan Shapiro gave an excellent summary on HIV resistance titled: “Resistance: what’s new and on the horizon, and a time to teach old dogs new tricks?”

Professor Shapiro explained that assessing viral resistance enabled better choices for patients and better new drugs that provided more durable lines of treatment.

Resistance testing was developed because, in early ART, many patients were failing virologically and individual mutations helped to guide future treatment. The benefit of resistance testing over and above expert opinion based on previous treatment experience was shown by studies such as Viradapt, GART and Havana.

Over recent years there have been more drugs available, new drugs without class cross-resistance, newer drugs with better resistance patterns and tolerability and simpler regimens, better adherence.

The SPREAD study in Europe showed that acquisition of resistant HIV virus had increased 35% from 2003 to 2013, even though overall prevalence of resistance hadn’t.

There was concern with the roll-out and widespread use of ART in low and middle income countries, resistant rates could sharply increase, but in low and middle income countries, resistance has remained stable 5-15%.

These days there is a need for resistance testing to optimise NRTI use in 2^nd and 3^rd line therapy and fine tune use of PIs e.g. to use darunavir once or twice daily.

Also resistance can be helpful in patients failing raltegravir or elvitegravir and deciding on dose of dolutegravir to use.

There is new technology that can provide for point of care testing for resistance by looking at specific mutations. Depending on requirements, specific point mutations are provided in a tiered kit:  for Tier 1, mutations are suited for 1^st time failure; Tier 2 guidance for suspected transmitted resistance; Tier 3 for NRTI choice in 2^nd or 3^rd line failure; and Tier 4 for PI resistance.

Laboratories providing resistance testing need to improve the format of reporting of resistance testing to make it more user-friendly and clinically relevant.

In the future, reporting will provide not only which drug are okay to use, but also what dose and how many active drugs are needed to be included in the regimen.

 Link to conference summary by Tripp Gurlick now on line, an excellent overview: http://aps.mediasite.com/mediasite/Play/467fcbe8af2d44f1997197f49161d4b21d 

Trip Gulick gave a truly excellent summation of both presentations at the conference and also what can be expected in the future of HIV therapy. I strongly recommend that once the webcasts become available http://hivglasgow.org/ you watch this presentation. I cannot do it justice, but in 20 minutes six key concepts were covered and importantly the contributions they might make to improved HIV treatment by 2020:

Activity

The capacity of a drug to have physiological impact, “may be maxed out at 90%”. Conceptually the drugs might be as active or as near active as they can be. Not an area that was identified as one where great leaps can be made.

Safety and Tolerance

Both areas where a lot of movement has been made but ones identified where work can  and still is being done. Dose reduction (reported on by Di Carey from the Kirby Institute with respect to EFV) and newer formulations such as is the case with TAF (the newer formulation of Tenofovir with improve renal tolerance).

Convenience

An area in which there is likely to be continued improvement. There are now 4 single pill regimens and more will emerge. Interestingly this was an area which was questioned during the conference where convenience was seen as an area for possible trade for cost.

Affordability

This is the area of continued and emerging contention. While this presentation focused on HIV, much of the discussion at the conference on hepatitis C focused on cost. Annual ART in developing countries is approaching $139 per annum. Costs will continue to come down as new compounds are introduced.

Accessibility

Greater access to treatment earlier is the goal and a dimension in which improvement is anticipated. Identification of the undiagnosed is important as is earlier commencement of treatment. But this was framed in a context in developed countries where treatment is delayed and late diagnoses common.

Life expectancy

This was a very interesting if not unexpected analysis. Based on CHIC and D:A:Ds data life expectancy of people living with HIV has greatly increased. This may not be able to be improved much. An otherwise healthy young person, infected today might have a life expectancy in their mid 70s this compares well to averages (men 78 – women 82). If they start treatment at a CD4 above 350 this is estimated to go up to 89 years. That is considerably better than the average and naturally it relates to their engagement with the patient’s life long health system and access to other preventative and restorative health care. So again an area in which we might be maxed out as far as future benefits are concerned.

