Between 24% and 42% of HIV-negative injecting drug users (IDUs) recently
infected with the hepatitis C virus (HCV) became spontaneously HCV-negative
within two years of being diagnosed with acute HCV infection, depending
on the definition of HCV diagnosis: HCV antibody-positive (42%) or a
detectable HCV viral load (24%). This retrospective cohort study from
Australia appears in the latest issue of the Journal of Infectious
Diseases, now available online.
Previous studies of spontaneous HCV clearance have estimated that
between 10% and 50% of people newly infected with HCV spontaneously
clear their infection in the absence of anti-HCV therapy before it
becomes chronic, usually defined as the persistence of HCV viral load
for more than six months. However, the majority of these studies have
been based on the presence of clinical symptoms of acute HCV infection,
which do not always appear, and not always in IDUs, despite the fact the
majority of new HCV infections occur through injecting drug use.
The authors of this study used data collected from a central Sydney free
health clinic, aimed at the prevention of HIV and other STIs in those
at-risk, including IDUs. A total of 99 IDUs who attended the clinic
between January 1992 and May 2002 had evidence of newly acquired HCV
infection, of whom only two were also HIV-positive. Just over half (53%)
were female, and 12% self-identified as Aboriginal. The cohort began
injecting drugs at a median age of 15, and became HCV infected at an
estimated median age of 22. The drug most commonly injected in the year
prior to HCV infection was heroin, with 64% injecting at least daily and
63% reporting sharing drug injecting equipment. The appearance of
clinical symptoms was rare, with only eight percent diagnosed with
documented jaundice; the majority being diagnosed through a positive HCV-antibody
test.
This study did not document cases acquired through sexual transmission.
Fifty-seven of the 99 IDUs in this clinic cohort had two or more
documented HCV viral load (RNA) test results after the estimated date of
infection, and viral clearance (defined as two consecutive undetectable
HCV RNA test results) occurred in 24 of the 57 (42%), with a median time
to viral clearance of 5.9 months. However, there was a wide variation in
the time taken for viral clearance to occur, from 1.4 to 11.2 months.
Analysis of the data using Kaplan-Meier estimates suggested that 23%,
38% and 40% would spontaneously clear their HCV infection after six,
twelve and 24 months, respectively.
Aware that some individuals are diagnosed with false-positive HCV
antibodies, the authors then restricted their analysis to the 33 of the
57 IDUs who also had a detectable HCV viral load within a year of the
estimated time of infection. Here, eight of the 33 (24%) experienced
spontaneous viral clearance. Analysis of the data using Kaplan-Meier
estimates suggested that 6%, 23% and 26% would spontaneously clear their
HCV infection after six, twelve and 24 months, respectively.
Further analysis revealed no significant demographic, clinical or
behavioural factors between those who cleared HCV and those who became
chronically infected. There were also no significant differences seen
between the 57 with HCV viral load data and the rest of the cohort.
Although those IDUs whose ALT liver function test normalised to less
than 40 IU/L were almost twice as likely to clear HCV than those who did
not, this did not reach statistical significance (hazard ratio, 1.90;
95% CI 0.77-4.65: p=0.16). Previous studies have found several factors
that predict viral clearance, including female gender, ethnicity,
symptomatic HCV, and lack of HIV co-infection. The authors suggest that
this cohort may be too homogenous (the majority being female, white,
asymptomatic and HIV-negative) to tease out these differences. Of note,
the one individual with documented HIV co-infection out of the 57
included in the analysis did not clear their HCV.
The authors conclude that in this cohort of young, mostly white,
injecting drug users, of whom 98% were HIV-negative, between 24% and 42%
cleared their HCV spontaneously in the two years following a positive
HCV antibody test. “Although estimated viral clearance rates varied
according to the strictness of the case definition, there were no
baseline demographic, clinical or behavioural factors associated with
clearance,” they write, adding that “the vast majority of clearances
occurred within the initial 12 months after the estimated time of
infection...The inclusion of IDUs who had experienced HCV antibody
seroconversion, rather than acute clinical hepatitis alone, makes our
study more broadly representative of newly acquired HCV infection than
most previous studies have been.”
Reference
Jauncey M et al. Clearance of hepatitis C virus after newly acquired
infection in drug users. J Inf Dis 190:1270-4, 2004.
Cost-effectiveness of Combination Peginterferon Alfa-2a
(Pegasys) and Ribavirin Compared with Interferon Alfa-2b (Intron A) and
Ribavirin in HCV Patients
Sustained virological response (SVR) is the primary objective in the treatment of chronic hepatitis C (CHC). Results from a recent clinical trial of patients with previously untreated CHC demonstrate that the combination of peginterferon alfa-2a and ribavirin produces a greater SVR than interferon alfa-2b and ribavirin combination therapy.
By
Sustained virological response (SVR) is the primary objective in the treatment of chronic hepatitis C (CHC). Results from a recent clinical trial of patients with previously untreated CHC demonstrate that the combination of peginterferon alfa-2a and ribavirin produces a greater SVR than interferon alfa-2b and ribavirin combination therapy.
However, the cost-effectiveness of peginterferon alfa-2a plus ribavirin in the US setting has not been investigated.
A Markov model was developed to investigate cost-effectiveness in patients with CHC using genotype to guide treatment duration. SVR and disease progression parameters were derived from the clinical trials and epidemiologic studies.
The impact of treatment on life expectancy and costs were projected for a lifetime. Patients who had an SVR were assumed to remain virus-free for the rest of their lives.
In genotype 1 patients, the SVRs were 46% for peginterferon alfa-2a plus ribavirin and 36% for interferon alfa-2b plus ribavirin.
In genotype 2/3 patients, the SVRs were 76% for peginterferon alfa-2a plus ribavirin and 61% for interferon alfa-2b plus ribavirin.
