Antiretroviral Initiation at ≥800 CD4+ Cells/mm3 Associated With Lower Human Immunodeficiency Virus Reservoir Size.

BACKGROUND: Identifying factors that determine the frequency of latently infected CD4+ T cells on antiretroviral therapy (ART) may inform strategies for human immunodeficiency virus (HIV) cure. We investigated the role of CD4+ count at ART initiation for HIV persistence on ART. METHODS: Among participants of the Strategic Timing of Antiretroviral Treatment Study, we enrolled people with HIV (PWH) who initiated ART with CD4+ T-cell counts of 500-599, 600-799, or ≥ 800 cells/mm3. After 36-44 months on ART, the levels of total HIV-DNA, cell-associated unspliced HIV-RNA (CA-US HIV-RNA), and two-long terminal repeat HIV-DNA in CD4+ T cells were quantified and plasma HIV-RNA was measured by single-copy assay. We measured T-cell expression of Human Leucocyte Antigen-DR Isotype (HLA-DR), programmed death-1, and phosphorylated signal transducer and activator of transcription-5 (pSTAT5). Virological and immunological measures were compared across CD4+ strata. RESULTS: We enrolled 146 PWH, 36 in the 500-599, 60 in the 600-799, and 50 in the ≥ 800 CD4 strata. After 36-44 months of ART, total HIV-DNA, plasma HIV-RNA, and HLA-DR expression were significantly lower in PWH with CD4+ T-cell count ≥ 800 cells/mm3 at ART initiation compared with 600-799 or 500-599 cells/mm3. The median level of HIV-DNA after 36-44 months of ART was lower by 75% in participants initiating ART with ≥ 800 vs 500-599 cells/mm3 (median [interquartile range]: 16.3 [7.0-117.6] vs 68.4 [13.7-213.1] copies/million cells, respectively). Higher pSTAT5 expression significantly correlated with lower levels of HIV-DNA and CA-US HIV-RNA. Virological measures were significantly lower in females. CONCLUSIONS: Initiating ART with a CD4+ count ≥ 800 cells/mm3 compared with 600-799 or 500-599 cells/mm3 was associated with achieving a substantially smaller HIV reservoir on ART.

Contribution of Serologic Assays in the Evaluation of Influenza Virus Infection Rates and Vaccine Efficacy in Pregnant Women: Report From Randomized Controlled Trials.

BACKGROUND.: The utility of serologic testing to evaluate vaccine efficacy of seasonal inactivated influenza vaccine (IIV) is controversial. We aimed to evaluate the efficacy of IIV against serologically diagnosed influenza infection (SDI) and reverse-transcription polymerase chain reaction-confirmed influenza illness (PCR-CI) in women vaccinated during pregnancy. METHODS.: We undertook a post hoc analysis of 2 randomized clinical trials evaluating IIV efficacy among human immunodeficiency virus (HIV)-uninfected and HIV-infected pregnant women. SDI was defined as ≥4-fold increase in paired hemagglutinin antibody inhibition titers from 1 month postvaccination until end-of-study participation. PCR-CI was defined as molecular diagnostic evidence of influenza virus in pharyngeal specimens collected during clinical illness. RESULTS.: Among placebo recipients, the respective incidence of PCR-CI and SDI was 5.6% and 35.0% in HIV-uninfected women and 20.5% and 43.6% among HIV-infected women. Vaccine efficacy in HIV-uninfected women was similar for PCR-CI (66.9%; 95% confidence interval [CI], -20.1% to 90.9%) and SDI (59.2%; 95% CI, 37.0%-73.5%); however, fewer women required vaccination to prevent 1 episode of SDI (5; 95% CI, 3-9) than PCR-CI (27; 95% CI, 12-∞). Also, vaccine efficacy was similar for PCR-CI (61.2%; 95% CI, 10.7%-83.2%) and SDI (60.9%; 95% CI, 33.9%-76.9%) in HIV-infected women, with 2-fold fewer women needing to be vaccinated to prevent SDI (4; 95% CI, 3-8) than PCR-CI (8; 95% CI, 4-52). CONCLUSIONS.: Although vaccine efficacy was similar when measured for PCR-CI or SDI, IIV vaccination prevented a greater number of SDI than PCR-CI; the clinical relevance of the former warrants interrogation.Clinical Trials Registration. NCT01306669 and NCT01306682.

