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 Co-infections, hepatitis B, hepatitis C and TB

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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.

 

From HIV and the Liver: Co- infection and Complications  

Nikoloz Chkhartishvilli presented an overview of the co-infection care cascade from Georgia, a country which has a high disease burden of HIV/HCV co-infection. Despite the differences in our countries political and presumably health care systems, the roll out of their HCV elimination program recalled similar population priorities to the Australian model.

During 2011- 2015, the Global Fund supported Georgia to reduce the disease burden of HCV by offering PEG/RBV to people living with HCV. From 2015, in partnership with Gilead Sciences and U.S. CDC to launch their National HCV Elimination Program and DAAs became available. Similar to the Australian model, there was no cost to the patients and current injection drug use was not a barrier to accessing treatment.

The care cascade is described as follows: 1) HIV/HCV co-infected; 2) Diagnosed for both HIV & HCV, 3) Treated for HCV, 4) Achieve SVR . Data were obtained from the national AIDS health information system

Results: Among 3300 co-infected individuals, 2201 (67%) were not aware of their HIV status, 1099 (33%) were diagnosed with both HIV/HCV, and of those 1099 (33%) persons, 697 (63%) were treated with either PEG/RBV or DAAs. 480 (69%) of those treated attained SVR with 44% for PEG/RBV and 89% with DAAs. So of the 697 (21% of the original cohort) individuals treated, approx. 480 achieved SVR, this being 69% of the treated cohort and 15% of the original co-infected cohort.

A gap in care was identified from time of diagnosis to time of treatment as the major contributor to the low uptake and completion of treatment, calling for tighter systems to support the elimination plan. Highlighted that it’s not just free or subsidised treatment availability, but also the systems and infrastructure required to support programs such as this.

 

Nadine Kronfli presented on trends in cause- specific mortality in HIV/HCV co- infected patients in Canada 2003- 2016 and the impact of early HCV treatment.

Liver related deaths (ESLD & viral hepatitis) account for 20-25% of deaths in Canadian co-infected population. Mortality rates have decreased since introduction of DAAs achieving SVR>85% and opportunity to reverse fibrosis, decrease sequelae.

Looking at which modifiable risk factors may contribute to excess mortality in co-infected population to help prevent potentially preventable deaths in an already high risk population (lifestyle, exposures related to IDU in co-infected pop).

They used the Canadian Co-infection Cohort which is a prospective multicentre cohort of 1695 co-infected patients from 19 sites in Canada (resulting in 6675 person- years follow up from 1477 eligible patients). Deaths were classified using a ‘coding of cause of death in HIV’ protocol. Event rates per 1000 person- years before (2003- 2009) and after (2010- 2016) the availability of widespread effective treatment stratified by age 20-50, 50-80 yrs were calculated.  

75% of the cohort were current smokers at baseline, 84% taking ART, 64% HV VL <50 copies/ml, 81% HCV treatment naïve, 21% APRI > 1.5, 9% prior ESLD dx.

Overall and cause specific mortality, with cause of death divided into 5 categories: ESLD (20%), smoking related (17%), drug OD (16%), other- including AIDS/infections/ cancer/ trauma/ suicide (22%), unknown (25%).

20- 50 yrs: 2003- 2009: 26.04 (13.91, 48.75); 2010- 2016: 19.29 (11.59, 32.11)

50- 80 yrs: 2003- 2009: 56.61 (28.09, 114.1); 41.97 (28.2, 62.46)

Key point from deaths- most had poorly treated HIV and did not achieve SVR as higher deaths on ‘non- ideal’ patient population (CD4 <350, APRI > 1.5, HIVRNA>50).

Concluded that all cause mortality decreased in both age groups over time, explained by a reduction in mortality from a variety of competing causes, no significant decrease in ESLD deaths overall however ESLD appears to be declining in 50-80 year olds, or those who have been successfully treated; immediate impact of HCV therapy most profound among those with fibrosis, and targeting modifiable risk factors such as smoking may confer the highest benefit.