Quality of life and costs were based on estimates from the literature. All costs were based on published U.S. medical care costs and were adjusted to 2003 U.S. dollars. Costs and benefits beyond the first year were discounted at 3%.
Results
In genotype 1, peginterferon alfa-2a plus ribavirin increases quality-adjusted life expectancy (QALY) by 0.70 yr compared to interferon alfa-2b plus ribavirin, producing a cost-effectiveness ratio of $2,600 per QALY gained.
In genotype 2/3 patients, peginterferon alfa-2a plus ribavirin increases QALY by 1.05 yr in comparison to interferon alfa-2b plus ribavirin.
Peginterferon alfa-2a combination therapy in patients with HCV genotype 2 or 3 is dominant (more effective and cost saving) compared to interferon alfa-2b plus ribavirin.
Results weighted by genotype prevalence (75% genotype 1; 25% genotype 2 or 3) also show that peginterferon alfa-2a plus ribavirin is dominant.
Peginterferon alfa-2a and ribavirin remained cost-effective (below $16,500 per QALY gained) under sensitivity analyses on key clinical and cost parameters.
Conclusion
In conclusion, the authors write, “Peginterferon alfa-2a (Pegasys) in combination with ribavirin with duration of therapy based on genotype, is cost-effective compared with conventional interferon alfa-2b in combination with ribavirin when given to treatment-naive adults with CHC.”
Commentary
The authors comparison of Pegasys/ribavirin vs Intron A (peginterferon vs standard interferon)/ribavirin in terms of cost effectiveness, and their conclusion that the former is more cost effective than the latter offers physicians and patients little useful guidance without knowing the results of a cost effectiveness comparison of Peg-Intron/ribavirin to Intron A/ribavirin (and possibly to Roferon/ribavirin).
The larger and more useful question to answer would be, is Pegasys/ribavirin more cost effective than Peg-Intron/ribavirin?
University of Washington, Seattle WA.
09/17/04
September 16, 2004
Natural killer cell interactions govern immunity to hepatitis C virus
By
NewsRx.com
Natural killer cell interactions govern immunity to hepatitis C virus.
According to a study from England, "natural killer (NK) cells provide a central defense against viral infection by using inhibitory and activation receptors for major histocompatibility complex class I molecules as a means of controlling their activity. We show that genes encoding the inhibitory NK cell receptor KIR2DL3 and its human leukocyte antigen C group1 (HLA-C1) ligand directly influence resolution of hepatitis C virus (HCV) infection."
"This effect was observed in Caucasians and African Americans with expected low infectious doses of HCV but not in those with high-dose exposure, in whom the innate immune response is likely overwhelmed," according to S.I. Khakoo and colleagues, University of Southampton, Division of Infection, Inflammation, and Repair.
"The data strongly suggest that inhibitory NK cell interactions are important in determining antiviral immunity and that diminished inhibitory responses confer protection against HCV," researchers concluded.
Khakoo and colleagues published the results of their research in Science (HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science, 2004;305(5685):872-874).
For additional information, contact M. Carrington, University Southampton, Division Infection Inflammat & Repair, Liver Group, Southampton 5016 6YD, Hants, England.
The publisher of the journal Science can be contacted at: American Association for the Advancement of Science, 1200 New York Avenue, NW, Washington, DC 20005 USA.
The information in this article comes under the major subject areas of Infectious Disease, Receptor Studies, and Virology.
This article was prepared by Biotech Week editors from staff and other reports. Copyright 2004, Biotech Week via NewsRx.com & NewsRx.net.
To see more of the NewsRx.com, or to subscribe, go to http://www.newsrx.com.
© 2004 NewsRx.com. All Rights
Reserved.;;©Copyright 2004, Biotech Week via NewsRx.com & NewsRx.net
Effects of Ribavirin Combined with Interferon Alfa-2b
on Viral Kinetics During First 12 Weeks of Treatment in Patients with
HCV Genotype 1 and High Baseline Viral Loads
This study aimed to find how ribavirin increases
viral eradication
in patients with hepatitis C virus (HCV)
genotype 1
and high baseline viral loads (>5.0 x105 copies/mL)
when given with
interferon (IFN).
Using
the real-time
quantitative polymerase chain reaction,
we measured serum HCV in 20 patients during the first 12 weeks of
therapy with
IFN-
2b
(Intron A) and ribavirin.
Controls were 10 similar patients given IFN-2b
alone.
IFN-2b
was given at 6 MU daily for 2 weeks, and then three times weekly.
Ribavirin was given at 600 or 800 mg daily.
Serum HCV RNA decreased rapidly in the first phase, during the first 24 h of therapy (day 0), and more slowly in the early second phase (days 1-14). The median decrease was by 1.41 and 0.078 log 10/day in these two phases in the combination therapy group, and 0.90 and 0.081 log 10/day in the monotherapy group.
The difference between groups in the first phase was not significant (P = 0.24), nor was that in the next phase (P = 0.68).
Later in the second phase, between days 14 and 84, the median decrease was larger in the combination therapy group (0.030 log 10/day) than in the monotherapy group (0.015 log 10/day, P = 0.035).
Conclusion
In
patients with HCV genotype 1 and high viral loads, the effects of
ribavirin with IFN-
appeared slowly, after the earliest days of treatment. A long-term
favorable outcome of combination therapy may be associated with a rapid
viral decline in this later phase of therapy.
FDA-approved Therapies for Hepatitis C
09/20/04
Reference
M Enomoto and
others.
Effects
of ribavirin combined with interferon-
2b
on viral kinetics during first 12 weeks of treatment in patients
with hepatitis C virus genotype 1 and high baseline viral loads.