Data Management and Data Quality in PERCH, a Large International Case-Control Study of Severe Childhood Pneumonia.

The Pneumonia Etiology Research for Child Health (PERCH) study is the largest multicountry etiology study of pediatric pneumonia undertaken in the past 3 decades. The study enrolled 4232 hospitalized cases and 5325 controls over 2 years across 9 research sites in 7 countries in Africa and Asia. The volume and complexity of data collection in PERCH presented considerable logistical and technical challenges. The project chose an internet-based data entry system to allow real-time access to the data, enabling the project to monitor and clean incoming data and perform preliminary analyses throughout the study. To ensure high-quality data, the project developed comprehensive quality indicator, data query, and monitoring reports. Among the approximately 9000 cases and controls, analyzable laboratory results were available for ≥96% of core specimens collected. Selected approaches to data management in PERCH may be extended to the planning and organization of international studies of similar scope and complexity.

Influenza vaccination of pregnant women and protection of their infants.

BACKGROUND: There are limited data on the efficacy of vaccination against confirmed influenza in pregnant women with and those without human immunodeficiency virus (HIV) infection and protection of their infants. METHODS: We conducted two double-blind, randomized, placebo-controlled trials of trivalent inactivated influenza vaccine (IIV3) in South Africa during 2011 in pregnant women infected with HIV and during 2011 and 2012 in pregnant women who were not infected. The immunogenicity, safety, and efficacy of IIV3 in pregnant women and their infants were evaluated until 24 weeks after birth. Immune responses were measured with a hemagglutination inhibition (HAI) assay, and influenza was diagnosed by means of reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assays of respiratory samples. RESULTS: The study cohorts included 2116 pregnant women who were not infected with HIV and 194 pregnant women who were infected with HIV. At 1 month after vaccination, seroconversion rates and the proportion of participants with HAI titers of 1:40 or more were higher among IIV3 recipients than among placebo recipients in both cohorts. Newborns of IIV3 recipients also had higher HAI titers than newborns of placebo recipients. The attack rate for RT-PCR-confirmed influenza among both HIV-uninfected placebo recipients and their infants was 3.6%. The attack rates among HIV-uninfected IIV3 recipients and their infants were 1.8% and 1.9%, respectively, and the respective vaccine-efficacy rates were 50.4% (95% confidence interval [CI], 14.5 to 71.2) and 48.8% (95% CI, 11.6 to 70.4). Among HIV-infected women, the attack rate for placebo recipients was 17.0% and the rate for IIV3 recipients was 7.0%; the vaccine-efficacy rate for these IIV3 recipients was 57.7% (95% CI, 0.2 to 82.1). CONCLUSIONS: Influenza vaccine was immunogenic in HIV-uninfected and HIV-infected pregnant women and provided partial protection against confirmed influenza in both groups of women and in infants who were not exposed to HIV. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov numbers, NCT01306669 and NCT01306682.).

Kinetics of Hemagglutination-Inhibiting Antibodies Following Maternal Influenza Vaccination Among Mothers With and Those Without HIV Infection and Their Infants.

BACKGROUND: We evaluated the immunogenicity of trivalent inactivated influenza vaccine (IIV3) in pregnant women with and those without human immunodeficiency virus (HIV) infection and the persistence of hemagglutination-inhibiting antibodies in mothers and infants. METHODS: Antibodies were measured before vaccination, 1 month after vaccination, at delivery, and at postpartum week 24 in mothers and within 1 week of birth and at 8, 16, and 24 weeks of age in infants. RESULTS: We enrolled 98 HIV-uninfected and 100 HIV-infected pregnant women, including 93% with a CD4(+) T-cell count of ≥ 200 cells/µL. Compared with HIV-uninfected women, HIV-infected women had lower seroconversion rates (ranging from 63%-92% vs 36%-40%), lower antibody titers through postpartum week 24, and overlapping antibody half-lives (ranging from 106-121 vs 87-153 days). Infant titers were lower than the maternal titers within 1 week of delivery, regardless of vaccine strain and HIV exposure status. Compared with HIV-unexposed infants, HIV-exposed infants had a similar transplacental influenza virus antibody transfer ratio, lower titers, and a lower frequency of titers ≥ 1:40 (ranging from 82%-95% vs 43%-79%) at birth and higher antibody half-lives (ranging from 43-45 vs 56-65 days). CONCLUSIONS: Compared with HIV-uninfected pregnant women, HIV-infected pregnant women had lower antibody responses and persistence. Compared with HIV-unexposed infants, HIV-exposed infants had lower antibody levels at birth but similar antibody levels after 8 weeks of life. Early IIV3 administration during pregnancy did not decrease antibody titers among infants at birth.

