Prevention of Spread of HCV

Miriam J. Alter, Ph.D.

Historically, the most reliable data on risk factors associated with acquiring hepatitis C virus (HCV) infection have been obtained from cohort (prospective) studies that determined the risk of developing acute infection after a specific exposure and case-control (retrospective) studies that determined if a history of exposure before onset of disease was associated with newly acquired (acute) hepatitis C. Risk factors identified by these studies in the United States included injecting drug use, blood transfusion and solid organ transplants from infected donors, occupational exposure to blood (primarily contaminated needle sticks), birth to an infected mother, sex with an infected partner, or multiple heterosexual partners.

The major limitation of such studies is that they are unlikely to identify associations with exposures that result only rarely in infections. For example, results of case-control studies have indicated no association between acquiring hepatitis C and exposures resulting from medical, surgical, or dental procedures. However, outbreaks of HCV infection have been associated with contaminated equipment in hemodialysis settings and unsafe injection practices in both inpatient and outpatient settings. Most of these outbreaks have involved patient-to-patient transmission. Only two instances of transmission have been reported from HCV-infected health care workers to patients in the United States. Neither of these was associated with the performance of exposure-prone invasive procedures, but rather with contamination of patients’ narcotics used for self-injection.

The contribution of these various risk factors to the overall burden of HCV infections is influenced both by their efficiency in transmitting HCV and by the frequency of the exposure in the population. In the United States, the relative importance of the two most efficient exposures associated with transmission of HCV, blood transfusion and injecting drug use, has changed over time. Blood transfusion, which accounted for a substantial proportion of HCV infections acquired >15–20 years ago, rarely accounts for recently acquired infections. In contrast, injecting drug use consistently has accounted for a substantial proportion of HCV infections and currently accounts for 60 percent of HCV transmission. The relative importance of other exposures has changed little over time.

Unprotected sex with an infected partner or with multiple partners has accounted for an estimated 15 percent of HCV infections. Although the role of sexual activity in the transmission of HCV remains controversial, and the virus is inefficiently spread in this manner, the relatively substantial contribution of sexual exposures to the burden of disease can be explained by the fact that sexual activity with multiple partners is a common behavior in the population and that the large number of chronically infected persons provides multiple opportunities for exposure.

In contrast to sexual exposures, occupational and perinatal exposures contribute to a small proportion overall of infections, and together with nosocomial or iatrogenic exposures, they account for about 5 percent of HCV infections. HCV is not transmitted efficiently through occupational exposure. The prevalence of HCV infection among health care or public safety workers averages 1–3 percent and has not been affected by changes or improvements in barrier precautions. Transmission rates from HCV infected mothers to their infants average 5 percent or less, no associations have been demonstrated with mode of delivery or type of feeding, and infants who acquire HCV infection at birth may be less likely to develop chronic infection.

Thus, about 90 percent of HCV infections can be accounted for by known percutaneous or mucosal exposures to blood. In the remaining 10 percent, no recognized source for infection can be identified. Numerous studies have attempted to identify additional risk factors for HCV infection. While case-control studies of acute hepatitis C reported no association with tattooing, acupuncture, ear piercing, military service, or foreign travel, cross-sectional and prevalence studies of volunteer blood donors, disease-specific clinic patients, and veterans receiving care in VA hospitals have yielded conflicting results for some of these risk factors. The lack of consistency among studies of highly selected groups for which the temporal sequence of exposure relative to the disease was unknown is cause for concern about the generalizability of such results.

Strategies for reducing or eliminating the potential risk for transmission include: (1) screening and testing of donors; (2) virus inactivation of plasma-derived products; (3) risk reduction counseling and services; and (4) implementation and maintenance of infection-control practices. Strategies for reducing risks for chronic disease include: (1) identification, counseling, and testing of at-risk persons; and (2) medical evaluation and management of infected persons.

Health care professionals in all patient care settings routinely should obtain a history that inquires about blood transfusion, use of illegal drugs (injection and non-injection) and evidence of high-risk sexual practices, such as multiple sex partners or history of STDs. Primary prevention of illegal drug injecting will eliminate the greatest risk factor for HCV infection in the United States. Although consistent data are lacking regarding the extent to which sexual activity contributes to HCV transmission, persons having multiple sex partners are at risk of STDs such as HIV, HBV, syphilis, gonorrhea, and chlamydia.

Testing should be offered routinely to persons most likely to be infected with HCV, which include persons who ever injected illegal drugs; received plasma-derived products known to transmit HCV infection that were not treated to inactivate viruses; received transfusions or solid organ transplants before July 1992; and were long-term hemodialysis patients. Based on a recognized exposure, testing also is indicated for health-care workers after needle sticks, sharps, or mucosal exposures to HCV-positive blood and for children born to HCV-positive women. Immune globulin and antiviral agents are not recommended for post-exposure prophylaxis of hepatitis C.

