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PubMed2000

Hepatitis C virus infection: immune responsiveness and interferon-alpha treatment.

Hepatitis C virus (HCV) is responsible for most cases of posttransfusion hepatitis and sporadic or community-acquired non-A, non-B hepatitis. Different generations of enzyme-linked immunosorbent assay have been generated for detecting antibodies to HCV epitopes. HCV-RNA quantitative analysis has been developed by means of polymerase chain reaction technique. This approach is the only reliable method for HCV-RNA tissue localization, being helpful in early diagnosis. HCV infected liver is characterized by an inflammatory infiltrate including CD4+, CD8+, and B lymphocytes. Evidence has been provided that in HCV patients CD8+ cell response is associated with low level of viraemia and higher level of disease activity. CD4+ T cells exhibit specificity for the core antigen, also correlating with disease activity and viraemia. Costimulatory molecules, cytokines, oxygen radicals, the complex Fas/Fas-ligand and soluble class I HLA structures are discussed as putative cofactors involved in disease evolution. Various forms of interferon (IFN)-alpha have been evaluated for the treatment of patients with HCV infection. Initial enthusiasm has been attenuated by the evidence of a low sustained virological response rate and the constant side effects of IFN-alpha therapy in patients with chronic HCV disease. Among possible markers for predicting therapeutic outcome in HCV-positive individuals, anti-core antibodies correlate positively with response to IFN-alpha administration, as well as reduction of interleukin-2 serum levels has been detected in patients with a good therapeutic response. Association between HCV infection and autoimmune phenomena, also in relation to IFN-alpha therapy has been reported. Finally, results of the combined treatment with IFN-alpha/ribavirin are illustrated.

Arachidonic Acid↗
PubMed2000

Genetic diversity and epidemiology of infectious hematopoietic necrosis virus in Alaska.

Forty-two infectious hematopoietic necrosis virus (IHNV) isolates from Alaska were analyzed using the ribonuclease protection assay (RPA) and nucleotide sequencing. RPA analyses, utilizing 4 probes, N5, N3 (N gene), GF (G gene), and NV (NV gene), determined that the haplotypes of all 3 genes demonstrated a consistent spatial pattern. Virus isolates belonging to the most common haplotype groups were distributed throughout Alaska, whereas isolates in small haplotype groups were obtained from only 1 site (hatchery, lake, etc.). The temporal pattern of the GF haplotypes suggested a 'genetic acclimation' of the G gene, possibly due to positive selection on the glycoprotein. A pairwise comparison of the sequence data determined that the maximum nucleotide diversity of the isolates was 2.75% (10 mismatches) for the NV gene, and 1.99% (6 mismatches) for a 301 base pair region of the G gene, indicating that the genetic diversity of IHNV within Alaska is notably lower than in the more southern portions of the IHNV North American range. Phylogenetic analysis of representative Alaskan sequences and sequences of 12 previously characterized IHNV strains from Washington, Oregon, Idaho, California (USA) and British Columbia (Canada) distinguished the isolates into clusters that correlated with geographic origin and indicated that the Alaskan and British Columbia isolates may have a common viral ancestral lineage. Comparisons of multiple isolates from the same site provided epidemiological insights into viral transmission patterns and indicated that viral evolution, viral introduction, and genetic stasis were the mechanisms involved with IHN virus population dynamics in Alaska. The examples of genetic stasis and the overall low sequence heterogeneity of the Alaskan isolates suggested that they are evolutionarily constrained. This study establishes a baseline of genetic fingerprint patterns and sequence groups representing the genetic diversity of Alaskan IHNV isolates. This information could be used to determine the source of an IHN outbreak and to facilitate decisions in fisheries management of Alaskan salmonid stocks.

Alaska↗
PubMed1990

Molecular analysis of the ets genes and their products.