Increased risk for group B Streptococcus sepsis in young infants exposed to HIV, Soweto, South Africa, 2004-2008(1).

Although group B Streptococcus (GBS) is a leading cause of severe invasive disease in young infants worldwide, epidemiologic data and knowledge about risk factors for the disease are lacking from low- to middle-income countries. To determine the epidemiology of invasive GBS disease among young infants in a setting with high maternal HIV infection, we conducted hospital-based surveillance during 2004-2008 in Soweto, South Africa. Overall GBS incidence was 2.72 cases/1,000 live births (1.50 and 1.22, respectively, among infants with early-onset disease [EOD] and late-onset [LOD] disease). Risk for EOD and LOD was higher for HIV-exposed than HIV-unexposed infants. GBS serotypes Ia and III accounted for 84.0% of cases, and 16.9% of infected infants died. We estimate that use of trivalent GBS vaccine (serotypes Ia, Ib, and III) could prevent 2,105 invasive GBS cases and 278 deaths annually among infants in South Africa; therefore, vaccination of all pregnant women in this country should be explored.

Trivalent inactivated influenza vaccine in African adults infected with human immunodeficient virus: double blind, randomized clinical trial of efficacy, immunogenicity, and safety.

BACKGROUND: Data on the efficacy of trivalent, inactivated influenza vaccine (TIV) in HIV-infected adults, particularly in Africa, are limited. This study evaluated the safety, immunogenicity, and efficacy of TIV in HIV-infected adults. METHODS: In Johannesburg, South Africa, we undertook a randomized, double-blind, placebo-controlled trial involving 506 HIV-infected adults. Subjects included 157 individuals who were antiretroviral treatment (ART) naive and 349 on stable-ART. Participants were randomly assigned to receive TIV or normal saline intramuscularly. Oropharyngeal swabs were obtained at illness visits during the influenza season and tested by shell vial culture and RT PCR assay for influenza virus. Immune response was evaluated by hemagglutinin antibody inhibition assay (HAI) in a nested cohort. The primary study outcome involved vaccine efficacy against influenza confirmed illness. This trial is registered with ClinicalTrials.gov, number NCT00757900. RESULTS: The efficacy of TIV against confirmed influenza illness was 75.5% (95% CI: 9.2%-95.6%); with a risk difference of 0.18 per 100 person-weeks in TIV recipients. Among TIV recipients, seroconversion, measured by HAI titers, was evident in 52.6% for H1N1, 60.8% for H3N2, and 53.6% for influenza B virus. This compared with 2.2%, 2.2%, and 4.4% of placebo recipients (P < .0001). The frequency of local and systemic adverse events post-immunization was similar between study groups. CONCLUSIONS: TIV immunization is safe and efficacious in African HIV-infected adults without underlying co-morbidities. Further evaluation of effectiveness is warranted in severely immunocompromized HIV-infected adults and those with co-morbidities such as tuberculosis.

Effect of Changes in Body Mass Index on the Risk of Cardiovascular Disease and Diabetes Mellitus in HIV-Positive Individuals: Results From the D:A:D Study.

BACKGROUND: Weight gain is common among people with HIV once antiretroviral treatment is commenced. We assess the effect of changes in body mass index (BMI), from different baseline BMI levels, on the risk of cardiovascular disease (CVD) and diabetes mellitus (DM). METHODS: D:A:D participants receiving antiretroviral treatment were followed from their first BMI measurement to the first of either CVD or DM event, or earliest of January 2, 2016 or 6 months after last follow-up. Participants were stratified according to their baseline BMI, and changes from baseline BMI were calculated for each participant. Poisson regression models were used to assess the effects of changes on BMI on CVD or DM events. RESULTS: There were 2104 CVD and 1583 DM events over 365,287 and 354,898 person-years [rate: CVD 5.8/1000 (95% confidence interval: 5.5 to 6.0); DM 4.5/1000 (95% confidence interval: 4.2 to 4.7)]. Participants were largely men (74%), baseline mean age of 40 years, and median BMI of 23.0 (IQR: 21.0-25.3). A risk of CVD by change in BMI from baseline, stratified by baseline BMI strata showed little evidence of an increased risk of CVD with an increased BMI in any baseline BMI strata. An increase in BMI was associated with an increased risk of DM across all baseline BMI strata. CONCLUSIONS: Although increases in BMI across all levels of baseline BMI were not associated with an increased risk of CVD, such changes were consistently associated with an increased risk of DM. There was also some evidence of an increased risk of CVD with a decrease in BMI.

