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.

HIV monitoring focuses on plasma RNA viral loads and CD4 T- cell counts from the blood, but this only represents a part of the total infection in other parts of the body such as the gut and genital tract. A better understanding of mucosal immunity at these sites has implications for both prevention (microbicides) and treatment research (immune reconstitution outside of PBMCs).

Laura Romas from the University of Manitoba, Canada presented data on the rectal mucosa from HIV-exposed seronegative (HESN) partners in discordant MSM couples and susceptibility to HIV-1 infection, the first time this has been investigated. She found 25 differentially expressed proteins (of 289 identified) that were overabundant in HESN MSM (p< 0.05), and had functions related to acute phase response, antimicrobial defence and Ig-mediated immunity. These proteins did not show a significant correlation (p>0.05) with clinical variables (frequency oral/anal sex, HIV-neutralizing IgA, and viral load of HIV+ partner). One in particular, Antiprotease 1 (AP1) reduced HIV infection by 50% in PBMC culture at physiologically relevant concentrations. Planned further research will aim to elucidate if increased AP1 expression is as a result of HIV-exposure or genetic variability. This could have very interesting implications for MSM prevention strategies and microbicide development.

The GI tract is know as an early site of viral replication and associated immunopathogenesis. Whilst ART stimulates CD4 T – cell recovery in blood, its effects on the GI tract are much less pronounced. However, as earlier initiation of ART seems to preserve more peripheral CD4 T – cells, Claire Deleage from the USA investigated the effect of early ART initiation on the GI tract (lamina propria CD4 T-cells) with a small cohort of Thai patients treated during Fiebig stage 1/2 or 3+ versus chronic controls. Unfortunately, there was no significant recovery of CD4 T-cells in the lamina propria after treatment initiation. After 6 months of HAART all acutely infected treated patients had significant depleted lamina propria CD4 T-cells that persisted through 24 months of treatment. Markers of GI damage, inflammation and immune activation returned to baseline levels after 6 months of ART following an increase during acute HIV-1 infection (day 0). Despite the positive effect of early ART initiation on GI damage markers, the stark lack of CD4 T-cell recovery is disappointing. Fully understanding the complexities of HIV infection in GI tract remains a great challenge, but it is essential if strategies to promote CD4 T-cell recovery in gut are ever to materialise.

Tagged in: AIDS 2014 IAS2014

 

Opportunities and Threats to ART success (session 36) and related CROI abstracts

Greetings from Atlanta, home to CDC, CNN and Coca Cola of which I have ingested output from all three during this visit.

For those interested in the obstacles to ART implementation and its therapeutic success including new antiretroviral drugs and formulations, there was a terrific symposium held yesterday that addressed these issues.

Jennifer Kates from Kaiser Family Foundation outlined issues arising from Obama’s Affordable Care Act (ACA) as they pertain to HIV care and treatment access. Like Australia, the US Federal- State divisions and discords can be disconcerting. In the US states have the choice of accepting the expansion of the public health fund Medicaid or not. For those states that accept it, people living with HIV will have greater access and financial support for their HIV care. Currently 68% of people living with HIV in the USA live in states that will support Medicaid’s expansion but this leaves the potential for disparate levels of care for people living in the remaining states who decline Medicaid expansion. A good talk for those who seek to better understand the ACA.

Sharon Lewin from Alfred/Burnet/Monash gave an outstanding talk on the impact of the residual inflammation experienced by virologically suppressed HIV positive people on ART.  Sharon addressed the impact of residual inflammation upon risk for mortality and non-AIDS diseases. She addressed the drivers of this inflammation and the current (largely theoretical) therapeutic approaches we could take to decrease inflammation. A must-watch talk on CROI’s webcast.

Raph Hamers from Academic Med Ctr of the University of Amsterdam gave a very good talk on ARV drug resistance. He discussed in detail transmitted drug resistance, which is a key issue for populations living in eastern and southern Africa where transmitted NNRTI resistance predominates. Also he addressed the recently published observation that K65R resistance appears to occur more rapidly in clade C infected patients whose first-line therapy included tenofovir. K65R is also selected in patients who have been treated previously with stavudine (d4t). He highlighted the importance of switch studies from first to second line therapy.

Of note ASHM President-elect Mark Boyd and his colleagues’ SECOND-LINE study’s 48-week results were presented as a late breaker poster (180LB).  The study results support switching to a boosted lopinavir + raltegravir, NRTI-sparing regimen for individuals failing their first-line NNRTI with 2N(t)RTIs regimens. This approach was non-inferior to switching to boosted lopinavir +2-3N(t)RTI regimens and was associated with a significantly higher CD4 cell recovery.