Journal of Viral Hepatitis
11(5): 448-455. September 2004.
http://www.hivandhepatitis.com/hep_c/news/2004/092004_b.html
Digestive and Liver Disease
Volume 36, Issue 10 , October 2004, Pages 646-654
doi:10.1016/j.dld.2004.06.011
Copyright © 2004 Editrice Gastroenterologica Italiana S.r.l. Published
by
Elsevier Ltd.
Clinical Review
A. Alberti, , a, b, L. Benvegnùa, S. Boccatoa, A. Ferraria and G.
Sebastiania
a Department of Clinical and Experimental Medicine, University of Padova,
Via Giustiniani, 2, 35128, Padua, Italy
b Venetian Institute of Molecular Medicine, Padua, Italy
Available online 4 August 2004.
Abstract
The hepatitis C virus is a leading cause of chronic liver disease,
cirrhosis
and hepatocellular carcinoma in western countries. Chronic hepatitis C
is
highly heterogeneous and many patients present with a mild form of liver
disease. Population-based studies have indeed demonstrated that around
50%
of hepatitis C virus carriers have persistently normal ALT and two-third
have mild histological liver lesions. Studies on the natural history of
initially mild chronic disease indicate that the short-term outcome is
always benign. However, progression of liver fibrosis can be observed at
long-term (>5–7 years) follow-up, particularly in those cases who have
elevated and/or fluctuating transaminase levels. Observational
prospective
studies and outcome modelling projections indicate that the risk of
liver
disease progression towards severe fibrosis/cirrhosis is minimal at
10–15
years in hepatitis C virus carriers with persistently normal ALT, around
5–10% in patients with elevated ALT and F0 (no fibrosis) in the initial
biopsy but >30–40% in chronic carriers with elevated ALT and F1 (portal
fibrosis) in the initial biopsy. Cofactors like age at infection,
alcohol,
coinfections and liver steatosis accelerate disease progression. On the
basis of these findings, patients with initially mild chronic hepatitis
C
and elevated ALT should be proposed for antiviral therapy in the absence
of
contraindications.
Author Keywords: Hepatitis C; HCV; Natural history
Corresponding author. Tel.: +39 049 821 2294; fax: +39 049 821 1826.
Spontaneous hepatitis C virus clearance occurs in up to 42% recently infected, HIV-negative IDUs
| Edwin J. Bernard, Wednesday, September 22, 2004 |
Hepatitis C Virus Elucidated
By YOUSUF BHAIJEE
Contributing Writer
Wednesday, September 1, 2004
UC Berkeley researchers have joined the battle against hepatitis C virus (HCV)
infection, the most common blood-born infection in the U.S., by helping to
elucidate the strategy that the virus uses to proliferate inside the human
body. Insights into the viral replication process could lead to more
effective drug treatment strategies.
“Hepatitis C is a serious pathogen, and it is particularly dangerous because in 80% of cases infection becomes chronic, leading to cirrhosis, liver cancer and death. Furthermore, no cure is available, and control with currently available therapies is difficult.” said postdoctoral researcher Chris Fraser.
Primary investigator and professor of biochemistry and molecular biology Jennifer Doudna and her lab focus on the structure and function of the virus’ ribonucleic acid (RNA), which serves as a template to produce the virus’ proteins within the infected cell.
Like all viruses, HCV uses the host cell’s ribosomes to translate its genetic blueprint, in the form of RNA, into the proteins needed to create more copies of the virus. The Doudna lab has uncovered how HCV takes over the ribosome and uses it to reproduce.
The initiation of protein synthesis is a complex and highly regulated process in all organisms. In viruses, the ribosome must be recruited to the RNA template prior to actual transcription. In most cases, this is achieved via a series of protein factors that guide and regulate synthesis.
“The amazing thing about the HCV virus is that it sidesteps many of these factors, and thus also sidesteps cellular regulation, because the RNA actively wraps itself around the ribosome and forces its way in rather than being guided by the cell’s protein factors.” said research scientist Hong Ji.
The Doudna lab has succeeded in visualizing this complex interaction, known as an internal ribosomal entry site (IRES). These visualizations have been pivotal in understanding the mechanism of viral RNA translation.
The Doudna lab now plans on conducting further analysis by characterizing how the protein factors bind to both the ribosome and to the virus’ RNA. This sets the background for designing future drug treatments.
“We have been working on this project for close to six years and we are very excited about where it is going,” Doudna said. “We believe that the IRES may be the so-called ‘Achilles heel’ of Hepatitis C and that our research may eventually help drug development efforts to treat this epidemic.”
Hepatitis C Virus Elucidated - The Daily Californian
Hepatitis C recurrence after living donor transplantation |
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| Hepatitis C virus recurrence is more severe in living donor liver transplantation compared to cadaveric liver transplantation, find doctors in the September issue of Hepatology. | |||
 |
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| Hepatitis C virus (HCV) infection may have a more aggressive course following living donor liver transplantation compared to cadaveric liver transplantation. In this study, doctors from Spain examined whether HCV disease recurrence differs between living donor liver transplantation and cadaveric liver transplantation. The team evaluated 116 consecutive HCV-infected patients undergoing 117 liver transplantations in a single center from March 2000 to August 2003. They defined severe recurrence as biopsy-proven cirrhosis and/or the occurrence of clinical decompensation. Median follow-up was 22 months. The team found that 22% of patients had severe recurrence of hepatitis C.
