Culture conversion and six months interim outcomes in retreatment cases of pulmonary MDRTB - a six month interim analysis.

OBJECTIVE: To estimate the time to culture conversion and factors associated with failure to culture conversion, six-month interim outcomes and associated risk factors with poor interim outcomes in multi-drug resistant tuberculosis patients previously treated with second-line drugs. METHODS: The prospective clinical case series study was conducted from March 2016 to January 2017 at the Indus Hospital Tuberculosis Clinic and seven other sites that are part of the hospital's Programmatic Management of Drug Resistant Tuberculosis initiative. All bacteriologically confirmed multi-drug resistant tuberculosis retreatment patients were enrolled. Data was collected on age, gender, site of enrollment, detailed history of previous treatment with anti-tuberculosis drugs, medical history, history of first-line drugs, history of second-line drugs, treatment outcomes, baseline sputum smear microscopy and monthly follow-up sputum smear microscopy and culture results. Data was subjected to univariate and multiple logistic regression analyses, and risk factors for failure to culture conversion were assessed using Cox Proportional Hazards Model. RESULTS: Out of 266 patients, 143(53.8%) were males, the overall largest age group was 5-24 years 97(36.5%), and 250 (94%) patients had previous history of treatment with first-line drugs. Overall, 101(40.1%) patients experienced poor interim outcome. Poor interim outcomes were significantly associated with higher number of drugs on the regimen, (odds ratio: 1.27; 95% confidence interval: 1.03-1.58) and high sputum smear grading (odds ratio: 4.56; 95% confidence interval: 3.30-18.71). Besides, 186(70.3%) patients experienced culture conversion within the initial six months of treatment. CONCLUSIONS: The success rate of re-treatment of multi-drug resistant tuberculosis with conventional regimen was found to be unacceptably low.

Treatment outcomes of the drug resistant tuberculosis cases previously exposed to second line anti Tuberculosis drugs in Pakistan: A multi-center cross-sectional study.

OBJECTIVE: To determine the treatment outcomes of the drug-resistant tuberculosis patients who were previously exposed to second line drugs. METHODS: The retrospective study was conducted at eight Programmatic Management of Drug Resistant Tuberculosis (PMDT) sites in Sindh and Balochistan. Data of patients who were previously exposed to second line drugs and re-enrolled in the drug-resistant tuberculosis register at PMDT sites in Sindh and Balochistan between 2008 and 2016 was included for analysis. Data of those still under treatment or transferred to another treatment site was excluded. Association was explored between treatment outcomes and other independent variables, while in order to identify the risk factors associated with poor treatment outcomes univariate and multivariate logistic regression was used. RESULTS: Overall, there were 3645 patients and 288(8%) were previously exposed to second line drugs. Of them, 95(33%) were excluded, and the final sample stood at 193; 99(51.3%) males and 94(48.7%) females. The median age of the sample was 29 years (inter-quartile range: 22-41 years). The mean duration of treatment was 20}11.14 months. Overall success rate of the re-treatment of previously treated patients was 105(54.4%). Observed relapse rate was 9(4.7%).. CONCLUSIONS: The success rate for re-treatment drug-resistant tuberculosis patients was found to be unacceptably low. New drugs and novel regimens should be made widely available.

Contemplating the Human Papillomavirus (HPV) Vaccine Introduction in Pakistan: Is Now the Time?

Human papillomavirus (HPV) vaccine introduction is anticipated in many countries in the coming years. This Perspective addresses the opportunities and challenges of introducing HPV vaccination in Pakistan. A substantial portion of the population within the high-risk age group necessitates the implementation of a robust vaccination strategy. Advocacy, community mobilization, and stakeholder engagement are the key elements for the successful implementation of the vaccination program. However, for long-term control strategies, a multifaceted approach is recommended. This approach should involve integrating HPV vaccination into the national immunization program, improving access to screening methods, and establishing comprehensive and cost-effective programs for preventing cervical cancer.

Efficacy of typhoid vaccines against culture-confirmed Salmonella Typhi in typhoid endemic countries: a systematic review and meta-analysis.

