Several presentations at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting this month in Boston focused on treating hepatitis C recurrence in liver transplant recipients, one of the most difficult populations to treat. Studies showed that a variety of interferon-free regimens containing the direct-acting antivirals sofosbuvir, simeprevir and daclatasvir led to high sustained virological response rates, often improved liver function, and were generally safe and reasonably well-tolerated in real-world use.
Hepatitis C virus (HCV) almost always re-infects the new donor liver after transplantation, often resulting in rapid disease progression leading to severe fibrosis or cirrhosis and potential graft loss. Liver transplant recipients have historically been difficult to treat because they do not respond as well to interferon-based therapy and often cannot tolerate its side-effects or interactions with immunosuppressant drugs used to prevent organ rejection.
New direct-acting antivirals (DAAs) that target different steps of the HCV lifecycle can now be combined in interferon-free regimens that are very well-tolerated and produce high cure rates – typically above 90% – in non-transplant patients. Clinicians are now learning how to use these drugs for liver transplant recipients and other patients who urgently need treatment in the real world.
Sofosbuvir + simeprevir
Gilead Sciences' nucleotide HCV polymerase inhibitor sofosbuvir (Sovaldi) and Janssen's HCV protease inhibitor simeprevir (Olysio) were the first next-generation DAAs to be approved. While this regimen has not been through phase 3 trials, the phase 2 COSMOS trial showed that sofosbuvir plus simeprevir with or without ribavirin cured more than 90% of genotype 1 patients, including those with liver cirrhosis. Both European and American treatment guidelines recommend this combination for people with HCV genotype 1 who are unwilling or unable to take interferon.
Robert Brown from Columbia University presented findings on the real-world experience of 227 people with hepatitis C treated with sofosbuvir-containing regimens after liver transplantation in HCV-TARGET, a consortium of more than 50 academic and community medical centres in the US, Canada and Germany.
About three-quarters were men, most were white and the mean age was 60 years. Most (78%) had HCV genotype 1 and 57% were treatment-experienced. Nearly 60% had progressed to cirrhosis in the new liver and 40% had a MELD score >10 (a biomarker index with higher scores indicating worse liver disease severity).
Treatment was administered according to local standards of care with patients and providers choosing which regimens to use. People with HCV genotype 1 most often used sofosbuvir plus simeprevir (62%), followed by sofosbuvir/simeprevir with ribavirin (18%) and sofosbuvir plus pegylated interferon/ribavirin (13%). All genotype 2 patients and most with genotype 3 used sofosbuvir with ribavirin alone.
Among the 131 people with genotype 1 treated with sofosbuvir plus simeprevir with or without ribavirin, 68 had enough follow-up time to be evaluated for sustained virological response at least 4 weeks post-treatment (SVR4); most were treated for 12 weeks, as those receiving 24 weeks were still on therapy. While SVR4 is generally reflective of outcomes at 12 weeks post-treatment (SVR12), it is too soon to declare a cure.
The SVR4 rate for these 68 patients was 90% overall, broken down to 83% for HCV subtype 1a and 95% for subtype 1b. SVR rates were similar for previously untreated and treatment-experienced people (89 vs 90%). People without cirrhosis had a higher response rate than people with cirrhosis (94% vs 86%) and those with MELD scores <10 did better than those with higher scores (92 vs 77%). People who added ribavirin appeared to have a lower response rate (82%), but the number was small.
Looking at other regimens, 10 of 12 people with genotype 1 (83%) treated with sofosbuvir plus pegylated interferon/ribavirin achieved SVR4, as did the single genotype 3 patient who used this regimen. Among those taking sofosbuvir plus ribavirin alone, SVR4 rates were 90% for genotype 2 and 60% for genotype 3.
Sofosbuvir plus simeprevir was generally safe and well-tolerated, with the usual side-effects of fatigue, headache, diarrhoea and nausea. There were five adverse events leading to treatment discontinuation. Ten per cent of people on this dual regimen had serious adverse events, rising to 21% among those who added ribavirin; 38% of ribavirin recipients developed anaemia. No one experienced acute liver graft rejection but there were three deaths.
Asked about the best time to start sofosbuvir-based treatment after transplantation, Brown said that "the earliest possible time as a pre-emptive regimen is probably beneficial, but early on there's more immunosuppression, so the optimal time to start remains to be determined."
