Matthew Shields

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.

Antiviral Therapy Session 1

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There was a theme to this stream with 3 presentations on simplified therapy built around dolutegravir (DTG)  either as DTG monotherapy in maintenance or novel bicombos for naïve patients.

The background to this is that, in addition to high DTG potency (-2.5 log in monotherapy studies), there is also evidence that DTG may have a genetic barrier similar to that of a boosted PI (PI/r) since no resistance associated mutations (RAMs) were seen in patients meeting protocol defined virological failure in its Phase 3 program: SINGLE, SPRING 2 and FLAMINGO.

If DTG proved to have a genetic barrier similar to a boosted PI, its clinical applicability would potentially involve simpler (?2 drug) regimens with reduced cost and toxicity for naïve patients. In addition there would also be scope for extension of DTG to our patients who have some compliance chaos and most importantly regimen simplification and reduced toxicity in our treatment experienced patients still dependent on boosted PIs.

These 3 studies put these aspirations for DTG to the test!

Pedro Cahn from Argentina presented the week 24 results of the PADDLE study, a single arm pilot study, where naïve patients (n=20) commenced 3TC/DTG as a novel nuc sparing bicombo. It was noted that although only patients with VL<100K were chosen for the study, 4 had VL >100K at baseline.

At 24 weeks 100% of patients were <50 copies

What is nice about this study is that it builds on the increasing proof of concept that 2 drugs is enough for durable viral suppression but pushes the bar in that it is not just as a maintenance but from outset.

The study is the sequel to Pedro’s other study GARDEL looking at 3TC/LPV/r which showed virological success at 48weeks, the 96 week data of which will be presented tomorrow.

Despite the success of GARDEL, LPV/r is not really standard of care making 3TC/DTG a much better option in terms of tolerability and toxicity.

In conclusion this was overall a promising result for a simple nontoxic bicombo although perhaps 24 weeks is too early to evaluate efficacy. We need to see durable viral suppression out to 96weeks in a larger study and this is recruiting now.

The next 2 studies were pilots looking at DTG monotherapy as maintenance, a very attractive option if the genetic barrier of DTG holds up!

The background to this off course are the PI/r monotherapy studies. This concept fell out of favour last year after the PILOT study taught us that although resistance can be avoided low grade viraemia was common and this is a both a headache for monitoring as well as potentially a concern in terms of chronic immune activation and potentiation of reservoirs in places such as brain.

Could it be that the increased potency of DTG over PI/r means that this low grade viraemia could be avoided?

Esteban Martinez and Christine Katlama both presented small pilot studies from their respective cities Barcelona and Paris

In both studies there was a high proportion of patients coming from stable PI/r monotherapy and so in that sense they were pre selected for virological success

In Esteban’s study (n=33), 55% of the patients were coming from stable PI/r mono therapy ( the rest from stable 2 and 3 drug regimens) and all maintained VL< 50 copies at 24 weeks except for one and DNA genotypic resistance testing revealed no integrase mutations at 4 and 24 weeks.

In Christine’s study (n=28), 32% were coming from stable PI/r monotherapy and 89% maintained VL<50 copies at 24 weeks

However there were 3 virological failures and all 3 were found to have INSTI RAMs as detailed below:

Patient1:  92Q and 74L (the latter being a polymorphism in 12% of patients)

Patient2: 138K, 140A and 148R

Patient3: 155H

Interestingly all 3 had had prior INSTI exposure but without known failure. This was clarified very competently with DNA genotypic resistance testing at baseline and therapeutic drug monitoring. None of the 3 patients had these RAMs at baseline verifying that they were treatment emergent and all 3 had DTG concentrations in the normal range.

I put these mutations into the Stanford Database and although all of them are signature for RAL and EVG none are signature for DTG. However 2 or more together were typically associated with a >10 fold loss of activity of DTG in vitro. (See the photo below)


b2ap3_thumbnail_HIVdb.jpg

Christine concluded by saying that the findings argued for clarification with a larger study with perhaps less treatment experienced patients, since the patients had been taking ART for a median of 17 years.

I actually think it is quite foreboding and would not be comfortable putting my patents in that study!

In conclusion it suggests the genetic barrier of DTG is not good enough for monotherapy

Tagged in: EACS2015
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