RESUMEN
BACKGROUND: Primary analysis of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) Trial showed long-term peginterferon therapy did not reduce complications in patients with chronic hepatitis C and advanced fibrosis or cirrhosis. AIM: To assess the effects of long-term peginterferon therapy and disease progression on health-related quality of life (HRQOL), symptoms and sexual health in HALT-C patients. METHODS: A total of 517 HALT-C patients received peginterferon alfa-2a (90 microg/week); 532 received no additional treatment for 3.5 years. Patients were followed up for outcomes of death, hepatocellular carcinoma and hepatic decompensation. Sexual health, SF-36 scores and symptoms were serially assessed by repeated-measures analyses of covariance. RESULTS: Patients with cirrhosis (n = 427) reported lower general well-being and more fatigue (P < 0.001) than patients with fibrosis (n = 622). Physical scores declined significantly over time, independent of treatment, and patients with cirrhosis reported lower scores. Vitality scores were lower in those with cirrhosis, and treated patients experienced a greater decline over time than untreated patients; HRQOL rebounded after treatment ended. Patients with a clinical outcome had significantly greater declines in all SF-36 and symptom scores. Among men, Sexual Health scores were significantly worse in treated patients and in those with a clinical outcome. CONCLUSION: Clinical progression of chronic hepatitis C and maintenance peginterferon therapy led to worsening of symptoms, HRQOL and, in men, sexual health in a large patient cohort followed up over 4 years (NCT00006164).
Asunto(s)
Antivirales/administración & dosificación , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/administración & dosificación , Cirrosis Hepática/tratamiento farmacológico , Polietilenglicoles/administración & dosificación , Calidad de Vida , Conducta Sexual/efectos de los fármacos , Adulto , Fatiga/complicaciones , Fatiga/psicología , Femenino , Hepatitis C Crónica/psicología , Hepatitis C Crónica/virología , Humanos , Interferón alfa-2 , Cirrosis Hepática/psicología , Cirrosis Hepática/virología , Masculino , Persona de Mediana Edad , Calidad de Vida/psicología , Proteínas Recombinantes , Conducta Sexual/psicología , Factores SocioeconómicosRESUMEN
Hepatic steatosis is common in hepatitis C virus (HCV)-infected patients and may be associated with the metabolic syndrome. We studied steatosis in patients treated with peginterferonalpha-2a plus ribavirin. Forty-five of 207 patients (22%) had >5% hepatic steatosis at baseline. Significantly more patients with steatosis than without were HCV genotype 3 (51%vs 14%; P < 0.0001) had higher HCV-RNA (P = 0.0045), body weight (P = 0.0176), body mass index (BMI, P = 0.0352) and serum triglycerides (TG) (P = 0.0364), hypertriglyceridaemia (P = 0.0009), elevated blood pressure/history of hypertension (P = 0.0229) and lower cholesterol (P = 0.0009). Significant steatosis predictors were genotype 3 (OR 9.04, 95% CI 3.85-21.21, P < 0.0001), HCV-RNA (OR 2.96, 1.49-5.88, P = 0.0019) and triglycerides (OR 1.06, 1.02-1.11, P = 0.0071). In genotype 3 patients, HCV-RNA was the only significant predictor (OR 11.15, 2.60-47.81, P = 0.0012). In non-genotype 3 patients, hypertriglyceridaemia was the only significant predictor (OR 1.07, 1.02-1.12, P = 0.0041). 134 of 207 patients (65%) achieved an sustained virological response (SVR) with peginterferon alpha-2a plus ribavirin, similar to the overall response rate. In genotype 3 patients with an SVR, steatosis decreased from 48% to 13% (baseline to end-point). No change was seen in the steatosis rate in non-genotype 3 patients with an SVR. This large and comprehensive analysis of a large data base from a multinational trial further adds to the observations that chronic HCV is associated with hepatic steatosis in approximately a fifth of patients. Further, features of the metabolic syndrome are associated with hepatic steatosis in most of these patients. Steatosis is significantly more common in genotype 3 compared with other genotypes, and in these patients, an SVR is associated with steatosis clearance.
