Abstract Background Sustained virological response (SVR) is achieved in a high proportion of patients with chronic hepatitis C infection, particularly those with genotype 2 or 3 HCV infection. However, data on long-term durability of virological response in patients who achieve SVR are limited. Aim To evaluate the long-term durability of virological response in patients who have achieved SVR with interferon-based combination therapy. Methods One hundred patients with chronic HCV infection who had obtained SVR after IFN and ribavirin combination therapy were followed up for up to 8 years with annual HCV RNA testing. Results During a followed up of 6 months to 8 years, 8 of 100 patients with initial SVR developed late relapse of HCV infection. Relapse was more common in patients who had cirrhosis (5/28 [18%] vs. (3/72 [4%]  with no cirrhosis; p=0.037). Conclusion SVR is durable in most patients, but some patients do have late relapse; long term follow up may be particularly important in a subset of patients with HCV infection who have liver cirrhosis

Ajit Sood

Amandeep Thara

Amarjeet Kaur

Neena Sood

Rasham Mittal

Sarit Sharma

Vandana Midha

Varun Mehta

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ORIGINAL ARTICLE
How sustained is sustained viral response in patients
with hepatitis C virus infection?
Ajit Sood & Vandana Midha & Varun Mehta &
Sarit Sharma & Rasham Mittal & Amandeep Thara &
Neena Sood & Amarjeet Kaur
Received: 14 October 2009 /Accepted: 28 May 2010 /Published online: 29 June 2010
# Indian Society of Gastroenterology 2010
Abstract
Background Sustained virological response (SVR) is
achieved in a high proportion of patients with chronic hepatitis
C infection, particularly those with genotype 2 or 3 HCV
infection. However, data on long-term durability of virolog-
ical response in patients who achieve SVR are limited.
Aim To evaluate the long-term durability of virological
response in patients who have achieved SVR with
interferon-based combination therapy.
Methods One hundred patients with chronic HCV infection
who had obtained SVR after IFN and ribavirin combination
therapy were followed up for up to 8 years with annual
HCV RNA testing.
Results During a followed up of 6 months to 8 years, 8 of
100 patients with initial SVR developed late relapse of
HCV infection. Relapse was more common in patients who
had cirrhosis (5/28 [18%] vs. (3/72 [4%] with no cirrhosis;
p=0.037).
Conclusion SVR is durable in most patients, but some
patients do have late relapse; long term follow up may be
particularly important in a subset of patients with HCV
infection who have liver cirrhosis.
Keywords Hepatocellular carcinoma .
Pegylated interferon . Sustained viral response
Introduction
Hepatitis C virus (HCV) infection is a major health problem
worldwide. Most of the infected persons develop a
persistent infection that can progress to chronic hepatitis,
cirrhosis and hepatocellular carcinoma (HCC).
Currently, pegylated interferon (Peg-IFN) alfa 2a/2b with
ribavirin is the standard treatment for chronic HCV
infection. Absence of serum HCV RNA 6 months after
discontinuation of therapy i.e., sustained virological re-
sponse (SVR) is generally taken as cure of HCV infection.
SVR rates with Peg-IFN-ribavirin treatment are 42–52% of
those with genotype 1 HCV infection, and 80% in those with
genotype 2 or 3 HCV infection [1]. Successful eradication
of HCV is associated with regression of fibrosis and clinical
improvement [2, 3].
However, despite treatment, HCV may persist in liver
tissues and extrahepatic locations like peripheral blood
mononuclear cells (PBMCs) leading to late relapse, defined
as reappearance of viremia after SVR has been achieved [4].
A. Sood (*) :V. Mehta : R. Mittal
Department of Gastroenterology,
Dayanand Medical College and Hospital,
Ludhiana 141 001, India
e-mail: ajitsood10@sify.com
V. Midha
Department of Medicine,
Dayanand Medical College and Hospital,
Ludhiana, India
S. Sharma
Department of Community Medicine,
Dayanand Medical College & Hospital,
Ludhiana, India
A. Thara
Dayanand Medical College & Hospital,
Ludhiana, India
N. Sood
Department of Pathology,
Dayanand Medical College and Hospital,
Ludhiana, India
A. Kaur
Department of Transfusion Medicine,
Dayanand Medical College & Hospital,
Ludhiana, India
Indian J Gastroenterol (2010) 29:112–115
DOI 10.1007/s12664-010-0006-3
Since, no data are available on long-term clinical
outcomes and virological relapse in Indian patients with
HCV infection who achieve SVR, [5, 6] we undertook a
prospective, long-term follow up study assessing of such
patients.
Methods
Patients with chronic hepatitis C who had achieved SVR