Severe recurrence developed in 18% of patients in the cadaveric liver transplantation group and in 41% of patients in the living donor liver transplantation group. The doctors calculated that the 2-year probability of severe recurrence was significantly higher in living donor liver transplantation compared to cadaveric liver transplantation. Using univariate analysis, the team found that living donor liver transplantation and an ALT higher than 80 IU/L 3 months after transplantation were predictors of severe recurrence. Using results from a subset of patients, they established that a lobular necroinflammatory score >1, living donor liver transplantation, and biliary complications were associated with severe recurrence. However, the only variables which were independently associated with severe recurrence were living donor liver transplantation and a lobular necroinflammatory score >1. Dr Montserrat Garcia-Retortillo and colleagues concluded, "HCV recurrence is more severe in living donor liver transplantation compared to cadaveric liver transplantation". "Although our results were based on a single-center experience, they should be considered in the decision-making process of transplant programs, since severe HCV recurrence may ultimately compromise graft and patient survival." |
| World J Gastroenterol. 2004 Oct 1;10(19):2867-9. |
Prospective study in 142 cases of hepatitis C virus infection.
Fan WM, Zhu WF, Yin LM, Wei L, Xu XY, Zhuang H.
Department of Microbiology, School of Basic Medicine, Health Science Center, Peking University, Beijing 100083, China. zhuwanfu@sun.bjmu.edu.cn
AIM: There is limited information on the natural history of HCV infection in China. We investigated the outcome of HCV infection after nine-year follow-up and the risk factors in blood donors in China in order to provide the foundation for prevention and therapy. METHODS: A total of 172 cases of HCV infection with anti-HCV positive and ALT abnormality were enrolled in the archives when was screened blood in Hebei Province in 1993. In them 142 blood donors were followed up till July 2002. No antiviral treatment was applied to them during the period of infection. In the present study, anti-HCV, HCV-RNA and aminotransferase were detected and genotyping was conducted by the method of restriction fragment length polymorphism(RFLP). B-type ultrasound detection was performed in all the patients. Age, sex, alcohol consumption and clinical symptoms were questioned. RESULTS: After nine years' follow-up, 10.56% (15/142) of the cases were negative for anti-HCV and 16.42% (12/134) of them were negative for HCV-RNA. The genotypes 1b, 2a and 1b/2a were 91.07%, 6.25% and 2.68% respectively. Twelve cases (8.45%) were negative for both HCV RNA and anti-HCV. The rate of chronicity in this group was 83.58% (112/134), and the rate of viral spontaneous resolution was 16.42% (22/134). The mean level of ALT, AST, gamma-GT in HCV RNA positive cases was significantly higher than that in HCV RNA negative cases (P<0.001). The abnormal rate of ALT and/or AST in male donors was significantly higher than that in female donors (P = 0.005). The rate of progression to liver cirrhosis from chronic hepatitis C was significantly higher in the cases of super-infection with HBV than that in the cases of single HCV infection. Overdose alcohol consumption promoted the progression to chronicity. CONCLUSION: This area (Hebei Province) has a higher rate of chronicity in HCV infection, and measures should be taken to prevent its progression to serious liver diseases, especially for patients super-infected with HCV and HBV.
PMID: 15334688 [PubMed - in process]
|
Hepatitis C infection and
injection drug use: The role of hepatologists in evolving treatment
efforts |
||
|
Hepatology, Volume 40, Issue 3, September 2004
Thomas F. Kresina 1 *, Leonard B. Seeff 2, Henry Francis 1 1Center on AIDS and other Medical Consequences of Drug Abuse, National Institute on Drug Abuse, Department of Health and Human Services, Bethesda, MD 2National Institute on Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD Abstract Treatment regimens for both substance abuse and hepatitis C infection are complex and evolving. New pharmacotherapy for opioid addiction allows for office-based treatment and, thus, an opportunity for expanded treatment in the context of hepatitis C infection. The current article addresses the newly evolving, complex issues in the medical management of hepatitis C and injection drug use. Article Text The majority of incident infections with the hepatitis C virus (HCV) are acquired through injection drug use practices. For most injection drug users, drug use occurred in the past. However, drug addiction is a chronic disease with a continuing possibility of former drug users' relapsing back to drug use. Injection drug users, both current and reformed, are at risk for HCV and other infectious diseases, and they commonly display comorbidities associated with drug use, such as psychiatric illnesses. Accordingly, drug users can undergo successful medical management through a team approach that addresses not only the medical consequences of drug use but also the frequently accompanying mental health, infectious disease, and behavioral and social problems. Thus, HCV infection in these individuals is a complex and challenging medical issue. HIV coinfection frequently co-occurs in HCV-infected drug users. Recent recommendations of an international panel of experts suggest that treatment of persons coinfected with HCV and HIV should be undertaken not only by hepatologists or gastroenterologists expert in dealing with HCV infection but also by infectious disease specialists in a step-by-step approach as part of the patient's global care and treatment.[1] HCV treatment of active drug users was recommended by the 2002 National Institutes of Health Consensus Conference panel on a case-by-case basis, but the NIH did not provide guidance and support for the hepatologists or gastroenterologists generally involved in administering such treatment. This article addresses the basis for HCV care and treatment and the manner in which they can be successfully administered to this challenging patient population. These recommendations include the need for hepatologists to: (1) become knowledgeable regarding substance use and abuse; (2) be comfortable and comprehensive in addressing the issue of substance use and abuse with patients, including risk reduction, relapse, and HCV reinfection; (3) become certified in treating opioid addiction with buprenorphine; and (4) participate in caring for HCV-infected injection drug users as part of a global care and treatment team, realizing the importance of managing the addiction problem in conjunction with treatment of the accompanying infectious disease or diseases. Understanding the Patient Injecting Drugs The 2002 National Survey on Drug Use and Health[2] reports that 3.7 million Americans above the age of 12 years have experimented with heroin use. Patterns of drug use can be categorized as experimental, as part of normal curiosity; recreational, based on peer support or acceptance; facilitation, to enhance skills or performance; abuse as a consequence of pleasure seeking; and compulsive use to avoid abstinence effects.