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.

 

STRIIVING

 

This is the eagerly anticipated large switch study for dolutegravir (DTG ) needed to round off the drug’s development and clinical applicability. The efficacy data was first presented at ICAAC in September with some focus here on secondary endpoints such as safety and satisfaction.

 

551 patients taking stable PI, INSTI and NNRTI based regimens were randomised to switch to ABC/3TC/DTG (n=277) or not (n=274). Switching to Triumeq was non-inferior to continuing ART, 85% vs 88%, difference -3.4% (CI95: -9.1%, 2.3%). No patients had protocol defined virologic failure and therefore no patients were evaluated for treatment-emergent resistance in either arm.  In conclusion this large, robust open label switch study had great results in terms of safety, satisfaction and efficacy.

 

On Thursday ( from Antiretroviral Therapy Session 1 ) I posted some very interesting pilot studies looking at DTG monotherapy in maintenance or novel bicombos in naïve patients such as 3TC/DTG. These are studies which are beginning to answer some of the burning questions that we have have about the genetic barrier of DTG.

 

STRIIVING is not one of those studies

 

The background to this is SWITCHMRK. In this study patients on stable PI based regimens who were randomised to switch to TDF/FTC/RAL exhibited virological failure if they had fostered NRTI mutations in the past.  Ever since this study switch studies have excluded patients at baseline who have had prior NRTI virological failure/resistance including the SPIRIT study (switch to TDF/FTC/RPV) and STRATEGY PI (switch toTDF/FTC/EVG/c). This study is no exception.

 

Therefore this study highlights an important point for clinicians considering switching patients it ABC/3TC/DTG. If the patient is on a stable PI based regimen one has to revise how they arrived there.  In essence this robust switch study does not yet answer the question “Can I put my first line failures on ABC/3TC/DTG?” It may be possible in the future as we discern more about DTG genetic barrier.

 

The answer to this question will likely come from a second line study recruiting now where NNRTI failures are randomised to receive either ABC/3TC/DTG or DTG/LPV/r viewable here on the clinicaltrials.gov site:

 

https://clinicaltrials.gov/ct2/show/NCT02227238?term=dolutegravir+second+line&rank=1

 

This study is called DAWNING.

Tagged in: EACS2015
Data from the BMS-955176 Phase IIa proof of concept study was presented.
 
Short 10 day monotherapy were conducted for HIV-1 subtype B and C in treatment naive or experienced subjects to demonstrate virologic suppression. 1.64 log was achieved at doses above 40mg for B and 1.35 log for C.
 
The study also concluded comparable virologic control over 28 days with standard of care TDF+FTC+ATV/R with a 2.23 log fall in viral load at Day 28.
 
Still too early to tell I think.
Tagged in: EACS2015
Results were presented from the 0109 study funded by Gilead. Results from the study have been presented at multiple recent meetings.
 These results compared patients on standard of care Truvada plus boosted atazanavir to those subsequently switched to TAF/E/C/F (elvitegravir/cobicistat/FTC).
 
Follow up to 48 weeks supported at least non-inferior (perhaps superior) virologic control.
 
In relation to drug toxicity:
- The TAF arm had a change in creatinine of 0.00 compared to 0.03 mg/dL in the control arm from baseline.
- All measures of urinary protein were superior in the TAF arm.
- All lipids were increased in the TAF arm but investigators argued it was not clinically significant in light of a preserved total/HDL ratio.
- Improvement in BMD already at Week 24 and by Week 48, about 2% improvement, which in some cases was sufficient to move osteopenic patients to normal range.
 
Overall, I think TAF is very promising.
Tagged in: EACS2015

There was a lot of really good information today, not just from this stream but several others and I will be adding more over the next 2 days. But for now, here is GARDEL at 96 weeks

GARDEL 96 weeks

The 96 week data of this argentinian study was presented to show durability of the novel nucleoside sparing bicombo of 3TC/LPV/r.

The 48 week data was presented at this same meeting in Brussels 2013 by Pedro Cahn

426 naïve patients were randomised to receive a 3 drug regimen of 2NRTI/LPV/r or the novel 2 drug regimen of 3TC/LPV/r.

Virological efficacy of the nuc sparing arm was equivalent to the 3 drug arm at 96 weeks, 90% vs 84% (CI95: -2.3% to 14.1%). Equivalence in the high viral load stratum >100K which we saw at 48 weeks was also maintained here.

It needs to be said however that AZT/3TC accounted for 54% of the NRTI backbones in the 3 drug arm. One could therefore expect AZT toxicity discontinuations leading to underperformance of the 3 drug arm bringing about equivalence with 3TC/LPV/r in this ITT analysis. This makes the overall study findings questionable.  The analysis of protocol defined virological failures (PDVF) and resistance is however reassuring. For 3TC/LPV/r vs 2NRTI/LPV/r, PDVFs were 7 vs 6% with 4 vs 3 cases of M184V but no other NRTI RAMs or primary PI RAMs.

The other downside of course is that LPV/r is not really standard of care considering other options and so this is not a regimen most clinicans would consider. Hence the pilot that I fed back on yesterday looking at 3TC/DTG instead which Pedro Cahn will now take into Phase 3 following success of the pilot.

The road to nuc sparing has been a rocky one with futility of the likes of RAL/ATV, MRC/ATV/r and MRC/DRV/r.

This study poses the question: “is the only good nuc sparing regimen the one with the nuc in it lol?!”. Not even. At least we still have RAL/DRV/r, although even this falls down in sicker patients (CD4<200 and VL>500K).

We do however eagerly watch the development of newer generation NNRTI/INSTI nuc sparing bicombos: CBV/RPV and DTG/RPV in LATTE and SWORD respectively.

 

 

 

 

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Tagged in: EACS2015

Matthew Shields has already done an excellent summary of the three most interesting presentations in "Antiviral therapy 1".

I will try to add a few points without doubling too much over the content.

Follow up of all small cohorts were to 24 weeks only.

The first presentation was on dolutegravir 50mg bd monotherapy in virologically suppressed treatment experienced individuals with healthy CD4 counts (many on atypical regimens including PI monotherapy) in a 33 patient "spur of the moment" pilot study. The authors explained 1 failure through extenuating psychosocial circumstances.

The second presentation from France was on dolutegravir 50mg once daily monotherapy in an older (mean 47, duration ART 17 years) virologically suppressed treatment experienced individuals (1/3 mono, 1/3 dual, 1/3 triple therapy). Three treatment failures were linked to resistance mutations in integrase but those identified were not classically for dolutegravir.

The third study was DTG+3TC in 20 treatment naive individuals and marked as sponsored by ViiV, who will fund a clinical trial soon in the area. Patients had viral loads less than 100,000 copies/ml and CD4 above 200. All patients had viral loads <400 copies by Week 3 and <50 by Week 8.

My conclusions were:

1. Follow up to 24 weeks was a significant limitation to these pilot studies. Further work is needed.

2. Dolutegravir resistance is certainly possible.

3. First line two drug dolutegravir containing therapy may certainly be a possibility, either with lamivudine or otherwise, but data is currently insufficient to support this.

4. Dolutegravir monotherapy could be considered in treatment experienced patients who have burnt out other options but there isn't enough to recommend switching for simplicity of regimen.

5. Early virological suppression does not necessarily translate to treatment efficacy.

 

 

 
 
Tagged in: EACS2015

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