Identifying delays in healthcare seeking and provision: The Three Delays-in-Healthcare and mortality among infants and children aged 1-59 months.

Delays in illness recognition, healthcare seeking, and in the provision of appropriate clinical care are common in resource-limited settings. Our objective was to determine the frequency of delays in the "Three Delays-in-Healthcare", and factors associated with delays, among deceased infants and children in seven countries with high childhood mortality. We conducted a retrospective, descriptive study using data from verbal autopsies and medical records for infants and children aged 1-59 months who died between December 2016 and February 2022 in six sites in sub-Saharan Africa and one in South Asia (Bangladesh) and were enrolled in Child Health and Mortality Prevention Surveillance (CHAMPS). Delays in 1) illness recognition in the home/decision to seek care, 2) transportation to healthcare facilities, and 3) the receipt of clinical care in healthcare facilities were categorized according to the "Three Delays-in-Healthcare". Comparisons in factors associated with delays were made using Chi-square testing. Information was available for 1,326 deaths among infants and under 5 children. The majority had at least one identified delay (n = 854, 64%). Waiting >72 hours after illness recognition to seek health care (n = 422, 32%) was the most common delay. Challenges in obtaining transportation occurred infrequently when seeking care (n = 51, 4%). In healthcare facilities, prescribed medications were sometimes unavailable (n = 102, 8%). Deceased children aged 12-59 months experienced more delay than infants aged 1-11 months (68% vs. 61%, P = 0.018). Delays in seeking clinical care were common among deceased infants and children. Additional study to assess the frequency of delays in seeking clinical care and its provision among children who survive is warranted.

Provider adherence to clinical care recommendations for infants and children who died in seven low- and middle-income countries in the Child Health and Mortality Prevention Surveillance (CHAMPS) network.

Background: Most childhood deaths globally are considered preventable through high-quality clinical care, which includes adherence to clinical care recommendations. Our objective was to describe adherence to World Health Organization recommendations for the management of leading causes of death among children. Methods: We conducted a retrospective, descriptive study examining clinical data for children aged 1-59 months who were hospitalized and died in a Child Health and Mortality Prevention Surveillance (CHAMPS) catchment, December 2016-June 2021. Catchment areas included: Baliakandi and Faridpur, Bangladesh; Kersa, Haramaya, and Harar, Ethiopia; Kisumu and Siaya, Kenya; Bamako, Mali; Manhiça and Quelimane, Mozambique; Makeni, Sierra Leone; Soweto, South Africa. We reviewed medical records of those who died from lower respiratory tract infections, sepsis, malnutrition, malaria, and diarrheal diseases to determine the proportion who received recommended treatments and compared adherence by hospitalization duration. Findings: CHAMPS enrolled 460 hospitalized children who died from the leading causes (median age 12 months, 53.0% male). Median hospital admission was 31 h. There were 51.0% (n = 127/249) of children who died from lower respiratory tract infections received supplemental oxygen. Administration of intravenous fluids for sepsis (15.9%, n = 36/226) and supplemental feeds for malnutrition (14.0%, n = 18/129) were uncommon. There were 51.4% (n = 55/107) of those who died from malaria received antimalarials. Of the 80 children who died from diarrheal diseases, 76.2% received intravenous fluids. Those admitted for ≥24 h more commonly received antibiotics for lower respiratory tract infections and sepsis, supplemental feeds for malnutrition, and intravenous fluids for sepsis than those admitted <24 h. Interpretation: Provision of recommended clinical care for leading causes of death among young children was suboptimal. Further studies are needed to understand the reasons for deficits in clinical care recommendation adherence. Funding: Bill & Melinda Gates Foundation.

Sustained Low Incidence of Severe and Fatal COVID-19 Following Widespread Infection Induced Immunity after the Omicron (BA.1) Dominant in Gauteng, South Africa: An Observational Study.

