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.

Comment: See abstract below.

This phase II study presents non-inferior results and several bictegravir phase III trials in both naïve and switch patients are underway in Australia and abroad. Its great to see a study comparing a new agent to DTG, essentially the gold standard integrase inhibitor at present. 

Bictegravir represents a potentially exciting addition to the integrase inhibitor family-  a once daily, un-boosted medication with a high genetic barrier to resistance. It shares the same limitations as dolutegravir in terms of interaction with polyvalent cations and metformin boosting.

If all goes well, it will be co-formulated with F/TAF as a single pill regimen. Given its high barrier to resistance and absence of ABC, such a regimen may become an ideal option when initiating HAART in the absence of a resistance genotype/HLA-B*5701 result (eg in acute HIV infection or resource limited settings) or in individuals with high cardiovascular risk.

 

41 RANDOMIZED TRIAL OF BICTEGRAVIR OR DOLUTEGRAVIR WITH FTC/TAF FOR INITIAL HIV THERAPY

Paul E. Sax et al

Background: Bictegravir (BIC, GS-9883) is a novel, unboosted, once-daily INSTI that demonstrated potent activity in a 10-day monotherapy study and has in vitro activity against most INSTI-resistant viruses.

Methods: Treatment naive, HIV-infected adults randomized 2:1 to receive blinded treatment once daily with BIC 75 mg or dolutegravir (DTG) 50 mg; both were given with open label emtricitabine 200 mg/tenofovir alafenamide 25 mg (FTC/TAF). Treatments were administered without regard for food for 48 weeks. The primary endpoint was the proportion with HIV RNA <50 copies/mL (c/mL) at Week (W) 24 using snapshot analysis. Noninferiority was assessed through 95% confidence intervals (CI) at W24 and W48. Safety

(adverse events [AEs] and laboratory results through Week 48) was a secondary endpoint.

Results: Of 98 patients enrolled, 65 were randomized to BIC+FTC/TAF and 33 to DTG+FTC/TAF. Baseline characteristics were balanced between arms. Virologic success (HIV-1 RNA <50 c/mL) at W24 was 97% for the BIC arm and 94% for the DTG arm, and at W48 was 97% and 91%, respectively. One subject in the DTG arm had HIV-1 RNA >50 c/mL at W48. No viral resistance was detected in the BIC+FTC/TAF arm. Mean CD4 count increases at W48 were 258 cells/μL in the BIC arm and 192 cells/μL in the DTG arm. There were no treatment-related serious adverse events and no deaths. The most commonly reported adverse events were diarrhea (12% in each arm) and nausea (8% BIC, 12% DTG). One subject in the BIC arm discontinued due to an adverse event of urticaria following the W24 visit. Median changes in estimated glomerular filtration by Cockcroft-Gault (GFRCG) at W48 were -7.0 mL/min for BIC and -11.3 mL/min for DTG, with no discontinuations due to renal adverse events.

Conclusion: Bictegravir+FTC/TAF and DTG+FTC/TAF both demonstrated high virologic response rates at both W24 and W48. No treatment-emergent resistance was detected in the BIC+FTC/TAF arm through W48. Both treatments were well tolerated, and no significant safety signal was detected in either arm. Estimated GFR changes were consistent with known inhibition of tubular creatinine transport by BIC and DTG.

Tagged in: CROI 2017

Greetings from Seattle. I would like to start by thanking ASHM for giving me the opportunity to attend this world-class conference and also thank the readers for taking time to read my blog.

 

Gilead dominated the morning session that I attended, presenting 2 novel drugs in different stages of development. I will talk about the more conventional of the novel drugs, which is now undergoing phase 3 clinical trials (4 active trials).

 

Bictegravir (BIC) is a novel, once daily INSTI. In-vitro studies have demonstrated it’s high level of activity against wild-type and many INSTI-resistant viruses. The drug has good oral absorption and an excellent PK profile, with a trough level well above IC95. The drug is mainly metabolised through CYP3A4 and UGT1A1 and has a favourable DDI profile. Similar to dolutegravir (DTG), there can be increased metformin levels (39%) and potentially clinically relevant interactions in the presence of potent inducers such a rifampicin. The 50mg once daily BIC dose was selected in coformulation with FTC/TAF as a single tablet regimen to progress in further studies.

 

Paul Sax then presented the 48 week data from a relatively small randomised double-blind active control study. 98 participants were included (from 125 screened) BIC = 65, DTG = 33. Patients with chronic hepatitis (B and C) were excluded. Overall rates of viral suppression were excellent in both groups at 24 and 48 weeks. In the BIC group, viral suppression (Defined as VL < 50 copies/ml) was 97% at 24 and 48 weeks. There were 2 discontinuations in both arms (1 lost to follow-up in each arm, 1 non-compliance in DTG, 1 AE in BIC). In terms of adverse events, diarrhoea was the most common side-effect reported in 12% of subjects in the BIC arm. Overall, AE profiles and lab abnoralities were reassuring. A minor decline in eGFR of -7.0 ml/min was observed BIC. No treatment-emergent mutations (INSTI or NRTI) were noted through week 48 in either group.