 

Maud Lemoine presented ‘metabolic syndrome and obesity are the cornerstones of liver fibrosis in HIV monoinfected patients: results of the METAFIB study’

Metabolic syndrome and its hepatic manifestation, NAFLD, have emerged as new concerns for PLHIV (prevalence 25% and 35% respectively).

METAFIB study proposed to assess the impact of metabolic syndrome on the proportion and severity of liver fibrosis and analyse association between met syndrome, liver fibrosis, markers of adipose tissue and macrophage activation.

METAFIB is a single centre exposed- non exposed cohort of HIV monoinfected individuals without excessive alcohol consumption, viral hepatitis, or other causes of CLD.

Fibroscan used to measure liver stiffness.

Results from 405 participants (203 with metabolic syndrome, 202 without). Patients with met syndrome were older and 49% had insulin resistance, risk factors for fibrosis: Obesity with BMI >30, T2DM, elevated GGT and leptin.

Liver transaminase levels, ART exposure or HIV parameter levels were not associated with liver fibrosis.

Take home message was that HIV monoinfected patients with metabolic syndrome are at risk of liver fibrosis irrespective of transaminase levels and should be systematically screened. Mass fat measured by BMI and circulating leptin is strongly associated with fibrosis independent of HIV parameters or ART exposure. Adipose tissue, insulin resistance and macrophage activation are likely key players in the development of fibrosis.

There was an audience question regarding impact of some ART in regards tocausing/ association with insulin resistance. Answered that the cohort was older, and treatment experienced, however patients with good virological control were selected so didn’t feel the results could answer that question.

Recommendation to screen all PLHIV with metabolic syndrome regardless of LFTs for fibrosis using fibroscan cheap, easy, non-invasive.

 

Hugo Perazzo Pedroso Barbosa presented data from the PROSPEC- HIV study looking at predictor factors associated with liver fibrosis and steatosis in a monoinfected population.

Cross sectional study from a cohort of 4000 patients who have been followed from 1990. Exclusion was viral hepatitis co-infection and ART naïve.

 

Heavily pre- treated population inc. AZT and other early ART.

Clinical evaluation including alcohol assessment, fasting bloods and fibroscan was used.

 A total of 348 HIV mono-infected patients [61% female, median (IQR) age=44 (34-52) years, BMI=25.4 (23.0-29.3) kg/m²] were included. Median (IQR) time under c-ART and under the current c-ART regimen were 7.3 (4.1-12.8) and 4.3 (1.9-7.5) years, respectively. LSM and CAP were unreliable in 6% and 12%. Liver fibrosis and steatosis prevalence were 9% (n=30/326) and 33% (n=102/305). In age and gender adjusted multivariate analysis, factors associated [OR (95%CI)] with liver fibrosis were: age > 45 years [2.91 (1.19-7.15); p=0.020]; CD4 count < 200 cells [5.00 (1.38-18.21); p=0.014] and type-2 diabetes [3.04 (0.97-9.55); p=0.056]. Male gender [5.69 (2.68-12.04); p< 0.001]; dyslipidemia [2.86 (1.46-5.60); p=0.002]; type 2 diabetes [6.00 (2.08-17.28); p=0.001] and central obesity [10.24 (4.11-25.50); p< 0.001] were independently associated with liver steatosis.

Concluded that low CD4 count was independently associated with presence of liver fibrosis, metabolic syndrome features were independently associated with steatosis by CAP, higher duration of ART especially AZT as a backbone was associated with steatosis independently of metabolic factors.

 

 

Take home message from session: Importance of reducing modifiable risk factors to improve patient’s health outcome, especially smoking and factors contributing to development of metabolic syndrome. 

Tagged in: 2017 IAS Conference

A very brief blog on Hep B treatment and new agents presented by Jürgen Rockstroh

TAF works for Hep B

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Here's the data

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Can we cure Hep B like Hep C?

