Analysis of Host and Viral-Related Factors Associated to Direct Acting Antiviral Response in Hepatitis C Virus Patients.

Hepatitis C virus (HCV) signifies an important health issue as it is a globally prevalent pathogen and poses a great threat to human health. Direct antiviral therapy became a landmark in treatment against chronic HCV infection as they have proven to increase sustained virological response (SVR) rate, provide shortened and simplified regimens. This study aimed to evaluate efficacy of Sofosbuvir and classify factors of treatment success and their function in therapy continuation decision. We studied host and viral factors in 310 patients who received Sofosbuvir (DAA) at a dose of 400 mg daily along with ribavirin 10 mg/kg body weight for 24 weeks and followed by 12 weeks after completion of treatment. A total of 302 patients (97.42%) showed end-of-treatment response. However, 8 patients (2.58%) were virological nonresponders and 286 patients (94.70%) achieved SVR. Among 310 HCV positive, the percentage of viral genotype 3-infected patients was 89.6%, whereas only 10.32% were affected by HCV genotype 1. Multivariable analysis showed that baseline HCV RNA (≤8 × 106 IU/mL vs. >8 × 106 IU/mL) [95% confidence interval (CI), odds ratio (OR) 3.0, 2.0 to 8.4; p = 0.004], age (<50 vs. ≥50 years) (95% CI, OR 1.9, 3.0 to 10.1; p = 0.03), liver texture (normal liver vs. coarse) are related to virological response. None of the patients included in the study has S282T substitution in NS5b of HCV. No significant difference in response was observed in patients with different genotypes of rs12979860. Liver texture, age, and viral load are predictors of SVR. In this real-life data no substitution of S282T in NS5b was observed related to failure of therapy. Oral Sofosbuvir generally has a high tolerance and can effortlessly beat the safety concerns of past regimens.

Polymorphism of the IL28B gene (rs8099917, rs12979860) and virological response of Pakistani hepatitis C virus genotype 3 patients to pegylated interferon therapy.

BACKGROUND: The gold standard treatment for chronic hepatitis C virus (HCV) infection is pegylated interferon (PEG-IFN) in combination with ribavirin. Most patients treated with PEG-IFN achieve a sustained virological response (SVR). However host genetic factors play a vital role in the spontaneous and treatment-induced clearance of HCV infection from these infected patients. In the current study, polymorphisms of IL28B (rs8099917 and rs12979860) were analyzed and their association with the virological response to PEG-IFN alpha treatment was determined. METHODS: One hundred and fifty HCV genotype 3 patients were assessed to study the correlation of IL28B with a therapeutic regimen of PEG-IFN alpha plus ribavirin. Twenty patients were excluded due to a refusal to participate in the study and 25 patients failed to meet the inclusion criteria. Of the 105 patients recruited, 49 (46.7%) were male and 56 (53.3%) were female. In order to determine single nucleotide polymorphisms of rs8099917 and rs12979860, the sample was amplified by PCR and then IL28B typing was carried out by restriction fragment length polymorphism (RFLP) followed by standard sequencing. RESULTS: We found three types of genotype in rs8099917 of IL28B: wild-type TT in 60.0% of patients, heterozygous GT minor genotype in 36.2%, and GG in 3.8%. The frequency of the CC genotype of rs12979860 was 54.3%, CT was 37.1%, and TT was 8.6%. Overall, SVR was achieved in 68.6% of patients. A higher SVR was achieved for patients with the favorable genotype CC of rs12979860, with 84.2% as compared to 56.4% and 22.2% for minor genotype CT and TT, respectively (p=0.0001). We did not find a significant association for SVR to antiviral treatment in patients with genotype TT (rs8099917) (71.9%, p=0.36). The rapid virological response (RVR) rate was significantly higher in patients with major genotype TT (88.9%, p=0.04). These results show that IL28B polymorphism is highly associated with SVR to therapy in the Pakistani population infected with HCV genotype 3. CONCLUSIONS: HCV-infected patients carrying homozygous C/C have a higher chance of SVR. In addition, patients who carry T/T (rs8099917) have a higher chance of RVR.

