November 20, 2013

Thursday, November 21, 2013 by Proactive Investors

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Biotron Limited will conduct a three month Phase 2 dosing study of its BIT225 drug candidate for the treatment of the Hepatitis C virus.

Biotron Limited (ASX: BIT) has received ethics approval to conduct a three month Phase 2 dosing study of its BIT225 drug candidate for the treatment of the Hepatitis C virus.

The study will be conducted on 60 patients at up to six trial sites in Thailand with the primary site - Bangkok’s Siriraj Hospital – granting the ethics approval.

Initial patients are expected to commence dosing by the end of this month and the trial is expected to be fully recruited by mid 2014.

Preliminary data is expected to be released by November 2014.

The study is designed to generate safety and efficacy data of BIT225 when administered over a three month period in patients infected with Hepatitis C genotypes 1 or 3.

It will use the new capsule formulation of BIT225 that is expected to have an improved safety profile and ease of use compared to the previous powder formulation.

Biotron’s BIT225 compound is the first in a new class of direct acting antiviral drugs for Hepatitis C. It specifically targets the p7 protein, which is involved in virus assembly.

The previous BIT225 study in HCV patients focused on a four week dosing regimen. Phase 2a data demonstrated that 100% of trial subjects who received BIT225 (400mg) over four weeks had undetectable levels of virus in the blood at the 48 week follow up. This was compared to 75% of patients who received standard of care alone.

The Hepatitis C global market is currently estimated at US$3.3 billion, but is expected to expand to over US$15 billion as safe, effective therapies enter the market.

Proactive Investors Australia is the market leader in producing news, articles and research reports on ASX “Small and Mid-cap” stocks with distribution in Australia, UK, North America and Hong Kong / China.

Source

Aliment Pharmacol Ther. 2013 Nov 10. doi: 10.1111/apt.12543. [Epub ahead of print]

Younossi ZM, Reyes MJ, Mishra A, Mehta R, Henry L.

Department of Medicine, Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, VA, USA; Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA.

Abstract

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is an umbrella term, which encompasses simple steatosis and non-alcoholic steatohepatitis (NASH). The entire spectrum of NAFLD has been associated with metabolic syndrome. NASH is associated with increased mortality compared with that of the general population. Many therapeutic options for NASH have been studied. However, there is very little evidence supporting the efficacy of most regimens for the treatment of NASH.

AIM: To provide a review focusing on the current therapeutic options available for patients with NASH as well as to briefly introduce possible future interventions.

METHODS: A MEDLINE, Pubmed and Cochrane Review database search using a combination of keywords, which included non-alcoholic fatty liver disease, non-alcoholic hepatic steatosis, NAFLD, NASH, treatment, therapeutics, vitamin E, orlistat and bariatric surgery. An overall summary of the articles was developed for each section of discussion in this review.

RESULTS: NASH associated with metabolic syndrome can progress advanced fibrosis and cirrhosis. Weight loss and lifestyle modification have been shown to improve NASH. Other medications used for weight loss and metabolic syndrome have been evaluated, such as orlistat, metformin and thiazolidinediones. Alternative regimens using ursodeoxycholic acid, statins and probiotics as well as bariatric surgery have been evaluated, but have not been recommended as first-line treatment for NASH. Vitamin E for NASH patients without diabetes seems to be promising. The lack of effective treatment for NASH suggests the heterogeneity of patients presenting with the NASH phenotype. The best treatment strategy for these patients may be to identify their pathogenic target and develop personalised treatment protocols.

CONCLUSIONS: Currently, there are few options available for the management of NASH. Future targeted treatment strategies based on the pathogenic pathways may be needed to develop effective treatment for patients with NASH.

© 2013 John Wiley & Sons Ltd.

PMID: 24206433 [PubMed - as supplied by publisher]

Source

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A new federal government study provides the first estimates of the proportion of the population infected with the hepatitis B and C viruses, but experts say the figures significantly downplay the scale of the problem in Canada.

Helen Branswell, The Canadian Press
Published Wednesday, November 20, 2013 1:30PM EST

TORONTO -- A new federal government study provides the first estimates of the proportion of the population infected with the hepatitis B and C viruses, but experts say the figures significantly downplay the scale of the problem in Canada.

The projections are drawn from the Canadian Health Measures Survey, which actually tested the blood of people who took part to look for the viruses. They are based on data from 8,434 Canadians aged 14 to 79.

The study, published Wednesday by Statistics Canada, found 0.4 per cent of people surveyed were infected with hepatitis B and 0.5 per cent were infected with hepatitis C.

