0 false 18 pt 18 pt 0 0 false false false

Day 4’s morning session was focused largely on PrEP, making it interesting and relevant to the Australian context.

 

Chloe Orkin (from the Royal London Hospital) began by providing a brief summary of the current situation and future prospects for PrEP.

 

She noted the current use (as PrEP) of standard antiretrovirals; the development of new compounds from existing classes (e.g. EFdA [NRTI]; dapivirine, MIV-170 and IQP-0528 [NNRTIs]; cabotegravir and MK-2048 [IIs]; and entry inhibitors [vivriviroc, 5P12-RANTES, PIE-12, nifviroc and trimer-D-peptide]); as well as new compounds from new classes (VRC01 and griffithsin [Neutralising antibodies]).

 

She also mentioned novel means of drug formulation that’re being developed: rings, inserts, suppositories, gels, films, soft implants, injections and douche/enema.

 

 

Sheena McCormack (University College London) presented an update on the evidence for PrEP effectiveness.

 

She began by presenting the a summary of currently available evidence as below, reminding us that overall (especially in MSM) PrEP is very effective; that adherence was a major factor in many of the studies where effectiveness was less good (particularly in young black MSM in the USA and in heterosexual populations).

 

She focused on the PROUD (continuous truvada as PrEP; immediately or deferred) study which looked at effectiveness, risk compensation and STI rates This study showed an effectiveness of 86% (90% CI 64-96%), with NNT = 13 (90% CI 9-23) – Dr McCormack commented that this compares favourably with other medications (such as statins) that’re approved for preventive measures. She also commented that some of those in the immediate intervention (PrEP) arm had significantly more unprotected anal intercourse than those in the deferred arm, and that rates of unprotected anal intercourse in both arms were relatively high. In that study, a rectal STI indicated a 1 in 6 risk of HIV infection in the following year.

 

Australia’s EPIC study was mentioned, particularly with regard to the fact that it targeted those at high risk of HIV.

 

She provided a summary of worldwide PrEP demonstration projects between 2011-2015:

-       32 projects in 16 countries

-       8478 participants with 7061 cumulative years exposure

-       Total HIV seroconversions n=67

à Highest rates in MSM 18-25 years (7.7/100 person-years)

à However available intracellular data showed undetectable or very low tenofovir levels in nearly all of those with seroconversion while on PrEP.

 

Episodic vs daily dosing – the importance of choice to effectiveness

HPTN 067/ADAPT study was mentioned: this study compared the use of daily, twice weekly (and another tablet after sex) and episode-driven PrEP in 3 populations (Harlem MSM/TGW; Bangkok MSM/TGW; Cape Town WSM). It showed that in the Bangkok population (who were generally better educated and suffered less social disadvantage) there was little difference in effectiveness between treatment arms, whereas adherence was much poorer for event-based PrEP in the other two arms (compared with continuous PrEP). This suggests that a choice of event-based or continuous PrEP may be useful depending on the population in question, and that if a population is likely to be adherent to episodic PrEP, this may produce cost-savings (less drug used overall).

 

 HIV infection despite PrEP

Those two cases of HIV being contracted despite good adherence (and adequate drug levels) were mentioned, including the “Toronto case” and the second case recently reported of a MSM acquiring a strain of resistant HIV. This reinforces the importance of reminding those on PrEP that it is not 100% effective.

 

Possible use of maraviroc as PrEP

HPTN 069/ACTG 5305 (Phase II Study of Maraviroc-Based Regimens for HIV PrEP in MSM) was discussed. In this study of n=406 MSM, people were randomised to oral maraviroc (MVC) only; MVC+FTC; MVC+TDF or TDF+FTC. 5 seroconversions occurred (4 in MVC-only arm), but in 4 of those plasma drug levels were low or undetectable.

 

Dapivirine-impregnated vaginal ring as PrEP

ASPIRE (n=2629; 27% risk reduction) and Ring (n=1959; 31% reduction) studies. Both in Africa.

However risk reduction was 60% in women >25 years of age; based on further data from the studies poor adherence was thought to be responsible for the poorer effectiveness in younger women.

Dr McCormack also mentioned the possibility of including contraceptive drugs in the PrEP vaginal ring to provide combined PrEP/contraceptive effect.

 

Conclusions

-       Overwhelming evidence of effectiveness of biological efficacy of TDF+/-FTC – which is not compromised by STI or risk compensation.

-       Population effectiveness not compromised by resistance (to date)

0 false 18 pt 18 pt 0 0 false false false

-       Heterosexuals have a choice of drug; MSM have a choice of regimen; women will soon have a choice of delivery method.

Day 3.

 

This morning’s session was largely about psychosocial issues in people living with HIV.

