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.

Christian Callebaut, Clinical Virology, Gilead USA, presented the findings of their clinical trial GS-US-292-0119.

Virologically suppressed, treatment-experienced patients on complex multi-tablet regimens were randomised to either switch to a simpler, more convenient antiretroviral regimen or remain on their current optimised ART.

After 48 weeks:

  • The regimen consisting of E/C/F/TAF DRV demonstrated maintained viral suppression in 94.4% of patients.
  • In the DRV-containing “Stay on Baseline Regimen” arm, maintained viral suppression was 76.1%

All patients had documented resistance to 2 classes of antiretroviral (ARV) agents at baseline. Detailed ARV regimens and the resistance profile of the study population are described.

Study methods:

The Stanford HIVdb algorithm version 8.01 was used to calculate genotypic susceptibility scores (GSS).

For each drug, a 5-point scale was used:

  • Susceptible = 1
  • Potential low-level resistance = 0.75
  • Low-level resistance = 0.5
  • Intermediate-level resistance = 0.25
  • High-level resistance = 0

 The total GSS for a given regimen was calculated as the sum of the scores for each individual drug. 

Results:

A total of 94.8% had documented resistance to 2 classes of ARVs, including:

  • protease inhibitors: 34.8%
  • non-nucleoside RT inhibitors: 88.1% and
  • NRTIs 94.8%.

The most common resistance associated mutations (RAMs) were:

  • Protease Inhibitor RAMs: L90M (15.6%) and V82A/F/L/S/T (14.8%).
  • NNRTI-RAMs: K103N/S (63%) and Y181C/I/V (19.3%) and
  • NRTI-RAMs: M184V/I (83%) and K65R (23.7%).

Thymidine analog mutations (TAMs) were present in 42.2% of patients (59.6% with one or two TAMs and 40.4% with three TAMs). 

The distribution of GSS at study entry was similar across treatment groups.

Patients in the E/C/F/TAF DRV arm maintained virologic suppression similarly, regardless of the DRV dosage received before switching (33/33 and 51/56 with treatment success in the 600 mg BID and 800 mg QD groups, respectively).

In the E/C/F/TAF DRV arm,

  • 11/89 patients (12.4%) had GSS <2,
  • 51/89 patients (57.3%) had GSS ≥2 and <3, and
  • 27/89 patients (30.3%) had GSS ≥3.

Within each treatment group, patients maintained virologic suppression similarly regardless of their GSS at study entry.
 

Conclusions:

  • Despite the high incidence of pre-existing resistance in this population, including resistance to ≥2 classes of ARV agents and presence of K65R or ≤3 TAMs, strategic simplification to E/C/F/TAF DRV was statistically superior to staying on the baseline regimen.
  • Patients benefited from switching regimen regardless of their prior DRV dose and their GSS.
  • Treatment with E/C/F/TAF DRV offers a simpler and more convenient option for treatment-experienced patients on complex multi-tablet regimens.

Details of the study can be found here: https://clinicaltrials.gov/ct2/show/study/NCT01968551

 

 

 

 

96-week data from ATLAS – M trial – a multicenter, open labeled, randomized trial on simplification to atazanavir/ritonavir and lamivudine versus maintaining atazanavir/ritonavir with 2 NRTI (Triple therapy) in virologically suppressed HIV infected patients was presented by Roberta Gagliardini, Catholic University from Rome, Italy.

  • A total of 266 patients (78%males with a median CD4 of 603 cells, 79% of them had Tenofovir in their treatment regimen) were enrolled in this trial.
  • 96 week data were available for 254 (126 in dual therapy arm and 128 in triple therapy arm).

At 96 weeks, the proportion of patients free of treatment failure were 77.8% (95% CI  70.5 – 85.1) in the dual therapy arm compared to 65.6%  (95% CI  57.4 – 78.3) in the triple therapy arm.

Virological failure was observed in two patients (1.6%) randomized to dual therapy arm and eight (6.3%) patients in the triple therapy arm (p=0.056).

  • Data demonstrated non-inferiority of treatment simplification to dual therapy in virologically suppressed patients.
  • Additionally, switch was associated with improved renal function but with increased total cholesterol and bilirubin levels in dual therapy arm. 

ANRS 12286/MOBIDIP trial investigator Laura Ciaffi from France presented 96-week data to show that dual therapy with a boosted protease inhibitor plus lamivudine is an effective maintenance strategy in patients on second-line antiretroviral therapy in Africa. 

  • This randomised, open-label, clinical trial was conducted in Cameroon, Senegal and Burkina Faso.
  • Recruited HIV-1 positive patients on stable protease inhibitors plus NRTIs as second-line Antiretroviral therapy.
  • All patients had HIV viral load below 200 copies/mL, CD4 above 100 cells/mm3 and adherence was ≥90%.
  • Two arms of the trial compared monotherapy with the ongoing protease inhibitor/ritonavir(PI/r): darunavir (DRV/r) or lopinavir (LPV/r) with the same PI/r associated with lamivudine 300 mg in the dual therapy arm.
  • From March 2014 to January 2015, 265 patients were randomised (133 in mono-therapy arm and 132 in dual therapy arm).
  • Most patients were women (73%).
  • At failure of first line, 96% had the M184V mutation.

At 48 weeks, Data Safety Board instructed to stop mono therapy arm.