But please do look at this and the other online presentations when they become available http://hivglasgow.org/ This may be a little while as they go into post-production, but most of the presentations will be put online.

Tracy Swan from the Treatment Action Group in New Your provided a brief yet comprehensive over view of where we are at in relation to hepatitis C treatment access. The webcast from this session is now available on  the HIV Drug Therapy Glasgow 2014 website http://hivglasgow.org/

Or you can go to the specific talk. http://aps.mediasite.com/mediasite/Play/aae59f4f5518478ab61316c0e86530581d There is also an excellent talk at the end of this session which tries to explain the drug regulatory system, and role of generics, predominantly in Europe.  by Pauline Londeix

I have been party to a couple of discussion recently where there has been conjecture about the implications of an elusive undetectable viral load. Before I am attacked as a naysayer, I am not suggesting that total viral suppression is not the aim of antiviral therapy. It is and always has been. But some attention is now being directed at transient, persistent and recurrent low-level viral load. Along with virological and clinical implications, this may also have social and emotional costs for people living with HIV.

Some patients, particularly those who have been significantly pre-treated, no matter how compliant, do not achieve complete viral suppression. Others experience intermittent blips or periods of viraemia. What are the implications of these events? It is important to understand this as fully as we can because we must give people living with HIV reasoned and reasonable information; it fundamentally underpins the thinking behind approaches to cure research and, from a public health and prevention perspective, we must be careful not to alienate people.

Poster 136 (Silva, J. et.al.) from Portugal, present a retrospective observational analysis of low-level viraemia and its immunological and virological significance. It was a relatively large study of 2,161 patients 93% on ART 19% had low level viraemia 52% of whom were adherent. The mean VL was 46 (21 - 190) with an average CD4 of 665 (126 - 2,393). There was no documented virological failure, yet 51% had transient viraemia defined as one detectable VL in the study period, 40% had persistent (constantly detectable) virus and 9% had intermittent (2 occasions of detectable VL with undetectable VL in between).

Their conclusion was "in the absence of significant differences in immunological and virological outcomes and the absence of virological failure, suggests a scarce impact of low level viraemia in patient prognosis." This is qualified by suggesting that prospective and more accurate data are required. A number of oral presentations recommended treatment adherence counselling, rather than automatic switching in the presence of low level viraemia.

I caught up with Sanjay Bhagani and asked him about his comments from day 1 about the timing of hepatitis C treatment commencement:

Could you elaborate on the safety of delaying treatment in people with advancing hepatitis C disease both in mono infection and HIV co-infection:

The question is 'When is it too late to treat hepatitis C?' In other words, when are people started on hepatitis C treatment not going to benefit; when are you are not going to prevent decompensating and needing liver transplant? This is a key area where we are going to get data over the next year or two. A number of countries are advocating the treatment of people with end-stage liver disease because of the high cost of treatment. The NHS has put in an scheme to treat 500 people with advanced disease Child-Pugh B or liver cirrhosis and I can tell you that at the Royal Free we have a number of people who are decompensating despite having started treatment. This will certainly give us an idea of when is it too late to treat people.

So when should we start?

Hepatitis C is not just a disease affecting the liver. It is a multi-system disease. It can cause renal disease, brain disease, cardio vascular disease as well as liver disease. All of these need to be considered. The concept of simply waiting until the liver is diseased might be delaying too late.

Many of these comorbidities are seen in HIV. Do they have a cumulative effect?

Certainly the data is emerging that having another virus as well as hepatitis C means that you are doubling-up on your inflammatory response. Controlling HIV is all well and good and we have been able to do that fairly effectively for some time. But if you have another virus that causes inflammation that may defeat the objective of reducing the inflammatory effect.

Thank you.

Perhaps foolishly I was hoping we might get more data from either the PROUD or IPERGAY studies into PrEP trials, both of which have recently offered participants in their placebo arms active drug. But we will have to wait perhaps until CROI. This morning's plenary did, however, address ARV-Based Prevention.

