Real-world re-treatment outcomes of direct-acting antiviral therapy failure in patients with chronic hepatitis C.

Direct-acting antiviral (DAA) drugs are associated with high (>95%) sustained virological response at 12 weeks (SVR12) in chronic hepatitis C (CHC) patients. There is a paucity of data regarding the characteristics and re-treatment outcomes of DAA treatment failure patients. In a retrospective analysis of the prospectively collected database, we assessed the outcomes of re-treatment among patients with previous DAA failure. Patients' characteristics, viral characteristics, including resistance-associated substitutions (RAS) in a subgroup of patients, SVR12, and clinical outcomes were studied. Of 40 patients with DAA failure, among whom 36 were retreated, mean age was 45.7 years, 63.9% (n = 23) were male, 63.9% (n = 23) had a genotype-3 infection and 63.9% (n = 23) were cirrhotic. The re-treatment regimens included a combination of pan-genotypic DAA, mainly sofosbuvir and velpatasvir with or without ribavirin. Three patients who declined retreatment and one who was still on treatment was excluded. For patients who completed re-treatment, SVR12 was 100% irrespective of genotypes. SVR12 among genotype 3 was 75% (15 of 20) when lost to follow-up was considered a treatment failure. Six patients died due to liver-related causes, including five (83.3%) with hepatocellular carcinoma. RAS analysis in 17 randomly selected patients did not reveal any dominant substitutions in NS5A or NS5B region affecting SVR12, though several novel mutations were observed. In conclusion, re-treatment of CHC patients with prior DAA failure using pan-genotypic DAA is associated with high SVR12 rates irrespective of genotype or the presence of RAS.

Genotypic characterization of dengue virus strains circulating during 2007-2009 in New Delhi.

Dengue is an important arboviral disease of tropical and subtropical regions, with significant morbidity and mortality. Dengue virus is antigenically classified into four serotypes, which are further classified into 4-5 genotypes based on their genetic diversity. Since genotypes vary in their virulence, their detection and analysis of spatial and temporal transition are essential. We utilized sequence information from the E-NS1 gene region for molecular and phylogenetic characterization of dengue viruses isolated from dengue patients between 2007 and 2009. All four serotypes and multiple genotypes were detected, with predominance and emergence of DENV-1 genotype V. Phylogenetic analysis revealed the emergence of DENV-1 genotype V from India for the first time, which has replaced the earlier circulating genotype III and genotype I. The circulation of multiple genotypes and genotype replacement is critical, since genotypes vary in their virulence, and this should be a point of concern for healthcare agencies.

A study of Chikungunya outbreak in Delhi.

Chikungunya virus, an alphavirus belonging to the Togaviridae family, caused large scale outbreaks in several parts of southern, western and eastern India in 2006. We report Chikungunya outbreak in Delhi in 2010. This study was conducted in the virology laboratory of Maulana Azad Medical College and associated Lok Nayak Hospital, Delhi from August 2010 to February 2011. Serum samples of 324 patients presenting with fever, arthralgia, myalgia, rash etc. were tested for anti-Chikungunya IgM antibody using MAC ELISA. 148/324 (45.6%) samples were positive for anti Chikungunya IgM antibody. More females were affected compared to males (1: 1.34). The most common age group affected was 31-40 year. Characteristically, paediatric age group was least affected with cases in children accounting for only 3.3%. The number of cases increased with increasing age group. The commonest clinical presentation was arthralgia (100%) followed by fever (88%). Complications such as bleeding manifestations and encephalitis were seen in 2.7% patients. This report confirms emergence and establishment of CHIKV in the northern region of India, which is also endemic for dengue viruses. There is an urgent need for early and aggressive vector control and containment measures for risk reduction.

Levels of 25-hydroxy Vitamin D3 and Vitamin D Receptor Polymorphism in Severe Dengue Cases from New Delhi.