Rapid virological response tailors the duration of treatment in hepatitis C virus genotype 3 patients treated with pegylated interferon alfa-2a and ribavirin in Pakistan.

BACKGROUND: Rapid virological response (RVR) is now thought to be the strongest predictor of sustained virological response (SVR) in hepatitis C virus (HCV) patients undergoing antiviral therapy. It can be used as a guide to individualize treatment duration. The aim of this study was to assess the role of RVR in tailoring the duration of treatment. METHODS: Patients with HCV genotype 3 infections were enrolled and treated with pegylated interferon alfa-2a (PEG IFN alfa-2a) 180 µg/week and ribavirin. HCV RNA was analyzed at weeks 4, 12, 16, and 24. Treatment duration was individualized on the basis of RVR. Patients who achieved RVR and who were aged ≤ 40 years with a body mass index (BMI) ≤ 27 kg/m(2) received 16 weeks of treatment (group A). Patients who achieved RVR and were aged >40 years with a BMI >27 kg/m(2), aged >40 years with a BMI ≤ 27 kg/m(2), and aged ≤ 40 years with a BMI >27 kg/m(2) received 24 weeks of treatment (group B). Patients who did not achieve RVR but who achieved an early virological response (EVR; HCV PCR-negative or ≥ 2 log drop in HCV RNA at week 12) were treated with 24 weeks of therapy (group C). RESULTS: SVR was observed in 86% in group A, 82.2% in group B, and 46.8% in group C. A difference was observed in SVR for patients with and without RVR and receiving the standard duration of treatment (82.2% vs. 46.8%, p<0 .001). The results show that the rate of SVR is not inferior in those with RVR treated with 16 weeks of therapy compared to 24 weeks (86% vs. 82.2%, p=0.004). CONCLUSIONS: RVR is useful to individualize the duration of treatment and to predict the treatment outcome. A short treatment of 16 weeks is as effective as 24 weeks in HCV genotype 3 patients who achieve RVR, who have a low BMI, and are younger in age.

Analysis of variables and interactions among variables associated with a sustained virological response to pegylated interferon alfa-2a plus ribavirin in hepatitis C virus genotype 3-infected patients.

BACKGROUND: The recommended standard therapeutic regimen for chronic hepatitis patients with hepatitis C virus (HCV) genotype 3 is pegylated interferon plus ribavirin for 24 weeks. The aim of the present study was to evaluate treatment efficacy and variables predictive of treatment success, interactions among variables contributing to a response to therapy, and the utility of the rapid virological response (RVR; week 4 virological response) to predict treatment outcomes in HCV genotype 3-infected patients in routine clinical practice. METHODS: We prospectively studied baseline and during-treatment factors associated with a sustained virological response (SVR) in HCV genotype 3-infected patients who received pegylated interferon alfa-2a (PEG-IFN α2a) 180 µg/week plus ribavirin 800 mg daily for 24 weeks and who were followed for 24 weeks after the completion of treatment. RESULTS: Four hundred and twenty-six treated patients were included in the analysis; 320 (75.1%) showed an SVR. The following factors were assessed for their ability to predict SVR by means of univariable and multivariable logistic regression analysis: patient age, sex, pre-treatment viral load, pre-treatment alanine aminotransferase (ALT), body mass index (BMI), and RVR. Four factors - age, pre-treatment viral load, pre-treatment ALT, and RVR - were statistically significant predictors of SVR (p<0.05) in the univariable analysis. Factors showing a significant association with SVR were assessed by multivariable logistic regression analysis. In the multivariable analysis, independent factors associated with SVR were the attainment of RVR (odds ratio (OR) 11, 95% confidence interval (CI) 6.15-20.69; p<0.0001), patient age ≤40 years (OR 4.2, 95% CI 2.30-7.96, p<0.0001), and a low pre-treatment viral load (≤8 × 10(5) IU/ml; OR 3.4, 95% CI 1.87-6.25; p<0.0001). The effect of RVR in patients aged >40 years was more pronounced than in those aged ≤40 years: 81.1% of patients aged >40 years who achieved an RVR had an SVR, whereas only 7.5% of patients aged >40 years who did not achieve an RVR had an SVR (p<0.05). CONCLUSIONS: RVR is an independent variable that is predictive of SVR. Moreover older patients (>40 years) who achieve an RVR are likely to have an SVR, while patients who do not achieve an RVR and who have a high pre-treatment viral load (>8 × 10(5) IU/ml) are unlikely to have an SVR.

