Is there a role for treatment intensification with Maraviroc in addition to a standard cART for naïve patients with low CD4 counts, and will it decrease the risk of progression to AIDS? (ANRS 146 – GeSIDA OPTIMAL)

There is no clinical evidence that of successful treatment intensification by the addition of a 4^th antiretroviral agent; despite numerous trials.

This double-blinded trial in France , Italy and Spain compared Maraviroc (+cART) to placebo (+cART).   Over 400 naïve, HIV-1 infected patients with an AIDS defining illness or CD4 cells < 200cell/mm^3 were enrolled.

The primary endpoint was the occurrence of a severe morbidity (AIDS, SNAE, IRIS, Death or other HIV related disease). Baseline characteristics were comparable.

In the 72-week follow up period; treatment intensification made no impact on the risk of infections, serious events, mortality, virilogic control or on CD4 count recovery. A post hoc analysis suggested Maraviroc might demonstate benefit on the occurrence of clinical events in the first 6 months of treatment, however this benefit “subsequently disappeared”.

Peripheral Arterial Disease. 

HIV infection and the risk of peripheral arterial disease; an observational, longitudinal cohort of HIV positive U.S. Veterans matched 1:2 with HIV- uninfected veterans matched for age, race, ethnicity and site.  The sample was greater than 90,000.

The investigator presented data from 7 years of observation of this very large cohort. The participants were followed for peripheral arterial disease (PAD), death or their last follow up date.

Cumulative incidence of PAD was calculated and adjusted for confounders. A regression model was used to examine the association between HIV positivity, CD4 count and PAD after adjusting atherosclerotic risk.

In this study, the HIV positive veterans had significantly higher rates of peripheral arterial disease when compared with HIV uninfected veterans.

The speaker encouraged checking for ankle/feet pulses as PAD is often not diagnosed – this seems like a extraordinarily simple ‘practice-changing’ intervention for primary care.

An absence of a pulse should prompt vascular referral. Smoking cessation obviously remains a vital health intervention. A low CD4 cell count was also a strong predictor of PAD, with almost a 2-fold increase in the risk. Importantly, a CD4 count of greater than 500 showed no increase in risk. Lipid lowering treatment will be part of a future analysis and was not examined in this paper.

Is “on-demand” PrEP a suitable tool for MSM who participate in Chemsex?  From ANRS-Ipergay.

This was in an IPERGAY sub-study of 331 participants during the open-label extension (OLE) phase of the study who reported drug use during at least one sexual encounter.

 2 monthly data was collected regarding drug and alcohol use, sexual behaviors and PrEP adherence during the participant’s most recent sexual encounter(s) and analyzed with a multivariate regression model. PrEP use was self-reported by participants.

Among the MSM participants, 29% reported Chemsex at least once during the follow up period and16% reported chemsex at all visits.

Socio-demographics between those labeled chemsexers were not different from those labeled non-chemsexers, other than a higher use of anxiolytics in chemsexers.

 After adjustment, chemsexers were found to be more likely to use PrEP (OR (95% CI = 2.18 (1.04; 4.49)) and less likely to use condoms (p< 0.001)

Of note, when MSM reported chemsex during their most recent sexual encounter there was a grater likelihood of receptive anal sex, hardcore sexual practices, casual sexual partnerships and a higher perception of risk. All p-values <0.001

This important and interesting sub-study suggests that PrEP may therefore be a suitable tool for HIV prevention people practicing chemsex.

Transactional sex in MSM: How common is it? Who does it? What are the risk factors?

This presentation looked a cohort of MSM from Vancouver. Canada, to examine prevalence, trends and risk factors of transactional sex and ultimately if transactional sex constitutes an increased risk of HIV transmission.

The study design was a prospective cohort study with respondent driven sampling of approximately 700 MSM aged over 16 years. 201 participants were HIV positive. Participants used a computer assisted questionnaire with the main outcome was an exchange of money/drugs/goods or services for sex. The data was analyzed with a multivariate logistic regression model.

Transactional sex was found to be rare in this cohort (between 1-3%).

Transactional sex was more likely with the following factors:

1) partner was met online

2) a lower incomes

3) a lower level of education

4) identification as bisexual

5) having an older sexual partner and

6) having a partner who uses either crystal methamphetamine, GBL or GBH

Partner substance use was most strongly associated with transactional sex, No significant associations with HIV risk behaviour.

