This was an interesting oral abstract session regarding community knowledge and approaches to pre-exposure prophylaxis.  PrEP was discussed in detail and covered topics like barriers to uptake of PrEP, preferences for prevention technologies, measuring adherence in PrEP users and how the health system and study designs of PrEP trials can facilitate rapid enrolment of those at high risk of HIV acquisition.

The first speaker was Adeline Bernier from France.  Although PrEP is already available in Norway and France through government subsidised programmes it has not been widely taken up in the rest of Europe.  She presented results from The Flash! PrEP in Europe (FPIE) online survey.  This was a community-based research study aiming to assess interest in and barriers to PrEP uptake amongst respondents from 11 European countries.  They found low knowledge of PrEP amongst at-risk groups, high interest in PrEP but low uptake.  Most commonly cited barrier to taking PrEP was fear of side effects.

Darrell Tan presented results from an MSM survey conducted with those undergoing routine HIV testing.  They asked questions regarding preferred method of PrEP delivery (oral, injectable, topical) and whether the reliability of different technologies would influence their decision on which method to use.   The results were many and varied.  Further analysis is required to understand what influences each individual’s preference for PrEP.

James Ayieko from Kenya presented results from the ongoing SEARCH trial, 18% of 4,064 participants took up the offer of PrEP within 30 days.  Participants’ perception of own risk did not always match that from a risk score.  This indicates further community-based education regarding risk is required for those considering PrEP.

Edwina Wright presented data from the Melbourne cohort of the PREPX trial. Recruitment to the PrEP trial was facilitated by a high community PrEP awareness and involvement of GPs and Pharmacists who were remunerated for their services.The high PrEP awareness in Australia contributed to the high enrolment of the ongoing PrEP study.

Rupa Patel presented data from a US study which found a good correlation between adherence measured by 3-month MPR (medication possession ratio) and 7-day self-report with TFV-DP (tenofovir diphosphate) blood levels in DBS (dried blood spot) of MSM taking daily oral PrEP.  The good correlation of the 3-month MPR and 7-day self-report with biological measures of adherence in PrEP users suggests that this could be ideal for measuring adherence in the clinic setting.

Hanne Zimmermann from the Netherlands presented data from a longitudinal semi-structured interview in MSM using PrEP.  This revealed that MSM switched between daily and event-driven PrEP use or even stopped PrEP based on their personal situation and risk exposure.  Individuals made decisions on PrEP use based on perception of their own risk.  The authors concluded that in order to successfully support future PrEP users, a tailored approach, addressing choices for PrEP regimens as a continuum of flexible and changeable choices, is essential.  Appropriate education would be an essential part of this strategy.

As if there weren’t enough treatments for Hepatitis C already, results of another Hepatitis C treatment trial were presented on Monday at IAS 2017.

Karine Lacombe of Saint-Antoine Hospital in Paris presented findings from AbbVie's phase 3 EXPEDITION-2 trial, which evaluated an 8-week regimen of glecaprevir/pibrentasvir for people with both HIV and hepatitis C.

Glecaprevir is an HCV NS3/4A protease inhibitor and pibrentasvir is an NS5A inhibitor. Both are pangenotypic, or active against all HCV genotypes. The two drugs have been co-formulated in a once-daily combination pill, to be marketed under the brand name Maviret.

Studies in the DAA era have shown that HIV-positive people generally do as well on interferon-free regimens as those without HIV – though it is important to take into account the potential for drug interactions between DAAs and antiretrovirals – and they are no longer considered a "special population." Yet European and US HCV treatment guidelines currently do not recommend shorter treatment for people with HIV and HCV co-infection.  A shorter course of treatment could potentially improve adherence and reduce cost.