HCV-positive persons with a long-term steady partner do not need to change their sexual practices; however, they should discuss with their partner the need for counseling and testing, and the couple should be informed of available data on risk for sexual transmission of HCV to assist them in making decisions about precautions, including the low, but not absent, risk for transmission. HCV-positive persons do not need to avoid pregnancy or breastfeeding, and determining the need for cesarean delivery vs. vaginal delivery should not be made on the basis of HCV infection status. There are no recommendations for routine restriction of professional activities for HCV-infected health-care workers, and persons should not be excluded from work, school, play, child-care or other settings on the basis of their HCV infection status.

References

1. Centers for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR 1998;47(No. RR-19):1–33.
2. 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.
3. Polish LB, Tong MJ, Co RL, et al. Risk factors for hepatitis C virus infection among health care personnel in a community hospital. Am J Infect Control 1993;21:196–200.
4. Panlilio AL, Shapiro CN, Schable CA, et al. Serosurvey of human immunodeficiency virus, hepatitis B virus, and hepatitis C virus infection among hospital-based surgeons. J Am Coll Surg 1995;180:16–24.

Sexual Activity as a Risk Factor for Hepatitis C Infection

Norah A. Terrault, M.D., M.P.H.

Percutaneous exposures are well-recognized risk factors for HCV, hepatitis B virus (HBV), and HIV. However, there are clear differences between these viruses with respect to their frequency of transmission through sexual contact. The accumulated epidemiological evidence indicates that HCV can be sexually transmitted but much less efficiently than HBV and HIV.

Epidemiological studies evaluating the magnitude of risk of HCV transmission by sexual activity have several methodological shortcomings that tend to overestimate the proportion of HCV infections associated with sexual contact. Early studies used first-generation anti-HCV assays, which have a higher false positive rate than second- and third-generation assays. Studies vary in the completeness of risk ascertainment and many fail to carefully exclude HCV acquisition from non-sexual sources. Non-disclosure of injection drug use (IDU) as a risk factor is particularly important since assessing the contribution of sexual activity to HCV transmission is difficult in the presence of IDU. Finally, only a limited number of studies perform virological analyses to confirm that sexual partners are infected with the same virus and to exclude acquisition from outside sources.

Reported rates of HCV infection in sexual partners differ by geographical region, with higher rates reported in countries with higher endemic rates of HCV infection. Rates of anti-HCV positivity also vary by risk group, with higher rates of HCV reported in persons with a history of sexually transmitted diseases (STDs) and lower rates in heterosexual partners in long-term relationships. This difference may reflect the frequency of exposure to different HCV-infected sexual partners (higher in those with multiple partners than those in monogamous relationships). Alternatively, these risk groups may reflect differing rates of exposure to other non-sexual sources of HCV, such as IDU. The findings regarding sexual transmission in one group may not be generalizable to other groups or to the general population.

How Prevalent is the Risk Factor “Sexual Activity” in Persons with Acute Hepatitis C?

The Centers for Disease Control and Prevention collects detailed risk factor data on newly diagnosed cases of acute hepatitis C. In these surveillance studies, 15–20 percent of cases of acute community-acquired HCV occur in persons who report unprotected sexual contact with an anti-HCV positive person in the preceding 6-month period (two-thirds of cases) or multiple sexual partners (one-third of cases) as their only risk factor for HCV acquisition. Limited access to the sexual contacts prevents virological evaluation of the transmission events. 

What is the Prevalence of HCV in Persons at Risk for Sexually Transmitted Diseases?

In U.S. seroprevalence studies conducted among sex workers, persons attending STD clinics, or persons participating in HIV surveillance studies, 1.6–25.5 percent of individuals are anti-HCV positive. In studies including persons with a history of IDU, anti-HCV positivity is more strongly associated with IDU than with factors related to sexual practices. In studies limited to individuals without a history of IDU, anti-HCV positivity is identified in 1.6–7 percent of STD clinic attendees, and risk factors associated with HCV are number of recent and lifetime partners, high-risk sexual contact (variably defined), and anti-HIV positivity. In homosexual and bisexual men, rates of anti-HCV positivity range from 2.9–12.7 percent with higher rates among those with HIV infection, but again IDU rather than sexual risk factors is most strongly associated with being HCV-positive.

What is the Prevalence of HCV in Monogamous Heterosexual Couples?

Among steady heterosexual partners of HCV-infected, HIV-negative persons, 0–24 percent are anti-HCV positive, with marked geographical variability. The median rate of anti-HCV positivity in sexual partners is 1.0 percent in North America and Northern Europe, 6 percent in Southern Europe, and 11 percent in Southeast Asia. Studies using genotyping or viral sequence analysis to assess anti-HCV concordant couples find lower rates of HCV transmission than studies using antibody testing alone. The duration of the sexual relationship is not predictive of HCV positivity in partners after adjusting for age. In studies comparing HCV positivity among sex partners vs. other family members, the rates of HCV positivity are higher in spouses than in other family members. However, after controlling for age and other parenteral exposures, anti-HCV positivity is no longer consistently associated with the type of relationship.