Joe Eron from the University of North Carolina gave Trip Gulick’s talk on new ARVs, which was, thankfully optimistic. There are a number of new ARV formulations in the pipeline including atazanavir/cobicistat, darunavir/cobicistat which precludes use of ritonavir as a boosting agent. Rilpivirine is also being studied in a nanoparticle form and as a long-acting intramuscular injection. Efavirenz and atazanavir are also being considered for nanoparticle formulation. Antiretroviral agents can be formulated as solid or liquid suspension nanoparticles. Theoretically nanoparticles could afford better bioavailability and higher tissue concentrations as they are taken up and then released into tissues by mononuclear phagocytes. Abstract 513 reported on successful in vitro studies of Efavirenz formulated as solid drug nanoparticles.   

The talk provided an excellent table of all the up and coming drugs- check out this talk via the CROI webcast site to view the table.

Importantly Joe Eron mentioned the new tenofovir pro-drug tenofovir alafenamide (TAF). TAF is notable because its plasma levels are 90% lower than those of tenofovir but it has a 5-fold increase in intracellular TFV diphosphate compared to tenofovir, which affords it the potential for lower toxicity. Indeed significantly lower bone and renal toxicity was observed in the TAF arm of a phase 2 randomised, double blind trial presented as a late breaker oral presentation (abstract 99LB). Here elvitegravir/ cobicistat/ emtricitabine/tenofovir was compared to elvitegravir/cobicistat/emtricitabine/ tenofovir alafenamide. The two regimens had comparable efficacy at week 24 and the findings support scaling up to a phase 3 study. All points bulletin to bones and kidneys: watch this space!

 

 

Tagged in: CROI2013

Yesterday afternoon climaxed with some exciting late breaker oral presentations.

Headlines are:

CONSORT study- This study showed that isoniazid prophylaxis (vs placebo) reduced active Tuberculosis over a 4 year period. 1369 patients were given 12 months of INH. Participants were all HIV positive, and 50 on cART. Most benefit seemed to be in the first year, although an effect was seen over the full study course. The HR was 0.63 for active TB (95% CI 0.41-0.94) p=0.03.  They didn’t screen for latent T, unlike in Australia, because the Cape Town setting of this study meant that TB is exposure is the norm, indeed 40% had a history of prior TB. Interestingly 70% of the participants were already on cART, and 30% started cART at the commencement of the study. Resistance to INH in the 95 who did manifest TB remains to be determined. In such a high exposure environment, is this prophylaxis of latent TB or prophylaxis against new acquisition?

SPRING-2- Double blind double dummy RCT of 2 NRTIs plus dolutegravir or raltegravir in 800 treatment naives. VL 50 in 88% and 85% at 48 weeks respectively, proving non-inferiority. Both drugs were really well tolerated, andthere was little to choose between them. No treatment emergent II resistance was seen in the dolutegravir arm, and just one case in the raltegravir arm. There was no difference for VL 100,000 nor between truvada and kivexa as the backbone. Dolutegravir inhibits creatinine tubular secretion, so the eGFR appeared to drop by 15mls/min, but this was not a true reflection of renal function.. it muddies the waters a bit though when trying to interpret creatinines on people on tenofovir.

HPTN 052- this analysis of the treatment as prevention study analysed clinic events in those starting immediately, or waiting to CD4 of 250. A combined endpoint of nonAIDS and AIDS did not show a difference, but there was a statistically significant reduction in AIDS evets. Questions from the audience focussed on the fact that this was all driven by diagnoses of extrapulmonary TB from just one clinical site, and that the average CD4 at commencement in the delayed arm was about 220-230, so much lower than we would ever wait in Australia.

Tagged in: AIDS 2012

Drugs and therapeutic challenges were the themes of this morning’s session.

The plenary started with some excellent overview talks, especially one detailing the various attempts to induce activation of latently infected cells. Current strategies still in vogue are to use IL-7, (Eramune studies), or the HDACi inhibitor vorinostat. Studies using disulfiram or IFN-alpha have not been successful to date.

The next session was a series of important pharma-sponsored studies. First up Mills from Los Angeles presented 96 weeks data on maraviroc 150mg od with ritonavir boosted atazanavir, compared to truvada boosted atazanavir. It was a phase 2b study, so not many stats were presented. At 96 weeks 82% of the truvada arm were 50 copies/ml compared to 67.8% of the maraviroc arm. Most of the detectable VL in the maraviroc arm were in the 50-400 range, and the presenters focussed on this, and the lack of resistance and rather avoided discussing the primary outcome. I thought it was disappointing they appeared to gloss over this; surprisingly tese results have been taken as encouraging and a further study is planned, this time using ritonavir boosted darunavir and maraviroc.