Chlorhexidine maternal-vaginal and neonate body wipes in sepsis and vertical transmission of pathogenic bacteria in South Africa: a randomised, controlled trial.

BACKGROUND: About 500,000 sepsis-related deaths per year arise in the first 3 days of life. On the basis of results from non-randomised studies, use of vaginal chlorhexidine wipes during labour has been proposed as an intervention for the prevention of early-onset neonatal sepsis in developing countries. We therefore assessed the efficacy of chlorhexidine in early-onset neonatal sepsis and vertical transmission of group B streptococcus. METHODS: In a trial in Soweto, South Africa, 8011 women (aged 12-51 years) were randomly assigned in a 1:1 ratio to chlorhexidine vaginal wipes or external genitalia water wipes during active labour, and their 8129 newborn babies were assigned to full-body (intervention group) or foot (control group) washes with chlorhexidine at birth, respectively. In a subset of mothers (n=5144), we gathered maternal lower vaginal swabs and neonatal skin swabs after delivery to assess colonisation with potentially pathogenic bacteria. Primary outcomes were neonatal sepsis in the first 3 days of life and vertical transmission of group B streptococcus. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00136370. FINDINGS: Rates of neonatal sepsis did not differ between the groups (chlorhexidine 141 [3%] of 4072 vs control 148 [4%] of 4057; p=0.6518). Rates of colonisation with group B streptococcus in newborn babies born to mothers in the chlorhexidine (217 [54%] of 401) and control groups (234 [55%] of 429] did not differ (efficacy -0.05%, 95% CI -9.5 to 7.9). INTERPRETATION: Because chlorhexidine intravaginal and neonatal wipes did not prevent neonatal sepsis or the vertical acquisition of potentially pathogenic bacteria among neonates, we need other interventions to reduce childhood mortality. FUNDING: US Agency for International Development, National Vaccine Program Office and Centers for Disease Control's Antimicrobial Resistance Working Group, and Bill & Melinda Gates Foundation.

Study on knowledge about associated factors of Tuberculosis (TB) and TB/HIV co-infection among young adults in two districts of South Africa.

South Africa ranks third among 22 high burden countries in the world. TB which remains a leading cause of death causes one in five adult deaths in South Africa. An in-depth understanding of knowledge, attitudes and practices of young people towards TB is required to implement meaningful interventions. We analysed young men and women (18-24 years)'s TB knowledge including TB/HIV coinfections, testing rates and factors associated with them. A cross sectional cluster-based household survey was conducted in two provinces. Participants completed computer-assisted self-interviews on TB knowledge, testing history and TB/HIV coinfections. A participant was regarded as knowledgeable of TB if s/he correctly answered the WHO-adopted TB knowledge questions. We built three multivariate regression models in Stata 13.0 to assess factors associated with knowing TB alone, testing alone and both knowing and testing for TB. 1955 participants were interviewed (89.9% response rate). Their median age was 20 years (IQR19-22). Sixteen percent (16.2%) of the participants were social grant recipients, 55% were enrolled in a school/college and 5% lived in substandard houses. A total of 72% had knowledge of TB, 21% underwent screening tests for TB and 14.7% knew and tested for TB. Factors associated with TB knowledge were being female, younger, a student, social grant recipient, not transacting sex and having positive attitudes towards people living with HIV (PLWH). Factors associated with TB testing were being a student, receiving a social grant, living in OR Tambo district, HIV knowledge and having a family member with TB history. Factors associated with both TB knowledge and testing were being female, a student, using the print media, living in OR Tambo district and having a family member with a TB history. The study demonstrates the importance of demographic factors (gender, economic status, family TB history, and location) and HIV factors in explaining TB knowledge and testing. We recommend extending community TB testing services to increase testing.

