The first day of the HIV Drug Therapy conference in Glasgow today featured presentations and panel discussions of a number of complex clinical cases focussing on antiretroviral treatment choices in the context of other comorbidities, particularly Hepatitis C infection. 

Dr Alessia Dalla Pria from Chelsea and Westminster Hospital presented the case of a male patient with HIV-associated B cell lymphoma infiltrating the liver, complicated by HCV-related cirrhosis and acute renal insufficiency.  The timing of treatment of both the lymphoma and Hepatitis C infection was discussed, with the two conditions in this case being treated concurrently.  The take-home messages: it is important to consider not only CYP3A4 drug-drug interactions, but also P-glycoprotein P and other trans-membrane transporters in considering DDIs, as the concentration of R-CHOP chemotherapy can be increased by Hep C treatment leading to increased toxicity.  Interferon and Ribavirin are also contraindicated during cancer treatment due to overlap toxicity with chemotherapy and the unknown effects of interferon on lymphoproliferative disorders.  Protease inhibitors shouldn't be used in patients with Child-Pugh B or C decompensated cirrhosis.

The differences in rates of diagnosis of HIV, linkage to care, retention in care, appropriate ARV treatment and successful viral suppression (the HIV care cascade) in Italy, the USA and the UK were highlighted by Dr Cristina Mussini from the University of Modena.  The rates in the USA were surprisingly poor relative to those of Italy and the UK, with a large percentage of HIV positive people being lost to follow-up, emphasising the importance of universal health care in improving accessibility of HIV treatment and management of the HIV epidemic.  

In a study of the HIV care cascade among 12 infectious diseases clinics in Italy in 2013, approximately 7-9% of patients were lost in each successive column of the care cascade, prompting discussion on how retention in care can be optimised - in particular, clinic protocols for systematically monitoring retention rates and contacting patients who don’t attend planned reviews.  A study done at Chelsea and Westminster Hospital in 2011 showed that of patients presenting late with opportunistic infections, 62% had had a positive HIV test previously but had failed to be retained in care. 

Dr Laura Waters reported on a study conducted in the USA using point-of-care HIV tests administered in pharmacies in the community.  Of 1000 tests done, 1.5% had a positive result, at an overall cost per positive test (new diagnosis of HIV) of around $30.  This may be a potentially cost-effective approach to improving access to HIV testing if high-risk groups are targeted.

Linda-Gail Bekker from the Desmond Tutu HIV Centre in Cape Town talked about a study currently underway of the use of PrEP in 300 female sex workers in South Africa.  She reported that between 45 and 70% of female sex workers in the region are HIV positive, making this a particularly vulnerable group.  Elsewhere it was reported that non-oral forms of PrEP (such as injection, implant or ring, if available) would be preferred by 55% of African women due in part to the stigma associated with taking anti-retroviral medication.

Today there were a few other abstracts presented about Prep.

A Siegler presented a demonstration project about a home testing system for Prep in the US. This involved sending out kits for STI testing and taking a few drops of blood for tests as wel as a questionnaire. Interesting idea- parts of which might be useful for future planning of Prep systems. 

P-C Crouch presented a San Francisco implementation of non-physician based Prep program using nurse and peer support volunteers. This has been successful in delivering Prep to a lot of people there. Again, food for thought about how we may be able to do things differently, even though their model is really in response to the barriers in their health system which are different in Australia. Since November 2014, they have screened over 1250 people with 95.5% enrolment and 71% retention and no HIV seroconversions.

I Zablotska presented details of the EPIC- NSW Prep implementation - good to see this being presented on a world stage and we all await the results of this and the other state based programs.

R Heffron presented data about renal screening- comparing the 3 months screening in the Partner Prep study to the Partner demonstration project whi did it six-monthly. There showed no difference between the two, so it supported the US CDC guidelines of six month renal screening being recommended.

All in all, some things to think about as we use more Prep.