[3] Treatment of compulsive or addictive drug use may result in complete recovery or a relapsing scenario in which the use of drugs is intermingled with periods of long remissions.[4] Indeed, vulnerability to relapse can last years or a lifetime. Recent neurological imaging studies[5][6] have shown that addiction results in profound metabolic changes in the brain. The national drug control strategy has characterized injection drug use as a disease with a need for treatment and support services from effective programs that include faith- and community-based organizations.[7] A recent study[8] has shown that for individuals who use tobacco and alcohol, there is a greater exposure opportunity and hence likelihood for use of illegal drugs, such as cocaine or heroin. Indeed, many drug users regard the use of illegal drugs as a personal choice, similar to tobacco and alcohol use. Injection drug users do not fully utilize health care services,[9] are disenfranchised from the medical care system, and frequently require inducement and support to access and engage in medical care and treatment.[10] Individuals who do enter substance abuse programs often have associated comorbidities, such as physical injuries and mental health disorders.[11] Relapse to drug use and HCV reinfection remain medical issues of concern for drug users in treatment. HCV screening studies have shown that for both adolescents and adults entering the criminal justice system, nearly one in five individuals are infected with HCV.[12][13] Thus, community mental health clinics and psychiatric hospitals, community based walk-in clinics, prison-related health systems, HIV clinics, and methadone clinics are common locations for these individuals either at high risk for new HCV infection or with already existing HCV infection. Accordingly, these are venues in which hepatologists and others with HCV treatment expertise could participate in providing health care services to individuals infected with HCV. HCV Care and Treatment and Injection Drug Use An evolving body of data indicates that either current injection drug use or substance abuse are not necessarily barriers to care and treatment. Indeed, injection drug users respond to HCV treatment in a fashion similar to those without a history of substance abuse.[14][15] Interim data from a recent study suggest that treatment of HCV-infected individuals utilizing methadone maintenance for the control of opioid addiction is as effective as treatment for non-drug users with HCV infection, although general management issues are more difficult to handle.[16] Currently, treatment recommendations for individuals on methadone maintenance therapy, endorsed by the American Association for the Study of Liver Disease and the Infectious Diseases Society of America,[17] state that the use of methadone does not preclude medical management of hepatitis C. However, it must be noted that patients on methadone maintenance therapy may have difficulty in completing interferon-based therapy regimens. An increasing number of cohort studies report that combination therapy for hepatitis C can be effective even for active drug users.[18][19] However, active drug users with HCV often have substantial comorbidities that challenge their medical management. Two essential aspects of management are that an interactive and trusting patient-provider relationship must be established and that patients must be deemed treatment-ready, much as is the case for patients with HIV infection who are brought to treatment readiness prior to the initiation of antiretroviral therapy.[20] Similarly, care programs focused on bringing active drug users to HCV treatment readiness, with or without modification of their drug use, would maximize HCV treatment outcomes for this hard-to-reach and hard-to-treat population. This approach of careful monitoring of drug-related issues together with aggressive intervention, as needed, would increase the likelihood that injection drug users and substance abusers who are HCV-infected and have associated psychiatric illness would complete their HCV treatment. In this context, clinicians must be prepared to address psychiatric conditions and drug use, including relapse to drug use, and to integrate early interventions for these conditions into their HCV treatment algorithm. Unfortunately, few programs or treatment models are designed to systematically manage substance use and comorbidities of patients with HCV prior to and during interferon-based therapy. Medical Management of HCV for Injection Drug Users The basic principles of medical ethics, including the Kantian principle of respect for person, principle of beneficence, and principle of distributive justice, mandate healthcare services for injection drug users.[21] These principles relate that drug-using individuals are neither inferior to other patients nor less deserving of care and treatment, as well as that health care providers should act to best advance the medical interests of their patients. However, medical management of HCV in active drug users is more difficult and more time consuming than is HCV treatment of non-drug users. There are also concerns regarding medication noncompliance without an adherence intervention and the possibility of HCV reinfection with relapse to drug use.[22] Although HCV reinfection has been demonstrated both in chimpanzees[23] and humans,[24] the evidence is based largely on serologic markers rather than on clinical manifestations. Thus, active injection drug users should not be automatically denied treatment on the basis of continued drug use. When treatment decisions are considered, it is imperative for the provider to discuss the various care and treatment options with appropriate informed consent, detailing the risks versus the benefits of medical options. The hoped-for benefit, of course, is the eradication of the HCV infection, thus reducing the likelihood of life-threatening liver disease. Unfortunately, factors associated with a poor response, such as infection with HCV genotype 1 and coinfection with HIV, are commonly represented among drug users.