Association of maternal prepregnancy BMI with metabolomic profile across gestation.

BACKGROUND/OBJECTIVES: Elevated prepregnancy body mass index (pBMI) and excess gestational weight gain (GWG) constitute important prenatal exposures that may program adiposity and disease risk in offspring. The objective of this study is to investigate the influence of pBMI and GWG on the maternal metabolomic profile across pregnancy, and to identify associations with birth weight. SUBJECTS/METHODS: This is a longitudinal prospective study of 167 nondiabetic women carrying a singleton pregnancy. Women were recruited between March 2011 and December 2013 from antenatal clinics affiliated to the University of California, Irvine, Medical Center. Seven women were excluded from analyses because of a diagnosis of diabetes during pregnancy. A total of 254 plasma metabolites known to be related to obesity in nonpregnant populations were analyzed in each trimester using targeted metabolomics. The effects of pBMI and GWG on metabolites were tested through linear regression and principle component analysis, adjusting for maternal sociodemographic factors, diet, and insulin resistance. A Bonferroni correction was applied for multiple comparison testing. RESULTS: pBMI was significantly associated with 40 metabolites. Nonesterified fatty acids (NEFA) showed a strong positive association with pBMI, with specificity for mono-unsaturated and omega-6 NEFA. Among phospholipids, sphingomyelins with two double bonds and phosphatidylcholines containing 20:3 fatty acid chain, indicative of omega-6 NEFA, were positively associated with pBMI. Few associations between GWG, quality and quantity of the diet, insulin resistance and the maternal metabolome throughout gestation were detected. NEFA levels in the first and, to a lesser degree, in the second trimester were positively associated with birth weight percentiles. CONCLUSIONS: Preconception obesity appears to have a stronger influence on the maternal metabolic milieu than gestational factors such as weight gain, dietary intake and insulin resistance, highlighting the critical importance of preconception health. NEFA in general, as well as monounsaturated and omega-6 fatty acid species in particular, represent key metabolites for a potential mechanism of intergenerational transfer of obesity risk.

Pregnant immigrant Nigerian women: an exploration of dietary intakes.

OBJECTIVE: The aim of the study is to explore the dietary intakes of a prominent ethnic minority group of women from Sub-Saharan Africa during pregnancy, in order to identify nutritional issues of concern which may impact on pregnancy outcomes and whether different food based dietary guidelines may be required to meet their needs. STUDY DESIGN: This is an observational study with quantitative assessment of nutrient intakes and an exploration of meal composition and food choices. METHODS: Fifty-two Nigerian pregnant women in their second or third trimester of pregnancy were recruited from antenatal clinics in the National Maternity Hospital, Dublin, Ireland. Early pregnancy weight was measured and body mass index recorded. A 24 h dietary recall was used to assess food and nutrient intakes. RESULTS: Eighty-nine per cent of the study population were classified as overweight or obese. These women appear to be maintaining traditional African dietary habits and have a healthy macronutrient composition in the diet. The intake of key pregnancy micronutrients such as calcium, vitamin D and folate may be insufficient from diet alone to meet requirements and supplements may be inadequately utilized in a timely manner. CONCLUSIONS: These women represent a vulnerable obstetric group that may be at risk of adverse pregnancy outcomes due to high obesity rates and inadequate micronutrient status in early pregnancy. Provision of dietary advice should be tailored to suit their cultural dietary practices and food preferences. Pre-conception counselling on healthy lifestyle and appropriate supplement usage may be beneficial, although larger studies are required to assess the need for specific nutrition policy recommendations.

Antigen-specific T lymphocyte proliferation decreases over time in advanced chronic hepatitis C.

To evaluate T cell immunity in advanced liver disease, antigen-specific lymphoproliferative (LP) responses were prospectively studied in the context of the Hepatitis C Antiviral Long-term Treatment against Cirrhosis trial. Peripheral blood responses to hepatitis C virus (HCV), tetanus and Candida protein antigens were measured at baseline, month 12 (M12), M24, M36 and M48 in 186 patients randomized to either low-dose peginterferon-alfa-2a (PEG-IFN) only or observation. Liver histology was evaluated at baseline, M24 and M48. Patients with cirrhosis (Ishak 5-6) were less likely to have positive LP responses to HCV at baseline than patients with fibrosis (15%vs 29%, P = 0.03) and had lower levels of HCV c100 responses at baseline, M24 and M48 (P = 0.11, P = 0.05, P = 0.02, respectively). For 97 patients with complete longitudinal data, the frequency of positive LP responses to HCV, tetanus and Candida antigens declined over time (P < 0.003), and the slope of this decline was greater in the PEG-IFN treatment group than the observation group (P < 0.02). Lower levels of tetanus LP responses were associated with fibrosis progression and clinical outcomes (P = 0.009). Poorer CD4+ T cell proliferative function was associated with more advanced liver disease in chronic hepatitis C and may be further affected by long-term PEG-IFN treatment.

