Sofosbuvir/Velpatasvir/Voxilaprevir for Hepatitis C Virus Retreatment in Difficult-to-treat Patients: A Real-life Observational Study from India.

Background and aim: Hepatitis C virus (HCV) treatment fails to achieve sustained virological response at 12 weeks (SVR12) in 5-10 % and requires retreatment with second-line drugs. We report our experience of sofosbuvir/velpatasvir/voxilaprevir use for HCV retreatment in a small cohort of difficult-to-treat Indian patients. Methods: We reviewed our HCV databases to identify the patients who had failed to achieve SVR12 after treatment with sofosbuvir in combination with either daclatasvir, ledipasvir, or velpatasvir with/without ribavirin on one or more occasions. Participants were excluded if they had (i) decompensated cirrhosis, (ii) HIV coinfection or (iii) chronic kidney disease, or (iv) prior organ transplantation. All the participants were treated with sofosbuvir/velpatasvir/voxilaprevir plus ribavirin for 12 weeks. Treatment outcome was categorized as successful or failure if HCV RNA was undetectable or detectable at SVR12, respectively. Results: Fifteen patients (male 67 %; genotype-3 80 %) were included in the analysis. Ten (67 %) had cirrhosis. Five, eight, and two participants had previously failed one, two, and three courses of pegylated-interferon free, sofosbuvir containing direct acting antiviral (DAA) regimens respectively. Fourteen participants had failed to at least one course of the sofosbuvir/velpatasvir combination. Fourteen patients achieved SVR12, and one patient was lost to follow-up. Treatment was successful in 100 % and 93.3 % of per-protocol (PP) and intention to treat (ITT) analyses, respectively. Conclusion: Sofosbuvir/velpatasvir/voxilaprevir combination is an effective second-line therapy in India for difficult-to-treat HCV patients.

Humoral and cellular immune response in patients of liver cirrhosis and immunocompetent recipient of ChAdOx1nCoV-19 Vaccine (Covishield).

Despite the effectiveness of COVID-19 vaccination in reducing the severity of the disease, the demand for booster is increasing in vulnerable populations like elderly and immunocompromised individuals especially with each new wave of COVID-19 in different countries. There is limited data on the sustained immunity against COVID-19 in patients with liver cirrhosis. The study was aimed to compare the T cell and humoral immune response after 1 year of ChAdOx1nCoV-19 Vaccine in patients with liver cirrhosis and healthy health care workers (HCW). This was a prospective observational study including 36 HCW, 19 liver cirrhosis patients and 10 unvaccinated individuals. Anti-SARS-CoV-2S antibody, neutralizing antibody and memory T cell subsets were evaluated by ELISA and flow cytometry, respectively, in all three groups after 1 year of initial vaccination. Compared to HCW and unvaccinated individuals, liver cirrhosis patients had significantly depleted T cells, although CD4:CD8 + T cell ratio was normal. Both cirrhotic patients and HCW developed memory T cell subset [effector memory RA (P = 0.141, P < 0.001), effector memory (P < 0.001, P < 0.001), central memory (P < 0.001, P < 0.01), stem cell memory (P = 0.009, P = 0.08) and naïve (P < 0.001, P = 0.02)] compared to unvaccinated unexposed individuals of CD4 + T and CD8 + T, respectively. However, among HCW and cirrhotic group no difference was noted on central memory and stem cell memory cells on T cells. Patients with liver cirrhosis developed comparable memory T cells after vaccination which can evoke sustainable immune response on reinfection. Therefore, additional vaccine doses may not be necessary for cirrhosis patients.

Hepatitis C Retreatment With First-Line Direct Acting Antiviral Drugs.

