Alanine Aminotransferase Flares Research Articles

Switching to adefovir monotherapy after emergence of lamivudine‐resistant mutations in patients with liver cirrhosis

Switching to adefovir (ADV) monotherapy is effective in patients with lamivudine (LAM)-resistant hepatitis B virus (HBV) mutations (rtM204 I/V). However, it was recommended to continue LAM therapy for months after starting ADV therapy for safety concern. The safety and efficacy of switching to ADV monotherapy was examined in compensated and decompensated patients with liver cirrhosis. The clinical, biochemical and virological responses were compared between ADV monotherapy in 18 cirrhotic patients and ADV add-on LAM therapy in 10 comparable cirrhotic patients with LAM-resistant rtM204 I/V. After switching to ADV monotherapy, Child-Pugh's score, serum alanine aminotransferase (ALT), bilirubin, albumin and HBV DNA levels improved significantly (P < 0.01). Serum HBV DNA response, defined as HBV DNA decreased to below 10(5) copies/mL or > or =2 log(10) reduction form baseline, was achieved in all patients. A transient ALT flare without concurrent changes in serum bilirubin or prothrombin time was observed in only two patients (11%). The efficacy and safety profile was similar to those with ADV add-on LAM therapy. In conclusion, switching to ADV monotherapy after emergence of LAM-resistant rtM204 I/V is effective and safe in cirrhotic patients, even in those with hepatic decompensation. To stop LAM and switch to ADV in patients with breakthrough is a reasonably safe and cost-effective approach.

Telbivudine: an upcoming agent for chronic hepatitis B

Telbivudine, the prototype member of β-l-2´-deoxynucleosides, has proven to be safe in in vitro animal and human studies. Telbivudine given for 4 weeks resulted in an 8-log reduction of woodchuck hepatitis virus DNA, and a 3.8-log reduction of hepatitis B virus DNA in human. After 52 weeks of telbivudine treatment there was an approximate 6-log reduction of hepatitis B virus DNA levels, hepatitis B virus DNA became undetectable by PCR assay in 61% of patients. Its antiviral efficacy is significantly better than lamivudine. The probability of tyrosine-methionine-aspartate-aspartate mutations at 52 weeks of telbivudine therapy is low, although still occurring in 4.5% of patients. After 96 weeks of therapy, the proportion of patients with undetectable hepatitis B virus DNA by PCR assay increased to 71%, but genotypic resistance also increased to 18.2%, with only 4.5% showing alanine aminotransferase flares. Telbivudine is probably one of the most potent antiviral agents for hepatitis B virus that will become available in the near future.

Mathematical modeling of primary hepatitis C infection: Noncytolytic clearance and early blockage of virion production

Although hepatitis C virus kinetics and immune determinants during primary infection have been described, the virus-host interplay is not fully understood. We used mathematical modeling to elucidate and quantify virus-host dynamics. Ten chimpanzees were infected intrahepatically with H77-RNA (n = 3) or intravenously with infected serum. Blood samples were taken 1-3 times per week for 6 months. A new model was fitted to the observed HCV RNA and alanine aminotransferase (ALT) kinetics. After infection, viral levels increased in a biphasic manner with a transient decline in between. This can be explained by a partial block (mean, 91%) of virion production, possibly due to an endogenous type I interferon response. After reaching maximum levels, a long viral plateau (mean, 6.1 log cp/mL) can be explained by blind homeostasis and lack of susceptible cells. Modest elevations in ALT levels (21-93 IU/L) were concurrently observed, indicating a shorter half-life of infected versus noninfected hepatocytes (mean ratio, 2.6). Following the ALT flare, viral titers rapidly declined to a lower (mean, 4.5 log cp/mL; n = 6) or undetectable level (n = 4). This decline is compatible with increased cell death (mean minimal estimate half-life, 28.7 days) and noncytolytic clearance (mean maximal estimate half-life, 24.1 days) of infected cells. Our results quantify virus-host dynamics during primary HCV infection and suggest that endogenous type I interferon slows virus production in the early acute phase. Partial or effective virus control correlates with the half-life of infected cells regulated by both cytolytic and noncytolytic mechanisms.

