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.

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As if there weren’t enough treatments for Hepatitis C already, results of another Hepatitis C treatment trial were presented on Monday at IAS 2017.

Karine Lacombe of Saint-Antoine Hospital in Paris presented findings from AbbVie's phase 3 EXPEDITION-2 trial, which evaluated an 8-week regimen of glecaprevir/pibrentasvir for people with both HIV and hepatitis C.

Glecaprevir is an HCV NS3/4A protease inhibitor and pibrentasvir is an NS5A inhibitor. Both are pangenotypic, or active against all HCV genotypes. The two drugs have been co-formulated in a once-daily combination pill, to be marketed under the brand name Maviret.

Studies in the DAA era have shown that HIV-positive people generally do as well on interferon-free regimens as those without HIV – though it is important to take into account the potential for drug interactions between DAAs and antiretrovirals – and they are no longer considered a "special population." Yet European and US HCV treatment guidelines currently do not recommend shorter treatment for people with HIV and HCV co-infection.  A shorter course of treatment could potentially improve adherence and reduce cost.

EXPEDITION-2 enrolled 153 HIV-positive people with chronic hepatitis C in Europe, the United States and Russia. More than 80% were men and the median age was approximately 45 years. About two-thirds had HCV genotype 1 (mostly with harder-to-treat subtype 1a), followed by genotypes 3 (17%) and 4 (11%); a small number had genotypes 2 or 6.  People with Hep B co-inbfection were excluded.

Sixteen participants (10%) had liver cirrhosis, and most of the rest had absent or mild fibrosis. Nearly 20% were previously treated with interferon and ribavirin, and three had also used sofosbuvir (Sovaldi).  Study participants had well-controlled HIV infection with a median CD4 count of nearly 600 cells/mm3.  All but nine were on antiretroviral therapy, and about three-quarters of treated people were taking the integrase inhibitors raltegravir (Isentress) or dolutegravir (Tivicay), which were shown to have minimal interactions with glecaprevir and pibrentasvir.  They had variable backbones including TDF, FTC, TAF, lamivudine.  I’ve included the drug-drug interaction profiles out of interested, as presented at the session.

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Participants without cirrhosis received glecaprevir/pibrentasvir for 8 weeks, while those with cirrhosis were treated for 12 weeks. Everyone received the study drugs and there was no placebo arm.

 Treatment was highly effective, with 98% having continued undetectable HCV RNA at 12 weeks post-treatment (SVR12). The cure rate rose to 99%, with no virological failures, for people without cirrhosis who were treated for 8 weeks.

A single patient with HCV genotype 3 and cirrhosis, who reported less than complete (85%) adherence, experienced virological failure during treatment. Another participant had missing data at 12 weeks post-treatment, but returned for care at 24 weeks post-treatment and was found to be cured.

 Glecaprevir/pibrentasvir was generally safe and well tolerated. Adverse events were similar to those seen in studies of HIV-negative people. One participant with cirrhosis stopped treatment early due to an adverse event that was not considered drug-related (stroke and brain haemorrhage). The most common adverse events were fatigue, nausea, headache, and nose and throat inflammation.

 "These results suggest that the glecaprevir/pibrentasvir regimen could be the first 8-week, pangenotypic treatment option for HCV/HIV-1 coinfected patients without cirrhosis," the researchers concluded.

This could be a bonus for co-infected patients but caution with drug-drug interactions is still an issue.  However, given the short duration of therapy these may or may not be significant.

 

I'll admit it now, I haven't been very up-to-date on the global approach to Hep C treatment, but this talk really brought me up to speed on several aspects.  Thanks to Dr Joseph Doyle for the great talk.

 

Global elimination targets

  • worldwide there are 2.2 million people living with HCV/HIV
    • compares to 37 million with HIV
    • odds of HCV infection were 6 times higher in people living with HIV
    • most HepC infections related to IVDU but some sexual exposure
  • target: 30% reduction in infections and 10% reduction in deaths (2020)

 

Elements needed for elimination

  • testing
    • early reliable diagnosis, frequent, regular testing
    • diagnosis allows connection with care and treatment, education, harm minimisation services, may influence at risk behaviour
    • Aust: recommends annual testing
      • but may need to recommend more frequent testing if we are serious about eradication
  • access to care
    • recent PBS listing to many new drugs
    • all are now interferon free
    • community prescribing is encouraged (after discussion with ID/hepatology)
    • no disease stage or drug/alcohol restrictions
      • in contrast to other countries where drugs are restricted to those with cirrhosis
      • this restriction would reduce costs but won't make much headway into eradication
  • effective treatment
    • sofosbuvir and velpatasvir (single pill regimen for all genotypes)
    • others are also coming soon
  • treating people at risk
    • target IVDU, MSM, born overseas in HPC
  • cost effective allocation
    • $20k for 4 years of extra life (if severe disease)
    • $60k for 6 years of extra life (if mild disease)
    • therefore even cost-effective to treat mild disease
      • many other options cost >$20k per year of life
  • harm reduction strategies
  • HCV vaccine

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

The medications are effective, the funding is there to support the clinicians, patients are enthusiastic and actively seeking treatment - I think this is an exciting time for Hep C management and I am optimistic to see the future.

