Occurrence of group A rotavirus mixed P genotypes infections in children living in Goiânia-Goiás, Brazil.

Group A rotaviruses (RVA) are the main causing agents of acute gastroenteritis worldwide, having a great impact on childhood mortality in developing countries. The objective of this study was to identify RVA-positive fecal samples with mixed P genotypes by hemi-nested reverse transcriptase-polymerase chain reaction (RT-PCR), followed by sequencing confirmation. Our results showed that, from the 81 RVA-positive samples, 25 were positive for more than one P genotype by hemi-nested RT-PCR. Of these 25 samples, 12 (48%) had their mixed P genotypes confirmed by sequencing and, from these, 10 were identified as P[6]P[8], one as P[4]P[6], and one as P[4]P[6]P[8]. Our results confirm the occurrence of RVA mixed infections among children in Brazil and reinforce the importance of the constant monitoring of RVA circulating strains for the efficacy of control/prevention against these agents.

Lamivudine treatment can overcome cytotoxic T-cell hyporesponsiveness in chronic hepatitis B: new perspectives for immune therapy.

The hepatitis B virus (HBV) cytotoxic T lymphocyte (CTL) response in patients with chronic HBV infection is generally weak or totally undetectable. This inability to mount protective CTL responses is believed to be a crucial determinant of viral persistence, and its correction represents an important objective of immune therapies for chronic hepatitis B. However, amplification of CTL responses in vivo may be ineffective if HBV-specific CD8 cells are either absent or nonresponsive to exogenous stimulation. In this study, we asked whether antiviral treatments able to inhibit viral replication and to reduce viral and antigen load can successfully reconstitute CTL responses creating the appropriate conditions for their therapeutic stimulation. For this purpose, the HBV-specific CTL response before and during lamivudine therapy was studied longitudinally in 6 HLA-A2-positive patients with HBeAg+ chronic hepatitis B. Both HBV-specific cytotoxic T cell activity measured by chromium release assay on peptide stimulation in vitro and CD8+ T cell frequency measured ex vivo by HLA-A2/peptide tetramer staining were significantly augmented by lamivudine therapy. This enhancement followed the reconstitution of CD4 reactivity and the decline of viral load induced by therapy. Our study shows that lamivudine treatment in chronic hepatitis B can restore CTL reactivity, making CTL susceptible to exogenous stimulation. This effect may enhance the probability that T cell-based immune therapies delivered after lamivudine treatment can successfully reconstitute a protective CTL response able to cure chronic HBV infection.

Conserved hepatitis C virus sequences are highly immunogenic for CD4(+) T cells: implications for vaccine development.

The HLA class II-restricted T-cell response to hepatitis C virus (HCV) antigens is believed to influence the final outcome of hepatitis C, because it is vigorous in patients who recover from acute hepatitis C, but it is weak in those who develop a chronic infection. For this reason, exogenous stimulation of T-cell responses in chronic HCV infection may represent a strategy to cure patients with chronic hepatitis C by approximating the vigor of their T-cell reactivity to that of patients who succeed in recovering from hepatitis. It may also be a preventive approach to avoid spread of the virus by facilitating the development of a vigorous protective response at the very early stages of infection. T-cell-based vaccines composed of immunodominant, promiscuous, and conserved T-cell epitopes may represent a powerful tool to achieve optimal stimulation of the T-cell reactivity. To identify HLA class II-restricted T-cell epitopes useful for this purpose, 22 subjects with acute HCV infection were studied and followed for an average time of 29 months. Eight of them recovered from hepatitis, and 14 developed a chronic infection. Overlapping 20-mer peptides covering the entire core and NS4 antigens and a panel of peptides representing highly conserved regions of core, NS3, NS4, and NS5 were used. By direct peripheral blood T-cell stimulation and by fine-specificity analysis of HCV-specific T-cell lines and clones, highly immunogenic T-cell epitopes were identified within core, NS3, and NS4. All these epitopes are immunodominant and highly conserved among the known HCV isolates. Moreover, they are promiscuous, because they can be presented to T cells by different HLA class II molecules. Immunodominance, sequence conservation, and promiscuity make these epitopes ideal components of preventive or therapeutic T-cell-based vaccines against HCV.