Asunto(s)
Hígado Graso/etiología , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , Ribavirina/uso terapéutico , Antivirales/uso terapéutico , Ensayos Clínicos como Asunto , Combinación de Medicamentos , Genotipo , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/fisiopatología , Hepatitis C Crónica/virología , Interferón alfa-2 , Ensayos Clínicos Controlados Aleatorios como Asunto , Proteínas Recombinantes , Estudios RetrospectivosRESUMEN
Attempts to investigate changes in various forms of intrahepatic hepatitis B virus (HBV) DNA during antiviral therapy have been hampered by limitations in technologies and scarcity of adequate tissue for analysis. We used a sensitive, specific assay to detect and quantitate covalently closed circular DNA (cccDNA) from total intrahepatic HBV DNA in clinical liver specimens. Total HBV DNA and cccDNA from 21 needle-biopsy specimens were quantified, with levels ranging from 0.1 to 9.8 copies/cell and 0.3 to 491.0 copies/cell, respectively. Then, we performed the same determinations on baseline and week-52 liver needle-biopsy specimens from eight patients enrolled in a clinical trial and evaluated the association between intrahepatic HBV DNA levels and serological and virological endpoints. In most patients, levels of intrahepatic HBV DNA, including cccDNA, decreased over the 52-week study, regardless of therapy or serological outcome. Higher ratios of cccDNA to total HBV DNA were detected at week 52 than at baseline indicating a shift in predominance of nonreplicating virus in posttreatment specimens. In patients who achieved treatment-related or spontaneous hepatitis B e antigen (HBeAg) responses, including those harbouring tyrosine-methionine-aspartate-aspartate-mutant HBV, levels of intrahepatic and serum HBV DNA suppression were greater than those in patients without HBeAg responses. In conclusion, this pilot study of intrahepatic HBV replicative forms in patients with chronic hepatitis B indicated that total intrahepatic and, specifically, cccDNA levels are not static but change as a reflection of serological and virological events.
Asunto(s)
Antivirales/uso terapéutico , ADN Circular/análisis , Virus de la Hepatitis B/genética , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/virología , Interferón-alfa/uso terapéutico , Lamivudine/uso terapéutico , Alanina Transaminasa/sangre , Secuencias de Aminoácidos , Biopsia con Aguja Fina , Sondas de ADN/genética , ADN Circular/genética , ADN Viral/genética , Quimioterapia Combinada , Antígenos e de la Hepatitis B/sangre , Hepatitis B Crónica/sangre , Hepatitis B Crónica/patología , Humanos , Mutación , Proyectos Piloto , Replicación Viral/efectos de los fármacosRESUMEN
BACKGROUND: Activation of hepatic stellate cells is the earliest step in fibrogenesis. Alpha-smooth muscle actin (alpha-SMA), expressed by activated hepatic stellate cells, and C-terminal procollagen alpha1(III) propeptide (PIIICP) are early markers of fibrogenesis and should precede fibrosis. AIM: Determine if suppression of hepatitis B virus replication with lamivudine would decrease fibrogenesis as measured by immunohistochemical markers. METHODS: Paired liver biopsies from patients with hepatitis B before and after therapy with lamivudine (n=47) or placebo (n=33) were studied. alpha-SMA and PIIICP were detected in paraffin-embedded tissue by immunohistochemistry and quantified in a blinded manner by video imaging analysis. RESULTS: Liver biopsies from patients treated with lamivudine showed a significant decrease in alpha-SMA expression (1.06+/-0.23 vs. 0.58+/-0.11, pre vs. post, P<0.05). Placebo recipients had increased levels of alpha-SMA (0.82+/-0.14 vs. 1.32+/-0.21, P<0.05). PIIICP was similarly decreased after lamivudine. Among subjects whose Histologic Activity Index fibrosis score was unchanged or worsened, the mean change in alpha-SMA expression was significantly decreased in the lamivudine group compared with placebo. CONCLUSIONS: Lamivudine decreased markers of hepatic stellate cell activation and collagen synthesis. Immunohistochemical techniques are sensitive for assessing fibrogenesis and will be useful in trials of antiviral and antifibrotic agents.