The majority of the published studies use genotyping rather than viral sequence analysis to evaluate anti-HCV concordant couples. Genotyping is suboptimal since HCV genotypes that are prevalent in the population may be present in partners even though they may have acquired the virus from different sources. For example, a study of 24 anti-HCV concordant couples found that 12 had concordant genotypes, 7 had discordant genotypes, and 5 were un-typable. Seven of the 12 couples could be analyzed by sequence analysis, and only 3 were highly homologous and consistent with transmission. Thus, overestimation of HCV sexual transmission occurs if genotyping rather than sequence analyses is used to evaluate infected partners.

What is the Incidence of HCV Infection in “At Risk” Individuals?

In prospective studies (1–3.7 years follow-up) conducted in high-risk cohorts of non-IDU sex workers and patients in STD clinics, the incidence of HCV is 0.4–1.8/100 person-years (~1 percent). Small sample size precludes evaluation of specific sexual practices as risks for HCV acquisition. Undisclosed IDU may contribute the higher incidence of infection in this subgroup.

Based upon results from a prospective cohort of 499 Italian couples followed for a mean of 12.4 months, the incidence of new infection in sexual partners is 12 per 1,000 person-years.  Sequence analysis of the HCV-positive couples reveals a high degree of sequence homology in only 50 percent of the couples, suggesting non-sexual sources of HCV acquisition and a true incidence of no more than 6 per 1,000 person-years. In retrospective cohorts of female partners of hemophiliacs, the incidence is 1 to 1.87 per 1,000 person-years; among male partners of women infected by contaminated anti-D immunoglobulin, the incidence is 0.28 per 1,000 person-years; and among liver clinic patients and their sexual partners, the incidence is 1 to 3.86 per 1,000 person-years.

Factors That May Affect the Risk of HCV Transmission by Sexual Contact

In studies involving persons at risk for STDs, HIV co-infection is an independent predictor of anti-HCV positivity in the majority of studies. In studies involving hemophiliacs with HIV and HCV, the rate of anti-HCV positivity is higher in female partners of dually-infected men compared to men with HCV infection only. Studies from STD clinic attendees also suggest that co-infection with other STDs or sexual practices which may traumatize the mucosa (anal receptive sex) may increase the risk of sexual transmission of HCV. Whether the risk of HCV transmission differs for males vs. females is unclear. In one study of heterosexual couples in STD clinics, females with HCV-positive partners were 3.7 times more likely to have HCV than females with HCV-negative partners; this pattern was not evident in males. The titer of HCV RNA and HCV genotype do not appear to influence the risk of HCV transmission, but high-quality studies to assess these virological factors are lacking.

Summary

The available data indicate that HCV can be sexually transmitted but the efficiency of transmission by the sexual route is low. The risk of sexual transmission of HCV is estimated to be 0.03 percent to 0.6 percent per year for those in monogamous relationships, and 1 percent per year for those with multiple sexual partners. Given these estimates of risk, the current recommendations are: 1) HCV-positive individuals in longer-term monogamous relationships need not change their sexual practices. If couples wish to reduce the already low risk of HCV transmission by sexual contact, barrier precautions may be used. Partners of HCV-positive persons should be considered for anti-HCV testing and 2) For HCV-infected individuals with multiple or short-term sexual partners, barrier methods or abstinence are recommended. Additional common-sense recommendations include the use of barrier precautions if other STDs are present, if having sex during menses, or if engaging in sexual practices that might traumatize the genital mucosa. Finally, couples should not share personal items that may be contaminated by blood such as razors, toothbrushes, and nail-grooming equipment.

References

1. Centers for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR 1998;47 (No. RR-19):1–33.
2. Leruez-Ville M, Kunstmann JM, De Almeida M, et al. Detection of hepatitis C virus in semen of infected men. Lancet 2000;356:42–3.
3. Neumayr G, Propst A, Schwaighofer H, et al. Lack of evidence for the heterosexual transmission of hepatitis C. Q J Med 1999;92:505–8.
4. Piazza M, Sagliocca L, Tosone G, et al. Sexual transmission of the hepatitis C virus and efficacy of prophylaxis with intramuscular immune serum globulin. Arch Intern Med 1997;157:1537–44.
5. Rooney G, Gilson RJC. Sexual transmission of hepatitis C virus infection. Sex Transm Inf 1998;74:399–404.
6. Thomas DL, Zenilman JM, Alter HJ, et al. Sexual transmission of hepatitis C virus among patients attending sexually transmitted disease clinics in Baltimore—An analysis of 309 sex partnerships. J Infect Dis 1995;17:768–75.
7. Zylberberg H , Thiers V, Lagorce D, et al. Epidemiological and virological analysis of couples infected with hepatitis C virus. Gut 1999;45:112–116.

