The Treatment Evolution: New Drugs, New Reality session on Thursday afternoon was the most important session so far at the conference from the point of view of therapeutics.  Of great interest was the 48 week data for injectable cabotegravir + rilpivirine.

At this session the 48 week results for the ‘Cabotegravir + rilpivirine as long-acting maintenance therapy: LATTE‑2 week 48 results’ were presented by David Margolis (THAB0206LB).    This phase 2b study compared 4 week and 8 week injections vs oral therapy (CAB + ABC/3TC) to maintain viral suppression of HIV-1.

 309 patients ART-naïve HIV infected adults were treated during the 20 week induction period to reach a RNA< 50 c/mL with daily oral CAB 30 mg + ABC/3TC then were  randomized 2:2:1 to IM CAB LA + RPV LA every 4 weeks (Q4W), every 8 weeks (Q8W), or oral CAB + ABC/3TC (PO) in the Maintenance Period (MP).

 Key findings from this study were 

-          At Week 48, 92% (Q8W), 91% (Q4W), and 89% (PO) remained suppressed (ITT).  

-          More patients on Q8W (5%) than Q4W (< 1%) and PO (0%) had HIV-1 RNA >50 c/mL at Week 48. 

-          There were more discontinuations in Q8W (8%) and PO (9%) arms versus Q4W arm (1%).   

-          Injection sited reactions were common but resulted in < 1% withdrawal.  

-          Three subjects met criteria for viral failure during maintenance, one Q8W subject with emergent RPV and CAB resistance

 Q4W dosing resulted in lower rates of virologic non-response than Q8W so was selected for progression into phase 3 studies.  This treatment appears to be very effective and safe.   Questions remain about the acceptability of monthly injections in various clinical settings but this is a potentially the beginning of a whole new approach to HIV therapy.

Catherine Orrell  presented ‘Superior efficacy of dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) fixed dose combination (FDC) compared with ritonavir (RTV) boosted atazanavir (ATV) plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in treatment-naïve women with HIV-1 infection (ARIA Study)’.   (THAB0205LB) DTG/ABC/3TC was superior to ATV+RTV+FTC/TDF, with 82% and 71%, respectively, achieving HIV-1 RNA < 50 c/mL at Week 48.

Differences were driven by lower rates of both discontinuations due to adverse events (AEs) and virologic failures in the DTG/ABC/3TC group.  Of six DTG/ABC/3TC subjects who met protocol-defined virologic withdrawal criteria, none had resistance mutations, compared with 4 ATV+RTV+TDF/FTC subjects who met virologic withdrawal criteria of which one had an NRTI mutation, M184M/I/V. This study was very important in that it showed superiority and was female only.

Jean-Michel Molina  presented ‘Who benefited most from immediate treatment in START? A subgroup analysis’ (THAB0201).  In asymptomatic ART-naïve adults with >500 CD4 cells/mm³, immediate ART was superior to deferral across all subgroups.  People > 50, higher plasma HIV RNA level, lower baseline CD4 count, and higher Framingham risk had the greatest benefit.

Alejandro Arenas-Pinto presented ‘Increased risk of suicidal behaviour with use of efavirenz: results from the START trial’ (THAB0202). These findings suggest that participants using EFV in the immediate ART group had an increased risk of suicidal behaviour compared to ART-naïve controls. A prior psychiatric diagnosis increased the risk.

Michael Aboud  presented ‘STRIIVING: switching to abacavir/dolutegravir/lamivudine fixed dose combination (ABC/DTG/3TC FDC) from a PI, INI or NNRTI based regimen maintains HIV suppression at week 48’ (THAB0203).  Treatment experienced patients were randomized to continue current ART on Day 1 or switched to ABC/DTG/3TC.  The current treatment arm then switched at week 24.   In this switch arm 92% maintained viral suppression at 48 weeks (note the 24 week data has previously been presented).

Of the plenary session today what really stood out was Anton Pozniaks session ‘TB and Co-infections: the long game.  During the session he reminded us that TB is now the leading cause of death for people living with HIV.  He detailed steps to disease elimination for TB, hepatitis B and C – a very long game indeed.