 

Moisés Agosto-Rosario (an educator and advocate for people living with HIV) spoke about communication and ways in which we can improve this. He emphasised that it must be patient-focused, and must consider the sensitivities of those “key groups” at risk of HIV (sex workers; MSM; PWID; trans people; CALD people). He finished by stating that by 2020, 70% of people living with HIV will be >50yo (I imagine that this was a US statistic, but he didn’t specify), so we must be prepared for the increase in comorbidities that’ll come along with an ageing population living with HIV.

 

David Stuart (from Dean Street Clinic, London) spoke about the change in culture of the MSM community, with specific reference to:

-       The social scene (hookups often through apps as opposed to in person)

-       The drugs used (crystal/GBL/mephedrone in London)

-       Risk-taking behaviour

Of the HIV-infected patient group they see, several have died in the past 12 months – but all were from drug-related issues (not from HIV/AIDS), highlighting the importance and risk of drug use in this population. He also emphasised the importance of doing “well-being” checks at each visit, including social and emotional well-being.

 

Changes in morbidity/mortality/HIV care – a cohort study over 10 years in France.

Charles Cazanave spoke about research they’re doing in Aquitaine, France, with the ANRS CO3 cohort, to assess how the needs and morbidity of people living with HIV change over time. They had a cohort of n=2138 that they recruited in 2004 and followed until 2014, following their HIV-related characteristics, as well as other patient factors and co-morbidities.

-       71% male (40% MSM)

-       52% were over 50 in 2004 (and obviously 62% in 2014)

-       91% had HIV VL<50 in 2014 (compared with 51% in 2004)

-       72% had CD4>500 in 2014 (c/w 44% in 2004)

-       ART regimens changed little between 2004 and 2014 (except integrase inhibitors being used in 6.5% in 2014).

-       Dyslipidaemia rates increased by 40% and hypertension by 37% over the 10 years

-       Cardiovascular (increased by 6.1%) and CNS adverse events increased over time; rate of people with EGFR<60mL/min increased by 5.1%; those with Framingham score indicating high risk increased.

Unfortunately there was no control group with which to compare these increases. However they concluded that monitoring for and management of co-morbidities is imperative in an ageing population with HIV.

 

Effect of lipodystrophy on morbidity/mortality.

Esteban Martinez presented research on the connection between lipodystrophy on risk of morbidity and mortality – their hypothesis was that lipodystrophy may increase the risk of comorbidities/mortality in people living with HIV.

They studied a population (n=494) that began CART between 1996 and 1999 – this CART initially involved 2 x NRTIs and at least 1 PI. 76% were men; 28% were MSM; 39% IVDU. Follow-up was until Dec 2015 or death (14%) or loss to follow-up (21%).

-       24% had lipoatrophy

-       4% had lipohypertrophy

-       18% had lipodystrophy (both lipoatrophy and lipohypertrophy)

Analysis of death rates, morbidity and lab testing by the end of Dec 2015 revealed:

-       Fewer AIDS events and fewer deaths in those with LA/LD, however no association with lipohypertrophy (however note the small number of people with lipohypertrophy).

-       Less hepatic decompensation in those with LA/LD.

-       Hypertension/diabetes rates increased in those with LD/LA/LH.

Conclusions were, unsurprisingly, that lipoatrophy was a proxy for effective CART and viral suppression, so morbidity/mortality overall less in this group.

 

Dolutegravir and cessation due to neuropsychiatric effects.

Michael Sabranski presented an analysis of all those beginning integrase inhibitors in Germany between Jan 2007-April 2016. All discontinuation reasons, start and stop dates were analysed.

-       In those that took dolutegravir, other covariables were analysed.

N=1704

The study found that:

-       The discontinuation rate of dolutegravir due to neuropsychiatric adverse effects was almost 6% within 12 months – this rate was higher than that reported in RCTs (and higher than for raltegravir/elvitegravir)

-       Women, older patients and patients who simultaneously initiated abacavir had a 2-3 fold higher risk of DTG discontinuation due to neuropsychiatric adverse events.

-       Such adverse events were reversible and not severe.

0 false 18 pt 18 pt 0 0 false false false

It was acknowledged that a higher rate of people ceased DTG in 2016 (after research had already come out linking DTG with neuropsych side-effets. However even when those patients were removed, the relationships listed above were still significant.

Today began with an interesting talk by Prof. Julio Montaner. He spoke about HIV treatment as prevention (TasP) – I found it interesting that based on a couple of models (from Hlabisa, Africa and BC, Canada), for every 1% increased coverage (with ARV and undetectable VL), one can estimate a 1% decrease in HIV incidence.

Prof Montaner also presented research on the HIV strains found in British Columbia. Phylogenetic studies of the strains found show that, even with high rates of diagnosis, treatment and viral suppression (Vancouver on-track to reaching 90/90/90 goals by 2020), significant clusters of new infections still continue to occur, and that investigation, prevention and treatment strategies must focus on these clusters. Contact and partner tracing were strongly emphasised.