Background and Aims: Sofosbuvir (S), daclatasvir (D), ledipasvir, or velpatasvir (V) containing first-line hepatitis C virus (HCV) treatment regimens fail to cure viremia in 5-10%. We report our experience of HCV retreatment using these first-line drugs, in a setting where second-line anti-HCV drugs are not available. Methods: Adults, who had relapsed after first complete course of a sofosbuvir-containing first-line, pegylated interferon free, anti-HCV treatment regimen with or without ribavirin (Riba) were included. Retreatment regimen, tailored to the failed anti-HCV regimen, was based on principle of using first-line drugs for 24 weeks with ribavirin and swapping between pangenotypic and genotype-specific regimens. Retreatment outcome was categorized as successful (achieved undetectable HCV RNA at the end of treatment [ETR] and sustained viral response at week 12 [SVR12]), non-responder (failed to achieve ETR), or relapse (achieved ETR but not achieved SVR12). Results: Twelve patients (9 male; 7 cirrhosis; all genotype 3) who had relapsed to prior anti-HCV treatment (4 SD12, 4 SD24, 1 SDRiba12, 1 SDRiba24, 2 SV12) were included. Following retreatment (2 SDRiba24, 10 SVRiba24), all achieved ETR but only 9 (75%) achieved SVR12. Two among three, in whom retreatment failed, achieved SVR12 following another course of sofosbuvir/velpatasvir/ribavirin for 24 weeks. Overall, 11/12 (92%) patients achieved SVR12 following retreatment with the first-line anti-HCV drugs. Conclusion: HCV retreatment could be a treatment option if second-line anti-HCV drugs are not available. Successful retreatment could be achieved, in a large proportion, with the use of first-line drugs for 24 weeks with ribavirin and swapping of pangenotypic/genotype-specific regimens (NCT03483987).

Eight versus twelve weeks of sofosbuvir-velpatasvir in treatment-naïve non-cirrhotic patients with chronic hepatitis C virus infection: Study protocol for a multicentric, open labelled, randomized, non-inferiority trial (RESOLVE trial).

BACKGROUND: Hepatitis C virus (HCV) is a common cause of liver cirrhosis and hepatocellular carcinoma. Globally, nearly 71 million people have chronic HCV infection, and approximately 399,000 dies annually. In patients without cirrhosis, HCV infection is treated with 12 weeks of sofosbuvir/velpatasvir combination. Results from available small, single-centre observational studies suggest that the sofosbuvir/velpatasvir combination given for 8 weeks may be as effective as the standard 12 weeks of treatment. We propose to compare the treatment response of 12 weeks versus 8 weeks of sofosbuvir/velpatasvir in non-cirrhotic people with chronic HCV infection. METHODS: This multicentric, randomized, open-label, non-inferiority trial will include 880 (2 arms x 440) treatment naïve, viraemic (HCV RNA >10,000 IU/mL), non-cirrhotic adults (age >18 years) with chronic hepatitis C. People who are at high-risk for HCV reinfection such as haemophiliacs, people who inject drugs, those on maintenance hemodialysis or having HIV will be excluded. The presence or absence of cirrhosis will be determined with a combination of history, examination, ultrasound, liver stiffness measured with transient elastography, APRI, FIB-4, and esophagogastroduodenoscopy. Participants will be randomized to receive either 8- or 12-week sofosbuvir/velpatasvir treatment. A blood specimen will be collected before starting the treatment (to determine the HCV genotype), after 4 weeks of treatment (for early virological response), and at 12 weeks after treatment discontinuation for SVR12. DISCUSSION: The study will provide data on the efficacy of 8 weeks of treatment as compared to the standard of care (12 weeks) in non-cirrhotic patients with chronic HCV infection. Treatment for a shorter duration may improve treatment compliance, reduce the cost of treatment, and ease the treatment implementation from a public health perspective. TRIAL REGISTRATION: Registered with Clinical Trial Registry of India (http://ctri.nic.in) Registration No. CTRI/2022/03/041368 [Registered on: 24/03/2022]-Trial Registered Prospectively.

Antibody response to ChAdOx1 nCoV-19 (Covishield®) vaccine in people on maintenance hemodialysis.

