Just a short not re PrEP implant - Poster 879

Looks like a implanon - looks easy to insert and to remove - Initially seems to deliver effective drug concentrations for 3 months - but surely this will improve.

" developed a biodegradable TFPD for subcutaneous delivery of TAF for HIV PrEP. The size, shape, and release rate of the device are tunable over a >8-fold range"

Fantastic - surely multiple compounds could be delivered this way

Surely a device that lasts for 12 months or would be perfect for PrEP.

The Dapivirine vaginal ring empowers women by giving them a device that they can use to protect themselves from HIV infection and which in no way requires agreement or permission from their male partner/s. Two landmark studies were presented at CROI. Adherence had always been the problem seen in previous studies of similar technologies.

MTN 020/ Aspire Study

This was a placebo controlled RTC. 2629  <50% married women from 4 African countries were randomised to two arms - one was the Dapivirine containing ring the other was a placebo ring. Dapivirine is an nnrti. The median age of the women was 26 - ranging from 18 to 45. The ring is replaced every four weeks and meant to be in situ all of the time.

Adherence was assessed by measuring blood levels - levels >95 pg/ml was consistent with > 8 hrs of use. 82% of plasma samples were at this level or greater. Adherence would be over estimated if the ring was inserted > 8 hrs prior to the clinic visit. Returned rings were also assessed for residual drug. 84% were found t have levels < 23.5 suggesting adequate compliance.

median followup was 1.6 years. Women attended 91% of expected visits.

Overall there was a 37% reduction in expected HIV infections in the women on the active treatment arm. Interestingly in women <21 years of there was NO reduction in infections and in women above 21 years there was a 51% reduction in expected infections. Analysis suggested poor adherence in women < 21 yrs of age.

The rings were well tolerated in both arms with essentially no significant adverse events.

The Ring Study  IPM 027

This was an RCT double blinded trial studying the safety and efficacy of a Dapivirine vaginal ring. 1959 women from two African countries were randomised 2:1 Dapivirine ring and placebo. The women aged 18 - 45 received HIv prevention counselling. Adherence was objectively assessed by plasma levels throughout the trial and measurement of residual drug in returned rings. Rings were replaced every 4 weeks. The study concluded end 2015 after most women had been tudied for two years. All women will be offered an active ring at the first visit after conclusion of the study.

Expected HIV infections were reduced by 31% in the group using the active ring.

The study organisers concluded that the ring was safe and well tolerated with an overall reduction of 31%. They noted that was a high incidence of HIV infection in the group studied of 8 % per year.

These number do not sound that great to me. However they do compare pretty well to the IPPREX findings presented in 2011 re oral Truvada as PrEP.  It may be that adherence would be much better in an open label situation with better levels of education and understanding about the importance of always having the ring in situ no matter what else is happening. So that as we see in community settings adherence is much better and the protection against infection almost absolute.

Alternative PrEP Regimen

Maraviroc + FTC may be the first alternative PrEP regimen to become available. Obviously this is great for people who for some reason cant take or tolerate TDF/FTC.

Roy Gulick presented 48 week data from HPTN 069 - a RCT   double blinded safety and tolerability trial comparing four treatments arms

      Maraviroc alone

      maraviroc + FTC

     maraviroc + TDF

     Tenofovir DF + FTC

THIS WAS NOT A TRIAL OF EFFICACY

406 HIV-ve MSM older than 18 years deemed to be at some risk for acquiring HIV ( needed to have a self reported history of unprotected anal intercourse with either a known HIV+ve man or a man of unknown HIV sero-status within the previous 90 days.) were randomised to one of the four arms and followed up for 48 weeks. 28% were black, 22% latino. eGFR at enrolment needed to be > 70.

Maraviroc was studied because it was an available ARV, it was already known to be concentrated in rectal tissue, and it was known to be well tolerated.

Findings - All arms were well tolerated - no significant safety or tolerability differences were found. There were 5 seroconvresions in the study- 2 of these had no detectable drug; the other three had detectable drug and these were all in the maraviroc alone arm. But this study was not set up to look at efficacy.

Injectable Cabotegravir - PrEP Study in Monkeys but with Intravenous challenge.

Could Cabotegravir LA protect against IV transmission of HIV?  Long acting Depot CAB injection would suit IV drug users but would it work?