Half of the people with hepatitis B said they were unaware of the infection; 70 per cent of the people with hepatitis C said they did not know they were infected.

Experts have been warning that Canada is facing an unrecognized health-care crisis with hepatitis C, because undetected and untreated infections in the baby boom generation will trigger a surge in cases of liver failure and liver cancer.

The chairman of the board of the Canadian Liver Foundation suggests the new estimates are actually unhelpful, because they give a falsely reassuring sense of the scope of the problem.

"I think they're actually harmful, counterproductive. Because I think it's minimizing the true state of affairs," said Dr. Morris Sherman, a hepatologist (liver specialist) at Toronto General Hospital.

The survey estimates 138,600 Canadians have hepatitis C. But Statistic Canada's own website reports that the number of diagnosed cases of hepatitis C in the country -- it is a reportable disease -- is nearly 300,000, Sherman notes.

The Canadian Health Measures Survey is designed to test a representative sample of Canadians for a range of different conditions -- things like high blood pressures, diabetes and obesity. It does not include First Nations people living on reserves, prison inmates, members of the Armed Forces or people living in some remote regions.

To get a good idea of the scale of the hepatitis B and C problems, the survey would need strong representation from certain population groups that typically don't agree to take part in this kind of a study, says Dr. Mel Krajden, a hepatitis C expert with the B.C. Centre for Disease Control.

Those groups include injection drug users, the homeless, First Nations people, prison inmates and immigrants from parts of the world where hepatitis B and C infections are more common than they are in Canada. Those include South Asia, China and Eastern Europe.

"The study wasn't designed to specifically understand the epidemiology of (hepatitis) B and C. Unless you sample these populations correctly, you may not accurately estimate what's going on," Krajden says.

He notes it is typically extremely hard to accurately sample these groups. In particular, immigrants from some parts of the world where rates of these infections are high may be distrustful of this type of study and refuse to take part, he says.

Krajden says British Columbia knows the hepatitis C status of about one-quarter of its population, because a lot of testing has been done there. About 1.4 per cent of the province's total population is hepatitis C positive; among baby boomers, where the risk is greatest, the rate is three per cent, he says.

Krajden says B.C. rates may be higher than other provinces, because there are higher rates of injection drug users there. While he called the new data "a step in the right direction," he too believes the estimates in this new report are artificially low.

In related news Wednesday, Janssen Inc. announced that Health Canada has approved its new hepatitis C drug Galexos, (its generic name is simeprevir).

Doctors who treat people with hepatitis C have been anxiously awaiting approval of this and another pending new drug as they are expected to be significantly easier for patients to take and should have a higher success rate.

But the new drugs are expected to be very costly, and experts worry that may slow their adoption.

Source

AIDS

Thomas C.S. Martin, Natasha K. Martin, Matthew Hickman, Peter Vickerman, Emma E. Page, Rhiannon Everett, Brian G. Gazzard, Mark Nelson

AIDS. 2013;27(16):2551-2557.

Abstract and Introduction

Abstract

Objective: Liver disease secondary to hepatitis C virus (HCV) infection in the context of HIV infection is one of the leading non-AIDS causes of death. Sexual transmission of HCV infection among HIV-positive MSM appears to be leading to increased reports of acute HCV infection. Reinfection after successful treatment or spontaneous clearance is reported among HIV-positive MSM but the scale of reinfection is unknown. We calculate and compare HCV reinfection rates among HIV-positive MSM after spontaneous clearance and successful medical treatment of infection.

Design: Retrospective analysis of HIV-positive MSM with sexually acquired HCV who subsequently spontaneously cleared or underwent successful HCV treatment between 2004 and 2012.

Results: Among 191 individuals infected with HCV, 44 were reinfected over 562 person-years (py) of follow-up with an overall reinfection rate of 7.8/100 py [95% confidence interval (CI) 5.8–10.5]. Eight individuals were subsequently reinfected a second time at a rate of 15.5/100 py (95% CI 7.7–31.0). Combining all reinfections, 20% resulted in spontaneous clearance and treatment sustained viral response rates were 73% (16/22) for genotypes one and four and 100% (2/2) for genotypes two and three. Among 145 individuals with a documented primary infection, the reinfection rate was 8.0 per 100 py (95% CI 5.7–11.3) overall, 9.6/100 py (95% CI 6.6–14.1) among those successfully treated and 4.2/100 py (95% CI 1.7–10.0) among those who spontaneously cleared. The secondary reinfection rate was 23.2/100 py (95% CI 11.6–46.4).