A late breaker poster was presented Tuesday showing the 48 weeks data comparing Bictegravir co-formulated with FTC/TDF in a fixed dose combination (B/F/TAF) vs. DTG/F/TAF in treatment naïve HIV-1 positive adults. The study is phase 3 multi-centered RCT with a primary endpoint of HIV-1 RNA < 50 copies /mL at 48 weeks, powered for non-inferiority.

B/F/TAF was safe, well tolerated and non-inferior to DTG/F/TAF in treatment naïve adults. Discontinuations due to adverse events were uncommon in both arms . There was no evidence of treatment-emergent resistance to study medication. Interestingly there was less of a decrease in the e GFR observed in the B/F/TAF participants. No difference observed in lipids.  

On-demand oral TDF/FTC for PrEP: is it an option? 4 speakers put forward their argument for (and perhaps against) on demand PrEP. On-demand PrEP is an attractive and cost saving was of delivering PrEP but has only a limited number of studies to demonstrate its efficacy.

The first speaker presented strong evidence that both daily and multiple non-daily oral TDF/FTC were highly protective against the rectal and vaginal acquisition of SHIV in macaques. Various pre and post dose models were examined with “double” pre and post event dosing showing increased efficacy.

A pharmacologist followed up with a presentation demonstrating pharmacokinetic data that TDF/FTC reaches mucosal sites quickly, at appropriate concentrations and with a long enough “residence” to cover residual virus.

Bob Grant spoke following this about clinical experience of non-daily PrEP. Worldwide. Various non-daily PrEP studies (e.g. Holland, Montreal) show a significant cost saving as well as high patient satisfaction and preference. However, data from HPTN 067 showed fewer sex events were covered by non-daily PrEP use when compared with daily PrEP use.

The final speaker elaborated on the HPTN067 study. Non-daily PrEP regimens in this study were found to me more appropriate in participants who could adhere, had fewer sexual exposures and who could plan for sex.

There was a flavor of dual therapy around Mondays Plenary. An interesting study for Australian audience was the ACTG A5353 study which is a pilot study of Dolutegravir  + lamivudine for the initial treatment of HIV-1 infected individuals with viral loads of less than 500,000 copies/mL.  The 24 weeks data was presented using the FDA snapshot definition. There were 120 participants with no baseline resistance identified. There were no discontinuations. This regimen demonstrated potent virilogical efficacy at 24 weeks. 3 patients met the criteria for a protocol defined virilogical failure (PDVF), one had emergent M184V.

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The other interesting update was the 48 week data for Bictegravir(B)/F/TAF vs. ABC/DTG/3TC. This is a phase 3 RCT for treatment naïve adults. The primary endpoint HIV-1 RNA < 50 copies, powered for non-inferiority. B/F/TAF was non-inferior at 48 weeks. It was well tolerated and there were no adverse events leading to discontinuation. Nausea was significantly greater in patients taking ABC/DTG/3TC.  Gastrointestinal, Neuropsychiatric and sleep related problems were also more common in the ABC/DTG/3TC patients. Changes in BMD and renal function were comparable. The speaker felt that B/F/TAF was an “attractive” option for rapid commencement of antiretroviral therapy as no HLA status is needed and it could likely be commenced irrespective of Hepatitis B status and renal function.

Tuesday mornings Oral Abstract session was titled PreP: Demonstration for Implementation presented the initial findings from at least four studies into issues such as adherence and uptake. The studies examined some key affected populations. 

Of particular interest was an abstract from the U.S about PreP in Young MSM (YMSM) and transgendered women by the adolescent trials network (ATN) study 110. YMSM are at particularly high risk of HIV acquisition and remain relatively understudied with respect to PreP.

The ATN 110 study has some locally relevant points. 

ATN 110 was an open label study or once daily TDF/FTC across 12 U.S cities of men aged between 18-22. 

The primary objectives were to 

• provide additional safety data on FTC/TDF use in YMSM
• to examine the acceptability, patterns of use, rates of adherence and drug levels when YMSM are provided open label Truvada and 
• to examine patterns of sexual behaviour when YMSM are provided PreP

The 200 enrolled participants had self-reported high sexual risk in the last 6 months and were HIV negative. 

The mean age of participants was 20 years, 78% identified as gay, more than 80% reported condoles anal intercourse in the last six months, almost 60% receptive anal intercourse and 22% were positive for an STI at screening. More then 50% were black.

There were very few adverse events but 25 discontinued primarily due to personal choice or a self perceived change in their sexual risk.