540 Alanine aminotransferase (ALT) flares are uncommon both on- and post-treatment in entecavir treated HBeAg(+) patients

540 Alanine aminotransferase (ALT) flares are uncommon both on- and post-treatment in entecavir treated HBeAg(+) patients

Viral kinetics during antiviral therapy in patients with chronic hepatitis C and persistently normal ALT levels†

To the Editor: We read with great interest the article of Kronenberger et al.1 evaluating viral kinetics in patients with chronic hepatitis C and normal or elevated alanine aminotransferase (ALT) levels. The main conclusions of this study were that viral kinetics did not differ between the two groups of patients, although those with elevated GGT levels showed reduced efficacy of blocking virus production and lower infected cell loss. Although this study did accurately compare virological, demographic, and histological features between patients with normal and elevated ALT levels, fewer data are given about the differences among those with normal ALT. Indeed, patients with normal ALT might be stratified into three different groups: patients with persistently “low-normal” (updated healthy) ALT levels; patients with “high-normal” ALT levels, and subjects with normal ALT but occasional ALT flares.2, 3 Two recent prospective studies4, 5 have shown that many subjects referred to as hepatitis C virus (HCV) carriers with persistently normal ALT (PNALT) could have ALT flare-ups during the follow-up, thus proving that even prolonged observation periods might not be adequate to distinguish patients with persistent or transient ALT normality. It has been suggested that at least two different subsets of HCV carriers exist: patients with wide temporal ALT fluctuations, who could be within the normal range for several months, and true “biochemically silent” carriers, who show persistently normal ALT values.6 Although it is not clear whether these subgroups have different natural history and disease progression, liver histological activity was found to be significantly more marked among subjects with ALT flare-ups during the follow-up than in those with PNALT, and progression of fibrosis seems to accelerate after ALT flare-ups.3 Thus, we wonder if significant differences in viral kinetic were found between the 6 patients with “healthy” updated ALT levels and the 14 patients with “high-normal” ALT, and between the 5 patients with ALT flares and the 15 with PNALT. Indeed, it would be very interesting to understand whether ALT flare-ups among HCV carriers with PNALT might be due to viral factors (e.g., lower efficacy of blocking virus production/lower infected cell loss) or to nonviral factors (steatosis, drugs, alcohol). Finally, as to the patients with elevated GGT levels, we ask whether liver steatosis has been ruled out as a possible cause of GGT elevation. In particular, we wonder if significant differences were found in terms of presence and severity of steatosis between the 5 patients with PNALT and elevated GGT, and the 15 subjects with both normal ALT and GGT levels. Claudio Puoti*, Lia Bellis*, Roberto Castellacci*, Fabrizio Montagnese*, * Department of Gastroenterology and Internal Medicine, Genzano Hospital, Rome, Italy.

Lack of association between occult hepatitis B virus DNA viral load and aminotransferase levels in patients with hepatitis C virus‐related chronic liver disease

Occult hepatitis B virus (HBV) infection in hepatitis C virus (HCV)-infected patients might enhance the severity of chronic liver disease (CLD). To elucidate the correlation between occult HBV infection and the clinical course of HCV-related CLD, we evaluated whether the fluctuation of occult HBV-DNA directly affects the serum alanine aminotransferase (ALT) level. Forty-one patients with HCV-related CLD who received regular outpatient treatment and 42 age-, sex-, and antibody to hepatitis B core antigen positivity-matched healthy volunteers were enrolled. Serum HBV-DNA was quantitatively detected using real-time detection polymerase chain reaction (RTD-PCR). Serial serum samples in three patients were measured for HBV-DNA, ALT and HCV core antigen. Hepatitis B virus DNA was amplified in eight of the HCV-related CLD patients (19.5%), which was significantly higher than that of healthy volunteers (2.4%). No significant difference between the genotype 1 HCV-related CLD group and the genotype 2 group was found. Based on the analyses using serial serum samples, the elevation of HBV-DNA did not occur before the ALT flares, but occurred at the same time or after the ALT flares. The prevalence of occult HBV infection of HCV-related CLD is significantly higher than that of control. Occult HBV infection has no influence on ALT flares among patients with HCV-related CLD.

Increasing serum levels of IgM anti-HCV are diagnostic of recurrent hepatitis C in liver transplant patients with ALT flares.