Maternal-Infant Transmission

Eve A. Roberts, M.D., F.R.C.P.C.

With the advent of effective screening methods for hepatitis C virus (HCV), new cases of transfusion-associated hepatitis C have become infrequent in children. Consequently, childhood acquisition of HCV infection through maternal-infant transmission has assumed new importance. Vertical, or more precisely, mother-to-infant, hepatitis C will likely be the major type of childhood chronic hepatitis C within 6–8 years. It has been difficult to determine the rate of mother-to-infant transmission, partly because reports of mother-to-infant transmission of HCV were based on small numbers of patients, with differing disease definitions and study design. These reports tended to be heterogeneous and conflicting. Moreover, factors which promote mother-to-infant transmission and the outcome of chronic HCV infection acquired by this route still require clarification.

The first problem encountered with mother-to-infant transmission of HCV infection relates to its scope. Available estimates as to the prevalence of detectable anti-HCV among pregnant women range from 0.6 percent to 4.5 percent (median of 11 reports: 1.2 percent), with considerable geographic variation. Women with chronic hepatitis C appear to tolerate pregnancy as well as other women with non-cirrhotic chronic liver disease. Trivial improvement in serum aminotransferases may occur. Maternal viral titers may rise toward the end of the third trimester.

A second important problem is how exactly to define mother-to-infant transmission of HCV infection. Many infants of mothers chronically infected with HCV are found to have detectable anti-HCV in their blood, acquired through passive transplacental transfer of the IgG-antibody. This passively-acquired antibody continues to be detectable in the infant for the first 12–15 months of life, occasionally as long as the first 18 months. Possible criteria for a more rigorous definition of mother-to-infant transmission of HCV infection include: detectable anti-HCV in an infant who is more than 18 months old, detection of HCV RNA in an infant who is 3–6 months old, detection of HCV RNA in the infant on at least two occasions, finding elevated serum aminotransferases in the child, or confirming identical genotype between mother and child. A reasonable diagnostic approach in the infant is positive serum HCV RNA on two occasions 3–4 months apart after the infant is 2 months old and/or anti-HCV detected after the infant is 18 months old.

Reports detailing mother-to-infant transmission of HCV have been reviewed from time to time. We carried out a critical review of the world literature published between 1992 and 2001. For inclusion, each study was required to have at least 10 mother-infant pairs; language restrictions were largely avoided. Criteria used for identifying mother-to-infant transmission of infection were (1) anti-HCV detected in an infant over 1 year old or (2) HCV RNA detected at least once in an infant 18 months old or less. Studies using first-generation ELISA or RIBA techniques without confirmatory PCR testing were excluded. A weighted rate of incidence was used to adjust for sample size and variance. Seventy-seven studies were included for review: almost all of these were prospective cohort studies. The number of mother-infant pairs in each study ranged from 10 to 1,338. Taken altogether, 383 cases of mother-to-infant hepatitis C were identified. If the mother was known only to be anti-HCV positive, the weighted rate of mother-to-infant transmission was 1.7 percent (compared to a crude rate of number positive/number at risk = 5.6 percent). If the mother was known to be viremic, that is, HCV RNA positive, the weighted rate of mother-to-infant transmission was 4.3 percent (crude rate = 8.1 percent).

Geographic variation was apparent from these studies. In Italian studies with viremic mothers, the mother-to-infant transmission rate (weighted) was 5.6 percent, in similar Japanese studies, 6.9 percent, and in studies with viremic mothers from elsewhere, 3.1 percent. As previously shown, co-infection with the human immunodeficiency virus (HIV) greatly increased mother-to-infant transmission of HCV: weighted rates from these studies were 19.4 percent for HIV-positive mothers compared to 3.5 percent for HIV-negative mothers. In six studies examining the importance of previous or ongoing intravenous drug abuse (IVDU), a subset of anti-HCV positive mothers (where maternal viremia was not reported) at higher risk for transmission of HCV was identified: the weighted rate of transmission was 8.6 percent in mothers who were anti-HCV positive and IVDU, compared to 3.4 percent in anti-HCV positive mothers without known IVDU.