Asunto(s)
Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/patología , Lamivudine/uso terapéutico , Hígado/patología , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Actinas/metabolismo , Adulto , Biopsia , Colágeno Tipo III/metabolismo , Femenino , Hepatitis B Crónica/metabolismo , Humanos , Inmunohistoquímica , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Músculo Liso/metabolismo , Procolágeno/metabolismoRESUMEN
In patients with chronic hepatitis C, 48 weeks of therapy with interferon (IFN) plus ribavirin results in a sustained virologic response of 40%. Preliminary analysis suggests that measuring HCV RNA at week 24, rather than week 12, might provide the best prediction of treatment response. To assess the clinical utility of serum HCV RNA determinations at different times during therapy as a predictor of a sustained virologic response we evaluated 912 treatment-naïve patients. Patients were randomized to receive IFN-alpha2b, 3 million units (MU) three times weekly (tiw), for 24 or 48 weeks with either ribavirin or placebo, and then followed for 24 weeks. Serum HCV RNA was measured at weeks 4 and 12 in patients treated for 24 weeks; at 4, 12, and 24 weeks during therapy in those treated for 48 weeks, and week 24 post-therapy in all patients. Sustained response was defined as loss of serum HCV RNA at week 24 follow-up. Other patients were considered virologic nonresponders. For patients receiving 48 weeks of combination therapy, detectable serum HCV RNA at week 24 predicted nonresponse (positive predictive value) in 99% of patients compared to 89% at week 12. In patients treated for 24 weeks, testing at week 12 was more predictive of nonresponse than testing at week 4 in the combination-therapy group but not in the monotherapy group. Hence, for combination therapy, testing for serum HCV RNA as a predictor of nonresponse is most accurate at week 24 of therapy; a positive test correctly identified 99% of nonresponders.
Asunto(s)
Antivirales/uso terapéutico , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Interferón-alfa/uso terapéutico , ARN Viral/sangre , Ribavirina/uso terapéutico , Alanina Transaminasa/sangre , Enfermedad Crónica , Quimioterapia Combinada , Femenino , Genotipo , Anticuerpos contra la Hepatitis C/sangre , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Factores de TiempoRESUMEN
There is currently no universally accepted numbering convention for the antiviral drug-related resistance mutations in the reverse transcriptase (rt) domain of the human hepatitis B virus (HBV) polymerase. The published inconsistencies have resulted from different HBV genotypes. A standardized numbering system for HBV polymerase is proposed. The new system is based on functional observations of HBV surface gene proteins (preS1, preS2, and HBsAg) and on the current convention used for human immunodeficiency virus type 1 (HIV-1) polymerase proteins (protease, rt, and integrase), in which the amino acid numbering restarts at the first codon position of each domain. The HBV polymerase protein can be divided into 4 domains (terminal protein, spacer, rt, ribonuclease H) and each of these can be numbered separately. In this proposal, the HBV rt domain starts with the highly conserved EDWGPCDEHG motif, contains 344 amino acids, and the lamivudine-related resistance mutations are found at amino acid rtL180M (previously amino acid 528, 526, 515, or 525) and rtM204V/I (previously 552, 550, 539, or 549). The new consensus rt domain numbering system is genotype independent and allows investigators to number any previously and newly discovered antiviral-related amino acid change in a standardized manner.
Asunto(s)
Antivirales/farmacología , Productos del Gen pol/genética , Virus de la Hepatitis B/genética , Mutación , Terminología como Asunto , Secuencia de Aminoácidos/genética , Resistencia a Medicamentos , Genoma , Genotipo , Humanos , Datos de Secuencia MolecularRESUMEN
Hepatitis B viremia and emergence of hepatitis B virus (HBV) YMDD variants with reduced susceptibility to lamivudine were analyzed in patient sera from a phase II study of extended lamivudine therapy. Within 12 weeks, all patients exhibited a marked virologic response to lamivudine: >99% reduction (median 5 log decrease) in serum HBV DNA levels. Virus remained at >104 genomes/mL in 11 patients and decreased to <104 genomes/mL in the remaining 12 patients. In 10 patients, detectable YMDD variants emerged during the course of treatment. Six patients, including 3 with YMDD variants, experienced hepatitis B e antigen seroconversion while on lamivudine therapy or soon after its discontinuation. No patients with HBV DNA levels >104 genomes/mL seroconverted. Thus, patients who respond to lamivudine therapy with dramatic reductions in viral DNA level (to <104 genomes/mL) appear more likely to seroconvert than patients who do not achieve this level of HBV clearance.