Conclusion: Despite efforts at reducing risk behaviour, HIV-positive MSM who clear HCV infection remain at high risk of reinfection. This emphasizes the need for increased sexual education, surveillance and preventive intervention work.

Introduction

Following the introduction of effective antiretroviral therapy (ART), liver disease has become the leading non-AIDS cause of death among HIV-positive individuals in the resource rich world.[1] The majority of liver disease in HIV-positive patients is caused by coinfection with the hepatitis C virus (HCV).[1–3] Coinfection with HIV and HCV is associated with accelerated liver fibrosis and shorter time to progression to cirrhosis and hepatic decompensation when compared with those with HCV monoinfection.[4–8]

Over the past decade, an epidemic of sexually transmitted HCV among HIV-positive MSM in Europe, the USA and Australia has been reported.[9–17] Phylogenetic analyses of circulating HCV strains in European countries suggest sexual transmission occurring since the mid-1990s.[10,18] The incidence of HCV infection among HIV-positive MSM is increasing with recent reports of rates as high as 2–5 per 100 person-years (py).[18–21] Identified risk factors for transmission include ulcerating genital infections, unprotected anal intercourse and high-risk sexual activity such as toy use, group sex, fisting and recreational drug use.[9,17,21–23]

Reinfection with HCV following either treatment or spontaneous clearance has been demonstrated in animal models, people who inject drugs (PWID) and, more recently, HIV-positive MSM.[24–27] Among PWID, weak evidence exists to suggest that individuals who spontaneously clear HCV monoinfection are at lower risk of developing chronic reinfections. This lower risk may in part be explained by the development of partial immunity leading to a higher probability of spontaneous clearance of reinfection. However, study results are highly heterogeneous and conflicting results may in part be explained by variable testing intervals during follow-up.[24,28] One retrospective study in the Netherlands revealed an alarmingly high HCV reinfection rate of 15.2 per 100 py among HIV-positive MSM who had previously been treated for acute HCV infection.[29] No studies to date have investigated the rate of reinfection among HIV-positive MSM in the United Kingdom, and whether there are differing reinfection rates among those who spontaneously clear their infections and those who are successfully treated.

We, therefore, calculated and compared the HCV reinfection rate among individuals who had either been treated for acute or chronic HCV infection, or who had spontaneously cleared their HCV infection within a cohort of over 8000 HIV-infected individuals attending clinic at Chelsea and Westminster Hospital in London, United Kingdom.

Methods

Study Population

All HIV-positive MSM who had a positive HCV antibody result between January 2004 and April 2012 who attended the dedicated HIV clinic at Chelsea and Westminster Hospital were identified. Individuals were excluded if their primary documented mode of transmission was via contaminated blood products or injecting drug use. The following subgroups were extracted for inclusion within the study.

  1. Successfully treated HCV infection with results indicating a sustained viral response (SVR) defined as undetectable viral replication 24 weeks following end of treatment and at least one subsequent HCV PCR measurement.

  2. Spontaneously cleared HCV infection with evidence for undetectable HCV PCR for at least 24 weeks following infection and at least one subsequent HCV PCR measurement.

  3. Spontaneously cleared or treated HCV infection who were subsequently reinfected with a different HCV genotype from their previous infection but within the 24-week period required to formally reach SVR.

Data Collection

All HCV PCR results subsequent to the first identified HCV infection were recorded. Basic HIV infection and patient characteristics were collected from medical files including age, HIV viral load, CD4+ lymphocyte subset count, ART details, HCV genotype and peak alanine transaminase (ALT) levels. Behavioural data was not routinely collected at the centre and was, therefore, unavailable for our study.

Case Definitions

HCV reinfections were defined as any newly detectable HCV PCR following SVR for treated infections or 24 weeks after spontaneous clearance. In addition, cases were defined as reinfection if patients had detectable HCV viraemia within 24 weeks of end of treatment or spontaneous clearance if there was an HCV genotype switch.

Patients were subdivided depending on whether it was possible to determine that the initial infection was their primary infection (shown by a negative HCV antibody within a year prior to positive HCV antibody detection), or that the nature of the initial infection was uncertain (no previous antibody result available or previously HCV antibody positive).