Treatment outcomes with long acting octreotide in inoperable hepatocellular carcinoma: a local experience and review of literature.

OBJECTIVE: To determine the efficacy of long acting octreotide (LAR) in the treatment of inoperable hepatocellular carcinoma; as well as to estimate the improvement in the quality of life. METHODS: This study was carried out at the Shifa International Hospital, Islamabad between February and September 2003. Patients were recruited after an informed consent. There were 22 patients who decided to take the medication whereas 20 patients refused due to socio-economic issues. They served as controls. The patients agreeable for treatment were administered octreotide 100 mcg subcutaneously thrice daily for two weeks. This was followed by monthly administration of 20 mg intramuscular octreotide. The patients were followed up for 6 months. Tumor size, alpha-fetoprotein levels, and improvement in quality of life (QOL) were monitored during therapy. RESULTS: Out of 22 patients, 19 patients completed the treatment. All were males. Mean age at presentation was 55 years. Tumor size regression was seen in 10 out of 22 patients (45.5%). Mean alpha-fetoprotein levels decreased in 11 out of 22 (50%) patients. An improvement in the quality of life was seen in 10 out of 22 (45.5%) patients after treatment with long acting octreotide. In the treatment arm, 14 out of 22 (64%) patients were alive at the end of six months as compared to 10 out of 20 (50%) in the control group. CONCLUSION: LAR causes tumor size regression, decreases AFP levels and improves quality of life in patients with inoperable hepatocellular carcinoma.

Percutaneous endoscopic gastrostomy: nine years experience in a tertiary care centre in Pakistan.

OBJECTIVE: To review the experience of percutaneous endoscopic gastrostomy (PEG) tube placement and its management in the last nine years, at a tertiary care center in Pakistan. METHODS: All patients who underwent percutaneous endoscopic gastrostomy from January 1995 to January 2004 at Shifa International Hospital, Islamabad, were included in this study. The indications, technique, complications and follow up were reviewed. RESULTS: A total of 182 persons underwent this procedure. There were 118 (65.0%) males and 64 (35.0%) females. Age ranged from 55-86 years. One hundred seventy five (96.0%) patients had cerebro-vascular accident, five (2.75%) had Parkinson's disease and two (1.25%) malignancy. More than 99% procedures were successful and no procedure related mortality was noted. Mild PEG site infections were encountered in eighteen (9.8%) patients which were manageable with local treatment and oral antibiotics. Four (2.2%) patients had severe tube site infection and needed parenteral antibiotics. Tube dislodgement took place in five (2.75%) patients and had to be removed and reinserted. Thirty days follow up was uneventful with regard to the tube. Longest follow up was 736 days. CONCLUSION: Percutaneous endoscopic gastrostomy had proved a viable means of enteral nutrition in patients with neurological impairment. Complications were insignificant. However, patient and care giver's education could be improved for more effective tube management, and prevention of PEG insertion site infection.

Treatment of chronic hepatitis B with lamivudine.