Recurrent hepatitis and acute rejection share common features which make difficult for diagnosis in liver transplant hepatitis C virus (HCV) positive patients. We studied the usefulness of quantitative monitoring of HCV RNA and immunoglobulin (Ig)M anti-HCV in the differential diagnosis between recurrent hepatitis and acute rejection in 98 consecutive anti-HCV positive liver transplant patients. Aminotransferase levels, serum HCV RNA and IgM anti-HCV were measured at the time of transplantation and monthly thereafter. A liver biopsy (LB) was obtained when serum aminotransferase levels increased to twice or more than normal. During a mean follow-up of 16 months 86 aminotransferase flares were observed. Histology was compatible with recurrent hepatitis C in 44 cases and with acute rejection in 28, doubtful in 14. The fluctuations of HCV RNA serum levels were not significantly different in the three groups. Serum IgM anti-HCV levels increased (from negative to positive or with value variations > or = 0.18) in 36 of 44 cases with recurrent hepatitis C at the time of alanine aminotransferase (ALT) flare. IgM anti-HCV remained unchanged in all rejection cases (P < 0.001), but increased in 10 of 11 histologically doubtful cases that were diagnosed as hepatitis at the second LB. Increasing serum levels of IgM anti-HCV at the time of ALT flares are significantly associated with recurrent hepatitis C in liver transplant patients. The quantitative monitoring of IgM anti-HCV appears to be an additional diagnostic tool for distinguishing recurrent hepatitis C from acute graft rejection with a 100% specificity; 100% positive predictive value and 88.9% diagnostic accuracy.

Changes in alanine aminotransferase (ALT) and YMDD mutation profile associated with switching from lamivudine (LAM) to either adefovir dipivoxil (ADV) or combination LAM plus ADV in chronic hepatitis B (CHB) patients with LAM resistance

Back,ground cmd Aims: YMDD mutations m hepatitis B virus (HBV) polymemse emerge in 24% (rauge 16 to 32%) of CHB patients alter one }-ear of I.AM therapy, increasing to 69% alter 5 }'ears ADV has potent activity against YMDD mutant and wild type (WT) HBV Study GS 00 461 evaluated 3 regimens: contirmed [.AM 100 mg, adding ADV 10 mg to cuntinued L,~M or switching trom L~M to ADV Methods: Eligible patients were: HBeAg+ with CHB; ALl ~ 1 2 x upper limit of normal (ULN); HBV DNA > 6 log~0 copies/mL (Roche Amplicor PCE) despite ongoing tAM therapy; confirmed YMDD mutant HBV Fifty eight patients received ADV (n= 19), ADV + LAM (n=20), or LAM (n= 19) Treatment duration was 48 weeks: ALT was evaluated dnnng therapy by treatment arm tor possible associations w~th change in regimen (.ALT elevations - 10 x ULN) associated with change in regimen (- 3 x baseline at W12: this resols, ed on continued tleaIment, was not associated with signs of hepatic decompensation, and the patient subsequem/y ttBeAg seroconverted at W24 YMDD sequencing (position rtM204) demonstrated that by W16, W 3 2 and W48 of therapy 4 6 and 7 of 19 ADV patients reverted to wild type, respectively No L4M patients and 1 of 20 ADV + LAM patients lost YMDD nmtations through W48. Reversion to WT HBV occurred without increases m serum HBV DNA or AIT. Serum HBV DNA decreased similarly in ADV treated patients who reverted to WT HBV or retained YMDD Conclusions: ADV, alone or in combination with LAM, signitlcandy reduced serum HBV DNA in patients with IAM resistant HBV Reversion to WT HBV trom YMDD occurred more frequently m patients receiving ADV monotherapy Neither directly switching to ADV from LAM nor loss of YMDD mutations through 48 weeks was associated with severe ALT flare or evidence of hepatic decompensation.

Hepatitis flares and hepatitis B e antigen seroconversion: implication in anti-hepatitis B virus therapy.

