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.

The Treatment Evolution: New Drugs, New Reality session on Thursday afternoon was the most important session so far at the conference from the point of view of therapeutics.  Of great interest was the 48 week data for injectable cabotegravir + rilpivirine.

 

At this session the 48 week results for the Cabotegravir + rilpivirine as long-acting maintenance therapy: LATTE‑2 week 48 results’ were presented by David Margolis (THAB0206LB).    This phase 2b study compared 4 week and 8 week injections vs oral therapy (CAB + ABC/3TC) to maintain viral suppression of HIV-1.

 309 patients ART-naïve HIV infected adults were treated during the 20 week induction period to reach a RNA< 50 c/mL with daily oral CAB 30 mg + ABC/3TC then were  randomized 2:2:1 to IM CAB LA + RPV LA every 4 weeks (Q4W), every 8 weeks (Q8W), or oral CAB + ABC/3TC (PO) in the Maintenance Period (MP).

 Key findings from this study were 

-          At Week 48, 92% (Q8W), 91% (Q4W), and 89% (PO) remained suppressed (ITT).  

-          More patients on Q8W (5%) than Q4W (< 1%) and PO (0%) had HIV-1 RNA >50 c/mL at Week 48. 

-          There were more discontinuations in Q8W (8%) and PO (9%) arms versus Q4W arm (1%).   

-          Injection sited reactions were common but resulted in < 1% withdrawal.  

-          Three subjects met criteria for viral failure during maintenance, one Q8W subject with emergent RPV and CAB resistance

 Q4W dosing resulted in lower rates of virologic non-response than Q8W so was selected for progression into phase 3 studies.  This treatment appears to be very effective and safe.   Questions remain about the acceptability of monthly injections in various clinical settings but this is a potentially the beginning of a whole new approach to HIV therapy.

 

Catherine Orrell  presented ‘Superior efficacy of dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) fixed dose combination (FDC) compared with ritonavir (RTV) boosted atazanavir (ATV) plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in treatment-naïve women with HIV-1 infection (ARIA Study)’.   (THAB0205LB) DTG/ABC/3TC was superior to ATV+RTV+FTC/TDF, with 82% and 71%, respectively, achieving HIV-1 RNA < 50 c/mL at Week 48.

Differences were driven by lower rates of both discontinuations due to adverse events (AEs) and virologic failures in the DTG/ABC/3TC group.  Of six DTG/ABC/3TC subjects who met protocol-defined virologic withdrawal criteria, none had resistance mutations, compared with 4 ATV+RTV+TDF/FTC subjects who met virologic withdrawal criteria of which one had an NRTI mutation, M184M/I/V. This study was very important in that it showed superiority and was female only.

 

 

 

Jean-Michel Molina  presented ‘Who benefited most from immediate treatment in START? A subgroup analysis’ (THAB0201).  In asymptomatic ART-naïve adults with >500 CD4 cells/mm3, immediate ART was superior to deferral across all subgroups.  People > 50, higher plasma HIV RNA level, lower baseline CD4 count, and higher Framingham risk had the greatest benefit.

 

Alejandro Arenas-Pinto presented ‘Increased risk of suicidal behaviour with use of efavirenz: results from the START trial’ (THAB0202). These findings suggest that participants using EFV in the immediate ART group had an increased risk of suicidal behaviour compared to ART-naïve controls. A prior psychiatric diagnosis increased the risk.

 

Michael Aboud  presented ‘STRIIVING: switching to abacavir/dolutegravir/lamivudine fixed dose combination (ABC/DTG/3TC FDC) from a PI, INI or NNRTI based regimen maintains HIV suppression at week 48’ (THAB0203).  Treatment experienced patients were randomized to continue current ART on Day 1 or switched to ABC/DTG/3TC.  The current treatment arm then switched at week 24.   In this switch arm 92% maintained viral suppression at 48 weeks (note the 24 week data has previously been presented).

 

 

 

It’s amazing how far we have come in the potential of neutralizing monoclonal antibodies against HIV. John Mascola from the Vaccine Research Centre gave a great plenary on “Harnessing antibodies for HIV prevention and treatment.”

Antibodies have been used in infectious diseases for passive immunization eg RSV, zoster, hepatitis B.

Many potent broadly neutralizing antibodies have been discovered in HIV since 2009, which can bind to various sites on HIV gp41 and block viral entry into cells. These newly discovered antibodies are 500x more potent than previously and more are being found.

Studies in monkeys have demonstrated that passive immunization with these newer antibodies such as VRC01 can prevent SHIV infection.

There are early phase studies in humans. The treatment appears safe and well tolerated. Protective levels of antibodies remain in circulation for 2 months – this period can be extended by creating mutations in the Fc region that increase the antibody affinity.

Can antibodies protect against infection in humans? How much is required (as more potent antibodies are discovered, they will require lower doses and last longer, thus reducing cost. Lower dosage also means they can be administered subcutaneously rather than IV). There also needs a greater understanding of how and where exactly these antibodies work in the body.

A large scale HIV prevention study is planned using broadly neutralizing antibodies to provide antibody mediated protection in 2400 MSM in North and South America and 15000 women in Africa.  The goal – safe effective administration sc every 4/12 for PrEP.

There needs to be protection against wide variety of HIV strains – combining antibodies acting at different sites will achieve this.

Other potential roles for these neutralizing antibodies include preventing mother to child transmission intrapartum and with breast feeding – animal models show this is viable.