Comparison of community-based HIV counselling and testing (CBCT) through index client tracing and other modalities: Outcomes in 13 South African high HIV prevalence districts by gender and age.

BACKGROUND: To increase HIV case finding in a Community-based HIV counselling and testing (CBCT) programme, an index client tracing modality was implemented to target index clients' sexual network and household members. OBJECTIVE: To compare index client tracing modality's outcomes with other CBCT recruitment modalities (mobile, workplace, homebased), 2015-2017. METHODS: Trained HIV counsellors identified HIV positive clients either through offering HIV tests to children and sexual partners of an HIV index client, or randomly offering HIV tests to anyone available in the community (mobile, home-based or workplace). Socio-demographic information and test results were recorded. Descriptive comparisons of client HIV test uptake and positivity were conducted by method of recruitment-index client tracing vs non-targeted community outreach. RESULTS: Of the 1 282 369 people who tested for HIV overall, the index modality tested 3.9% of them, 1.9% in year 1 and 6.0% in year 2. The index modality tested more females than males (55.8% vs 44.2%) overall and in each year; tested higher proportions of children than other modalities: 10.1% vs 2.6% among 1-4 years, 12.2% vs 2.6% among the 5-9 years and 9.6% vs 3.4% among the 10-15 years. The index modality identified higher HIV positivity proportions than other modalities overall (10.3% 95%CI 10.0-10.6 vs. 7.3% 95%CI 7.25-7.36), in year 1 (9.4%; 8.9-9.9 vs 6.5%; 6.45-6.57) and year 2 (10.6%; 10.3-10.9 vs 8.2%; 8.09-8.23). Higher proportions of females (7.5%;7.4-7.5) than males (5.5%;5.4-5.5) tested positive overall. Positivity increased by age up to 49y with year 2's increased targeting of sexual partners. Overall linkage to care rose from 33.3% in year 1 to 78.9% in year 2. CONCLUSIONS: Index testing was less effective in reaching large numbers of clients, but more effective in reaching children and identifying HIV positive people than other modalities. Targeting HIV positive people's partners and children increases HIV case finding.

Social franchising of community-based HIV testing and linkage to HIV care and treatment services: an evaluation of a pilot study in Tshwane, South Africa.

INTRODUCTION: Although HIV testing services (HTS) have been successfully task-shifted to lay counsellors, no model has tested the franchising of HTS to lay counsellors as independent small-scale business owners. This paper evaluates the effectiveness of a social franchisee (SF) HTS-managed pilot project compared to the Foundation for Professional Development (FPD) employee-managed HTS programme in testing and linking clients to care. METHODS: Unemployed, formally employed or own business individuals were engaged as franchisees, trained and supported to deliver HTS services under a common brand in high HIV-prevalent communities in Tshwane district between 2016 and 2017. SFs were remunerated per-HIV test and received larger payments per-HIV-positive client linked to care. In the standard HTS, FPD employed counsellors received similar training and observed similar standards as in the SF HTS, but were remunerated through the normal payroll. We assessed the proportion of clients tested, HIV positivity, linkage to care and per-counsellor cost of HIV test and linkage to care in the two HTS groups. RESULTS: The SF HTS had 19 HIV counsellors while FPD HTS employed 20. A combined total of 84,556 clients were tested by SFs (50.5%: 95% confidence interval (CI) 50.2 to 50.8)) and FPD (49.5%: 49.2 to 49.8). SFs tested more females than FPD (54.1%: 53.6 to 54.6 vs. 48%: 47.7 to 48.7). SFs identified more first-time testers than FPD (21.5%: 21.1 to 21.9 vs. 8.9%: 8.6 to 9.1). Overall, 8%: 7.9 to 8.2 tested positive with more clients testing positive in the SF (10.2%: 9.9 to 10.5) than FPD (5.9%: 5.6 to 6.1) group. The SFs identified more female HIV-positive clients (11.1%: 10.7 to 11.6) than FPD (6.5%: 6.2 to 6.9). The SFs linked fewer clients to HIV care and treatment (60.0%: 58.5 to 61.5) than FPD (80.3%: 78.7 to 81.9%). It cost four times less to conduct an HIV test using SFs ($3.90 per SF HIV test) than FPD ($13.98) and five times less to link a client to care with SFs ($62.74) than FPD ($303.13). CONCLUSIONS: SF HTS was effective in identifying more clients, first-time HIV testers and more HIV-positive people, but less effective in linking clients to care than FPD HTS. The SF HTS model was cheaper than the FPD-employee model. We recommend strengthening SFs particularly their linkage to care activities.