Maternal nutrition among women from Sub-Saharan Africa, with a focus on Nigeria, and potential implications for pregnancy outcomes among immigrant populations in developed countries.

Pregnant women in countries of Sub-Saharan Africa (SSA) are at risk of poor nutritional status and adverse outcomes as a result of poverty, food insecurity, sub-optimal healthcare facilities, frequent infections and frequent pregnancies. Studies from Nigeria, for example, have revealed a high prevalence of both under- and over-nutrition, as well as nutrient deficiencies, including iron, folate, vitamin D and vitamin A. Subsequently, obstetric complications, including hypertension, anaemia, neural tube defects, night-blindness, low birth weight and maternal and perinatal mortality, are common. Migration patterns from SSA to the Western world are on the rise in recent years, with Nigerians now representing the most prevalent immigrant African population in many developed countries. However, the effect of immigration, if any, on the nutritional status and pregnancy outcomes of these women in their host countries has not yet been studied. Consequently, it is unknown to what extent the nutritional deficiencies and pregnancy complications occurring in Nigeria, and other countries of SSA, present in these women post-emigration. This may result in missed opportunities for appropriate antenatal care of a potential high-risk group in pregnancy. The present review discusses the literature regarding nutrition in pregnancy among SSA women, using Nigeria as an example, the common nutrition-related complications that arise and the subsequent obstetric outcomes. The concept of dietary acculturation among immigrant groups is also discussed and deficiencies in the literature regarding studies on the diets of pregnant immigrant women are highlighted.

Intrahepatic lymphocyte phenotypes in hepatitis C virus infection: a comparison between cirrhotic and non-cirrhotic livers.

AIM: The pathogenesis of viral hepatitis involves the activation of cellular immunity, including intrahepatic lymphocytes (IHL). Lym-phocyte phenotypes play a fundamental role in the pathogenesis of chronic hepatitis C virus (HCV) infection, the progression of liver fibrosis and subsequent hepatocellular carcinoma. The aim of this study was to evaluate the frequency of intrahepatic mononuclear cell phenotypes in patients with chronic HCV. Another aim was to assess the relationship of nonparenchymal cells with liver fibrosis. METHODS: Liver fibrosis was evaluated with the Histologic Activity Index. Fourteen liver biopsies showed mild fibrosis (group 1), and 11 bridging fibrosis (group 2). Fourteen samples were explants from HCV patients who underwent liver transplantation (group 3). CD4 and CD8 T-lymphocytes, CD20 (B lymphocytes), CD16 (macrophage), and CD57 (NK) cells were detected using monoclonal antibodies on paraffin-embedded tissue. RESULTS: A minority of lobular cells stained for T- or B-lymphocytes. Most lobular cells stained with macrophage antibodies, and were more common in bridging fibrosis, compared to mild fibrosis. The percentages of lobular CD4 and CD8 cells were significantly lower in regenerative nodules of cirrhotic livers. There was a strong negative correlation between lobular CD8 and fibrosis score (R= -0.65), and a strong positive correlation between CD16-stained mononuclear cells (macrophages) and fibrosis score (R=0.66). In portal and periportal areas, CD4 but not CD8 lymphocytes decreased in parallel with fibrosis. B-lymphocytes were more commonly found in the portal areas than in the lobule. CD57-positive cells were rare in both lobule and portal areas, and their frequency was not different in the three groups studied. CONCLUSIONS: In hepatitis C, lobular mononuclear cells are mostly macrophages and appear associated with bridging fibrosis. Cirrhotic livers display significantly lower numbers of lobular CD4 and CD8 lymphocytes. This finding could help explain a decrease in immune surveillance and the promotion of neoplastic growth in HCV-associated cirrhosis.

Ultrastructure of hypertensive rat aorta. Increased basement membrane-like material.

