Partial Virological Response Research Articles

Hepatitis C in the HIV-Infected Patient

Hepatitis C virus (HCV) coinfection in the presence of HIV raises several challenging issues for the treating clinician. Some evidence indicates that concomitant HIV infection alters HCV virology in ways that are relevant for treatment. Pegylated interferon plus ribavirin is the recommended therapy for HCV in HIV-infected patients. Proportionately fewer HIV/HCV-coinfected patients achieve a sustained virologic response (SVR) compared with those infected with HCV alone. Possible reasons for this include higher levels of HCV viremia and inadequate ribavirin exposure. Strategies under study for optimizing therapeutic response include weight-based ribavirin dosing, use of growth factors to avoid dose reduction, and longer duration of therapy. Aggressive management of adverse effects to avoid dose reduction or treatment discontinuation is also crucial. An integrated multidisciplinary team, including a psychiatrist and addictions specialist, can increase the proportion of HIV/HCV-coinfected patients eligible for treatment. Investigational options exist for patients who relapse after treatment is discontinued and for those with a partial virologic response. Promising therapies that are under development include protease and polymerase inhibitors.

Genetic distance and heterogenecity between quasispecies is a critical predictor to IFN response in Egyptian patients with HCV genotype-4

BackgroundHCV is one of the major health problems in Egypt, where it is highly prevalent. Genotype 4 is the most common genotype of HCV and its response to treatment is still a controversy.MethodsHCV genotype 4 quasispecies diversity within the 5' untranslated region (5'UTR) was studied in a series of 22 native Egyptian patients with chronic hepatitis C virus with no previous treatment who satisfied all NIH criteria for combined treatment of pegylated IFN and ribavirine and was correlated with the outcome of treatment. The study also included 7 control patients with no antiviral treatment. HCV sequencing was done using the TRUGENE HCV 5-NC genotyping kit.ResultsAt the 48th week of treatment, 15 patients (68%) showed virological response. Whereas HCV-RNA was still detected in 7 patients (32%) in this period; of those, 6 experienced a partial virological response followed by viral breakthrough during treatment. Only one patient did not show any virological or chemical response. The four females included in this study were all responders. There was a significant correlation between the response rate and lower fibrosis (p = 0.026) as well as the total number of mutation spots (including all the insertions, deletions, transitions and transversions) (p = 0.007, p = 0.035).ConclusionPatients who responded to interferon treatment had statistically significant less number in both transitions (p = 0.007) and the genetic distances between the quasispecies (p = 0.035). So, viral genetic complexity and variability may play a role in the response to IFN treatment. The consensus alignment of all three groups revealed no characteristic pattern among the three groups. However, the G to A transitions at 160 was observed among non responders who need further study to confirm this observation.

Chronic hepatitis C: Treatment of pegylated interferon/ ribavirin nonresponders

Patients with chronic hepatitis C virus (HCV) who were nonresponders to previous treatment with pegylated interferon and ribavirin are a growing population. The vast majority have genotype 1, a high viral load, advanced fibrosis or cirrhosis, and are of African American race. The evaluation of these patients should include a thorough review of the previous treatment record and characterization of the previous nonresponse. Patients with prior null response are likely resistant to the effects of interferon. In contrast, patients with partial virologic response, breakthrough, and relapse could potentially achieve sustained virologic response if one or more correctable factors that contributed to the prior nonresponse are identified and addressed before and during retreatment. Many HCV nonresponders, especially those with no fibrosis or mild fibrosis, have an excellent prognosis, are at low risk to develop cirrhosis, and should simply be monitored at periodic intervals until more effective therapy has been developed.

Chronic hepatitis C: Treatment of pegylated interferon/ ribavirin nonresponders

Patients with chronic hepatitis C virus (HCV) who were nonresponders to previous treatment with pegylated interferon and ribavirin are a growing population. The vast majority have genotype 1, a high viral load, advanced fibrosis or cirrhosis, and are of African-American race. The evaluation of these patients should include a thorough review of the previous treatment record and characterization of the previous nonresponse. Patients with prior null response are likely resistant to the effects of interferon. In contrast, patients with partial virologic response, breakthrough, and relapse could potentially achieve sustained virologic response if one or more correctable factors that contributed to the prior nonresponse are identified and addressed before and during retreatment. Many HCV nonresponders, especially those with no fibrosis or mild fibrosis, have an excellent prognosis, are at low risk to develop cirrhosis, and should simply be monitored at periodic intervals until more effective therapy has been developed.