Data Analysis

For those individuals who underwent HCV antiviral treatment, the commencement of follow-up was taken from the end-of-treatment date. For those who spontaneously cleared their HCV infection, start of follow-up was the midpoint between the last positive and first negative HCV PCR. The date of reinfection for all patients was taken as the midpoint between the last undetectable HCV PCR and the first positive HCV PCR.

Reinfection rates were calculated by dividing the number of reinfections by the total number of patient-years of follow-up. Kaplan–Meier survival curves were created to assess the proportion reinfected over time. Comparisons of median testing intervals, age and peak ALT levels were performed using Kruskal–Wallis rank test. Analysis of proportion of patients on ART was performed using Fisher's exact test. Equality of variances was assessed using Bartlett's test. All statistical calculations were performed using Stata 10.0 (Stata Corp, College Station, Texas, USA).

Results

Eight hundred and fifty-eight individuals were identified with a positive HIV and HCV antibody result. Of these, 191 HIV-positive MSM with HCV who fulfilled our inclusion criteria were identified, representing 562 patient-years of follow-up. Among these patients, 145 had a documented primary infection and 46 had uncertain initial infection details. The stratification of patients is summarized in Fig. 1.

812514-fig1

Figure 1. Flow schematic of patients included in the study. HCV, hepatitis C virus; SVR, sustained viral response.

Flow schematic of patients included in the study. HCV, hepatitis C virus; SVR, sustained viral response.

Among the 145 who had either spontaneously cleared or had been successfully treated for a primary HCV infection, there were 400 py of follow-up with a median follow-up time of 2.1 years. The median testing intervals during follow-up were 105 and 173 days among those successfully treated and those who spontaneously cleared their primary infection, respectively. The difference in testing interval was statistically significant (P < 0.0001). The median age of patients included was 41 years. Group characteristics and follow-up details are summarized in .

Table 1.  Group characteristics divided by hepatitis C virus infection status during initial primary infection and during follow-up post primary infection.


 
Treated HCV infection Spontaneously cleared HCV infection
All patients Nonreinfected Reinfected Nonreinfected Reinfected
Incident infection
   Total 145 87 27 26 5
   Median age (IQR)   41 (38–47) 41 (37–43) 39 (34–43) 36 (35–42)
Incident genotype (%)
   1 97 67 (77) 22 (82) 7 (27) 1 (20)
   2 1 1 (1) 0 (0) 0 (0) 0 (0)
   3 6 5 (6) 0 (0) 1 (4) 0 (0)
   4 18 13 (15) 4 (15) 0 (0) 1 (20)
   Unknown 23 1 (1) 1 (1) 18 (69) 3 (60)
   Median peak ALT of incident infection (IQR)   476 (251–1014) 414 (216–832) 359 (145–755) 95 (54–327)
Follow-up
   Median testing interval, days (IQR) 112 (62–224) 106 (62–210) 99 (55–161) 189 (89–343) 99 (63–247)
   cART use during follow-up (%) 129 (89) 82 (94) 22 (81) 21 (81) 4 (80)
   Median peak ALT during follow up (IQR)   38 (26–55) 254 (140–892) 58 (35–125) 226 (168–499)
   Median CD4þ at last negative HCV RNA PCR/first positive HCV RNA (IQR)   547 (444–681) 429 (379–624) 531 (392–687) 397 (280–710)
Reinfection genotype (%)
   1 22 (69)   19 (70)   3 (60)
   2 0 (0)   0 (0)   0
   3 1 (3)   1 (4)   0
   4 2 (6)   1 (4)   1 (20)
Unknown 7 (22)   6 (22)   1 (20)
ALT, alanine transaminase; IQR, interquartile range.Of the 145 patients with documented primary infection, 32 reinfections occurred yielding a HCV reinfection rate of 8.0/100 py [95% confidence interval (CI) 5.7–11.3]. Among the 114 who had been successfully treated for their primary HCV infection, 27 reinfections occurred at a reinfection rate of 9.6/100 py (95% CI 6.6–14.1). Twenty-five percent of patients treated for HCV virus infection became reinfected within 2 years of follow-up. Among the 31 individuals who spontaneously cleared their primary HCV infection, five reinfections occurred yielding a reinfection rate of 4.2/100 py (95% CI 1.7–10.0). The difference in reinfection rate between those treated successfully and those who spontaneously cleared their primary infections did not reach significance (P = 0.15). The Kaplan–Meier curve giving proportion of patients free from reinfection is shown in Fig. 2 for the two groups. Seventeen of the 32 reinfected patients spontaneously cleared or were successfully treated of which eight had a subsequent second reinfection over 34 py of follow-up yielding a second reinfection rate of 23.2/100 py (11.6–46.4). Median follow-up time per patient following second reinfection was 1.5 years.