Findings in the most recent prospective studies are similar. In a study from Ireland of 314 infants born to 296 anti-HCV-positive women, the rate of mother-to-infant transmission was 3.5 percent (minimum rate)–6.4 percent (based on observed cases). No significant differences were found with spontaneous rupture of membranes, duration of membrane rupture, vaginal delivery or cesarean section, or evident fetal distress. Infants tended to be small for gestational age, but this could not be attributed solely to maternal chronic hepatitis C. In a study of 2447 HIV-negative pregnant women from Italy, 78 women were identified as anti-HCV positive and these mother-child pairs were monitored for 2 years; 60 women were found to be HCV RNA positive. Eight infants were identified as infected with HCV: thus the mother-to-infant transmission rate was 13.3 percent. At 2 years of age, only two infants were still positive for HCV RNA, and therefore the overall mother-to-infant transmission rate was put at 3.3 percent. Mother-to-infant transmission correlated with high maternal viral load.

The maternal viral titer appears to be an important determinant of probability of mother-to-infant transmission of HCV infection. The critical level appears to be 10 ⁵ –10 ⁶ copies per ml. Not all studies show a clear correlation between maternal viral titer and vertical transmission: the timing of when the titer determination was performed may be a confounder. In one study, high maternal titers of HCV correlated with virus detectable in colostrum. Data are inadequate to assess whether viral genotype makes a difference to the rate of mother-to-infant HCV transmission.

Mode of delivery has been examined as a possible determinant of mother-to-infant transmission of HCV infection. In most studies suitable for evaluation the mode of delivery did not make an important difference to virus transmission. One study from Japan showed that vaginal delivery was associated with increased risk of mother-to-infant transmission of HCV compared to caesarean section when high viral load (≥2.5 x 10 ⁶ copies/mL) was present; however, maternal HIV status was not documented, and cesarean section operations were not classified as elective or emergency. Another study suggested that elective, but not emergency, cesarean section confers protection against mother-to-infant transmission. This study, however, was not stratified for HIV status. Anti-HCV positive mothers may be more likely to have cesarean section for reasons related to general obstetric management. Whether prolonged rupture of membranes prior to delivery enhances the mother-to-infant transmission rate remains uncertain. Use of fetal monitoring might be a risk factor for virus transmission but has not been investigated adequately.

Breastfeeding is generally not considered to be a risk factor for mother-to-infant transmission of HCV. In published studies the rate of transmission is nearly identical in breast- or bottle-fed infants. Whether these studies are adequate is open to question since duration and exclusivity of breastfeeding are not routinely described in detail. The safety of breastfeeding operates on the assumption that traumatized or cracked nipples are not present.

The outcome of mother-to-infant hepatitis C requires clarification. Subtleties of disease course are relevant to this discussion. Some infants may have transient viremia without real infection. Other infants may have acute, self-limited infection which is clinically inapparent (very early spontaneous resolution). Data relating to these early patterns of mother-to-infant HCV exposure/disease are scanty, mainly because of reluctance to take repeated blood samples from apparently healthy infants. Thus, outcome of mother-to-infant transmission of HCV is usually considered in terms of evolution to chronic hepatitis C, with later spontaneous clearance of HCV infection or progressive chronic liver disease. Whether children are more likely to clear chronic HCV infection than adults and whether transfusion-associated chronic hepatitis in children runs a different clinical course from chronic hepatitis C acquired by mother-to-infant transmission remain unanswered questions currently being investigated.

References

1. Bernard O. Mother-to-infant transmission of hepatitis C. Acta Gastroenterol Belg 1998;61:192–4.
2. Thomas SL, Newell ML, Peckham CS, Ades AE, Hall AJ. A review of hepatitis C virus (HCV) vertical transmission: risks of transmission to infants born to mothers with and without HCV viraemia or human immunodeficiency virus infection. Int J Epidemiol 1998;27:108–17.
3. Yeung LT, King SM, Roberts EA. Mother-to-infant transmission of hepatitis C virus. Hepatology 2001;34:223–9.
4. Ohto H, Terazawa S, Sasaki N, Sasaki N, Hino K, Ishiwata C, et al. Transmission of hepatitis C virus from mothers to infants. N Engl J Med 1994;330:744–50.
5. Healy CM, Cafferkey MT, Conroy A, Dooley S, Hall WW, Beckett M, et al. Outcome of infants born to hepatitis C infected women. Ir J Med Sci 2001;170:103–6.
6. Ceci O, Margiotta M, Marello F, Francavilla R, Loizzi P, Francavilla A, et al. Vertical Transmission of Hepatitis C Virus in a Cohort of 2,447 HIV-Seronegative Pregnant Women: A 24-Month Prospective Study. J Pediatr Gastroenterol Nutr 20

1. 01;33:570–5.
2. Gibb DM, Goodall RL, Dunn DT, Healy M, Neave P, Cafferkey M, et al. Mother-to-child transmission of hepatitis C virus: evidence for preventable peripartum transmission. Lancet 2000;356:904–7.
3. Hillemanns P, Dannecker C, Kimmig R, Hasbargen U. Obstetric risks and vertical transmission of hepatitis C virus infection in pregnancy. Acta Obstet Gynecol Scand 2000;79:543–7.