Pegylated IFN-α 2b added to ongoing lamivudine therapy in patients with lamivudine-resistant chronic hepatitis B

To investigate the role of pegylated-interferon (IFN) alpha-2b in the management of patients with lamivudine-resistant chronic hepatitis B. Twenty consecutive anti-HBe positive patients were treated with pegylated IFN alpha-2b (100 mug sc once weekly) for 12 mo. There was no interruption in lamivudine therapy. Hematology, liver biochemistry, serum HBV DNA levels were detected by PCR, and vital signs were also assessed. Liver histology was assessed in some patients at entry and at wk 52 for comparison. Nine patients (45%) had a partial virological end-treatment response; seven patients (35%) showed complete virological end-treatment response. Eight patients (40%) showed biochemical end-treatment response. There was a trend for higher virological response rates in patients who had previously responded to IFN and relapsed compared to IFN non-responders (four out of seven patients vs none out of six patients, respectively; P=0.1). Patients without virological end-treatment response showed significant worsening of fibrosis [median score 2 (range, 1 to 3) vs median score 3 (range, 1 to 4)], in the first and second biopsy respectively (P=0.014), whereas necroinflammatory activity was not significantly affected. Patients with complete or partial virological end-treatment response did not show any significant changes in histological findings, possibly due to the small number of patients with paired biopsies (n=5). Nevertheless, after 12 mo of follow-up, only one patient (5%) showed sustained virological response and only 2 patients (10%) showed sustained biochemical response. Two patients (10%) discontinued pegylated IFN both after 6 mo of treatment due to flu-like symptoms. Pegylated IFNalpha-2b, when added to ongoing lamivudine therapy in patients with lamivudine-resistant chronic hepatitis B, induces sustained responses only in a small minority of cases.

PEGylated interferon alfa‐2b and ribavirin treatment in patients with hepatitis C virus–related systemic vasculitis

Type II mixed cryoglobulinemia (MC) is a systemic vasculitis usually associated with hepatitis C virus (HCV), which may involve the skin, kidneys, and nervous system. Molecular evidence of antigen-driven B cell proliferation is definitively provided in HCV-associated type II MC, and HCV appears to be the key trigger. The present trial was established to investigate the efficacy of therapy with PEGylated interferon alfa-2b (PEG-IFN alfa-2b) plus ribavirin in patients with HCV-related MC vasculitis. Nine consecutive patients with HCV-related MC received PEG-IFN alfa-2b (1.5 microg/kg/week) subcutaneously plus oral ribavirin (800-1,200 mg/day) for at least 6 months. The response to treatment was analyzed by comparing clinical, immunologic, and virologic parameters at the initial evaluation with those observed during followup. The mean +/- SD duration of therapy with PEG-IFN alfa-2b plus ribavirin was 13.5 +/- 2.8 months. After a mean period of 18.6 months following discontinuation of treatment, all 9 patients are alive. Seven patients (78%) had a sustained virologic response and were complete clinical responders. Serum cryoglobulin disappeared in 5 of 9 patients (56%), and complement levels normalized in 80% of the patients. One patient had a partial virologic response with a complete clinical response. In another patient, a clinical relapse of MC vasculitis occurred in association with the reappearance of HCV RNA. Treatment was well tolerated, and no patient had side effects for which discontinuation of therapy was required. Treatment with PEG-IFN alfa-2b plus ribavirin can achieve a complete clinical response in most patients with HCV-related MC vasculitis. Complete clinical response correlates with the eradication of HCV and requires a shorter treatment period than that previously reported for IFNalpha plus ribavirin.