We conducted an epidemiologic survey to determine the seroprevalence of SARS-CoV-2 anti-nucleocapsid (anti-N) and anti-spike (anti-S) protein IgG from 1 March to 11 April 2022 after the BA.1-dominant wave had subsided in South Africa and prior to another wave dominated by the BA.4 and BA.5 (BA.4/BA.5) sub-lineages. We also analysed epidemiologic trends in Gauteng Province for cases, hospitalizations, recorded deaths, and excess deaths were evaluated from the inception of the pandemic through 17 November 2022. Despite only 26.7% (1995/7470) of individuals having received a COVID-19 vaccine, the overall seropositivity for SARS-CoV-2 was 90.9% (95% confidence interval (CI), 90.2 to 91.5) at the end of the BA.1 wave, and 64% (95% CI, 61.8 to 65.9) of individuals were infected during the BA.1-dominant wave. The SARS-CoV-2 infection fatality risk was 16.5-22.3 times lower in the BA.1-dominant wave compared with the pre-BA.1 waves for recorded deaths (0.02% vs. 0.33%) and estimated excess mortality (0.03% vs. 0.67%). Although there are ongoing cases of COVID-19 infections, hospitalization and death, there has not been any meaningful resurgence of COVID-19 since the BA.1-dominant wave despite only 37.8% coverage by at least a single dose of COVID-19 vaccine in Gauteng, South Africa.

Population Immunity and Covid-19 Severity with Omicron Variant in South Africa.

BACKGROUND: The B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified on November 25, 2021, in Gauteng province, South Africa. Data regarding the seroprevalence of SARS-CoV-2 IgG in Gauteng before the fourth wave of coronavirus disease 2019 (Covid-19), in which the omicron variant was dominant, are needed. METHODS: We conducted a seroepidemiologic survey from October 22 to December 9, 2021, in Gauteng to determine the seroprevalence of SARS-CoV-2 IgG. Households included in a previous seroepidemiologic survey (conducted from November 2020 to January 2021) were contacted; to account for changes in the survey population, there was a 10% increase in the households contacted, with the use of the same sampling framework. Dried-blood-spot samples were tested for IgG against SARS-CoV-2 spike protein and nucleocapsid protein with the use of quantitative assays. We also evaluated Covid-19 epidemiologic trends in Gauteng, including cases, hospitalizations, recorded deaths, and excess deaths from the start of the pandemic through January 12, 2022. RESULTS: Samples were obtained from 7010 participants, of whom 1319 (18.8%) had received a Covid-19 vaccine. The seroprevalence of SARS-CoV-2 IgG ranged from 56.2% (95% confidence interval [CI], 52.6 to 59.7) among children younger than 12 years of age to 79.7% (95% CI, 77.6 to 81.5) among adults older than 50 years of age. Vaccinated participants were more likely to be seropositive for SARS-CoV-2 than unvaccinated participants (93.1% vs. 68.4%). Epidemiologic data showed that the incidence of SARS-CoV-2 infection increased and subsequently declined more rapidly during the fourth wave than it had during the three previous waves. The incidence of infection was decoupled from the incidences of hospitalization, recorded death, and excess death during the fourth wave, as compared with the proportions seen during previous waves. CONCLUSIONS: Widespread underlying SARS-CoV-2 seropositivity was observed in Gauteng before the omicron-dominant wave of Covid-19. Epidemiologic data showed a decoupling of hospitalizations and deaths from infections while omicron was circulating. (Funded by the Bill and Melinda Gates Foundation.).

Review: [corrected] The changing face of the HIV epidemic in sub-Saharan Africa.

The widespread roll-out of antiretroviral therapy (ART) has substantially changed the face of human immunodeficiency virus (HIV). Timely initiation of ART in HIV-infected individuals dramatically reduces mortality and improves employment rates to levels prior to HIV infection. Recent findings from several studies have shown that ART reduces HIV transmission risk even with modest ART coverage of the HIV-infected population and imperfect ART adherence. While condoms are highly effective in the prevention of HIV acquisition, they are compromised by low and inconsistent usage; male medical circumcision substantially reduces HIV transmission but uptake remains relatively low; ART during pregnancy, delivery and breastfeeding can virtually eliminate mother-to-child transmission but implementation is challenging, especially in resource-limited settings. The current HIV prevention recommendations focus on a combination of preventions approach, including ART as treatment or pre- or post-exposure prophylaxis together with condoms, circumcision and sexual behaviour modification. Improved survival in HIV-infected individuals and reduced HIV transmission risk is beginning to result in limited HIV incidence decline at population level and substantial increases in HIV prevalence. However, achievements in HIV treatment and prevention are threatened by the challenges of lifelong adherence to preventive and therapeutic methods and by the ageing of the HIV-infected cohorts potentially complicating HIV management. Although current thinking suggests prevention of HIV transmission through early detection of infection immediately followed by ART could eventually result in elimination of the HIV epidemic, controversies remain as to whether we can treat our way out of the HIV epidemic.