Recombinant interferon alpha (rIFN-alpha) does not potentiate the effect of iodine excess on the development of thyroid abnormalities in patients with HCV chronic active hepatitis.

OBJECTIVE: To determine whether the administration of pharmacological quantities of iodine during interferon-alpha (rIFN-alpha) treatment of chronic viral hepatitis B and C (HCV) would exacerbate the potential adverse effects of rIFN alpha on thyroid function. DESIGN: Thyroid function tests were carried out in 48 euthyroid patients before and during rIFN-alpha therapy of HCV. Twenty-one of these patients were also treated with 10 drops saturated solution of potassium iodine (SSKI, approximately 350 mg iodine daily). Eight patients with HCV but not treated with rIFN-alpha received 10 drops SSKI. PATIENTS: All patients were enthyroid prior to rIFN-alpha therapy for HCV or iodine and thyroid function tests were similar in the three groups. MEASUREMENTS: Serum free T4, free T3, and TSH concentrations were measured prior to and at 30 and 60 days of rIFN-alpha therapy in the three groups of patients. The serum TSH response to TRH was assessed before rIFN-alpha therapy and on day 60. Thyroid peroxidase antibodies were measured before and during therapy. RESULTS: During the 2-month study period, similar small but significant decreases in serum FT4 and FT3 and compensatory small significant increases in TSH concentrations were observed in the patients treated with rIFN-alpha + iodine and iodine alone but not in the patients receiving rIFN-alpha alone. Abnormal thyroid function tests were observed more frequently in patients receiving rIFN-alpha + iodine and iodine alone compared to those receiving rIFN-alpha alone. CONCLUSIONS: Excess iodine administered to patients treated with rIFN-alpha induced small changes in thyroid function similar to those observed in patients treated with iodine alone. Thus, rIFN-alpha and iodine do not appear to be synergistic in the development of abnormal thyroid function tests over a 2-month treatment period.

A randomized, double-blind trial on the use of a triple combination including nevirapine, a nonnucleoside reverse transcriptase HIV inhibitor, in antiretroviral-naive patients with advanced disease.

The immunologic and virologic activity of nevirapine in combination with two nucleosides (zidovudine [ZDV] and didanosine [ddI]) was evaluated in antiretroviral-naive patients with a CD4 count <200/mm3 or clinical AIDS. In all, 68 patients were enrolled in a 48-week double-blind, placebo-controlled trial. A group of 32 patients received ZDV + ddI + nevirapine, and 36 patients received ZDV + ddI. Primary efficacy parameters were the activity on HIV-1 RNA and on peripheral blood CD4+ cells, with differences between groups analyzed by the Wilcoxon's nonparametric two-sample test. Baseline RNA was high in both treatment groups (median values, 5.8 and 5.7 log10). RNA and CD4 responses were significantly higher with the triple combination (median RNA reductions, 2.69 versus 1.05 log10 at 24 weeks and 1.97 versus 1.20 log10 at 48 weeks; median CD4 increases, 81 versus 64 cells/mm3 at 24 weeks and 101 versus 27 cells/mm3 at 48 weeks). This study demonstrates that a triple combination of ZDV + ddI + nevirapine used as first-line regimen in antiretroviral-naive patients can induce sustained virologic and immunologic response in patients with low CD4 count or a previous diagnosis of AIDS.

Lamivudine treatment can restore T cell responsiveness in chronic hepatitis B.