[1] Also, there is a relatively high rate of adverse effects of the treatment in addition to the risk for relapse to drug use. Clearly, treatment of HCV infection in injection drug users represents a major challenge requiring a comprehensive approach by multiple health care providers that address all conditions that may coexist[25] and the utilization of novel approaches for care and treatment.[19] Models of care range from referral and consultative services to integrated care and one-stop shopping for health care. Subspecialty consultation can occur within community-based outreach programs,[19] through partnerships with community-based organizations that provide coordinated psychiatric care, counseling, and case management,[26] in risk-reduction programs,[27] within HIV clinics,[28] or in newly evolving HIV/HCV coinfection clinics. Fully integrating HCV care and treatment can occur in an HIV setting[28] or a substance abuse treatment program, such as that of methadone maintenance.[30] In the latter settings, support services are provided by nonhepatologists who would greatly benefit from the participation of those experienced in treating liver disease. As HCV infection becomes accepted as a primary care issue in the context of HIV and substance-abuse management, hepatologists can support the process of integrative management by becoming more knowledgeable about opioid addiction and the use of buprenorphine treatment. This pharmacotherapeutic approach will permit office-based management of opioid addiction[31] within the setting of general internal medicine. A waiver to the Drug Addiction Treatment Act of 2000 is obtained through physician training events for the practice of opioid addiction therapy using buprenorphine (see http://buprenorphine.samhsa.gov/training.html). Liver disease remains a serious medical issue for injection drug users with HCV infection. For persons with HIV/HCV coinfection, liver disease is now the leading cause of morbidity and mortality.[1][32] A recent multicenter epidemiological study indicated that 46% of coinfected patients had severe liver disease.[33] Without HCV care, management of their addiction and associated comorbidities, and treatment for their liver disease, these individuals are at high risk of progression to end-stage liver disease. Thus, it is critical that hepatologists and others with the necessary expertise become full-fledged participants in the care and treatment of injection drug users with HCV infection (Table 1). Table 1. Recommendations for Hepatologists in the HCV Care and Treatment of Substance Abusers with HCV Infection (a) become knowledgeable regarding substance use and abuse (b) be comfortable and comprehensive in addressing the issue of substance use and abuse with patients, including risk-reduction, relapse and HCV re-infection (c) become certified in treating opioid addiction with buprenorphrine (d) participate in caring for HCV-infected injection drug users as part of a global care and treatment team, realizing the importance of managing the addiction problem in conjunction with treatment of the accompanying infectious disease or diseases A final issue that needs to be addressed: How might a hepatologist obtain support/reimbursement for forming new collaborations and providing needed health services to drug users? Noting that private and federal health insurance programs may not fully support addiction treatment services,[34] new collaborations and models of care for HCV care and treatment can be supported as demonstration projects through Health Services Resources Administration (www.hrsa.gov) or Substance Abuse and Mental Health Services Administration (www.samsha.gov). In addition, both the National Institute on Drug Abuse (www.nida.nih.gov) and the National Institute on Alcoholism and Alcohol Abuse (www.niaaa.gov) support health services research programs that can fund treatment and health care services research projects, as do certain foundations and pharmaceutical companies. Currently, long-term funding sources for these services remains elusive and needs to be addressed. In Europe, the use of buprenorphine and the expansion of opioid addiction treatment into an office-based and primary care setting has gained wide acceptance.[35][36] In addition, legal access to syringes and equipment are available in selected countries to reduce the transmission of both hepatitis C and HIV.[37] In both the Netherlands and Canada, safe injection facilities are available to reduce the spread of bloodborne diseases.[38][39] Thus, health services research and support by federal and international agencies, such as the World Health Organization, encompass both safe injection strategies and treatment issues. References 1 Soriano V, Puoti M, Sulkowski M, Mauss S, Cacoub P, Cargnel A, et al. Care of patients with hepatitis C and HIV coinfection. AIDS 2004; 18: 1-12. 2 Substance Abuse and Mental Health Services Administration's 2002 National Survey on Drug Use & Health. Available at: www.drugabusestatistics.samhsa.gov. Accessed June 26, 2004. 3 Comerci GD, Schwebel R. Substance abuse: an overview. Adolesc Med 2000; 11: 79-101. 4 McLellan AT. Have we evaluated addiction treatment correctly? Implications from a chronic perspective. Addiction 2002; 97: 249-252. 5 Daglish MRC, Nutt. Brain imaging studies in human addicts. Eur Neuropsychopharmacol 2003; 13: 453-458. 6 Wilson SJ, Sayette M, Fiez JA. Prefrontal responses to drug cues: a neurocognitive analysis. Nat Neurosci 2004; 7: 211-214. 7 2003 Annual Report. The President's National Drug Control Strategy. Office of the National Drug Control Policy. Available at: www.whitehousedrugpolicy.gov/policy. Accessed June 26, 2004. 8 Wagner FA, Anthony JC. Into the world of illegal drug use: exposure opportunity and other mechanisms linking the use of alcohol, tobacco, marijuana and cocaine. Am J Epidemiol 2002; 155: 1-8. 9 Sterk CE, Theall KP, Elifson KW. Health care utilization among drug using and non-drug using women. J Urban Health 2002; 79: 586-599. 10 Villano CL, Rosenblum, Magura S, Fong C. Improving treatment engagement and outcomes for cocaine-using methadone patients. Am J Drug Alcohol Abuse 2002; 28 213-230. 11 Mertens JR, Lu YW, Parthasarathy S, Moore C, Weisner CM. Medical and psychiatric conditions among alcohol and drug treatment patients in an HMO. Arch Intern Med 2003; 163: 2511-17. 