To determine the effect of elevated blood pressure on the ultrastructure of rat aorta, hypertension (average mean pressure 163 +/- 17 mm Hg) was produced by suprarenal aortic coarctation. After 3 weeks, the subendothelium of the hypertensive thoracic aorta showed significantly increased volume measurements for mononuclear leukocytes and basement membrane-like material compared with the sham-operated control group. Focal areas of rarefaction of the subendothelial extracellular material were associated with the nearby presence of mononuclear leukocytes. None of these alterations were found in the normotensive abdominal aorta. The tunica media of hypertensive thoracic aorta also contained significantly increased basement membrane-like material. This new finding in an animal hypertension model is the direct result of the quantitative morphological approach employed in this study. In some rats, the partially constricting aortic ligature compromised the right renal artery leading to ischemic atrophy of the right kidney and hyperreninemia in addition to hypertension. In this group, excluded from the previous analysis and evaluated separately, subendothelial thickening and accumulation of basement membrane-like material in the thoracic aorta were greatly increased compared with the control group and other hypertensive rats. This result could not be attributed to an effect of blood pressure alone and might have been caused in part by humoral factors. Basement membrane accumulation appears to be an important early response of the arterial wall to hypertension or other factors in this rat model.

Management of chronic hepatitis in special populations.

Over the last several years, much progress has been made in the treatment of adult patients with chronic viral hepatitis and compensated liver disease in the absence of significant other illnesses. However, the treatment of chronic viral hepatitis in other patient populations is still experimental. These groups include children, patients immunocompromised by human immunodeficiency virus infection or immunosuppression following organ transplantation, those with end-stage renal disease, and patients with extrahepatic manifestations of hepatitis viral infection. Data on the treatment of chronic hepatitis in these special populations are reviewed.

Increased hepatic iron deposition resulting from treatment of chronic hepatitis C with ribavirin.

Increased levels of hepatic iron may impair the response of patients with chronic hepatitis C to treatment with interferon-alfa, but combination therapy with ribavirin has demonstrated efficacy in the treatment of hepatitis C. When used alone or with interferon-alfa, ribavirin may cause a dose-dependent reversible hemolytic anemia. We compared the extent and cellular localization of iron deposition in liver tissue from biopsy specimens obtained before and after 36 weeks of therapy with ribavirin or placebo for 59 patients with chronic hepatitis C. Paired slides were available for review from 26 ribavirin and 27 placebo recipients. Iron deposition was assessed using coded slides stained with Perls Prussian blue and was semi-quantitated in hepatocytes, Kupffer cells, and areas of fibrosis. The overall iron score fell by 0.96 in the placebo group and increased 1.69 in the ribavirin recipients. Iron was deposited mainly in hepatocytes; the hepatocyte iron score increased from 2.19 to 3.81 in the ribavirin group. The amount of iron staining in Kupffer cells declined in the placebo group and increased slightly in the ribavirin group. Iron changes in areas of fibrosis were minor and did not differ between groups. Increased total hepatic iron deposition occurred during a 9-month course of ribavirin. Ribavirin-associated hemolysis deposits iron preferentially in hepatocytes. This increased deposition of hepatic iron does not seem to affect the biochemical or histologic response to ribavirin therapy but may have implications for hepatocyte susceptibility to future injury.

Therapy of hepatitis C: overview.

Based on the first decade of research on alpha interferon in viral hepatitis, one can conclude that up to 40% of patients with compensated chronic hepatitis C and elevated alanine aminotransferase (ALT) levels will respond at least transiently to interferon. Four forms of alpha interferon have been evaluated in large numbers of patients with chronic hepatitis C: alfa-2b, alfa-2a, alfa-n1, and consensus interferon (CIFN). Responses are defined on the basis of biochemical (ALT) or virological (hepatitis C virus [HCV] RNA testing by polymerase chain reaction [PCR]) end points, and as end-of-treatment response (ETR) or sustained response (SR). Biochemical ETR rates to 6 months of therapy range from 35% to 50%, and SR rates 6 months after treatment from 8% to 21%. Although 6-month treatment courses are associated with a significant rate of relapse, 12 months of initial treatment and re-treatment regimens markedly improve the SR rate. Long-term follow-up evaluation in patients with an SR to interferon consistently show long-lasting and significant clinical, virological, and histological improvement. Finally, baseline factors that have been shown to be associated with SR to 6 months of treatment are not accurate enough to predict response. Therefore, the best treatment strategy is a therapeutic trial. Further studies of interferon therapy of hepatitis C are needed to define better virological end points useful in stopping therapy, to understand and better manage significant side effects of interferon, and to evaluate the histological effects of interferon in biochemical nonresponders. Also needed is a better understanding of the causes of resistance to interferon. Finally, newer therapeutic regimens such as the use of induction therapy and combination therapies with ribavirin, other antiviral agents, cytokines, and cytokine modifiers are of primary importance in eventually developing safe and effective means of treatment of hepatitis C.