In a similar analysis, Surakit Pungpapong reported on the real-world experience of genotype 1 liver transplant patients treated with sofosbuvir plus simeprevir, with or without ribavirin, at three Mayo Clinic sites in Jacksonville, Florida, Scottsdale, Arizona, and Rochester, Minnesota.
Again, most were white men. The majority were treatment-experienced, including 12% who had previously used first-generation HCV protease inhibitors or prior sofosbuvir. 62% had HCV subtype 1a and 29% had advanced fibrosis or cirrhosis (Metavir stage F3-F4). The median time since transplantation was 29 months.
Out of 109 treated patients – of whom 24 used ribavirin – 90 had reached 4 weeks post-treatment and 66 had reached 12 weeks post-treatment and were assessed for SVR12, which is considered a cure.
The overall SVR12 rate was 91% in an intent-to-treat analysis, broken down to 88% for people with HCV subtype 1a and 96% for those with 1b. Response was a bit lower for those who added ribavirin (89%) or were previously treated with protease inhibitors or sofosbuvir (80%). People with severe fibrosis or cirrhosis did not do as well as those with moderate fibrosis or less (76 vs 96%, respectively). This difference was driven by patients with HCV 1a (64 vs 97%), while those with 1b did well regardless of fibrosis stage (100 vs 94%).
The most common side-effects were fatigue, elevated bilirubin, nausea and headache. More than 40% of those who added ribavirin developed anaemia, all reduced their doses and half needed erythropoietin. One patient developed acute but temporary pancreatitis and went on to achieve SVR12. Another died from lung damage considered possibly related to drug toxicity. There were no cases of acute rejection and no immunosuppressant-related adverse events.
In a related study, Anjali Basil from the University of Massachusetts looked at outcomes among liver transplant recipients with impaired kidney function who were treated with sofosbuvir plus simeprevir – a potential concern as the main metabolite of sofosbuvir is excreted by the kidneys.
In this prospective study of 26 post-transplant patients, 16 had unchanged glomerular filtration rate (GFR; a measure of kidney function), while seven experienced improvement – including one who was able to stop dialysis – and three declined. Again, virological response was good and treatment was generally well-tolerated.
Robert Fontana from the University of Michigan presented findings from a study of Bristol-Myers Squibb's HCV NS5A inhibitor daclatasvir (Daklinza) for liver transplant recipients with severe, life-threatening recurrent hepatitis C. This includes fibrosing cholestatic hepatitis, an uncommon but potentially fatal condition characterised by high viral load, hepatocyte damage, rapid fibrosis progression and bile blockage.
Twenty-six investigators in Europe (58%) and the US (42%) enrolled 106 patients between October 2010 and August 2014. This analysis looked at 30 people who took daclatasvir-containing regimens without interferon. Again, a majority (60%) were men, the median age was 58 years and they were about evenly divided between HCV subtypes 1a and half 1b. Nearly one-third had cirrhosis and 57% had fibrosing cholestatic hepatitis. Half were classified as Child-Pugh-Turcotte (CPT) class A, 20% as CPT B and 27% as CPT C. The median time from transplantation to treatment was 17 months.
All participants received 60mg once-daily daclatasvir for up to 24 weeks (average 21 weeks). Additional agents were chosen by treating physicians: 23 received daclatasvir plus sofosbuvir while seven received daclatasvir plus simeprevir, both with or without ribavirin.
Among the 12 patients with sufficient follow-up time, the SVR12 rate was 75%. One daclatasvir/sofosbuvir recipient relapsed at 12 weeks post-treatment.
Liver function significantly improved from baseline through the last study visit. The mean MELD score decreased from 11.9 to 9.8 while the mean CPT score fell from 7.3 to 5.8 (from class B to A). ALT levels typically normalised.
Although 12 people (40%) experienced serious adverse events, none were attributed to daclatasvir. Anaemia occurred among ribavirin recipients, with 20% needing to reduce their dose and 10% starting erythropoietin. There were no cases of acute graft rejection or immunosuppressant-related toxicity due to drug interactions. Six patients died from liver failure or sepsis.
"Most patients experienced stabilisation or improvement in their laboratory and clinical status, with significantly improved [CPT] and MELD scores," the researchers concluded. "These data support the use of daclatasvir-based all-oral antiviral therapy combined with sofosbuvir or simeprevir +/- ribavirin as a potentially safe and effective salvage therapy for patients with severe recurrent HCV infection post-liver transplant."