Hepatitis flares or acute exacerbations, defined as an abrupt elevation of serum alanine aminotransferase (ALT) over fivefold the upper limit of normal (ULN), of chronic hepatitis B virus (HBV) infection are the results of HLA-I restricted, cytotoxic T lymphocyte (CTL)-mediated immune response against HBV and its downstream mechanisms. Higher ALT levels reflect a more vigorous immune response and a more extensive hepatolysis that, in the extreme situation, may lead to decompensation and failure. In contrast, higher ALT also reflects a more robust immune clearance of HBV and, therefore, a higher chance of HBV-DNA loss and hepatitis B e antigen (HBeAg) seroconversion, both in the setting of natural course and drug therapy. Alanine aminotransferase of fivefold the ULN appears to be a significant cut-off level to categorize the patients in terms of endogenous immune response against HBV. Patients with ALT levels less than fivefold the ULN or those with a less vigorous immune response require immunomodulation to induce robust immune response to enhance HBV clearance. In contrast, those with a more vigorous immune response or those with ALT flare over fivefold the ULN should be monitored closely for spontaneous HBV clearance/HBeAg seroconversion or to start direct antiviral therapy in time to prevent the occurrence or deterioration of hepatic decompensation. In conclusion, a better understanding of the pathogenetic mechanisms and natural course of hepatitis flares, wiser selection of patients and the timing of drug therapy are crucial to achieve better treatment results.

Short-Term Lamivudine Therapy in Patients with Chronic Hepatitis B

Lamivudine is a nucleoside analogue with potent inhibitory effects on hepatitis B virus (HBV) polymerase/reverse transcriptase activity. The rate of hepatitis B e antigen (HBeAg) seroconversion in a large series of Asian patients treated with lamivudine 100 mg daily for 1 year was only 16% and the incidence of YMDD mutants was 14%. Further analysis of this Asian trial has shown that patients with a pretreatment alanine aminotransferase (ALT) level higher than 5-fold the upper limit of normal (ULN) have a much higher HBeAg seroconversion rate as compared with patients with a pretreatment ALT level <2 × upper limit of normal (64 vs. 5%; p < 0.001). In order to avoid the development of YMDD mutants, we selected 186 patients with acute exacerbation for treatment with lamivudine during 9 months, if possible, and not more than 15 months. They were all seropositive for both hepatitis B surface antigen and HBeAg for more than 6 months and also had serum HBV DNA; 138 (74%) of them were male. HBV genotypes were A in 2 (1%), B in 115 (62%), C in 65 (35%), D in 2 (1%) and F in the remaining 2 (1%). Four patients (2%) had liver cirrhosis. They had mean pretreatment levels of ALT at 608 IU/l (range: 184–2,400 IU/l), total bilirubin at 1.5 mg/dl (0.3–14.8 mg/dl), and HBV DNA at 2,246 pg/ml (0.5–25,903 pg/ml). After a median of 8.2 months (3–15 months) on lamivudine, 96 patients (51%) achieved HBeAg seroconversion, while the other 90 (48%) patients did not. Genotype B was detected comparably frequently in seroconverters and nonconverters (63 vs. 61%). During 1-year follow-up after withdrawal of lamivudine, 56 (58%) of the 96 seroconverters experienced flare-ups with ALT levels elevated higher than 5 × ULN in 50 (89%). Of 90 patients who remained HBeAg-positive, in contrast, 80 (86%) experienced ALT flares (with ALT >5 × ULN in 84%) within 1 year. YMDD mutants did not develop in any of these 186 patients during the course of lamivudine therapy. In conclusion, short-term lamivudine therapy in patients with chronic active hepatitis B can reduce the incidence of YMDD mutants and achieve an acceptable HBeAg seroconversion rate. However, the relapse rate was high (60% during 1-year follow-up). Further study is needed to establish how to improve a sustained HBeAg response.

Serum alanine aminotransferase flares during interferon treatment of chronic hepatitis B: Is sustained clearance of HBV DNA dependent on levels of pretreatment viremia?