812514-fig2

Figure 2.  Kaplan–Meier curves of survival free from reinfection for patients who were either spontaneously cleared or achieved sustained viral response for their primary infection. CI, confidence interval; SVR, sustained viral response.

There was no evidence of a difference in CD4+ cell count, age, use of ART or peak ALT during primary infection between patients who underwent reinfection and those who did not or between those who were treated and those who spontaneously cleared their primary HCV infection. Use of ART during follow-up was high (89%) and did not differ between groups (P = 0.11). Peak ALT levels did not significantly differ between primary infection and primary reinfection. However, peak ALT among patients who were reinfected was significantly higher than peak ALT during follow-up of patients who had no reinfection (median 253 vs. 41 U/l, P < 0.0001).

When including those with uncertain incident infection details, the overall reinfection rate was similar at 7.8/100 py (95% CI 5.8–10.5). Among the 191 patients there were 44 reinfections of whom seven (16%) spontaneously cleared their infection. Seventeen were successfully treated and the remainder failed therapy (n = 6) opted out of treatment (n = 1) or are pending final SVR results (n = 13).

Twenty-four patients had available HCV PCR results following successful treatment or spontaneous clearance of their first reinfection. Among these patients there were eight second reinfections yielding a second-reinfection rate of 15.5/100 py (95% CI 7.7–31.0). From these eight, four (50%) spontaneously cleared their infection, one opted out of treatment developing chronic infection and three were treated with results pending. From the four patients who spontaneously cleared their second reinfection, two patients underwent a third reinfection: one was successfully treated and the other is pending SVR. A summary of the eight patients who were reinfected more than once is shown in Fig. 3.

812514-fig3

Figure 3. Flow chart of eight individuals with more than one reinfection.

Combining first, second and third reinfections, there were 54 reinfections in total. Thirty-two (59%), one (2%), two (4%), seven (13%) and twelve (22%) were genotype 1, 2, 3, 4 and unknown genotype, respectively. From the 54 reinfections, 11 patients (20%) spontaneously cleared HCV. Among patients who spontaneously cleared their reinfections, the median time to achieve undetectable viraemia was 43 days [interquartile range (IQR) 28–76.5] and the median number of positive HCV PCRs per infection was one (IQR 1–3). A total of 76% (41 of 54) of those with reinfection underwent treatment. Following reinfection, the median period until treatment was initiated was 57 days (IQR 38–112). The SVR rate among reinfections was 73% (16 of 22) for genotypes one and four and 100% (2 of 2) for genotypes two and three. Ten patients are pending SVR results.

Discussion

Our results demonstrate a high risk of HCV reinfection among HIV-positive MSM who are either treated for or who spontaneously clear their initial HCV infection. As many as 25% of individuals treated for HCV will become reinfected within 2 years. These results emphasize the need for effective sexual education for HIV-positive MSM presenting with primary HCV infection and the implementation of preventive interventions to reduce the risk of reinfection. Given their high risk, we recommend enhanced surveillance of previously infected individuals to enable the early detection and treatment of any reinfections. New UK guidelines have been updated to reflect this by recommending HCV PCR testing every 3–6 months among individuals who remain at risk following incident infection clearance.[30]

Our rate of reinfection among spontaneous clearers was lower than treated individuals (4.2/100 py vs. 9.6/100 py); however, the evidence for a difference lacked power (P = 0.15) and may have been influenced by different median testing intervals in the two groups (173 vs. 105 days, P < 0.0001), therefore providing only weak evidence for protective immunity.[24,28] The rate of reinfection among spontaneous clearers was high overall and this group should, therefore, be followed up with regular HCV PCR testing as for individuals who have been previously treated for their HCV infection.

SVR rates for individuals treated for their HCV reinfection were generally high (73% for genotype 1 and 4 and 100% for genotype 2 and 3). The majority of reinfections were treated in the acute phase of the infection (median time to treatment following first positive HCV PCR was 57 days) and SVR rates were consistent with studies treating acute HCV infections in HIV-positive MSMs.[31]

Our spontaneous clearance rate of reinfection (11 of 54 reinfections, 20%) is consistent with spontaneous clearance rates of primary HCV infection in HIV-positive MSM (5–40%).[32–36] The true spontaneous clearance rate of reinfection is likely to be higher, although, as spontaneously cleared infections may have been missed due to variable testing intervals (median 112 days, IQR 62–224). This study provides the first large cohort estimates of spontaneous clearance of HCV reinfection among HIV-infected individuals and supports monitoring for spontaneous clearance of reinfection before initiating treatment as for primary infection with HCV.