EXPEDITION-2 enrolled 153 HIV-positive people with chronic hepatitis C in Europe, the United States and Russia. More than 80% were men and the median age was approximately 45 years. About two-thirds had HCV genotype 1 (mostly with harder-to-treat subtype 1a), followed by genotypes 3 (17%) and 4 (11%); a small number had genotypes 2 or 6.  People with Hep B co-inbfection were excluded.

Sixteen participants (10%) had liver cirrhosis, and most of the rest had absent or mild fibrosis. Nearly 20% were previously treated with interferon and ribavirin, and three had also used sofosbuvir (Sovaldi).  Study participants had well-controlled HIV infection with a median CD4 count of nearly 600 cells/mm³.  All but nine were on antiretroviral therapy, and about three-quarters of treated people were taking the integrase inhibitors raltegravir (Isentress) or dolutegravir (Tivicay), which were shown to have minimal interactions with glecaprevir and pibrentasvir.  They had variable backbones including TDF, FTC, TAF, lamivudine.  I’ve included the drug-drug interaction profiles out of interested, as presented at the session.

Participants without cirrhosis received glecaprevir/pibrentasvir for 8 weeks, while those with cirrhosis were treated for 12 weeks. Everyone received the study drugs and there was no placebo arm.

 Treatment was highly effective, with 98% having continued undetectable HCV RNA at 12 weeks post-treatment (SVR12). The cure rate rose to 99%, with no virological failures, for people without cirrhosis who were treated for 8 weeks.

A single patient with HCV genotype 3 and cirrhosis, who reported less than complete (85%) adherence, experienced virological failure during treatment. Another participant had missing data at 12 weeks post-treatment, but returned for care at 24 weeks post-treatment and was found to be cured.

 Glecaprevir/pibrentasvir was generally safe and well tolerated. Adverse events were similar to those seen in studies of HIV-negative people. One participant with cirrhosis stopped treatment early due to an adverse event that was not considered drug-related (stroke and brain haemorrhage). The most common adverse events were fatigue, nausea, headache, and nose and throat inflammation.

 "These results suggest that the glecaprevir/pibrentasvir regimen could be the first 8-week, pangenotypic treatment option for HCV/HIV-1 coinfected patients without cirrhosis," the researchers concluded.

This could be a bonus for co-infected patients but caution with drug-drug interactions is still an issue.  However, given the short duration of therapy these may or may not be significant.

This was an oral abstract session focusing on some novel approaches to HIV treatment and modifying treatment in special risk groups.

Jean-Michel Molina presented some switch data from the EMERALD study, a randomized (2:1), open-label, international, multicenter, parallel-group, non-inferiority, 48-week study.  Virologically suppressed individuals were switched from boosted-protease inhibitors (PI/r)+emtricitabine/TDF to darunavir/cobicistat/emtricitabine/tenofovir alafenamide (TAF).  This showed good virologic efficacy and better bone and renal profile at the wk24 interim analysis.

Jose Gatell presented data from an elegant study focused on virologically suppressed individuals with high cardiovascular risk.  They were aged 50 years or older and had Framingham cardiovascular risk greater than or equal to 10 percent.  They switched from PI/r-based to dolutegravir-based regimen and showed non-inferior virologic efficacy with improvements in lipid profile at wk48.  Other outcomes from this ongoing trial are awaited.

Laura Ciaffi showed data from a switching study.  After viral suppression with second-line PI/r+NRTIs, maintenance with PI/r+lamivudine showed virologic efficacy at wk 96 despite the presence of the M184V mutation.   This study was conducted in Africa.  This is an example of the increasing number of dual therapy studies presented at IAS this year.

Kathleen Squires presented data comparing a fixed dose combination of doravirine/lamivudine/TDF to efavirenz/emtricitabine/TDF in treatment-naïve adults with HIV-1 infection.  It showed non-inferiority at week 48 regardless of the baseline HIV RNA.  Doravirine also showed superior neuropsychiatric and lipid profile in these results of the Phase 3 DRIVE-AHEAD study.  A useful extension of this study would be a co-formulation of doravirine with FTC/TAF to reduce the renal and bone effects well known with TDF.

