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.

A picture paints a thousand words - Dual Drug Therapy.. a blog in pictures (a Plog?)

This is the history of therapies in HIV

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3 drugs work, why are we going back to 2? It's not like we haven't done it before with poor resultsb2ap3_thumbnail_2_20170604-065801_1.jpg

Why do we even need a 2 drug regimenb2ap3_thumbnail_3_20170604-065757_1.jpg

Some definitely don't work - don't try these at home, but some bear looking at againb2ap3_thumbnail_4_20170604-065755_1.jpg

Eg.

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and

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Hmmm

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Think about this

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Is DTG the deal breaker?

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PADDLE - the proof of concept

The follow on is GEMINI 1 and 2, current Phase 3 trials - data to follow........

Watch this space?

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Tagged in: APACC 2017

Day 2 CROI

My colleagues have already commented on the new HIV integrase strand transfer inhibitor, Bictegravir, so onto other potential new agents/formulation:

Presented by Gilead, the HIV Capsid Inhibitor was discussed in relation to its antiviral activity and proof of concept work. The Capsid Inhibitor, GS-CA1, is a first in class. The agent acts at multiple sites in the HIV life cycle - at the assembly site of the capsid core essential for the virion and at the disassembly site of the capsid which is necessary for nuclear translocation after reverse transcriptase. The capsid inhibitor binding site is highly conserved.  The capsid inhibitor associated mutations map exclusively to the inhibitor binding site.

The EC 50 = 140 picamolar. With the activity of GC-CA1 a defective virion is produced that is non-infectious. The agent is active against all HIV1 clayds (slightly less potent against HIV2). So far, PK data in rats is maintained over ten weeks, leading to a proof of concept for monthly injectable dosing and is ideal for low dose, long acting administration.

CS-CA1 is currently in a preclinical programme.

Nanoparticle antiretroviral formulation was broadly outlined in relation to two ARVs, Efavirenz and Lopinavir (the agents were chosen in 2009, so are not necessarily in line with current ARVs).  In principle, nanoparticle formulation has two benefits: it allows for lower dosing of dry nanoparticle formulations and can be used for Paediatric formulations as they can be dispersed in water. The data thus far, confirms potential for a 50% dose reduction while maintaining therapeutic exposure for a future novel combination ARV.

One final comment in this session on ARVs: Jose L Balanco et al presented on the pathways of resistance in subjects failing Dolutegravir monotherapy. It was noted that selection of genotypic resistant mutations was rapid. The Chairman noted that Dolutegravir is not approved by the regulatory body for use in monotherapy and expressed some disquiet as it appears that consent was not obtained from all patients. Refer a recent article in Antiviral Therapy (?end of 2016) on ethical issues and monotherapy.

 

 

 

Tagged in: CROI 2017

 

  1. Since the advent of integrase inhibitors, bringing about our latest highly effective combination therapy, with viral suppression rates approaching 97%+, many clinicians have questioned a place for new antiretrovirals. How do we get much better? Will there be any compelling reasons to switch our patients to newer agents? In addition, studies such as SWORD have shown simplification strategies can be highly effective, using exisiting drugs, without the need for a third agent. Studies examining cabotegravir, a long-acting integrate inhibitor which can be given as a depot injection, have now entered phase 3 clinical trials, which may possibly negate the need for daily oral treatment. So what does this mean for future drugs? How will they find their niche in what is becoming a rather crowded market? I think given the aforementioned advances, new drugs will need to be highly effective, have high genetic barriers to resistance, thus possibly lending themselves to either dual or monotherapy. Additionally, long-acting drugs which may be able to be given less frequently (through depot or implant), may have an important role in the future of ART. Finally, drugs with novels modes of action, may have a continued role in treatment experienced patients with resistant virus.

     

    This presentation from Gilead Sciences (abstract below) introduced a novel first-in-class capsid inhibitor which leads to a defective HIV-1 virion through interference in the capsid core assembly. In-vitro assays have revealed CS-CA1 to be a highly potent drug with no measurable toxicity in target and non-target cells. The drug binds to a largely conserved region on the capsid protein. In addition, the drug appears to have activity blocking some of the post-entry capsid functions. Pharmacokinetic studies in rats have demonstrated sustained plasma concentrations and the drugs limited aqueous solubility make a drug possibly well suited to long-acting depot administration.

     

     

    I feel that this novel drug offers exciting promise, especially if the in-vitro activity translates to highly effective antiviral activity in-vivo - possibly leading to a long-acting drug lending itself to simplified depot administration.

