Rob Burton

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.

Robert Burton

Robert Burton

I studied medicine a St George’s Hospital Medical School, University of London before going on to specialise in general practice. I undertook my GP training through University College London Hospitals. It was during this time that my interest in sexual health was sparked after working in a busy London sexual health clinic. After completing my GP specialty training, I moved to Sydney and began work as a registrar at Sydney Sexual Health Centre, Sydney Hospital. I spent two years at SSHC, during which time I completed the s100 HIV prescriber course. Following this I joined Taylor Square Private Clinic in May 2014 and I continue to work there now. I particularly enjoy the opportunity to work in this high case-load practice where I can combine my joint interests in sexual health/HIV medicine and general practice.

So far there have been two well documented cases of individuals on PrEP contracting HIV despite good adherence and high TDF levels. This poster presents a case where a 50 year old gentleman, who had optimal TDF levels (on 2 dried blood spot examinations) - 8 months in to the AMPrEP study he tested antibody reactive, antigen negative on a 4th generation Ab/Ag HIV test. During this visit he described symptoms of fever and dysuria. Western blot reveleaved a single band at gp160. At the time the patient had tested negative on pol PCR (DNA and RNA) of bulk PBMCs and sigmoid colon biopsy, and had no detectable HIV viral load. PrEP was subsequently stopped due to concerns around inducing resistance (looks like this was done within a few days of the results - see attached poster). 3 weeks later, HIV RNA was detected in plasma (40,000 copies/ml). No resistance mutations were identified. The patient was commenced on treatment and 1 month later had an undetectable viral load.

 

The presenter highlights this as being a probable third case of HIV seroconversion in a PrEP-adherent individual. This would be a first case of wild-type virus being transmitted under these conditions. They postulate possible reasons for PrEP failure such as very high exposures, and repeated trauma.

 

What’s not clear to me is whether the possibility of a false reactive HIV Ab/Ag was considered. The poster does not detail the reactivity score (i.e. was this a borderline result) on the LIAISON XL platform. If this result was a borderline reactive, was this more of a PEP failure, i.e. the patient did not have a long enough PrEP-tail following last UPAI, or was this indeed a PrEP failure? Did they stop the PrEP too soon? This brings us to question how we go about managing indeterminate HIV results in the the context of PrEP.

 

What do you think?

Tagged in: CROI 2017

           Cerebral small-vessel disease (CSVD) is a common problem with increasing age and accounts for approximately 20% of strokes and 45% of dementia. In addition to age, hypertension is a major risk factor for the development of CSVD.  CSVD is characterised by white matter hyperintensities, silent infarcts and microbleeds.

           This cross sectional study examined the prevalence of CSVD in PLHIV (who immunovirologically controlled for at least 2 months on cART), comparing them with age and sex matched controls. A 3T MRI scanner was used and the diagnosis of CSVD was made by 2 neuro-radiologists who were blinded to serostatus.

           After adjusting for known risk factors, the prevalence of CSVD was twice higher in middle aged PLHIV (aOR 2.3).

           This study adds to the continually growing list of conditions that are more common in PLHIV, even where they are immunovirologically controlled. This therefore leads us to the question of how we go about managing or mitigating this effect. I did some further reading around up-to-date guidelines on CSVD. It seems that aside from managing blood pressure, there is little evidence to support the routine use of other agents, including statins or anti-platelets. These studies however have been done primarily in HIV negative individuals. The pathophysiological mechanisms underlying (at least some of) CSVD in PLHIV may be different. Given the extensive interest in the anti-inflammatory effects of statins in HIV, one wonders whether there may be a role in managing CSVD.

Tagged in: CROI 2017

 

  1. Since the advent of integrase inhibitors, bringing about our latest highly effective combination therapy, with viral suppression rates approaching 97%+, many clinicians have questioned a place for new antiretrovirals. How do we get much better? Will there be any compelling reasons to switch our patients to newer agents? In addition, studies such as SWORD have shown simplification strategies can be highly effective, using exisiting drugs, without the need for a third agent. Studies examining cabotegravir, a long-acting integrate inhibitor which can be given as a depot injection, have now entered phase 3 clinical trials, which may possibly negate the need for daily oral treatment. So what does this mean for future drugs? How will they find their niche in what is becoming a rather crowded market? I think given the aforementioned advances, new drugs will need to be highly effective, have high genetic barriers to resistance, thus possibly lending themselves to either dual or monotherapy. Additionally, long-acting drugs which may be able to be given less frequently (through depot or implant), may have an important role in the future of ART. Finally, drugs with novels modes of action, may have a continued role in treatment experienced patients with resistant virus.