Neutralizing antibodies may also have a role in treating HIV infection – either alone, or complementary to ART. They may be able to reduce viraemia in primary infection, or in those with chronic infection, to treat HIV, and to assist in killing of infected cells by marshalling immune response.

So while there is work to do in translating this knowledge into viable HIV prevention and treatment options, there has been major progress in this area. Watch this space.

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Tagged in: CROI2016
Key Antiviral Therapy RCT's Cabotegravir LA injection and TAF(again)

GS - US- 311-1089   Switching Tenofovir DF to Tenofovir Alafenamide in virally suppressed patients

48 week data was presented; RCT, double blinded  evaluated safety and efficacy of switching from F/TDF to F/TAF  vs continuing F/TDF while remaining on the third agent. 50% of third agent was a boosted PI.  663 patients were randomised to the two arms. Patients vl were < 50 copies and stable. eGFR was > or= to 50

Very little failure described. The nature of the third agent made no difference to outcomes. Very foew AE's leading to discontinuation occurred.

eGFR improved and proteinuria decreased when switched to F/TAF.    BMD did not worsen in the F/TDF group. BMD improved in the F/TAF group at both 24 and 48 weeks. Lipids increased in the F/TAF group.  F/TAF was shown to be not inferior in terms of virological suppression.

 

Latte 2  week 32 results - Cabotegravir + Rilpilvirine as long acting maintainence therapy,  INSTI and NNRTI long acting injectable nano-suspension. 

Phase 2b open label study ART naïve. 20 week induction daily oral CAB + ABC/3TC randomised to one of three arms - IM CAB LA + IM RPV LA every 4 weeks ; or the same every 8 weeks ; or to remain on the oral CAB + ABC/3TC

309 subjects enrolled.  median age 35.  8% female.  15% African American  Median CD4 ^400  19% viral load > 100,000.

32 week data. 286 subjects randomised to maintainence therapy. most common AE was injection site pain with 99 of these reported as mild. These lasted a median of 3 days with all resolved by 7 days. 1% eventually withdrew citing injection site reaction. most non ISR AE's were fever, fatigue , and flulike symptoms. There was one death unrelated to study due to epileptic eizure.  > 95% cited high level of satisfaction with the injectable therapy.

All arms demonstrated comparable antiviral activity. At this time no regimen has been ruled out.

 

 

 

 

Tagged in: CROI2016
Plenary 2 - Joe Eron - Where we are and where we are going

Tuesday plenary 2 - A great overview of the current situation and where we are headed

90 90 90 are high targets

Integrases will help achieve these higher proportion of fully suppressed patients for longer before resistance occurs and needing fewer regimen changes over the projected treatment period for some of 80 years.

Hurdles include

     -persisting treatment gap - those in care and not in therapy > 10 % in most clinic populations

     -whole life treatment from diagnosis despite

          -adverse events, pregnancy, childhood and adolescence, periods of poor adherence, drug interactions

     -Toxicity - but this is decreasing

              eg TDF will be replaced by TAF - lessening BMD loss and reducing proximal renal tubule issues

                   Duel therapies - eg Dolutegravir + 3TC - less exposureto potential toxicities

     - Resistance - but the use of potent therapies up front has made resistance rare

     - Are there enough agents to last 80 years

            New agents/ different classes will overcome resistance to previously used drugs

                         Dolutegravir

                         TAF

                         Doravirine

                         Maturation inhibitors

                         Attachment inhibitors

                         Monoclonal antibodies

     - Adherence issues - particularly at some stages in their life for some patients - adolescents and drug                   users for example - Long acting therapies like Cabotegravir and Rilpilvirine will help

               Drug implants

               Vector delivery

Tagged in: CROI2016
Plenary 1 - Overview of Monoclonal Antibodies

The use of Monoclonal antibodies in HIV therapy seems to be close at hand. The first plenary of the conference focussed on this.

First potential compound identified in 2009 - today there are over 500 individual isolates. Initially investigated to better understand pathways to effective vaccination there seem to be clear applications for use in preventing HIV infection (PrEP) as well as suppressing viral replication.

Two attributes of MA are of interest

                - Potency - dose required to neutralise the majority of viruses, and

                 -Breadth - the % of different HIV "strains" neutralised.

Currently no human data regarding passive protection from infection with monoclonal antibodies. Within a short time should have antibodies that bind four different sites.  There is PK data and safety data from phase 1 trials. Animal data shows effectiveness.

The first trial in humans to assess the protectivity of MA will begin later in 2016.   Based on earlier studies this will be a placebo controlled trial in high risk males in North America and high risk females in Africa.

It is likely that future compounds will be more potent and it is also likely that multiple compounds will need to be used at once to provide greater breadth.

There are a number of areas where monoclonal antibodies would have application clinically.

         -Acute HIV infection  to prevent or limit seeding of viral reservoirs

         -to maintain long term viral suppression  - given by injection every two -three months  

         - to reduce cell associated reservoirs.

Advantages of proposed compounds are

         - they are distinctly different current medications and their resistance profiles will be different

         - they have the potential to eliminate infected cells and may have a role in eradication

Limitations include

         - they are unlicensed biologicals

         - single compounds do not cover %100 of virus

In any case these exciting developments seem to indicate that we will have effective new tools within a relatively short time frame that will be effective at preventing infection as well as maintaining viral suppression. They may also have a role in assisting with eradication of the HIV infected cells.

 

 

Tagged in: CROI2016

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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