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.

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

This was a poster presentation session focussing on new drugs and new strategies for the treatment of people living with HIV.  I will focus on results relevant to MSM populations.  

The first presenter was from Thailand.  T. Bunupuradah reported on results from a trial comparing 200 mg of boosted atavanavir  to 300 mg of boosted atazanavir in virologic suppressed HIV-infected Thai adults.  This was a randomised, open-label trial.  He showed that the lower dose atazanavir is non-inferior in terms of efficacy.  There was higher discontinuation due to intolerance in the 300 mg group.  there is difficulty extrapolating these results to other ethnicities though due to possible weight and genetic differences.  These results could not be generalised to treatment naive or those failing first line therapy either.

The second speaker was Tony Mills from California.  He presented data from a switching study which is at the 48 week mark.  This study switched patients from a tenofovir disoproxil fumarate (TDF)-based regimen to a tenofovir alafenamide (TAF)-based regimen.  The results are very encouraging for improved bone mineral density on the TAF based regimen.  Before switching, patients were on elvitegravir, cobicistat, FTC and TDF (stribild), or efavirenz, FTC and TDF (atripla), or boosted atazanavir and truvada.  They all had eGFR greater than 50.  Then they were switched to elvitegravir, cobisitat, FTC and TAF or continued on their TDF-based regimen.  I think this study was flawed however, given that in some patients the tenofovir component was not the only part of the regimen which was switched.  This introduced a confounding factor into the analysis.  Nonetheless, there was a significant increase in bone mineral density in the TAF group compared to the TDF-based regimens.  The TAF group also maintained virologic suppression and showed a significant improvement in proteinuria and other markers of renal function Compared to the TDF group.

J. Gatell from Barcelona presented data on a new NNRTI doravirine at 100 mg once daily with a truvada backbone compared with  efavirenz and truvada.  The study authors saw a need for a new NNRTI given the CNS side effect profile of efavirenz.  It was a double-blind study in ART-naive patients with HIV-1.  At the 24 week mark, the doravirine group had less CNS adverse events than efavirenz.  Furthermore, doravirine demonstrates similar viral suppression to efavirenz at the 24 week mark.  This study is ongoing.

Finally, C. Hwang from BMS presented data on a second generation HIV-1 maturation inhibitor called BMS-955176.  This was used in combination with boosted or unboosted atazanavir.  The need for another class of drug is clear given treatment emergent or transmitted resistance.  Newer drugs with fewer adverse events and less DDI's are still needed.  Maturation inhibitors maybe beneficial in this context.  BMS-955176 inhibits the last protease cleavage event between capsid protein p24 and spacer peptide 1 in Gag, resulting in the release of immature, non-infectious virions.  The inclusion criteria of this study include HIV-1 subtype B-infected subjects.  They were treatment naive or treatment experienced patients.  It was conducted over a 28 day dosing period to asses the safety and tolerability of 176 and the change in plasma HIV RNA levels From baseline.  176 was generally wel tolerated with no SAEs or AEs leading to discontinuation.  It also resulted in very good virologic response compared to standard of care.  A phase 11b study is now underway in treatment experienced patients.

 

Tagged in: IAS2015

 Greetings from CROI

 

 Clinical pharmacology of HIV prevention- Marta Boffito (Chelsea and Westminster NHS Trust / Imperial College, London)

 

Marta Boffito presented a fascinating look at the pharmacology data of current drugs used in PrEP, the potential use of alternative drugs such as integrase inhibitors and CCR5 inhibitors and also data on the long acting nano technology of the future injectable drugs such as long acting Rilpiverine and Cabotegravir.

 

So what makes an ideal drug for PrEP?

  • It needs to have good tissue distribution to achieve tissue drug levels
  • It needs drug persistence (a long half-life)
  • Protein binding affects penetration
  • Affinity for transporter membranes

Tenofovir/FTC

 The data from large PrEP studies such as iPREX shows that Tenofovir/FTC achieved these targets when good adherence levels were achieved, however there was marked differences in drug levels in rectal samples compared to vaginal samples even with lower rates of adherence to the drugs in male group. This opens up some interesting questions on the optimal adherence needed for women to achieve adequate protective  vaginal drug levels.

 

CCR5 inhibitor

Maraviroc was looked at in men and women looking at serum samples, vaginal tissue and rectal tissue.  After only 2 hrs post standard dose of Maraviroc, protective drug levels were achieved in rectal and vaginal tissue samples. Rectal and vaginal drug levels were higher than serum levels( with x 30 times higher in rectal tissue than plasma).

 

Integrase inhibitors

Raltegravir - blood, vaginal and rectal samples. In vaginal fluid the half-life of standard dose of Raltegravir (400mg twice daily) was 17hrs compared to 7 hrs in blood sample. Both vaginal fluid and rectal samples had higher drug levels than found in blood samples. Drug levels  in rectal samples was higher than levels found in vaginal samples.

 

 Dolutegravir at standard dose, the drug levels in both vaginal and rectal samples were 10% and 17% higher than blood samples.

 

Long acting injectable drugs

 The SSAT040 study looked at drug levels in both vaginal and rectal tissue and fluid samples after a dose Rilpivirine (1200mg) from male and female participants. This study found that drug levels in the rectal samples were significantly higher than found plasma levels.

 Protective drug levels were found in both rectal and vaginal tissue at 1 month post treatment. It was also noted that lower drug levels were found in participants with a higher BMI.

