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.

Matthew Shields

Matthew Shields



Matt Shields is a sexual health physician and general practitioner working in a primary care setting at Taylor Square Private Clinic in Sydney. His special interests are HIV medicine and viral hepatitis, STIs and dermatology.

Posted by on in Workforce Development

I have a couple more blogs planned from the excellent Hepatitis session on Friday that I should get done on the flight home depending on sedation titration but I wanted to take the opportunity before I leave BCN to thank ASHM for the sponsorship. It has been a great meeting of great educational value that will not doubt translate to better patient care.I hope you also found my blogs of educational value
Special thanks to Levinia Crooks and also to Samantha Williamson for the logistics.

Lastly, it is a long way to fly but sharing the cabin with the Stenmark twins certainly helped:

b2ap3_thumbnail_Twins.jpg

#22hourstarebear

Dr matt

Tagged in: EACS2015

 

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

I am quite of fan of the EACS guidelines particularly for co-morbidities and on  Friday they had a session detailing what's new in version 8.0 October 2015

 
1. ART
presented by Jose Gatell
 
The Europeans are now on page with everyone else with treatment recommended for all persons with established HIV infection regardless of CD4 count, the exception being elite controllers. This brings all 4 sets of guidelines into agreeance: DHHS, IAS and WHO (see table below)
 
b2ap3_thumbnail_Initiation-of-ART.jpg
The next slide is the greatly revised table of what to start with. Key features are:
 
13 regimens downsized to 6 (the DHHS guidelines have just 5, choosing to omit TDF/FTC/RPV whereas the EACS retains)
 
Increasing number of INSTI based regimens
 
Rentention of one each of PI and NNRTI based regimens
 
b2ap3_thumbnail_Initial-Combination-Regimens.jpg
 
 
2. PrEP
also presented by Jose Gatel
 
A whole new chapter in the guidelines and the only set of guidelines internationally to recommend "on demand" PrEP based on IPERGAY. CDC guidelines continue to support daily PrEP.  Ongoing concerns about on demand PrEP include reduced efficacy in MSM who may not be having sex as often as the men in IPERGAY or who may not be as good as tailoring Intermittent PrEP usage to perceived risk of sexual events as the men in IPERGAY. You can't deny the overall efficacy however. Will intermittent PrEP's inclusion in guidelines influence your practice?
 
 
b2ap3_thumbnail_PrEP.jpg
 
 
3. HCV/HBV Co-infection
Presented by Jurgen Rockstroh
 
Highly revised guidelines on which HCV patients to treat with DAAs. See the photo below. This table is adapted from the EASL guidelines drawn up in May and includes a footnote on who should be given priority for treatment independent of liver fibrosis. I think it is very forward thinking as it includes those with debilitating fatigue, extra hepatic manifestations such as cryoglobulinaemia and those at risk of HCV transmission including high risk MSMs. It is interesting how we are beginning to apply TasP principles to HCV. Applying TasP principles to the co-infection epidemic in MSM is not unfounded because it is concentrated and networked but it is probably unfounded in monoinfection with only an estimated 40% people diagnosed in most countries. 
 
 
b2ap3_thumbnail_Mngt-Chronic-HVCHIV-Coinfection.jpg
 
Finally the table below is a useful clinical tool for monitoring acute HCV infection. Spontaneous clearance is indicated by viral decay in log at certain time points. It still  lists IFN/RBV as treatment for acute infection only because we have not yet consolidated the evidence base for this with DAAs. That is about to change however with 3 datasets of DAA treatment in acute HCV almost ready. 
 
 
b2ap3_thumbnail_Acute-HCV.jpg
 
 
 
 
 
 
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.

 

 

 

 

Normal.dotm 0 0 1 272 1552 TSPC 12 3 1905 12.0 0 false 18 pt 18 pt 0 0 false false false

 

Tagged in: EACS2015
Antiviral Therapy Session 1

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

Day 1 of EACS always features a comorbidity workshop and this year all 5 of the presentations in the workshop were about bone loss.

The background to this of course is that in 2010 the metabolic sub-study of ACTG 5052 showed a 2-4% bone loss as measured by BMD over 96 weeks when naive patients commenced ART. Since then more studies have echoed this, we continue to worry about it and the pendulum has swung between how much of this is ART and how much is immune activation-reconstitution bone loss.

The current evidence base suggests it is mostly TDF, particularly when it is boosted and the robust evidence for this comes from studies such at TROP, PROGRESS and the newer naive and switch studies for TAF

The first presentation was a retrospective analysis of markers of bone turnover from 52 patients in the MACS cohort who initiated ART during seroconversion. Seroconversion is indeed a state of heightened immune activation and disturbances of bone markers having a net negative effect on bone formation were seen in both the seroconversion and ART initiation stages.

The other compelling argument for bone loss being driven by ART as opposed to immune activation is PrEP because these are men without either viraemia or immune activation. This brings us to the best presentation in the workshop which is the title above 

ATN 110 is an open label PrEP safety and demonstration study that enrolled 200 at risk young men who have sex with men (YMSM) in panamerican sites. 54% are black. DXA scans of the spine, hip and whole body (WB) were performed at baseline, 24 and 48weeks and adherence is assessed objectively using RBC TFV-DF levels in dried blood spots.

Interestingly baseline median BMD Z scores were below zero (spine -0.50, hip -0.45, WB -0.40). At week 24 there was a modest but significant decrease in BMD by WB (-0.61%, p<0.001). The iPrEx study also reported a similar bone loss.

What is good about this study however is, unlike iPrEx, it included stratification of the BMD analysis according to objective adherence. At week 48, a comparison was made between YMSM who had TFV-DP levels indicative of dosing 4 or more days a week and the subset that had levels below the level of quantification. Respective changes in BMD from baseline to week 48 in these subgroups were: spine -1.33% vs +1.54% (p<0.001); hip -1.68% vs 0.00% (p<0.001); WB -1.01% vs 0.34% (P=0.33)

So in conclusion there is a statistically significant TDF driven signal

In terms of clinical applicability however I think overall it is reassuring that there was no substantial bone loss from PrEP here. One could argue that 48 weeks is only a snapshot and what will accumulate with time but you have to remember that PrEP is not for life and does not share the same concerns as treating established HIV infection with TDF. Even in the case of naive HIV patents starting ART there seems to be some stabilization of the loss after 96 weeks and the fracture studies we have in HIV patients are based on population data which is subject to confounding such that we can't really say that any of this is tipping over into fractures.

Don't forget that bone is a very dynamic tissue as well with changes likely to be reversible with therapy change, not to mention lifestyle modification.

Additionally for our HIV patients the greatly reduced signals for bone of TAF over TDF in the naive and switch trials are really quite promising.

Putting my GP hat back on, the other interesting finding from this study is the baseline low BMD. Avoiding osteoporosis is still mostly about encouraging young people to reach their peak bone mass through adequate nutrition, tension loaded exercise and not smoking.

There is not much else to report back on today, it is opening ceremony day

There will be much more to report tomoz, here from sunny Barthththththththelona

CLINICAL APPLICABILITY OF THIS DATA:

Tagged in: EACS2015

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