 

 

Jens Lundgren spoke next regarding the START (early ART) study update.

-       Hazard ratio of 0.43 of serious AIDS/non-AIDS events in early treatment arm (compared with delayed treatment) – so unblinded early.

-       Significantly decreased rates of OI in early treatment arm.

-       Cancer occurrence had a 64% risk reduction in early treatment arm.

-       No evidence of a change in hazard ratio for cardiovascular disease; no evidence of a change in FEV1 between arms; no evidene of different in neuropsych testing results.

-       Bone mineral density testing showed total spine BMD decreased in immediate vs delayed ART – clinical implications unclear.

 

Chloe Orkin spoke about a couple of studies involving TAF – study 1089 involved switching from TDF to TAF in those virologically suppressed. n=663; all initially on TDF/FTC + 3^rd agent. Half had TDF switched to TAF.

-       No difference in rate of discontinuation or adverse events between arms.

-       No difference in efficacy at 96 weeks – TAF/FTC noninferior.

-       Average EGFR and BMD improved in TAF arm.

-       Slight increase in LDL/TC in TAF arm, but no change in total cholesterol:HDL ratio.

 

Finally Patrick Sullivan spoke about the importance of convenience in improving HIV care. He discussed strategies including:

-       Integration into routine clinical encounters

-       Self-service options

-       Home delivery of investigation/treatment/PrEP

-       Reminder systems for routine screening.

His team has developed a mobile app called Healthmindr (still under trial and only US-based I think) that helps with behaviour screening, PrEP assessment and advice and reminders about STI screens.

0 false 18 pt 18 pt 0 0 false false false

They’re also trialling STI testing and PrEP at home – involves initiation and follow-up to three months in the clinic, then visits and monitoring after that can be done at home (a kit is mailed and self-collected swabs/FCU/blood tests, as well as survey). Acceptability has been high and sample quality adequate.

Dr Laura Waters talk on HIV treatment cascade and other HIV population prevention/treatment issues.

 

2020 goals aiming for 90% of people with HIV diagnosed/90% diagnosed on treatment/90% on treatment undetectable - corresponds to 74% of those with HIV having undetectable viral load.

•  Currently (globally) only 32% of those with HIV are on treatment with undetectable VL.

 

June 2016 paper (Lazarus et al) on adding a “fourth 90” to the 90-90-90-90 targets; that 90% of those on ARVs with undetectable VL have good health-related quality-of-life. Especially pertinent considering incidence of co-morbidities and ageing HIV-infected population (in developed countries).

 

2016 research from Toronto (Wilton et al) on high-risk populations and perception of risk studied 420 MSM who were objectively high risk:

 

•       68.3% didn’t perceive themselves to be at moderate to high risk
•      23.6% unaware of PrEP
•      40.1% unwilling to use prep
•    47% lacked a family physician with whom they could discuss HIV issues

 

 

Survey of Glasgow2016 audience on new directions for treatment - 40% of attendees believe that non-oral ART will be first-line by 2026.

 

Transmitted drug resistance by geographical region (START trial) - Australia highest (17.5% had any transmitted drug resistance)

Talk by Professor Ian McGowan on long-acting ARVs (LAARVs).

 

-       Research from NYC (MSM) indicates high rates of willingness, and that a majority would prefer an injection.

-       Research from Africa (women) indicates that injection/implant/vaginal ring (as PrEP) would be preferred.

 

Current development of LAARVs is both for treatment and prevention.

 

Requirements for LAARVs as injection:

-       Infrequent dosing (every 2-3 months)

-       Practical injection volume (<4mL)

-       Doesn’t require cold-chain storage

 

Rilpivirine and cabotegravir most likely candidates of current generation of medications.

-       Have only been evaluated in the context of clinical trials (phase 1 and 2); adherence data likely to vary in the real world (and depending on whether being given as PrEP or treatment)

-       Tolerability good; patient satisfaction overall good

-       Efficacy signal in cabotegravir (animal studies)

-       Injection-site reactions reasonably frequent over time (highest at first injection)

-       Long-acting rilpirivine detectable in tissue (plasma/endocervical and vaginal fluid) up to >500 days (!) later – which is concerning for risk of resistance. Therefore cabotegravir more promising for use as long-acting PrEP (and phase 3 studies planned) – cabotegravir involves 4 week oral lead-in then Q8 weekly injection.

 

Novel NRTI “EFdA” also promising based on animal modelling; currently at phase 1 studies in humans. Animal models indicate that long-acting formulation could be effective up to 1yr.

 

As mentioned elsewhere – TAF silicone tubing implant and biodegradable implants both promising for use as PrEP.

 

Main challenges with LAARVs:

-       Safety (need oral lead-in)

-       Acceptability (needs real-world data)

-       Adherence

-       Resistance

-       Pharmacokinetics

-       Delivery