High viral and/or antigen load may be an important cause of the T cell hyporesponsiveness to hepatitis B virus (HBV) antigens that is often observed in patients with chronic HBV infection. Reduction of viral and antigen load by lamivudine treatment represents an ideal model for investigating this hypothesis. HLA class II restricted T cell responses and serum levels of HBV-DNA, HBsAg, and HBeAg were studied before and during lamivudine treatment in 12 patients with hepatitis B e antigen positive chronic active hepatitis B to assess possible correlations between viral and/or antigen load and vigor of the T cell response. Cell proliferation to HBV nucleocapsid antigens and peptides and frequency of circulating HBV nucleocapsid-specific T cells were assessed to characterize CD4-mediated responses. A highly significant enhancement of the CD4-mediated response to HBV nucleocapsid antigens was already detectable in most patients 7-14 d after the start of lamivudine treatment. This effect was dramatic and persistent in 10 patients but undetectable in 2. It occurred concomitant with a rapid and marked reduction of viremia. Interestingly, lamivudine also enhanced the responses to mitogens and recall antigens, showing that its effect was not limited to HBV-specific T cells. In conclusion, an efficient antiviral T cell response can be restored by lamivudine treatment in patients with chronic hepatitis B concurrently with reduction of viremia, indicating the importance of viral load in the pathogenesis of T cell hyporesponsiveness in these patients. Since lamivudine treatment can overcome T cell hyporeactivity, combining lamivudine with treatments directed to stimulate the T cell response may represent an effective strategy to induce eradication of chronic HBV infection.

Transjugular intrahepatic portosystemic shunt versus endoscopic sclerotherapy for the prevention of variceal bleeding in cirrhosis: a randomized multicenter trial. Gruppo Italiano Studio TIPS (G.I.S.T.).

Transjugular intrahepatic portosystemic shunt (TIPS), a new technique for the treatment of portal hypertension, has been successful in preliminary studies to treat acute variceal hemorrhage and to prevent variceal rebleeding. The purpose of this multicenter, randomized controlled trial is to compare the efficacy of TIPS with that of endoscopic sclerotherapy in the prevention of variceal rebleeding in cirrhosis. Eighty-one cirrhotic patients, with endoscopically proven variceal bleeding, were randomized to either TIPS (38 patients) or endoscopic sclerotherapy (43 patients). Randomization was stratified according to the following: if bleeding occurred < 1 week (stratum I); if bleeding occurred 1 to 6 weeks (stratum II); and if bleeding occurred 6 weeks to 6 months (stratum III) before enrollment. Follow-up included clinical, biochemical, Doppler Ultrasound, and endoscopic examinations every 6 months. During a mean follow-up of 17.7 months, 51% of the patients treated with sclerotherapy and 24% of those treated with TIPS rebled (P = .011). Mortality was 19% in sclerotherapy patients and 24% in TIPS patients (P = .50). Hepatic encephalopathy (HE) developed in 26% and 55%, respectively (P = .006). A separate analysis of the three strata showed that TIPS was significantly more effective than sclerotherapy (P = .026) in preventing rebleeding only in stratum I patients. TIPS is significantly better than sclerotherapy in preventing rebleeding only when it is performed shortly after a variceal bleed; however, TIPS does not improve survival and is associated with a significantly higher incidence of HE. The overall performance of TIPS does not seem to justify the adoption of this technique as a first-choice treatment to prevent rebleeding from esophageal varices in cirrhotic patients.

Antiviral cell-mediated immune responses during hepatitis B and hepatitis C virus infections.

Cell-mediated immune responses to hepatitis B (HBV) and hepatitis C virus (HCV) antigens are vigorous and multispecific in acute, self-limited infections. Moreover, the prevalent cytokine pattern of circulating virus-specific T cells from patients who recover spontaneously from acute hepatitis is Th1-like. Longitudinal analysis of the T cell response to HCV antigens from the early stages of HCV infection in patients who recover from hepatitis and those who do not indicates that weaker responses and a prevalent Th2 pattern of cytokine production is associated with viral persistence and chronic evolution of disease. Although similar sequential studies are missing in hepatitis B, the observation that HBV-specific T cell responses are very weak or totally undetectable in the peripheral blood of patients with long-lasting chronic hepatitis B suggests that strength and quality of virus-specific T cell responses at the early stages of infection may influence the final outcome of both hepatitis B and C. While T cell hyporesponsiveness seems to be an important determinant for HBV persistence once chronic hepatitis has developed, this mechanism appears to be less critical in chronic HCV infection, because the vigor and quality of HCV-specific T cell responses seem to improve as a function of the duration of infection. This is shown by the finding that HCV-specific CD4- and CD8-mediated responses are easily detectable in the peripheral blood of patients with long-lasting chronic hepatitis C and that production of Th1 cytokines predominates within their livers. HCV therefore seems to be able to persist even in the face of an active T cell response and to acquire the capacity to survive within a host environment apparently unfavorable to its persistence. The high variability of HCV may explain its efficiency in escaping immune surveillance.