Micheal Aboud presented week 24 interim data from the DAWNING study.  This looked at individuals with first-line NNRTI-based regimen failure.  The superior efficacy of dolutegravir (DTG) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) compared with lopinavir/ritonavir (LPV/RTV) plus 2 NRTIs in second-line treatment was demonstrated.

Finally, Trevor Crowell presented data from a study using one of the newer approaches to HIV treatment, broadly neutralising antibodies.  In virologically suppressed individuals who initiated ART during acute HIV infection, VRC01 was well-tolerated.  However, VRC01 monotherapy was insufficient to maintain viral suppression.  This is an early setback but this will benefit future research in this area.  Broadly neutralising antibodies are being used in a growing area of research to assess alternative approaches to therapy besides daily oral therapy.  On a more reflective note, another theme from the conference this year was to start treatment as soon as possible to reduce the potential viral reservoir which we know is concentrated in lymphoid tissues.  This is likely to enhance prospects of cure or functional cure when future therapies become available.

IAS2017 Tuesday 11 am 25/7/2017

This session provided updates from various oral, topical and long-acting injectable PrEP clinical trials.

Sheena McCormack presented long-term PROUD study data from 2-4 years post enrolment.  This indicated that reduction in HIV incidence was sustained, and confirmed high adherence and durable effectiveness of PrEP in the study population.  However, as suspected rectal chlamydia and gonorrhoea and syphilis diagnoses remained high re-iterating the need for structured regular followup of these high risk patients.

A qualitative analysis exploring PrEP perceptions among PROUD participants, found that most viewed PrEP as a temporary HIV prevention option. Participants described psychosocial benefits in terms of reducing fear and providing relief when taking PrEP.  They didn’t discuss some of the stigma that still persists in the community about people who take oral PrEP however.  Acceptability seems to be increasing however.

Guillemette Antoni presented data from a double-blind, randomised sub-study of IPERGAY which found a significant reduction in HIV infection risk with on-demand TDF/FTC vs. placebo, in MSM having infrequent sex.  Oral PrEP with tenofovir/emtricitabine is now subsidised in France.

Sharon Hillier presented data from the completed FAME study.  This study found that FGT and plasma drug levels of dapirivine were not affected by Lactobacillus or G. vaginalis microbiome.  Tenofovir levels in FGT and plasma however are adversely affected by vaginal disbiosis (bacterial vaginosis). The potential influence of vaginal microbiome on topical and plasma PrEP drug levels emphasises the need for HIV prevention products that work in women with vaginal dysbiosis.

Ian McGowan from the USA presented data from the MWRI-01 multi-dose Phase I study.  They found long-acting IM rilpivirine to be safe. Drug accumulation was significant in plasma, rectal, and female genital tract (FGT) tissue.

Finally, Raphael Landovitz presented data from HPTN077, a double-blind, randomised, placebo-controlled tolerability and pharmacokinetics trial.  They found LA cabotegravir was well tolerated at 800mg/600mg doses in HIV-uninfected low-risk males and females.

Updated safety, acceptability and pharmacokinetic data on LA IM rilpivirine and cabotegravir provides hope for the viability of long-acting injectable PrEP formulations and circumvention of the adherence challenges associated with oral or topical PrEP.

IAS2017 11 am Monday 14/7/2017

This session was about emerging therapies for HIV and new approaches to specific patient populations.  The topics covered in this session included immunodeficiency at the time of ART initiation and the use of various ART combinations in different settings such as advanced immunodeficiency, second-line ART resistance and the use of novel 2 and 3 drugs combinations in ART-naive individuals.