Asunto(s)
Antivirales/uso terapéutico , Variación Genética , Virus de la Hepatitis B/aislamiento & purificación , Hepatitis B Crónica/virología , Lamivudine/uso terapéutico , Viremia/virología , ADN Viral/análisis , ADN Viral/sangre , Ensayo de Inmunoadsorción Enzimática , Anticuerpos contra la Hepatitis B/sangre , Antígenos e de la Hepatitis B/sangre , Virus de la Hepatitis B/genética , Hepatitis B Crónica/tratamiento farmacológico , Humanos , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo de Longitud del Fragmento de Restricción , Inhibidores de la Transcriptasa Inversa/uso terapéuticoRESUMEN
BACKGROUND AND METHODS: Although the nucleoside analogue lamivudine has shown promise in patients with chronic hepatitis B, long-term data on patients from the United States are lacking. We randomly assigned previously untreated patients with chronic hepatitis B to receive either 100 mg of oral lamivudine or placebo daily for 52 weeks. We then followed them for an additional 16 weeks to evaluate post-treatment safety and the durability of responses. The primary end point with respect to efficacy was a reduction of at least 2 points in the score on the Histologic Activity Index. On this scale, scores can range from 0 (normal) to 22 (most severe abnormalities). RESULTS: Of the 143 randomized patients, 137 were included in the efficacy analysis: 66 in the lamivudine group and 71 in the placebo group. The other six patients were excluded at the base-line visit because of the absence of a documented history of hepatitis B surface antigen for at least six months. After 52 weeks of treatment, lamivudine recipients were more likely than placebo recipients to have a histologic response (52 percent vs. 23 percent, P<0.001), loss of hepatitis B e antigen (HBeAg) in serum (32 percent vs. 11 percent, P=0.003), sustained suppression of serum hepatitis B virus (HBV) DNA to undetectable levels (44 percent vs. 16 percent, P<0.001), and sustained normalization of serum alanine aminotransferase levels (41 percent vs. 7 percent, P<0.001), and they were less likely to have increased hepatic fibrosis (5 percent vs. 20 percent, P=0.01). Lamivudine recipients were also more likely to undergo HBeAg seroconversion, defined as the loss of HBeAg, undetectable levels of serum HBV DNA, and the appearance of antibodies against HBeAg (17 percent vs. 6 percent, P=0.04). HBeAg responses persisted in most patients for 16 weeks after the discontinuation of treatment. Lamivudine was well tolerated. Self-limited post-treatment elevations in serum alanine aminotransferase were more common in lamivudine recipients: 25 percent had serum alanine aminotransferase levels that were at least three times base-line levels, as compared with 8 percent of placebo recipients (P=0.01). The clinical condition of all patients remained stable during the study. CONCLUSIONS: In U.S. patients with previously untreated chronic hepatitis B, one year of lamivudine therapy had favorable effects on histologic, virologic, and biochemical features of the disease and was well tolerated. HBeAg responses were generally sustained after treatment.