Effects of excess iodine administration on thyroid function in euthyroid patients with a previous episode of thyroid dysfunction induced by interferon-alpha treatment.

OBJECTIVE: To determine the effects of pharmacological quantities of iodide (SSKI) on thyroid function in euthyroid patients previously treated with recombinant interferon-alpha (rIFN-alpha) for chronic viral hepatitis B and C (HCV), a cytokine which may induce thyroid dysfunction. DESIGN: Thyroid function tests were carried out in 16 euthyroid patients, 8 of whom had previously developed thyroid dysfunction during rIFN-alpha therapy for HCV, before, during and after the administration of 10 drops of saturated solution of potassium iodide (SSKI) (approximately 350 mg iodide). PATIENTS: All 16 patients had been treated in the past with rIFN-alpha for HCV. Eight patients had developed rIFN-alpha induced abnormalities in thyroid function (5 inflammatory thyrotoxicosis, 1 Graves' disease, and 2 impaired thyroid organification of iodide) and 8 had not developed thyroid dysfunction. MEASUREMENTS: After baseline serum free T4 (FT4) and free T3 (FT3) concentrations, basal and TRH stimulated TSH concentrations, and TSH-receptor (TSH-R-Ab) and thyroid peroxidase (TPO-Ab) antibodies were measured, 10 drops saturated solution of potassium iodide (SSKI, approximately 350 mg iodide) were given daily for 60 days and the above parameters assessed during and after SSKI was discontinued. RESULTS: Five of 8 patients with a previous history of rIFN-alpha induced thyroid dysfunction developed mild iodide induced abnormalities of thyroid function (subclinical hypothyroidism (slightly elevated basal and TRH stimulated serum TSH concentrations with normal serum FT4 and FT3 concentrations) or hyperthyroidism) compared with the 8 patients who had no previous evidence of thyroid dysfunction during rIFN-alpha therapy. CONCLUSIONS: In view of the present observations, it is prudent to avoid the administration of excess iodine to euthyroid subjects with a previous episode of thyroid dysfunction during rIFN-alpha therapy, adding a new group of patients susceptible to iodine induced thyroid disease.

Molecular features of the hepatitis B virus nucleocapsid T-cell epitope 18-27: interaction with HLA and T-cell receptor.

The strength of the cytotoxic T lymphocyte (CTL) response is believed to influence the final outcome of hepatitis B virus (HBV) infection. Among the different CTL epitopes so far identified, the sequence 18-27 of the HBV nucleocapsid antigen is widely recognized by CTL of HLA-A2-positive patients with acute self-limited HBV infection, and represents the main component of a peptide-based therapeutic vaccine aimed at stimulating the antiviral CTL response in patients with chronic hepatitis B. In the present study, we further analyzed the features of this important HBV region by the following: 1) defining the contribution of individual residues of the epitope to the interaction with the T-cell receptor (TCR) and with the HLA-A0201 molecule; 2) assessing the antigenicity of this viral region in the context of the different HLA-A2 subtypes; and 3) testing whether this sequence can stimulate not only HLA-class I but also HLA class II restricted T-cell responses. A clear hierarchy was observed in the ability of individual residues to act as TCR or HLA binding sites. Furthermore, the sequence HBc18-27 was able to be recognized by specific CTL when presented in the context of different HLA-A2 subtypes. Finally, this HBV region was also found to stimulate HLA class II restricted T-cell responses. These data further increase the potential coverage and efficacy of therapeutic vaccines based on the HBc18-27 sequence.