BACKGROUND: Typhoid is a serious public health threat in many low-income and middle-income countries. Several vaccines for typhoid have been recommended by WHO for typhoid prevention in endemic countries. This study aimed to review the efficacy of typhoid vaccines against culture-confirmed Salmonella enterica serovar Typhi. METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase for studies published in English between Jan 1, 1986 and Nov 2, 2023. We included randomised controlled trials (RCTs) comparing typhoid vaccines with a placebo or another vaccine. This meta-analysis evaluated the efficacy and safety of several typhoid vaccines, including live attenuated oral Ty21a vaccine, Vi capsular polysaccharide (Vi-PS), Vi polysaccharide conjugated to recombinant Pseudomonas aeruginosa exotoxin A vaccine (Vi-rEPA), and Vi-tetanus toxoid conjugate vaccine (TCV). The certainty of evidence for key outcomes was evaluated using Grading of Recommendations, Assessment, Development, and Evaluations methodology. The outcome of interest was typhoid fever confirmed by the isolation of Salmonella enterica serovar Typhi in blood and adverse events following immunisation. This study is registered with PROSPERO (CRD42021241043). FINDINGS: We included 14 RCTs assessing four different vaccines (Ty21a: four trials; Vi-PS: five trials; Vi-rEPA: one trial; TCV: four trials) involving 585 253 participants. All trials were conducted in typhoid endemic countries and the age of participants ranged from 6 months to 50 years. The pooled efficacy against typhoid fever was 45% (95% CI 33-55%; four trials; 247 649 participants; I2 59%; moderate certainty) for Ty21a and 58% (44-69%; five trials; 214 456 participants; I2 34%; moderate certainty) for polysaccharide Vi-PS. The cumulative efficacy of two doses of Vi-rEPA vaccine at 2 years was 91% (88-96%; one trial; 12 008 participants; moderate certainty). The pooled efficacy of a single shot of TCV at 2 years post-immunisation was 83% (77-87%; four trials; 111 130 participants; I2 0%; moderate certainty). All vaccines were safe, with no serious adverse effects reported in the trials. INTERPRETATION: The existing data from included trials provide promising results regarding the efficacy and safety of the four recommended typhoid vaccines. TCV and Vi-rEPA were found to have the highest efficacy at 2 years post-immunisation. However, follow-up data for Vi-rEPA are scarce and only TCV is pre-qualified by WHO. Therefore, roll-out of TCV into routine immunisation programmes in typhoid endemic settings is highly recommended. FUNDING: There was no funding source for this study.

Longevity of serologic responses following a single dose of typhoid conjugate vaccine among children living with HIV in Pakistan: A prospective cohort study.

BACKGROUND: This study aimed to assess the longevity of serologic response and seroconversion rates at several time points following TCV vaccination among children living with HIV aged 6 months to 15 years in Pakistan. METHODS: From November 20, 2020, to January 2, 2021; 336 children were enrolled and followed up prospectively for 12 months. Blood samples were collected before the administration of TCV and at 4-6 weeks, 6 months, and 1 year after administration of a single dose (0.5 ml) of intramuscular Typbar TCV®. Samples were analyzed for anti-Vi-IgG antibodies using ELISA. Geometric mean titers (GMTs), seroconversion rates (fourfold rise in anti-Vi-IgG from baseline), and factors associated with sustained seroconversion at 1 year were evaluated using generalized linear mixed models. FINDINGS: The seroconversion rates were significantly lower in children aged 6 months to 5 years compared to children > 5 years; (127/216 (58·8%)) versus (81/111 (73·0%)) at 6 months and (110/217 (50·7%)) versus (78/109 (71·6%)) at 1 year, only two-third; 188/326 (57·7%) remained seroconverted at 1 year. The GMTs (95 % CI) were significantly lower in children aged 6 months to 5 years compared to children > 5 years, 9·6 (7·6, 12·0) versus 28·9 (20·2, 41·4) at 6 months, and 6·6 (5·4, 8·0) versus 23·1 (16·4, 32·5) at 1 year time point. The odds of sustained seroconversion significantly decreased with time (adjusted odds ratio (aOR): 0·232; 95 % CI: 0·136,0·396). The odds of sustained seroconversion following 1 year of TCV vaccination were significantly higher among children with non-severe HIV clinical disease (aOR: 10·6; 95 % CI: 1·5, 73·9) and children in elder age group (aOR: 7·45; 95 % CI: 11·2, 47·0). CONCLUSIONS: There was a decline in seroconversion after one year of TCV in children living with HIV. The decline was significant in children with severe or advanced HIV disease. A significant decrease in seroconversion rates was observed among children living with HIV following one year of TCV administration.

Exploring Natural Immune Responses to Shigella Exposure Using Multiplex Bead Assays on Dried Blood Spots in High-Burden Countries: Protocol From a Multisite Diarrhea Surveillance Study.