 

In summary, bictegravir is an exciting novel INSTI which has moved on to phase 3 clinical trials. Should it progress and eventually receive approval, it will be coformulated with FTC/TAF in a single tablet regimen, joining what is becoming a rather crowded market.

 

Tagged in: CROI 2017

Oral session 38: Discovery of a novel potent HIV Capsid inhibitor

GS-CA1 is a first-in-class small molecule Capsid (p24) inhibitor. GS-CA1 was demonstrated to be more potent than EFV, DTG and ATV with no measurable toxicity in target and non-target primary cells. It was also highly active against major HIV mutations, with high breadth and potency of action. The inhibitor acts at multiple steps in the HIV replication cycle, impairing Capsid core assemble, core disassembly and nuclear transcription. The binding site to the Capsid is highly preserved, and while resistance has been demonstrated, the HIV mutations have reduced fitness compared to wild-type HIV.

A single subcutaneous dose in rats have shown maintained plasma concentrations out to 10 weeks. The compound shows promise as a long-acting, low-dose monthly injection in humans.

Oral session 39: Confirmation of oral dose reduction potential of nanoparticles

Solid drug nanoparticles (SDN) have shown promise as a method to reduce drug dosage while maintaining therapeutic exposure. SDN Lopinavir and SDN Efavirenz were studied using population pharmacokinetic modelling strategies. Both formulations proved well tolerated at the studied doses. With the potential of a 50% dose reduction, there is an estimated saving of USD$243 million per year

Oral session 40: Pharmacology of the HIV integrase strand inhibitor Bictegravir and Oral session 41: Randomised trial of Bictegravir or Dolutegravir with FTC-TAF

Bictegravir (BIC) is a novel integrase strand transfer inhibitor (INSTI) that is currently in Phase 3 trials. The medication has been demonstrated to have low toxicity, no effect on the QT interval and no impact on glomerular filtration. It is well absorbed (>70%) and is highly plasma protein bound (>99%). It primarily circulates as the parent drug, with clearance through oxidation (CYP3A4) and glucuronidation (UGT1A1). There is low potential for drug-drug interactions, but as with all INSTIs, they are chelated by cation-containing antacids. Therefore administration should be staggered by at least 2 hours with antacids. BIC itself does not inhibit or induce CYP3A4 or UGT1A1. Phase 2 trials developed as a single tablet regimen with FTC/TAF demonstrated that there was improved bioavailablity and a reduced food effect for the 75mg dose of BIC chosen. Therefore the dose of BIC was reduced to 50mg for Phase 3 trials, with a formulation of BIC/FTC/TAF of 50/200/25mg.

A double blind randomised control trial of BIC vs DTG with FTC/TAF demonstrated the study drug being 97% successful at achieving virologic suppression after 24 weeks and 48 weeks. There was no statistically significant difference in the outcome between the study and control drug formulations. No resistance to study medication was detected in either arm of the study. There was a rapid and robust CD4 response in both arms. Adverse events, grade 2 to 4 laboratory abnormalities and mild changes to eGFR were similar in both groups.  The trial demonstrated BIC/FTC/TAF is safe and well tolerated

Oral session 43: Prevalence and impact of pretreatment drug resistance in the ANRS 12249 TASP trial

Early initiation of ART and improved access to HIV care will lead to long-term decreased morbidity and mortality. However, there is a concern regarding an increase of pretreatment drug resistance (PDR) could lead to a delayed time to viral suppression and an increased risk of virological failure after ART initiation. New advanced technologies - Next Generation Sequencing (NGS) - have become available for low-level variant detection (at around 1% viral population), however their impact on ART outcome is still controversial.

There has been limited study of PDR in low to middle income populations or resource limited settings. The ANRS 12249 TASP trial was established to evaluate the effect of early ART, initiated irrespective of CD4 count, on HIV incidence in the general population in the same setting. The study is being conducted in the KwaZulu-Natal province of South Africa. ANRS 12249 TASP included an analysis of PDR in chronically infected and and recently infected participants. The definition of PDR used was >20% of viral population, with separate analysis using NGS of resistant virus at 2% levels. 

The prevalence of PDR detected was about 9% in both recently and chronically infected participants, with two times more low-level variants detected with NGS. NNRTI use is mostly compromised by PDR but NRTIs are still active. About 10% of PDR have multiple drug resistance (3 or more up to 7), suggesting previous exposure to ART. Interestingly, PDR did not significantly impact the cumulative probability of achieving virologic suppression at the 12 months mark, with around 95% of subjects virally suppressed at 12 months, regardless if PDR was present or not. The two consistent predictors of poor viral suppression remain high baseline viral load and poor adherence. 

Oral session 44LB: Phase III SWORD 1 & 2 SWITCH to DTG+RPV maintains virologic suppression through 48 weeks

With the high resistance barrier of DTG, SWORD 1 & 2 evaluated whether the 2-drug regimen of DTG+RPV once daily was as effective as traditional cART. The primary endpoint at 48 weeks was a snapshot of subjects with a viral load <50 copies/mL. 