In ‘The Living with HIV: Long-Term Effects’ Amanda Mocroft (PDB0101) examined renal function in patients in the START study.  eGFR was significantly lower in the deferred arm versus the immediate treatment arm. This finding reached significance in the non-adjusted analysis despite the use of potentially nephrotoxic drugs such as tenofovir.  Yet another reason to start ART early.

PrEP has been a major theme at this conference.  More good news was provided by Jean-Michel Molinain the extension arm of the Ipergay study  (WEAC0102).   This study used intermittent PrEP and previously reported the high efficacy of PrEP with TDF/FTC taken ‘on demand’ in high risk MSM – an 86% relative reduction in HIV-incidence in the TDF/FTC arm vs Placebo (95% CI: 40-98, P=0.002).  All participants were offered open-label TDF/FTC.  During 515 person-years only 1 HIV infection occurred giving a risk of HIV of 0.19 (0.01-1.08) per 100 per year.  This patient reported that he had ceased PrEP.

 Also continuing good news for HIV/HCV co-infection.  In the ‘Bad Bugs’ session Norbert Bräu  (WEAB0301) presented the results of the ASTRAL-5 study Sofosbuvir/velpatasvir was given for 12 weeks to 106 patients.  The genotype distribution was 62% GT1a, 11% GT1b, 10% GT2, 11% GT3, and 5% GT4. No patient experienced confirmed HIV virologic rebound (HIV-1 RNA ≥400 copies/mL).  SVR rates were 95% overall, and 100% with cirrhosis and 97% the previously treated.

As this combination will be widely used in Australia the next session was very relevant. AnnieLuetkemeyer (WEAB0302)  presented ‘Drug-drug interactions studies between HCV antivirals sofosbuvir/velpatasvir and HIV antiretrovirals’.  This was a Phase 1 study conducted in healthy volunteers to evaluate potential drug-drug interactions (DDIs) between SOF/VEL and HIV antiretroviral (ARV).

-       Increased TFV exposure (~40%) was observed with SOF/VEL when administered as TDF

-       Decreased velpatasvir (53%) when given with efavirenz

The author concluded that all study combinations could be used except efavirenz-containing ART.  This is an important finding given the number of patients taking Atripla.

And for the rare patients who does not achieve SVR with DAA therapy with sofosbuvir/ledipasvir (Harvoni)?  Well they can be retreated with…. Harvoni for 6 months combined with ribavirin.   Annie Luetkemeyer  (WEPEB060) presented data on 9 HIV/HCV who had not cleared with 12 weeks of Harvoni who were then retreated with 8/9 achieving a SVR.

Day 1 plenaries continued the themes from the opening ceremony with great presentations on the epidemiology of the HIV pandemic from Steffanie Strathdee.  Alex Coutinho presented data on Universal Access, the stage beyond the 90:90:90 target set by WHO.  Some countries in Africa appear to be close to passing these benchmarks include Rwanda and Swaziland.  There were few dry eyes at the conference as Edwin Cameron, a South African judge described his life living openly as a HIV positive gay man since 1986.  He introduced his godson who has been living with HIV since his birth 22 years.

A Clinical highlight of the morning was the PrEP:New Drugs session.  Robert Grant (TUAC01) reviewed the risk of drug resistance versus the benefit of HIV prevention across 6 randomized clinical trials and one demonstration project. This study was of great interest to those doctors involved in PrEP studies in Australia so the take home messages are:

1)    FTC resistance occurred in 10 who received FTC/TDF PrEP, including 33% (5/15) with acute infection when starting PrEP, and in 3% (5/157) with established infection. 98 infections were prevented giving 10 (98/10) infections prevented for every FTC resistant infection.