OBJECTIVE: To study the efficacy of antiviral drug lamivudine for treatment of chronic hepatitis B in Pakistani population. DESIGN: Experimental study. PLACE AND DURATION OF STUDY: A tertiary Care Center, from January 2000 to January 2004. PATIENTS AND METHODS: Patients who had positive hepatitis B surface antigen (HBsAg) and elevated ALT were recruited. Both hepatitis Be antigen (HBeAg) positive and HBeAg negative patients were included. Treatment was given with lamivudine 100mg once a day for 12 months and they were followed every 2-3 months with ALT, HBeAg, and in certain cases with, HBV DNA (PCR). Those patients who were HBeAg positive were considered to have achieved end of treatment response (ETR) when ALT was normal and HBeAg was negative and this was documented at two consecutive occasions, at least one month apart. Those patients who were HBeAg negative were considered to have achieved ETR when their ALT was normal and HBV DNA was undetectable. Patients were followed for further 6 months to evaluate for any relapse. RESULTS: A total of 105 patients were included. Eighty-two (78.1%) were males and 23 (21.9%) were females. Mean ALT of all patients was 87.15 +/- 46.01 u/dl. Seventy-two HBeAg positive and 15 HBeAg negative patients completed treatment with 23.6 % and 80.0 % response rate respectively (p <0.001). CONCLUSION: The response of lamivudine in chronic hepatitis B in Pakistani population is encouraging in HBeAg negative patients but is rather low in those who are HBeAg positive.

Successful treatment of resistant chronic hepatitis C virus infection with high dose pegylated interferon.

We present the case of a 49 years old male, who was HCV RNA positive with an ALT of 260, showing no response to standard interferon (INF) plus ribavirin treatment for 48 weeks and to a further therapy with high dose standard IFN plus ribavirin for 24 weeks. Pegylated (PEG) IFN was then started at a dose of 80 mcg/week with ribavirin, but proved to be of no avail. Finally, a dose of 120 mcg/week of PEG INF and ribavirin was administered for 48 weeks. This resulted in negative HCV RNA PCR after two months and remained undetectable with normal ALT. A six-month follow-up showed a sustained viral response.

Interspousal transmission of hepatitis C virus.

OBJECTIVE: To estimate the sero-prevalence of anti-HCV among the spouses of HCV positive patients. DESIGN: A cross-sectional survey. PLACE AND DURATION OF STUDY: Shifa International Hospital, Islamabad, from January 2001 to January 2004. PATIENTS AND METHODS: Spouses of patients of hepatitis C were studied. Spouses of patients who had hepatitis C by the presence of anti-HCV and HCV RNA (PCR) were tested for anti-HCV by ELISA method. RESULTS: A total of 347 consecutive patients were included in the study. Fifty-three patients were single, 48 were widows or divorced and 19 individuals refused to be tested. Thus, 227 patients were available for anti-HCV testing. Out of these 227 spouses tested, 10 (4.4%) were found to be positive for anti-HCV. The mean age of HCV-positive spouses was 44.2 +/- 8.31 years, while that of HCV-negative spouses was 46.37 +/- 11.31 years (p = 0.55). The mean years of marriage of HCV-positive spouses was 20.1 +/- 9.79 years as compared to 21.1 +/- 9.96 years for HCV-negative spouses (p = 0.75). The male proportion of HCV-positive spouses was 60% as compared to 57.6% for HCV-negative spouses (p = 0.9). The patients and spouses had common risk factor of history of injections. CONCLUSION: A positive anti-HCV was found in 4.4% spouses and common risk factors of history of injection and transfusion were noted in the patients and spouses.

General seroprevalence of hepatitis C and hepatitis B virus infections in population.