Introduction to Therapy of Hepatitis C

Karen L. Lindsay, M.D.

Since the 1997 NIH Consensus Development Conference: Management of Hepatitis C, several important advances have occurred which have significantly impacted therapy of hepatitis C, notably the availability of sensitive, specific, and standardized assays for identifying HCV RNA in the serum, (1) and the evaluation and FDA-approval of ribavirin and pegylated alpha interferon. The vast majority of treatment data has been collected in patients with chronic hepatitis C viral infection (HCV), clinically compensated liver disease due to HCV, elevated ALT or AST, no medical contraindication to treatment, and no other significant medical illness.

Therapeutic End Points

Sustained Virological Response

HCV RNA testing is conducted before, during, and at the end of treatment and 24 weeks later. It is now clear that sustained virological response (SVR), defined by the absence of detectable HCV RNA in the serum by RT-PCR at the end of treatment and 24 weeks after the end of treatment, is the optimal end point of therapy. Although a surrogate end point (2) (a biomarker intended to substitute for a clinical end point), SVR is associated with important clinical end points (characteristics that measure how a patient feels, functions, or survives).  Marked improvements in health-related quality of life in patients with SVR has been demonstrated using standardized quality of life instruments (3). The effects of SVR on survival of patients with chronic HCV have not yet been precisely measured because of the necessity for long-term follow-up and the inclusion of large numbers of untreated patients or treated patients without SVR. Evaluation of other clinical end points which are likely to be associated with survival [liver histology, recurrence of detectable viremia, residual HCV in the liver, development of hepatocellular carcinoma (HCC)] has been conducted. In patients with SVR, followup liver biopsies (4–6) taken 1–11 years after treatment demonstrate clear improvement in 89–100 percent, and serial serum HCV RNA testing (4,5,7) revealed a recurrence of viremia (late virologic relapse) in only 0–4 percent. A low likelihood of late virologic relapse is supported by a recent large study in 400 patients with SVR (8) in whom HCV RNA was detectable in only 2 percent of liver biopsies taken 24 weeks after the end of treatment. These observations strongly suggest that the absence of detectable serum HCV RNA measured 24 weeks after the end of treatment will be associated with improvement in how patients feel and function, resolution of liver injury and reduction in hepatic fibrosis, and a very low likelihood of recurrent HCV infection, all of which are highly likely to improve patient survival. And, in two large recent studies from Japan, (9,10) treatment with interferon was associated with a reduction in development of hepatocellular carcinoma which was more pronounced in patients with SVR. These and other long-term follow-up studies in progress will be extremely important in defining the effect of SVR on survival in years to come.  Since the Conference in 1997, large Phase III clinical trials in HCV patients naïve to treatment have demonstrated several major advancements in therapeutic agents. Lengthening the course of unmodified alpha interferon (α -IFN) monotherapy from 24 to 48 weeks, adding ribavirin to α interferon (α-IFN) for 24 or 48 weeks (11,12) and using pegylated alfa interferon (PEG IFN) compared to α interferon (α-IFN) for 48 weeks (13–15) increases the likelihood of SVR. And, in two recent large trials (16,17) in which ribavirin was given in combination with either PEG IFN or α –IFN, the overall rate of SVR was 54 percent and 56 percent with PEG IFN compared to 47 percent and 45 percent with α -IFN.

In these trials, multivariate analyses of baseline factors have identified several variables as being associated with the likelihood of SVR: HCV genotype other than 1, lower baseline viral load, lighter baseline weight or lower body surface area, younger age, absence of bridging fibrosis/cirrhosis, higher ALT quotient, and female sex. In several analyses, sex is no longer significant when weight is taken into account. Of these variables, viral genotype, HCV RNA level, and body weight are most strongly associated with SVR, but none of these factors singly or in combination are highly predictive of SVR. The patient’s race, in particular, being an African-American, although not identified in multivariate analyses of these large trials, also appears to be potentially associated with response. (18) On-treatment factors have also been evaluated, and virologic response during the first 24 weeks of treatment has been identified as highly predictive of SVR. (17) In addition, the patient’s ability to adhere to the regimen by taking 80 percent of the intended dose of the two therapeutic agents for at least 80 percent of the intended duration of treatment is also associated with higher SVR rates. (19) The optimal approach, therefore, is the initiation of a therapeutic trial and identification of the appropriate time for determination of virologic response (stopping rules). Further work is needed to understand and optimize adherence to therapy.

Virologic Response with Relapse

Virologic response with relapse is defined by the absence of detectable HCV RNA in the serum by RT-PCR at the end of treatment (virologic response) followed by subsequent detectability of HCV RNA in the 24 weeks after the end of treatment. In such patients, HCV is either present in the serum at levels too low for the assay to detect, or potentially sequestered in other compartments. The availability of more sensitive assays, such as TMA, (20) will be extremely useful in such patients. Future studies are needed to determine whether lengthening the course of treatment in patients with detectable serum HCV RNA using a more sensitive assay is associated with SVR.