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.

 

 

 

 

 

John Brooks from the CDC in Atlanta provided an update on the HIV outbreak first identified in Indiana in December 2014. I reported on his first update from the IAS Conference in Vancouver in July last year.

A couple of things are very noteworthy from these presentations. The response to the outbreak was dramatic, all be it very costly, and effective. What is hugely upsetting is that it could have been prevented with a good public health approach to HIV in the first instance.

A small cluster of HIV infections were identified in a rural county in Indiana. Case follow-up and contact tracing has identified 188 infections. The vast majority of these were identified in the first half of last year with only 11 being identified more recently, and of those the majority had been approached but declined testing previously.

A lot of features made this a perfect storm: no needle and syringe program; high levels of injecting (4 - 15 times daily and sharing with 1 - 6 partners) the reason for this is that the main drug injected was oxymorphone, which sells on the street for up to $140 per tablet, so people inject small doses, regularly to manage withdrawal. High levels of intergenerational sharing, with the belief that this was protective.

The county has the lowest socio-economic profile. Access to health care was limited, many people were uninsured and not registered for social security, unlicensed, not working and did not have common documents such as birth certificates.

This is an excellent presentation which show how a significant epidemic can occur in close knit community with limited access to resources, education and information. Viral sequencing has demonstrated that these were very recent infections and all linked. 

The plenary

http://www.croiwebcasts.org/console/player/29695?mediaType=podiumVideo&

and all of the slides amd MP3 are available at http://www.croiwebcasts.org/y/2016/25?link=nav&linkc=date

There was an HCV positive rate of >90%. But the HCV, unlike the HIV was well established in the cohort, coming from multiple sources over many years. A complementary presentation by Sumathi Ramachandran, Networks of HCV Transmissions Among Persons Who Inject Drugs: Indiana, 2015  looks at hepattiis C infection in this community can be found at http://www.croiwebcasts.org/console/player/29742?mediaType=slideVideo& 

There has been considerable discussion about the potential for outbreaks in rural and remote communities in Australia. This experience is one which should be viewed by all involved in the public health response to HIV and by all those involved in policy making which impacts public health.

 

Excellent plenary session lead by Ed Gane discussing an overview of the swift evolution of HCV over 25 years!

I've summarised the main points: 

- HCV first identified in 1989 as non A non B

 

Current epidemic

- 80-100 million (300,000 in Aust & NZ) and is overtaking HBV as liver mortality 

- infection leads to premature death - especially co-infected HIV/HCV

- the disease burden will continue to rise as infected (ageing) patients develop complications such as cirrhosis and liver cancer.

 

So, how do we eliminate HCV? 

Vaccination?

- genomic diversity (both virus & host)

- funding diminished now DAAs so potent 

- likely not to lead to eradicate HCV

 

Public Health interventions?

- eg harm reduction in PWID (syringe programs etc)

- can only do so much - decrease prevalence by 1/3 in countries which employ reduction methods ( and most countries don't)

 

DAA therapy?

- we need patients to be diagnosed prior to any dent being made in HCV prevalence

- currently Aust has reasonable diagnosis rates, but very poor treatment rates

- DAAs offering a new treatment paradigm for HCV by combining effective drugs with minimal SE and short durations

- e.g. Ledipasvir/Sofosbuvir (Gilead) - daily, oral, 12 week program, IFN & RBV free with excellent SVRs (97%) in GT1. Even in Pugh B/C patients, SVR nudging 90%. In the co-infected cohort the results are equally exciting

- Abbvie & Merck also have similar products 

 

We CAN eliminate HCV with:

- FUNDING

- better diagnosis rates 

- access to fibroscan 

- significant increased capacity to treat and uptake 

- employ treatment as prevention 

- make prescribing more accessible (in discussion in AUST) 

- FUNDING!!

 

Exciting to think that Australia looks to be leading the way!

There were many highlights today but I will focus on some of the topics that resonated most with me related to technologies or interventions which could benefit marginalised groups in Australia. 

 

- Shoena Mitchell-Foster spoke on the higher uptake of self collected specimens versus othere traditional methods for cervical screening in a low income country setting in both HIV positive  and negative women. This study identified some of the barriers to traditional testing including the invasive nature of a pelvic examination and cultural considerations. Also to consider is ease of access to a primary health care provider particularly in very remote areas. Self collected specimens could negate the need for nurses or doctors to perform a Pap test. Considering the lower rates of cervical screening in Australian indigenous women, a national screening program using self collected specimens could be of great benefit in both urban and rural settings.