At the Prep symposia yesterday, here was discussion about microbicides research- which agents to use and wil there be a need with oral Prep proven effective, the long acting injectables and infuseable (VRC01) agents as a possible for the future, It was also mentioned the research around rectal microbicides, suppository being investigated, the idea of a douche that might deliver the agent and ongoing research in vaginal rings.

Overall a very informative an interesting conference- the best I have been to. There is a sense that the world is coming together demanding the best treatment and access for all. The program's being rolled out in developing countries can be very impressive which should inspire us to reach and exceed the 90-90-90 targets.

J-M Molina this morning presented the Ipergay extension study results. Participants of Ipergay were offered to go onto an open label extension study to remain on episodic use of Prep. Ipergay was the placebo controlled study of use of truvada 2-24 hours before and 24 and 48 hours after sex as Prep. Some new participants were also enrolled. There were 362 participants. There was 1 HIV seroconversion in a person who was not taking the Prep. The mean pills per month taken was 18, There was no significant increase in number of sexual partners. Self-reported adherence was slightly improved. There was a significant reduction in comdomless receptive anal sex, but the STI rate remianed the same. 

This study is very assuring for us in Australia as there are several such programmes that either have or about to begin. It is good to know that we should expect high levels of risk reduction with Prep, even though there is still active debate about episodic vs daily Prep. It would appear that episodic Prep is also very effective.

There were also many posters on Prep displayed today. INterestingly, there was a study from Amsterdam comparing acceptability of episodic versus daily Prep. 73% of participants preferred daily Prep. These men tended to be younge and had more sex. 

I think it would be good to have both options but I suppose patients may do it anyway.

Another poster from Thailand using Prep in MSM found it feasible as they were able to deliver Prep for USD1- which includes cost of their generic drug and associated services. I am to sure if this was a daily cost or per visit cost.

Many Prep posters about acceptability in many settings around the world- some in MSM, some in young females, some about newer topical methods, All ver promising for the future and nice to see many places taking Prep seriously as a method of eliminating new HIV infections

several prep presentations on Tuesday covering different aspects of prep.

Brocca-Cofano presented a study about using maraviroc on infant macaques as prep. The conclusion was that it offered no protection from SIV in infant macaques. This may be different in human populations.

Gulick then presented a phase II study on maraviroc tolerability in US women. There were 188 women in the study, 160 completed. This was a four arm double blind study comparing maraviroc, maraviroc + TDF , maraviroc + FTC , and TDF + FTC . This was a purely safety and tolerability study over 48 weeks and there was shown to be no difference between the four arms.

McGowan presented a study about the persistence of Rilpivirine after a single long acting injection. N=36, they compared plasma and genital fluid and rectal fluid  and compared either single dose, 600 or 1200mg vs 1200 every two months. In 7/7 of the participants who had 1200mg im single dose, there was Rilpivirine present in their genital fluid and plasma after 18 months. This raises issues about he use of this as prep due to concerns about development of resistance due to this long residual level of Rilpivirine . 

Grant presented a study about the benefits of prep relative to drug resistance. They showed that across all prep studies, the risk of drug resistance was very low 0.05% risk. Most of the resistance occurred in people who were HIV infected at entry into the trial. They concluded that the benefit of prep far outweighed the low risk of drug resistance. As this occurred mainly at the start of prep, it was important to exclude anyone who might have and acute vital illness from starting prep to ensure that it was not a HIV infection. It was also suggested that it might be important to do HIV Ag testing or dna before commencing prep.

Brown presented an interesting study about the use of dapavirine vaginal rings from the aspire study. The level of drug level in the ring after use gave an idea about adherence levels. After some stratification, they found that in the moderate to high adherence women, the risk reduction improved from 27% to 56-75% risk reduction.

late breakers

hosek presented data about the safety of prep in 15-17 yo msm in the US. The numbers were small -60 due to recruitemnt and consent issues but the conclusion was that it was are to use with no real differences. There is the bone data presented in the past that still needs clarification.

Rawlings presented data on prep use in the US between 2013-2015. This data was collected from prescription data with PEP and treatment prescriptions excluded. Almost 80,000 people used prep in this period, with a significant increase in men using prep in the last two years. The study also looked at seroconversion rates across multiple prep studies. They had about 8,500 participants and there was  a seroconversion rate of 1.03% in men, 0.25% in women.