BACKGROUND: Dengue is the "phoenix" that never went to ashes. First identified in 1943, in Japan, dengue virus has worldwide distribution and is a grave public health concern in developing countries like India; Methods: A cross sectional study was conducted among adults suspected of having dengue fever and attending Lok Nayak Hospital, New Delhi. Restriction Fragment Length Polymorphism was completed for the detection of vitamin D receptor (VDR) gene polymorphism; Results: Serum 25-hydroxy vitamin D3 (vitamin D) levels were found to be 1.6 times elevated in severe dengue cases as compared to healthy controls. Vitamin D levels were significantly higher in secondary infections compared to primary infections as well as secondary severe dengue cases as compared to secondary non-severe cases (p value < 0.05). A significant association of the T allele (rs2228570) was seen in severe dengue cases, while, when comparing the A/A with A/C and C/C genotypes (rs7975232) among dengue cases and healthy controls, the odds ratio was estimated to be 1.24 (0.55-2.75, p > 0.05) and 0.28 (0.08-0.96, p < 0.05) respectively; Conclusions: The present study is an attempt at decoding the role of vitamin D in dengue disease pathogenesis and exploring the role of genetic polymorphism in dengue disease pathogenesis.

Systematic review with meta-analysis: impact of baseline resistance-associated substitutions on the efficacy of glecaprevir/pibrentasvir among chronic hepatitis C patients.

BACKGROUND: The effect of baseline resistance-associated substitutions (RAS) on the sustained virologic response at 12 weeks (SVR12) among chronic hepatitis C (CHC) patients receiving the second generation, pan-genotypic glecaprevir/pibrentasvir (G/P) regimen is unclear. AIM: To assess the effect of RAS on the SVR12 in CHC patients treated with G/P regimen. METHODS: The EMBASE, MEDLINE and Cochrane central register of controlled trials databases were searched for relevant studies published before 1 March 2019. The principal outcome was to compare the SVR12 in CHC patients with and without baseline RAS, particularly in genotype-1, genotype-3 and direct-acting anti-virals (DAAs) failure patients. The outcomes were pooled using a random-effects model and odds ratio (OR) was calculated. The risk of bias was assessed using the Cochrane risk of bias tools for randomised and nonrandomised interventional studies. RESULTS: After initially identifying 410 studies, 3302 patients from 17 studies were included. Among 50 cases of virologic failures, 48% had genotype-3 infection, 44% genotype-1 infection and 36% DAA-failure patients. Baseline RAS were present in 44(88%) patients. The most common NS5a and NS3 mutations were Y93H and A166S respectively. The odds of SVR12 were significantly reduced in patients with any baseline RAS (NS3 and/or NS5a) (OR 0.32, 95%C I[0.15, 0.65], I2  = 0%) and NS5a substitutions (OR 0.36, 95%CI [0.18,0.73]). The impact of RAS on SVR12 was significant among genotype-3 patients, but not among genotype-1 or DAA-failure cases. The presence of Y93H and A30K mutations significantly impacted SVR12 rates in genotype-3 patients. CONCLUSION: Baseline NS3 or NS5a RAS, especially the NS5a substitutions-A30K, Y93H, decrease the odds of achieving SVR12 in genotype-3 CHC patients.

Frequency of nucleotide sequence variations in the internal ribosome entry site region of hepatitis C virus RNA isolated from responding and non-responding patients with hepatitis C virus genotype 3 infection.

Located within 5' untranslated region of HCV RNA is internal ribosome entry site (IRES) which directs cap-independent translation of viral polyprotein. Mutations in IRES sequence have been shown to cause changes in efficiency of protein translation in vitro in few instances. No study has been done to investigate association between frequency of nucleotide sequence variations in IRES region of HCV-3 RNA and response to pegylated interferon-α plus ribavirin therapy. Hence, this study was planned to analyze relationship between frequency of nucleotide sequence variations of HCV-3 IRES region and response to therapy. Twenty-seven HCV-3 patients were studied, of whom 19 responded to therapy and 8 did not. Alanine aminotransferase and aspartate aminotransferase levels were significantly lower in responders compared to non-responders. HCV RNA detection and genotyping was performed by nested-PCR and RFLP respectively. Viral load quantification in pre and post therapy samples was done by real time PCR. The viral load was significantly lower in the patients after treatment as compared to before treatment. HCV IRES region from pre-treatment sera of 27 HCV-3 infected patients was amplified by nested PCR and sequenced. Secondary structure of IRES region of HCV-3 was predicted using the M fold Web Server. Mutational analysis revealed hot spot of mutations in HCV-3 IRES region from 40-80 and 210-280 nucleotides. Though more mutations were found in non-responders as compared to responders, this difference was statistically insignificant. Therefore, in addition to IRES region of HCV-3, some other host and viral factors may contribute to therapy outcome.