- Gail Matthews spoke about the CEASE study. She showed an excellent slide which illustrated the dense concentration of people co-infected with HIV and HCV in Sydney, NSW.. The slide also supported the idea that this would mean access to most of the clients could occur through only five or so health services where many of these individuals were already linked in. There are also a number of community S100 prescribers in the area. Eradication of HCV in this group seems a realistic prospect as many are well engaged with services however there is possibly a subgroup of very marginalised individuals who may find adherence more challenging and may require additional support to access and complete treatment. Definitely exciting times ahead in relation to HCV treatment!

- Prof Greg Dore spoke about HCV prevention and treatment in the criminal justice setting. Although not without its challenges, prison is quite a good setting to initiate, if not complete HCV treatment. The overall prevalence rate is a staggering 50% including the inmates who do not reporting injecting drug use. The nurse-led model is a fantastic way to increase access for  a population in great need and it's also a wonderful opportunity for nurses to use and develop skills and to work in an autonomous role. 

Looking forward to tomorrow's sessions!

 

No impact of HIV on HEPC treatment outcome

95-97% cure rates even in co-infected

Improvement in quality of life occurs v. Quickly with new oral medIcations due to suppression of the Hep C virus.

If there is cirrhosis of the liver, treat for 24 weeks. De compensated cirrhosis may be reversible, but not always.

In Australia, HIV/HCV co infected numbers approx 2,500-3,000

 

John Brooks presented two papers on behalf of the Indiana Dept of Health and CDC which described the recent HIV outbreak in a small town in Indiana and then looked in more detail at the molecular epidemiology of the events. This is a truly shocking story. Some of you may have been following it on HIV list serves, but these two papers eloquently and emphatically demonstrated just what can go wrong and how quickly. This should be essential viewing for many politicians and policy makers, particularly those who oppose harm minimisation strategies or question the need for surveillance.

The location is a small town in Indiana late last year 3 new HIV diagnoses were made in one month. Previously only 8 diagnoses had occurred in town. A surveillance office saw this and look into it.  It became apparent that they were connected through a common vector and were all injected oxymorphone (morphine prescription tablets) 8 additional cases were identified and an outbreak notified to the CDC.

Subsequent contact tracing has revealed 170 infections (as of 14 June) where the data was analysed and a further four cases have been identified since then. The outbreak has plateaued.

There is a very high level of injecting prescription morphine pills in the town. Many families have 3 generations injecting, unemployment is high, until recently NSP was illegal in Indiana. There was no HIV education and education levels low. Many people were not registered for Medicaid. There was very low HIV literacy, and little education there was no school based HIV education program. People thought injecting "at home" or "with the family" protected from HIV.

Philogentic testing had been performed on about 60 samples. These showed 2 groups one of three individual and all the rest in one amorphous mass. These are the clearest clusters i have ever seen. When HCV sequencing was performed on the same samples it revealed a number of clusters and a great many unrelated cases. What this shows is that HCV had entered this community over time from many different sources and that the HIV  outbreak is an actual outbreak. Once HIV came into the community it spread like wildfire.

The response has been excellent. It took a little while to get into full swing. But this was put done to the need for confidentiality and to initiate contact tracing in a confidential and privacy sensitive manner. Indiana has passed a law allowing NSP (perhaps just in this location) and they have mobile as well as a fixed site. People have been registered for Medicade, tested for a range of STI and BBV, vaccinated where needed and available. Linked to care and encouraged into treatment. 70% are in care and of those 40% are on treatment and this is being actively pursued.

There are billboards promoting HIV prevention and public campaigned promoting safety. Ryan Whites mother has addressed a public meeting in the town, in an attempt to curb discrimination. A number of people are on PrEP and even more are asking for it as awareness about it grows.

As was commented in the session. It is terrible that this is occurring now in a developed country. NSP should be universally available. The costs associated with this outbreak will keep on costing. What is scary is just how quickly this occurred. They were recent infections and so highly infectious. Injecting provided a very efficient route of transmission. If those 3 people had not been identified late last year would it even have been noticed now. But even more scary, could this be happening elsewhere.

 

 

 

 

Cindy Zahnd reported on data modeled from the Swiss HIV and hepatitis C Cohort. Specifically the considered the impact of deferring treatment initiation in HIV-HCV co-infected patients. There was not difference starting in a month or 12 months. But treatment outcomes were heavily impacted by fibrosis score at treatment commencement. Delaying till F3 doubled the risk of disease progression and delaying till F4 saw a five fold increase.

Interestingly patients with F4 were more likely to have a serious or fatal liver event even after having had an SVR on treatment. This is probably because even though the virus was cleared irreversible damage was sustained. A salient message for clinicians and patients who might be waiting for the next best drug to come along.

You can view this and other coinfection oral presentations from the http://www.croiwebcasts.org/ it was session O-12 Curing hepatitis C: Mission accomplished