Our reinfection rate following treatment for HCV infection (9.6/100 py 95% CI 6.6–14.1) is comparable to that found by Lambers et al. (15.2/100 py 95% CI 8.0–26.5).[29] Strengths of our study in comparison to Lambers et al. are the considerably larger sample size (191 patients and 562 py follow-up vs. 56 patients and 72 py follow-up), the inclusion of spontaneous clearers in the analysis and the analysis of individuals who subsequently had multiple reinfections. The higher incidence of reinfection found by Lambers et al. may be explained by their inclusion of patients who underwent reinfection with the same genotype but different phylogeny within the 24 weeks required for definitive SVR and also shorter testing intervals during follow-up (median 91 days, IQR 58–130 vs. 112 days, IQR 62–224).[28]

Limitations of our study include its retrospective nature, the absence of behavioural data and the lack of phylogenetic analysis to prove reinfection in cases where reinfection was with the same genotype. The true reinfection rate in our cohort is likely to be higher for the following reasons: the testing interval postprimary infection was variable and long in comparison to the duration of possibly missed spontaneous clearances; and we excluded patients who developed recurrent viraemia within the 24 weeks required for SVR, whereas previous phylogenetic studies have shown a proportion of these 'relapses' to, in fact, be true reinfections.

Unfortunately, it remains difficult, as in previous studies, to definitively say that the reappearance of viraemia following treatment is not the emergence of a nondominant quasispecies or superinfection after treatment of a dominant HCV strain.[32,37] However, we believe the reemergence of viraemia is most likely to represent reinfection in our study, supported by the long duration to reinfection in most cases with multiple negative HCV PCR results between infections and the excellent response of reinfection to treatment. Finally, the patients included in our study were all from a single HIV clinic and as such our results may not be representative of other areas in London, the United Kingdom or Europe.

In conclusion, our results show high HCV reinfection rates for HIV-positive MSM who have previously cleared the infection either spontaneously or through treatment. We recommend enhanced surveillance of patients who have cleared HCV infection to allow the early detection and treatment of any reinfection. In addition, we recommend directed education and prevention interventions to HIV-positive MSMs with HCV infection. Future work will include evaluation of interventions and prospective studies to evaluate further protective immunity in this population.

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29. Lambers FAE, Prins M, Thomas X, Molenkamp R, Kwa D, Brinkman K, et al. Alarming incidence of hepatitis C virus re-infection after treatment of sexually acquired acute hepatitis C virus infection in HIV-infected MSM. AIDS (London, England) 2011; 25:F21–F27.

30. Wilkins E, Nelson M, Bhagani S, Fisher M, Kulasegaram R, James R, et al. on behalf of the BHIVA Guidelines Subcommittee. Guidelines for the management of coinfection with HIV-1 and hepatitis viruses 2013. www.bhiva.org/ClinicalGuidelines.aspx

31. Vogel M, Rockstroh JK. Treatment of acute hepatitis C in HIV infection. J Antimicrobial Chemother 2010; 65:4–9.

32. Thomson EC, Fleming VM, Main J, Klenerman P, Weber J, Eliahoo J, et al. Predicting spontaneous clearance of acute hepatitis C virus in a large cohort of HIV-1-infected men. Gut 2011; 60:837–845.

33. Gilleece YC, Browne RE, Asboe D, Atkins M, Mandalia S, Bower M, et al. Transmission of hepatitis C virus among HIV-positive homosexual men and response to a 24-Week course of pegylated interferon and ribavirin. J Acquir Immune Defic Syndr 2005; 40:41–46.

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35. Thomson EC, Nastouli E, Main J, Karayiannis P, Eliahoo J, Muir D, et al. Delayed anti-HCV antibody response in HIV-positive men acutely infected with HCV. AIDS (London, England) 2009; 23:89–93.

36. Vogel M, Page E, Mathew G, Guiguet M, Dominguez S, Dore G, et al., the NEAT Study Group. Use of week 4 HCV RNA after acute infection to predict chronic HCV infection; 17th Conference on Retro-viruses and Opportunistic Infections. San Francisco, California, USA, 2010; Abstract 640.