Asunto(s)
Hepatitis B Crónica/tratamiento farmacológico , Lamivudine/uso terapéutico , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Adolescente , Adulto , Anciano , Alanina Transaminasa/sangre , ADN Viral/sangre , ADN Viral/genética , Método Doble Ciego , Femenino , Antígenos e de la Hepatitis B/sangre , Virus de la Hepatitis B/genética , Hepatitis B Crónica/sangre , Hepatitis B Crónica/patología , Hepatitis B Crónica/virología , Humanos , Lamivudine/efectos adversos , Hígado/patología , Masculino , Persona de Mediana Edad , Mutación , Estudios Prospectivos , Inhibidores de la Transcriptasa Inversa/efectos adversos , Estados UnidosRESUMEN
In patients with chronic hepatitis B, brief lamivudine therapy suppresses hepatitis B virus (HBV) DNA but results infrequently in sustained losses of virus replication posttreatment. We evaluated treatment response and its posttreatment durability during up to 18 months of lamivudine therapy (100 mg/d) in 24 patients who had hepatitis B e antigen (HBeAg) despite 1 to 3 months of prior therapy. Therapy was to be stopped after HBeAg loss or seroconversion (acquisition of antibody to HBeAg); posttreatment monitoring continued for 6 months. During therapy, which was well tolerated, HBV DNA became undetectable in all evaluable patients, accompanied by reduced alanine transaminase (ALT) activity. The cumulative 18-month confirmed loss of HBeAg during therapy was 9 of 24 (38%) and seroconversion was 5 of 24 (21%). Therapy was discontinued after HBeAg loss/seroconversion in 7 patients, and HBeAg status was maintained in all. Four of the patients with HBeAg responses lost HBsAg at least once. In 10 (43%) of 23 patients tested, we identified HBV polymerase YMDD mutations, 3 with detectable HBV DNA (2 with ALT elevations) and 7 without virological/biochemical breakthrough. In conclusion, up to 18 months of lamivudine therapy was well tolerated, suppressed HBV replication consistently, and tripled the frequency of HBeAg losses observed during brief-duration therapy; HBeAg loss/seroconversion remained durable posttreatment. The emergence of YMDD-variant HBV was relatively common but occurred typically without reappearance of detectable HBV DNA or ALT elevation. Our observations suggest that lamivudine can be stopped after confirmed HBeAg loss or seroconversion.
Asunto(s)
Hepatitis B Crónica/tratamiento farmacológico , Lamivudine/administración & dosificación , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Adulto , Alanina Transaminasa/sangre , ADN Viral/análisis , Farmacorresistencia Microbiana , Femenino , Antígenos de Superficie de la Hepatitis B/análisis , Antígenos e de la Hepatitis B/análisis , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/inmunología , Virus de la Hepatitis B/aislamiento & purificación , Hepatitis B Crónica/sangre , Hepatitis B Crónica/enzimología , Hepatitis B Crónica/virología , Humanos , Lamivudine/efectos adversos , Lamivudine/uso terapéutico , Masculino , Persona de Mediana Edad , Retratamiento , Inhibidores de la Transcriptasa Inversa/efectos adversos , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Terapia RecuperativaRESUMEN
A striking association has been demonstrated recently between mutations in amino acid residues 2209-2248 of the nonstructural protein 5a (NS5a) region of hepatitis C virus (HCV) and sustained responses to interferon in Japanese patients infected with genotype 1b. Therefore, analysis of this sequence has been suggested as a predictor of treatment response. We sought to determine whether mutations in this region predict outcome in U.S. patients infected with genotype 1b hepatitis C virus (HCV-1b). We analyzed stored pretreatment sera retrospectively from 22 patients with HCV-1b infection who had received interferon alpha-2b (IFNalpha-2b) as part of a controlled trial. Two patients were sustained responders (SR), 7 were transient responders (TR), and 13 were nonresponders (NR). We performed nested reverse transcription-polymerase chain reaction (RT-PCR) on extracted RNA using primers flanking HCV amino acids 2209-2248 and sequenced the PCR products directly. The deduced amino acid sequences were compared with the prototype HCV-J. Isolates with four or more deviations from the prototype were defined as "mutant" type, those with one to three substitutions as "intermediate" type, and those matching the prototype as "wildtype." Of the 22 HCV-1b isolates, 6 were wildtype, 11 intermediate type, and 5 mutant type. Both of the SRs were intermediate type. The 20 TRs and NRs were distributed among mutant (5), intermediate (9), and wildtype (6). Of the five patients with mutant virus, four were NR and one a TR. Variation in NS5a(2209-2248) fails to predict interferon responsiveness in this cohort of American patients infected with HCV-1b. Thus, the utility of this sequence as a predictor of interferon responsiveness appears to be specific to Japanese patients and may reflect differences between patient groups in treatment regimens, host genetic background, or alterations in the interferon signaling pathway induced by surrounding sequences within or outside NS5a. Overall, NS5a is not as integral a determinant of interferon responsiveness as previously suggested.