During interferon treatment of chronic hepatitis B, an alanine aminotransferase (ALT) flare may herald a sustained loss of viral replication, but the relationship between virologic response, the extent of a flare, and pretreatment hepatitis B virus (HBV) DNA level has not been defined. We retrospectively examined the impact of an ALT flare on sustained virologic response in 121 interferon-treated patients and 42 untreated controls with either low-level (<100 pg/mL) or high-level (≥100 pg/mL) viremia. The degree of ALT flare was classified as mild (increase in ALT of 86-171 IU/L above baseline), moderate (increase of 172 to 343 IU/L above baseline), and severe (increase of ≥344 IU/L above baseline). Undetectable serum HBV DNA and hepatitis B e antigen (HBeAg) loss were significantly more likely at the end of follow-up in patients having a flare (P = .0001 and .001, respectively). In the high viremia group, a proportionate increase in virologic response was observed as the degree of flare increased. By multivariate analysis, high baseline HBV DNA, high pretreatment ALT, and both moderate and severe ALT flare were independently predictive of a virologic response with severe flare being the most powerful predictor for a sustained loss of serum HBV DNA (odds ratio, 5.3; P = .004). Severe flare was predictive of a virologic response in the high but not low viremia group. We conclude that a virologic response in patients with high-level viremia is dependent on the degree of ALT flare. Induction of a robust flare may enhance virologic response when high-level viremia is detected. (HEPATOLOGY 2001;34:1021-1026.)

Emergence of the precore mutant late in chronic hepatitis B infection correlates with the severity of liver injury and mutations in the core region

OBJECTIVE: The reason that precore negative mutants (e-minus DNA) gradually become predominant in some patients during chronic hepatitis B virus infection is not clear. Theoretically, as long as both e-plus and e-minus DNA share the same epitopes in the core region, HBcAg-specific cytotoxic T lymphocytes (CTLs) cannot distinguish between the target peptides expressed by e-plus and e-minus DNA. Therefore, e-minus DNA may be accompanied by additional mutations in the core region, which may affect cytotoxic T lymphocyte recognition. To examine this possibility, the sequences of the precore and the entire core region of the hepatitis B virus genome were analyzed from paired serum samples in CH-B patients who experienced HBeAg to anti-HBe seroconversion (SC). METHODS: Patients were divided into two groups. Group A patients (n = 17) genome-converted to e-minus DNA in the precore region, which abolished HBeAg secretion within 3–4 yr after SC. Group B patients (n = 16) retained precore wild-type DNA for more than 3–4 yr after SC. To investigate the impact of the emergence of precore mutant type DNA on liver injury, alanine aminotransferase (ALT) levels were also examined. RESULTS: ALT flares were more severe among patients in group A than in group B. The average mean ALT level during the HBeAg negative phase of chronic infection was 54 ± 38 in group A and 28 ± 24 in group B. The average maximal ALT level during the HBeAg negative phase was 235 ± 249 in group A and 83 ± 106 in group B. Furthermore, all 17 patients in group A developed new core mutants during genome conversion. The average number of mutations in the core gene was 0.9 ± 1.2 before genome conversion (e-plus DNA dominant phase) and increased to 2.8 ± 1.3 for the 3–4 yr during genome conversion (e-minus DNA dominant phase). In contrast, only 56% (nine of 16) of patients in group B developed new core mutations after the loss of HBeAg. The average number of mutations in the core gene was 1.8 ± 1.3 before SC (HBeAg-positive and e-plus DNA dominant phase), and decreased to 1.1 ± 1.1 for 3–4 yr after seroconversion (anti-HBe–positive and e-plus DNA dominant phase). CONCLUSIONS: These data indicate that the emergence of a predominant precore negative genotype late in chronic hepatitis B virus infection is associated with the selection of additional mutations in the core gene, as well as with liver injury.

Famciclovir in chronic hepatitis B: results of a dose-finding study

Background/Aims: Famciclovir, an orally available nucleoside analogue with potent in vitro activity against HBV, is being investigated for treatment of chronic hepatitis B.Methods: A dose-finding study was conducted in patients with hepatitis B e antigen present in serum. Patients received famciclovir 125 mg, 250 mg, 500 mg three times daily (tid) or placebo for 16 weeks, followed by 8 months post-treatment observation, and 16 weeks open-label treatment. More than 90% of patients had previously received alpha-interferon or had baseline characteristics indicating a high likelihood of poor response to alpha-interferon.Results: Famciclovir induced rapid, dose-dependent suppression of viral replication and reduction in alanine aminotransferase (ALT), with greatest efficacy in the 500-mg tid treatment group. HBV DNA reduction was maintained throughout the treatment period. ALT also steadily declined during the treatment period. Approximately 40% of patients with pretreatment ALT>upper limit of normal (ULN) receiving famciclovir 500 mg tid, experienced sustained normalization of ALT at the end of the 8-month follow-up. Anti-HBe seroconversion occurred more frequently in patients receiving famciclovir 500 mg tid compared with placebo (p=0.04). Famciclovir was generally well tolerated; the incidence of adverse events was comparable to placebo. Exacerbation of liver disease or serious ALT flares were not observed.Conclusion: Famciclovir 500 mg three times daily may offer an alternative to alpha-interferon for treatment for chronic hepatitis B. Anti-HBe seroconversion in the famciclovir 500-mg tid group suggests that 16 weeks treatment has the potential for HBV clearance. Further studies with a longer treatment duration are warranted.