Organisms from human to Drosophila have been found to contain cellular sequences and transcripts that are homologous to the ets region of the avian retrovirus, E26. Ets-related sequences are present on at least two distinct functional loci in chickens and mammals, and have been designated ets-1 and ets-2. The E26 virus transduced sequences from the chicken ets-1 locus, which encompasses over 60 kb of DNA. The ets genes characterized so far from sea urchin and Drosophila are most closely related to the 3' end of the known ets genes. The predicted viral and avian ets proteins are very similar, except at the termini. The similarity between the predicted ets proteins so far described is discussed. The ets proteins have been identified and localized by immunoprecipitation and immunofluorescence. While the ets-1 proteins are found in the nuclear and cytoplasmic fractions, the viral gag-myb-ets protein (p135) and the ets-2 proteins are nuclear. The ets-1 and ets-2 genes are differentially regulated in different cell types, probably reflecting unique controlling elements. Because chromosomal translocations have been associated with different human leukemias, studies addressing the possible association with the ETS1 (11q23) or ETS2 (21q22.3) loci are reviewed.

Alzheimer Disease↗
PubMed2003

Phylogenetic relationships between Puerto Rico and continental USA HIV-1 pol sequences: a shared HIV-1 infection.

In order to investigate the existing notion that the human immunodeficiency virus type 1 (HIV-1) infection in Puerto Rico (PR) was imported from the continental United States of America (USA) we sequenced and analyzed 900 bases of the HIV-1 pol sequence from individuals in PR for comparison with pol sequences from the USA mainland. The sequences were derived by direct sequencing of reverse transcription-polymerase chain reaction products generated from plasma virus. The products were sequenced in both directions and the complementary strands were compared prior to analysis. These processed sequences and GenBank sequences from the continental USA were subjected to phylogenetic analyses. The PR and USA sequences did not form independent clusters, indicating a shared HIV-1 infection. This may be due to the continuous human traffic or, less likely, may indicate a similar evolution of a common source virus. Analysis of drug resistance mutations, fairly similar in frequency in the PR and USA sequences analyzed here, supports human traffic as a rationale for the common infection. This work indicates that an efficacious vaccine developed for use in the USA mainland will also be effective in prevention in PR and perhaps the other countries of the Caribbean region.

Drug Resistance, Viral↗
PubMed1986

Genetic relatedness of Palyam serogroup viruses by RNA-RNA blot hybridization.

Cognate genes of members of the Palyam serogroup of orbiviruses have been identified previously, and their relatedness to the prototype virus was determined by blot hybridization of the genome segments of members of the serogroup using Palyam genomic RNA and isolated Palyam RNA segments as probes. In this study, the genetic relatedness of nine Palyam serogroup isolates was determined by reciprocal blot hybridizations of genomic RNA from each virus to the segments of all members of the group. The number and identity of highly related genes varied between isolates. For example. CSIRO Village and Palyam were related in genes 2 and 6, while Bunyip Creek and Vellore were related in genes 2 and 6. However, CSIRO Village and Bunyip Creek were highly related to D'Aguilar in all genes except 2 and 6, suggesting that there may have been genetic reassortment of Palyam serogroup dsRNA segments. Genes 2 and 6 were correlated consistently with serotype specificity. Genes 5, 7 and 9 were highly related among all members of the group. The Indian strains, Palyam and Vellore, were highly related in genes 1, 3 and 8, and they exhibited weak homology to genes 1, 3 and 8 of the Australian and African strains. However, one Indian isolate, Kasba, was more closely related to strains from Africa and Australia than it was to other Indian strains. There was little evidence which indicated that geography was predictive of the genetic relationships of the strains. Thus, immunological pressure may be the most important factor affecting the Palyam serogroup gene pool.

Australia↗
PubMed1998

Resected RNA pseudoknots and their recognition by histidyl-tRNA synthetase.