Three arms  injected with CAB LA with varying doses at week 0 and week four. one group received only one dose at week 0.  IV challenge given at week 2.    8 macaques in each group     Five macaques remained untreated as controls.

All 5 macaques were found to be infected one week after challenge

two 50mg doses given at week 0 and 4weeks resulted in 7 out of 8 macaques remaining uninfected

one 50mg dose at week 0 resulted in all 8 macaques in that group remaining uninfected

one 25mg dose at week0 plus one 50mg dose at week 4 resulted in 6 out of 8 macaques remaining uninfected

Notwithstanding the difficult to explain single infection in the first group these results suggest that adequate dosing with CAB LA will protect IVDU's from IV infection with HIV. Fwurther study ill be done.

ECLAIR - Long acting Injectable PrEP   Safety and PK study

This would be great for a subsection of our patients at some stages in their lives.

Phase 2a randomised trial of Cabotegravir LA - INSTI . Doses based on Phase 1 data, supported by animal studies. 127 patients randomised receive injections given at 3 monthly intervals of CAB LA or saline.

There was a 4 week induction period of oral therapy. Safety tolerability and PK was assessed through the trial until the 41 week endpoint.

Avaerage age 30. 57% white

Both oral and LA doses were well tolerated. Absorption rates were faster than expected higher peaks and lower troughs with 21% falling below the IC90. Most significant AE's were injection site reactions in the active treatment arms. There weren't many problems with the saline injections. ISR's lasted 5 days on average. There were two seeroconversions - one receiving saline, the other occurring in the followup phase of the CAB LA group. The dose is being reviewed in light of the PK data.

Topical Rectal microbiocide - MTN 017

Phase 2 three period randomised sequence open label safety acceptability

comparing rectally applied reduced glycerine 1% tenofovir with oral TDF/FTC

in each 8 week study period 195  MSM > 18yrs with a history of being ano-receptive either used the topical rectal gel daily; used the rectal gel before and after anoreceptive sex; or took TDF/FTC orally. Participant switched method every 8 weeks with a "washout " period of one week between each change.

Subjects were given lots of support to be adherent - eg daily texts to ensure daily use of the rectal gel . Very frequent interviews and questionairres. Adherence was objectively by collecting blood, rectal fluid and rectal tissue samples. Adherence was found to consistent with >80% of expected doses taken/used.

138 were screened "out" because of the presence at enrolment of STI's or HIV infection

There were few AE's. All methods were well tolerated. All methods were "liked" by the participants. There was found to be high levels of adherence in all arms. Further studies will now be done.

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.

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

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.

First Conference session that I have attended.  really a preconference workshop for "young Researchers"

Three perspectives HIV -ve African women, traditional urban PLWHIV communities, young ( <25yrs) men of colour.

Some common themes emerged. HIV positivity and higher risk of becoming infected need to be examined within the contexts of peoples general health needs and risk activities.  eg young black women feel only of interest to HIV researchers if their body contains a foetus. High maternal mortality rates in Uganda certainly relate to many factors not just HIV. Often Researchers are older white males - that young urban blacks have difficulty relating to. Often little is understood about young black or white males - how they see themselves in terms of sexual identity or sexual health risk. Wrong to transfer knowledge/ notions about what are now older black gay men to younger age groups. Recent PrEP studies with young men of colour did not engage well with at risk groups. No members of the target group were involved in the development of the studies and only belatedly involved in the implementation of the study. Best to find out first how they like to be categorised. eg MSM is not a term commonly used or related to by this group.  Young men of colour will say very different things to peer researchers as opposed to older black or white gay male researchers. Rebellion is a normal part of growing up needs to be taken into account. "Rebellion" in these studies ( lack of cooperation/ failure to complete followup etc ) directly related to lack of consultation around what words were used/ recognition of individuals time constraints from their perspective etc.

Maybe we used to know this when "we" were young - but we have all gotten older and are now part of the establishment/ authority structures that we used to come up against.

Tokenism was discussed by all- Are representatives of the targets of research included in all stages of the development and implementation of social research. Are these bona fide reps or are they individuals with little actual community attachment ( there to make the research proposal look good) and therefore not really useful conduits of information back with little community accountability.