There were several great talks given on the final day of the ASHM conference. The morning HIV&AIDS symposium s100 prescriber session, entitled ‘changing landscapes in therapy’, discussed current and future issues pertaining to antiretroviral therapy, their interactions with other medications and their role in co-morbidities. Professor Mark Boyd from the University of Adelaide gave an interesting talk on ‘When is 2 drugs better than 3’. Antiretroviral therapy (ART) has often been referred to as ‘triple therapy’, reflecting the current guidelines and current practice of prescribing 3-drug combinations to achieve full virologic suppression.

This has come to question recently with a few trials completed or ongoing that assess dual therapy vs standard triple therapy. There are obvious benefits to dual therapy – reduced pill burden in the ageing cohort would have the effect of reduced drug interactions, as well as possibly improved adherence and drug tolerability. In the same session we heard from Ms Krista Siefred from St Vincent’s about polympharmacy and its associated adverse effects, as well as from pharmacist Ms Alison Duncan on the complexities of drug interactions between ART and other medications. Simplification of ART regimens would greatly assist in these matters

Mark presented several studies comparing dual therapy vs triple therapy. A meta-analysis was performed comparing this, looking at effect on dual vs triple therapy on virologic suppression. Overall, pooled results did not demonstrate a superior result for triple therapy over dual therapy for both viraemic patients and patients switching ART. In more recent studies using integrase inhibitors, again dual therapy (including a dlutegravir + lamivudine regimen, or an intramuscular cobotegravir + rilpivirine regimen) was shown to be non-inferior to standard triple therapy for virologic suppression.

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Although interim data looks promising, long-term safety and efficacy of dual therapy is still yet to be fully examined. As such, it is not yet recommended for clinicians to routinely change patients to dual therapy regimens, although this switch may be a feasible option in the future.

Jennifer Hoy: Director HIV Medicine, Alfred Hospital and Monash University

Most cities and countries have now achieved the 90-90-90 HIV target: 90% of people living with HIV (PLHIV) are diagnosed, 90% of HIV-positive people receiving antiretroviral (ARV) treatment and 90% of PLHIV have viral load suppression. Now a push for a 4th 90 is on the table – 90% receiving Quality HIV care.  

Jennifer discussed two perspectives on this approach to quality care: the patient’s and the healthcare provider’s perspective.

From a patient’s perspective, approaches to quality care can be measured through patient satisfaction surveys and reported patient outcome measures. Such reportable measures includes individualised patient-centred care encounters, experiences of HIV related discrimination and stigma and ease of access to care.

From the healthcare providers perspective, quality care means establishing appropriate management, monitoring and screening of HIV related co-morbidities, ensuring efficient care in a patient-centred manner delivery.

Adapting a new culture of quality of care improvement in HIV treatment would be crucial. This new culture is the key to future sustainability of this 4th 90% target, with clinical audit being its main driver. Clinical audit scrutinises care delivery at different care provision levels. Starting at individual healthcare level providers, to health care settings, the state level and to the highest national level. Vital shortfalls in care delivery could then be identified, feedback these outcomes, for crucial brainstorming of targeted intervention strategies. 

Therefore, to achieve this 4th 90% of HIV care which is ‘Quality of Care’, audits are important! The “measurement-intervention-measurement-intervention” approach to care, because viral suppression is not the end goal of HIV treatment. It is health-related ‘quality of life’.

The Future of HIV Therapy

Dr Roy Gulick (Professor of Medicine and Chief of the Division of Infectious Diseases at Weill Medical College of Cornell University) from New York provided a great summary of current treatment guidelines and new developments underway with ART.

In summary:

ART is now recommended to commence at any CD4 count when a patient is also ready to start. If resources are a priority then treatment should be offered first to those with a CD4 <350.

There are currently 29 approved HIV medications and up to 10 starting regimes.

5 broad mechanistic classes (NRTI, NNRTI, PI, INSTI,EI)

Recommended standard strategy is 2NRTI +(NNRTI,PI,or INSTI)

If there is multiclass failure to the 29 drugs two new entry inhibitor class drugs are showing promise.

1 Fostemsavir (oral HIV attachment inhibitor with Phase 2 results soon to be released)

2 Ibalizumab (monoclonal antibody given parenteral, binds to CD4 receptor/works as HIV entry inhibitor)

2 New classes of HIV Rx being developed:

1 HIV Maturation Inhibitors

2 HIV Capsid Inhibitors

Newer approaches to safety and tolerability in the future ART include:

Using lower doses of drug eg (EFV 400mg vs 600mg). Other studies in progress are ATV 300mg, DRV 400mg

Newer drugs eg tenofovir alafenamide(TAF). Switching TDF to TAF improved renal/bone markers

2 Drug regimes: PI/r+3TC (or FTC), PI/r+ integrase inhibitor, NNRTI +integrase inhibitor , DTG+3TC/Paddle Study(results showed VL all suppressed by 8 wks)

Less frequent dosing eg RAL daily formulation

New co formulations eg ATV/c and DRV/c

New injectable drugs RPV LA, Cabotegravir

Latte 2 study is looking at IM CAB +IM RPV with conclusions showing IM is comparable to PO and well tolerated. Phase 3 studies are evaluating IM q4wks.