with antiviral treatment between January 2000 and June
2007, who agreed for follow-up using annual HCV RNA
testing, were enrolled in the study. All patients provided
written informed consent. The study protocol was approved
by our hospital’s ethics committee.
Chronic hepatitis C was defined as presence of anti-HCV
antibodies (Ortho, Raritan, NJ, or Abott, Chicago, IL, USA),
detectable serum HCV RNA (Roche Amplicor; Hoffmann–
LaRoche, Basel, Switzerland) and elevated (twice the upper
limit of normal) serum alanine aminotransferase (ALT)
levels. SVR was defined as undetectable serum HCV RNA
levels 6 months after stopping therapy.
The patients underwent a clinical follow-up every 3–
6 months for 1 year and yearly thereafter. At each visit,
physical examination, hemogram, liver function tests and
prothrombin time were done. Patients with ultrasound (US)
or histological evidence of cirrhosis were screened for HCC
by alpha-fetoprotein measurement every 6 months and
ultrasound every year. HCV RNA was tested every year.
Decompensation was defined as development of jaundice,
ascites, encephalopathy or variceal bleed. Diagnosis of HCC
was based on elevated AFP (>500 pg/mL), space occupying
lesion in the liver on US, computed tomogram or magnetic
resonance imaging, or / and US-guided FNAC.
Data are expressed as mean (SD). A time-to-event
analysis was done using life table method. Fisher’s exact
test was used to compare proportions. P values below 0.05
were considered significant.
Results
Between January 2000 to June 2007, 128 patients received
anti-HCV treatment. Of these, 9 patients did not complete
the treatment due to adverse effects (n=4), decompensation
of disease (n=1) or financial reasons (n=4). Of the 119
patients who completed treatment, 100 achieved SVR and
were followed up. The baseline demographic, clinical,
virologic, histologic characteristics and treatment of these
100 patients are shown in Table 1.
All the study patients were negative for HBsAg and anti-
HIV. None had decompensated cirrhosis at enrollment, or
evidence suggesting HCC on US or serum AFP levels.
Table 1 Baseline characteristics of study subjects (n=100)
Characteristic Value
Age (mean [SD]) (years) 41.4 [11.0]
Gender (M:F) 78:22
BMI (mean [SD]) 26.3 [4.3]
Cirrhosis 28
Alcohol intake 54
Opium intake 11
Diabetes 4
Genotype: 1 / 3/ othersa 16 / 74 / 10
Liver fibrosisb stage 0–2 / 3–4 65 / 7
Type of IFN used: Conventional / pegylated 15/85
Ribavirin dose (mg/kg) (mean [SD]) 11.54 (2.17)
a Others include one patient with a mixed (genotype 1 and 3) infection and
9 in whom genotype could not be identified
b These data were available only for 72 patients
120
96100
7380
60
41
40
N
u
m
b
er
 o
f 
p
at
ie
n
ts
27
22
1820 14
8
2 2 3 1 0 0 0 0
0
1 2 3 4 5 6 7 8
Long term follow up duration (Years)
Fig. 1 Long term follow up
results
Indian J Gastroenterol (2010) 29:112–115 113
Twenty-one patients had US evidence of cirrhosis; of the
remaining patients, 72 had undergone pretreatment liver
biopsy whereas 7 had refused biopsy. Patients had received
either conventional IFN (n=15) or pegylated IFN (n=85) in
combination with ribavirin (weight-based); the duration of
treatment was 24 weeks for those with genotype 3 HCV
infection and 48 weeks for the other patients.
Duration of follow up was 6–96 months. The number of
patients completing 1st to 8th year of follow up was 96, 73,
41, 27, 22, 18, 14 and 8, respectively (Fig. 1).
Two patients died during follow up, including one of
head injury following a road traffic accident and one of
HCC, decompensated cirrhosis, and liver failure. No other
patient developed decompensation or HCC.
Eight of 100 patients had virological relapse during follow
up, including two each during the first and the second year,
three in the third year and one in the fourth year of follow up,
and none subsequently. Hence, the cumulative proportion of
virological relapses was 0.02, 0.03, 0.07, and 0.04, respec-
tively at 1, 2, 3, 4 years of follow up (Fig. 1).
Clinical, virologic and treatment details of these patients
are shown in Table 2. Relapse occurred more often in
patients with liver cirrhosis (5/28 [18%]) than in those
without cirrhosis (3/72 [4%]; p=0.037), and in those treated
with conventional interferon and ribavirin (3/15 [20%]) than
in those who had received Peg-IFN and ribavirin (5/85 [6%];
p=0.096) (Table 3). The mean (SD) dose of ribavirin was
10.7 (2.4) mg/kg body weight in those with relapse and 11.6
(2.2) mg/kg in those who maintained remission (p=0.27).
Discussion
This is the first study from India on long-term outcomes of
anti-viral therapy for chronic HCV infection. Our study
shows that SVR is durable in a majority of patients but late
