It's official: there has been an HIV Neurology spring uprising in Seattle. This conference saw over 60 posters, two themed discussions, an oral abstract session and a presentation on HIV neurology in the closing clinical session- all devoted to HIV neurology. Early CNS infection, screening for HAND, Aging and neurocognitive impairment, identifying biomarkers in plasma and CSF for HAND diagnosis, neuroimaging studies and HAND in longterm virologically suppressed populations were the key themes. The two leading topics in HIV neurology at the moment are (1) whether high CNS penetrating regimens are superior to low penetrating regimens for patients with HAND and (2) whether asymptomatic neurocognitive impairment (ANI) leads to more severe symptomatic HAND. The latter was in a presentation from the CHARTER group (Poster 77) wherein patients with ANI and the symptomatic minor neurocognitive disorder (MND) were likelier to have neurocognitive decline over 36 months than neurocognitively normal controls. Not all patients with ANI/MND were virologically suppressed. Given that ANI is the commonest form of HAND in our populations, if it is shown to lead to MND or HIV dementia this will be a finding of import at a patient and population health level. Abstracts came from a number of groups including Alan Winston's group at Imperial College London, Johns Hopkins, (Justin McArthur) the CHARTER group, the Belgian group led by Bernard Du Pasquier, Serena Spudich's group at Yale, Richard Price from UCSF, Magnus Gisslen from Gothenberg, Beau Ance's group from Washington University, Lucette Cysique and Bruce Brew from Sydney, UNSW, Victor Valcour (UCSF) and Brad Navia from Tufts. It was an enjoyable meeting but, as always, too much to take in at once- hence jump onto the CROI website and watch some of the presentations and search for the abstracts also. Signing off for now.
ASHM Report Back
Clinical posts from members and guests of the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM) from various international medical and scientific conferences on HIV, AIDS, viral hepatitis, and sexual health.
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.
One thread at the conference was the outcomes of, and associations with, renal dysfunction.
In the D:A:D Study (abstract 865) 2.1% of the cohort developed an eGFR of less than 70 after a median follow-up of 4.5 years. The investigators identified that TDF, LPV/r and ATV (boosted in 75% of cases) were all associated with an incidence rate ratio (IRR) of approximately 1.1 per year of exposure for the development of an eGFR less than 70. Switching off TDF was more common at eGFR levels between 60 and 70. Predictors of eGFR less than 70 were age, prior AIDS, current CD4 count, HCV or HBV coinfection and diabetes.
More data from the SMART study (abstract 866) were presented. This time eGFR and cystatin C levels were associated with mortality and other events in a sample of over 4000 subjects. They comment that cystatin C (a potential marker of GFR) may be affected by other issues in HIV infection and may not be an ideal marker of GFR in this population.
Others identified an independent association between renal impairment and cardiovascular events (abstract 868, from the ICONA cohort in Italy) and microalbuminuria in cART naive individuals and death (abstract 869).
In all, there is accumulating evidence that markers of renal dysfunction in the HIV infected population are likely to have similar prognostic significance as in the general population. This is worth discussing if people are considering whether to commence therapy above a CD4 count of 350 where a survival benefit has been convincingly demonstrated. The results from the START study are even more keenly awaited in light of these new data.
The renal effects of tenofovir were associated with blood levels (abstract 603) at the conference. Another presentation (abstract 103) examined a prodrug of tenofovir, GS-7340, in a 10 day monotherapy study. This produg was associated with 88% lower plasma levels of tenofovir than when the currently prescribed prodrug TDF (tenofovir disproxil fumarate) was administered. It was highly potent and is likely to be studied further as an alternative to TDF.
The new "booster" drug, COBISTAT, is part of the "QUAD" single pill (see QUAD post) and a number of studies are in planning and in progress looking at the use of this agent. It may allow new regimens such as a once daily combination pill with a protease inhibitor for the first time.