Duplexes constituted by closed or open RNA circles paired to single-stranded oligonucleotides terminating with 3'-CCAOH form resected pseudoknots that are substrates of yeast histidyl-tRNA synthetase. Design of this RNA fold is linked to the mimicry of the pseudoknotted amino acid accepting branch of the tRNA-like domain from brome mosaic virus, known to be charged by tyrosyl-tRNA synthetases, with RNA minihelices recapitulating accepting branches of canonical tRNAs. Prediction of the histidylation function of the new family of minimalist tRNA-like structures relates to the geometry of resected pseudoknots that allows proper presentation to histidyl-tRNA synthetase of analogues of the histidine identity determinants N-1 and N73 present in tRNAs. This geometry is such that the analogue of the major N-1 histidine determinant in the RNA circles faces the analogue of the discriminator N73 nucleotide in the accepting oligonucleotides. The combination of identity elements found in tRNAHis species from archaea, eubacteria, and organelles (G-1/C73) is the most efficient for determining histidylation of the duplexes. The inverse combination (C-1/G73) leads to the worst histidine acceptors with charging efficiencies reduced by 2-3 orders of magnitude. Altogether, these findings open new perspectives for understanding evolution of tRNA identity and serendipitous RNA functions.

Evolution, Molecular↗
PubMed1996

Roles of the sequence encoding tobacco etch virus capsid protein in genome amplification: requirements for the translation process and a cis-active element.

The roles of the capsid protein (CP) and the CP coding sequence of tobacco etch potyvirus (TEV) in genome amplification were analyzed. A series of frameshift-stop codon mutations that interrupted translation of the CP coding sequence at various positions were introduced into the TEV genome. A series of 3' deletion mutants that lacked the CP coding sequence beyond each of the frameshift-stop codon mutations were also produced. In addition, a series of 5' CP deletion mutants were generated. Amplification of genomes containing either frameshift-stop codon insertions after codons 1, 59, 103, and 138 or genomes containing the corresponding 3' deletions of the CP coding sequence was reduced by 100- to 1,000-fold relative to that of the parental genome in inoculated protoplasts. In contrast, a mutant containing a frameshift-stop codon after CP position 189 was amplified to 27% of the level of the parental virus, but the corresponding 3' deletion mutant lacking codons 190 to 261 was nonviable. Deletion mutants lacking CP codons 2 to 100, 2 to 150, 2 to 189, and 2 to 210 were amplified relatively efficiently in protoplasts, but a deletion mutant lacking codons 2 to 230 was nonviable. None of the amplification-defective frameshift-stop codon or deletion mutants was rescued in transgenic cells expressing TEV CP, although the transgenic CP was able to rescue intercellular movement defects of replication-competent CP mutants. Coupled with previous results, these data led to the conclusions that (i) TEV genome amplification requires translation to a position between CP codons 138 and 189 but does not require the CP product and (ii) the TEV CP coding sequence contains a cis-active RNA element between codons 211 and 246. The implications of these findings on mechanisms of RNA replication and genome evolution are discussed.

Capsid↗
PubMed1999

In vivo selection of RNA-binding peptides from combinatorial libraries.

We have used a two step procedure to identify peptides that bind strongly to the Rev-response element (RRE) of HIV. In the first step, RRE-binding peptides were screened from a combinatorial peptide library generated by "randomization" using a small subset of the 20 amino acids. In the second step, one such RRE-binding peptide, RSG-1, was "evolved" into an even stronger RRE-binding peptide using a codon-based mutagenesis procedure. After 2 rounds of evolution, RSG-1.2 bound the RRE with 7-fold higher affinity than wild-type Rev peptide.

Amino Acid Sequence↗
PubMed2005

The ASCH superfamily: novel domains with a fold related to the PUA domain and a potential role in RNA metabolism.

