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.

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.

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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 4th 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”.

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This was an oral abstract session focusing on some novel approaches to HIV treatment and modifying treatment in special risk groups.

Jean-Michel Molina presented some switch data from the EMERALD study, a randomized (2:1), open-label, international, multicenter, parallel-group, non-inferiority, 48-week study.  Virologically suppressed individuals were switched from boosted-protease inhibitors (PI/r)+emtricitabine/TDF to darunavir/cobicistat/emtricitabine/tenofovir alafenamide (TAF).  This showed good virologic efficacy and better bone and renal profile at the wk24 interim analysis.

Jose Gatell presented data from an elegant study focused on virologically suppressed individuals with high cardiovascular risk.  They were aged 50 years or older and had Framingham cardiovascular risk greater than or equal to 10 percent.  They switched from PI/r-based to dolutegravir-based regimen and showed non-inferior virologic efficacy with improvements in lipid profile at wk48.  Other outcomes from this ongoing trial are awaited.

Laura Ciaffi showed data from a switching study.  After viral suppression with second-line PI/r+NRTIs, maintenance with PI/r+lamivudine showed virologic efficacy at wk 96 despite the presence of the M184V mutation.   This study was conducted in Africa.  This is an example of the increasing number of dual therapy studies presented at IAS this year.

Kathleen Squires presented data comparing a fixed dose combination of doravirine/lamivudine/TDF to efavirenz/emtricitabine/TDF in treatment-naïve adults with HIV-1 infection.  It showed non-inferiority at week 48 regardless of the baseline HIV RNA.  Doravirine also showed superior neuropsychiatric and lipid profile in these results of the Phase 3 DRIVE-AHEAD study.  A useful extension of this study would be a co-formulation of doravirine with FTC/TAF to reduce the renal and bone effects well known with TDF.

Micheal Aboud presented week 24 interim data from the DAWNING study.  This looked at individuals with first-line NNRTI-based regimen failure.  The superior efficacy of dolutegravir (DTG) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) compared with lopinavir/ritonavir (LPV/RTV) plus 2 NRTIs in second-line treatment was demonstrated.

Finally, Trevor Crowell presented data from a study using one of the newer approaches to HIV treatment, broadly neutralising antibodies.  In virologically suppressed individuals who initiated ART during acute HIV infection, VRC01 was well-tolerated.  However, VRC01 monotherapy was insufficient to maintain viral suppression.  This is an early setback but this will benefit future research in this area.  Broadly neutralising antibodies are being used in a growing area of research to assess alternative approaches to therapy besides daily oral therapy.  On a more reflective note, another theme from the conference this year was to start treatment as soon as possible to reduce the potential viral reservoir which we know is concentrated in lymphoid tissues.  This is likely to enhance prospects of cure or functional cure when future therapies become available.

 

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Presented as part of the mixed bag "Co-chair's Choice" session this study aimed to assess dolutegravir (DTG) in pregnancy. There are many benefits to DTG as treatment, highly effective, well tolerated, once daily with high barriers to resistance.  However, despite being a drug with many desirable qualities, the lack of data in pregnancy have resulted in DTG not being recommended in pregnancy by the WHO.  This study addresses some of the research shortfalls and compared pregnancy outcomes from patients who used EFV/TDF/FTC between August 2014 and August 2016 and those who used DTG/TDF/FTC from November 2016 to April 2017 

 

Much of the groundwork for this study was laid out by the Tsempano study, which demonstrated that EFV/TDF/FTC was associated with lower rates of any adverse birth outcomes as well as lower rates of severe adverse birth outcomes compared with other ART regimens (NVP/TDF/FTC, NVP/ZDV/3TC, LPV/r/TDF/FTC, LPV/r/ZDV/3TC).  A similar framework was adopted for the comparison of DTG/TDF/FTC with EFV/TDF/FTC in women who commence ART pregnancy.

 

Maternal demographics were well matched in both groups for age, employment, parity, gestational age at presentation, previous pregnancy losses and smoking and alcohol consumption.  They were also well matched with regards to the gestational age at which ART was commenced as well as their CD4 counts.

 

Outcomes were startlingly similar as listed below:

 

Total and severe adverse birth outcomes 34% in the DTG/TDF/FTC group, with 11% being a severe adverse birth outcome.

 

Total and severe adverse birth outcomes 35% in the EFV/TDF/FTC group, with 11% being a severe adverse birth outcome.

 

 

 

Birth at less than 37 weeks gestation 18% and less than 32 weeks gestation 4% in the DTG/TDF/FTC group

 

Birth at less than 37 weeks gestation 19% and less than 32 weeks gestation 4% in the EFV/TDF/FTC group

 

 

 

19% small for gestational age and 6% very small for gestational age in the DTG/TDF/FTC group

 

19% small for gestational age and 7% very small for gestational age in the EFV/TDF/FTC group

 

 

 

2.1% stillbirth in the DTG/TDF/FTC group

 

2.3% stillbirth in the EFV/TDF/FTC group

 

 

 

1 major congenital abnormality in the form of skeletal dysplasia in the EFV/TDF/FTC group

 

This preliminary data suggests that DTG may well be considered safe in pregnancy at some point but further research is needed in the following areas:

 

Birth outcomes associated with exposure to DTG from conception

 

Combination with other backbones eg ABC/3TC

 

Maternal viral load at delivery

 

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A late breaker poster was presented Tuesday showing the 48 weeks data comparing Bictegravir co-formulated with FTC/TDF in a fixed dose combination (B/F/TAF) vs. DTG/F/TAF in treatment naïve HIV-1 positive adults. The study is phase 3 multi-centered RCT with a primary endpoint of HIV-1 RNA < 50 copies /mL at 48 weeks, powered for non-inferiority.

 

B/F/TAF was safe, well tolerated and non-inferior to DTG/F/TAF in treatment naïve adults. Discontinuations due to adverse events were uncommon in both arms . There was no evidence of treatment-emergent resistance to study medication. Interestingly there was less of a decrease in the e GFR observed in the B/F/TAF participants. No difference observed in lipids.  

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