Treatment of Recurrent Hepatitis C

First author
Total n; % of male
% of Genotype 1
Treatment regimen
Virologic response
Adverse events
Forns 2003 [9]
30, 83
83
Interferon alfa-2b + ribavirin for 12 weeks
9 Patients (30 %) were negative for HCV RNA at the time of transplantation; of these, 20 % remained negative after transplantation
Hepatic encephalopathy (n = 3), ascites (n = 2), and variceal bleeding (n = 1), neutropenia (n = 18)
Crippin 2002 [10]
15, n/a
n/a
Interferon alfa-2b daily or interferon alfa-2b three times weekly or interferon alfa-2b daily + ribavirin
No patient had sustained response, 2 who underwent transplantation had recurrence of HCV, and the study was halted because of serious side effects
Thrombocytopenia was the most common adverse event. Two infectious complications occurred; one of these had a fatal outcome.
Everson 2005 [5]
124, 65
70
Low accelerating dose regimen of interferon alfa-2b or PEGIFN alfa-2b + ribavirin for 6 months for genotypes 2 and 3 or 12 months for genotypes 1, 4, and 6
46 % were HCV RNA–negative at ETR and 22 % achieved SVR. 12/15 patients (80 %) who were HCV RNA–negative pre-LT had no post-transplantation recurrence. All 32 patients who were HCV RNA–positive pre-LT recurred after transplantation 2 weeks after LT
Infection (n = 5), worsening ascites (n = 5), encephalopathy (n = 6), gastrointestinal bleeding (n = 2), diabetes mellitus, severe thrombocytopenia
Carrión 2009 [11]
51 Treatment and 51 controls, n/a
n/a
PEGIFN—alfa-2a and ribavirin
29 % had undetectable HCV-RNA at the time of transplantation and 20 % achieved SVR
Higher incidence of bacterial infections in treated patients vs. controls
Everson 2013 [12], LADR-A2ALL trial
79, 75
56
Low accelerating dose regimen with PEGIFN alfa-2b and RBV
None of the 13 controls but 26/44 (59 %) treated patients achieved undetectable HCV RNA by the time of transplantation (p < 0.0001). 11/44 (25 %) had undetectable HCV RNA at week 12 post-LT
Infections (12 %) and cytopenias (19 %) were more common in treated patients
Lin 2014 [8]
48, n/a
60
Peg-IFN—alfa-2a + RBV for 4 weeks
HCV RNA was undetectable at transplantation in 26/48 (54 %) patients. 13 /48 (26 %) patients remained free of HCV infection 6 months after transplant
Most patients experienced cytopenias during treatment, but no mortality was noted
HCV hepatitis C virus, LT liver transplantation, IFN interferon, PEGIFN pegylated interferon, n/a not available, ETR end of treatment response defined as undetectable HCV RNA at the end of treatment, SVR sustained virological response