Reduction in early mortality on antiretroviral therapy for adults in rural South Africa since change in CD4+ cell count eligibility criteria.

OBJECTIVE: To explore the impact of expanded eligibility criteria for antiretroviral therapy (ART) on median CD4⁺ cell count at ART initiation and early mortality on ART. METHODS: Analyses included all adults (≥16 years) initiated on first-line ART between August 2004 and July 2012. CD4⁺ cell count threshold 350 cells per microliter for all adults was implemented in August 2011. Early mortality was defined as any death within 91 days of ART initiation. Trends in baseline CD4⁺ cell count and early mortality were examined by year (August to July) of ART initiation. Competing risks analysis was used to examine early mortality. RESULTS: A total of 19,080 adults (67.6% female) initiated ART. Median CD4⁺ cell count at ART initiation was 110-120 cells per microliter over the first 6 years, increasing marginally to 145 cells per microliter in 2010-2011 and more significantly to 199 cells per microliter in 2011-2012. Overall, there were 875 deaths within 91 days of ART initiation; early mortality rate was 19.4 per 100 person-years [95% confidence interval (CI) 18.2 to 20.7]. After adjustment for sex, age, baseline CD4⁺ cell count, and concurrent tuberculosis (TB), there was a 46% decrease in early mortality for those who initiated ART in 2011-2012 compared with the reference period 2008-2009 (subhazard ratio, 0.54; 95% CI: 0.41 to 0.71). CONCLUSIONS: Since the expansion of eligibility criteria, there is evidence of earlier access to ART and a significant reduction in early mortality rate in this primary health care programme. These findings provide strong support for national ART policies and highlight the importance of earlier ART initiation for achieving reductions in HIV-related mortality.

Decreased chronic morbidity but elevated HIV associated cytokine levels in HIV-infected older adults receiving HIV treatment: benefit of enhanced access to care?

BACKGROUND: The association of HIV with chronic morbidity and inflammatory markers (cytokines) in older adults (50+years) is potentially relevant for clinical care, but data from African populations is scarce. OBJECTIVE: To examine levels of chronic morbidity by HIV and ART status in older adults (50+years) and subsequent associations with selected pro-inflammatory cytokines and body mass index. METHODS: Ordinary, ordered and generalized ordered logistic regression techniques were employed to compare chronic morbidity (heart disease (angina), arthritis, stroke, hypertension, asthma and diabetes) and cytokines (Interleukins-1 and -6, C-Reactive Protein and Tumor Necrosis Factor-alpha) by HIV and ART status on a cross-sectional random sample of 422 older adults nested within a defined rural South African population based demographic surveillance. RESULTS: Using a composite measure of all morbidities, controlling for age, gender, BMI, smoking and wealth quintile, HIV-infected individuals on ART had 51% decreased odds (95% CI:0.26-0.92) of current morbidity compared to HIV-uninfected. In adjusted regression, compared to HIV-uninfected, the proportional odds (aPOR) of having elevated inflammation markers of IL6 (>1.56 pg/mL) was nearly doubled in HIV-infected individuals on (aPOR 1.84; 95%CI: 1.05-3.21) and not on (aPOR 1.94; 95%CI: 1.11-3.41) ART. Compared to HIV-uninfected, HIV-infected individuals on ART had >twice partial proportional odds (apPOR=2.30;p=0.004) of having non-clinically significant raised hsCRP levels(>1 ug/mL); ART-naïve HIV-infected individuals had >double apPOR of having hsCRP levels indicative of increased heart disease risk(>3.9 ug/mL;p=0.008). CONCLUSIONS: Although HIV status was associated with increased inflammatory markers, our results highlight reduced morbidity in those receiving ART and underscore the need of pro-actively extending these services to HIV-uninfected older adults, beyond mere provision at fixed clinics. Providing health services through regular community chronic disease screening would ensure health care reaches all older adults in need.