     

    DISCOVERY OF NOVEL POTENT HIV CAPSID INHIBITORS WITH LONG-ACTING POTENTIAL
    Winston C Tse
    , John O. Link, Andrew Mulato, Anita Niedziela-Majka, William Rowe, John R. Somoza, Armando G. Villasenor, Stephen R. Yant, Jennifer R. Zhang, Jim Zheng

    Gilead Scis, Inc, Foster City, CA, USA

    Background: While HIV capsid (CA) plays an essential role in multiple stages of the viral life cycle, it remains an unexplored target for antiretroviral (ARV) therapy. Here, we report the discovery of a novel class of exquisitely potent and metabolically stable HIV capsid inhibitors (CAIs) that exhibit pharmacokinetic (PK) profiles suitable for slow-release parenteral administration.
    Methods: In vitro CA binding and assembly assays, together with X-ray co-crystal structures of CAIs with cross-linked CA hexamers, were used to optimize compounds for
    high binding affinity to CA. Medicinal chemistry approaches were employed to optimize the antiretroviral activity and drug-like properties using a cytopathic antiviral assay in conjunction with extensive metabolism and pharmacokinetic profiling. CAI resistance-associated mutations were identified by in vitro resistance selections. CAI mode-of-action was defined by inhibitor time-of-addition, virion electron microscopy and viral DNA quantification.
    Results: GS-CA1, an exemplified member of a novel class of CAIs, is a highly potent inhibitor of HIV-1 replication in T cell lines (EC50 = 0.24 nM) and displays similar potency against multiple HIV-1 clinical isolates from all major clades in human PBMCs. Identified CAIs bind to a broadly conserved site at the interface of two adjacent monomers within a CA hexamer and accelerate CA assembly in vitro. The identified CAIs maintain full activity against HIV-1 mutants resistant to licensed ARVs and select for HIV CA variants L56I, M66I, Q67H or N74D with an attenuated in vitro replication phenotype. Mechanistic studies revealed a dual mode of action targeting both the late-stage virion maturation and post-entry CA functions. GS-CA1 shows high in vitro metabolic stability and favorable PK profiles in multiple preclinical species with low systemic drug clearances (0.08–0.33 L/ hr/kg) and long half-lives (7.2–18.7 hr). Low aqueous solubility provides for an extended-release preclinical PK profile following subcutaneous administration of a solid depot formulation.
    Conclusion: We have identified novel HIV-1 capsid inhibitors with uniquely potent antiviral activity and a favorable resistance profile orthogonal to existing ARVs. The high metabolic stability and low aqueous solubility of this new inhibitor class should enable the development of an extended-release parenteral formulation with the potential to be used as a novel long-acting antiretroviral treatment. 

Tagged in: CROI 2017

Comment: Abstract follows:

Doravirine seeks to address the limitations of the currently available NNRTIs: avoidance of neuropsychiatric side effects, no food requirements or concerns re co-administration with antacids/PPIs, fewer drug-drug interactions and a once daily option with a higher genetic barrier to resistance than efavirenz or rilpivirine.

83.8% (321/383) of subjects on the doravirine arm had an undetectable viral load at week 48 when compared to the darunavir/r arm  79.9% (306/383). When comparing this to the phase II F/TAF/BIC versus F/TAF/DTG data presented earlier this session (97% and 91% respectively), I wonder what role doravirine will play in the treatment naïve setting. Ideally a treatment naïve phase III trial comparing doravirine to an integrase inhibitor such as dolutegravir would help to answer this question. 

Perhaps it will find a place as a once daily salvage option?

 

45LB DORAVIRINE IS NON-INFERIOR TO DARUNAVIR/R IN PHASE 3 TREATMENT-NAIVE TRIAL AT WEEK 48

Jean-Michel Molina et al

Background: Doravirine (DOR) is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with once-daily dosing and potent in vitro activity against the most common NNRTI resistant variants (K103N, Y181C, G190A). In a phase 2b study, DOR 100 mg once daily (QD) demonstrated similar efficacy to efavirenz, with favourable safety and tolerability through Week 48.

Methods: DRIVE-FORWARD is an ongoing, phase 3, multicenter, double-blind, non-inferiority trial in antiretroviral treatment-naive adults with HIV-1 infection and pre-treatment HIV-1 RNA 1,000 c/mL. Participants were stratified by screening HIV-1 RNA ( or >100,000 c/mL) and investigator-selected NRTI backbone therapy (TDF/FTC or ABC/3TC) and randomized in a 1:1 ratio to receive DOR 100 mg QD or darunavir 800 mg with ritonavir 100 mg (DRV/r) QD, in combination with the selected NRTI, for up to 96 weeks. The primary endpoint was the proportion (%) of participants achieving HIV-1 RNA <50 c/mL at Week 48 (NC=F, FDA Snapshot approach) with predefined non-inferiority margin of 10%. A secondary objective was to evaluate the effects of DOR and DRV/r on fasting serum lipids.