Dr Gulick concluded by saying that future ART Rx will involve greater use of sub dermal implants and injections with potentials for dosing going from weekly up to every 1-3 months. Costs will radically decline and affordability improve. Convenience will also continue to improve. We have already seen the dosing levels of 20 tablets a day reduce to one a day in the last 10 years. Interestingly life expectancy in ART uses from recent studies in US, Canada and UK were showing higher figures than for the average population!  Presumably regular medical intervention can be a good thing for our species!

Greetings from the 9th IAS Conference on HIV Science in Paris, France. As usual the content is broad, but (as the new branding signals) science dominates the agenda. On this occasion there is no great breakthrough or advance that might electrify the event and set tongues wagging.

From a global access to care point of view it is clear that funding is at best flat-lining (and this has been the case for the past 7 years) and in some cases falling as we move well beyond the Millennium Development Goals and firmly into the era of the Sustainable Development Goals.

It seems unlikely that the Trump administration will increase U.S. President's Emergency Plan for AIDS Relief (PEPFAR) funding and most likely will withdraw funding during this Presidency. According to UNAIDS. 19.5 million people are now receiving ART around the world. However it is estimated that 40% of all those infected are unaware of their HIV-status and that for every 1 person dying from AIDS every year 2 become HIV-infected. Thus, while the UNAIDS 90-90-90 goals are commendable, we are a long way from getting even close to achieving them. In this context the goals are in danger of being perceived as an impossible dream.

Such musings inevitably focus attention on the critical need for an effective vaccine to truly augment efforts to eradicate the HIV pandemic. Unfortunately there is little news on this front and we need to be realistic and understand that this may be a task beyond us given our current understanding of HIV pathogenesis. This is also the case with the cure, which despite intensive investigation over the past decade has little to show for all the effort. As with the HIV vaccine, a true advance will most likely come from a profound and unpredictable (and unfundable) paradigm shift in our understanding of HIV pathogenesis and immune protection. Let’s hope that occurs in our lifetime, but if I were a betting man…

Better news comes from the fields of therapeutics and PrEP

PrEP rollout is going well but is to a large extent restricted to those countries in which the research has been conducted – France, USA and Australia. Efforts are being made to introduce PrEP into Africa, but a major drawback is the lack of efficacy often seen in younger women (16-24 yo) with oral TDF/FTC. This may be overcome with the use of injectable long acting ART agents like cabotegravir and rilpivirine, and also possibly intra-vaginal rings containing ART (e.g. Doravirine). These rings could also be impregnated with other pharmaceuticals (e.g. oral contraception, anti HSV products, antimicrobials). We await the science.

This conference also saw the presentation of the phase 2b RCT of 2 drug maintenance of initial triple therapy induced virological suppression with long acting injectable cabotegravir and rilpivirine. Over 2 years in the once monthly injection group no virological failures were observed. This once monthly strategy is now enrolling participants in pivotal phase 3 RCTs. Joe Eron (UNC, USA) who presented the data at the conference said that the 2-monthly strategy is also still under active consideration. The result was reported by a few media outlets including the BBC.

See Injections 'next revolution' in HIV - study by James Gallagher:

http://www.bbc.com/news/health-40703336

The conference was also the venue for the public presentation of Phase 3 RCTs of Gilead’s unboosted once daily InSTI ‘Bictegravir’ versus Dolutegravir. The results of 2 Phase 3 placebo-controlled, double-blinded RCTs were presented; one with a backbone of TAF/FTC in both arms and one with BIC/F/TAF versus DTG/ABC/3TC. Non-inferiority was demonstrated in both cases with good tolerability across all groups. Importantly, no resistance was seen in the rare virological failures in both studies, consistent with what we have seen with DTG to date in trials and clinical practice. It is expected that the BIC/F/TAF fixed dose combination product will be licensed in the USA by Q4 2017 and most likely be listed on the PBS by Q3 2018 in Australia.

Is there a role for treatment intensification with Maraviroc in addition to a standard cART for naïve patients with low CD4 counts, and will it decrease the risk of progression to AIDS? (ANRS 146 – GeSIDA OPTIMAL)

There is no clinical evidence that of successful treatment intensification by the addition of a 4^th antiretroviral agent; despite numerous trials.

This double-blinded trial in France , Italy and Spain compared Maraviroc (+cART) to placebo (+cART).   Over 400 naïve, HIV-1 infected patients with an AIDS defining illness or CD4 cells < 200cell/mm^3 were enrolled.

The primary endpoint was the occurrence of a severe morbidity (AIDS, SNAE, IRIS, Death or other HIV related disease). Baseline characteristics were comparable.

In the 72-week follow up period; treatment intensification made no impact on the risk of infections, serious events, mortality, virilogic control or on CD4 count recovery. A post hoc analysis suggested Maraviroc might demonstate benefit on the occurrence of clinical events in the first 6 months of treatment, however this benefit “subsequently disappeared”.