Background: Molecular diagnostics on human fecal samples have identified a larger burden of shigellosis than previously appreciated by culture. Evidence of fold changes in immunoglobulin G (IgG) to conserved and type-specific Shigella antigens could be used to validate the molecular assignment of type-specific Shigella as the etiology of acute diarrhea and support polymerase chain reaction (PCR)-based microbiologic end points for vaccine trials. Methods: We will test dried blood spots collected at enrollment and 4 weeks later using bead-based immunoassays for IgG to invasion plasmid antigen B and type-specific lipopolysaccharide O-antigen for Shigella flexneri 1b, 2a, 3a, and 6 and Shigella sonnei in Shigella-positive cases and age-, site-, and season-matched test-negative controls from all sites in the Enterics for Global Health (EFGH) Shigella surveillance study. Fold antibody responses will be compared between culture-positive, culture-negative but PCR-attributable, and PCR-positive but not attributable cases and test-negative controls. Age- and site-specific seroprevalence distributions will be identified, and the association between baseline antibodies and Shigella attribution will be estimated. Conclusions: The integration of these assays into the EFGH study will help support PCR-based attribution of acute diarrhea to type-specific Shigella, describe the baseline seroprevalence of conserved and type-specific Shigella antibodies, and support correlates of protection for immunity to Shigella diarrhea. These insights can help support the development and evaluation of Shigella vaccine candidates.

Coverage survey of typhoid conjugate vaccine among children aged 6 months to 15 years in an urban slum settlement of Lyari Town Karachi, Pakistan.

OBJECTIVE: To estimate the coverage rate of typhoid conjugate vaccine (TCV) among children aged 6 months to 15 years in Lyari Town Karachi, Pakistan. METHODS: A cross-sectional survey was conducted to estimate the vaccine coverage of Typbar TCV in Lyari Town Karachi utilizing the World Health Organization (WHO) recommended rapid vaccine coverage assessment technique (30 clusters × 7 households). Sampling was powered at town level and multistage cluster sampling was used. Four union councils were randomly selected from a total of 11 and the survey was conducted in those union councils. After consent was obtained, parents of age-eligible children living in the selected union councils were invited to participate in the survey and information was collected on Typbar TCV vaccination status of children aged 6 months to 15 years. RESULTS: Overall, 2325 children were included in the survey. The mean age of the participants was 7.60 ± 3.84 years. The ratio of males to females was equal in the survey sample; 1163 (50.02%) were male. In the total target population, 82% children were found to be vaccinated; however, the vaccination status could be verified for 80%. The vaccine coverage of TCV was comparable among the four union councils and the overall coverage of TCV vaccine in Lyari Town was found to be 80%. The coverage was significantly lower in younger children, 5% and 17% among children aged 6 months to < 2 years and 2 years to < 5 years respectively and 78% among children aged 5 years to 15 years. CONCLUSION: The overall immunization coverage rate with TCV was found to be satisfactory. Immunization coverage was comparable among both sexes and the selected union councils but it was relatively low among children in younger age groups.

Parental acceptance of typhoid conjugate vaccine for children aged 6 months to 15 years in an outbreak setting of Lyari Town Karachi, Pakistan.

BACKGROUND: This study aimed to evaluate the parental acceptance of Typhoid Conjugate Vaccine (TCV) and to determine the predictors of TCV vaccination status among children in an outbreak setting of extensively drug resistant (XDR) typhoid fever in Karachi, Pakistan. METHODS: A cross-sectional survey using the WHO recommended rapid vaccine coverage assessment technique was conducted. Out of 11, four union councils (UCs) in Lyari Town were randomly selected. A parent or primary caretaker from the eligible household was interviewed. Data were collected using a locally validated vaccine attitudes scale (VAS). Sum of scores was calculated for VAS. A higher score denoted negative attitudes and perceptions regarding TCV and vice versa. Multivariable logistic regression was performed to determine the predictors of TCV vaccination status. RESULTS: Based on the 14-item parental VAS, 78.0 % of the parents had a score between 0 to <40 and 22 % had a score ≥40. VAS score of <40 was significantly associated with higher odds of receiving TCV during the campaign setting (adjusted Odds Ratio (aOR): 1.30; 95 % Confidence Interval (CI): 1.02, 1.66). The odds of receiving TCV vaccination were higher among children whose parents were aware of the ongoing vaccination campaign in the area (aOR: 4.57; 95 % CI: 2.93, 7.12) and expressed willingness to get their child vaccinated against typhoid fever (aOR: 2.54; 95 % CI: 1.82, 3.55). CONCLUSION: Parental awareness of the ongoing vaccination campaign, positive perception and attitudes towards vaccine were found to be significantly associated with TCV vaccination among children. Appropriately structured pre-vaccination awareness campaigns focused on childhood vaccination targeted towards parents are necessary to improve parental awareness, attitude and behavior towards vaccination.