The 2-drug combination demonstrated non-inferiority to cART with comparable viral suppression rates, similar rates of adverse events, a neutral effect of lipids and a statistically significant improvement in bone turnover biomarkers. There were two confirmed virologic failures in both study groups, however no integrase resistance was found.

The study supports DTG+RPV being filed as a treatment regimen and leads the way for exploration of other 2-drug regimens in the future.

Oral session 45LB: Doravirine is non-inferior to Darunavir/r in Phase 3 treatment-naive trial at week 48

Doravirine (DOR) is a novel next generation NNRTI with a unique resistance profile, low potential for drug-drug interactions and can be taken once daily without regard to food. A Phase 3, multi-centre, double-blind randomised control trial was conducted in treatment naive HIV-1 infected adults. DOR was compared to DRV/r in combination with TDF/FTC or ABC/3TC. The demographics of study participants were almost identical in both arms of the study.

There was no genotypic or phenotypic drug resistance observed in participants with protocol defined virological failure through week 48. One participant discontinued due to noncompliance at week 24 and developed DOR resistance. Approximately 80% of subjects experienced one or more adverse event, with about 30% having drug-related adverse events. Study discontinuation was 2-3% due to adverse events. Similar proportions experienced adverse events of clinical interest -  rash (7-8%) and neuropsychiatric (11-13%). DOR had a neutral effect on lipids compared to DRV/r

DOR demonstrated potency with non-inferior efficacy with a low rate of resistance (1/383 subjects). DOR is generally well tolerated and safe. 

Tagged in: CROI 2017

The single-most incredible presentation at the conference.  Dr Kedar Narayan presented on some amazing new technology which is allowing us to view HIV in a completely different light.  He somehow managed to explain what is clearly a very complex principle in simple terms, and with plenty of humour sprinkled in.

 

  • traditional electron microscopy only provides a 2D image of the cell
  • focuses ion beam scanning electron microscopy (FIB-SEM) allows a 3D image
    • the tissue is embedded in a block, with the side face open to the EM scanning
    • the FIB laser is used to slice the tissue (like a deli slicer/cutting a loaf of bread) to reveal the next layer of the tissue
    • the EM can then image the 2nd layer
    • this is repeated 1000s of times to obtain a stack of images (like a CT scan)
    • computer software can generate a 3D image of the tissue, including all the internal structures
  • FIB-SEM can be applied to HIV
    • HIV virons actually use small tunnels from intracellular vesicles to the extracellular surface to escape the cell
      • this explains why other studies have found that the pH of vesicles were less acidic than expected (i.e. because they were actually connected to the extracellular membrane)
    • virological synapse
      • the dendritic cell actually “hugs” the T cell
        • rather than individual projections from the cell, the DC actually has lasagne like sheets (veils) to connect with the T cell
        • this excludes all drugs since the synapse is covered by the “hug”
      • often thought that the T cell is passive in receiving antigen presentation
        • not so - they can reach into the DC to sample for virus

 

What an exciting start to the day (following on from the excellent trainee sessions this morning), and the rest of the session proved equally as informative...stay tuned

Roy Gulick, from the Division of Infectious Diseases, Weill Cornell Medical College, New York City, gave answers to the question "What next for ARVs?" during his presentation today.

But before we talk about the future, let's pause and look at ART in the year 2016:

  • When to start:
  • Currently 29 approved drugs:
    • From five broad mechanistic classes:
      • EI, NRTI, NNRTI, PI & INSTI
  • We currently have up to 10 recommended first-line regimens:
    • 1 standard strategy: 2 NRTI + [NNRTI, PI or INSTI]
  • Properties of ART:
    • Virologic activity
    • Safety and tolerability
    • Convenience
    • Access and cost
    • Life expectancy

 

Newer strategies, formulations and investigational ARV agents:

  • Long acting compounds under investigation:
    • Injectable formulation of the NNRTI, Rilpivirine LA (long acting)
    • Injectable formulation of a new INSTI, Cabotegravir
  • Formulations of implantable devices that provide sustained release of ARVs
  • A new NNRTI, Doravirine (DOR):
    • Active agains drug-resistant strains
    • In vitro active against viral strains with K103N, Y181C, G190A, E101K, E138K or K103N/Y181C
  • A new INSTI, Bictegravir:
    • In vitro active agains viral strains with integrase resistance
  • Two new mechanistic classes under investigation and in clinical development:
    • An oral CD4 attachement inhibitor, BMS-663068:
      • BMS-663068 is a prodrug of BMS-626529 an inhibits CD4 binding to gp120 
    • HIV maturation inhibitor (MI), BMS-955176:
      • Binds tightly to HIV GAG
      • In vitro active agains strains with polymorphisms and PI resistance

There has also been a lot of talk at the conference about two-drug regimens and Dolutegravir monotherapy, but until we have conclusive data to support the efficacy, three-drug regimens remain the current gold standard.

Conclusion:

Currently, we can control HIV infection long-term with potent, safe and convenient ART that leads to prolonged healthy survival in our patients. The development of newer drugs and new drug classes opens up options for patients with multiple resistances. 

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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