Immunogenicity and safety of quadrivalent and 9-valent human papillomavirus vaccines in Indian clinical trial participants.

The quadrivalent human papillomavirus (qHPV; HPV6/11/16/18) and 9-valent HPV (9vHPV; HPV6/11/16/18/31/33/45/52/58) vaccines have demonstrated efficacy, immunogenicity, and safety in international clinical trials. We report outcomes from three completed clinical trials in India: a single-arm study (V501-029 [NCT00380367]) in Indian girls (aged 9-15 years; N = 110) evaluating qHPV vaccine immunogenicity and safety; a subgroup analysis (n = 225) of Indian girls/boys (9-15 years) and women (16-26 years) from a global study (V503-002 [NCT00943722]) evaluating 9vHPV vaccine immunogenicity and safety; and a qHPV vaccine post-marketing safety surveillance study (V501-125) in Indian females (aged 9-45 years; N = 188) vaccinated during routine care. In V501-029 and V503-002, HPV vaccines were administered as 3 doses (Day 1, Month 2, Month 6). Serum HPV antibodies were evaluated by competitive Luminex immunoassays at Day 1 and Month 7 (both studies) and Months 12, 24, and 36 (V503-002 only). Adverse events (AEs) were collected by Vaccination Report Card. In V501-125, participants were actively surveilled for serious AEs (SAEs) within 30 days post-qHPV vaccination. In per-protocol analyses, qHPV and 9vHPV vaccines induced robust anti-HPV6/11/16/18 (V501-029) and HPV6/11/16/18/31/33/45/52/58 (V503-002) responses, respectively; ≥97% of participants seroconverted at Month 7 for each vaccine HPV type in both studies, and antibody responses persisted through 36 months in V503-002. The most common AEs were injection-site-associated. Most AEs were mild/moderate; no deaths, vaccine-related SAEs, or discontinuations due to AEs were reported. In V501-125, no SAE was reported. Overall, the qHPV and 9vHPV vaccines elicited robust antibody responses and were generally well tolerated in Indian participants.

The impact and cost-effectiveness of 9-valent human papillomavirus vaccine in adolescent females in Hong Kong.

INTRODUCTION: In Hong Kong (HK), a single-cohort vaccination program for 10-12-year-old girls with the 9-valent human papillomavirus (HPV) vaccine (9vHPV; types 6/11/16/18/31/33/45/52/58) has been launched. This study assessed the public health impact and cost-effectiveness of implementing routine 9vHPV vaccination (12-year-olds) with or without catch-up 9vHPV vaccination (13-18-year-olds) in HK. METHODS: The health impact and costs of implementing routine 9vHPV vaccination with or without catch-up vaccination over a 100-year time horizon were evaluated using a validated HPV-type transmission dynamic model adapted to the HK population; analyses were performed from a healthcare payer perspective. Routine vaccination (12-year-old girls) and catch-up vaccination (13-18 years) assumed vaccine coverage rates of 70% (base case) and 30%, respectively. The model also assumed herd immunity, lifelong vaccine protection, a discount rate of 3%, and a cost per dose of HK dollars (HKD) 858 [United States dollars (USD) 110] and HKD 1390 (USD 179) for the 2-valent HPV (2vHPV) and 9vHPV vaccines, respectively. HPV disease-related incidence and the incremental cost-effectiveness ratio (ICER) per quality-adjusted-life-year (QALY) were estimated. Cost-effectiveness was determined at a ceiling threshold of HK dollars (HKD) 382,046 (USD 49,142) or 1.0 times the gross domestic product per capita of HK. RESULTS: Compared with routine 9vHPV alone, routine plus catch-up 9vHPV is projected to reduce cervical cancer incidence by 3.4%. Routine plus catch-up 9vHPV will also reduce genital warts incident cases for males/females by 2.6%/5.4%. The incremental cost-effectiveness ratios were HKD 29,911 (USD 3847)/quality-adjusted life-year (QALY) for routine plus catch-up 9vHPV versus routine 9vHPV alone and HKD 25,524 (USD 3283)/QALY for routine 9vHPV alone versus screening only. Sensitivity analyses indicated that routine plus catch-up 9vHPV compared with routine 9vHPV alone remained cost-effective at coverage rates of 30% and 90%. CONCLUSIONS: This analysis predicts that the current HK vaccination strategy can be considered cost-effective and will provide maximum health benefit. These results support addition of the routine 9vHPV vaccine with or without catch-up 9vHPV vaccination to the regional vaccination program in HK.

Incremental healthcare resource utilization and costs for patients with cervical, vaginal, vulvar, anal, and oropharyngeal cancer in the United States.