INTRODUCTION: People on renal replacement therapy (RRT) have a high risk of COVID-19 infection and subsequent death. COVID-19 vaccination is strongly recommended for those on RRT. Data are limited on the immune response of the ChAdOx1 nCoV-19/AZD1222 (Covishield®) vaccine in patients on RRT. METHODS: A prospective cohort of adult (age > 18 years), on RRT in the form of hemodialysis were included and received two intramuscular doses of Covishield®. A blood specimen of 5.0 mL was collected at two time points, within a few days before administering the first dose of the vaccine and at 4-16 weeks after the second dose. According to their prior COVID-19 infection status, the participants were grouped as (i) prior symptomatic COVID-19 infection, (ii) prior asymptomatic COVID-19 infection, and (iii) no prior COVID-19 infection. RESULTS: A large proportion (81%) of participants had anti-spike antibodies (ASAb) before vaccination, and a reasonable proportion (30%) also had neutralizing antibodies (NAb). The titer of ASAb was relatively low (207 U/mL) before vaccination. The ASAb titer (9405 [1635-25,000] U/mL) and percentage of NAb (96.4% [59.6-98.1%]) were markedly increased following the administration of two doses of the vaccine. The participants' prior COVID-19 exposure status did not influence the rise in ASAb titer and NAb percentage. Further, administering two doses of the Covishield vaccine helps them achieve a high ASAb titer. CONCLUSION: Two doses of ChAdOx1 nCoV-19/AZD1222 (Covishield®) vaccine, given 12 weeks apart, achieve a high titer of ASAb and a high percentage of NAb in people on hemodialysis.

Serological Immune Response Following ChAdOx1 nCoV-19 Vaccine (Covishield®) in Patients with Liver Cirrhosis.

Introduction: Data are limited on antibody response to the ChAdOx1 nCoV-19 vaccine (AZD1222; Covishield®) in cirrhosis. We studied the antibody response following two doses of the ChAdOx1 vaccine, given 4−12 weeks apart, in cirrhosis. Methods: Prospectively enrolled, 131 participants (71% males; age 50 (43−58); alcohol-related etiology 14, hepatitis B 33, hepatitis C 46, cryptogenic 21, autoimmune 9, others 8; Child−Turcott−Pugh class A/B/C 52/63/16). According to dose intervals, the participants were grouped as ≤6 weeks (group I), 7−12 weeks (group II), and 13−36 weeks (group III). Blood specimens collected at ≥4 weeks after the second dose were tested for anti-spike antibody titre (ASAb; positive ≥ 0.80 U/mL) and neutralizing antibody (NAb; positive ≥20% neutralization) using Elecsys Anti-SARS-CoV-2 S (Roche) and SARS-CoV-2 NAb ELISA Kit (Invitrogen), respectively. Data are expressed as number (proportion) and median (interquartile range) and compared using non-parametric tests. Results: Overall, 99.2% and 84% patients developed ASAb (titre 5440 (1719−9980 U/mL)) and NAb (92 (49.1−97.6%)), respectively. When comparing between the study groups, the ASAb titres were significantly higher in group II than in group I (2613 (310−7518) versus 6365 (2968−9463), p = 0.027) but were comparable between group II and III (6365 (2968−9463) versus 5267 (1739−11,653), p = 0.999). Similarly, NAb was higher in group II than in group I (95.5 (57.6−98.0) versus 45.9 (15.4−92.0); p < 0.001), but not between the groups II and III (95.5 (57.6−98.0) versus 92.4 (73.8−97.5); p = 0.386). Conclusion: Covishield® induces high titres of ASAb and NAb in cirrhosis. A higher titre is achieved if two doses are given at an interval of more than six weeks.

Antibody Response to ChAdOx1 nCoV-19 (AZD1222) Vaccine in Kidney Transplant Recipients.

Kidney transplant recipients (KTRs) are at a much higher risk of complications and death following COVID-19 and are poor vaccine responders. The data are limited on the immune response to Covishield® in KTRs. We prospectively recruited a cohort of 67 KTRs aged >18 between April 2021 and December 2021. Each participant was given two intramuscular doses of Covishield®, each of 0.5 mL, at an interval of 12 weeks. A blood specimen of 5.0 mL was collected from each participant at two points within a few days before administering the first dose of the vaccine and at any time between 4−12 weeks after administering the second dose. The sera were tested for anti-RBD antibody (ARAb) titre and neutralising antibody (NAb). An ACE2 competition assay was used as a proxy for virus neutralization. According to the prior COVID-19 infection, participants were grouped as (i) group A: prior symptomatic COVID-19 infection, (ii) group B: prior asymptomatic COVID-19 infection as evidenced by detectable ARAb in the prevaccination specimen, (iii) Group C: no prior infection with COVID-19, (iv) group D: Unclassified, i.e., participants had no symptoms suggestive of COVID-19, but their prevaccination specimen was not available for ARAb testing before vaccination. Fifty of sixty-seven participants (74.6%) provided paired specimens (group A 14, group B 27, and group C 9) and 17 participants (25.4%) provided only postvaccination specimens (group D). In the overall cohort (n = 67), 91% and 77.6% of participants developed ARAb and NAb, respectively. Their ARAb titre and NAb proportion were 2927 (520−7124) U/mL and 87.9 (24.4−93.2) %, respectively. Their median ARAb titre increased 65.6 folds, from 38.2 U/mL to 3137 U/mL. Similarly, the proportion of participants with NAb increased from 56% to 86%, and the NAb proportion raised 2.7 folds, from 23% to 91%. A comparison of vaccine response between the study groups showed that all those with or without prior COVID-19 infection showed a significant rise in ARAb titre (p < 0.05) and NAb proportion (p < 0.05) after the two doses of vaccine administration. The median value of folds rise in anti-RBD and NAb between groups A and B were comparable. Hence, ARAb is present in more than 3/4th of KTRs before the ChAdOx1 vaccine in India. The titer of ARAb and the proportion of NAb significantly increased after the two doses of the ChAdOx1 vaccine in KTRs.