Effects of long-term lamivudine therapy in renal-transplant patients

Following renal transplantation (RT), chronic immunosuppression is associated in hepatitis B virus (HBV) (+) patients with a flare-up of the disease, which might be harmful in the long term. We report on the effect of long-term lamivudine therapy given at an initial daily dose of 100mg in 18 HBV (+) RT patients. When lamivudine therapy was commenced, 14 patients (77%) had an increase in their aspartate (AST) and alanine (ALT) aminotransferase levels. During a mean follow-up, under treatment, of 36.5 +/- 3.5 months (up to 66 months), 10 patients (55%) had a sustained partial (HBV DNA < 4 x 10(5)copies/ml) (n = 4) or complete (HBV DNA < 400 copies/ml) (n = 6) virological response. Overall, 12 virological breakthroughs were observed. Of those who were HBe Ag(+) prior to lamivudine therapy (n = 4), one seroconverted to HBe Ab during therapy. At the last follow-up, AST and ALT levels were normal in 13 patients. When liver biopsy was repeated during treatment (n = 15), the virological responders showed a significant decrease in total Knodell score from 10 +/- 0.6 to 7 +/- 1 (P = 0.04), but no significant change in the stage of fibrosis. Conversely, in those patients with high HBV DNA titers, there were no significant changes in the total Knodell score or in the grade of fibrosis. In conclusion, lamivudine therapy is safe in HBV(+)ve renal-transplant patients. However, even if the full and partial virological response rates are still high (55%) in the long term, relapse or primary non-responses occur. The implementation of alternative efficient strategies is warranted.

Effect of antiviral treatment in patients with chronic HCV infection and t(14;18) translocation

AbstractHepatitis C virus (HCV) may be associated with the mixed cryoglobulinemia syndrome and other B-cell lymphoproliferative disorders (LPDs). The t(14;18) translocation may play a pathogenetic role. Limited data are available regarding the effects of antiviral therapy on rearranged B-cell clones. We evaluated the effects of interferon and ribavirin on serum, B-lymphocyte HCV RNA, and t(14; 18) in 30 HCV+, t(14;18)+patients without either mixed cryoglobulinemia syndrome or other LPDs. The t(14;18) translocation was analyzed by bothbcl-2/JHpolymerase chain reaction andbcl-2/JHjunction sequencing in peripheral blood mononuclear cells in all patients. Fifteen untreated patients with comparable characteristics served as controls. Throughout the study, the presence or absence of both t(14;18) and HCV RNA sequences were, in most cases, associated in the same cell samples. At the end of treatment, t(14;18) was no longer detected in 15 patients (50%) with complete or partial virologic response, whereas it was persistently detected in nonresponders (P< .05), as well as in 14 of 15 control patients. In 4 responder patients, t(14;18) and HCV RNA sequences were no longer detected in blood cells after treatment, but were again detected after viral relapse; the same B-cell clones were involved in the pretreatment and posttreatment periods. In conclusion, this study suggests that antiviral therapy may induce regression of t(14;18)–bearing B-cell clones in HCV+patients and that this phenomenon may be related, at least in part, to the antiviral effect of therapy. This in turn suggests that antiviral treatment may help prevent or treat HCV-related LPDs.

Novel deletion of HIV type 1 reverse transcriptase residue 69 conferring selective high-level resistance to nevirapine.

A novel deletion of residue 69 of the HIV-1 reverse transcriptase (RT) gene was detected in combination with mutations V75I/V and F77L/F in a patient with partial virological response to several antiretroviral drug regimens, including stavudine (D4T), didanosine (DDI), lamivudine (3TC), saquinavir (SQV), and nevirapine (NVP). Longitudinal analysis of samples revealed that this deletion emerged upon reinitiation DDI/D4T therapy following a toxicity-induced short discontinuation of all antiretrovirals. Analysis of the resistance phenotype showed a greater than 62-fold increase of the IC50 of NVP, but no significant change in sensitivity to other single nonnucleoside reverse transcriptase inhibitors (NNRTIs). The mutated virus showed only a moderately reduced sensitivity to DDI (6.7-fold) and D4T (4.8 fold). In a subsequent sample 3 months later additional RT mutations were found, including A62V, Y188L, and Q151M, conferring high-level cross-resistance to multiple nucleoside analogs. Our findings provide evidence that the deletion of RT residue 69 selectively confers high-level NVP resistance.