Several studies show that transcription coactivators are often bi-functional ribonucleoprotein complexes that also regulate pre-mRNA processing and splicing decisions. Using sensitive sequence profile searches and structural comparisons we show that the C-terminal domain of the human coactivator protein ASC-1 defines a novel superfamily, the ASC-1 homology (ASCH) domain. The approximately 110 amino acid long ASCH domains are widely represented in all the three superkingdoms of life and several prokaryotic viruses. We show that the ASCH superfamily adopts a beta-barrel fold similar to the PUA domain superfamily. Using multiple lines of evidence, we suggest that members of the ASCH superfamily are likely to function as RNA-binding domains in contexts related to coactivation, RNA-processing and possibly prokaryotic translation regulation. Structural analysis of ASCH domains reveals the presence of a potential RNA-binding cleft associated with a conserved sequence motif, which is characteristic of this superfamily. Despite their similar structure, the ASCH and PUA domains appear to occupy distinct functional niches, with the former domains typically occurring in a standalone form in polypeptides, and the latter domains showing fusions to a variety of RNA-modifying enzymes.

Animals↗
PubMed2002

Kinetics of hepatitis C (HCV) viraemia and quasispecies during treatment of HCV associated cryoglobulinaemia with pulse cyclophosphamide.

OBJECTIVE: To investigate the effect of pulse cyclophosphamide treatment on hepatitis C virus (HCV) kinetics and quasispecies in interferon alpha (IFNalpha) resistant HCV related cryoglobulinaemic vasculitis. METHODS: Reports on two patients with severe manifestations of HCV related cryoglobulinaemia who failed to respond to interferon alpha are given. Both patients were treated with pulse cyclophosphamide (750-1000 mg/month for six and 11 months, respectively). HCV RNA was quantified and HCV quasispecies determined in cryoprecipitates and supernatants before and during treatment. RESULTS: Cryocrit and complement activation decreased in both patients with rebound of cryocrit in one case during continuing pulse cyclophosphamide treatment. Vasculitic symptoms improved. Alanine aminotransferase (ALT) levels and HCV viral load (0.2-0.4 log) increased slightly and reached pretreatment levels after cyclophosphamide was stopped. A highly heterogeneous quasispecies was found in the cryoprecipitate and supernatant of one patient, whereas the viral population was homogeneous in the other patient. After six cycles of cyclophosphamide, viral distances decreased non-significantly. However, phylogenetic analysis showed the evolution of distinct viral strains in one patient and replacement of the main viral population by another population in the second patient. CONCLUSIONS: Immunosuppressive treatment with pulse cyclophosphamide has a temporary limited effect on HCV associated cryoglobulinaemia and leads to a reversible increase of ALT levels and HCV viral load. Short term immunosuppression does not affect the viral heterogeneity as measured by amino acid and nucleotide distances in the hypervariable region 1 of HCV. A change of quasispecies was observed, but further studies are needed to evaluate if this does affect the outcome of IFNalpha treatment in such patients.

Aged↗
PubMed1978

RNA-tumour-virus genes and transforming genes: patterns of transmission.

RNA tumour virus genes are contained in the chromosomal DNA of most vertebrates, and may be transmitted vertically from parent to progeny along with other cellular genes, as well as horizontally as infectious particles. Activation of these viral genes may be part of the means by which RNA tumour viruses produce cancer. Viral genes and their possible gene products have been characterized. The envelope glycoprotein, for example, interacts with specific membrane receptors on cell surfaces and the major phosphoprotein binds to specific viral RNA sequences. Type-C viral gene sequences have evolved as the species have evolved, and have been transferred between distantly related species under natural conditions. The presence of genetically transmitted viral genes in several vertebrate species, including primates, and the evidence that they may provide normal functions beneficial to the species carrying them, suggests that the potential to cause cancer is a pathological manifestation of a normal physiological process.

Animals↗
PubMed1981

5'-terminal nucleotide noncoding sequences of retroviruses: relatedness of two old world primate type C viruses and avian spleen necrosis virus.