Virologic Non-Response

Virologic non-response is defined as the presence of detectable HCV RNA at the end of treatment. In general, this category of patients treated with interferon-based therapy have been inadequately studied as regards the role of viral resistance, treatment adherence, and specific immunologic, environmental, genetic, or other factors which play a role.

Non-Virologic Therapeutic End Points

Biochemical response [the lowering of ALT to within the normal range at the end of treatment or at the end of treatment and for 24 weeks following treatment (sustained biochemical response)] continues to be evaluated in large trials, but there are few studies describing the long-term benefit of a sustained biochemical response in the absence of SVR. Although these studies suggest that long-term biochemical response is associated with a decreased frequency of hepatocellular carcinoma, (21–23) the groups are not controlled for baseline stage of fibrosis.

Histologic response or histologic improvement has been evaluated as a secondary end point in large, Phase III trials in which fixed-duration therapy was given. Comparing paired liver biopsies using standardized scoring systems, it is conventionally defined as at least a 2-point decrease from baseline biopsy in the inflammation score or in the total score or a 1-point decrease in the fibrosis score. (11–17)

The clinical value of a biochemical or histological response as a primary end point will be of great importance in ongoing and future treatment trials in patients for whom interferon-based therapy is contraindicated, those who cannot tolerate interferon treatment, or those whose infection does not virologically respond to interferon-based therapy. Long-term pegylated interferon therapy in virologic non-responders is being studied in several trials. Current and future studies using anti-inflammatory and anti-fibrotic agents will also assess these end points. And, in the future, these end points will be extremely important in studies using specific inhibitors of viral replication currently in development in order to determine the effects of virologic suppression as an end point of therapy.

Other Patient Populations

Large, definitive treatment trials have been conducted and reported in more than 10,000 adult patients with elevated aminotransferases, clinically compensated chronic liver disease due to HCV, and no other significant medical disorder. However, results from adequately designed and statistically powered studies of other patient populations (children, normal aminotransferases; decompensated liver disease; post-organ transplant; HIV co-infection; inherited blood disorders; renal disease; neuropsychiatric disorders; vascular disease; indigent, homeless, or substance-addicted) are not available. In order to determine the safety and effectiveness of HCV treatment in these populations, definitive trials need to be performed.