Disengagement from care in a decentralised primary health care antiretroviral treatment programme: cohort study in rural South Africa.

OBJECTIVE: To determine rates of, and factors associated with, disengagement from care in a decentralised antiretroviral programme. METHODS: Adults (≥16 years) who initiated antiretroviral therapy (ART) in the Hlabisa HIV Treatment and Care Programme August 2004-March 2011 were included. Disengagement from care was defined as no clinic visit for 180 days, after adjustment for mortality. Cumulative incidence functions for disengagement from care, stratified by year of ART initiation, were obtained; competing-risks regression was used to explore factors associated with disengagement from care. RESULTS: A total of 4,674 individuals (median age 34 years, 29% male) contributed 13 610 person-years of follow-up. After adjustment for mortality, incidence of disengagement from care was 3.4 per 100 person-years (95% confidence interval (CI) 3.1-3.8). Estimated retention at 5 years was 61%. The risk of disengagement from care increased with each calendar year of ART initiation (P for trend <0.001). There was a strong association between disengagement from care and higher baseline CD4+ cell count (subhazard ratio (SHR) 1.94 (P < 0.001) and 2.35 (P < 0.001) for CD4+ cell count 150-200 cells/µl and >200 cells/µl respectively, compared with CD4 count <50 cells/µl). Of those disengaged from care with known outcomes, the majority (206/303, 68.0%) remained resident within the local community. CONCLUSIONS: Increasing disengagement from care threatens to limit the population impact of expanded antiretroviral coverage. The influence of both individual and programmatic factors suggests that alternative service delivery strategies will be required to achieve high rates of long-term retention.

Health, wellbeing, and disability among older people infected or affected by HIV in Uganda and South Africa.

OBJECTIVE: To describe and compare the health status, emotional wellbeing, and functional status of older people in Uganda and South Africa who are HIV infected or affected by HIV in their families. METHODS: Data came from the general population cohort and Entebbe cohort of the Medical Research Council/Uganda Virus Research Institute, and from the Africa Centre Demographic Information System through cross-sectional surveys in 2009/10 using instruments adapted from the World Health Organization (WHO) Study on Global Ageing and Adult Health (SAGE). Analysis was based on 932 people aged 50 years or older (510 Uganda, 422 South Africa). RESULTS: Participants in South Africa were slightly younger (median age - 60 years in South Africa, 63 in Uganda), and more were currently married, had no formal education, were not working, and were residing in a rural area. Adjusting for socio-demographic factors, older people in South Africa were significantly less likely to have good functional ability [adjusted odds ratio (aOR) 0.72, 95% CI 0.53-0.98] than those in Uganda, but were more likely to be in good subjective wellbeing (aOR 2.15, 95% CI 1.60-2.90). South Africans were more likely to be obese (aOR 5.26, 95% CI 3.46-8.00) or to be diagnosed with hypertension (aOR 2.77, 95% CI 2.06-3.73). DISCUSSION AND CONCLUSIONS: While older people's health problems are similar in the two countries, marked socio-demographic differences influence the extent to which older people are affected by poorer health. It is therefore imperative when designing policies to improve the health and wellbeing of older people in sub-Saharan Africa that the region is not treated as a homogenous entity.

Poor long-term outcomes for cryptococcal meningitis in rural South Africa.

OBJECTIVES: To explore linkage to and retention in HIV care after an episode of cryptococcal meningitis (CM) in rural South Africa. Design. A retrospective case series of adult individuals (> or = 16 years old) with laboratory-confirmed CM from January - December 2007 at Hlabisa Hospital--a district hospital in northern KwaZulu-Natal. OUTCOME MEASURES: Inpatient mortality and associated risk factors were analysed. The proportion alive and on antiretroviral therapy (ART) at 2 years was determined by linkage to the HIV treatment programme. RESULTS: One hundred and four individuals were identified with laboratory diagnosis of CM; 74/104 (71.2%) with complete records were included in the analysis. Inpatient mortality was high (40.5%) and was significantly associated with reduced conscious level (aHR 3.09, 95% CI 1.30 - 7.33) and absence of headache (aHR 0.33 for headache, 95% CI 0.13 - 0.87). Only 8 individuals (10.8% of all study subjects) were alive and receiving ART 2 years after the CM episode. CONCLUSIONS: Long-term outcomes of CM are poor in routine practice. Interventions to strengthen linkage to HIV treatment and care and continuation of secondary fluconazole prophylaxis are critical.