DAA compassionate use
Several groups reported findings on experimental DAA regimens used in compassionate use programmes for patients with severe recurrent hepatitis C after liver transplantation.
Vincent Leroy from CHU Grenoble and colleagues evaluated the safety and efficacy of new DAA regimens in 23 people with post-transplant fibrosing cholestatic HCV recurrence in the French ANRS CO23 CUPILT study.
Most were men and the median age was 57 years. Eight patients had HCV subtype 1a, eight had 1b, two had genotype 3 and three had genotype 4. Almost all were treatment-experienced, with about one-third having used first-generation HCV protease inhibitors. About 17% had already progressed to advanced fibrosis or cirrhosis, more than one-third had ascites (abdominal fluid accumulation) and one patient had hepatic encephalopathy (brain impairment). The average time between transplantation and treatment was about seven months.
Regimens were chosen by study clinicians: thirteen people used sofosbuvir plus daclatasvir with ribavirin, two used sofosbuvir plus daclatasvir without ribavirin, six used sofosbuvir with ribavirin alone and two used sofosbuvir plus pegylated interferon/ribavirin, all for 24 weeks. Patients taking sofosbuvir plus ribavirin (with or without interferon) and those taking sofosbuvir plus daclatasvir (with or without ribavirin) were grouped together for comparison.
Eighty-eight per cent of participants taking sofosbuvir plus ribavirin and 100% taking sofosbuvir plus daclatasvir achieved SVR12. One person with HIV and HCV co-infection and cirrhosis taking sofosbuvir plus ribavirin alone relapsed.
Bilirubin, ALT, AST, alkaline phosphatase and GGT levels declined in both treatment groups, indicating improvement, while albumin and platelet counts increased. Patients with ascites experienced improvement or resolution. Overall, 20 people (87%) achieved 'complete clinical response', defined as being still alive without re-transplantation, normalised bilirubin and no ascites or hepatic encephalopathy.
Half of the participants experienced serious adverse events but none were attributed to sofosbuvir or daclatasvir. The two people who started on pegylated interferon discontinued early. One-quarter developed anaemia, with 24% stopping ribavirin and 71% reducing their dose.
In conclusion, the researchers summarised, sofosbuvir and daclatasvir-based regimens led to "100% survival without re-transplantation at week 36, major clinical improvement, high rates of SVR12, satisfactory tolerance," and no significant drug interactions with calcineurin inhibitor immunosuppressants.
In a related study presented as a late-breaker poster, María-Carlota Londoño from Hospital Clinic in Barcelona and colleagues presented findings on the safety and efficacy of simeprevir in combination with sofosbuvir or daclatasvir for people with severe post-transplant recurrent hepatitis C in European compassionate use programmes.
This retrospective analysis included 28 liver transplant recipients considered to have a high risk of death within 12 months, including three with fibrosing cholestatic hepatitis, 18 with cirrhosis and 12 with liver decompensation. A majority (68%) were men and the median age was 59 years. Most (93%) had HCV genotype 1b while two people had genotype 4. The median MELD and CPT scores were 11 and 6, respectively; 12 had ascites and three had hepatic encephalopathy at the start of treatment.
With regard to treatment, 12 patients received simeprevir plus sofosbuvir (six of whom used ribavirin) while 16 received simeprevir plus daclatasvir (12 of whom added ribavirin) for up to 24 weeks. The median time between transplantation and treatment was 20 months.
Preliminary results showed that at the end of 24 weeks of treatment, 100% of patients taking simeprevir/sofosbuvir and 89% of those taking simeprevir/daclatasvir had undetectable HCV viral load. Among 10 patients with sufficient follow-up time, SVR12 rates were 100% with simeprevir/sofosbuvir and 62% with simeprevir/daclatasvir. Two people experienced viral breakthrough during treatment and one relapsed after treatment.
Again, viral suppression was associated with improved liver function. Four of 12 patients had resolved ascites and all three with hepatic encephalopathy experienced resolution. There was a trend toward reduction in MELD and CPT scores, though the difference did not reach statistical significance.
Eight patients experienced serious adverse events – including two people taking ribavirin who developed severe anaemia requiring transfusions – but no one discontinued therapy for this reason. There were no cases of toxicity due to drug interactions with immunosuppressants, no episodes of graft rejection and no deaths.