Treatment of chronic hepatitis C: comparative virologic response rates among the different interferons.

End-treatment and sustained virologic response rates are similar in large, comparative controlled trials which have compared the standard dosing regimens of interferon alpha-2b to interferon alpha-nl and consensus interferon, as well as to virologic response rates recently reported with interferon alpha-2b monotherapy for 24 weeks. For patients who have responded and relapsed after an initial course of alpha interferon, retreatment with consensus interferon for 48 weeks demonstrates a high sustained virologic response rate, similar to that reported with interferon alpha-2b combined with ribavirin for 24 weeks. Based on available pharmacokinetic and pharmacodynamic data, pegylation of interferon alpha-2a shows promise in demonstrating high sustained serum levels and 2',5' OAS activity. Preliminary data from a Phase II clinical trial of a 48-week treatment in naive patients demonstrates end-treatment and sustained virologic response rates similar to that seen with interferon alpha-2b combined with ribavirin for 48 weeks.

Spontaneous Arizona hinshawii peritonitis in cirrhosis with ascites.

Arizona hinshawii, a gram-negative enteric pathogen, causes serious infections in fowl, reptiles, and other animals. In humans, gastroenteritis, enteric fever, septicemia, and localized infections due to Arizona have occurred. There are no previous reports of spontaneous bacterial peritonitis secondary to Arizona, however. We report here a case of spontaneous bacterial peritonitis due to Arizona occurring in a patient with cirrhosis of the alcoholic type. The patient was treated with a 10-day course of gentamicin, and although she improved clinically, Arizona was cultured from the blood and bile postmortem.

Comparison of aortic intima and inner media in young adult versus aging rats. Stereology in a polarized system.

Age-related ultrastructural changes in the intima and inner media of rat thoracic aorta were examined by new morphometric techniques. Young adult male rats, 10 weeks old, were compared with 1-year-old male rats. The most marked changes were found in the sub-endothelium, which increased in thickness more than five-fold. Basement-membrane-like and granular material accounted for the bulk of this thickening. Certain other structures were increased sevenfold or more in subendothelium. These structures and the volume fractions they occupied in 1-year-old rats were as follows: banded collagen, 4.3%; mononuclear leukocytes, 4.5%; cystic structures, 3.3%; and fibrillar elastin, 1.0%. Changes were also demonstrated in the fenestrae of and at selected depth levels below the innermost, or alternatively the internal, elastic lamina. Collagen increased strikingly within fenestrae and just below the elastic lamina. This was associated with a 28% increase in the thickness of the elastic lamina and a recession of smooth muscle cytoplasm to a deeper position within the first musculoelastic medial layer. The alterations in subendothelial tissues imply an altered basis for mechanical support for aortic endothelium in aging rats. These results mark the successful application of micro-computer-based stereology to a situation of polarized geometry.

Hepatitis B vaccine: low postvaccination immunity in hospital personnel given gluteal injections.

Although other investigators have found excellent response rates to the hepatitis B vaccine, we report here an unusually low rate of seroconversion following hepatitis B vaccination in a group of apparently healthy medical center personnel. Only 67% of these individuals developed adequate postvaccination antibodies to HBsAg, in contrast to 85 to 96% in other studies. A significant decrease in seroconversion with increasing age was noted with a 54% seroconversion rate in vaccines over the age of 40; all of whom had received gluteal injections. Employees at another facility had been given deltoid injections from the same vaccine lot and had an overall seroconversion rate of 90%. Subsequently, nonresponders from the first group were revaccinated. Seven of the ten individuals tested developed anti-HBs. We believe the relatively low rate of seroconversion in individuals above the age of 40 may have been related to gluteal injection of the hepatitis B vaccine, and further investigation is warranted.

Endothelial denudation and myointimal thickening in the rat carotid artery induced by the passage of bubbles.