Computer-assisted comparison of the 5'-terminal regions of mammalian type C viruses serves as a useful model of evolutionary divergence of noncoding nucleic acid sequences. It has led to the concept that regions of conserved nucleic acid sequences, the slowly divergent sequences, contain signals of translational, transcriptional, or integrative significance. Interspersed among the conserved regions are rapidly divergent sequences in which base changes, insertions, and deletions are especially prevalent. In the present study, CPC-1, a type C virus isolated from Colobus polykomos, was shown to be related to another Old World type C monkey virus, endogenous stump-tailed monkey virus, MAC-1, by analysis of their 5'-terminal nucleotide sequences. The 5'-terminal regions of CPC-1 and MAC-1 showed a 76% nucleotide correspondence and were of similar lengths, 132 and 127 nucleotides, respectively. Previous strong-stop analyses of other type C viruses have defined two subgroups: (i) Rauscher murine leukemia virus and gibbon ape leukemia virus and (ii) baboon endogenous virus and endogenous cat virus RD114. Based on the present sequence analysis of their 5'-terminal sequences, CPC-1 and MAC-1 formed a third subgroup. Computer-assisted comparison of the 5'-terminal sequences of CPC-1 and MAC-1 to the previously reported sequence of avian spleen necrosis virus (SNV) (Shimotohno et al., Nature [London] 285:550-554, 1980) showed SNV to be a member of that subgroup of mammalian type C viruses. Consistent with the inclusion of SNV in this subgroup of mammalian type C viruses, SNV was distantly related to other mammalian type C viruses. Interestingly, the SNV 5'-terminal sequences showed no significant evolutionary relationship by these criteria to the avian leukemia and sarcoma viruses. CPC-1, MAC-1, and SNV contained conserved regulatory signals in similar positions in their 5'-terminal RNA sequences analogous to those observed in other mammalian type C retroviruses. These sequences included the canonical AAUAAA sequence, a palindrome, a putative ribosome binding site, and an integration site. Some of these highly conserved subsequences were common to 3'- and 5'-terminal noncoding sequences of nonviral eucaryotic mRNA's (Efstratiadis et al., Cell 21:653-668, 1980). Thus, analysis and comparison of 5'-terminal nucleotide sequences have been useful in defining common functional signals and in extending the matrix of relationships among retroviruses.

Base Sequence↗
PubMed1988

A mammalian viral enhancer confers transcriptional regulation in yeast.

Transcriptional enhancers are DNA sequences that regulate RNA transcription from linked promoters by binding to cellular proteins (trans-activators). In the mammalian virus SV40, initiation of transcription is controlled, in part, by a strong 72-base pair enhancer. We show that yeast cells contain a factor that binds specifically to a key DNA motif in the SV40 enhancer, the P element that is essential for viral transcription in mammalian cells. The P element shows sequence similarity to a yeast DNA transcriptional regulatory element, GCN4, that controls transcription of genes that code for amino acid biosynthetic enzymes. Insertion of the SV40 enhancer or single or multiple copies of the P element itself upstream from the cytochrome Cyc-1 promoter places the hybrid viral-yeast transcription unit under metabolic control in yeast cells. These studies suggest that the SV40 P element and its complementary trans-activator represent a conserved transcriptional control mechanism that operates on widely divergent functions in evolution.

Base Sequence↗
PubMedDate not supplied

Hepatitis C virus: kinetics and quasispecies evolution during anti-viral therapy.