"Simeprevir in combination with daclatasvir or sofosbuvir seems to be effective and safe in liver transplant recipients with severe hepatitis C recurrence," the researchers concluded. "In some cases viral eradication is associated with an improvement in liver function."
Finally, in another late-breaker poster, Pietro Andreone from Università degli Studi in Bologna and colleagues reported outcomes using sofosbuvir for patients with severe post-transplant HCV recurrence in the Italian AISF-SOFOLT compassionate use programme.
This analysis included 45 transplant recipients with end-stage liver disease (ESLD) and 24 with fibrosing cholestatic hepatitis. Most were men and the mean age was 54 years. Nearly one-third had HCV subtype 1a, half had 1b and a few had genotypes 2, 3 or 4.
Most were treated with sofosbuvir plus ribavirin alone, with smaller numbers receiving sofosbuvir plus pegylated interferon/ribavirin, sofosbuvir plus daclatasvir or sofosbuvir plus simeprevir and ribavirin.
Among the patients with sufficient follow-up, the overall SVR12 rate was 73%, with all failures being post-treatment relapses. Everyone treated with sofosbuvir plus daclatasvir achieved SVR12, as did 89% of those using sofosbuvir plus pegylated interferon/ribavirin and 64% of those using sofosbuvir plus ribavirin alone.
Again, improvement was seen in liver function biomarkers including bilirubin, creatinine and albumin levels. MELD and CPT scores decreased on average. Four patients died and one required re-transplantation.
"Our results confirm a good virological and clinical outcome of sofosbuvir-based treatment in ESLD patients with life expectancy <6 months in severe HCV recurrence, with or without fibrosing cholestatic hepatitis," the researchers concluded.
Taken together, these real-world findings show that interferon-free DAA regimens containing combinations of sofosbuvir, simeprevir and daclatasvir can cure most liver transplant recipients with recurrent hepatitis C, including a majority of those with severe post-transplant liver disease. In addition to viral suppression, treatment also improves liver function. DAA treatment is generally safe and well-tolerated – certainly more so than interferon-based therapy – though anaemia remains a concern for people taking ribavirin.
"HCV reinfection post-transplant is 100% and patients often develop severe liver disease," AASLD president Adrian DiBisceglie said at his opening press conference. Now, with effective new interferon-free DAA regimens, "we can potentially fix that."
Brown RS et al. Safety and Efficacy of new DAA-based therapy for hepatitis C post-transplant: interval results from the HCV-TARGET longitudinal, observational study. American Association for the Study of Liver Diseases (AASLD) Liver Meeting, Boston, abstract LB-4, 2014.
Pungpapong S et al. Multicenter experience using sofosbuvir and simeprevir with/without ribavirin to treat HCV genotype 1 after liver transplantation. American Association for the Study of Liver Diseases (AASLD) Liver Meeting, Boston, abstract 9, 2014.
Basil A et al. Renal function in liver transplant patients treated for recurrent hepatitis C with sofosbuvir and simeprevir. American Association for the Study of Liver Diseases (AASLD) Liver Meeting, Boston, abstract LB-24, 2014.
Fontana R et al. High efficacy and favorable safety profile of daclatasvir based all oral antiviral therapy in liver transplant recipients with severe recurrent HCV. American Association for the Study of Liver Diseases (AASLD) Liver Meeting, Boston, abstract LB-22, 2014.
Leroy V et al. High rates of virological response and major clinical improvement during sofosbuvir and daclatasvir-based regimens for the treatment of fibrosing cholestatic HCV-recurrence after liver transplantation: the ANRS CO23 CUPILT study. American Association for the Study of Liver Diseases (AASLD) Liver Meeting, Boston, abstract 21, 2014.
Londoño M et al. Safety and efficacy of simeprevir in combination with daclatasvir or sofosbuvir in patients with severe hepatitis C recurrence after liver transplantation: results from compassionate use in Europe. American Association for the Study of Liver Diseases (AASLD) Liver Meeting, Boston, abstract LB-34, 2014.
Andreone P et al. Sofobuvir for severe HCV recurrence post-transplant: AISF-SOFOLT Italian compassionate use. American Association for the Study of Liver Diseases (AASLD) Liver Meeting, Boston, abstract LB-9, 2014.