Serum Bile Acid Levels in Women With Intrahepatic Cholestasis of Pregnancy in India.

Introduction: Intrahepatic cholestasis of pregnancy (ICP) manifests as unexplained intense pruritus in the third trimester of pregnancy and is often diagnosed based on elevated serum bile acid measurement. There are no data from India on serum bile acid levels in pregnant women with ICP. Methods: Pregnant women with significant pruritus during the third trimester of gestation and with elevated serum alanine aminotransferase and/or aspartate aminotransferase (normal: <40 IU/L) were taken as having ICP. Serum BA levels were measured in them and in nonpregnant women and healthy pregnant women without itching. Results: Of the 3735 pregnant women screened, 105 (2.8%) had ICP (age 28 [26-32] years; gestational age 32 [30-36] weeks; primigravida 32.3%, and 95.3% normal fetal growth). Median (interquartile range) serum bile acid levels in nonpregnant women (n = 61; 28 [25-31] years) and pregnant women without ICP (n = 59; 28 [25-31] years) were similar (3.7 [1.6-5.1] µmol/L and 3.7 [2.2-5.8] µmol/L, respectively). By comparison, serum bile acid level in women with ICP (n = 105; 28 [26-32] years) was significantly higher (20.2 [12.7-39.5] µmol/L; P < 0.05 each), being above 10 µmol/L in 88 (83.8%). The optimum cut-off for the diagnosis of ICP in our population was ≥8.6 µmol/L, with sensitivity of 87.6%, specificity of 93.3% and area under the receiver-operator characteristics curve of 0.937 (95% CI: 0.904-0.970). Conclusion: Serum BA levels in healthy Indian nonpregnant and pregnant women are similar to those in other populations and can be used to diagnose ICP with an optimal cut-off being 8.6 µmol/L.

Use of Sofosbuvir/Velpatasvir/Voxilaprevir for Sofosbuvir Nonresponder Genotype 3 HCV Infection in India.

In India, hepatitis C virus (HCV) infection is treated with sofosbuvir in combination with NS5A inhibitor (Daclatasvir, Ledipasvir, or Velpatasvir). A small proportion of them fail to achieve sustained virological response at 12 weeks (SVR12) and need retreatment. Triple-drug combination (Sofosbuvir/Velpatasvir/Voxilaprevir) is one of the options for retreatment. Here we describe a patient with cirrhosis and genotype 3a infection who was successfully treated with a triple-drug combination after relapse with two courses of Sofosbuvir-containing regimens.

Durability of ChAdOx1 nCoV-19 (Covishield®) Vaccine Induced Antibody Response in Health Care Workers.