The theme of access equality rights now is palpable. There is a mood of activism to overcome these barriers in HIV . Quite exciting to be around!

Five of 404 men who have sex with men (MSM) or transgender women taking a maraviroc-containing preexposure prophylaxis (PrEP) regimen or tenofovir/emtricitabine (TDF/FTC) picked up HIV infection in the 48-week HPTN 069/ACTG A5305 trial [1]. All infected men had no, low, or variable drug levels at HIV seroconversion. But results of a substudy suggested maraviroc alone may be less potent than maraviroc/TDF or maraviroc/FTC [2]. 
 
Maraviroc is a reasonable PrEP candidate because it concentrates in the genital tract and rectum and can be taken once daily. To explore maraviroc's potential as PrEP alone or with TDF or FTC, HPTN and ACTG collaborators recruited HIV-negative men or transgender women who did not inject drugs and who had condom-free anal sex with one or more HIV-positive or serostatus-unknown men in the past 90 days. The researchers randomized them to 48 weeks of maraviroc alone, maraviroc/FTC, maraviroc/TDF, or TDF/FTC, all once daily. Thus each man took 3 pills daily (including matching placebo).
 
The trial enrolled 406 people, all male at birth and 7 (2%) transgender women. Median age stood at 30 years and ranged from 18 to 70. Of the 406 people randomized, 404 started study drugs and 340 (84%) completed the study. Thirty-seven participants (9%) stopped study drugs early, with no differences by study arm. Time to permanent drug discontinuation did not differ between arms. Analysis of 18 men per study arm showed that TDF or FTC did not affect maraviroc concentrations. In a random subset of 160 participants, all drugs could be detected in 83% of participants at week 24 and 77% at week 48, with no difference between arms.
 
Ninety men (22%) had 115 sexually transmitted infections diagnosed during follow-up, a finding indicating a high rate of continuing sex. Five men became infected during follow-up for an annual incidence of 1.4% (95% confidence interval 0.8% to 2.3%). Four were taking maraviroc alone and one was taking maraviroc/TDF.(The study was not powered to evaluate efficacy.)
 
At HIV seroconversion, the man taking maraviroc/TDF had undetectable levels of both drugs. One man on maraviroc alone had no detectable maraviroc at seroconversion, while the other three had levels of 0.7, 6.7, and 145 ng/mL. The expected predose maraviroc level is 32 ng/mL, so only one man had good maraviroc levels at seroconversion. But in all 3 men with detectable maraviroc at seroconversion, levels were highly variable throughout the study, indicating off-and-on PrEP use. All 5 men got infected with virus using the R5 receptor (which maraviroc blocks) and none had genotypic resistance to maraviroc.
 
The HPTN/ACTG team proposed that "maraviroc-containing regimens should be considered for testing in clinical efficacy trials." Whether to go ahead with solo maraviroc or maraviroc plus TDF remains an open question. A substudy in which researchers tested the four regimens in colorectal tissue explants of 55 study participants found significantly less viral suppression with maraviroc alone than with the three combination regimens [2]. But the HPTN/ACTG team noted that they have yet to correlate those results with pharmacokinetic adherence data. Also, the same regimens are being tested in women, so decisions on future trials must await those results.

Take home message: Maraviroc is a promising alternative oral HIV PrEP agent but research is still at very early stages.

References
1. Gulick R, Wilkin TJ, Chen Y, et al. HPTN 069/ACTG 5305: phase II study of maraviroc-based regimens for HIV PrEP in MSM. Conference on Retroviruses and Opportunistic Infections (CROI), February 22-25, 2016, Boston. Abstract 103

2. McGowan I, Nikiforov A, Young A, et al. PrEP impact on T-cell activation and explant infection: HPTN 069/ACTG 5305 substudy. Conference on Retroviruses and Opportunistic Infections (CROI), February 22-25, 2016, Boston. Abstract 104.