Dr Michael Seah

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.

New HIV drugs, formulations, combinations and resistance

Posted by on in New ARV Treatment, clinical trials emerging therapy
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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
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Guest Sunday, 16 December 2018