Asunto(s)
Hepacivirus/efectos de los fármacos , Hepatitis C/terapia , Interferones/uso terapéutico , Proteínas no Estructurales Virales/genética , Secuencia de Aminoácidos , Genotipo , Hepacivirus/genética , Hepatitis C/sangre , Humanos , Datos de Secuencia Molecular , Mutación , Pronóstico , ARN Viral/sangre , ARN Viral/efectos de los fármacos , ARN Viral/genética , Estudios Retrospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de ADN , Homología de Secuencia de AminoácidoRESUMEN
OBJECTIVE: Hepatitis C virus (HCV) is a well recognized cause of hepatocellular carcinoma (HCC). The pathogenic significance of HCV genotypes in hepatocarcinogenesis is undefined. The aim of this study was to investigate the genotypic distribution and viremic level of HCV in patients with HCV-associated cirrhosis with or without HCC. METHODS: A total of 28 HCV-infected patients with HCC (HCC+) and 38 patients with HCV-associated cirrhosis without HCC (HCC-) were studied. HCV genotype was assessed by the genotype-specific polymerase chain reaction (PCR) method of Okamoto and restriction fragment length polymorphism (RFLP) of the 5' untranslated region (5' UTR). Hepatitis C viremia was quantitated with the branched-chain DNA (bDNA) assay. RESULTS: Using the Okamoto method, we found genotype 1b in 64% of the HCC+ group and 74% of the HCC- group, 36% of the HCC+ group and 16% of the HCC- group were coinfected with a combination of genotype 1b and another genotype. Using the RFLP method, we found genotype 1b in 41% of the HCC+ group and in 24% of the HCC- group. Other genotypes accounted for 18% of the HCC+ group and 55% of the HCC- group; no combination genotypes were identified. Poor concordance occurred between the two genotyping methods. Mean bDNA levels were not significantly different between the two groups. CONCLUSIONS: Our study demonstrates that no particular HCV genotypes were associated with HCC and genotype did not appear to influence the development of HCV-associated HCC.
Asunto(s)
Carcinoma Hepatocelular/virología , Hepacivirus/genética , Hepatitis C/complicaciones , Neoplasias Hepáticas/virología , Viremia/complicaciones , Femenino , Flaviviridae , Genotipo , Hepatitis Viral Humana/complicaciones , Humanos , Cirrosis Hepática/virología , Masculino , Persona de Mediana Edad , ARN Viral/análisis , Estados UnidosRESUMEN
Fibrosing cholestatic hepatitis (FCH) has recently been described after solid organ transplantation in patients with hepatitis C virus (HCV) infection. Typically, FCH is characterized by an ominous clinical course leading to progressive hepatic failure and death if liver transplantation is not performed. Two HCV-infected patients underwent cadaveric renal transplantation for end-stage renal disease resulting from membranous nephropathy and diabetic nephropathy. The time intervals between transplantation and the biopsy diagnosis of FCH for the two patients were 7 months and 10 years. Both patients presented with jaundice, hyperbilirubinemia, and mild-to-moderate elevations in serum aspartate aminotransferase. One patient was also found to have type II mixed cryoglobulinemia. Interferon-alpha therapy was begun after a diagnosis of FCH was established by liver biopsy. Liver test abnormalities normalized rapidly. When cholestatic hepatic deterioration develops in an HCV-infected organ allograft recipient, the diagnosis of FCH should be considered and a liver biopsy performed. Our observations indicate that FCH can respond to antiviral therapy.