Seasonality, incidence, and repeat human metapneumovirus lower respiratory tract infections in an area with a high prevalence of human immunodeficiency virus type-1 infection.

BACKGROUND: There is limited information regarding the epidemiology of human metapneumovirus (hMPV) from Africa, despite it being identified as a common pathogen in children with pneumonia. OBJECTIVES: Determine the epidemiology of severe hMPV-associated lower respiratory tract infection (LRTI) in human immunodeficiency virus type-1 (HIV) infected and uninfected children. METHODS: Nasopharyngeal aspirate samples from children hospitalized for LRTI between January 2000 and December 2002 were analyzed for common respiratory viruses using an immunofluorescence assay; and 2715 available nasopharyngeal aspirate samples were tested for hMPV by reverse-transcriptase polymerase chain reaction targeting its fusion protein. Phylogenetic analysis of the fusion (F) gene was performed on samples associated with repeat hMPV infections in the same child. RESULTS: hMPV was identified perennially and was the second most commonly identified respiratory virus (11.3% versus 21.1% for respiratory syncytial virus, P < 0.0001) in HIV-uninfected children. The burden of hospitalization for hMPV-LRTI was 5.4 (95% CI: 3.5-7.5) fold greater in HIV-infected (2935 per 100,000) compared with HIV-uninfected children [575 (95% CI: 472-695) per 100,000]. HIV-infected children had greater evidence of bacterial coinfection and a higher mortality rate than did uninfected children. Repeat hMPV associated hospitalizations involved homologous (B2 subgroup) and heterologous (A1 and B2) hMPV. CONCLUSIONS: There is a high burden of hMPV-LRTI and repeat severe infections occur from homologous and heterologous subgroups of the virus.

Usefulness of C-reactive protein to define pneumococcal conjugate vaccine efficacy in the prevention of pneumonia.

OBJECTIVES AND METHODS: This study explored whether C-reactive protein (CRP) and/or procalcitonin levels were useful to measure vaccine efficacy (VE) and impact against the burden of pneumonia of a 9-valent pneumococcal conjugate vaccine (PCV), compared with chest radiograph-confirmed alveolar consolidation (CXR-AC) as an outcome. Sera obtained from children participating in a phase 3 PCV efficacy trial who were hospitalized for treatment of clinically diagnosed lower respiratory tract infection (C-LRTI) were retrospectively analyzed for CRP and procalcitonin measurements. RESULTS: For non-human immunodeficiency virus (HIV)-infected children, the VE estimates for C-LRTI with CRP levels of > or =40 mg/dL (VE 26.3%; P = 0.003) or CRP levels of > or =120 mg/dL (VE 41.0%; P = 0.003) were 1.7-fold (P = 0.002) and 2.7-fold (P < 0.0001) greater, respectively, than that for CXR-AC (VE 15.1%; P= 0.15). The sensitivity of CXR-AC as an outcome to detect the burden of pneumonia prevented by PCV was 44% (95% confidence interval, 36-55%) in comparison with C-LRTI with CRP levels of > or =40 mg/dL and 73% (95% confidence interval, 58-92%) in comparison with C-LRTI with CRP levels of > or =120 mg/dL. CRP also helped to measure the PCV efficacy for children with C-LRTI but the absence of CXR-AC, for whom the outcome of C-LRTI with CRP levels of > or =40 mg/dL (VE 31.5%; P = 0.007) increased the VE estimate 19.8-fold (P < 0.0001) in comparison with C-LRTI alone (VE 1.6%; P = 0.78) and 3.2-fold (P = 0.005) in comparison with WHO-defined severe pneumonia (VE 10.0%; P = 0.17). Although there was a significant correlation between CRP and procalcitonin levels (Spearman's rho = 0.45; P < 0.0001), the use of procalcitonin levels did not improve either the specificity or sensitivity of measuring the effect of PCV against pneumonia for non-HIV-infected children. The observations were similar for HIV-infected children. CONCLUSIONS: CRP levels of > or =40 mg/dL provide a better measure than chest radiographs to assess the effect of PCV in preventing pneumonia.