A new technique for the selective removal of endothelium in the rat carotid artery has been developed, and subsequent events in the vascular wall have been examined. To achieve de-endothelialization, more than 2,000 bubbles of nitrogen in phosphate-buffered saline are passed through a temporarily isolated segment of rat carotid over a period of 3 min. Bubbles are generated by a simple apparatus, consisting of a pressurized tilting chamber and catheter. Endothelium is removed while subendothelial basement membrane and other subjacent structures remain intact. Platelets attach to the denuded surface within minutes after re-establishment of blood flow. Myointimal thickening is found at 5 weeks and 4 months after de-endothelialization. The method is quite reliable and will facilitate further studies of reactions to carotid endothelial injury in young adult rats.

Utility of a discriminant score for diagnosing advanced fibrosis or cirrhosis in patients with chronic hepatitis C virus infection.

OBJECTIVE: The aim of the study was to assess the utility of a modified three-parameter cirrhosis discriminant score (CDS) for diagnosing advanced fibrosis or cirrhosis in patients with evidence of chronic hepatitis C. METHODS: We examined liver tissue from 79 patients. Patients with a histological fibrosis score of 0-2 made up group A, and patients with a score of 3 or 4 (advanced fibrosis or cirrhosis) group B. RESULTS: The modified CDS (possible total score 0-11) was derived from three laboratory parameters: platelets, ALT/AST ratio, and PT. The total score was significantly lower in group A (4.3 +/- 2.0) than in group B (7.9 +/- 1.4) (p < 0.0001). There was a positive correlation between the CDS and histological fibrosis score (r = 0.64,p < 0.0001). With 8 or above as the cutoff value, the CDS had a sensitivity of 46% and a specificity of 98% for the diagnosis of histological fibrosis scores of 3 or 4. CONCLUSIONS: We conclude that a three-parameter CDS is useful for identifying patients with hepatitis C and a high likelihood of cirrhosis. Patients with a CDS < or =7 still require histological examination to identify advanced fibrosis or cirrhosis.

Delayed HBsAg clearance in chronic hepatitis B viral infection.

Seven patients are described in whom HBsAg persisted for 13 to 98 months after acute viral hepatitis B and then became nondetectable. All patients subsequently developed anti-HBs. During the period of HBs-antigenemia, liver biopsies in five patients showed persistent viral hepatitis. Retrospectively, impending negativity of HBsAg was predictable in five patients by a decrease in HBsAg titer, and in four patients by persistent normalization of serum alanine aminotransferase. Although delayed clearance of HBsAg in patients with chronic hepatitis B virus infection is uncommon, it appears to be predictable.

Chronic hepatitis C in ethnic minority patients evaluated in Los Angeles County.

OBJECTIVE: The aim of this study was to compare demographic, clinical, and histological features of hepatitis C in four ethnic groups seen at the Los Angeles County/University of Southern California Hepatitis Clinic. METHODS: We evaluated 256 patients with chronic hepatitis C, with 132 (52%) receiving a liver biopsy as part of their evaluation. We estimated fibrosis progression in 103 patients with known duration of disease. RESULTS: Asians (6%) were underrepresented in the hepatitis C cohort, whereas Latinos (51%) were overrepresented, as compared with the entire county population. A history of injection drug use was more frequent in whites (65%) than in African Americans (45%, p = 0.05), Latinos (47%, p = 0.01), or Asians (0%) and more frequent in Latinos (59%) than in Latinas (26%, p = 0.003). Such a gender difference was not found in African Americans or whites. Baseline laboratory values were comparable. The amount of alcohol consumed daily was higher in African Americans than in Asians (p = 0.0001) and whites (p = 0.10). African Americans (0.077 fibrosis stages/yr) and whites (0.084/yr) had significantly lower mean estimated progression of liver fibrosis than Latinos (0.215/yr) with hepatitis C virus infection (ps = 0.03 and 0.02, respectively): this was likely related to their longer estimated duration of disease. CONCLUSION: Minorities represent the majority of chronic hepatitis C cases in the Los Angeles County Hepatitis Clinic. Asians, Latinas, and African Americans are less likely to report injection drug use as a risk factor for hepatitis C virus. Latinos seem to have faster liver fibrosis progression rates than either African Americans or whites.

Diagnostic usefulness of testing for anti-HBc IgM in acute hepatitis B.