The first speaker, Nanina Anderegg showed that median CD4 count at ART initiation was <350 cells/µL, with >25% of individuals at CD4 count <200 cells/µL, in low, middle and high income countries in 2015.They analysed data from the International epidemiology Databases to Evaluate AIDS (IeDEA) in sub-Saharan Africa, Latin America, Asia-Pacific and North America regions and from the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE). They included all HIV-positive adults (≥16 years) initiating cART between 2002 and 2015.  This demonstrated that a substantial number of individuals still initiated ART at advanced immunodeficiency. Additional efforts and resources are needed to improve testing coverage, linkage to care, and ART initiation globally.  There was a general trend to start ART at higher CD4 counts in the later years of the study though, which is encouraging.

Lelièvre found that the addition of maraviroc (MVC) to standard ART in advanced HIV infection had no impact on the risk of occurrence of infections, serious events and mortality, virological control or CD4 count recovery.  However, post hoc analysis showed a trend for a beneficial effect of the addition of MVC in the first 24 weeks in CD4 count recovery that disappeared thereafter.  Therefore miraviroc may be of some benefit in immune system reconstitution in early stages of therapy.

 Moh reported that in individuals failing second-line PI-based regimens, a phase of intense adherence reinforcement with HIV-RNA monitoring may help determine whether switching to a third-line regimen is required. 

 Joel Gallant showed that bictegravir/emtricitabine/tenofovir alafenamide was non-inferior to dolutegravir/abacavir/lamivudine in terms of virologic efficacy and was well tolerated. This was in treatment naïve subjects and their data extends to 48 weeks.  The single-tablet formulation bictegravir/emtricitabine/tenofovir alafenamide is potentially suited to the setting of same day/rapid ART initiation as it can be safe to start pending hepatitis B screening results, has high virological efficacy and favourable safety profile.  This study is ongoing.

In other treatment-naïve individuals, simplified combinations such as ritonavir-boosted darunavir/lamivudine was shown to be non-inferior to ritonavir-boosted darunavir/lamividuine/tenofovir in achieving HIV-RNA <400 copies/mL at week 24 as presented by Pedro Cahn.  Dolutegravir/lamivudine also demonstrated potent virologic efficacy at week 24 in individuals with entry HIV-RNA <500,000 copies/mL thanks to data presented by Babafemi Taiwo.  Early data suggest that simplified regimens consisting of ART with a high resistance barrier and lamivudine may be non-inferior in virologic control in treatment-naïve individuals. Data with larger sample sizes and longer follow-up are needed to confirm these findings.

This was a poster presentation session focussing on new drugs and new strategies for the treatment of people living with HIV.  I will focus on results relevant to MSM populations.  

The first presenter was from Thailand.  T. Bunupuradah reported on results from a trial comparing 200 mg of boosted atavanavir  to 300 mg of boosted atazanavir in virologic suppressed HIV-infected Thai adults.  This was a randomised, open-label trial.  He showed that the lower dose atazanavir is non-inferior in terms of efficacy.  There was higher discontinuation due to intolerance in the 300 mg group.  there is difficulty extrapolating these results to other ethnicities though due to possible weight and genetic differences.  These results could not be generalised to treatment naive or those failing first line therapy either.

The second speaker was Tony Mills from California.  He presented data from a switching study which is at the 48 week mark.  This study switched patients from a tenofovir disoproxil fumarate (TDF)-based regimen to a tenofovir alafenamide (TAF)-based regimen.  The results are very encouraging for improved bone mineral density on the TAF based regimen.  Before switching, patients were on elvitegravir, cobicistat, FTC and TDF (stribild), or efavirenz, FTC and TDF (atripla), or boosted atazanavir and truvada.  They all had eGFR greater than 50.  Then they were switched to elvitegravir, cobisitat, FTC and TAF or continued on their TDF-based regimen.  I think this study was flawed however, given that in some patients the tenofovir component was not the only part of the regimen which was switched.  This introduced a confounding factor into the analysis.  Nonetheless, there was a significant increase in bone mineral density in the TAF group compared to the TDF-based regimens.  The TAF group also maintained virologic suppression and showed a significant improvement in proteinuria and other markers of renal function Compared to the TDF group.

