The outcome of re-treatment of relapsed hepatitis C virus infection in a resource-limited setting

Abstract

The aim of this study was to compare efficacy and safety of different combination regimens in re-treatment of HCV in the setting of inaccessibility of resistance testing. This real-life prospective study included 86 chronic HCV infected patients who experienced failure of treatment treated at Faculty of Medicine Ain shams Research Institute (MASRI) since 2018. 64% of the patients were males, with median age 50.2 years. They were re-treated using 1 of 3 proposed regimens of DAA combinations. One group received PAR/OMB/SOF/RBV for 12 weeks, another group received SOF/DAC/SIM/RBV for 12 weeks and a third received SOF/DAC/RBV for 24 weeks. Response to different regimens was assessed by comparing sustained virologic response (SVR) of each. Monitoring the occurrence of adverse events was performed. SVR was achieved in all but 3 patients (96.5% SVR), one in the SOF/DAC/SIM/RBV group and two in the SOF/DAC/RBV group. The group receiving RBV had more anaemia and hyperbilirubinemia. The first treatment regimen used was a significant predictor to SVR achievement. This study presents alternative treatment regimens for re-treatment of HCV patients in areas with limited resources in the case of non-availability of other regimens as velpatasvir, voxilaprevir, grazoprevir, elbasvir.

Introduction

Hepatitis C virus is a worldwide major cause of morbidity and mortality [1]. It is a human pathogen affecting around 3% of the global population [2–4] which is the most prevalent blood-transmitted infection [5, 6].

Egypt was considered to have the highest prevalence rate globally, evaluated as 14.7% nationally [7, 8] and genotype 4 accounts for more than 90% [8, 9].

Previously, HCV was treated using pegylated interferon alfa and ribavirin which was an ineffective regimen where sustained virologic response was reached in only 50% of cases in addition to many serious side effects [10, 11].

DAAs act by interfering with many stages of the virus life cycle targeting NS3 protease, NS5A phosphoprotein and NS5B polymerase as their sites of action [12].

Treatment failure may be associated with many factors as advanced liver fibrosis stages, previous history of antiviral treatment intake and viral factors as viral load [10].

HCV genotype determines the response to DAAs and also progression of fibrosis may differ in different genotypes [13].

Advantages of DAAs are improved response rates, short duration and simplicity but these properties may be challenged by the appearance of resistance-associated variants (RAVs), resulting in creation of resistant phenotypes which may reduce DAAs effectiveness [1, 14].

A resistant variant may be caused by mutation or substitution of amino acid [15].These RAVs usually appear after few days of starting DAAs and are considered to be responsible for treatment failure. But also, they can be detected in treatment naïve HCV infected patients [1, 16].

Re-treatment should be guided either by identification of previous treatment regimen used, if resistance test is not available, or if resistance testing is available, by probabilities of response according to the resistance profile known and the treating team experience [17].

The regimens used in this study are due to non-availability of other regimens as velpatasvir, voxilaprevir, grazoprevir, elbasvir at the time of the study.

This work aimed to compare the efficacy and safety of different sofosbuvir based combination regimens used in re-treatment of HCV infected Egyptian patients who experienced failure of previous course of DAAs.

Methods

Study design and study population

This prospective observational study included 86 HCV patients who were referred to Ain shams university treatment and research unit (MASRI) in the period between 2016 and 2018. All Patients included experienced previous HCV treatment failure.

Exclusion criteria

1. Pregnancy

2. Age less than 18 years old

3. Co-infection with HBV

4. Hepatocellular carcinoma except after 6 months of intervention with no new active lesions.

5. Renal failure

Intervention

They were divided into 3 groups according to the re-treatment DAAs regimens prescribed after giving a written consent:

• Group I: included 26 patients who received PAR/OMB/SOF/RBV for 12 weeks.

• Group II: included 53 patients who received SOF/DCV/SIM/RBV regimen for 12 weeks

• Group III: included 7 patients who received SOF/DAC/RBV regimen for 24 weeks

Doses given: SOF (400 mg), OMB (25 mg), PAR (150 mg), and ritonavir (100 mg) in fixed daily doses. RBV was given in the form of 200 mg capsules; the prescribed dose was 1000 mg/day (for those patients with body weight < 75 kg) or 1200 mg/day (for those patients with body weight $\ge$ 75 kg) unless significant side effects happened. In cirrhotic patients starting RBV dose was 600 mg/day. This treatment was given according to the national committee for control of viral hepatitis (NCCVH) protocol. The regimens used in this study were the ones available for re-treatment at the time.