INTRODUCTION: Human papillomavirus (HPV) cause cancers in a variety of anatomic sites presenting at various stages of disease. Current economic assessments rely on HPV-related cancer cost estimates from data prior to the launch of the nonavalent HPV vaccine (2014). The goal of the present study was to assess and describe the current direct medical care burden of HPV-related cancers in the US. METHODS: Using Clinformatics Data Mart, patients in the US who were newly diagnosed with cervical, vulvar, vaginal, anal, and oropharyngeal cancers between 2012 and 2015 were compared to non-cancer matched (propensity score) controls. Health care resource utilization and direct medical cost (2020 USD) were assessed over a 2-year follow-up period following index diagnosis from a payer perspective. The cost for censored time was estimated using generalized linear model while adjusting for survival probability using cox-proportional hazard model. Confidence intervals were calculated with bootstrapping technique. RESULTS: The analyses included 4128 cervical, 1580 vulvar, 538 vaginal, 1827 anal, and 6106 oropharyngeal cancers and matched controls. Cases and controls had similar baseline clinical characteristics and length of follow-up. The 2-year incremental direct medical costs were $93,272, $81,676, $141,096, $129,366, and $134,045 for cervical, vulvar, vaginal, anal, and oropharyngeal cancers respectively. Outpatient care costs was the biggest driver of the total incremental medical costs. Most cancer costs were incurred during the first 6 months of follow-up and then stabilized during follow-up. CONCLUSION: HPV-related cancers are responsible for substantial health care expenditure each year.

Systematic literature review of neutralizing antibody immune responses to non-vaccine targeted high-risk HPV types induced by the bivalent and the quadrivalent vaccines.

INTRODUCTION: Studies on the cross-protective effect of HPV bivalent and quadrivalent vaccines demonstrated inconsistent findings against additional HPV types covered by the nonavalent vaccine. The objective of this study was to conduct a systematic literature review to assess the consistency and durability of the cross-protective neutralizing antibody immune responses of the currently licensed bivalent and quadrivalent vaccines to non-vaccine HPV types targeted by the nonavalent vaccine (HPV 6, 11, 31, 33, 45, 52, and 58). METHODS: PubMed and EMBASE databases were searched from 2008 to 2019 to identify studies reporting antibody/immune response after vaccination with either the bivalent, quadrivalent, or nonavalent vaccine. Key outcomes were seroconversion, seropositivity or geometric mean titers against HPV types 6, 11, 31, 33, 45, 52, and 58. RESULTS: Eighteen publications met inclusion criteria, reporting on 14 interventional and five observational studies. Across all studies, immune responses to non-vaccine high-risk HPV types after bivalent vaccination were higher than baseline or quadrivalent vaccine. Nonavalent vaccine elicited near total seroconversion to HPV types 31, 33, 45, 52, and 58, with seropositivity remaining near 100% up to 24 months post-dose 1. In contrast, bivalent and quadrivalent vaccination resulted in lower seroconversion levels for non-vaccine types, which waned over time. CONCLUSIONS: The cross-protection antibody/immune response among participants having received all three doses of bivalent or quadrivalent vaccine is not comparable to the specific response elicited by HPV vaccine types. Even in cases where a statistically significant cross-reactive immunological response is reported, long-term data on the duration of the response beyond two years are very limited. Further, the lack of a standard for assays limits comparability of results between studies.

Systematic literature review of cross-protective effect of HPV vaccines based on data from randomized clinical trials and real-world evidence.

BACKGROUND: The extent of cross-protection provided by currently licensed bivalent and quadrivalent HPV vaccines versus direct protection against HPV 31-, 33-, 45-, 52-, and 58-related disease is debated. A systematic literature review was conducted to establish the duration and magnitude of cross-protection in interventional and observational studies. METHODS: PubMed and Embase databases were searched to identify randomized controlled trials (RCT) and observational studies published between 2008 and 2019 reporting on efficacy and effectiveness of HPV vaccines in women against non-vaccine types 31, 33, 45, 52, 58, and 6 and 11 (non-bivalent types). Key outcomes of interest were vaccine efficacy against 6- and 12-month persistent infection or genital lesions, and type-specific genital HPV prevalence or incidence. RCT data were analyzed for the according-to-protocol (bivalent vaccine) or negative-for-14-HPV-types (quadrivalent vaccine) efficacy cohorts. RESULTS: Data from 23 RCTs and 33 observational studies evaluating cross-protection were extracted. RCTs assessed cross-protection in post-hoc analyses of small size subgroups. Among fully vaccinated, baseline HPV-naïve women, the bivalent vaccine showed statistically significant cross-protective efficacy, although with wide confidence intervals, against 6-month and 12-month persistent cervical infections and CIN2+ only consistently for HPV 31 and 45, with the highest effect observed for HPV 31 (range 64.6% [95% CI: 27.6 to 83.9] to 79.1% [97.7% CI: 27.6 to 95.9] for 6-month persistent infection; maximal follow-up 4.7 years). No cross-protection was shown in extended follow-up. The quadrivalent vaccine efficacy reached statistical significance for HPV 31 (46.2% [15.3-66.4]; follow-up: 3.6 years). Similarly, observational studies found consistently significant effectiveness only against HPV 31 and 45 with both vaccines. CONCLUSIONS: RCTs and observational studies show that cross-protection is inconsistent across non-vaccine HPV types and is largely driven by HPV 31 and 45. Furthermore, existing data suggest that it wanes over time; its long-term durability has not been established.