Stafano Vella provided an update on prevention targets and reflected on the challenges of 90:90:90. He pointed out that drug efficacy should make reaching 90% viral suppression for people on treatment the most achievable of the three. Linking the tested to treatment he saw as a significant challenge and, particularly in the global south, as a difficult goal. But the real challenge globally he saw as reaching the diagnosis of 90% of people living with HIV.

Unfortunately he did not have any magic bullet for reaching the untested and pointed out that the majority of infection occurs before people are aware they are themselves infected. No further light was shone on this issue in question time, although most of the questions did concentrate on PrEP.

Presented by Simon Collins of I-base, this discussion was a thorough recap of PrEP. There is no doubt, that if taken, PrEP offers protection from infection. Yet uptake remains low. Simon showed an interesting slide previously presented at CROI in 2013 by Bob Grant from the iPrEx group which showed the variable risk of HIV acquisition over their study. (If you have not seen it, it is slide 10 in this link www.iprexnews.com/content/croi2013/Grant-Gap-Seroconversion.pdf )

This really is important as much of the debate around PrEP seems to centre on it being a life-long issue. Clearly that is not the case, at least in iPrEx. Simon characterised PrEP as an option which men may want to access a times of particular risk. He also raised the issue of cost. Often PrEP is characterised as the use of drug which would otherwise be able to be directed to people already living with HIV and in need of treatment. There is the capacity to make more drug and generic formulations are also on the horizon. Interestingly the Simon suggested that the cost (using the Gates rate) would be less than $100 per annum, leaving room for a substantial mark-up.

Poster 199 was also mentioned. It describes two MSM on multi-year Tenofovir treatment for hepatitis B who, with high compliance and demonstrable drug on board, sero-converted to HIV following high risk exposure. Both were identified early and notwithstanding treatment both established HIV infection and their "PrEP" did not prevent the establishment of a significant viral reservoir. (Davies et.al).

There clearly remain reservations about PrEP, but it seems like the tide is turning.

Jonathan Shapiro has twice spoken very compellingly about the needs for simplified, clinically relevant advice to help guide decision making. In the opening debate on Sunday he argued that the difficulties of drug - drug interactions could be ameliorated by better interaction tables and desktop guidance.

He has just presented the lead review talk Resistance: What's new and on the horizon. On this occasion, while clearly indicating the continued relevance of resistance, he made a number of key observations:

• "we now have drugs that allow us to ask patients to adhere" reflecting on the greater tolerability of current regimens
• that resistance testing falls into a number of camps:
  transmitted resistance In this regard he predicted that there was unlikely to be a dramatic change and that transmitted drug resistance would remain between 5 and 15%
  treatment optimisation where resistance profiles are used to determine second and third line therapy; determining which NRTI to use and/or fine tuning PI selection, particularly among heavily pre-treated patients

Again he emphasised that resistance interpretation needs to be made easier. His rationale was that we are no longer in a position where drug changes are as frequent. The majority of the drugs commonly in use now are not the drugs which were being used when resistance monitoring first came into being and that as the capacity to adhere has increased, so too has the development of resistance decreased.

He urged clinicians to tell those who develop assays and their interpretation systems what they want to know. He suggested that it should be possible to provide a virtual phenotype interpretation system which would, for example, indicate what PI options were available and what additional drugs to add to optimise a salvage regimen.

He also described a setting where those with limited resources might be able to purchase a basic analysis to assist in continuation or switch strategies through to a more costly tier for complex pre-treated patients. He referred people to the Stanford database http://hivdb.stanford.edu/pages/poc.html

It is not so long ago we had discussions about using standardised resistance interpretations in Australia and trying to make reports more digestible and useful. This seems to be a recurring theme at this conference. How can we make decision making easier? The webcasts from this conference will be posted some time soon and those with an interest in resistance might be interested in viewing O33 Resistance and Tropism.

There has been a theme running through the conference, and I believe through the UK and Europe about where is the best place to provide HIV care. The Australian concept of the highly trained and experienced General Practitioner or Primary Care physician seems to be missing. This is interesting given the very regulated structure of general practice in the UK. But also perhaps understandable because of the existence of GUM clinics.