Numerous tests to detect anti-HBc IgM have been developed and shown to have different degrees of sensitivity and specificity. One of these assays, Corzyme-M (Abbott Laboratories, North Chicago, Ill.), recently became commercially available. The present study was undertaken to evaluate the clinical utility of this anti-HBc IgM test in establishing the diagnosis of acute hepatitis B using sera from a group of 42 prospectively followed individuals who had been exposed to hepatitis B virus. The Corzyme-M test was highly sensitive in detecting recent hepatitis B virus infection. All 30 patients with symptomatic and 12 with asymptomatic acute hepatitis B virus infection developed anti-HBc IgM. However, the timing of sample testing relative to onset of symptoms in symptomatic patients was important, inasmuch as 2 of 23 patients were negative for anti-HBc IgM early in the symptomatic period, although all were HBsAg positive. The duration of anti-HBc IgM positivity after acute infection was variable, ranging from 2 to 134 weeks. In 14% of patients, anti-HBc IgM remained detectable for more than 1 year. From the data, recommendations are given regarding the usefulness of anti-HBc IgM testing in the diagnosis of acute hepatitis B virus infection.

Patients co-infected with human immunodeficiency virus and hepatitis C virus demonstrate higher levels of hepatic HCV RNA.

Serum and liver hepatitis C virus (HCV) RNA levels in patients with hepatitis C have previously been quantified using different techniques. In this work, we used an automated, multicycle, polymerase chain reaction (PCR)-based technique to quantify HCV RNA in 1-2 mm of frozen liver tissue, and in serum, from 70 patients with antibodies to HCV (anti-HCV), with and without human immunodeficiency virus (HIV) co-infection. Stored liver tissue and sera collected at the time of liver biopsy were used for measurement of HCV RNA. Forty-eight HCV patients and 22 HIV/HCV co-infected patients were studied. Co-infected patients had significantly higher median serum and liver HCV RNA (6.7 log copies ml-1 serum and 2.90 log copies microg-1 liver nucleic acids) than patients with HCV alone (6.2 log copies ml-1 serum and 2.19 log copies microg-1 liver nucleic acids). There was only a weak correlation between serum and liver HCV RNA (r = 0.43). There was no correlation between liver and serum HCV RNA and host factors such as duration of disease, CD4 counts, alanine aminotransferase levels or histological score. There was no correlation with HCV genotype. Co-infected patients were more likely to harbour HCV genotype 1 (85%) when compared to patients with HCV alone (58%). An identical genotype was found in liver and serum in 89% of those tested; in 11%, a mixed genotype was present in serum. Patients with HCV genotypes 1 and non-1 had similar histological scores. Hence, an automated PCR-based technique is useful for measuring both liver and serum HCV RNA. Serum HCV genotypes closely paralleled those found in liver tissue. HIV co-infection was associated with higher serum, as well as intrahepatic, HCV RNA levels, by mechanisms not directly related to CD4 counts. The lack of correlation between liver HCV RNA and histology suggests that HCV is not directly cytopathic.

Tolerance and efficacy of oral ribavirin treatment of chronic hepatitis C: a multicenter trial.

Hepatitis C is a common cause of chronic liver disease that may progress to cirrhosis. We conducted a multicenter double-blind placebo-controlled trial of ribavirin 600 mg given orally twice daily for 36 weeks with follow-up off therapy for an additional 16 weeks. Fifty-nine patients with compensated chronic hepatitis C were entered. Efficacy was measured at the end of therapy and after follow-up by normalization of alanine aminotransferase (ALT), improvement in liver histology, reduction in hepatitis C virus (HCV) RNA level and improvement of symptoms. Among the ribavirin recipients, 12 of 29 (41.4%) had normal ALT values at 36 weeks compared with only 1 of 30 (3.3%) placebo recipients (P < .001). No patient maintained a normal ALT when therapy was stopped. No significant decrease in level of HCV RNA was observed during the study. Histological improvement among subjects who normalized ALT (-1.67 Knodell index) was significantly greater than that in other treated patients (+0.33 Knodell index; P < .05). Fatigue improved in 19.2% of ribavirin-treated subjects and in 8.3% of placebo recipients whereas no worsening of fatigue was reported by ribavirin recipients compared with 16.7% of controls. This difference in fatigue was significant at weeks 36 and 52 (P < .05; .02, respectively). Adverse events were generally comparable between treatment groups except for a reversible hemolytic anemia experienced by ribavirin recipients. Chest pain was noted in four patients on ribavirin. Ribavirin was well tolerated and improved aminotransferase values and reduced fatigue in patients with hepatitis C viral infection while treatment was being administered. Because this action was produced without change in viral level, the mechanism of action of this agent requires further investigation.