The once daily dosed integrase inhibitor DOLUTEGRAVIR was the subject of a handful of presentations at the conference. Week 96 results from the SPRING-1 study were reported. This was a phase 2 study of 205 people comparing different doses of Dolutegravir (10, 24 and 50mg) with efavirenz, both in combination with a TDF/FTC or ABC/3TC backbone. At week 96 the proportion with a HIV viral load less than 50 copies per ml was 88% in the 50mg dolutegravr arm and 72% in the efavrenz arm (a non signficant difference). The treatment appeared well tolerated, although there was a mild elevation in serum creatinine, thought to be due to effects on renal secretion of creatinine and not real impairment of GFR. Phase 3 studies of this agent, which could provide a once daily integrase inhibitor regimen, are underway.
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.
People will recall that iPrEx investigators questioned whether adherance to prophylaxis was the cause for transmissions in the active arm of the iPrEx study. Late Breaker #31LB reports on this. They compare plasma drug levels to those in an unrelated observed therapy trial STRAND with doing at 2, 4 and 7 days per week. The active arm had an overall preventative effect of 90% but when broken down by similarity to the STRAND data they found 76% efficacy at 2 day per week dosing levels, 96% at 4 and 99% at daily.
You will find the paper on the CROI Website, as well as the Oral Abstract session from 6 March 2012 in the 10am session.
Session 35: New Frontiers in HIV Testing
Bernie Branson from CDC gave a fabulous talk on HIV Diagnosis: New Tests and New Algorithms. Those of us involved in any of the current disucssion about testing really should view this whole talk. It should be up on the CROI Website shortly.
His slides are most informative, particulaly a graph which plots back from when a Western Blot would detect HIV infection, indicating how many days before a Western Blot 2nd, 3rd and 4th generation tests can identify infection.
He describes a number of the initiatives to increase testing and is encouraging the adoption of the recently updated algorithm for HIV testing in the laboratory. The algorithm and supporting evidence is published in the December 2011 issue of The Journal of Clinical Virology. He also disucsses mechanisms to get conventional testing more available and review a number of Point of Care Tests.
He raises the issue of the implications of new tests including home based tests. He is cautious about some of the tests failing to identify new sero-conversions and makes reference to findings that men are reporting they would use test results to assist them in sero-sorting (so having the wrong result could have significant implications).
It is a great talk I suggest you view it and share it with your colleagues.
The second talk in the symposium is by Blayne Cutler, from New York City Health and Mental Hygiene. She reviews a number of strategies which have been put in place in the Bronx and more recently Brooklyn to increase HIV testing. She approaches this from the point of who has never tested and their attempts to reverse this. 60% of people have never tested and of these the majority are adult men. She also examines some strategies to move testing into the community and get programs supported at implementation level.
These two talks have been hugely informative.
People who know me will know that this is a particular interest of mine. There are a number of posters focusing on the role of very early infection in onward transmission of HIV and it has been mentioned by a number of speakers.You can access the poster abstracts from the CROI Website but I will give you a few points about particularly interesting ones here.
Poster 1107 A French analysis of genotypic profiles for 987 patients between 1999 and 2010. Identified manyclustered transmission ranging up to 24 months, Often associated with younger MSM, while 54% were in Paris, 19 or 56 were in distant French regions and 13 of the 19 involved at least one person from Paris. Their conclusion is that primary HIV infection is a significant source of onward transmission especially in MSM and contributed to regional as well as Paris-base infections.
Poster 557 Acute infection would be missed in a small but important number of cases using Architect HIV Ab+ p24 Combo. 5 of 14 early not detected. Interestingly this 5 were in ramping up fase and had distinguishably different HIV dynamics. The do an analysis of cost on the basis of onward infections and argue the case for HIV NAAT.
Poster 552 Chance of transmission in early HIV infection 13 x higher via UAI. In a San Francisco sample early is considered less than 100 days. Gay men with acute infection comprise 2% of the infeted population (49% untreated and 49% on treatment) but account for 22% of new infections.
CROI 2012 is huge with more than 1000 abstracts to digest and multiple parallel sessions.
Highlights of Tuesday6 March were plenary sessions.