12 Abram KM, Teplin LA, McClelland GM, Dulcan MK. Comorbid psychiatric disorders in youth in juvenile detention. Arch Gen Psychiatry 2003; 60: 1097-1108. 13 Allen SA, Spaulding AC, Osei AM, Taylor LE, Cabral AM, Rich JD. Treatment of chronic hepatitis C in a state correctional facility. Ann Intern Med 2003; 138: 187-190. 14 Neri S, Bruno CM, Abate G, Ierna D, Mauceri B, Cilio D, et al. Controlled clinical trial to assess the response of recent heroin abusers with chronic hepatitis C virus infection to treatment with interferon-n2b. Clin Ther 2002; 24: 1627-1635. 15 Van Thiel DH, Anantharaju A, Creech S. Response to treatment of hepatitis C in individuals with recent history of intravenous drug abuse. Am J Gastroenterol 2003; 98: 2281-2288. 16 Sylvestre DL. Treating hepatitis C in methadone maintenance patients: an interim analysis. Drug Alcohol Depend 2002; 67: 117-23. 17 Strader DB, Wright TL, Thomas DL, Seeff LB. American Association for the Study of Liver Disease Guidelines: diagnosis, management and treatment of hepatitis C. HEPATOLOGY 2004; 39: 1147-1171. 18 Sylvestre DL, Hauser, P, Loftis JM, Genser S, Cesari H, Borek N, et al. Co-occurring hepatitis C, substance use and psychiatric illness: treatment issues and developing models of care. J Urban Health 2004, in press. 19 Hepatitis C infection and substance abuse: Medical management and developing models of integrative care. Proceedings Clin Inf Dis (Suppl) 2004, in press. 20 Dybul M, Fauci AS, Bartlett JG, Kaplan JE, Pau AK. Panel on clinical practices for treatment of HIV. Guidelines for using antiretroviral agents among HIV-infected adults and adolescents. Ann Intern Med 2002; 137: 381-433. 21 Beauchamp T, Childress J. Principles of biomedical ethics. 5th edition. Oxford: Oxford University Press 2001; 57-272. 22 Edlin BR. Prevention and treatment of hepatitis C in injection drug users. HEPATOLOGY 2002; 36 (Suppl): S210-S219. 23 Farci P, Alter HJ, Govindarajan S, Wong DC, Engle R, Lesniewski RR, et al. Lack of protective immunity against reinfection with hepatitis C virus. Science 1992; 258: 135-140. 24 Mehta SH, Cox A, Hoover DR, Wang XH, Mao Q, Ray S, et al. Protection against persistence of hepatitis C. Lancet 2002; 359: 1478-1483. 25 Wang CS, Wang ST, Yao WJ, Chang TT, Chou P. Community-based study of hepatitis C virus infection and type 2 diabetes: an association affected by age and hepatitis severity status. Am J Epidemiol 2003; 158: 1154-1160. 26 Taylor LE, Schwartzapfel B, Allen S, Jacobs G, Mitty J. Extending treatment for HCV infection to HIV/HCV coinfected individuals with psychiatric illness and drug dependence. Clin Inf Dis 2003; 36: 1501-1502. 27 Macalino GE, Springer KW, Rahman ZS, Vlahov D, Jones TS. Community-based programs for safe disposal of used needles and syringes. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 18 (Suppl): S111-119. 28 Clannon KA. Strategies for managing hepatitis C virus infection in HIV-infected patients. Top HIV Med 2003; 11: 50-54. 29 Stringari-Murray S, Clayton A, Chang J. A model for integrating hepatitis C services into an HIV/AIDS Program. J Assoc Nurses AIDS Care 2003; 14 (Suppl): 95s-107s. 30 Strauss SM, Astone J, Vassilev ZP, DesJarlais DC, Hagan H. Gaps in the drug-free and methadone treatment program response to hepatitis C. J Sub Abuse Treat 2003; 24: 291-297. 31 Fudala PJ, Bridge TP, Herbert S, Willford WO, Chiang CN, Jones K, et al. Burprenorphine/naloxone collaborative study group. Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine/naloxone. N Engl J Med 2003; 349: 949-958. 32 Bica I, McGovern B, Dhar R, Stone D, McGowan K, Scheib R, et al. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Inf Dis 2001; 32: 492-497. s 33 Martin-Carbonero L, Benhamou Y, Puoti M, Berenguer J, Mallolas J, Querada C, et al. Incidence and predictors of severe liver fibrosis in human immunodeficiency virus-infected patients with chronic hepatitis C: a European Collaborative Study. Clin Inf Dis 2004; 38; 128-133. 34 Starr SB. Simple fairness: ending discrimination in health insurance coverage for addiction treatment. Yale Law J 2002; 111: 2321-2365. 35 Krantz, MJ Mehler PS. Treating opioid dependence. Growing implications for primary care. Arch Intern Med 2004; 164: 277-288. 36 Uchtenhagen A. Substitution management in opioid dependence. J Neural Transm Suppl 2003; 66: 33-60. 37 Dolan K, Rutter S, Wodak AD. Prison-based syringe exchange programmes: a review of international research and development. Addiction 2003; 98: 153-158. 38 Elliott R, Malkin I, Gold J. Establishing safe injection facilities in Canada: legal and ethical issues. Can HIV AIDS Policy Law Rev 2002; 6: 7-10. 39 van der Poel A, Barendregt C, van de Mheen D. Drug consumption rooms in Rotterdam: an explorative description. Eur Addict Res 2003; 9: 94-100. |
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Can You Have Multiple Genotypes? |
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"Changes in the Prevalence of Hepatitis C Virus
Genotype among Injection Drug Users: A Highly Dynamic Process"
The Journal of Infectious Diseases 2004;190:1199-1200 Matthias Schröter, Bernhard Zöllner, Rainer Laufs, and Heinz-Hubert Feucht Zentrum für Klinisch-Theoretische Medizin I, Institut für Infektionsmedizin, Universitätsklinikum Hamburg Eppendorf, Hamburg, Germany To the Editor—With great interest we have read the article by van Asten et al. in The Journal of Infectious Diseases [1]. An important aspect of their study is its detailing of the introduction and spread of "new" hepatitis C virus (HCV) genotypes among injection drug users (IDUs). Changes of subtype distributions in a given population were shown, for the first time, by our group several years ago [2]. In that study, it was demonstrated that subtype 1b was the prevailing subtype in the German population until subtype 1a started spreading in the early 1980s [2]. This led to a substantial change of the most prevalent HCV subtype, especially in younger people. To highlight the question of whether this change was a single effect, a multicenter study was performed 2 years ago [3]. In that study, we demonstrated that the epidemiology of HCV genotypes in IDUs is subjected to highly dynamic changes. Profound changes in the prevalence of different HCV genotypes were noted between 1994--1995 and 2000--2001, when large populations of IDUs (n = 144 and n = 172, respectively) were compared. These changes are summarized in figure 1. The introduction of genotypes that were formerly unknown in this risk population (4 and 2a/b) and the