Effects of interferon treatment on the antiviral T-cell response in hepatitis C virus genotype 1b- and genotype 2c-infected patients.

The viral genotype may influence the response to interferon (IFN) treatment in chronic hepatitis C virus (HCV) infection. To characterize potential mechanisms responsible for this effect, we assessed whether IFN modulation of HCV-specific T-cell responses differs in patients infected by different genotypes. The T-cell response to HCV core protein was sequentially analyzed before and during IFN treatment in two groups of patients chronically infected with HCV genotype 1b (eight patients) or 2c (eight patients). Overlapping 20 mer peptides corresponding to the amino acid sequence of the prevalent viral population identified in the serum of each patient were used for the analysis of the T-cell proliferative response to avoid possible problems caused by amino acid differences between infecting virus and HCV proteins used in vitro. Recombinant HCV core antigen was used in parallel. The level of viremia was monitored by competitive polymerase chain reaction (PCR). The T-cell response to HCV peptides and recombinant core protein detected throughout the follow-up was significantly more vigorous in genotype 2c- than in genotype 1b-infected patients. This difference was the result of a greater enhancement of the T-cell response caused by IFN treatment in genotype 2c- compared with genotype 1b-infected patients. The different IFN modulatory effect on T cells from genotype 1b- and genotype 2c-infected patients illustrates an aspect of the virus-host interaction, which may contribute toward the explanation of why different genotypes differ in responsiveness to IFN treatment.

[Pancreatitis caused by Cryptosporidium parvum in patients with severe immunodeficiency related to HIV infection]. / Pancreatite da cryptosporidium parvum in pazienti con grave deficit immunitario correlato ad infezione da HIV.

Up to the present, pancreatic complications due to cryptosporidium parvum infection have been described only in a few patients with acquired immunodeficiency syndrome (AIDS). We report our experience with 3 subjects with AIDS who presented with acute or chronic pancreatitis related to cryptosporidiosis. All 3 patients had abdominal pain resistant to analgesics, increased serum amylase and abnormalities at both sonography and computed tomography. Endoscopic retrograde cholangiopancreotography revealed papillary stenosis in all patients; one patient also had stenosis of the Wirsung duct. Cryptosporidium was found in both bile and stool samples in all patients, while viral cultures were negative, even in the 2 patients who had cytomegalovirus retinitis. Endoscopic sphincterotomy temporally relieved abdominal pain in all patients, but did not prevent either acute or recurrent pancreatic inflammation. Several antibiotic therapeutic protocols were ineffective against the parasite.

Predominant T-helper 1 cytokine profile of hepatitis B virus nucleocapsid-specific T cells in acute self-limited hepatitis B.

The cytokine pattern secreted by T cells on viral antigen recognition is believed to exert a profound influence on both the type of disease caused by the infecting agent and the final outcome of the viral infection. To characterize the cytokine pattern associated with spontaneous resolution of acute hepatitis B, we analyzed interferon gamma (IFN-gamma), interleukin (IL)-4, and IL-5 production by a wide series of hepatitis B virus (HBV) nucleocapsid-specific T-cell lines (34 lines) and T-cell clones (71 clones) derived from the peripheral blood of 13 patients during the acute or recovery phase of hepatitis B (2 and 7 of them were studied only in the recovery or the acute phase, respectively, and 4 during both). Most T-cell lines (67%) and clones (77%) isolated during the acute phase of infection expressed a T-helper (Th) 1 cytokine profile dominated by the production of IFN-gamma. A larger proportion (74%) of T-cell lines produced several years after resolution of hepatitis was able to secrete not only IFN-gamma, but also IL-4 and IL-5 (Th0-like cells). Results indicate that the antigen-specific fraction of peripheral blood T cells in acute self-limited hepatitis B selectively secrete Th1-type eytokines, suggesting that Th1-mediated effects may contribute not only to liver cell injury, but probably also to recovery from disease and successful control of infection.