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Names in black are in the pipeline

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Tagged in: APACC 2017
Managing HIV / HepC; Sofosbuvir / Velpatasvir effective with management well suited to primary care settings.

     

Doyle,J (session presentation) ; coEC Study

Lu,Y (2 poster presentations) ; ASTRAL-5 Study

This presentation by J Doyle from the Burnet Institute highlighted the findings from the first year of the co-EC study in Melbourne. Modelling presented by Scott, et al at EASL 2017, proposes that treatment of 515 co-infected individuals in Victoria will reduce the prevalence of hepatitis C within the GBM community by 80%.

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In the first year clinical data was collected on 160 chronic HIV/HepC co-infected individuals on ART. This included biochemical, haematological and fibrosis data. Primary care clinicians assessed this data and individuals either:

  • received immediate DAA therapy (40%)
  • received DAA therapy after specialist advice (31%)
  • were referred for specialist care (19%)

Referrals were predominantly required for known cirrhosis, APRI score >1, malignancy, renal/cardiac disease or fibroscan >12.5Kp.

This study highlighted the capacity for the majority of non-cirrhotic HIV/Hepatitis C individuals to be effectively managed by a primary care clinical team. This model of care fits comfortably with Australia's move toward patient centred, community based care within health care homes. 

ASTRAL-5 (2 poster presentations)

The efficacy, tolerability and safety of Sofosbuvir / Velpatasavir in HIV / Hep C co-infection was presented. 106 patients were enrolled for 12 weeks of SOF/VEL therapy. SVR at 12 weeks was demonstrated in the majority of patients across the 5 genotypical variants assessed. 

ASTRAL-5: SVR12 rates by genotype.

  •        Genotype                             SVR12%   (n/N)
  •        Total                                    95%
  •        GT1a                                    95%
  •        GT1b                                    92%
  •        GT2                                     100%
  •        GT3                                      92%
  •        GT4                                     100%

No patient experienced HIV virological rebound.

Side effects were similar to other available DAAs with fatigue (25%), headache (13%) and nausea (7%) reported. 

  • Drug-Drug interaction studies demonstrated no clinically significant interaction with a wide range of commonly used ART regimes. The only exception is that of EFV. There was a 53% reduction in VEL levels and thus EFV is currently not recommended for use with Velpatasvir. 

These presentations highlighted the suitability of primary care teams to effectively manage HIV/Hep C co-infection. This community based, patient centric model of care will enhance our capacity to eliminate Hepatitis C among the HIV cohort within Australia. The combination of Sofosbuvir with Velpatasvir provides pan-genotypical efficacy, good tolerability and limited drug interaction with ART. These characteristics will further enhance the ability of HIV/HepC to be safely and effectively managed in primary care settings within Australia.

Tagged in: APACC 2017

Comment: Abstract follows.

Modelling studies presented at CROI in 2016 predicted that prompt treatment of Hepatitis C with direct acting antivirals (DAAs) may substantially decrease the incidence of acute Hepatitis C in HIV + MSM. This study applies modelling to assess the impact of the rapid uptake of Hepatitis C DAA therapy on the incidence of acute Hepatitis C infection among HIV+MSM in the Netherlands.

In November 2014, all oral DAA therapy became available for F3-4 fibrosis and from September 2015 for F0-2 as well, resulting in rapid DAA uptake in Dutch HIV+MSM with chronic HCV. 65% were cured or on DAA therapy 6 months after unrestricted DAA availability (CROI 2017 Boerekamps et al). Also, in 2014 and again in 2016, individuals with acute Hepatitis C were offered immediate therapy in DAHHS study centres across the Netherlands.

 In 2014, 93 acute infections occurred in 8290 PYFU while in 2016, 49 acute cases were diagnosed in 8961 PYFU. The incidence in 2014 of 11.2/1000 showed a continuous decline to 6.9/1000 and 4.0/1000 within the first and second half of 2016. 1 year after unrestricted DAA availability in the Netherlands, the incidence of acute HCV in HIV+MSM decreased by 52%.