The balance of virus production and clearance for untreated patients with chronic hepatitis C changes into a decline of viraemia when initiating effective anti-viral treatment. During the first phase of interferon-alpha (IFN-a) therapy, the kinetics of the viral load is characterised by a rapid dose-dependent decline starting after a delay of about eight to nine hours. This early response can be observed for almost all patients treated with IFN-a. After about 24 to 48 hours, the viral decline slows down leading to a second phase with a relatively stable exponential decay. Some non-responding patients show a nearly constant viraemia and some even a rebound throughout this second phase. Kinetic models allow the estimation of rates of viral production and clearance and reveal high turnover rates of hepatitis C virus (HCV) and an in vivo half-life of hepatitis C virions of a few hours, only. Due to the continuous and high replication rate in vivo, the low fidelity of the ribonucleic acid (RNA)-dependent RNA polymerase, and the immune surveillance of the host, HCV exists in an individual patient as a heterogeneous population of related viruses (quasispecies). A high degree of quasispecies variability correlates with a lower response to IFN-a therapy. Changes of the quasispecies population are more pronounced after initiation of treatment with IFN-a or interleukin-12 than during the natural course of disease. Ribavirin, however, has not been found to affect the HCV quasispecies population. Identification of a specific region within an envelope-encoding gene as the most variable region of HCV and as a critical neutralisation domain suggests that viral escape mechanisms are a possible cause for chronification and poses a major challenge for the development of a broadly reactive vaccine against HCV.

Adjuvants, Immunologic↗
PubMed2002

Evolution of antiretroviral phenotypic and genotypic drug resistance in antiretroviral-naive HIV-1-infected children treated with abacavir/lamivudine, zidovudine/lamivudine or abacavir/zidovudine, with or without nelfinavir (the PENTA 5 trial).

PURPOSE AND METHODS: To describe the evolution of resistance to zidovudine (ZDV), lamivudine (3TC), abacavir (ABC) and nelfinavir (NFV), 113 previously untreated children in the PENTA 5 trial had resistance assayed at baseline, rebound and/or 24, 48, 72 weeks (VIRCO: phenotyping and genotyping with 'Virtual Phenotype' interpretation). RESULTS: At baseline, few reverse transcriptase mutations and no primary protease inhibitor mutations were observed. Time to detectable HIV-1 RNA with reduced phenotypic susceptibility to any drug was shortest in the ZDV+3TC arm (overall logrank P=0.02). Through a median follow-up of 55 weeks, at their last assessment 11 (28%), 16 (40%) and 13 (32%) children with detectable HIV-1 RNA and a resistance test available had mutations conferring resistance to none, one, or two or more trial drugs, respectively, according to the virtual phenotype. Reduced phenotypic susceptibility to ABC only occurred in the 3TC+ABC arm and required K65R and/or L74V in addition to M184V. NFV-resistant virus was selected slowly through D30N or L90M pathways, and selection of ZDV-resistant virus was rare. CONCLUSIONS: Selection of 3TC-resistant virus was most frequent, followed by NFV and/or ABC; selection of ZDV-resistant virus was rare. Importantly, although in vitro, ABC selects for M184V as the first mutation, ABC did not select for M184V when combined with ZDV without 3TC. The most sustained HIV-1 RNA response was in the 3TC+ABC arm, but mutations conferring reduced susceptibility to 3TC and/or ABC evolved more frequently if virological failure occurred with 3TC+ABC than with ZDV+ABC.

Acquired Immunodeficiency Syndrome↗
PubMed1978

Human foamy virus: further characterization, seroepidemiology, and relationship to chimpanzee foamy viruses.

A foamy virus present in human nasopharyngeal carcinoma tissue was studied for a number of biological properties, including range of cellular susceptibility, growth curve, evolution of cytopathic effect in relation to cellular fusion and intracellular viral distribution, reverse transcriptase activity, and buoyant density. The virus was also studied immunologically and found to be closely related to the chimpanzee foamy viruses, particularly simian foamy virus type 6, with which it shares common antigens in complement-fixing, fluorescent, and neutralizing antibody tests. In view of this close immunological relationship and the failure to find antibody to the human isolate in sera from more than 250 humans, including 50 patients with nasopharyngeal carcinoma and Burkitt's lymphoma, it is suggested that the isolate is not a human representative of the foamy virus group but rather a variant strain of chimpanzee foamy virus.

Animals↗
PubMed2005

Australian bat lyssavirus: a recently discovered new rhabdovirus.