     

    This presentation from Gilead Sciences (abstract below) introduced a novel first-in-class capsid inhibitor which leads to a defective HIV-1 virion through interference in the capsid core assembly. In-vitro assays have revealed CS-CA1 to be a highly potent drug with no measurable toxicity in target and non-target cells. The drug binds to a largely conserved region on the capsid protein. In addition, the drug appears to have activity blocking some of the post-entry capsid functions. Pharmacokinetic studies in rats have demonstrated sustained plasma concentrations and the drugs limited aqueous solubility make a drug possibly well suited to long-acting depot administration.

     

     

    I feel that this novel drug offers exciting promise, especially if the in-vitro activity translates to highly effective antiviral activity in-vivo - possibly leading to a long-acting drug lending itself to simplified depot administration.

     

    DISCOVERY OF NOVEL POTENT HIV CAPSID INHIBITORS WITH LONG-ACTING POTENTIAL
    Winston C Tse
    , John O. Link, Andrew Mulato, Anita Niedziela-Majka, William Rowe, John R. Somoza, Armando G. Villasenor, Stephen R. Yant, Jennifer R. Zhang, Jim Zheng

    Gilead Scis, Inc, Foster City, CA, USA

    Background: While HIV capsid (CA) plays an essential role in multiple stages of the viral life cycle, it remains an unexplored target for antiretroviral (ARV) therapy. Here, we report the discovery of a novel class of exquisitely potent and metabolically stable HIV capsid inhibitors (CAIs) that exhibit pharmacokinetic (PK) profiles suitable for slow-release parenteral administration.
    Methods: In vitro CA binding and assembly assays, together with X-ray co-crystal structures of CAIs with cross-linked CA hexamers, were used to optimize compounds for
    high binding affinity to CA. Medicinal chemistry approaches were employed to optimize the antiretroviral activity and drug-like properties using a cytopathic antiviral assay in conjunction with extensive metabolism and pharmacokinetic profiling. CAI resistance-associated mutations were identified by in vitro resistance selections. CAI mode-of-action was defined by inhibitor time-of-addition, virion electron microscopy and viral DNA quantification.
    Results: GS-CA1, an exemplified member of a novel class of CAIs, is a highly potent inhibitor of HIV-1 replication in T cell lines (EC50 = 0.24 nM) and displays similar potency against multiple HIV-1 clinical isolates from all major clades in human PBMCs. Identified CAIs bind to a broadly conserved site at the interface of two adjacent monomers within a CA hexamer and accelerate CA assembly in vitro. The identified CAIs maintain full activity against HIV-1 mutants resistant to licensed ARVs and select for HIV CA variants L56I, M66I, Q67H or N74D with an attenuated in vitro replication phenotype. Mechanistic studies revealed a dual mode of action targeting both the late-stage virion maturation and post-entry CA functions. GS-CA1 shows high in vitro metabolic stability and favorable PK profiles in multiple preclinical species with low systemic drug clearances (0.08–0.33 L/ hr/kg) and long half-lives (7.2–18.7 hr). Low aqueous solubility provides for an extended-release preclinical PK profile following subcutaneous administration of a solid depot formulation.
    Conclusion: We have identified novel HIV-1 capsid inhibitors with uniquely potent antiviral activity and a favorable resistance profile orthogonal to existing ARVs. The high metabolic stability and low aqueous solubility of this new inhibitor class should enable the development of an extended-release parenteral formulation with the potential to be used as a novel long-acting antiretroviral treatment. 

Tagged in: CROI 2017

Greetings from Seattle. I would like to start by thanking ASHM for giving me the opportunity to attend this world-class conference and also thank the readers for taking time to read my blog.

 

Gilead dominated the morning session that I attended, presenting 2 novel drugs in different stages of development. I will talk about the more conventional of the novel drugs, which is now undergoing phase 3 clinical trials (4 active trials).

 

Bictegravir (BIC) is a novel, once daily INSTI. In-vitro studies have demonstrated it’s high level of activity against wild-type and many INSTI-resistant viruses. The drug has good oral absorption and an excellent PK profile, with a trough level well above IC95. The drug is mainly metabolised through CYP3A4 and UGT1A1 and has a favourable DDI profile. Similar to dolutegravir (DTG), there can be increased metformin levels (39%) and potentially clinically relevant interactions in the presence of potent inducers such a rifampicin. The 50mg once daily BIC dose was selected in coformulation with FTC/TAF as a single tablet regimen to progress in further studies.