The clinical and economic benefits of school-based quadrivalent HPV vaccination in Singapore.

OBJECTIVE: To investigate the clinical and economic impacts of school-based administration of the quadrivalent HPV vaccine. METHODS: A retrospective health-economic analysis was conducted using data collected in Singapore between 2004 and 2005. A dynamic transmission model was adapted for universal vaccination that provided 80% coverage among students aged 11-12 years. Strategy 1 involved only girls, with a 5-year catch-up vaccination to provide 50% coverage among those aged 13-17 years. Strategy 2 included both girls and boys with no catch-up vaccination. Outcomes included the predicted incidence of HPV-related disease over 100 years. RESULTS: Current coverage was assumed to be 5%. Strategy 1 would reduce cervical intraepithelial neoplasia grade 1 (CIN1) by 63.8%, cervical intraepithelial neoplasia grade 2-3 (CIN2-3) by 62.9%, cervical cancer by 50.9%, and genital warts by 78.0% (female individuals) and 73.6% (male individuals). Strategy 2 would reduce CIN1 by 64.0%, CIN2-3 by 63.1%, cervical cancer by 50.7%, and genital warts by 79.9% (female individuals) and 80.1% (male individuals). The incremental cost-effectiveness ratio was S$12 464 for strategy 1 and $27 837 for Strategy 2. These values decreased to $7477 and $22 574, respectively, if a two-dose regimen was adapted. CONCLUSION: School-based quadrivalent HPV vaccination offered clinical and economic benefits, and is cost-effective in Singapore.

Immunogenicity and safety of the pentavalent human-bovine (WC3) reassortant rotavirus vaccine (PRV) in Indian infants.

OBJECTIVE: To evaluate the immunogenicity and safety of a pentavalent rotavirus vaccine (PRV) in Indian infants. STUDY DESIGN: Open-label, single-arm multicentric study. SETTING: Hospital facilities (out patients): SUBJECTS: One hundred and ten (110) healthy Indian infants were enrolled between the ages of 6 weeks and 12 weeks. INTERVENTION: Three doses of oral pentavalent rotavirus vaccine (PRV) were administered with an interval of 4 to 10 weeks (28 to 70 days). MAIN OUTCOME MEASURES: Immunogenicity of PRV was based on the proportion of infants exhibiting a > 3-fold rise in serum anti rotavirus IgA antibodies (from pre dose 1 to 14 days post dose 3). Safety was evaluated for 14 days after each dose. RESULTS: Of the 110 infants enrolled, 83% exhibited at least a 3-fold rise (seroconversion) in serum anti rotavirus IgA antibodies. There were no clinically significant adverse events reported. CONCLUSIONS: A 3-dose regimen of PRV was found to be immunogenic and well tolerated in healthy Indian infants. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov; NCT00496054:

Liver function tests and their interpretation.

Liver function tests (LFT) are a helpful screening tool, which are an effective modality to detect hepatic dysfunction. Since the liver performs a variety of functions so no single test is sufficient to provide complete estimate of function of liver. Often clinicians are faced with reports that do not tally with the clinical condition of the patient and they face difficulty in interpreting the LFT. An attempt is being made to study and understand the LFT and simplify their interpretation with algorithms.

Congenital intrahepatic porto-systemic venous shunt with galactosemia.

We report a 51-day-old infant with congenital intrahepatic porto-systemic venous shunt associated with galactosemia, who presented with cholestatic jaundice. He was treated with ursodeoxycholic acid, calcium supplements and galactose-free diet. The child was asymptomatic six weeks later.

Pancytopenia in a child associated with hepatitis A infection.

Pancytopenia is a very rare condition associated with hepatitis A infection. We managed a 12 year old boy who had hepatitis A infection with anemia. His hemogram and bone marrow examination were suggestive of pancytopenia. Pancytopenia recovered without any specific therapy. There are case reports of severe aplastic anemia with hepatitis A infection that required immunosuppressive therapy. The present case did not require any aggressive therapy and recovered. In a young child with hepatitis A infection and anemia, bone marrow depression should be suspected. The pancytopenia may be transient as exemplified by the present case.

Mitochondrial neuro-gastrointestinal encephalopathy syndrome.

Mitochondrial neurogastrointestinal encephalomyopathy is a rare disorder affecting the pediatric age group with a heterogeneous multisystem involvement. We happen to manage a young child with symptoms of constipation since infancy along with cachexia, seizures and peripheral neuropathy. The child later went into encephalopathy preterminally. This clinical syndrome fitted very well with mitochondrial neurogastrointestinal encephalomyopathy. The child had elevated lactate levels and electron microscopy of the rectal biopsy was suggestive of a mitochondrial disorder To the best of our knowledge there is no case report of this syndrome from India and since this presents with diagnostic difficulties so is being reported.