Different cytokine profiles of intraphepatic T cells in chronic hepatitis B and hepatitis C virus infections.

BACKGROUND & AIMS: The cytokine pattern secreted by T cells at the site of viral replication may influence the final outcome of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. The aim of this study was to assess whether a cytokine imbalance oriented toward T helper (Th) 1 or Th2-type responses may play a role in chronic hepatitis B or C. METHODS: Production of interferon (IFN)-gamma, interleukin (IL)-4, and IL-5 by wide series of T-cell clones derived from the liver of 6 patients with chronic hepatitis B (291 clones) and 9 patients with chronic hepatitis C (260 clones) was studied. T-cell clones were generated by limiting dilution from freshly isolated mononuclear cells derived from liver tissue to give a reliable representation of the intrahepatic inflammatory infiltrates. RESULTS: The majority of liver-infiltrating T cells in chronic hepatitis C were Th1 cells able to secrete IFN-gamma but unable to secrete IL-4 or IL-5, whereas in hepatitis B, most CD4+ and CD8+ liver T cells were ThO-like cells able to produce not only IFN-gamma but also IL-4 and IL-5. CONCLUSIONS: The different cytokine profiles of T cells within the liver in chronic HBV and HCV infections illustrate a different behavior of the local immune response in these two infections that may have pathogenetic implications.

Multiple changes in thyroid function in patients with chronic active HCV hepatitis treated with recombinant interferon-alpha.

OBJECTIVE: Recombinant human interferon-alpha (r-IFN-alpha) is often successfully used in the treatment of patients with chronic viral hepatitis B and C. Thyroid dysfunction has been reported to occur with variable frequency during r-IFN-alpha therapy especially in patients with preexisting thyroid autoimmunity. We have prospectively evaluated the effect of r-IFN-alpha on various aspects of thyroid function in patients with HCV chronic hepatitis. DESIGN: Thirty-two patients with HCV chronic active hepatitis were studied prospectively before and during r-IFN-alpha therapy. Serum TSH, FT4, FT3, and thyroid receptor (TSR) and thyroid peroxidase (TPO) antibodies, and the iodide-perchlorate discharge test (I-C10(4)) to detect subtle defects in the thyroid organification of iodide were carried out during the study. Thyroid radioactive iodine uptakes (RAIU) were obtained in patients who developed thyrotoxicosis. RESULTS: All patients were clinically and biochemically euthyroid prior to r-IFN-alpha therapy with negative I-C10(4) discharge tests. Four patients became thyrotoxic, 3 secondary to destructive or inflammatory thyroiditis with a low thyroid RAIU, and 1 patient developed hypothyroidism. The I-C10(4) discharge test became positive in 7 of the 32 patients studied prospectively; 5 of these patients did not develop other evidence of thyroid dysfunction and did not have positive TPO antibodies. In these 5 patients the test became negative after r-IFN-alpha was discontinued. Appropriate therapy of the patients with thyrotoxicosis (methylprednisolone for 3 patients with destructive thyroiditis and methimazole for 1 patient with hyperthyroidism) or with hypothyroidism (L-thyroxine) was successful. CONCLUSIONS: Thyroid dysfunction, especially destructive or silent thyroiditis resulting in thyrotoxicosis, is not infrequently observed in patients receiving r-IFN-alpha therapy for chronic active hepatitis. Although underlying autoimmune thyroid disease appears to predispose patients to develop thyroid dysfunction, other patients become thyrotoxic or hypothyroid in the absence of baseline positive TPO-Ab. Subtle defects in the thyroidal organification of iodine as determined by the I-C10(4) discharge test, in the absence of autoimmune thyroid disease, was observed in 5 patients who remained euthyroid, suggesting that r-IFN-alpha directly reduces the intrathyroidal organification of iodine.