4.1.2 Interferon-Free Regimens (Combination of DAA)

Interferon-free DAA combination is currently being tested in patients awaiting liver transplantation. In an open label single arm study, 61 patients awaiting LT with HCV cirrhosis, but with CTP score 7 or less, were treated with sofosbuvir (SOF), an NS5B nucleotide polymerase inhibitor, in combination with RBV [16]. Of the 43 patients who achieved pre-transplant viral levels of HCV RNA <25 IU/mL, 30 (70 %) were able to maintain a post-transplant virologic response at 12 weeks. Notably, recurrence of HCV was inversely related to the number of consecutive days of undetectable HCV RNA before transplantation. The main adverse reactions noted with this combination were fatigue, headache, and anemia due to RBV, but the drug discontinuation rates due to adverse events were low. In addition to treating patients before LT, there is anecdotal evidence of benefit by extending the therapy to immediate post-LT period if HCV RNA undetectability prior to LT is less than 30 days [17]. These anecdotal observations require further corroboration before such a strategy is recommended.
The cure rates in patients with well-compensated cirrhosis, whether treatment naïve or treatment experienced, with recently approved DAA regimens (Harvoni or Viekira Pak with or without RBV) is over 90 % with 12–24 weeks of treatment. Those with HCC and compensated HCV cirrhosis (Child A) could be treated with above regimens if there are no obvious contraindications. While SOF/ledipasvir (Harvoni) is contraindicated in people with renal failure, Viekira Pak could be used in the presence of renal failure, except those on dialysis. The side effect profile of these regimens is excellent with fatigue and headache being the most common side effects. When RBV is used, hemoglobin should be monitored closely especially in those with renal impairment. Use of these regimens in the pre-LT setting is preliminary in nature and requires further evaluation in larger studies. Moreover, the current studies comprised patients with compensated or mildly decompensated liver disease undergoing transplantation and studies involving patients with more advanced disease are currently in progress. The cure rates with DAA regimens in well-compensated cirrhosis (Child A) are shown in Table 4.2.
Table 4.2
Clinical trials with IFN-free regimens in patients with HCV cirrhosis
Therapeutic regimen
Treatment duration in weeks in specific arms
Predominant genotype
Prior treatment experience
% of cirrhosis in the study
Virological response in cirrhosis
LDV/SOF ± RBV (ion-1)
12, 24
1
Treatment naive
16
SVR12 97 and 100 % ± RBV in 12 and 24 wks
LDV/SOF ± RBV (ion-2)
12, 24
1
Treatment experienced
20
SVR12 82–86 % in the 12 wk arm (± RBV) and 100 % 24 wk arm
DCV + ASV (hallmark-dual)
24
1b
Treatment naïve, IFN intolerant, ineligible and nonresponders
30
SVR12—91 %,87 %, and 81 % in the naïve, nonresponders, and intolerant/ineligible, respectively
ABT-450/r + ombitasvir + dasabuvir + RBV (turquoise II)
12, 24
1
Treatment naïve and experienced
100
SVR12 92 and 96 % in 12 and 24 wks
SOF + RBV (fusion)
12,16
2, 3
IFN nonresponders
35 %—12 wk arm and 33 %—16 wk arm
SVR 12—60 and 78 % in G2, 19 and 61 % in G3 (12 and 16 wk, respectively)
SOF + RBV (valence)
12 G2
2, 3
Treatment naïve and experienced
14 %—12 wk arm and 22 %—24 wk arm
SVR 12—100 and 88 % in G2, 92 and 60 % in G3 (12 and 16 wk, respectively)
24 G3
SOF + RBV (positron)
12
2, 3
IFN intolerant
15
SVR 12—94 % in G2 and 21 %in G3
SOF + RBV (fission)
12
2, 3
Treatment naive
20
SVR 12—47 %
SOF + LDV ± RBV (Cohort B) (Lonestar)
12
1 (85 % G1a)
Nonresponder to protease inhibitor regimen
55
SVR 12—100 % and 95 % with and without ribavirin, respectively
SMV + SOF ± RBV (Cohort 2) (cosmos)
12, 24
1 (78 % G1a)
Naïve and null responders
25
SVR 12—91 % and 94 % in null responders and naïve, respectively
SOF + RBV or GS-0938 or GS-0938 + SOF (± RBV) (quantum)
12, 24
1–4
Treatment naive
9
SVR 12—50 % in the SOF + RBV arm, 24 wk
Wk weeks, G genotype, SVR12 sustained virologic response 12 weeks after the end of treatment, SVR24 sustained virologic response 24 weeks after the end of treatment, SMV simeprevir, DCV daclatasvir, SOF sofosbuvir, LDV ledipasvir, ASV asunaprevir, ABT-267 ombitasvir, ABT-333 dasabuvir, RBV ribavirin