 

Paul Sax then presented the 48 week data from a relatively small randomised double-blind active control study. 98 participants were included (from 125 screened) BIC = 65, DTG = 33. Patients with chronic hepatitis (B and C) were excluded. Overall rates of viral suppression were excellent in both groups at 24 and 48 weeks. In the BIC group, viral suppression (Defined as VL < 50 copies/ml) was 97% at 24 and 48 weeks. There were 2 discontinuations in both arms (1 lost to follow-up in each arm, 1 non-compliance in DTG, 1 AE in BIC). In terms of adverse events, diarrhoea was the most common side-effect reported in 12% of subjects in the BIC arm. Overall, AE profiles and lab abnoralities were reassuring. A minor decline in eGFR of -7.0 ml/min was observed BIC. No treatment-emergent mutations (INSTI or NRTI) were noted through week 48 in either group.

 

In summary, bictegravir is an exciting novel INSTI which has moved on to phase 3 clinical trials. Should it progress and eventually receive approval, it will be coformulated with FTC/TAF in a single tablet regimen, joining what is becoming a rather crowded market.

 

Tagged in: CROI 2017

This lecture on recreational drug use by Marta Boffito from London was a nice summary of some of the trends they are seeing in the UK and how this may affect treatment.

 

Marta started by highlighting a paper from 2014 - the ASTRA study which identified significant polydrug use (of recreational drugs) amongst MSM in the UK and its association with condomless sex. Whilst this may be a risk for HIV transmissions, the potential interactions with antiretrovirals in people living with HIV should also be considered. The Liverpool website neatly summarises some of these interactions here.

 

 

Of particular concern is the use of GHB or GBL (collectively known as ‘G’) as a party drug. This synthetic version of an endogenous hormone is rapidly absorbed and has a relatively short half life, leading to people sometimes taking multiple doses to maintain their ‘high’. The main concern with it is the fact that it has a narrow therapeutic range, and doses up to 3ml can cause death. In addition, ethanol interferes with the metabolism, as do ARVs such as PIs and cobicistat. Whilst crystal meth seems to be getting much attention at the moment (and something I see in my clinical practice in central Sydney frequently), the use of ‘G’ is of significant concern, particularly in patients with these potential drug-drug interactions. When reviewing or commencing PIs or pharmaco-enhancers such as cobicistat, it is crucial to take a full drug history and warn patients about potential interactions, even if they do not freely admit to using such drugs. 

 

Tagged in: EACS2015

I’m going to present two studies looking at HIV-1 RNA in the genital tract in the context of integrase inhibitors. The background of this issue relates to the fact that the male genital tract forms a separate reservoir of HIV.

 

The first study presented looked elvitegravir levels in seminal plasma in HIV-1 infected patients. This was a small study of just 10 patients who had already suppressed plasma viral loads at baseline with a median time on ARVs of 50 months. Patients were switched to elvitegravir/cobicistat/emtricitabine/tenofovir (EVG/COBI/FTC/TDF) single tablet regimen and paired blood plasma and seminal plasma samples were examined. All patients had undetectable blood and semen viral loads (<40 copies/ml) 4 weeks later. Some might argue the 4 week follow-up assessment may have missed a transient viral rebound in the seminal plasma. It could also have been too soon to identify viral rebound in this group, especially considering the extensive prior time on treatment (median 50 months). 

 

The second study from the same group examined the rates of HIV-1 RNA decay in seminal (SP) and blood plasma (BP) in naive patients commencing dolugravir (on ABC/3TC backbone). 15 patients were recruited to this open-label, single-arm study. Rate of HIV-1 RNA decay was initially higher in the BP compared with SP. Due to the lower baseline seminal HIV-1 RNA, viral suppression was achieved sooner in SP, although both groups were quite rapid. By the end of week 24, all but one patient had achieved an undetectable VL (<40 copies/ml) in the seminal fluid despite the groups median DTG concentrations being just 7.8% of total concentrations in the blood plasma.

 

What is the significance of this? Clearly these are very small studies, however they demonstrate promising findings in terms of efficacy in the male genital tract with these two new INSTI agents. In the day and age of treatment as prevention, viral suppression in this reservoir may be an important consideration. Further information around HIV transmission in MSM on ART should be gained from the Opposites Attract study which also has a semen analysis sub-study.

Tagged in: EACS2015

Two sub-studies, which formed part of START trial, were presented this morning.

 

The first study looked at lung-function decline in the immediate versus deferred arms of the START trial. The authors acknowledge the emergence of COPD as a co-morbidity in HIV, with prior studies showing mixed results on the the effects of ART on COPD risk.

 

This sub-study involved approximately 1000 patients divided between immediate and deferred treatment arms. The median follow-up time was relatively short - just 2 years. No difference of FEV1 slope was detected between the study arms, in both smokers and non-smokers.

 

This study suggests immediate vs deferred ART has no impact on lung function decline in HIV with CD4 >500. Further longitudinal data continues to be collected on this study population.