ability of these genotypes to establish significant prevalence within a period of only 6 years are remarkable. The theory of 2 independently developing HCV epidemics had been proposed elsewhere [4], because the epidemiology of HCV subtype 3a and other subtypes seemed to be very different between IDUs and non-IDUs. However, there are indications that the dynamics observed among IDUs also influence the genotypic distribution among the entire population of patients. Although subtype 3a was detected nearly exclusively among IDUs in 1994--1995, 〜45% of patients infected with subtype 3a had never been IDUs. In the majority of these people, high-risk sexual behavior (HRSB) was the most probable risk factor for acquiring HCV infection [3]. It can be assumed from these data that the higher the prevalence of a certain genotype among the population of IDUs, the higher is the risk of this genotype spreading beyond the boundaries of the IDU scene. This is most probably due to HRSB, which, today, is one of the major risk factors for acquiring HCV [3, 5]. On the other hand, new genotypes can be introduced in the population of IDUs. This has been demonstrated very convincingly for genotype 4, which was introduced by immigrants from northern Africa and the Arabian peninsula [1, 3], and for genotype 2 [3]. In our population of patients, these genotypes established a prevalence of 7% and 8%, respectively, within only 6 years (figure 1). In analogy to the findings for subtype 3a, these genotypes may also spread over the boundaries of the IDU scene with increasing prevalence. However, knowledge of these dynamic changes of the distribution of HCV genotypes provides information regarding not only the epidemiology, but also the treatment, of HCV. In a population with a high risk of repeated HCV infections, the probability of infection with different HCV genotypes is associated with the speed of changes of the genotype distribution. We have shown that, in at least 18% of IDUs with long-term follow-up (up to 7 years), multiple HCV infections detected by intraindividual changes of the predominant HCV genotype occurred [6]. It is well known that, in patients infected with multiple HCV genotypes, one of the infecting virus strains establishes predominance, and, by use of polymerase chain reaction--based methods, usually only the actual prevailing strain can be detected in these patients [7]. However, minor strains do not become eliminated, and we have demonstrated in various patients that these minor strains can reappear [6, 8]. These findings are of importance, especially in the context of therapy with pegylated interferon and ribavirin. It has been shown that reemergence of minor strains is a possible cause for failure of therapy [6, 8]. Therefore, the recommendation was made to repeat genotyping in patients who do not respond to therapy as expected. This enables adjustment of the regimen to the actual predominant HCV genotype. These findings underline the importance of the described dynamic changes of the epidemiological distribution of HCV genotypes among IDUs They are important for better understanding (1) the epidemiology of HCV and (2) possible factors influencing outcome of therapy. References 1. van Asten L, Verhaest I, Hernandez-Aguado I, et al. Spread of hepatitis C virus among European injection drug users infected with HIV: a phylogenetic analysis. J Infect Dis 2004; 189:292--302. 2. Feucht HH, Schröter M, Zöllner B, Polywka S, Nolte H, Laufs R. The influence of age on the prevalence of hepatitis C virus subtypes 1a and 1b. J Infect Dis 1997; 175:685--8. 3. Schröter M, Zöllner B, Schäfer P, et al. Epidemiological dynamics of hepatitis C virus among 747 German individuals: new subtypes on the advance. J Clin Microbiol 2002; 40:1866--8. 4. Pawlotsky JM, Tsakiris L, Roudot-Thorval F, et al. Relationship between hepatitis C virus genotypes and sources of infection in patients with chronic hepatitis C. J Infect Dis 1995; 171:1607--10. 5. Alter MJ, Kruszon-Moran D, Nainan OV, et al. Prevalence of hepatitis C virus infection in the United States. N Engl J Med 1999; 341:556--62. 6. Schröter M, Zöllner B, Schäfer P, Laufs R, Feucht HH. The rapidly changing epidemiology of HCV genotypes: consequences for the individual therapeutic regimen [session WD4]. In: Program and abstracts of the 11th International Symposium on Viral Hepatitis and Liver Disease (Sydney). Adelaide: Australian Centre for Hepatitis Virology, 2003:95. 7. Widell A, Mansson S, Persson NH, Thysell H, Hermodsson S, Blohme I. Hepatitis C superinfection in hepatitis C virus (HCV)--infected patients transplanted with an HCV-infected kidney. Transplantation 1995; 60:642--7. 8. Schröter M, Feucht HH, Zöllner B, Schäfer P, Laufs R. Multiple infections with different HCV genotypes: prevalence and clinical impact. J Clin Virol 2003; 27:200--4. J Clin Virol. 2003 Jul;27(2):200-4. Multiple infections with different HCV genotypes: prevalence and clinical impact. Schroter M, Feucht HH, Zollner B, Schafer P, Laufs R. Institut fur Medizinische Mikrobiologie und Immunologie, Universitatsklinikum Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany. mschroet@uke.uni-hamburg.de BACKGROUND: In a HCV genotype 3a-infected patient, viremia with a different genotype (1b) was detected after 16 weeks of ineffective therapy. Serological typing revealed that this genotype had already been present prior to therapy. OBJECTIVES: To investigate the epidemiology of multiple HCV infections and the therapeutical consequences for patients superinfected with a new HCV strain. METHODS: Sera of 600 patients were screened for infection with multiple genotypes by using sequencing and a serological assay in parallel. RESULTS: Infection with two different HCV types was detected in 13 patients. The prevailing strain was genotyped by sequencing. From two of these patients additional sera were available which had been drawn up to 24 and 28 months prior to the current sample, respectively. Those early samples showed viremia with a HCV subtype that could not be detected by PCR afterwards. Only antibodies to the initial strain were detectable in the later samples. CONCLUSION: In patients serially infected by different HCV strains, one strain will prevail as the viremic virus. Under antiviral therapy, the displaced strain may become viremic again and may influence the outcome of therapy. Detection of inferior strains by serological assays before antiviral therapy may be important for choosing the adequate regimen. http://www.natap.org/ |
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