4.2 Antiviral Therapy Immediately After Liver Transplantation

Another approach to chronic HCV patients who undergo LT is to treat them with antiviral agents immediately after LT before histological evidence of inflammation or fibrosis is established (i.e., begin treatment within 4 weeks after LT; this is also known as preemptive strategy). The rationale for such treatment is that fibrosis is absent in the early period after LT, and therefore these patients are more likely to respond antiviral therapy. The experience with interferon-based regimens immediately after LT showed that interferon-based regimens are poorly tolerated in the immediate postoperative period, and it is not very practical to treat these patients in the immediate postoperative period with interferon-based regimes (Table 4.3) when they have many other issues related to the transplant surgery. There is only anecdotal experience with DAA regimens in this setting, but we are likely to see more studies in this area in the near future.
Table 4.3
Preemptive treatment with IFN-based antiviral therapy: prospective and randomized studies
First author
Total (N)
Predominant genotype
Antiviral therapy
Transplantation treatment interval
Virological response
Histological results
Adverse events
Singh [19]
24
1a
IFN vs. no treatment for 24 weeks
<2 weeks
0 in both groups
HCV recurrence: 50 % in the IFN group vs. 42 % in the control group, P = NS
IFN group: Leucopenia (17 %) Headache, asthenia (33 %)
Sheiner [20]
71
1a and 1b
IFI IFN vs. no treatment for 48 weeks
<2 weeks
ETR: IFN—17 % control—5 %; P = NS
No difference in severity of recurrence; incidence of early recurrence reduced in IFN group: 26 % vs. 54 % in control group (P = 0.017)
Thrombocytopenia (17 %) in IFN group
Shergill [21]
44
n/a
IFN or Peg-IFN vs. IFN + Ribavirin for 48 weeks
<6 weeks
SVR: IFN—5 % IFN + RIB—18 %; P = NS
n/a
IFN—cytopenias, headache; hemolytic anemia with ribavirin
Chalasani [18]
54
n/a
Peg-IFN vs. no treatment for 48 weeks
<3 weeks
SVR: IFN—8 %, no treatment—0; P = NS
HAI score and increase in fibrosis are lower in IFN group, however not statistically significant
IFN group: headache, pyrexia, thrombocytopenia, and anemia
Bzowej [22] (PHOENIX Study Group)
115
80 % genotype 1
Escalating-dose regimen of Peg-IFN alfa-2a + RBV for 48 weeks to prophylaxis patients upon enrollment and Observation patients received the same regimen only upon significant HCV recurrence
10–26 weeks
SVR—22.2 % in prophylaxis patients and 21.4 % in the observation arm (SVR rates—18.6 % and 33.3 % for HCV genotype 1 and non-type 1 prophylaxis patients, respectively)
Similar rates of histological HCV recurrence at 120 weeks in the prophylaxis arm (61.8 %) and the observation arm (65), P = 0.725
Anemia, fatigue, headache, and neutropenia were noted in 100 % of the prophylaxis patients and 97 % of all observation patients
N number of patients, IFN interferon, Peg pegylated, Rib ribavirin, HCV hepatitis C virus, ETR end of treatment response defined as undetectable HCV RNA at the end of treatment, SVR sustained virological response, NS not statistically significant, n/a not available
Treatment with standard interferon, as a part of preemptive strategy, has been largely unsuccessful in reducing recurrence of HCV [1820]. Peg IFN and RBV combination regimen for preemptive therapy after LT has shown better efficacy than interferon monotherapy, but the SVR rates for genotypes 1, 2, and 3 were not encouraging. In one study, only 51 of 124 patients were eligible for preemptive therapy suggesting that this therapy is difficult to administer in the immediate postoperative period [21]. Additionally, 27 % of patients had serious adverse events, 85 % required dose reductions, and 37 % required discontinuation of treatment [20]. The large PHOENIX study [22] evaluated the preemptive strategy using Peg IFN/RBV and concluded that rates of histological recurrence, graft loss, and death were similar in the active and control groups. Although adding TVR/BOC to conventional dual therapy (interferon/RBV) improved SVR rates [23], there are only anecdotal case reports of using these combinations as a preemptive strategy, and moreover, the higher rates of serious adverse reactions make these combinations unsuitable for preemptive treatment. Other drugs such as SOF and simeprevir (SMV) have not been studied for this purpose. Based on the current evidence, the preemptive therapy using interferon-based regimen is currently not recommended.

4.3 Antiviral Therapy After Histological Recurrence

This approach is currently the most accepted method to treat patients transplanted for hepatitis C. The histological recurrence is established with a combination of invasive and noninvasive factors as discussed in the previous chapter. Most centers would currently recommend therapy only when there is established recurrence of progressive disease, but this strategy may change in the near future with the availability of safer DAA regimens. It is more than likely that most patients with HCV will be treated with these regimens, perhaps after 3–6 months post-LT, with an intention to cure HCV. Although interferon-based regimens are going to become obsolete, it will be discussed for historical perspective on this topic.