 

The second START sub-study presented looked at the effects of immediate versus deferred ART on bone density (abstract not available at time of writing this post). 424 naive patients with CD4 counts over 500 were enrolled (206 in the immediate group, 218 in the deferred arm).

 

Bone mineral density (BMD) was assessed by DEXA at the hip and lumbar spine at baseline and annually. The median age was young, 32 years old, with 26% female patients. Osteoporosis and low BMD were lower than in other cohorts (3.3% and 38%, respectively).

 

Over the course of the follow-up, 37% of patients in the deferred arm ended up on treatment. In the immediate treatment arm, 79% were on tenofovir containing regimens. Controlling for variables, significantly greater BMD loss was seen at both the hip and spine in those randomised to immediate ART. This effect was most pronounced in the first year, after which point it stabilised. No difference in the development of osteoporosis was seen between groups (or fractures - as presented in the results from the full START study population).

 

Both of these studies were extremely well presented, as one would expect from such a large multi-centre, multi-national trial. The presenter of the lung function sub-study acknowledges that they do not anticipate significant differences between the two study arms at the 3 year mark.

 

Clearly smoking status remains the most significant risk factor for lung function decline in HIV-infected individuals, and our focus should remain on supporting smoking cessation in this group. As for the bone sub-study, with the advent of TAF, I suspect the relevance of this study and associated concerns, certainly in Australia, will be further diminished.

Tagged in: EACS2015

 

Things got off to an early start this morning at EACS, starting with 4 different ‘Meet the Expert’ sessions to chose from. I attended the session on vaccination in HIV.

This session provided a nice overview of recommended vaccinations and their rationale in HIV positive patients. This was a good reminder to me to ensure patients are appropriately vaccinated at baseline and to intermittently check antibody status where indicated. In a day and age where many patients seem to be commencing antiretroviral therapy so early in their care (and at increasingly higher CD4 counts), it is easy to forget that such individuals still carry an elevated risk of complications.

Four Cases

Four cases were used to demonstrate infections that were preventable through vaccination. The first case was about measles. The presenter highlighted the fact that in some European countries, up to 13% of patients with HIV have no detectable antibodies against measles (particularly in patients born after 1983).

Many patients are unsure of their vaccination history and it may therefore be important to check antibody status. Another important consideration relates to the measles vaccine being a live attenuated vaccine (along with Yellow fever and varicella). European guidelines recommend only using live attenuated vaccines in people well controlled on ART with CD4 counts >200 (14%), or off ARVs with higher CD4 counts (500, >20%).

The presenter suggested considering antibody titres where indicated. However, it is important to remember that antibody responses are used as a surrogate marker and may not reflect impaired cell-mediated immunity in HIV positive patients.

The second case was a reminder to ensure all patients with HIV have an annual influenza vaccine. They highlighted a study which showed no increase in immunogenicity through booster doses or increased antigen dose of influenza vaccine in HIV positive patients.

The second presenter discussed a case of a patient with pneumococcal pneumonia. Whilst the most vulnerable patients are those with low CD4 counts and those not on ART, strep pneumonia remains a problem even in the HAART era, with patients with HIV at greater risk of complications. I found this particularly interesting as I feel there is a lot of uncertainty around appropriate pneumococcal vaccine choice and timing in patients with HIV. 

In patients with HIV, conjugate vaccines (such as 13-PCV) have been shown to have greater immunogenicity (compared with polysaccharide vaccines such as 23-PPV) and it is for that reason they are recommended for initial vaccination where available in the EACS guidelines (and DHHS). EACS guidelines do not recommend booster doses at present. whereas the DHHS guidelines do. 23-PPV can be given 8 weeks after 13-PCV (or after CD4 increases over 200 on ART). In patients who has 23PPV initially, 13-PCV can be given after 1 year. The full DHHS guidelines can be found here: http://aidsinfo.nih.gov/guidelines

The final case discussed was around hepatitis B vaccination. Serological responses to standard dose vaccines are impaired in HIV-infected individuals (with lower response in low CD4 setting and off-ART). There are numerous schemes for non-responders which can be used - one study showed good response (86%) with re-vaccination with the standard schedule (especially if less than 3 months from the last dose of first schedule). Additionally, both double-dose schedules and intradermal vaccination showed improved response rates.

If you made it to the end of this blog, my take home points from this session were: 

  • don’t assume prior vaccination (particularly with primary vaccines), take a full vaccine history and check titres where indicated
  • use live attenuated vaccines with caution and as per guidelines
  • conjugate vaccines appear to have higher immunogenicity and are therefore preferred (e.g. pneumococcal vaccine)
  • double dose Hep B vaccinations in non-responders are easy to administer and show improved response rates 

 

Tagged in: EACS2015

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