Transition to dolutegravir-based ART in 35 low- and middle-income countries: a global survey of HIV care clinics.

OBJECTIVE: We studied the transition to dolutegravir-containing antiretroviral therapy (ART) at HIV treatment clinics within the International epidemiology Databases to Evaluate AIDS (IeDEA). DESIGN: Site-level survey conducted in 2020-2021 among HIV clinics in low- and middle-income countries (LMICs). METHODS: We assessed the status of dolutegravir rollout and viral load and drug resistance testing practices for patients on ART switching to dolutegravir-based regimens. We used generalized estimating equations to assess associations between clinic rollout of both first- and second-line dolutegravir-based ART regimens (dual rollout) and site-level factors. RESULTS: Of 179 surveyed clinics, 175 (98%) participated; 137 (78%) from Africa, 30 (17%) from the Asia-Pacific, and 8 (5%) from Latin America. Most clinics (80%) were in low- or lower-middle-income countries, and there were a mix of primary-, secondary- and tertiary-level clinics. Ninety percent reported rollout of first-line dolutegravir, 59% of second-line, 94% of first- or second-line and 55% of dual rollout. The adjusted odds of dual rollout were higher among tertiary-level (aOR 4.00; 95% CI 1.39 to 11.47) and secondary-level clinics (aOR 3.66; 95% CI 2.19 to 6.11) than in primary-level clinics. Over half (59%) of clinics that introduced first- or second-line dolutegravir-based ART required recent viral load testing before switching to dolutegravir, and 15% performed genotypic resistance testing at switch. CONCLUSIONS: Dolutegravir-based ART was rolled out at nearly all IeDEA clinics in LMICs, yet many switched patients to dolutegravir without recent viral load testing and drug resistance testing was rarely performed. Without such testing, drug resistance among patient switching to dolutegravir may go undetected.

Tuberculosis and latent tuberculosis infection among healthcare workers in Kisumu, Kenya.

OBJECTIVE: To assess prevalence and occupational risk factors of latent TB infection and history of TB disease ascribed to work in a healthcare setting in western Kenya. METHODS: We conducted a cross-sectional survey among healthcare workers in western Kenya in 2013. They were recruited from dispensaries, health centres and hospitals that offer both TB and HIV services. School workers from the health facilities' catchment communities were randomly selected to serve as the community comparison group. Latent TB infection was diagnosed by tuberculin skin testing. HIV status of participants was assessed. Using a logistic regression model, we determined the adjusted odds of latent TB infection among healthcare workers compared to school workers; and among healthcare workers only, we assessed work-related risk factors for latent TB infection. RESULTS: We enrolled 1005 healthcare workers and 411 school workers. Approximately 60% of both groups were female. A total of 22% of 958 healthcare workers and 12% of 392 school workers tested HIV positive. Prevalence of self-reported history of TB disease was 7.4% among healthcare workers and 3.6% among school workers. Prevalence of latent TB infection was 60% among healthcare workers and 48% among school workers. Adjusted odds of latent TB infection were 1.5 times higher among healthcare workers than school workers (95% confidence interval 1.2-2.0). Healthcare workers at all three facility types had similar prevalence of latent TB infection (P = 0.72), but increasing years of employment was associated with increased odds of LTBI (P < 0.01). CONCLUSION: Healthcare workers at facilities in western Kenya which offer TB and HIV services are at increased risk of latent TB infection, and the risk is similar across facility types. Implementation of WHO-recommended TB infection control measures are urgently needed in health facilities to protect healthcare workers.

A four-month gatifloxacin-containing regimen for treating tuberculosis.

BACKGROUND: Shortening the course of treatment for tuberculosis would be a major improvement for case management and disease control. This phase 3 trial assessed the efficacy and safety of a 4-month gatifloxacin-containing regimen for treating rifampin-sensitive pulmonary tuberculosis. METHODS: We conducted a noninferiority, randomized, open-label, controlled trial involving patients 18 to 65 years of age with smear-positive, rifampin-sensitive, newly diagnosed pulmonary tuberculosis in five sub-Saharan African countries. A standard 6-month regimen that included ethambutol during the 2-month intensive phase was compared with a 4-month regimen in which gatifloxacin (400 mg per day) was substituted for ethambutol during the intensive phase and was continued, along with rifampin and isoniazid, during the continuation phase. The primary efficacy end point was an unfavorable outcome (treatment failure, recurrence, or death or study dropout during treatment) measured 24 months after the end of treatment, with a noninferiority margin of 6 percentage points, adjusted for country. RESULTS: A total of 1836 patients were assigned to the 4-month regimen (experimental group) or the standard regimen (control group). Baseline characteristics were well balanced between the groups. At 24 months after the end of treatment, the adjusted difference in the risk of an unfavorable outcome (experimental group [21.0%] minus control group [17.2%]) in the modified intention-to-treat population (1356 patients) was 3.5 percentage points (95% confidence interval, -0.7 to 7.7). There was heterogeneity across countries (P=0.02 for interaction, with differences in the rate of an unfavorable outcome ranging from -5.4 percentage points in Guinea to 12.3 percentage points in Senegal) and in baseline cavitary status (P=0.04 for interaction) and body-mass index (P=0.10 for interaction). The standard regimen, as compared with the 4-month regimen, was associated with a higher dropout rate during treatment (5.0% vs. 2.7%) and more treatment failures (2.4% vs. 1.7%) but fewer recurrences (7.1% vs. 14.6%). There was no evidence of increased risks of prolongation of the QT interval or dysglycemia with the 4-month regimen. CONCLUSIONS: Noninferiority of the 4-month regimen to the standard regimen with respect to the primary efficacy end point was not shown. (Funded by the Special Program for Research and Training in Tropical Diseases and others; ClinicalTrials.gov number, NCT00216385.).