Results: Of 769 participants randomized, 766 (383 in each group) received study drug and were included in the efficacy and safety analyses (mean age 35.2 years, 84% male, 73% white, 87% on TDF/FTC). DOR was non-inferior to DRV/r on the primary endpoint, with 83.8% (321/383) and 79.9% (306/383), respectively, achieving HIV-1 RNA <50 c/mL at Week 48 (difference 3.9%, 95% CI [-1.6, 9.4]). In the subgroup with baseline HIV-1 RNA >100,000 c/mL, 81.0% (64/79) on DOR and 76.4% (55/72) on DRV/r achieved HIV-1 RNA <50 c/mL at Week 48 (OF approach). Adverse event rates (overall, serious, drug-related, and leading to treatment discontinuation) were similar across treatment groups. The most common drug-related AEs (>5% in one or more treatment groups) were diarrhea (5.5%, 12.8%), nausea (6.5%, 7.6%), and headache (6.0%, 2.6%) for DOR and DRV/r, respectively. Fasting LDL-C and non-HDL-C were reduced by DOR and increased by DRV/r (see table) with statistically significant treatment differences (p<0.0001).

Conclusion: At Week 48, DOR demonstrated potent efficacy and was non-inferior to DRV/r on a background of 2 NRTIs in HIV-1 treatment-naive adults. Efficacy was similar regardless of baseline HIV-1 RNA. DOR was generally safe and well-tolerated with a superior lipid profile for fasting LDL-C and non-HDL-C compared to DRV/r.

 

 

 

 

Tagged in: CROI 2017

Comment: Abstract follows:

This study demonstrates non-inferiority of treatment switch to dolutegravir/rilpivirine at 48 weeks versus remaining on current antiretroviral therapy. Its satisfying to hear in person, data presented from a trial being conducted at our site.

Since 1996, triple therapy has been standard of care in treating HIV. As the HIV population ages, we are increasingly concerned by the potential toxicities associated with either TDF or abacavir use. While the development of TAF attempts to address this important clinical issue, its exciting that NRTI limiting strategies are also being pursued as an alternative strategy.

 Given its high genetic barrier to resistance, dolutegravir is an obvious candidate to explore this strategy and in addition to this study, late-breaker data regarding dolutegravir as maintenance monotherapy (Poster 451LB) will be presented in the coming days. A study of cabotegravir/rilpivirine as oral maintenance therapy is also being presented (Poster 442). 

 

44LB PHASE III SWORD 1&2: SWITCH TO DTG+RPV MAINTAINS VIROLOGIC SUPPRESSION THROUGH 48 WKS

Josep M. Llibre et al

Background: The requirement for life-long antiretroviral therapy (ART) of HIV infection has highlighted interest in 2-drug regimens (2DR) to minimize cumulative drug exposure. Dolutegravirs (DTG) potency, safety and resistance barrier make it an optimal core agent for 2DR. Rilpivirines (RPV) safety, tolerability and efficacy in switch regimens make it an ideal potential partner.

Methods: Two identical open-label, multicenter, global, phase III, non-inferiority studies evaluated the efficacy and safety of switching from a 3 or 4-drug current antiretroviral regimen (CAR) to DTG+RPV once daily in HIV-1-infected adults, with HIV-1 RNA<50c/mL (VL<50c/mL) for at least 12 months and no history of virologic failure. Participants (pts) were randomized 1:1 (stratified by baseline 3rd agent class; age.

Results: 1024 pts were randomized and exposed (DTG+RPV 513; CAR 511), across both studies. Switching to DTG+RPV was non-inferior to continuing CAR at Wk48 for VL<50c/mL in pooled analysis of both the ITTe population [95% vs. 95%; difference: -0.4% (95% CI: -3.1%, 2.3%)] and the per-protocol population [96% vs. 96%; difference: 0.7% (95% CI: -3.3%, 1.8%)]. Efficacy results for SWORD-1 (VL<50c/mL in ITTe [95% vs. 96%; difference: -0.6% (95% CI: -4.3%, 3.0%)]) and SWORD-2 (VL<50c/mL in ITTe [94% vs. 95%;

difference: -0.2% (95% CI: -4.2%, 3.8%)]) were comparable. Low rates of snapshot virologic failures (VFs) at Wk48 were observed for both studies (Table 1). One pt on DTG+RPV with protocol defined VF had an NNRTI RAM (K101K/E); no pts had any INI RAMs. More adverse events (AEs) were reported and led to discontinuation in the DTG+RPV arm; no unexpected AEs were identified for either drug.

Conclusion: A switch to a novel, once daily 2DR of DTG+RPV demonstrated high efficacy and was non-inferior to the continuation of CAR in virologically suppressed HIV-1-infected adults. The safety profiles of both DTG and RPV were consistent with the respective labels. A DTG+RPV 2DR offers the potential for reduction in cumulative ART exposure, without an increased risk of virologic failure.

 

 

Tagged in: CROI 2017

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