relapses do occur. These relapses occur more commonly in
patients with cirrhosis.
The issue of late relapses in hepatitis C infection has been
reported earlier [7–11]. A meta-analysis of eight European
trials by Veldt et al. reported late relapse rate of 4.7% over
5 year follow up [12]. Similarly, Camma et al. reported 8.7%
late relapse in a meta-analysis of 14 trials [13]. The
noteworthy limitations of trials included in these meta-
analysis were: use of conventional IFN monotherapy, and
use of less sensitive diagnostic assays which could have
resulted in an over estimate of SVR. The results of durability
of SVR after treatment with pegylated IFN and ribavirin
were 100% and approximately 99% in two recent studies
from western countries [14, 15]. Our study revealed late
relapses in 20% patients treated with conventional IFN +
ribavirin and 5.9% in those treated with pegylated IFN +
ribavirin over 8 year follow up. One reason for high late
relapse in our study could be due to presence of poor
baseline predictors of response: obesity i.e., BMI >30 (n=3),
alcohol intake (n=4) and cirrhosis (n=5). In addition, on
retrospective analysis we found that mean dose of ribavirin
used in patients treated with conventional IFN was subop-
timal as dose reductions were required more frequently in
earlier years as erythropoietin use was infrequent.
Table 2 Characteristics of patients who had a relapse following sustained virological response
Sr.
No
Age Sex BMI
(kg/m2)
Alcohol Genotype Cirrhosis Viral load log
(IU/mL)
Interferona Ribavirin dose
(mg/kg)
Time to relapse
(year)
1 48 M 32.1 Y 3 Y NA C 8.88 1st
2 45 M 30.4 N 3 Y NA C 10 1st
3 52 M 23.7 Y 3 Y NA C 9.38 3rd
4 45 M 21.6 Y 1 Y 3.72 Peg 14.03 2nd
5 52 F 24.6 N 3 N 5.40 Peg 8.84 2nd
6 40 M 28.3 N 3 N 5.39 Peg 8.95 3rd
7 38 F 33.7 N 1 Y 5.71 Peg 14.81 3rd
8 38 M 24.4 Y 3 N 5.80 Peg 10.95 4th
aC conventional; Peg pegylated
Table 3 Comparison of relapsers and non-relapsers
Non-relapsers
n=92 (%)
Relapsers
n=8 (%)
P
Gender (M) 72 (78.3) 6 (75) 1
Age ≤40 47 (51.1) 3 (37.5) 0.72
BMI ≤30 74 (80.4) 5 (62.5) 1
Alcohol intake 50 (54.3) 4 (50) 1
Opium intake 9 (9.8) 2 (25) 0.21
Cirrhosis 23 (25) 5 (62.5) 0.037
Ribavirin dose ≤12 mg/kg 58 (63) 6 (75) 0.71
Type of IFN:
conventional/pegylated
12/80 3/5 0.097
Genotype: 1/3/others 14/68/10 2 / 6 / 0 1
114 Indian J Gastroenterol (2010) 29:112–115
A theoretical explanation for late relapse could be
persistence of undetected occult hepatitis C virus in hepato-
cytes, PBMCs, lymphocytes or macrophages. Earlier studies,
possibly using less sensitive assays, have shown that 95% of
patients with SVR have no liver HCV RNA 1–2 years after
therapy [16]. Another study supporting this reported that
clearance of liver HCV RNAwas sustained upto 12 years off
treatment [17]. However; several recent reports contradict
these findings. In a small study, only 2 of 17 patients with
SVR remained HCV RNA negative on long term follow up
when all body compartments were analyzed [9]. Similarly, in
another study viral sequence could be amplified during
follow up of 5 years from sera or PBMC in all patients with
SVR [18]. More recently, a large cohort of 344 patients
followed up for up to 18 years after cessation of treatment,
revealed undetectable HCV RNA in serum and PBMCs in
all patients, but HCV RNA was detected in 2 of 114 (1.7%)
liver biopsies tested [4].
It is known that unlike hepatitis B virus, HCV does not
have a latent stage in its replication cycle and cannot
integrate into the host genome [4]. Hence, the presence of
persistent HCV infection after successful antiviral therapy
raises interesting clinical issues like disease progression,
hepatocarcinogenesis, reactivation and furthermore, a po-
tential source of HCV spread.
Our study has some limitations. Liver biopsy was not
done at follow up in our patients with late relapse; hence it
is not possible to comment on occult HCV in liver.
Similarly, retesting of genotype/sequencing was not done
and a possibility of re-infection cannot be ruled out. Re-
infection appears to be unlikely as all the relapses were
observed in first 4 years after SVR.
SVR once achieved is sustained in majority of patients. The
treating hepatologist need to be aware of occurrence of late
relapses in patients with chronic HCV infection with cirrhosis.
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How sustained is sustained viral response in patients with hepatitis C virus infection?

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How sustained is sustained viral response in patients with hepatitis C virus infection?

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