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Acknowledgements
T.C.S.M. designed the study, collected and analysed the data and wrote the article. N.K.M. contributed to the study design, statistical analysis and article editing. MH and PV contributed to study design, analysis and paper editing. E.E.P. contributed to data analysis and article editing. R.E. assisted with data collection. B.G.G. and M.N. contributed to study design, data analysis and article editing.
T.C.S.M acknowledges funding to attend conferences from St Stephens AIDS Trust. N.K.M.: This work is produced by N.K.M. under the terms of the postdoctoral research training fellowship issued by the NIHR. The views expressed in this publication are those of the authors and not necessarily those of the NHS, The National Institute for Health Research or the Department of Health. P.V.: Medical Research Council New Investigator Award G0801627. M.H.: NIHR School of Public Health, Nationally Integrated Quantitative Understanding of Addiction Harm (NIQUAD) MRC addiction research cluster, and support of The Centre for the Development and Evaluation of Complex Interventions for Public Health Improvement (DECIPHer), a UKCRC Public Health Research: Centre of Excellence. Funding from the British Heart Foundation, Cancer Research UK, Economic and Social Research Council (RES-590-28-0005), Medical Research Council, the Welsh Assembly Government and the Wellcome Trust (WT087640MA), under the auspices of the UK Clinical Research Collaboration, is gratefully acknowledged. E.E.P., R.E., B.G.G. and M.N. received no direct funding for the study.

AIDS. 2013;27(16):2551-2557. © 2013  Lippincott Williams & Wilkins

Lippincott Williams & Wilkins

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Provided by Clinical Care options
 
Capsule Summary

Date posted: 11/4/2013

  • Observational study[1]
Summary of Key Conclusions
  • Sofosbuvir plus ribavirin (RBV), with or without peginterferon (pegIFN), well tolerated and active in patients with severe HCV recurrence after liver transplantation
    • Marked clinical improvement and/or disease stabilization in majority of patients (75%)
    • More than one half of patients (56%) achieved SVR12
    • Liver function tests improved during treatment
  • Substantial mortality due to disease progression (25%)
  • Sofosbuvir-containing regimens well tolerated, with only 1 serious adverse event attributed to treatment
Background
  • Recurrent HCV infection of allograft unavoidable if HCV RNA not suppressed to undetectable levels before liver transplantation
    • Severe recurrence common (eg, fibrosing cholestatic hepatitis)[2]
    • Recurrent infection may result in graft loss and poor short-term outcomes[2]
  • Limited treatment options for patients with severe HCV recurrence after liver transplantation
    • Interferon-based treatment poorly tolerated with limited efficacy and frequent unfavorable interactions of HCV protease inhibitors with immunosuppressive drugs
  • Sofosbuvir: HCV NS5B polymerase inhibitor
    • Administered orally once daily
    • Broad activity against genotypes 1-6
    • High genetic barrier to resistance
    • No food effects or significant drug interactions with immunosuppressive agents
    • Favorable safety, tolerability to date in more than 3000 patients
  • Current compassionate-use study analyzed efficacy and safety of sofosbuvir plus RBV, with or without pegIFN, in patients with severe recurrent HCV following liver transplantation[1]
Summary of Study Design
  • Patients enrolled in sofosbuvir compassionate-use program included in analysis
    • Individual requests for sofosbuvir use based on patient medical history and clinical assessment
    • All patients who received treatment had severe HCV recurrence, including fibrosing cholestatic hepatitis
  • Patients treated with sofosbuvir 400 mg/day plus RBV for ≤ 48 weeks; pegIFN could be added at physician’s discretion
  • Current report includes 44 patients treated with sofosbuvir plus RBV with or without pegIFN

Baseline Characteristics

Characteristic

Sofosbuvir + RBV
(n = 32)

Sofosbuvir + RBV + PegIFN
(n = 12)

Mean age, yrs (range)

56 (27-71)

57 (45-66)

Male, n (%)

21 (65)

10 (83)

Mean HCV RNA, log10 IU/mL (range)

7.6 (1.4-10.0)

7.0 (1.3-7.5)

HCV genotype, n (%)

   
  • 1a

9 (28)

5 (42)

  • 1b

17 (53)

3 (25)

  • 2

0 (0)

1 (8)

  • 3

4 (13)

1 (8)

  • 4

0 (0)

1 (8)

  • Mixed

2 (6)

1 (8)

Mean laboratory values

   
  • Bilirubin, mg/dL (range)

7.9 (0.4-27.1)

2.6 (0.4-5.1)

  • Albumin, g/L (range)

3.2 (1.3-12.2)

3.4 (2.0-4.8)

  • INR (range)

1.4 (0.9-3.9)

1.2 (1.0-1.6)

  • ALT, IU/L (range)

124 (13-717)

81 (8-197)

  • AST, IU/L (range)

223 (14-1331)

112 (36-270)

Histologically documented fibrosing cholestatic hepatitis, n (%)

15 (47)

5 (33)

Mean MELD score (range)

16 (6-43)

13 (8-22)

Mean time from liver transplantation, mos (range)

40 (3-178)

31 (5-124)

INR, international normalized ratio; MELD, Model for End-Stage Liver Disease.