OBJECTIVE: To determine the prevalence of hepatitis C virus (HCV) and hepatitis B virus (HBV) infection by detection of anti-HCV and hepatitis B surface antigen (HbsAg) in general population of Pakistan. DESIGN: Observational. PLACE AND DURATION OF STUDY: Community clinic of Shifa International Hospital, Islamabad, from January 1998 to June 2004. MATERIALS AND METHODS: Sera of healthy adult individuals who presented for medical evaluation as a pre-employment criteria in the Gulf region were examined for presence of hepatitis B surface antigen and anti-HCV antibody. Alanine aminotransferase levels were also determined. RESULTS: A total of 47,538 individuals were examined. Out of these, 2528 (5.31%) were positive for anti-HCV and 1221 (2.56%) individuals had positive HBsAg. Hepatitis B surface antigen and anti-HCV both were found in 92 (0.19%) individuals. Mean age of subjects, positive for HCV antibody was 44 years and 40.5 years for HBV. Ninety-four percent individuals were males and 6% were females. Alanine aminotransferase (ALT) was normal in 56 % of subjects with positive HCV and 84% of individuals with HBV. CONCLUSION: This study which evaluated predominantly a healthy male population, showed a high seroprevalence of anti-HCV and average seroprevalence of hepatitis B virus infection. A large majority of these patients was young and had normal ALT.

Serological profile of incidentally detected asymptomatic HBsAg positive subjects (IDAHS).

OBJECTIVE: To evaluate the serological profile of patients with incidentally detected positive hepatitis-B surface antigen (HBsAg) and to asses the risk factors. DESIGN: An observational study. PLACE AND DURATION OF STUDY: This study was conducted at Shifa International Hospital, Islamabad from 1999 to 2003. PATIENTS AND METHODS: All patients who presented to gastroenterology clinic of Shifa International Hospital, Islamabad with positive HbsAg, detected incidentally, were tested for alamine transaminase (ALT), hepatitis Beantigen (HbeAg) and in certain cases hepatitis-B virus DNA (HBV DNA) by polymerase chain reaction (PCR). Their risk factors for acquisition of infection were assessed with specific questions. RESULTS: A total of 224 patients were examined. One hundred sixty-four (73.2%) were male and 60 (26.8%) female. Mean age fo all the subjects was 32.45 -/+ 11.85 years. Out of 224 patients, 48 (21.4%) were positive for HBeAg and 176 (78.6%) were negative. Out of 48 subjects who were positive for HBeAg, 36 underwent HBV DNA determination and 32 (88.8%) were positive for HBV DNA. Out of 176 subjects who had negative HBeAg, 46 had elevated ALT and in those HBV DNA was performed and 14 had positive HBV DNA. Most common risk factors detected in these patients were intramuscular injections and surgery, however, in a large number, risk factors were unknown. CONCLUSION: Twenty-one percent asymptomatic subjects with positive HBsAg were found to be HBeAg positive. A large number of subjects with negative HBeAg had HBV DNA positive suggesting presence of precore mutants. Intramuscular injections and surgery were noted to be frequent risk factors in these subjects.

Endoscopic dilation of esophageal strictures.

OBJECTIVE: To review the experience of endoscopic dilation of esophageal strictures at a tertiary care hospital. DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Shifa International Hospital, Islamabad January 1985 to January 2003. MATERIALS AND METHODS: Patients presenting with dysphagia who presented at our institution during the past 8 years were reviewed. Their etiology and the number of dilations required for improvement in dysphagia and follow up with any complications were reviewed. All procedures were performed with savary dilators using guide wire without fluoroscopy. RESULTS: A total of 369 patients were seen during this period and 583 procedures were performed. Two hundred thirty-five (63.7%) patients had peptic stricture, 123 (33.3%) had malignant strictures, 08 (2.2%) had non obstructive dysphagia and 6 (1.6%) had corrosive ingestions. The age ranged from 28-68 years. There were 254 (88.5%) males and 115 (31.2%) females. Sixty-seven (11.5%) procedures were performed as inpatient and 516 (88.5%) procedures were done as outpatient. Two to three attempts at dilatation were required to achieve satisfactory swallowing. There were no serious complication. Follow-up period was 6-8 weeks on an average. CONCLUSION: Most common esophageal stricture found in our practice were peptic strictures. Dilation with savary system was safe and effective and was able to relieve dysphagia in large number of patients. No fluoroscopic guidance was needed.