Next up J Gallant presented the 48 weeks results of a ritonavir vs cobcistat booster comparison study. When used with truvada and atazanavir cobcicistat was non-inferior to ritonavir, in fact there was little to choose between them, except for the known rise in creatinine with cobicistat as it blocks creatinine active secretion in the tubules. Although non-significant, 5/6 who had renal dysfunction with cobicistat had proximal tubular disease, compared to 2/5 of renal dysfunction cases on ritonavir. Lipids were the same.

Pallela then presented the SPRIT study, which is a switch study from 2NRTIs plus a boosted PI to Eviplera. Patients were 50/ml prior to switching. Results showed switching did not compromise virological control, and lipids improved a bit. Thy did not stratify lipid changes by which PI was used. Interestingly, all 17 patients who were known to harbour the K103N mutation successfuly suppressed on a rilpivirine based regimen.

Finally Elion et al presented the 96 weeks data on study 145, a raltegravir versus elvitegravir double blind double dummy study in treatment experienced patients. I think all patients had a boosted PI in their regimen already, which makes interpreting differential lipid and GI toxicity difficult. Results were pretty equal between the arms with around 55-60% 50copies/ml, a CD4 rise of 200 cells,  and about 40% discontinuations. Each arm developed resistance mutations to integrase inhibitors in 7% of cases. The resistance pattern was different however, with less N155H mutations in the elvitegravir arm, and a broader range of mutations seen. How this will impact on sequencing IIs and the role of dolutegravir aftr either raltegravir or elvitegravir failure was unfortunately not discussed.

Tagged in: AIDS 2012

Greetings from Washington DC. Nice to be back. I used to live here and went to George Washington University as an undergraduate. I couldn’t understand why all the guys at University wore pink cashmere jumpers and tartan trousers until a friend from Australia sent me a book on ‘Preppies’.

Today we had a retrospective symposium on SMART: “Five Years after the SMART study, a Paradigm-shifting Trial” (SUSA56)

Some of the speakers’ points are outlined below

Tony Fauci opened the Symposium noting that SMART one of the most influential trials in HIV medicine, that it helped us understand the importance of chronic immune activation and coagulation in HIV disease and, finally, that it was the result of major collaborative efforts.

Wafaa El-Sadr reflected on HIV Treatment Research in 2002
She reflected on the background to the SMART study: the idea was conceived in her apartment in New York city one evening with Jim Neaton, Fred Gordin and Birgit Grund.

Wafaa noted:

  • The impact of SMART was to immediately change guidelines such that treatment interruptions were not recommended at a guideline level
    - Objective evidence of SMART’s impact upon treatment patterns comes from an analysis of the Royal free database: after SMART the percentage of people using intermittent ART decreased from 5-6% to 2%-3%.
  • A paradigm shift occurred as a result of SMART vis-a-vis a greater understanding of the pathogenesis of HIV disease.
  • With all the bio specimens that were collected in SMART it created the opportunity to engage with non-HIV doctors who became interested and utilized the samples from SMART in collaboration with SMART investigators => excellent synergies from working with people outside of the HIV field

Wafaa’s final slide noted

  • SMART challenged the status quo
  • Getting an unexpected answer to a question is often more profound than getting the expected answer
  • Seeking definitive answers to tough questions is not easy, requires patience and may be costly but is well worth it
  • Other tough questions of the hour remain that will have to be answered

Andrew Wilson addressed HIV Treatment Research Post SMART
He noted:

  • That SMART was the first trial that used serious non-AIDS events as a major trial endpoint
  • That 92% of all deaths in SMART were serious non-AIDS events
  • Clinical event risk at high CD4 count range are nearly all related to non-AIDS conditions - these events were not being collected in most HIV cohort studies at the time
  • The key question is what is the ongoing excess risk of morbidity due to HIV in people with successful viral suppress on compared to HIV negative controls ART

Jens Lundgren addressed why the START trial is necessary and how it stands on the shoulders of SMART
He posited that one must consider the case that START may show early ART is harmful and he invoked the physician’s creed: Primum non nocere (first do no harm).

This argument runs as follows:

  • Morbidly and mortality in early HIV in young persons are LOW
  • ART may adversely effect a variety of organ functions
  • If this scenario turns out to be correct we will know whether early ART is harmful within 3 years
  • Jens also noted that only 3 RCTs had addressed early versus deferred ART: The Haiti trial (NEJM 2010), the SMART subgroup (JID 2008) and HPTN 052 (NEHM 2011) but none of these used the same CD4 criteria as START
  • He also noted that 4 observational studies had addressed early versus deferred ART: When to start, NA ACCORD, Causal collaboration and CASCADE
    - However using the GRADE classification (see www.gradeworkinggroup.org) these studies would be graded as C whereupon a score of A is best

It was an excellent retrospective.

Tagged in: AIDS 2012

Please join us for a memorial event celebrating the life of one of Australia’s leading HIV advocates, Levinia Crook… https://t.co/N7dof5xaGa

ASHM ASHM