Association of age with mortality and virological and immunological response to antiretroviral therapy in rural South African adults.

OBJECTIVE: To assess whether treatment outcomes vary with age for adults receiving antiretroviral therapy (ART) in a large rural HIV treatment cohort. DESIGN: Retrospective cohort analysis using data from a public HIV Treatment & Care Programme. METHODS: Adults initiating ART 1(st) August 2004-31(st) October 2009 were stratified by age at initiation: young adults (16-24 years) mid-age adults (25-49 years) and older (≥50 years) adults. Kaplan-Meier survival analysis was used to estimate mortality rates and age and person-time stratified Cox regression to determine factors associated with mortality. Changes in CD4 cell counts were quantified using a piecewise linear model based on follow-up CD4 cell counts measured at six-monthly time points. RESULTS: 8846 adults were included, 808 (9.1%) young adults; 7119 (80.5%) mid-age adults and 919 (10.4%) older adults, with 997 deaths over 14,778 person-years of follow-up. Adjusting for baseline characteristics, older adults had 32% excess mortality (p = 0.004) compared to those aged 25-49 years. Overall mortality rates (MR) per 100 person-years were 6.18 (95% CI 4.90-7.78); 6.55 (95% CI 6.11-7.02) and 8.69 (95% CI 7.34-10.28) for young, mid-age and older adults respectively. In the first year on ART, for older compared to both young and mid-aged adults, MR per 100 person-years were significantly higher; 0-3 months (MR: 27.1 vs 17.17 and 21.36) and 3-12 months (MR: 9.5 vs 4.02 and 6.02) respectively. CD4 count reconstitution was lower, despite better virological response in the older adults. There were no significant differences in MR after 1 year of ART. Baseline markers of advanced disease were independently associated with very early mortality (0-3 months) whilst immunological and virological responses were associated with mortality after 12 months. CONCLUSIONS: Early ART initiation and improving clinical care of older adults are required to reduce high early mortality and enhance immunologic recovery, particularly in the initial phases of ART.

A missing piece in the puzzle: HIV in mature adults in sub-Saharan Africa.

Healthcare and social needs for mature adults aged 50 years or older differ from those of younger adults due to stigma concerning HIV in older people, beliefs that engagement in sexual activity no longer applies, age driven comorbidities and responses to antiretroviral treatment, which complicate HIV diagnosis and management. In the face of a growing HIV epidemic in mature adults, mostly due to infected people aging with HIV, but also due to new infections in this age group, HIV services, which mostly cater for HIV in young adults and children, and HIV education messages and interventions, which mainly target young adults, leave the mature adult exposed and vulnerable to HIV transmission and to a lack of care and treatment thereafter.

Retention in HIV care for individuals not yet eligible for antiretroviral therapy: rural KwaZulu-Natal, South Africa.

OBJECTIVES: To determine retention in HIV care for individuals not yet eligible for antiretroviral therapy (ART) and to explore factors associated with retention in a rural public health HIV program. METHODS: HIV-infected adults (≥16 years) not yet eligible for ART, with CD4 cell count >200 cells per microliter from January 2007 to December 2007 were included in the analysis. Retention was defined by repeat CD4 count within 13 months. Factors associated with retention were assessed using logistic regression with clustering at clinic level. RESULTS: Four thousand two hundred twenty-three were included in the analysis (83.9% female). Overall retention was 44.9% with median time to return 201 days [interquartile range (IQR): 127-274]. Retention by initial CD4 count 201-350, 351-500, and >500 cells per microliter was 51.6% [95% confidence interval (CI): 49.1 to 54.0], 43.2% (95% CI: 40.5 to 45.9), and 34.9% (95% CI: 32.4 to 37.4), respectively. Compared with CD4 201-350 cells per microliter, higher initial CD4 count was significantly associated with lower odds of retention [CD4: 351-500 cells/µL adjusted odds ratio (aOR): 0.72, 95% CI: 0.62 to 0.84; CD4 >500 cells/µL aOR: 0.51, 95% CI: 0.44 to 0.60]. Male sex was independently associated with lower odds (aOR: 0.80, 95% CI: 0.67 to 0.96), and older age with higher odds of retention (for each additional year of age aOR: 1.03, 95% CI: 1.03 to 1.04). CONCLUSIONS: Retention in HIV care before eligibility for ART is poor, particularly for younger individuals and those at an earlier stage of infection. Further work to optimize and evaluate care and monitoring strategies is required to realize the full benefits of the rapid expansion of HIV programs in sub-Saharan Africa.