2)    Tenofovir resistance occurred in 1 who received TDF PrEP, including 10% (1/10) with acute infection when starting PrEP, and none (of 90) with established infection. 53 infections were prevented by TDF PrEP giving 1 (53/1) infection prevented for every tenofovir resistant infection

3)    A screen for acute viral symptoms in PrEP assessments led to deferral of PrEP among 30 of 1603 (1.9%) of whom 2 (6.7%) were found to have acute HIV.  No acute infections were missed using this screen.

At the Late Breaker session K Rawlings presented data on the uptake of PrEP in the USA with almost 80 000 people started PrEP in the USA to end of 2915, 76% are men.  No data was available on longer term use of PrEP.

The highlight of the ‘Cancer and HIV’ program was a presentation by Andrew Grulich from Kirby Anal cancer in people with HIV  (TUSY0803).

To summarise.  Historically anal cancer is the third most common cancer in HIV +ve males after KS and lymphoma. In heterosexual males it is 10 x more common, in gay males it is 50 X more common than the general population with an incidence of up to 100 / 100  000. Following ART and CD4 recovery there has been a rapid decline in KS and lymphoma but only a slight decline in anal cancer incidence which remains high even with normal CD4.

In terms of primary prevention HPV vaccination results in a 75% reduction in high grade disease in young gay men but preliminary data did not show that it was effective in males older than 26 although further studies are needed.

In terms of secondary prevention – screening and treatment is complicated by the 75% prevalence of high risk virus with 30 – 40% high grade disease but there appears to be less progression to cancer compared with cervical disease.   Treatment pathways are currently uncertain. In comparison to colposcopy anosocpy requires much more training.

In terms of tertiary prevention detection of anal cancer remains controversial with some recommendations to perform annual PR examinations

In the epidemiology session Alison Rodger presented results from the PARTNER (TUAC0206).  This prospective, observational study enrolled 1166 HIV sero-discordant couples who reported condomless sex and HIV-1 RNA load suppressed to less than 200 copies/mL.  1166 enrolled couples, 548 heterosexual and 340 MSM provided had a median follow-up of 1.3 years. No HIV transmissions occurred within the studied couples.  11 infections occurred from ‘unlinked’ partners. This gave rate of within-couple HIV transmission of zero with upper 95% confidence limit of 0.30/100 couple-years, and for condomless anal sex 95% CI of 0.71 per 100 couple-years of follow-up. These results are very encouraging in terms of the tremendous value of treatment as prevention.

Tonight was a very moving opening ceremony for opening of the 21 st International AIDS conference.  Many speakers made reference to the World AIDS meeting in 2000 and the great achievements of the last 16 years.  From almost no access to treatment in Africa then, now more than 12 million people are receiving ART. 

Today is also the birthday of Nelson Mandela.  At the 2000 meeting he famously said "AIDS is caused by HIV".   Leading up to the 2000 conference and at the opening the then president of South Africa, Thabo Mbeki, denied the role of HIV as the cause of AIDS.

I attended the 2000 meeting so it is exciting to be back in Durban. I am very much looking forward to reporting on new developments in HIV and HIV/HCV co-infection.

But I will leave it to Charlize Theron.  Talking about a cure for HIV she said ".... we have to stop meeting like this..."

Protease inhibitors are known to increase plasma concentrations of inhaled fluticasone, resulting in secondary adrenal insufficiency. Two papers 810 and 811 reported on the safety of the inhaled steroid, beclomethasone dipropionate (BDP) with ritonavir (RTV) or darunavir/ritonavir (DRV/r).

Paper 810 was an open-label, prospective, randomized study to determine whether inhaled BDP when combined with ritonavir (RTV) or darunavir/ritonavir (DRV/r) significantly influences adrenal function in HIV^– healthy volunteers.  Combined use of BDP and RTV or DRV/r for 28 days did not cause significant adrenal suppression in healthy volunteers.

Paper 811 from the same study found that  DRV/r does not significantly increase the AUC of 17-BMP, while RTV alone produces a statistically significant (p .05)—but clinically inconsequential—2-fold increase in 17-BMP exposure.

In summary patients receiving PIs and requiring an inhaled corticosteroid inhaled BDP is preferable to fluticasone.