In the ITT analysis, 3.0% (95% CI 0.8–7.6) in the dual therapy arm and 22.6% (95% CI 15.8–30.6) in the mono- therapy arm had virological failure (p<0.001).

  • Median time to failure was 24 weeks.
  • All failing patients, except one, re-suppressed to less than 200 copies/mL in a median time of 12 weeks after reintroduction of the NRTI backbone.
  • Increase in CD4 was significantly higher in the dual therapy arm (48 vs 7 cells/mm3).
  • No differences in adverse events were observed.

Investigators concluded that

  1. after viral suppression with PI/r plus NRTIs in second-line therapy, maintenance with PI/r plus lamivudine is associated with a high rate of success despite the presence of M184V.
  2. PI/r mono therapy cannot be recommended.

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Another captivating day of presentations and lectures.

There was robust discussion regarding treatment strategies during the morning session.

Christian Callebaut from Gilead Sciences clinical virology presented on the resistance profile of treatment experienced HIV infected patients switching to elvitegravir/cobistat/emtricitabine/ tenofovir alafenamide plus darunavir. This population is known to have a high pre-existing resistance profile. 

. The regimen was found to be statistically superior to staying on baseline regimen @ 48 weeks

. Treatment was simpler 

. More convenient option for treatment experienced patients on complex multil pill regimens

Chloe Orkin of the Department of Infection and Immunity at the London Hospital, presented new clinical data on switching from rilpiravine/emtricitabine/tenofovir alafenamide and its safety and efficacy through 48 weeks.

. Found to be very effective

. Increased rates of viral suppression

. No emergence of resistance mutations

. Well tolerated

. Low incidence of adverse events

. Low discontinuation rates

. Improved renal and bone safety

A very full day culminated in spending time with other Australian delegates.

Busy day ahead tomorrow, starting off early with an industry symposium on helping patients stay the course.

Hello from Glasgow. What an amazing first day we have had.

The program today was a great mix of new information and case studies.

I was surprised to start the day with a Hepatitis C session but it was really informative. 

Take Home message from this session - in the context of HIV positive individuals, it may take 12 months for the HCV antibody yest to become positive - hence if suspicious , do HCV PCR.

Ian Mc Gowan from the University of Pittsburgh discussed long acting ARVs for both treatment and prevention which will be a great advancement for those patients with adherence problems - drug and alcohol usage and mental health issues.

Currently phase 2 studies for Rilpivirine and Cabotegravir - an analogue of Dolutegravir -  a booster dose initially and then dosing every 4-8 weeks.

Also EFdA which is a long acting formulation which would last 12 months - an implanon like device.

The highlight of the day for me was Dr Anthony Fauci from the National Institute of Allergy and Infectious Diseases who delivered the Joep Lange and Jacqueline van Tongeren Memorial Lecture.

He spoke of Ending the HIV/AIDS pandemic by following the science. He spoke of the advances since the first HIV notifications in 1981 and how far we had come. South Africa are about to enter into a phase 2 trial with a vaccine!! it was incredible to reflect on how far we have come in the last 35 years but looking at the incidence around the world, how for we still have to go.

Is 90,90,90 really achievable? Some of the audience felt that it would never be achievable in their country but ....... did we ever envisage the possibility of a vaccine? We live in hope.

Andrew Hill from St Stephens AIDS Trust at the Chelsea and Westminster Hospital spoke the the difference in cost of drugs in different countries - a really contentious issue. We do not know how lucky we re in Australia to be able to treat as many patients as we want for HCV.

Looking forward to Day 2. Thank you ASHM for this amazing opportunity!

Talk by Professor Ian McGowan on long-acting ARVs (LAARVs).

 

-       Research from NYC (MSM) indicates high rates of willingness, and that a majority would prefer an injection.

-       Research from Africa (women) indicates that injection/implant/vaginal ring (as PrEP) would be preferred.

 

Current development of LAARVs is both for treatment and prevention.

 

Requirements for LAARVs as injection:

-       Infrequent dosing (every 2-3 months)

-       Practical injection volume (<4mL)

-       Doesn’t require cold-chain storage

 

Rilpivirine and cabotegravir most likely candidates of current generation of medications.

-       Have only been evaluated in the context of clinical trials (phase 1 and 2); adherence data likely to vary in the real world (and depending on whether being given as PrEP or treatment)

-       Tolerability good; patient satisfaction overall good

-       Efficacy signal in cabotegravir (animal studies)

-       Injection-site reactions reasonably frequent over time (highest at first injection)

-       Long-acting rilpirivine detectable in tissue (plasma/endocervical and vaginal fluid) up to >500 days (!) later – which is concerning for risk of resistance. Therefore cabotegravir more promising for use as long-acting PrEP (and phase 3 studies planned) – cabotegravir involves 4 week oral lead-in then Q8 weekly injection.

 

Novel NRTI “EFdA” also promising based on animal modelling; currently at phase 1 studies in humans. Animal models indicate that long-acting formulation could be effective up to 1yr.

 

As mentioned elsewhere – TAF silicone tubing implant and biodegradable implants both promising for use as PrEP.

 

Main challenges with LAARVs:

-       Safety (need oral lead-in)

-       Acceptability (needs real-world data)

-       Adherence

-       Resistance

-       Pharmacokinetics

-       Delivery

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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