References

1. Pawlotsky J-M, Bouvier-Alias M, Hezode C, Darthuy F, Remire J, Dhumeaux D. Standardization of Hepatitis C Virus RNA Quantification. Hepatology 2000;32:654–9.
2. Definitions Working Group. Biomarkers and Surrogate Endpoints: Advancing Clinical Research and Applications. Sponsored by National Institutes of Health and the Food and Drug Administration, April 15–16, 1999; Bethesda, Maryland.
3. Bonkovsky HL, Woolley M, and the Consensus Interferon Study Group. Reduction of Health-Related Quality of Life in Chronic Hepatitis C and Improvement with Interferon Therapy. Hepatology 1999;29:264–70.
4. Marcellin P, Boyer N, Gervais A, Martinot M, Pouteau M, Castelnau C, Kilani A, Areias J, Auperin A, Benhamou JP, Degott C, Erlinger S. Long-Term Histologic Improvement and Loss of Detectable Intrahepatic HCV RNA in Patients with Chronic Hepatitis C and Sustained Response to Interferon-alpha Therapy. Ann Intern Med. 1997;127:875–81.
5. Lau D T-Y, Kleiner DE, Ghany MG, Park Y, Schmid P, Hoofnagle JH. 10-Year Follow-up After α Interferon for Chronic Hepatitis C. Hepatology 1998;28:1121-27
6. Shiratori Y, Imazeki F, Moriyama M. Yano M, Arakawa Y, Yokosuka O, Kuroki T, Nishiguchi S, Sata M, Yamada G, Fujiyama S, Yoshida H, Omata M. Histologic Improvement of Fibrosis in Patients with Hepatitis C Who Have Sustained Response to Interferon Therapy. Ann Intern Med 2000;132:517–24.
7. McHutchison, JG, Davis GL, Esteban-Mur R, Poynard T, Ling M-H, Garaud J-J, Albrecht J for The International Hepatitis Interventional Therapy Group. Durability of Sustained Virologic Response in Patients with Chronic Hepatitis C after Treatment with alpha interferon 2b alone or in combination with ribavirin.  Hepatology. 2002;35:688-93
8. McHutchison JG, Poynard T, Esteban-Mur R, Davis GL, Goodman ZD, Harvey J, Ling M-H, Garaud J-J, Albrecht JK, Patel K, Dienstag JL, for the International Hepatitis Interventional Therapy Group. Hepatic HCV RNA before and after treatment with interferon alone or combined with ribavirin. Hepatology 2002;35:688–93.
9. Ikeda K, Saitoh S, Arase Y, Chayama K, Suzuki Y, Kobayashi M, Tsubota A, Kobayashi M, Nakamura I, Murashima N, Kumada H, Kawanishi M. Effect of Interferon Therapy on Hepatocellular Carcinogenesis in Patients With Chronic Hepatitis Type C: A Long-Term Observation Study of 1,643 Patients Using Statistical Bias Correction with Proportional Hazard Analysis. Hepatology 1999;29:1124–30.
10. Yoshida H, Shiratori Y, Moriyama M, Arakawa Y, Ide T, Sata M, Inoue O, Yano M, Tanaka M, Fujiyama S, Nishiguchi S, Kuroki T, Imazeki F, Yokosuka O, Kinoyama S, Yamada G, Omata M, for the IHIT Study Group. Interferon Therapy Reduces the Risk for Hepatocellular Carcinoma: National Surveillance Program of Cirrhotic and Noncirrhotic Patients with Chronic Hepatitis C in Japan. Ann Intern Med 1999;131:174–81.
11. Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, Bain V, Heathcote J, Zeuzem S, Trepo C, Albrecht J, for the International Hepatitis Interventional Therapy Group (IHIT). Randomised trial of interferon alfa-2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alfa-2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet 1998;352:1426–32.
12. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, Goodman ZD, Ling M-H, Cort S, Albrecht JK, for the Hepatitis Interventional Therapy Group. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998;339:1485–92.
13. Zeuzem S, Feinman V, Rasenack J, Heathcote EJ, Lai MY, Gane E, O’Grady J, Reichen J, Diago M, Lin A, Hoffman J, and Brunda MJ. Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med 2000;343:1666–72.
14. Heathcote EJ, Shiffman ML, Cooksley WGE, Dusheiko GM, Lee SS, Balart L, Reindollar R, Reddy RK, Wright TL, Lin A, Hoffman J, DePamphilis J. Peginterferon Alfa-2a in Patients with Chronic Hepatitis C and Cirrhosis. N Engl J Med 2000;343:1673–80.
15. Lindsay KL, Trepo C, Heintges T, Shiffman ML, Gordon SC, Hoefs JC, Schiff ER, Goodman ZD, Laughlin M, Yao R, Albrecht JK. A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C. Hepatology 2001;34:395–403.
16. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M-H, Albrecht JK, and the International Hepatitis Interventional Therapy Group. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958–65.
17. Fried MW, Shiffman ML, Reddy RK, Smith C, Marino G, Goncales F, Haeussinger D, Diago M, Carosi G, Zarski J-P, Hoffman J. Pegylated (40kDa) Interferon Alfa-2a (PEGASYS ® ) in Combination With Ribavirin: Efficacy and Safety Results From a Phase III, Randomized, Actively-Controlled, Multicenter Study. Gastroenterology 2001;120:288.
18. Reddy KR, Hoofnagle JH, Tong MJ, Lee WM, Pockros P, Heathcote EJ, Albert D, Joh T. Racial differences in responses to therapy with interferon in chronic hepatitis C. Hepatology 1999;30:787–93.
19. McHutchison JG, Manns M, Patel K, Poynard T, Lindsay KL, Trepo C, Dienstag J, Lee WM, Mak C, Garaud J-J, Albrecht JK, for the International Hepatitis Interventional Therapy Group. Adherence to combination therapy enhances sustained response in patients with chronic hepatitis C infection (submitted for publication).
20. Sarrazin C, Teuber G, Kokka R, Rabenau H, Zeuzem S. Detection of residual hepatitis C virus RNA by transcription-mediated amplification in patients with complete virologic response according to polymerase chain reaction-based assays. Hepatology 2000;32:818–23.
21. Kasahara A, Hayashi N, Mochizuki K, Hiramatsu N, Sasaki Y, Kakumu S, Kiyosawa K, Okita K, and the Osaka Liver Disease Study Group. Clinical characteristics of patients with chronic hepatitis C showing biochemical remission, without hepatitis C virus eradication, as a result of interferon therapy. J Vir Hep 2000;7:343–51.
22. Toyoda H, Kumada T, Tokuda A, Horiguchi Y, Nakano H, Honda T, Nakano S, Hayashi K, Katano Y, Nakano H, Hayakawa T, Nishimura D, Kato K, Imada K, Imoto M, Fukuda Y for the Yon-Ken HCV-HCC Follow-up Study Group. Long-term follow-up of sustained responders to interferon therapy, in patients with chronic hepatitis C. J Vir Hep 2000;7:414–9.
23. Shindo M, Hamada K, Oda K, Okuno T. Long-term follow-up study of sustained biochemical responders with interferon therapy. Hepatology 2001;33:1299–1302.