4.3.1 Peg IFN/Ribavirin

With combination of Peg IFN and RBV, SVR was achieved in approximately 20–48 % of patients with recurrent HCV as summarized in Table 4.4 [18, 2429]. Higher viral load and increased prevalence of genotype 1 in the post-transplant setting was associated with a lower response rates when compared to non-LT patients. The major limitations with this regimen were dose reduction (75 %) and discontinuation of treatment (25 %) due to adverse events [3032].
Table 4.4
Treatment of histological recurrent HCV with interferon-based regimens
First author
Total (N), % of genotype 1
Antiviral therapy regimen and duration
Discontinuation (N)
ETR
SVR
Adverse events
Gane [24]
30, 47
IFN vs. Ribavirin for 12 weeks
2 in ribavirin group
IFN group: 46 % Rib group: 17; P = NS
0
Anemia, leucopenia
Cotler [25]
12, 33
IFN vs. no treatment for 48 weeks
2 in IFN group
IFN group: 4 (50 %) Control group: 0
IFN: 1 (13 %) Control group: 0
Asthenia, depression
Chalasani [18]
67, 77
Peg-IFN vs. no treatment for 48 weeks
10 (30 %) in treated group vs. 6 (19 %) in control group
IFN group: 9 (27 %) Control group: 0
IFN group: 4 (12 %) Control group: 0
Flu like symptoms
Angelico [26]
42, 83
Peg-IFN vs. Peg-IFN + Ribavirin for 48 weeks
Withdrawals: monotherapy: 6/21 combination therapy: 7/21
Monotherapy: 76 combination therapy: 71
Monotherapy: 38 combination therapy: 33
Headache asthenia, thrombocytopenia, hemolytic anemia
Ghalib [27]
10, 80
IFN + Ribavirin for 24 weeks vs. 48 weeks
5
24 weeks group: 3/348 weeks group: 1/2
24 weeks group: 1/348 weeks group: 1/2
Flu like symptoms, mild fatigue
Samuel [28]
52, 83
IFN + Ribavirin vs. no treatment for 48 weeks
12/28 (43 %) in treated group 4 (17 %) in control group
Treated group: 32 % Control group: 0: P = 0.02
Treated group: 21 % Control group: 0 P = 0.04
Anemia psychiatric disorders 1 chronic rejection
Carrion [29]
81, 90
Peg-IFN + Ribavirin vs. no treatment for 48 weeks
Treatment interruptions 39 %, dose reductions 49/54
n/a
Treated group: 18 (33 %) Control group: 0
Anemia, asthenia, fever
N number of patients, IFN interferon, Peg pegylated, Rib ribavirin, HCV hepatitis C virus, ETR end of treatment response defined as undetectable HCV RNA at the end of treatment, SVR sustained virological response, NS not statistically significant, n/a not available

4.3.2 Peg IFN/Ribavirin + First Generation Protease Inhibitors

TVR and BOC are first generation NS3/4A protease inhibitors with potent activity against HCV replication. There have been few studies with triple therapy (Peg IFN/RBV + TVR or BOC) in post-LT patients with histological HCV recurrence (Table 4.5). The major disadvantage with TVR or BOC was the drug–drug interaction with commonly used immunosuppressive agents. Both TVR and BOC [3337] are inhibitors of the enzyme cytochrome P450 3A which are also responsible for the metabolism of calcineurin inhibitors such as cyclosporine and tacrolimus, and hence these drugs will increase the blood concentrations of both cyclosporine and tacrolimus significantly. When TVR or BOC is used in transplant recipients, significant dose reductions and frequent drug level monitoring of immunosuppressive agents is required. Despite these limitations, there were many studies that had explored this regimen in liver transplant recipients (Table 4.5).
Table 4.5
Data on first generation protease inhibitor-based triple therapy for HCV recurrence after liver transplantation
First author (ref)
Coilly [36]
Pungpapong [33]
Werner [35]
Burton [34]
Patients (n)
37
60
9
81
Regimen
Boc/TVR (n/n)
18/19
25/35
0/9
8/73
SVR 12 (%)
50 (20 % in Tel group vs. 71 % in Boc group)
n/a
n/a
63
Adverse events and management of anemia
RBV dosage reduction (%)
70
93
56
80
Blood transfusion (%)
35
53
67
57
Infections (%)
27
11.6
NA
27
Death (n)
3
2
0
7
Oct 6, 2016 | Posted by in GASTROENTEROLOGY | Comments Off on Treatment of Recurrent Hepatitis C

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