Long-lasting memory T cell responses following self-limited acute hepatitis B.

The molecular and cellular basis of long-term T cell memory against viral antigens is still largely undefined. To characterize anti-viral protection by memory T cells against non-cytopathic viruses able to cause acute self-limited and chronic infections, such as the hepatitis B virus (HBV), we studied HLA class II restricted responses against HBV structural antigens in 17 patients with acute hepatitis B, during the acute stage of infection and 2.2 to 13 yr after clinical resolution of disease. Results indicate that: (a) significant T cell proliferative responses to HBV nucleocapsid antigens were detectable in all patients during the acute phase of infection and in 14/17 also 2-13 yr after clinical resolution of disease; b) long-lasting T cell responses were sustained by CD45RO+T cells, predominantly expressing the phenotype of recently activated cells; c) limiting dilution analysis showed that in some patients the frequency of HBV-specific T cells was comparable to that observed in the acute stage of infection and, usually, higher than in patients with chronic HBV infection; d) the same amino acid sequences were recognized by T cells in the acute and recovery phases of infection; and e) HBV-DNA was detectable by nested-PCR in approximately half of the subjects. to conclusion, our results show that vigorous anti-viral T cell responses are detectable in vitro several years after clinical recovery from acute hepatitis B. Detection of minute amounts of virus in some recovered subjects suggests that long-term maintenance of an active anti-viral T cell response could be important not only for protection against reinfection but also for keeping the persisting virus under tight control.

Different clinical behaviors of acute hepatitis C virus infection are associated with different vigor of the anti-viral cell-mediated immune response.

The anti-viral T cell response is believed to play a central role in the pathogenesis of hepatitis C virus infection. Since chronic evolution occurs in > 50% of HCV infections, the sequential analysis of the T cell response from the early clinical stages of disease may contribute to define the features of the T cell response associated with recovery or chronic viral persistence. For this purpose, 21 subjects with acute hepatitis C virus infection were sequentially followed for an average time of 44 wk. Twelve patients normalized transaminase values that remained normal throughout the follow-up period; all but two cleared hepatitis C virus-RNA from serum. The remaining nine patients showed persistent viremia and elevated transaminases. Analysis of the peripheral blood T cell proliferative response to core, E1, E2, NS3, NS4, and NS5 recombinant antigens and synthetic peptides showed that responses to all hepatitis C virus antigens, except E1, were significantly more vigorous and more frequently detectable in patients who normalized transaminase levels than in those who did not. By sequential evaluation of the T cell response, a difference between the two groups of patients was already detectable at the very early stages of acute infection and then maintained throughout the follow-up period. The results suggest that the vigor of the T cell response during the early stages of infection may be a critical determinant of disease resolution and control of infection.

Hepatic encephalopathy after transjugular intrahepatic portosystemic shunt. Incidence and risk factors.

Forty-seven consecutive patients were prospectively evaluated to study the incidence of hepatic encephalopathy as well as modifications in the PSE index after TIPS. Various clinical, laboratory, and angiographic parameters were also recorded to identify risk factors for the development of post-TIPS hepatic encephalopathy (HE). Mean follow-up was 17 +/- 7 months. During follow-up, six patients died and one underwent transplantation. All other patients were followed for at least a year. Fifteen patients (32%) experienced 20 acute episodes of precipitated HE (hospitalization was necessary in 10 instances), and five patients (11%) presented a continuous alteration in mental status with frequent spontaneous exacerbation during follow-up. Both precipitated and spontaneous HE occurred more frequently during the first three months of follow-up. Moreover the PSE index was significantly worse than basal values one month after TIPS, thereafter returning to near basal values. HE was successfully treated in all patients but one who required a reduction in the stent/shunt diameter. Increasing age (>65 years) and low portacaval gradient (<10 mm Hg) were predictors of HE after TIPS. A gradual dilation of the stent/shunt should be performed to obtain a portacaval gradient >10 mm Hg to avoid an unacceptable rate of HE after TIPS.