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
Today was a good day for HIV Neurology with a themed discussion on advances in diagnosis and management of cryptococcal meningitis (Session 15). This included a review by Rolfes et al of the concordance between a new point-of-care assay for plasma- the lateral flow assay- and serum /CSF cryptococcal antigen and CSF culture. Overall the concordance was high - hence important early findings for a test that should prove promising in resource limited settings (Abstract 953).
Another presentation by Chang et al revealed that achieving CSF sterility prior to commencement of cART was significantly associated with decreased risk of neurological deterioration and decreased risk of mycological persistence or relapse at 24 weeks of cART therapy (Abstract 955). These data are important because cryptococcal meningitis remains a common AIDS illness in resource poor settings and because cryptococcal IRIS is a relatively common sequelae when cART is introduced. Lots of excellent posters today also with an emphasis on findings in early HIV infection.
Tomorrow we see sessions on ageing and neurocognitive impairment and on the natural history, markers and treatment of HIV neurological disease. Goodnight!
Two important HIV HCV coinfection phase 2 studies of HCV protease inhibitor therapy in combination with PEG-IFN and ribavirin for HCV genotype 1 were presented today with SVR12 data (sustained virological response 12 weeks after treatment cessation) available. Both studies found approximately 30% higher response rates (a marked advance in this patient group), but there were some caveats.
Abstract 46 (presented by Doug Dieterich) reported that Telaprevir with PEG-IFN-alpha-2a and ribavirin had higher SVR12 rates than with PEG-IFN-alpha-2a and ribavirin alone (74 vs 45%).
Abstract 47 (presented by Mark Sulkowski) examined Boceprevir with PEG-IFN-alpha-2b and ribavirin (n=64) which was compared with PEG-IFN-alpha-2b and ribavirin in people with genotype 1 HCV infection with significant differences in SVR12 (61 vs 27%).
The sample sizes were small (less than 100) and both studies reveal expected toxicity profiles with the addition of the HCV protease inhibitor.
Other data presented at the conference revealed the very significant drug-drug interactions (including with many HIV drugs) with these compounds that will mean that their use will need careful thought. Jurgen Rockstroh summarised the state of play with these agents in abstract 72 and suggested management strategies based on the current evidence.
The therapeutic outlook for people with HIV and HCV coinfection looks much more promising with these early data and phase 3 studies in progress or planned and a number of new HCV agents in the pipeline. Watch this space.
Wafaa El-Sadr presented a comprehensive over view of treatment as prevention strategies and studies. the data came from both African and US studies. Importantly she indicated that all aspects of a program were important, increasing test, increasing engagement with care, lowering the CD4 count at which treatment is initiated and treatment ahderance. She estimated that of the approximate 1,200,000 Americans living with HIV approximately 850,000 were not successfully on treatment. This theme is maintained in the posters, where an interesting poster from New Jersey #1075 by Ruthie Birger provides a hierarchy of interventions necessary to impact community transmission.
Wafer's talk is now available from the CROI website and it is well worth a viewing, particularly for anyone thinking about test and treat. It was very suprising for me to really get a handle on just how poor coverage of treatment is in parts of the USA, given there is so much research which comes from here.
Greetings from Seattle. Very much looking forward to this conference. There are a lot of presentations about HIV neurology and PrEP. There is a very positive atmosphere at the conference, buoyed I think by all the great HIV prevention work that is coming out. Goodnight for now.
Quarraisha and Salim Abdool Karim opened with the N'Galy- Mann lecture. Their talks chronicled 20+ years of HIV research and epidemiology in Africa.
The CAPRISA 004 study into tenofavir gel used vaginally to prevent transmission was discussed. Salim gave a particularly interesting review of the analyses they did into why the results were not better. Adherence of >80% was associated with better protection, but concurrent genital inflamation, resulting in increased cytokine involvement in the vaginal region, was associated with a 14 times greater risk of HIV Infection. The whole presentation which went into a number of other issues will be avaiable on the CROI site soon, but the take home message from this was the importance of STI screening and the impact that STI s can have on priming HIV binding sites.
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...