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Sustained Virologic Response in HCV: Can We Say "Cure"?

David L. Thomas, MD, MPH

Chief of Infectious Diseases
Johns Hopkins University School of Medicine
Baltimore, Maryland

Introduction

In the treatment of hepatitis C, the word cure means more to most
patients than sustained virologic response (SVR). To patients, a cured
infection means they are back to "normal" and that the hepatitis C
virus (HCV) infection has been cleared from their body. The
psychological impact of receiving this news is difficult to measure,
but experienced providers recognize that it is significant. Recent
data showing that HCV infection recurs in some people after SVR have
called into question the scientific validity of using the terms cure
and SVR interchangeably. Nonetheless, a study by Swain and coworkers,
[1] recently presented at the 2007 Digestive Disease Week meeting in
Washington, DC, provided additional evidence that patients with an SVR
can be considered cured.

Background

More than 10 publications address the recurrence of HCV infection
after SVR; however, their data are difficult to compare because the
dose, duration, and formulation of interferon alfa differ, as does the
use of ribavirin. Likewise, major differences exist in patient
attributes, such as age, sex, race, HCV risk factor, baseline disease
stage (cirrhosis), HCV genotype, and coinfection with hepatitis B
virus (HBV) or HIV-1. The sensitivity of HCV RNA assays used to detect
HCV infection also differ, along with the duration of follow-up,
frequency of HCV RNA monitoring, and rigor with which recurrence is
identified.

Despite substantial heterogeneity in these available studies, the
cumulative HCV recurrence incidence reported is remarkably similar and
at low enough rates to comfort the clinician and patient. No
recurrences were reported among 187 patients over an average of 2.4
years in an Austrian study when patients achieving SVR were tested
with an HCV RNA assay capable of detecting viral loads as low as 50 IU/
mL.[2] Likewise, no recurrences were detected in a small but carefully
conducted cohort from the US National Institutes of Health.[3] In an
Australian study, 1 instance of HCV recurrence was detected among 147
patients followed for an average of 2.3 years after treatment.[4]
Finally, 3 instances of recurrence were detected among 80 patients who
achieved SVR in one of the first studies evaluating recurrence,
conducted in France.[5]

Risk Factors and Risk Groups

In most studies, the incidence of recurrence is insufficient to
identify risk factors for the event. Injection-drug use, however, is
an expected risk factor for recurrence resulting from reexposure to
the virus. In one study, 18 injection-drug users were followed after
SVR, and recurrence was detected in 2 participants; 1 individual was
infected 10 months after treatment with the same genotype, whereas the
other was infected 4 years after treatment with a new genotype.[6]
Separate analyses have shown that HIV-infected people or those with
cirrhosis do not appear to have an increased risk of recurrence.[7,8]

Clinical profile of patients with recurrence

The clinical correlates of recurrent infection are not typically well
characterized. In the few studies in which they have been reported,
the level of viremia on recurrence tended to be similar to
pretreatment levels and within the range typically detected in chronic
hepatitis C (4-7 log10 IU/mL). However, in one study, a patient was
described whose HCV RNA level fluctuated from 2-3 log10 IU/mL to
undetectable over 2 years, before returning to pretreatment levels.[9]
In the French study, where 3 patients experienced recurrence, 2 had
intermittent detection of low-level viremia (< 3.5 x 105 genome
equivalents/mL), whereas the other appeared to have persistent viremia.
[5] Some investigators have noted that patients with recurrence have
fluctuating and elevated ALT levels during treatment, even after the
virologic response is achieved.[10] Thus, in some instances,
recurrence seems to mirror relapse; that is, HCV RNA and liver enzyme
levels return to pretreatment ranges. In other instances, HCV RNA
"blips" are detected and would not have been recorded without
sensitive RNA monitoring. Insufficient clinical data are available to
judge the meaning of these blips or to provide a basis for retreatment
recommendations. Nonetheless, monitoring such patients more frequently
would be prudent.

Reasons for recurrence

HCV recurrence represents a failure to eradicate the infection with
treatment, a new exposure to virus, or a laboratory error. The first
cause is generally assumed, raising the question of where the
infection resides at low levels for ≥ 6 months posttreatment such that
HCV RNA cannot be detected in serum. One hypothesis suggests an
ongoing viral replication in the liver that does not generate
sufficient HCV RNA to enable detection with conventional assays. An
alternative conjecture is that HCV RNAs persist in a latent state in
liver or extrahepatic reservoirs to then serve as a template for
initiating replication months or years later; the possible reasons for
this are unclear.

Although the hypothesis that recurrence represents a reawakening of
dormant virus (or RNA) may be the best explanation, recurrence is
rare. In most studies, no HCV RNA is detected in posttreatment liver
tissues from people achieving SVR.[5,9] Unlike HBV and HIV-1, HCV is
not known to integrate into host DNA and does not have a DNA
intermediate, raising the question of how HCV RNA persists in a latent
state and what might trigger its reactivation. With HBV, tuberculosis,
Epstein Barr virus, cytomegalovirus, and other latent pathogens,
reactivation occurs with immunosuppression.