Scale-up of a decentralized HIV treatment programme in rural KwaZulu-Natal, South Africa: does rapid expansion affect patient outcomes?

OBJECTIVE: To describe the scale-up of a decentralized HIV treatment programme delivered through the primary health care system in rural KwaZulu-Natal, South Africa, and to assess trends in baseline characteristics and outcomes in the study population. METHODS: The programme started delivery of antiretroviral therapy (ART) in October 2004. Information on all patients initiated on ART was captured in the programme database and follow-up status was updated monthly. All adult patients (> or = 16 years) who initiated ART between October 2004 and September 2008 were included and stratified into 6-month groups. Clinical and sociodemographic characteristics were compared between the groups. Retention in care, mortality, loss to follow-up and virological outcomes were assessed at 12 months post-ART initiation. FINDINGS: A total of 5719 adults initiated on ART were included (67.9% female). Median baseline CD4+ lymphocyte count was 116 cells/microl (interquartile range, IQR: 53-173). There was an increase in the proportion of women who initiated ART while pregnant but no change in other baseline characteristics over time. Overall retention in care at 12 months was 84.0% (95% confidence interval, CI: 82.6-85.3); 10.9% died (95% CI: 9.8-12.0); 3.7% were lost to follow-up (95% CI: 3.0-4.4). Mortality was highest in the first 3 months after ART initiation: 30.1 deaths per 100 person-years (95% CI: 26.3-34.5). At 12 months 23.0% had a detectable viral load (> 25 copies/ml) (95% CI: 19.5-25.5). CONCLUSION: Outcomes were not affected by rapid expansion of this decentralized HIV treatment programme. The relatively high rates of detectable viral load highlight the need for further efforts to improve the quality of services.

The tuberculosis challenge in a rural South African HIV programme.

BACKGROUND: South Africa remains the country with the greatest burden of HIV-infected individuals and the second highest estimated TB incidence per capita worldwide. Within South Africa, KwaZulu-Natal has one of the highest rates of TB incidence and an emerging epidemic of drug-resistant tuberculosis. METHODS: Review of records of consecutive HIV-infected people initiated onto ART between 1st January 2005 and 31st March 2006. Patients were screened for TB at initiation and incident episodes recorded. CD4 counts, viral loads and follow-up status were recorded; data was censored on 5th August 2008. Geographic cluster analysis was performed using spatial scanning. RESULTS: 801 patients were initiated. TB prevalence was 25.3%, associated with lower CD4 (AHR 2.61 p = 0.01 for CD4 <50 cells/microl) and prior TB (AHR 1.58 p = 0.02). Incidence was 6.89 per 100 person-years from 81 cases over 1175 person-years analysis time and was highest in the first 3 months after ART initiation; associated with male sex and higher log HIV RNA. Prevalent and incident TB were significantly associated with mortality (OR 1.81 p = 0.01 and 2.02 p = 0.01 respectively). Incident TB was associated with a non-significant trend towards viral load >25 copies/ml (OR 1.75 p = 0.11). A low-risk cluster for incident TB was identified for patients living near the local hospital in the geospatial analysis. CONCLUSION: There is a large burden of TB in this population. Rate of incident TB stabilises at a rate higher than that of the overall population. These data highlight the need for greater research on strategies for active case finding in rural settings and the need to focus on strengthening primary health care.