All patients were subjected to the following before the procedure

1. Full history taking and clinical examinations, registering details of previously received HCV treatment.

2. Lab investigations included liver function tests, serum creatinine (S.cr), complete blood count (CBC), pregnancy test (B-HCG) for fertile females, fasting blood sugar (FBS), HbA1c for diabetic patients, HCV viral load by PCR, Hepatitis B surface antigen (HBSAg) and alpha fetoprotein (ΑFP).

3. Calculating FIB-4 score and Child score.

4. The FIB-4 index is calculated using the formula: FIB-4 = Age (years) × AST (U/L)/[PLT (10⁹/L) × ALT1/2 (U/L)] [18].

A threshold value of 1.45 has a negative predictive value for the exclusion of extended fibrosis (mild degree). A threshold value of 3.25 has a positive predictive value for the diagnosis of extended fibrosis (severe degree) [18].

The Child-Turcotte-Pugh (CTP) score is based on 5 variables, two clinical (ascites and encephalopathy) and three biochemical (serum albumin, normalized ratio (INR) and bilirubin) by assigning 1, 2 or 3 points to each of the five variables enabling the calculation of the score [19].

Child-Turcotte-Pugh (CTP) score ranges from 5 to 15, with scores of 5 and 6 corresponding to CTP class A, scores of 7–9 corresponding to CTP class B and scores of 10–15 corresponding to CTP class C [19].

The presence of liver cirrhosis was documented by abdominal ultrasonography and laboratory markers, like FIB-4 > 3.25 (advanced fibrosis or cirrhosis), albumin < 3.5, total bilirubin > 1.2, and also confirmed by clinical characteristics such as lower limb oedema and portal hypertension manifestations (like splenomegaly or oesophageal varices).

1. Abdominal ultrasonography to assess liver echo-pattern, presence of ascites and focal lesions.

2. ECG

3. B-HCG for females in childbearing period.

During treatment and follow up

During treatment all patients were monthly followed up at our clinic by CBC, AST, ALT, T.BIL, S.Albumin, INR and S.creatinine. Up to six months for those who received 24 weeks therapy.

After the end of treatment

Sustained virologic response (SVR12) was assessed, defined as undetectable viraemia (HCV RNA < 15 IU/ml) 12 weeks after end of treatment, was evaluated.

Data management and analysis

Data was revised, coded, entered on computer and analysed using SPSS package version 20. Quantitative data were described as mean, and standard deviation (SD). Qualitative data were expressed as frequencies (n) and percentage (%). Fisher exact test were used to test association between qualitative variables. P-value ≤ 0.05 was considered significant.

Results

Eighty-six HCV patients who experienced previous HCV treatment failure were included in the study. Patients were predominantly males (64%) with a mean age of 50.2 ± 11.3 years. According to Fib 4 score results, they had no or mild fibrosis (48.8%), moderate fibrosis (36.1%), or severe fibrosis (15.1%). About 24.4% of patients had liver cirrhosis where [71.4% of cirrhotic patients had Child score A (5–6), while 28.6% of cirrhotic patients had Child score B (7–9)]. Previous failed treatment regimens used among the studied patients were mainly SOF/DAC/RBV (23.2%), SOF/DAC (34.9%), and PAR/OMB/RBV (25.6%) as shown in Table 1.

Table 1.

Distribution of patients’ characteristics (as gender, co-morbidities, hepatic status and previous failed treatment) in the studied sample

	N	%	%
Gender	Male	55	64
	Female	31	36
Hypertension	No	77	89.5
	Yes	9	10.5
Other co-morbidities	No other diseases	77	89.5
	PVT	1	1.2
	Heart diseases	5	5.8
	Disc prolapse	1	1.2
	Gout	1	1.2
	HCC	1	1.2
Liver echo pattern	Normal	31	36.0
	Cirrhotic	14	16.3
	Abnormal echo pattern	41	47.7
Child score	A	15	71.4
	B	6	28.6
FIB 4 score	Mild (< 1.45)	42	48.8
	Moderate (1.45–3.25)	31	36.1
	Advanced (> 3.25)	13	15.1
Previous failed treatment regimen	SOF/DAC/R	20	23.2
	SOF/DAC	30	34.9
	PAR/OMB/R	22	25.6
	IFN protocol	6	7
	SOF/IFN	2	2.3
	SOF/RBV	4	4.6
	SOF/SIM	2	2.3