(i) Background: ChAdOx1 nCoV-19 (Covishield®) vaccine is widely used in India. We studied the Covishield® induced antibody response and its durability among health care workers (HCWs) (ii) Method: HCWs received two doses (0.5 mL) four weeks apart. Blood specimens, collected before each dose, day (D)60, D150 and D270 after second dose, were tested for anti-spike antibody (ASAb) titre and neutralising antibody (%) (NAb) using Elecsys Anti-SARS-CoV-2 S (Roche) and SARS-CoV-2 NAb ELISA Kit (Invitrogen), respectively. Data are expressed as proportions and median (interquartile range) and compared using non-parametric (iii) Result: Among 135 HCWs (83 males; age 45 (37−53); 36 had pre-existing ASAb), 29 (21.5%) acquired COVID-19 after 60 (39−68) days of vaccination. ASAb titre before second dose and at D60, D150, D270 were 77.2 (19.4−329.4), 512 (114.5−9212), 149 (51.6−2283) and 2079 (433.9−8644) U/mL, respectively. Compared to those without pre-existing ASAb, titres were significantly higher before second dose (5929 vs. 41, p < 0.001), D60 (3395 vs. 234, p = 0.007) and D150 (1805 vs. 103, p < 0.001) in participants with pre-existing ASAb; NAb were also higher (80 vs. 18, p < 0.001) before second dose. Between those who acquired infection or not after vaccination, ASAb titres were comparable before second dose (77 vs. 78, p = 0.362) but significantly higher at D60 (14,019 vs. 317, p < 0.001) and D150 (2062 vs. 121, p = 0.002) in the former group, though NAb percentage were higher at D60 (87 vs. 27, p < 0.001) and D150 (79 vs. 25, p = 0.007) only (iv) Conclusions: Covishield® induces a higher antibody titre in those with pre-existing ASAb. The vaccine induced antibody starts falling 5 months after vaccination.

Blood transfusion is unlikely to be a source for hepatitis E virus transmission in India.

INTRODUCTION: Transmission of hepatitis E virus (HEV) through transfusion has been reported from countries where genotype 3 virus is predominant. Data from countries with predominantly genotype 1 HEV, such as India, are limited. We studied the risk of HEV transmission following transfusion of blood or blood components in India. METHODS: Adult patients undergoing cardiac surgery who received transfusion of blood or blood products in the peri-operative period and who lacked history of any transfusion or surgery in the preceding 1 year were studied. A pre-transfusion blood specimen was collected for IgG anti-HEV antibody test. For the participants who were seronegative for anti-HEV, follow up specimens were collected at every 2-3-month intervals for up to 6 months after surgery and were tested for IgM and IgG anti-HEV antibodies. RESULTS: Of the 335 participants originally enrolled, 191 (57%) could be followed up. Of them, 103 (53.9%) were seropositive for HEV IgG at baseline and were excluded. Of the remaining 88 participants (age 42 ± 14.1 years; 55 [63%] male), none reported hepatitis-like illness during the follow up period of 81 ± 23 days. Also, none of these 88 participants was found to have seroconversion to anti-HEV IgM or IgG positivity in the follow up specimens. CONCLUSION: Transfusion-mediated transmission of HEV was not observed in our cohort and may be infrequent in the Indian population, where genotype 1 is the predominant HEV type.

Prevalence of hepatitis E viraemia among blood donors: a systematic review.

BACKGROUND: Hepatitis E virus (HEV) is usually transmitted by faecal-oral route. Recent reports have documented HEV viraemia in donated blood units and HEV transmission through blood transfusion. This systematic review summarizes the available data on prevalence of HEV viraemia in blood donors. METHODS: Electronic databases were searched on 17 December 2018 to identify full-text English papers reporting original data on prevalence of HEV RNA in donated blood units. Two authors independently extracted the relevant data, which were pooled using simple aggregation as well as a random-effects meta-analysis; heterogeneity was assessed using the I2 method. RESULTS: In all, 59 data sets from 28 countries were identified. The available data showed marked heterogeneity. Of a total of 2 127 832 units studied, 561 (263·6 [95% confidence intervals = 242·7-286·4] per million units) tested positive for HEV RNA. On random-effects meta-analysis, the pooled prevalence was 60·9 [6·7-155·4] per million units. In the viraemic units, HEV RNA titre varied by nearly one million-fold, and most had genotype 3 HEV. The prevalence was higher in blood units with anti-HEV antibodies or elevated alanine aminotransferase. Only nearly one-fourth of viraemic units had anti-HEV antibodies. CONCLUSIONS: The prevalence of HEV viraemia among healthy blood donors is low, though the available data had limited geographical representation and marked heterogeneity. There is a need for further data on HEV viraemia in blood donors from areas with non-3 HEV genotype preponderance.