Exposure to cats and dogs, and symptoms of asthma, rhinoconjunctivitis, and eczema.

BACKGROUND: Associations between exposure to cats and dogs and respiratory and allergic outcomes in children have been reported in affluent countries, but little is known about such associations in less-affluent countries. METHODS: The International Study of Asthma and Allergies in Childhood, phase 3 was carried out in children aged 6-7 years and adolescents aged 13-14 years across the world. Questions about cats and dogs in the home were included in an additional questionnaire. Using logistic regression, we investigated the association between such exposures and symptoms of asthma, rhinoconjunctivitis, and eczema. Adjustments were made for sex, region of the world, language, gross national income per capita, and 10 other covariates. RESULTS: Among children (6-7 years of age), cat exposure in the first year of life was associated with current symptoms of asthma, wheeze, rhinoconjunctivitis, and eczema, especially in less-affluent countries. Among adolescents (13-14 years of age), we found a positive association between exposure to cats or dogs and symptom prevalence in more-affluent and less-affluent countries. The global multivariate odds ratios for children with complete covariate data were 1.17 (95% confidence interval = 1.08-1.29) for current symptoms of asthma, 1.13 (1.05-1.23) for rhinoconjunctivitis, and 1.38 (1.26-1.52) for eczema. Smaller odds ratios were found for exposure to only dogs. Exposure to only cats was associated with eczema. CONCLUSION: Early-life exposure to cats is a risk factor for symptoms of asthma, rhinoconjunctivitis, and eczema in 6- to 7-year-old children, especially in less-affluent countries. Current exposure to cats and dogs combined, and only to dogs, is a risk factor for symptom reporting by 13- to 14-year-old adolescents worldwide.

The association between tobacco and the risk of asthma, rhinoconjunctivitis and eczema in children and adolescents: analyses from Phase Three of the ISAAC programme.

BACKGROUND: Exposure to parental smoking is associated with wheeze in early childhood, but in 2006 the US Surgeon General stated that the evidence is insufficient to infer a causal relationship between exposure and asthma in childhood and adolescents. AIMS: To examine the association between maternal and paternal smoking and symptoms of asthma, eczema and rhinoconjunctivitis. METHODS: Parents or guardians of children aged 6-7 years completed written questionnaires about symptoms of asthma, rhinoconjunctivitis and eczema, and several risk factors, including maternal smoking in the child's first year of life, current maternal smoking (and amount) and paternal smoking. Adolescents aged 13-14 years self completed the questionnaires on these symptoms and whether their parents currently smoked. RESULTS: In the 6-7-year age group there were 220 407 children from 75 centres in 32 countries. In the 13-14-year age group there were 350 654 adolescents from 118 centres in 53 countries. Maternal and paternal smoking was associated with an increased risk of symptoms of asthma, eczema and rhinoconjunctivitis in both age groups, although the magnitude of the OR is higher for symptoms of asthma than the other outcomes. Maternal smoking is associated with higher ORs than paternal smoking. For asthma symptoms there is a clear dose relationship (1-9 cigarettes/day, OR 1.27; 10-19 cigarettes/day, OR 1.35; and 20+ cigarettes/day, OR 1.56). When maternal smoking in the child's first year of life and current maternal smoking are considered, the main effect is due to maternal smoking in the child's first year of life. There was no interaction between maternal and paternal smoking. CONCLUSIONS: This study has confirmed the importance of maternal smoking, and the separate and additional effect of paternal smoking. The presence of a dose-response effect relationship with asthma symptoms suggests that the relationship is causal, however for eczema and rhinoconjunctivitis causality is less certain.

A pivotal registration phase III, multicenter, randomized tuberculosis controlled trial: design issues and lessons learnt from the Gatifloxacin for TB (OFLOTUB) project.