SOF sofosbuvir, DAC daclatasvir, R ribavirin, PAR Paritaprevir, OMB ombitasvir, IFN interferon, SIM simeprevir

Ribavirin was discontinued in one case at week 4 due to anaemia; however, this patient reached SVR. Another case developed hepatic decompensation and stopped treatment at week 8 due to severe hepatic decompensation. This patient reached SVR too and he was referred to liver transplantation.

An SVR was achieved in (96.5%) of cases in the re-treatment DAAs regimens, with a higher proportion of in patients receiving PAR/OMB/SOF/RBV regimen (100%), followed by SOF/DAC/SIM/RBV (98.1%), followed by SOF/DAC/RBV regimen (71.4%) (P-value = 0.017) as presented in Fig. 1. One of the non-responders had severe degree of fibrosis while the another two had moderate degree of fibrosis.

Fig. 1.

Response to treatment using re-treatment different DAAs combination regimens

There was no significant relationship between SVR and degree of viremia with cut-off value of 25,438 IU (AUC = 0.512, Sensitivity = 66.7%, and Specificity = 49.4%) (P-value are > 0.05). In the studied group, 49.4% of patients with SVR had low viremia and 50.6% had high viremia.

Previous treatment used had a significant impact on achieving SVR (p value = 0.007) as the patients who did not reach SVR were previously treated using SOF/INF (2 patients). SVR was achieved in 100% of those who took SOF/DAC/R, PAR/OMB/R, IFN protocol, SOF/RBV, and SOF/SIM as a previous failed regimen and in 96.7% of patients treated with SOF/DAC as stated in Table 2.

Table 2.

Relation between response to treatment and previous failed treatment regimen

		Results				P
		SVR		Non-SVR
		N	%	N	%
Previous treatment regimen	SOF/DAC/R	20	100.0	0	0.0	.007*
	SOF/DAC	29	96.7	1	3.3
	PAR/OMB/R	22	100.0	0	0.0
	IFN protocol	6	100.0	0	0.0
	SOF/IFN	0	0.0	2	100.0
	SOF/RBV	4	100.0	0	0.0
	SOF/SIM	2	100.0	0	0.0

Fisher exact test was used, p value < 0.05 is considered statistically significant

SOF sofosbuvir, DAC daclatasvir, R ribavirin, PAR paritaprevir, OMB ombitasvir, IFN interferon, SIM simeprevir

On the other hand, the re-treatment regimens used had no significant side effects except decrease HB level and hyper-bilirubinaemia in 2 cases (P-value are > 0.05). In general, treatment regimens were very well tolerated.

Discussion

Treatment failure has been caused by host factors, viral factors, and treatment-related factors and usually results from combination of two or more factors [20].

The percentage of viruses resistant to protease inhibitors progressively decrease after end of treatment. In contrast, resistance to NS5A inhibitors remains persistent for several years after end of treatment [21, 22].

Therefore, to achieve higher virological response, multiple groups of DAAs with different viral targets and non-overlapping resistance properties may be used for difficult-to-treat populations and for shorter durations of treatment [23].

The regimens used in this study were according to the national committee for control of viral hepatitis (NCCVH) recommendations, due to non-availability of other regimens as sofosbuvir, velpatasvir and voxilaprevir combination regimens at that time due to their excessive cost. Egyptian guidelines were placed according to the available resources.

In our study, re-treatment of patients, who had previously experienced failure of treatment, was completed using many DAAs combination regimens with a very good results achieving SVR in 96.5% of the patients. 100% in those who received PAR/OMB/SOF/RBV regimen, 98.1% in those who received SOF/DAC/SIM/RBV and 71.4% in those who received SOF/DAC/RBV regimen.

The correlation between SVR and previous failed treatment regimen was significant (p 0.007) with SVR reaching 100% in many of these groups specially those who received DAAs previously. Eight patients had received IFN ± SOF, 4 patients SOF/RBV, 50 patients SOF/DAC ± RBV and 22 patients had received PAR/OMB/RBV. Regarding this unexpected failure of PAR/OMB/RBV regimen, it is referred to non-compliance of the population who received this regimen as they were mainly had history of IV drug usage.