 

In this study there was one case of drug failure and HIV transmission in a female participant at the lower Rilpivirine dose of 300mg. (the HIV transmission is thought to have occurred 4 days post dose).

 

After an initial dose of 1200mg Rilpivirine, drug levels in rectal tissue was found to be at  protective at four months.

 

Finally the long acting GSK 744 Cabotegravir at an 800mg dose found good serum drug levels at 4/12 months.

 

In an animal study, Macaques who received Cabotegravir as treatment sustained a viral suppression for up to 20 weeks post dose.

 

Conclusions

  • Drug resistance to PrEP is rare.
  • The debate of which drug is best is still out there.
  • More work is required in this field to standardise intracellular drug concentrations.
  • Ongoing debate on regular vs episodic PrE.

Take home message for current and future clinical practice.

Good clinical data on alternative and emerging drugs to be considered for PrEP. This interesting data also has valuable implications that may be applied for clinical use in non-occupational PEP use for CCR5 inhibitor and integrase inhibitors, where HIV transmission risk is significantly increased in the presence of multiple concurrent STIs.

Tagged in: croi2015

 Link to conference summary by Tripp Gurlick now on line, an excellent overview: http://aps.mediasite.com/mediasite/Play/467fcbe8af2d44f1997197f49161d4b21d 

Trip Gulick gave a truly excellent summation of both presentations at the conference and also what can be expected in the future of HIV therapy. I strongly recommend that once the webcasts become available http://hivglasgow.org/ you watch this presentation. I cannot do it justice, but in 20 minutes six key concepts were covered and importantly the contributions they might make to improved HIV treatment by 2020:

Activity

The capacity of a drug to have physiological impact, “may be maxed out at 90%”. Conceptually the drugs might be as active or as near active as they can be. Not an area that was identified as one where great leaps can be made.

Safety and Tolerance

Both areas where a lot of movement has been made but ones identified where work can  and still is being done. Dose reduction (reported on by Di Carey from the Kirby Institute with respect to EFV) and newer formulations such as is the case with TAF (the newer formulation of Tenofovir with improve renal tolerance).

Convenience

An area in which there is likely to be continued improvement. There are now 4 single pill regimens and more will emerge. Interestingly this was an area which was questioned during the conference where convenience was seen as an area for possible trade for cost.

Affordability

This is the area of continued and emerging contention. While this presentation focused on HIV, much of the discussion at the conference on hepatitis C focused on cost. Annual ART in developing countries is approaching $139 per annum. Costs will continue to come down as new compounds are introduced.

Accessibility

Greater access to treatment earlier is the goal and a dimension in which improvement is anticipated. Identification of the undiagnosed is important as is earlier commencement of treatment. But this was framed in a context in developed countries where treatment is delayed and late diagnoses common.

Life expectancy

This was a very interesting if not unexpected analysis. Based on CHIC and D:A:Ds data life expectancy of people living with HIV has greatly increased. This may not be able to be improved much. An otherwise healthy young person, infected today might have a life expectancy in their mid 70s this compares well to averages (men 78 – women 82). If they start treatment at a CD4 above 350 this is estimated to go up to 89 years. That is considerably better than the average and naturally it relates to their engagement with the patient’s life long health system and access to other preventative and restorative health care. So again an area in which we might be maxed out as far as future benefits are concerned.

But please do look at this and the other online presentations when they become available http://hivglasgow.org/ This may be a little while as they go into post-production, but most of the presentations will be put online.

Tagged in: Glasgow2014

I have been party to a couple of discussion recently where there has been conjecture about the implications of an elusive undetectable viral load. Before I am attacked as a naysayer, I am not suggesting that total viral suppression is not the aim of antiviral therapy. It is and always has been. But some attention is now being directed at transient, persistent and recurrent low-level viral load. Along with virological and clinical implications, this may also have social and emotional costs for people living with HIV.

Some patients, particularly those who have been significantly pre-treated, no matter how compliant, do not achieve complete viral suppression. Others experience intermittent blips or periods of viraemia. What are the implications of these events? It is important to understand this as fully as we can because we must give people living with HIV reasoned and reasonable information; it fundamentally underpins the thinking behind approaches to cure research and, from a public health and prevention perspective, we must be careful not to alienate people.

Poster 136 (Silva, J. et.al.) from Portugal, present a retrospective observational analysis of low-level viraemia and its immunological and virological significance. It was a relatively large study of 2,161 patients 93% on ART 19% had low level viraemia 52% of whom were adherent. The mean VL was 46 (21 - 190) with an average CD4 of 665 (126 - 2,393). There was no documented virological failure, yet 51% had transient viraemia defined as one detectable VL in the study period, 40% had persistent (constantly detectable) virus and 9% had intermittent (2 occasions of detectable VL with undetectable VL in between).

Their conclusion was "in the absence of significant differences in immunological and virological outcomes and the absence of virological failure, suggests a scarce impact of low level viraemia in patient prognosis." This is qualified by suggesting that prospective and more accurate data are required. A number of oral presentations recommended treatment adherence counselling, rather than automatic switching in the presence of low level viraemia.

 

Tagged in: Glasgow2014 viraemia

Please join us for a memorial event celebrating the life of one of Australia’s leading HIV advocates, Levinia Crook… https://t.co/N7dof5xaGa

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