Hepatitis C in injecting drug-using women during and after pregnancy.

A high proportion of female injecting drug users (IDU) have evidence of hepatitis C virus (HCV) infection. We undertook a prospective study of patients attending a clinic for pregnant IDU to determine the impact of pregnancy on the course of HCV infection and whether pregnancy is affected by HCV infection. One hundred and thirty-one IDU were recruited and followed up with liver function tests, HCV serology and HCV-RNA tests. Of 131 patients, 125 had HCV antibodies (anti-HCV positive) at delivery, and of these 62% were HCV-RNA positive. The anti-HCV-negative women were younger and had a shorter duration of drug use than the anti-HCV-positive women. There were no differences between viraemic and non-viraemic women with respect to age, ethnicity, duration of injecting drug use, methadone maintenance dose, hepatitis B exposure or reported high-risk behaviour. Alanine aminotransferase (ALT) levels were higher and the proportion with ALT > 55 IU/L higher in viraemic women. Viraemia persisted in all 55 women who were viraemic at term. Eleven had an ALT flare post-partum that was unrelated to viral load and was clinically unsuspected. Four had concurrent elevated gamma-glutamyltranspeptidase and were considered to be drinking alcohol at hazardous levels. Four of 23 women who were HCV-RNA negative at term became positive during follow up. Pregnancy does not adversely affect the course of hepatitis C. A modest rebound in ALT levels, but not HCV-RNA, occurs after delivery in some viraemic women. This supports the theory that immune mechanisms rather than direct viral cytopathology are involved in hepatocyte injury during HCV infection. Hepatitis C infection did not influence pregnancy complications and outcomes.

Hepatitis B surface antigenemia at birth: a long-term follow-up study.

To investigate the prevalence and outcome of hepatitis B surface antigenemia in newborns of hepatitis B e antigen (HBeAg)-positive hepatitis B surface antigen (HBsAg) carrier mothers under the current immunoprophylaxis program. From 1984 to 1993, 665 high-risk newborns born to HBeAg-positive HBsAg carrier mothers were prospectively recruited. The newborns were tested for HBsAg soon after birth, before hepatitis B immune globulin administration. All newborns received hepatitis B immune globulin within 24 hours after birth plus subsequent hepatitis B vaccination. Those who were seropositive for HBsAg at birth were regularly followed up for their hepatitis B virus (HBV) markers, liver function profiles, and alpha-fetoprotein levels from 1984 to 1996. Sixteen (2.4%) of the 665 subjects were found to be seropositive for HBsAg at birth, and all remained HBsAg-positive at 6 months of age. Twelve of the 16 received long-term follow-up care, and all were confirmed to have chronic HBV infection. Of the 12, 2 had HBeAg seroconversion, and 1 had alanine aminotransferase flares without HBeAg seroconversion. Delayed appearance of hepatitis B core antibody (anti-HBc) occurred in 2 without alanine aminotransferase elevation. Current immunoprophylaxis strategy does not protect newborns with surface antigenemia, apparently acquired in utero, from becoming HBV carriers. Immunologic attempts to eliminate HBV may occur in carrier children infected in utero, despite their profound immune tolerance to HBV.

Genetic immunization of chimpanzees chronically infected with the hepatitis B virus, using a recombinant retroviral vector encoding the hepatitis B virus core antigen.