Similar to our results, a study done in 2018 which included 113 treatment-experienced Egyptian patients who were re-treated by SOF/OMB/PTV + RBV and they achieved an excellent SVR12 rate with 97% of patients achieving SVR [24].

In agreement with our results, SOF /DCV/ SIM/RBV regimen was used for re-treatment of 92 Egyptian patients with HCV GT4 infection; 97% of them had achieved SVR12 [23].

Additionally, a study conducted by Lawitz et al. [25], reported that treatment for 12 weeks with simeprevir, daclatasvir and sofosbuvir was well tolerated with achieving SVR in 100% of cirrhotic patients with decompensated liver disease or portal hypertension.

In another study, a total of 75 treatment-experienced patients received ombitasvir-paritaprevir-ritonavir, sofosbuvir with or without ribavirin as salvage therapy and achieved high SVR12 rates in chronic HCV Egyptian patients with previous sofosbuvir plus daclatasvir treatment failure in 93.4% of the patients. Also results included that ribavirin free regimen for 24 weeks exerted significantly less adverse effects [26].

A real-life prospective observational study included 1014 patients who were prior non-responders to 24-weeks SOF-RBV or 12-weeks SOF- RBV- PEG. Patients were re-treated with daily SOF/DCV/RBV for 12 (n = 270) or 24 weeks (n = 744). Overall, SVR12 was 90.6% [92.2% for 12 weeks therapy and 90.05% for 24 weeks therapy] [27].

A study used a combination of SOF and ribavirin for 24 weeks in treatment experienced patients with recurrent hepatitis C after living donor liver transplantation among patients from South Asia. SVR12 was noted in 95.2% of the patients while SVR24 was achieved in 93.7% of the patients [28].

A retrospective observational study done at the liver transplant unit of the University of Campinas with antiviral treatment consisted of the combination of sofosbuvir, daclatasvir and ribavirin according to the Brazilian hepatitis C treatment guidelines. 55 patients received HCV antiviral treatment. 58% of the patients were treated for 12 weeks and 42% for 24 weeks. The SVR rate was 98% [29].

Another multicentre study used LDV/SOF with/without RBV for 12–24 weeks in treatment of 45 HCV infected patients who had previously developed virological relapse after SMV + SOF regimen. Thirty-seven patients were treated using LDV/SOF for 24 weeks while 8 patients by LDV/SOF for 12 weeks and 96% of patients reached SVR. RBV treatment was complicated by significant anaemia in 45% of patients receiving it resulting in its dose reduction and/or discontinuation [30].

MAGELLAN-3 is a multicentre study evaluated the efficacy of Glecaprevir/pibrentasvir with sofosbuvir and twice-daily RBV for 12 or 16-week as a re-treatment regimen for patients with previous Glecaprevir/pibrentasvir failure. Ninety-six percent of the patients achieved SVR 12 with absence of indication for RBV dose reduction throughout treatment duration [31].

Another study used glecaprevir/pibrentasvir for re-treatment of 33 HCV infected patients who failed to achieve SVR after treatment with DAAs containing regimens. SVR12 was achieved by 31out of 33 (93.9%) patients [32].

Treatment failure may be associated with many factors as advanced liver fibrosis stages, previous history of antiviral treatment intake and viral factors as viral load [33–40].

Several studies stated that HCV 4a subtype is the dominant one in Egypt [41–43]; therefore, we depend on those studies in expecting the prevalent genotype in our study population due to the high cost of genotype testing.

This study presents alternative treatment regimens for re-treatment of HCV patients in areas with limited resources in the case of non-availability of other regimens as velpatasvir, voxilaprevir, grazoprevir, elbasvir. The limitation of the study may be the relatively limited sample size. So, larger studies on larger number of patients are recommended to document these findings.

Conclusion

This study presents alternative treatment regimens for re-treatment of HCV patients in areas with limited resources in the case of non-availability of other regimens as velpatasvir, voxilaprevir, grazoprevir, elbasvir. Additionally, the choice of the first line of treatment has a significant role in treatment response.

Author’s contributions

All the authors have participated in the research and have reviewed and agree with the content of the article after approval of ethical committee and under supervision of the national committee for control of viral hepatitis (NCCVH).

Funding

Self-funded.

Declaration

Conflict of interest

The authors report no conflicts of interest.