Five-year cohort study of hospitalization for respiratory syncytial virus associated lower respiratory tract infection in African children.

OBJECTIVES: To describe the epidemiology of respiratory syncytial virus (RSV) associated lower respiratory tract infection (RSV-LRTI) hospitalizations in South African children over a 5-year period, and determine the impact of gestational age (GA) on the incidence of RSV-LRTI hospitalization. STUDY DESIGN: A cohort of 39,836 children, 6.47% of whom were HIV infected, enrolled into a phase 3 trial were prospectively studied for respiratory viruses when hospitalized for LRTI. RESULTS: The incidence of hospitalization for RSV-LRTI was 19.4 per 1000 in HIV uninfected children and 2.5-fold (95% CI 2.04-3.03) greater in HIV infected children (45.0 per 1000). The incidence of RSV-LRTI was 4.9-fold greater (95% CI 3.9-6.8) in children born at <36 weeks of gestational age (GA) and repeat hospitalizations for RSV-LRTI was 3.7-fold (95% CI 1.4-9.4) more likely in these children (7.3%) than children born at > or =36 weeks of GA (1.9%). The burden of RSV-LRTI was greater in children born at <32 weeks of GA than those born at 32-35 weeks of GA between 6-12 months (P=0.008) and 12-24 months of age (P=0.001). The RSV epidemic occurred at the end of the rainy season and peaked when the monthly temperatures were at its lowest each year.

The impact of a 9-valent pneumococcal conjugate vaccine on the public health burden of pneumonia in HIV-infected and -uninfected children.

INTRODUCTION: Pneumococcal conjugate vaccine (PnCV) may be used as a probe to define the burden of pneumococcal disease and better characterize the clinical presentation of pneumococcal pneumonia. METHODS: This study used a 9-valent PnCV to define different end points of vaccine efficacy and the preventable burden of pneumococcal pneumonia in 39,836 children who were randomized in a double-blind, placebo-controlled trial in South Africa. RESULTS: Whereas the point-estimate of vaccine efficacy was greatest when measured against the outcome of vaccine-serotype specific pneumococcal bacteremic pneumonia (61%; P = .01), the sensitivity of blood culture to measure the burden of pneumococcal pneumonia prevented by vaccination was only 2.6% in human immunodeficiency virus (HIV)-uninfected children and 18.8% in HIV-infected children. Only 37.8% of cases of pneumococcal pneumonia prevented by PnCV were detected by means of chest radiographs showing alveolar consolidation. A clinical diagnosis of pneumonia provided the best estimate of the burden of pneumococcal pneumonia prevented through vaccination in HIV-uninfected children (267 cases prevented per 100,000 child-years) and HIV-infected children (2573 cases prevented per 100,000 child-years). CONCLUSION: Although outcome measures with high specificity, such as bacteremic pneumococcal pneumonia, provide a better estimate as to vaccine efficacy, the burden of disease prevented by vaccination is best evaluated using outcome measures with high sensitivity, such as a clinical diagnosis of pneumonia.

Use of procalcitonin and C-reactive protein to evaluate vaccine efficacy against pneumonia.

BACKGROUND: Pneumonia remains the leading cause of death in young children. The poor specificity of chest radiographs (CXRs) to diagnose pneumococcal pneumonia may underestimate the efficacy of pneumococcal conjugate vaccine in preventing pneumococcal pneumonia. METHODS AND FINDINGS: The efficacy of nine-valent pneumococcal conjugate vaccine among children not infected with HIV (21%; 95% confidence interval, 1%-37%) increased when CXR-confirmed pneumonia was associated with serum C-reactive protein of 120 mg/l (12 mg/dl) or more and procalcitonin of 5.0 ng/ml or more (64%; 95% confidence interval, 23%-83%). Similar results were observed in children infected with HIV. CONCLUSION: C-reactive protein and procalcitonin improve the specificity of CXR to diagnose pneumococcal pneumonia and may be useful for the future evaluation of the effectiveness of pneumococcal conjugate vaccine in preventing pneumococcal pneumonia.

Quantitative and qualitative antibody response to pneumococcal conjugate vaccine among African human immunodeficiency virus-infected and uninfected children.