Asunto(s)
Colestasis Intrahepática/etiología , Hepatitis C/complicaciones , Trasplante de Riñón/efectos adversos , Cirrosis Hepática/etiología , Anciano , Antivirales/uso terapéutico , Colestasis Intrahepática/tratamiento farmacológico , Colestasis Intrahepática/virología , Hepacivirus/inmunología , Hepatitis C/tratamiento farmacológico , Anticuerpos contra la Hepatitis C/sangre , Humanos , Interferón-alfa/uso terapéutico , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/virología , Masculino , Persona de Mediana EdadRESUMEN
Such nonpercutaneous routes of hepatitis C virus (HCV) transmission as sexual and perinatal spread are relatively inefficient. Several observations have been cited to support a role for sexual transmission of hepatitis C. Approximately 10% of persons with reported cases of acute hepatitis C in the United States report a history of potential sexual exposure. Anecdotal cases of sexual transmission have been reported, and HCV nucleotide sequence homology has been observed in viral isolates from sexual partners. Similarly, the prevalence of HCV infection is increased in groups with a high risk of exposure to sexually transmitted viral infections. Other observations, however, weigh against sexual transmission of HCV infection. Sexual transmission is negligible in sex-partner studies; alternative risk factors account for many cases of apparent sexual transmission between sexual partners; the prevalence of HCV infection in high-risk groups is much lower than that of other sexually transmitted infections; and the risk of apparently sexually transmitted HCV infection does not always correlate with intensity and duration of sexual exposure. The United States Public Health Service has estimated that the risk of sexual transmission is approximately 5%, well below the risk of sexual transmission of hepatitis B or human immunodeficiency virus (HIV). Similarly, perinatal HCV infection, though documented to occur, is unusual, except in babies born to mothers with very high levels of HCV RNA, including mothers with concomitant HIV infection. Weighing many, often conflicting reports, the United States Public Health Service has estimated that the likelihood of perinatal infection is low, on the order of 5% to 6%, and that breast feeding does not increase the risk of HCV infection in infants of mothers with hepatitis C. Current data do not support household exposure as a risk for HCV infection.
Asunto(s)
Hepatitis C/transmisión , Intercambio Materno-Fetal , Enfermedades de Transmisión Sexual , Salud de la Familia , Femenino , Humanos , EmbarazoAsunto(s)
Hepatitis C/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Adolescente , Adulto , Alanina Transaminasa/análisis , Alanina Transaminasa/metabolismo , Enfermedad Crónica , Consensus Development Conferences, NIH as Topic , Relación Dosis-Respuesta a Droga , Hepacivirus/genética , Hepatitis C/epidemiología , Hepatitis C/metabolismo , Humanos , Persona de Mediana Edad , ARN Viral/análisis , ARN Viral/genética , ARN Viral/metabolismo , Estados Unidos/epidemiologíaRESUMEN
To evaluate response rates to 3, 5, or 10 million units (MU) of interferon alfa-2b, given thrice weekly, and to determine whether higher doses of interferon increase the likelihood or durability of the response, a multicenter, randomized trial was performed at nine academic medical centers in the United States. Two hundred forty eight patients with chronic hepatitis C were randomized to receive 3, 5, or 10 MU of interferon alfa-2b thrice weekly for 12 weeks. Based on the alanine aminotransferase (ALT) response at treatment-week 12, the patients were rerandomized to additional therapy at the same or at increased doses for an additional 12 to 36 weeks; in the case of no response to the highest dose, the patients were discontinued from the study. Serum ALT concentrations and liver histology were measured. The overall complete response rates to 3, 5, or 10 MU were not different at treatment-week 12 (31% vs. 42% vs. 40%, not significant). The majority of week-12 responders continued to respond during additional treatment. When the treatment was discontinued, 15.4% to 19.0% of patients maintained their response. Of the nonresponders to 3 MU at week 12, who were continued on 3 MU for an additional 12 weeks, none responded. However, response to additional therapy occurred in 12% of week-12 nonresponders, whose dose was escalated from 3 or 5 MU to 10 MU. The only baseline features associated with the treatment response were the absence of fibrosis or cirrhosis on the pretreatment liver biopsy and viral genotype. We conclude that the initial response to interferon in patients with chronic hepatitis C is not increased by treatment with higher doses of the drug. Patients who do not respond to 3 MU by treatment-week 12 will not respond with continued therapy at that dose; however, a proportion of patients who do not respond to 12 weeks of treatment with 3 or 5 MU may respond to higher doses. Although the long-term sustained response rates are marginally increased with interferon doses above 3 MU three times per week, the side effects are difficult to tolerate. The analysis of baseline factors in relation to response identified no single baseline factor associated with a low-enough response rate to warrant withholding interferon therapy from patients with chronic hepatitis C.