Yesterday morning's symposium Making Health Care Resources Count: What is the Optimal Way of Managing HIV? gave a number of perspectives. Andrew Briggs gave an interesting and informative introduction to health economics and particularly focused on the concept of driving cost down while minimising any associated reduction in health benefit. This is basically the exact opposite of introducing new drugs or approaches, which have demonstrable benefits but come with commensurate increases in cost.

This theme was continued by Nathan Clumeck who looked at task shifting to minimise cost without compromising outcomes. I think many of us are familiar with this in the developing country setting. But diminishing health budgets are making the discussion of these issues more prominent in the developed setting. WHO has recently published approaches to task shifting in resource limited settings.

Jens Lungren introduced an additional concept to the cost benefit analysis, that of the additional contributory benefit of prevention and reduced transmission, gained by achieving durable suppressive therapy. In his cost benefit analysis a slightly lower benefit for some patients, might be traded for greater population benefit. For example having more people on adequate suppressive therapy, might have a better cost profile than less people on very high cost suppressive therapy, and some people getting no therapy at all.

Alain Volny-Anne presented an interesting patients' perspective reflecting that decentralised care and community care could mean that people living with HIV now needed to access multiple care providers if they were no longer having all their care needs provided by a specialist HIV facility. He referred to this as the "go away" trend. One of the Australian HIV Community S100 prescribers indicated that in Australia she would be able to provide the majority of that care in the general practice setting.

The outcomes from this session were that prevention is cheaper than treatment, no matter how treatment is delivered. Tasks can be shifted provided that there is adequate training, with supervision and support when required. Nathan Clumeck described a model which involved generalists, physicians assistants, nurses and peers in the delivery of routine care, with second and third line care being restricted to specialist physicians.

Additional Abstracts

Two additional abstracts were presented in this symposium. They related to regimen changes as a way of reducing drug costs in the UK. It has to be recognised that there were abstracts added to the symposium and not papers developed for the symposium. They both suggested considerable cost reductions:

• Hill by switching from brand name co-formulations to generic single drugs multi-pill regimens, and
• Walker by switching from triple-therapy to PI monotherapy

Questions and comments from the floor and subsequent discussions were mixed about the point of even considering these options. It was pointed out that the introduction of generics may result in people having their regimen dictated by their capacity to pay as well as by purchasing and discounting arrangements used by Foundation Trusts negotiating prices.

Two posters on the related themes of where best to provide care:

P139 A comparison or routine and targeted testing strategies Perez et. al. from Spain, Found that routine testing was ALWAYS better in primary care. Targeted testing was lower than routine, testing only 50% of the population. But the best result were found in routine targeted testing in Primary Care.

P160 Late diagnosis among our aging HIV population Mensforth et. al. UK. Found that 27 people over 50 with a HIV indicator condition were not tested for HIV in acute medical unit.

The Conference started yesterday and I attended a very interesting workshop on the ongoing relevance of Drug Drug Interactions. The debate, which found ongoing interested and need for attention to drug drug interactions, gave way to three very important case disucssions about DDIs in the context of coinfection and comorbidities.

Sanjay Bhagani presented on the HIV/HCV coinfected patient. While a complex case it was illustrative of some of the issues in managing not just coinfected, but also HCV mono-infected patients and just how long it is safe to delay the commencement of treatment and how much DAAs can rescue patients with advanced liver disease. I am going to try and talk to him in more detail about this during the conference.

Marta Boffito presented on recreational drug interactions with HIV therapy and suggested that some presumed interactions could simply be poor dosing or understanding of the variability of rereational drugs on the part of the patient.

Lastly Kelly Dooley, reporting on TB HIV coinfection raised the issue of whether to treat TB before starting HIV Therapy. Cautioning that the emergence of multi drug and XDRTB suggests treating HIV at the same time. Fortunately we do not see a lot of TB in Australia, but with changing epidemiology this may become more important.

Levinia