Therefore, other possible explanations for recurrent infection may
exist. In some instances, such as among injection-drug users,
reexposure appears to be the basis for recurrence. Although a less
interesting consideration, laboratory testing sensitivity and error
undoubtedly explain some instances of recurrence. The increasing
sensitivity of commercially available HCV RNA assays may increase the
frequency with which recurrence is detected, analogous to the
discovery of occult hepatitis B after deployment of sensitive HBV DNA
polymerase chain reaction testing. In studies that seek to confirm
recurrence, false-positive rates of 2% to 3% have been reported,
underscoring the importance of confirming all unanticipated laboratory
results.[4] This is a special concern when an isolated low-level HCV
RNA blip is interpreted as recurrence. Even greater caution must be
used when interpreting HCV RNA assays that are not commercially
available.

How Does the New Study Weigh In?

Swain and coworkers evaluated 997 patients who achieved an SVR in
trials that included treatment with peginterferon alfa-2a with or
without ribavirin.[1] Patients were tested yearly by use of the Roche
COBAS AMPLICOR HCV test v 2.0, with a reported sensitivity of 50 IU/
mL. Over a median of 4.1 years of follow-up, only 8 individuals (0.8%)
had evidence of recurrent infection. Although the details of this
study have not yet been published outside of a conference
presentation, the results are a welcome support for the body of data
indicating that SVR is indeed equivalent to cure for most patients.
References

1. Swain MG, Lai M-Y, Shiffman ML, et al. Sustained virologic response
(SVR) resulting from treatment with peginterferon alfa-2a (40KD)
(PEGASYS) alone or in combination with ribavirin (COPEGUS) is durable
and constitutes a cure: an ongoing 5-year follow-up. Digestive Disease
Week; Washington, DC: 2007. Abstract 444.

2. Formann E, Steindl-Munda P, Hofer H, et al. Long-term follow-up of
chronic hepatitis C patients with sustained virological response to
various forms of interferon-based anti-viral therapy. Aliment
Pharmacol Ther. 2006;23:507-511.

3. Lau DT, Kleiner DE, Ghany MG, Park Y, Schmid P, Hoofnagle JH. 10-
year follow-up after interferon-a therapy for chronic hepatitis C.
Hepatology. 1998;28:1121-1127.

4. Desmond CP, Roberts SK, Dudley F, et al. Sustained virological
response rates and durability of the response to interferon-based
therapies in hepatitis C patients treated in the clinical setting. J
Viral Hepat. 2006;13:311-315.

5. Marcellin P, Boyer N, Gervais A, et al. Long-term histologic
improvement and loss of detectable intrahepatic HCV RNA in patients
with chronic hepatitis C and sustained response to interferon-alfa
therapy. Ann Intern Med. 1997;127:875-881.

6. Backmund M, Meyer K, Edlin BR. Infrequent reinfection after
successful treatment for hepatitis C virus infection in injection drug
users. Clin Infect Dis. 2004;39:1540-1543.

7. Veldt BJ, Saracco G, Boyer N, et al. Long term clinical outcome of
chronic hepatitis C patients with sustained virological response to
interferon monotherapy. Gut. 2004;53:1504-1508.

8. Soriano V, Maida I, Nunez M, et al. Long-term follow-up of HIV-
infected patients with chronic hepatitis C virus infection treated
with interferon-based therapies. Antivir Ther. 2004;9:987-992.

9. McHutchison JG, Poynard T, Esteban-Mur R, et al. Hepatic HCV RNA
before and after treatment with interferon alone or combined with
ribavirin. Hepatology. 2002;35:688-693.

10. Reichard O, Glaumann H, Fryden A, Norkrans G, Wejstal R, Weiland
O. Long-term follow-up of chronic hepatitis C patients with sustained
virological response to alpha-interferon. J Hepatol. 1999;30:783-787.

Expert Viewpoints
September 2007
Road Map for On-Treatment Management of Chronic Hepatitis B

By:

Emmet B. Keeffe, MD, MACP

Professor of Medicine Emeritus
Stanford University School of Medicine
Stanford, California
March 2006
A Call for Participation in the Ribavirin Pregnancy Registry

By:

Karen L. Lindsay, MD

Associate Professor of Medicine
Gastroenterology and Liver Disease
Keck School of Medicine
Hepatitis Research & Treatment Center
University of Southern California
Los Angeles, California
Of Related Interest

   * Special Hepatic Issues and Populations
   * Update on Investigational Agents in HCV: 2007
   * Update on Investigational Agents in HCV: 2007
   * Depression and Suicidal Risk Associated With HCV Treatment
   * Advances in HCV Management Strategies With Approved Agents

CCO > Hepatitis > Resources > Expert Viewpoints > July 2007