Risk Factors Associated with Extensively Drug-Resistant Typhoid in an Outbreak Setting of Lyari Town Karachi, Pakistan.

Typhoid fever is endemic in Pakistan, with high annual incidence rates. An outbreak of extensively drug-resistant typhoid fever that first started in the Hyderabad District, Sindh Province, in November 2016 immediately spread to the entire province. We conducted an age-matched case-control study to assess the risk factors of typhoid fever in an outbreak setting of Lyari Town, Karachi. We enrolled 82 patients with blood culture-confirmed Salmonella typhi between August 2019 to December 2019, and 82 age-matched hospital and 164 age-matched community control subjects. In a matched conditional logistic regression model, consumption of meals outside the home more than once per month was associated significantly with developing culture-confirmed typhoid fever compared with no consumption of food outside the home (odds ratio, 4.11). Hygiene of the environment in which food is prepared, practices of adult food handlers, access to clean water, and food legislation play significant roles in the spread of typhoid fever.

Effectiveness of typhoid conjugate vaccine against culture-confirmed typhoid in a peri-urban setting in Karachi: A case-control study.

BACKGROUND: Enteric fever, caused by Salmonella Typhi and S. Paratyphi, is a cause of high morbidity and mortality among children in South Asia. Rising antimicrobial resistance presents an additional challenge. Typhoid Conjugate Vaccines (TCV) are recommended by the World Health Organization for use among people 6 months to 45 years old living in endemic settings. This study aimed to assess the effectiveness of TCV against culture-confirmed S. Typhi in Lyari Town, Karachi, Pakistan. This peri-urban town was one of the worst affected by the outbreak of extensively drug resistant (XDR) typhoid that started in November 2016. METHODS: A matched case-control study was conducted following a mass immunization campaign with TCV at three key hospitals in Lyari Town Karachi, Pakistan. Children aged 6 months to 15 years presenting with culture-confirmed S. Typhi were enrolled as cases. For each case, at least 1 age-matched hospital control and two age-matched community controls were enrolled. Adjusted odds ratios with 95% confidence intervals (CIs) were calculated using conditional logistic regression. RESULTS: Of 82 typhoid fever patients enrolled from August 2019 through December 2019, 8 (9·8%) had received vaccine for typhoid. Of the 164 community controls and 82 hospital controls enrolled, 38 (23·2%) community controls and 27 (32·9%) hospital controls were vaccinated for typhoid. The age and sex-adjusted vaccine effectiveness was found to be 72% (95% CI: 34% - 88%). The consumption of meals prepared outside home more than once per month (adjusted odds ratio: 3·72, 95% CI: 1·55- 8·94; p-value: 0·003) was associated with the development of culture-confirmed typhoid. CONCLUSION: A single dose of TCV is effective against culture confirmed typhoid among children aged 6 months to 15 years old in an XDR typhoid outbreak setting of a peri-urban community in Karachi, Pakistan.

Strategies to Improve Coverage of Typhoid Conjugate Vaccine (TCV) Immunization Campaign in Karachi, Pakistan.

The emergence and spread of extensively drug-resistant (XDR) typhoid in Karachi, Pakistan led to an outbreak response in Lyari Town, Karachi utilizing a mass immunization campaign with typhoid conjugate vaccine (TCV), Typbar TCV®. The mass immunization campaign, targeted Lyari Town, Karachi, one of the worst affected towns during the XDR typhoid outbreak. Here we describe the strategies used to improve acceptance and coverage of Typbar TCV in Lyari Town, Karachi. The mass immunization campaign with Typbar TCV was started as a school- and hospital-based vaccination campaign targeting children between the age of 6 months to 15 years old. A dose of 0.5 mL Typbar TCV was administered intramuscularly. A mobile vaccination campaign was added to cope with high absenteeism and non-response from parents in schools and to cover children out of school. Different strategies were found to be effective in increasing the vaccination coverage and in tackling vaccine hesitancy. Community engagement was the most successful strategy to overcome refusals and helped to gain trust in the newly introduced vaccine. Community announcements and playing typhoid jingles helped to increase awareness regarding the ongoing typhoid outbreak. Mop-up activity in schools was helpful in increasing coverage. Networking with locally active groups, clubs and community workers were found to be the key factors in decreasing refusals.