Study participants were incentivised $25 per visit and had study visits at weeks 4,8,12; then three monthly. 

There were 4 seroconversions by week 48. All four had undetectable levels of Truvada, None of them had drug resistant virus.

Generally, participants reporting higher sexual risk had higher levels of Truvada. This remained consistent though to week 48. The mean number of parterns and condomless sex acts was mostly unchanged. STI rates remained as high as there were at baseline.

Notably, adherence decreased for all participants over the 48 weeks. Adherence appeared to decrease as the study visits decreased in frequency. Some qualitative research will be done some time in the future. This could infer that YMSM may need more rigorous follow up or an ‘enhanced visit schedule’

Wednesday’s Plenary will further examine PreP

Monday afternoon Bridging session: The present and future of combination prevent for HIV sexual transmission. 

Thanks to the ’How do you like your PreP’ session in the neighbouring room, this session was poorly attended but highly interesting and relevant.

Five speakers gave different perspectives on HIV prevention strategies amongst varying populations. 

The overarching message was about a paradigm shift in HIV prevention away from an ‘insufficient’ ‘condom protection (CP)’ based message to a more ‘realistic’, nuanced and individualistic combination-prevention model which should demonstrate flexibility and adhere to cultural and community ethics (a bit vague… but prioritise making the prevention relevant to the person/population you are treating) 

A stand-out and, perhaps, more locally relevant talk was  given by Andrew Grulich. 

He specifically discussed the combination prevention strategies ‘TasP’ and ‘PreP’  in MSM. 

He reminded the audience that HPTN 052 included only 2% MSM and there are yet to be ‘published’ findings on ‘TasP’ in sero-different MSM couples. Despite this, in HPTN 052, no index-to-partner transmissions were observed if viral suppression was achieved. 

The “PARTNER” study and “Opposites Attract” will ultimately aim to quantify this in MSM and the preliminary results appear at least as promising as HPTN 052 (zero linked transmissions to date in Opposites Attract).

PreP however has clearly demonstrated very high efficacy in MSM in iPrex, PROUD and Ipergay. Andrew proposed PreP as being a ‘missing link’ in the combination prevention intervention strategies and highlighted this with an example of new HIV diagnoses across three comparable MSM populations in Sydney, London and San Francisco. PreP is readily accessible in SF and less readily available as a prevention strategy in Sydney and London. 

Whilst the number of HIV diagnoses may not necessarily represent a true increase in HIV incidence, San Francisco is the only setting to see a substantial decline in HIV since the introduction of PreP. 

This decrease is  despite increasing rates of condomless anal intercourse in MSM and increasing rates of and STIs in San Francisco compared with Sydney and London. 

HIV in vulnerable populations and within a public health framework. 

Monday’s Plenary included a session on co-morbidities in children and adolescents by Thanyawee Puthanakit. 

She detailed some important paediatric aspects to HIV care. Eventually these children 'graduate' to adult services thus appreciating the unique commodities in this population is important to all providers of HIV care. 

In addition to the co-morbidities seen in an adult population, children living with HIV are more likely to have delayed puberty/growth, have persistent proteinuria and tubular dysfunction, have impaired peak bone mass and low bone mineral density and suffer dyslipidaemia. 

Not surprisingly, there is a significant reduction in the risk of developing co-morbidites when commenced on HAART. This echoes the findings of START which, while it did not focus on a paediatric population, demonstrated a clear benefit to early commencement of HAART.

Of note, dyslipidaemia occurred in  approximately 22% of children and adolescents with a lack of clinical trial data that demonstrated benefits from statin use. In any case, the threshold at which to treat an adolescent remains undefined. The rates of cardiomyopathy, nephropathy, cognitive impairment and chronic lung disease are all reduced in paediatric populations that are on HAART.

Paediatric guidelines for ART are evolving somewhat like adult guidelines. The DHHS recommends integrase-based regimens with Raltegravir approved for age >2 and Dolutegravir age>12. There is no evidence yet for the use of TAF in a paediatric population. 

The barriers to optimising outcomes within the paediatric population are more evident in resource limited settings, where children and adolescents are more likely to be under-screened for HIV co-morbidities.  

The speaker alluded to 2 trials of interest 

1. ODYSSEY. Dolutergravir+2NRTIs vs standard of Care. This is an RCT of DTG based ART vs SOC in Children with HIV starting first line treatment or switching to second-line
2. IMPAACT P1093: investigating Dolutegravir use in children aged 6-12