 A delegate enquired whether this reduction may be due to a change in sexual practices of the participants with increased condom use in the era of sexual transmission of Hepatitis C. Review of syphilis and gonorrhoea rates in study participants however, showed a rise in these STIs and would suggest otherwise. Further, next door neighbours Belgium are yet to gain unrestricted access to DAAs and their incidence of acute hepatitis C remains unchanged in recent years. Although the presenter indicated that this modelling study doesnt provide proof, it strongly suggests that for the first time, real-life data shows that HCV treatment as prevention averts new HCV infections in HIV+MSM.

Exciting to document what we think we know! This strengthens the argument to treat acute Hepatitis C in high risk MSM and injecting drug users. The last word went to an American delegate who posed the question to the Dutch presenter: Does this mean you should build a wall between the Netherlands and Belgium?

 

137LB SUBSTANTIAL DECLINE IN ACUTE HCV INFECTIONS AMONG DUTCH HIV+MSM AFTER DAA ROLL OUT

Anne Boerekamps et al

1Erasmus Univ Med Cntr, Rotterdam, Netherlands,

Background: The incidence of acute HCV (AHCV) among Dutch HIV+MSM has been high for >10yrs. Recent modelling studies predict that prompt treatment with direct acting antivirals (DAA) may decrease this incidence substantially (CROI2016 A536) but confirmation from real-life data is awaited. In 11/2014 all oral DAA therapy became available for F3-4 fibrosis and from 09/2015 for F0-2 as well, resulting in rapid DAA uptake in Dutch HIV+MSM with chronic HCV with already 65% cured or on DAA therapy 6 months after

unrestricted DAA availability (CROI 2017 Boerekamps et al). Also, in 2014 (in DAHHS1 study NCT01912495) as well as in 2016 (in ongoing DAHHS2 study NCT02600325) patients with AHCV were offered immediate therapy in DAHHS centers across the Netherlands. We hypothesized that this rapid treatment uptake will result in a lower incidence of AHCV among HIV+MSM.

Methods: AHCV was defined as HCV-RNA positivity, preceded by a negative HCV-RNA or HCV-IgG within 12 months. When stored plasma could not be retested, a normal ALT preceding the first positive HCV-RNA test together with a negative IgG any time in the past or a positive HCV-RNA and a simultaneous negative IgG was also considered diagnostic for AHCV. The incidence of AHCV was calculated by dividing the cases by the patient years of follow-up (PYFU). Data were available from 18 HIV treatment centers, geographically

spread across the Netherlands having +/-80% of Dutch HIV+MSM in care. We compared the incidence in 2014 (year preceding DAA availability) to 2016 incidence (first year after DAA availability).

Results: In 2014, 93 AHCV infections occurred in 8290 PYFU (=11.2/1000 PYFU, 95% CI 9.1-13.7). In 2016, 49 AHCV were diagnosed in 8961 PYFU (=5.5/1000 PYFU, 95% CI 4.17.2, p<0.001). The incidence in 2014 of 11.2/1000 showed a continuous decline to 6.9/1000 and 4.0/1000 within the first and second half of 2016. A relative increase in genotype 4 infections was observed from 19% (n=18) to 31% (n=15) (p=0.02). The absolute number of AHCV infections decreased both in patients with a first AHCV infection as well as in

patients that had an AHCV reinfection (=patients previously cured of an AHCV infection), while the proportion of reinfections remained constant: 21/93 in 2014 and 12/49 in 2016 (p=0.8).

 

Conclusion: 1 year after unrestricted DAA availability in the Netherlands, the incidence of acute HCV in HIV+MSM decreased by 52%. For the first time, real-life data show that HCV treatment as prevention averts new HCV infections in HIV+MSM.

Tagged in: CROI 2017