Temporal profile of HEV RNA concentration in blood and stool from patients with acute uncomplicated hepatitis E in a region with genotype 1 predominance.

Acute hepatitis E virus (HEV) is associated with viremia and faecal excretion of the virus. The information on duration and temporal pattern of viremia and faecal shedding in HEV infection is important, but is not available. Serial serum and stool specimens were collected from patients with acute hepatitis E (typical clinical picture, serum alanine aminotransferase levels > 5-folds the upper limit of normal and presence of IgM anti-HEV), beginning from within 7 days of the onset of symptoms. HEV RNA concentrations were measured in sera and 10% stool suspensions, using a real-time Taqman-based nucleic acid amplification assay. Seventeen patients (median age 25 [range 19-61] years; all men) were enrolled within a median of 5 (range 3-8) days of the onset of the first symptom and provided 113 serum specimens and 71 stool specimens. The median (range) highest levels of serum bilirubin, alanine aminotransferase and aspartate aminotransferase in the patients were 10.3 (5.9-43.4) mg/dL, 1817 (442-4642) IU/L and 1016 (88-4561) IU/L, respectively. All the 17 patients had demonstrable viremia, and 12 of the 13 patients who were tested had faecal excretion at one or more time points. The HEV RNA titres were the highest in the early phase of disease and declined rapidly with time, becoming nondetectable in the serum by day 20 and in the stool by day 21. In most of the patients with acute uncomplicated acute hepatitis E, the degree of viremia and faecal shedding decline quickly after the onset of clinical illness and rapidly disappear in parallel with each other.

Prevalence of hepatitis E virus viremia and antibodies among healthy blood donors in India.

BACKGROUND: Hepatitis E virus (HEV) is transmitted primarily through contaminated water and food. Recently, HEV viremia in blood donors and transfusion-related transmission of HEV have been reported, leading to calls to screen donated blood for this virus. However, these data are from regions where genotype 3 HEV is predominant. In India, where human infections are caused only by genotype 1 HEV, the frequency of subclinical HEV viremia is unknown. METHODS: Minipools of sera prepared from three donor units each from our institution's  blood bank in Lucknow, India, were tested for HEV RNA using a sensitive amplification-based assay. A randomly selected subset was also tested for IgG anti-HEV antibodies using a commercial (Wantai) immunoassay. RESULTS: Sera from 1799 donors (median [range] age 30 [18-63] years; 1746 [97.0%] men) were collected (June-July 2016, 900; November-December 2016, 899). Of these, 17 (0.95%), 16 (0.90%), and 3 (0.17%) tested positive for HBsAg, anti-HCV, and anti-HIV antibodies, respectively. None of the donors tested positive for HEV RNA. Of 633 randomly selected donors (age 30 [18-63] years, 613 [96.8%] male) tested for IgG anti-HEV, 383 (60.5%) tested positive. Seropositivity rate increased with age, being 70/136 (52%), 177/299 (59%), 100/154 (65%), 30/34 (88%), and 6/10 (60%) in the 18-24, 25-34, 35-44, 45-54, and 55 years or older age groups, respectively. CONCLUSIONS: In healthy blood donors from northern India, HEV viremia is infrequent though anti-HEV antibody prevalence is high. This suggests that asymptomatic HEV viremia may be less frequent in areas with genotype 1 predominance than those with genotype 3 predominance.

Genotyping of hepatitis B virus isolates from Lahaul and Spiti district in Himachal Pradesh, India.

Hepatitis B virus (HBV) has several genotypes. In the Indian population, genotypes A and D are the most frequent. HBV infection is hyper-endemic in the Lahaul and Spiti district in Himachal Pradesh; however, the virus genotype in this area is not known. We sequenced a 398-nucleotide segment of HBV genome that included parts of pre-S1/S2 and polymerase genes from 17 specimens from this district, and assigned a viral genotype to these. Of the 17 specimens studied, 13 (76% [95% confidence interval = 50-92%]) showed the presence of genotype C HBV; the remaining four were genotype D (n = 4; 24%) HBV. Prevalence of genotype C HBV was much higher in the district than in other parts of India. This may reflect the historical mixing of this population with that in China. Since genotype C has a higher risk of chronicity and mother-to-child transmission, prevention of HBV infection may need particular emphasis in this area.