OBJECTIVE: To determine the quantitative and qualitative antibody responses to a pneumococcal conjugate vaccine (PnCV) in human immunodeficiency virus (HIV)-exposed infected and uninfected children. METHODS: Children were randomized to receive either a PnCV or placebo at 6, 10 and 14 weeks of age. PnCV serotype-specific antibody concentrations were measured by a standard enzyme immunoassay (EIA) and a 22F modified EIA (22F EIA) on single serum samples drawn at 21-42 days post-dose 3. Functional activities of the serotype-specific antibody to serotypes 6B, 19F and 23F were measured with an opsonophagocytic assay (OPA). RESULTS: The geometric mean antibody concentrations (GMC) were similar in HIV-infected and HIV-uninfected PnCV recipients for 7 of the 9 vaccine serotypes. In placebo recipients, the GMCs were significantly higher in HIV-infected than in uninfected children for 7 of the serotypes. In HIV-infected PnCV recipients, the GMCs were lower for 5 of the serotypes in children with severe acquired immunodeficiency syndrome than in children who were asymptomatic or mildly symptomatic with acquired immunodeficiency syndrome. HIV-infected PnCV recipients were less likely to have measurable functional antibody (OPA titer > or =1/8) to all 3 studied serotypes (6B, 19F and 23F) than in HIV-uninfected children. HIV-infected children required a higher concentration of anticapsular antibody to achieve 50% of the maximum uptake of labeled Streptococcus pneumoniae in the OPA assay than HIV-uninfected children for 2 of the 3 serotypes, although this was significant only for serotype 6B (P = 0.0005). CONCLUSION: HIV-infected children have similar quantitative antibody responses but poorer qualitative antibody responses to the PnCV.

Acquisition of Streptococcus pneumoniae in South African children vaccinated with 7-valent pneumococcal conjugate vaccine at 6, 14 and 40 weeks of age.

BACKGROUND: Seven-valent pneumococcal conjugate vaccine (PCV7) was introduced into the South African immunization program using 6, 14 and 40 weeks dosing schedule (2+1), with no catch-up in older children since April 2009. We investigated pneumococcal colonization acquisition in children who received this schedule and also compared it to historical cohorts of PCV-naïve children (n=123 in 2007) and children who received a 3+1 PCV7 schedule (n=124 in 2005/06). METHODS: Two hundred and fifty children aged 6-12 weeks were enrolled from December 2009 to April 2010. Participants had nasopharyngeal swabs collected on eight occasions between enrolment and 2-years of age. Standard methods were undertaken for bacterial culture and Streptococcus pneumoniae were serotyped using the Quellung method. Pneumococcal and Staphylococcus aureus colonization in the present study was compared to colonization in two historical longitudinal cohorts. RESULTS: S. pneumoniae was identified in 1081 (61.4%) of 1761 swabs collected in the current cohort. Pneumococcal colonization peaked at 41-weeks of age (76.8%) and decreased to 62.8% by 2-years of age (p=0.002); PCV7-serotype colonization decreased during the same period from 28.6% to 15.6% (p=0.001). Children from the current cohort compared to PCV-naïve children were less likely to be colonized by PCV7-serotypes from 40-weeks to 2-years of age and acquired PCV7-serotypes less frequently. No differences in overall pneumococcal, PCV7-serotype and non-PCV7-serotype colonization or new serotype acquisitions were detected comparing the current cohort to the historical cohort who received the 3+1 PCV7 schedule. Staphylococcus aureus colonization was similar in all three cohorts. CONCLUSION: A 2+1 PCV7 schedule implemented in South Africa was temporally associated with reduced risk of vaccine-serotype colonization compared to historically unvaccinated children. Also, vaccine-serotype acquisition rate using the 2+1 schedule was similar to that in the 3+1 dosing cohort, suggesting that similar indirect protection against pneumococcal disease could be derived from either schedule in South Africa.

Prospective cohort study comparing seasonal and H1N1(2009) pandemic influenza virus illnesses in HIV-infected children during 2009.

A cohort of 410 young HIV-infected children was prospectively investigated for seasonal and A(H1N1p)2009 influenza virus illness during 2009. The incidence of confirmed illness due to seasonal influenza was 3-fold greater than A(H1N1p)2009 (0.7 vs. 0.2 per 100 child-weeks, respectively; P = 0.0001), and the clinical presentations were similar. Illnesses due to seasonal and A(H1N1p)2009 influenza were self-limiting without neuraminidase inhibitor therapy.