Cytotoxic T lymphocyte (CTL) activity and CD4+ helper T cell responses to the hepatitis B virus (HBV) core antigen (HBcAg) have been implicated in clearance of acute and chronic HBV infections. We showed that intramuscular injections of a novel recombinant retroviral vector expressing an HBcAg-neomycin phosphotransferase II (HBc-NEO) fusion protein induces HBc/eAg-specific antibodies and CD4+ and CD8+ T cell responses in mice and rhesus monkeys. We have now immunized three chronically infected chimpanzees, each with 10(10) CFU of nonreplicating retroviral vector particles expressing the HBc-NEO fusion protein. Of two immunized chimpanzees examined for CTL responses, one developed HBcAg-specific CTLs and showed marginal, transient elevations of alanine aminotransferase (ALT) levels following injection. However, both chimpanzees remained positive for serum HBeAg, negative for anti-HBe antibody by conventional assays, and displayed no change in HBV viral load throughout the study. In contrast, the third chimpanzee exhibited a traditional seroconversion evidenced by a loss of serum HBeAg and the subsequent emergence of anti-HBe antibodies within 24 weeks after the first injection. Simultaneously, two transient ALT flares and a significant decrease in the serum HBV DNA levels were noted. Despite its limitations, the present study demonstrates (1) the safety of treatment with high titers of retroviral vector in chimpanzees, (2) the capability of a retroviral vector expressing HBcAg to stimulate immune responses in HBV chronic carrier chimpanzees, and (3) that retroviral vector immunization may be therapeutically beneficial in the treatment of chronic HBV infection.

Non-organ specific autoantibodies in children with chronic hepatitis C

Background/Aims: Recent studies in adult patients have established a relationship between hepatitis C virus infection and the presence of liver-kidney microsomal autoantibody type 1 (LKM1). Conversely, little is known regarding the relationship between hepatitis C and autoimmunity in children. In this study, we investigated non-organ specific autoantibodies in 40 otherwise healthy Italian children with chronic hepatitis C. Methods: All but four patients included in the study were asymptomatic. Liver histology, obtained in 35, showed features ranging from minimal to mild chronic hepatitis. Autoantibodies were investigated by indirect immunofluorescence. HCV RNA was assayed by the polymerase chain reaction in 34 cases and viral genotypes were determined. Results: Antinuclear antibodies were detected in three (7.5%) cases, one with a homogeneous pattern; smooth muscle autoantibodies in seven (17.5%) cases, always with V (vessels only) specificity and LKM1 in four (10%), at titers ranging from 1:20 and 1:2560. Clinical and virologic features did not significantly differ between autoantibody positive and negative cases, although infections with HCV genotypes 1a and 2 were more frequent in LKM1-positive patients. During observation, the child with the highest LKM1 titre was unsuccessfully treated with alpha interferon but responded to steroids. Twelve LKM1 negative children were also treated with interferon and one developed low LKM1 titers concomitant with an alanine aminotransferase flare. The sera of the five LKM1-positive children were investigated by immunoblotting with a human microsomal fraction and peptide 257–269 of cytochrome P450IID6. Only the serum of the child with the highest LKM1 titers was reactive. Conclusions: These results show that a consistent proportion of children with chronic hepatitis C circulate non-organ specific autoantibodies. The prevalence of LKM1 is greater than in adults and this could raise problems for the treatment of the disease with interferon. The analysis of LKM1 target antigens might help to identify putative cases of “true” autoimmune hepatitis with concomitant HCV infection that could benefit from steroid treatment.

The fluctuations of hepatitis C virus RNA and IgM anti-HCV (core) serum levels correlate with those of alanine aminotransferases during the hepatitis relapses of patients treated with interferon.

Variations in the serum levels of hepatitis C virus (HCV) RNA. IgM antibody against the HCV 'core' structural protein (c22) and alanine amino-transferase (ALT) were measured in 23 patients with chronic hepatitis C who underwent therapy with interferon-alpha 2a (IFN alpha 2a). Low pretreatment levels of viraemia and undetectable IgM anti-core were significantly associated with a long-term response to treatment. In patients with hepatitis relapses after the end of treatment, HCV RNA levels increased before or at the same time as ALT in 29 out of 34 cases (85%). ALT flares occurred before or simultaneously with IgM anti-core elevations in 18 out of 20 cases (90%). Therefore, post-treatment hepatitis C exacerbations show the same sequence of events seen as in hepatitis B exacerbations (increases of viraemia followed by those of ALT and IgM anti-'core'). These findings underscore the diagnostic and prognostic usefulness of monitoring anti-HCV-positive patients with quantitative assays for HCV markers.