Australian bat lyssavirus (ABLV), first identified in 1996, has been associated with two human fatalities. ABLV is genetically and serologically distinct from, but is closely related to, classical rabies. It has a bullet-shaped morphology by electron microscopy. There are two strains of ABLV known: one circulates in frugivorous bats, sub-order Megachiroptera, and the other circulates in the smaller, mainly insectivorous bats, sub-order Microchiroptera. Each strain has been associated with one human fatality. Surveillance indicates infected bats are widespread at a low frequency on the Australian mainland. It is unclear how long ABLV has been present in Australia, although molecular clock studies suggest the two strains separated 950 or 1,700 years ago based on synonymous or non-synonymous nucleotide changes, respectively. Recent serological surveys suggest a closely related virus may exist in the Philippines. Due to demonstrated cross-protection in mice, rabies vaccine is used to prevent infection. Rabies post-exposure prophylaxis (PEP) protocols have been adopted for when a human is scratched or bitten by a suspect bat. A long-term commitment to public health programs that test bats that have been involved in scratch or bite incidents, followed by PEP if appropriate, will be necessary to minimise further human infection.

Animals↗
PubMed2002

Interferon-alpha and ribavirin treatment in patients with hepatitis C virus-related systemic vasculitis.

OBJECTIVE: Hepatitis C virus (HCV)-related vasculitis may involve multiple organs, including the skin, kidneys, and nervous system, and may be life-threatening. Although HCV is increasingly recognized as a cause of systemic vasculitis, limited data are available regarding the optimal treatment of this potentially serious condition. Therefore, we retrospectively analyzed the response to treatment in patients with chronic hepatitis C complicated by systemic vasculitis who had received antiviral therapy with interferon-alpha (IFNalpha) and ribavirin. METHODS: This retrospective study included 27 patients with systemic vasculitis and chronic HCV infection. Each patient had received treatment with IFNalpha and ribavirin for at least 6 months. The response to antiviral treatment was analyzed by comparing clinical, immunologic, and virologic data at the time of entry and during followup. Clinical response was defined according to the evolution of weight, arthralgia, nervous system, renal system, and cutaneous involvement. The virologic and immunologic responses were defined by the absence of HCV RNA and the absence of cryoglobulinemia, respectively, both 6 months after stopping antiviral therapy and at the end of followup. RESULTS: Patients received IFNalpha for a mean +/- SD of 20 +/- 14 months and ribavirin (at a mean +/- SD dosage of 895 +/- 250 mg/day) for 14 +/- 12 months. Other treatments included low-dose corticosteroids and plasma exchange. After a mean +/- SD followup of 57 +/- 29 months, 25 of 27 patients are alive and are being followed up as outpatients. Because of the heterogeneity of anti-HCV treatments received, the main results were stratified according to patients with 6 months of followup after stopping antiviral treatment (group 1, n = 14) and those who were still undergoing antiviral therapy at the time of analysis (group 2, n = 13). Nine patients in group 1 had a sustained virologic response and were clinical and immunologic complete responders. Four patients in group 1 were virologic nonresponders, and 3 of these patients had partial clinical and immunologic responses. Overall, 10 patients in group 1 had a complete clinical and immunologic response of their vasculitis (all 9 of the sustained virologic responders and 1 of the 5 patients who remained viremic). At the end of followup, 7 patients in group 2 were negative for HCV RNA; 6 were complete clinical responders. Among the other 6 patients in group 2, who had persistent viremia, 4 had a partial clinical response. Among the patients in group 1, HCV RNA was more often undetectable and genotype 1 was less frequent in complete clinical responders compared with partial/nonresponders. Age, sex, clinical vasculitic involvement, mean duration or total cumulative dose of IFNalpha or ribavirin, and use of steroids or plasmapheresis did not differ significantly according to clinical response. CONCLUSION: Treatment with IFNalpha and ribavirin can achieve a complete clinical response in most patients with HCV-related systemic vasculitis. Complete clinical response correlates with the eradication of HCV.

Adult↗