J. Gatell from Barcelona presented data on a new NNRTI doravirine at 100 mg once daily with a truvada backbone compared with  efavirenz and truvada.  The study authors saw a need for a new NNRTI given the CNS side effect profile of efavirenz.  It was a double-blind study in ART-naive patients with HIV-1.  At the 24 week mark, the doravirine group had less CNS adverse events than efavirenz.  Furthermore, doravirine demonstrates similar viral suppression to efavirenz at the 24 week mark.  This study is ongoing.

Finally, C. Hwang from BMS presented data on a second generation HIV-1 maturation inhibitor called BMS-955176.  This was used in combination with boosted or unboosted atazanavir.  The need for another class of drug is clear given treatment emergent or transmitted resistance.  Newer drugs with fewer adverse events and less DDI's are still needed.  Maturation inhibitors maybe beneficial in this context.  BMS-955176 inhibits the last protease cleavage event between capsid protein p24 and spacer peptide 1 in Gag, resulting in the release of immature, non-infectious virions.  The inclusion criteria of this study include HIV-1 subtype B-infected subjects.  They were treatment naive or treatment experienced patients.  It was conducted over a 28 day dosing period to asses the safety and tolerability of 176 and the change in plasma HIV RNA levels From baseline.  176 was generally wel tolerated with no SAEs or AEs leading to discontinuation.  It also resulted in very good virologic response compared to standard of care.  A phase 11b study is now underway in treatment experienced patients.

In this session, 4 different speakers discussed the chronic inflammatory state that persists despite effective viral suppression with current ART regimens.

The first speaker (G Marchetti, Milan) highlighted that there is a persistent depletion of CD 4 cells in the gut despite normalisation in the peripheral blood.  There is also persistent damage to the gut tight epithelial barrier despite ART.  The altered gut tight epithelial barrier maybe a driver of inflammation.  This speaker also highlighted the fact that no matter which ART regimen is employed there is a similar reduction of T cell activation with effective viral suppression. 

The second speaker (P. Hunt, San Francisco) focussed on immune activation as a predictor of morbidity/mortality during ART.  As we know,age associated morbidities are increased in treated HIV infection.  Inflammatory markers are higher in treated HIV disease compared with HIV sero-negatives when adjusted for demographics and CV risk factors.  Chronic immune activation may also cause lymphoid tissue fibrosis.  He showed a graph which demonstrated that a single measurement of IL 6 or D-dimmer predicts morbidity or mortality over the next decade.  This indicates that some people are more susceptible to the inflammatory state of HIV than others.  However, bio markers that predict disease most strongly are not necessarily the best interventional targets.

The third speaker (N. Sander, Texas) looked at the role of interferon 1 in chronic treated HIV.  A lot of the data was based on nonhuman models.  Overal, type 1 interferons can improve protection against infection but because of immune system activation may not be suitable long term as adjuvant therapy.  This raised the question of whether there maybe a benefit of selective activation or blockade of the different pathways induced by IFN-1.

Finally, I. Pandreas (Pittsburgh) discussed approaches to reduce microbial translocation as a means of reducing immune activation.  These were with sevelamer and rifaximin.  However, in the presence of profound gut damage, these approaches are unlikely to have significant benefit.  She then examined other interfering factors on gut function such alcohol and fatty diets.  These results were based on nonhuman models.  Probiotics were shown to have benefit for gastrointestinal immunity in SIV-infected macaques.  This highlighted that lifestyle factors should be taken into consideration when designing clinical trials as they may all impact on immune system activation.  This also highlighted that therapies which target the underlying cause of immune activation and inflammation may be more effective than those aiming at reducing various bio markers increased during HIV infection.

All of these presentations highlight how complex and confusing the immune activation and inflammation process is in HIV infection!