Herpes zoster is a common condition especially in our aging cohort.  There is limited information about the use of HZ vaccine in this group.  Paper 96 presented results from a randomised, double-blind, placebo-controlled trial assessing safety and immunogenicity of 2 doses of ZV in HIV⁺ adults ≥18 years old (CD4 >200 copies/µL; HIV RNA  Preliminary data suggest that the vaccine is generally safe, and immunogenic. Further data from this study is awaited.

Chaiklang et al conducted a randomized trial in Thailand, in 132 HIV+ adults who were HBV– and had CD4 cell count of >200 cells/μL and undetectable viral load of 3 different hepatitis B vaccine schedules.

Patients were 1:1:1 randomly assigned to receive a standard vaccination (20 μg intramuscularly at month 0, 1, and 6 or 20 μg IM at month 0, 1, 2, and 6 or 40 μg IM at month 0, 1, 2, and 6. .Responders were patients who had hepatitis B surface antibody (anti-HBs) of at least 10 mIU/mL) at month 7.

The percentage of responders at month 7 was 88.6 in the IM 20x3 group, 93.2 in the IM 20x4 group (p = 0.458 vs IM 20x3 group), and 95.5% in the IM 40x4 group (p = 0.237 vs IM 20x3 group).

The standard HBV vaccination in HIV+ adults with CD4 cell counts >200 cells/μL and undetectable viral load is highly effective. Regimens of 4 injections of either standard or double doses may increase the response rate and induce higher level of protective antibody.

Session 26 on Wednesday was " State of ART and drug resistance” did not launch any new blockbuster antiretroviral – unlike some previous World AIDS or CROIs. However there was the first phase 3 results presented for QUAD.

Paper 101 is a 48 week phase 3 data on QUAD – Elvitegravir/Cobicistat/Emtricitabine/Tenofovir (trying saying that after 3 Seattle micro-brewery Pale Ales) versus Atripla involving 700 treatment naive patients. Quad was non-inferior to EFV/FTC/TDF with 88% and 84%, respectively, having viral suppression at week 48. Virologic failure rates at week 48 were 7% in both arms. Of AE occurring in ≥10% of subjects nausea was significantly more frequent in Quad than EFV/FTC/TDF, while dizziness, abnormal dreams, insomnia and rash were significantly less common in Quad than EFV/FTC/TDF. Of note creatinine clearance decrease was significantly greater than with EFV/FTC/TDF (–14.3 vs –3.0 mL/min by week 48).

A parallel phase 3 study is to be presented on Thursday (627) with the comparator arm being booster atavanavir /FTC/TDF in 708 treatment naive patients. Quad was non-inferior to EFV/FTC/TDF with 90% and 87% respectively, having viral suppression at week 48. Virologic failure rates at week 48 were 5% in both arms. Of AE occurring in ≥10% of subjects elevated bilirubin was significantly more frequent in the atavanavir arm. Of note creatinine clearance decrease was significantly greater than with the atavanavir arm (–12.7 vs –9.5 mL/min by week 48).

So in summary QUAD is a highly effective new STR (single tablet regimen) for HIV therapy. A concern is the decline in renal function with QUAD found in both studies which remains to be fully explained.

CROI 2012 is huge with more than 1000 abstracts to digest and multiple parallel sessions.

Highlights of Tuesday6 March were plenary sessions.

ART for Prevention by Wafaa El-Sadr.

Followed by Michael Emerman with a fascinating update on HIV, SIV and human evolution. 

Full coverage of these presentations is avaiable at http://retroconference.org

Great to get here and away from wet, wet, wet Sydney. I am starting my blog in front on the most dangerous wall in North America.

 A wall of gum under the Pike Street market - yes it has become a tourist attraction along with the first Starbucks around the corner.

Pike Street market has everything that Seattle is famous for - seafood, bars, coffee and of course my favorite cocktail...

Will try to bring you the most relevent primary care items from the conference. And maybe one or two tips from the bartenders of Downtown...