Description of Current Analysis
  • Data collected on patient characteristics, clinical assessments, laboratory abnormalities, and serious adverse events
  • Decompensation events included episodes of hepatic encephalopathy, ascites, and liver-related laboratory values
  • Recommended timing of assessments
    • Baseline
    • On-treatment Weeks 4, 12, 24, 36, and 48
    • Posttreatment Weeks 4, 12, and 24
  • Undetectable HCV RNA defined as lower limit of detection or lower limit of quantification, depending on treatment center
  • Intent-to-treat analysis
Main Findings
  • 24 of 44 patients (55%) completed treatment (48 weeks in 1 patient, 36 weeks in 4 patients, 24 weeks in 19 patients)
    • 5 patients (11%) discontinued treatment early
    • 7 patients (16%) died prior to completing treatment due to progressive liver disease or associated complications
    • 8 patients (18%) still receiving treatment
  • On-treatment virologic response occurred early (ie, by Week 4) in majority of treated patients and rate of response continued to increase over time during treatment

Undetectable HCV RNA During Treatment

Sofosbuvir + RBV
(n = 32)

Sofosbuvir + RBV + PegIFN
(n = 12)

Wk 4

69

67

Wk 12

91

75

Wk 24

83*

64

*3 patients who terminated treatment early not counted in denominator.
1 patient who terminated treatment early not counted in denominator.

Overall, 69% of patients attained SVR4; 56% attained SVR12

Deaths and posttreatment relapse accounted for nearly all cases of virologic failure

Virologic Outcome, n (%)

Sofosbuvir + RBV

Sofosbuvir + RBV + PegIFN

All Patients

Wk 4 posttreatment

(n = 27)

(n = 9)

(N = 36)

  • SVR4

20 (74)

5 (56)

25 (69)

  • Virologic failure
     
    • Relapse

1 (4)

1 (11)

2 (6)

    • Nonresponse

0

1 (11)

1 (3)

    • Death

6 (22)

2 (22)

8 (22)

Wk 12 posttreatment

(n = 20)

(n = 8)

(N = 28)

  • SVR12

12 (60)

4 (50)

15 (56)

  • Virologic failure
     
    • Relapse

2 (10)

2 (25)

4 (15)

    • Nonresponse

0 (0)

1 (13)

1 (4)

    • Death

6 (30)

1 (13)

7 (26)

  • Overall, 64% demonstrated improvement of decompensation events; 11% showed stabilization of events
  • Marked improvements in liver function tests observed during treatment, including reductions in ALT, bilirubin, and international normalized ratio
  • Hemoglobin levels decreased during treatment, likely in association with RBV
  • MELD score also decreased during treatment
  • Large proportion of patients experienced serious adverse events during treatment, majority attributed to disease progression and not to therapy
    • 1 treatment-related serious adverse event in sofosbuvir plus RBV arm involved neutropenia
    • 3 serious adverse events leading to treatment discontinuation involved acute renal failure, deep vein thrombosis, and multifocal hepatoma (1 event of each)

Safety Outcome, n (%)

Sofosbuvir + RBV
(n = 32)

Sofosbuvir + RBV + PegIFN
(n = 12)

Any serious adverse event

16 (50)

5 (42)

Treatment-related serious adverse event

1 (3)

0 (0)

Serious adverse event leading to treatment discontinuation

1 (3)

2 (17)

 
References

1. Forns X, Fontana RJ, Moonka D, et al. Initial evaluation of the sofosbuvir compassionate use program for patients with severe recurrent HCV following liver transplantation. Program and abstracts of the 64th Annual Meeting of the American Association for the Study of Liver Diseases; November 1-5, 2013; Washington, DC. Abstract 1084.

2. Crespo G, Mariño Z, Navasa M, Forns X. Viral hepatitis in liver transplantation. Gastroenterology. 2012;142:1373-1383.

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