BACKGROUND: There have been no major advances in tuberculosis (TB) drug development since the first East African/British Medical Research Council short course chemotherapy trial 35 years ago. Since then, the landscape for conducting TB clinical trials has profoundly changed with the emergence of HIV infection, the spread of resistant TB bacilli strains, recent advances in mycobacteriological capacity, and drug discovery. As a consequence questions have arisen on the most appropriate approach to design and conduct current TB trials. To highlight key issues discussed: Is a superiority, equivalence, or non-inferiority design most appropriate? What should be the primary efficacy outcome? How to consider re-infections in the definition of the outcome? What is the optimal length of patient follow-up? Is blinding appropriate when treatment duration in test arm is shorter? What are the appropriate assumptions for sample size calculation? METHODS: Various drugs are currently in the development pipeline. We are presenting in this paper the design of the most recently completed phase III TB trial, the OFLOTUB project, which is the pivotal trial of a registration portfolio for a gatifloxacin-containing TB regimen. It is a randomized, open-label, multicenter, controlled trial aiming to evaluate the efficacy and safety of a gatifloxacin-containing 4-month regimen (trial registration: ClinicalTrial.gov database: NCT00216385). RESULTS: In the light of the recent scientific and regulatory discussions, we discuss some of the design issues in TB clinical trials and more specifically the reasons that guided our choices, in order to best answer the trial objectives, while at the same time satisfying regulatory authority requirements. CONCLUSION: When shortening TB treatment, we are advocating for a non-inferiority, non-blinded design, with a composite unfavorable endpoint assessed 12 months post treatment completion, and added trial procedures specifically aiming to: (1) minimize endpoint unavailability; and (2) distinguish between relapse and re-infection.

Early life exposure to farm animals and symptoms of asthma, rhinoconjunctivitis and eczema: an ISAAC Phase Three Study.

BACKGROUND: Associations between early life exposure to farm animals and respiratory symptoms and allergy in children have been reported in developed countries, but little is known about such associations in developing countries. OBJECTIVE: To study the association between early life exposure to farm animals and symptoms of asthma, rhinoconjunctivitis and eczema in a worldwide study. METHODS: Phase Three of the International Study of Asthma and Allergies in Childhood (ISAAC) was carried out in 6- to 7-year-old children in urban populations across the world. Questions about early life exposure to farm animals (at least once/week) were included in an additional questionnaire. The association between such exposures and symptoms of asthma, rhinoconjunctivitis and eczema was investigated with logistic regression. Adjustments were made for gender, region of the world, language, gross national income and 10 other subject-specific covariates. RESULTS: A positive association was found between early exposure to farm animals and the prevalence of symptoms of asthma, rhinoconjunctivitis and eczema, especially in non-affluent countries. In these countries, odds ratios (ORs) for 'current wheeze', 'farm animal exposure in the first year of life' and 'farm animal exposure in pregnancy' were 1.27 [95% confidence interval (CI) 1.12-1.44] and 1.38 (95% CI 1.21-1.58), respectively. The corresponding ORs for affluent countries were 0.96 (95% CI 0.86-1.08) and 0.95 (95% CI 0.84-1.08), respectively. CONCLUSION: Exposure to farm animals during pregnancy and in the first year of life was associated with increased symptoms of asthma, rhinoconjunctivitis and eczema in 6- to 7-year-old children living in non-affluent but not in affluent countries.

Which population level environmental factors are associated with asthma, rhinoconjunctivitis and eczema? Review of the ecological analyses of ISAAC Phase One.

The International Study of Asthma and Allergies in Childhood (ISAAC) Phase One showed large worldwide variations in the prevalence of symptoms of asthma, rhinoconjunctivitis and eczema, up to 10 to 20 fold between countries. Ecological analyses were undertaken with ISAAC Phase One data to explore factors that may have contributed to these variations, and are summarised and reviewed here.In ISAAC Phase One the prevalence of symptoms in the past 12 months of asthma, rhinoconjunctivitis and eczema were estimated from studies in 463,801 children aged 13 - 14 years in 155 centres in 56 countries, and in 257,800 children aged 6-7 years in 91 centres in 38 countries. Ecological analyses were undertaken between symptom prevalence and the following: Gross National Product per capita (GNP), food intake, immunisation rates, tuberculosis notifications, climatic factors, tobacco consumption, pollen, antibiotic sales, paracetamol sales, and outdoor air pollution.Symptom prevalence of all three conditions was positively associated with GNP, trans fatty acids, paracetamol, and women smoking, and inversely associated with food of plant origin, pollen, immunisations, tuberculosis notifications, air pollution, and men smoking. The magnitude of these associations was small, but consistent in direction between conditions. There were mixed associations of climate and antibiotic sales with symptom prevalence.The potential causality of these associations warrant further investigation. Factors which prevent the development of these conditions, or where there is an absence of a positive correlation at a population level may be as important from the policy viewpoint as a focus on the positive risk factors. Interventions based on small associations may have the potential for a large public health benefit.

Global variations in prevalence of eczema symptoms in children from ISAAC Phase Three.

BACKGROUND: In 1999, The International Study of Asthma and Allergies in Childhood (ISAAC) Phase One reported the prevalence of eczema symptoms in 715,033 children from 154 centers in 56 countries by using standardized epidemiologic tools. OBJECTIVE: To update the world map of eczema prevalence after 5 to 10 years (ISAAC Phase Three) and include additional data from over 100 new centers. METHODS: Cross-sectional surveys using the ISAAC questionnaire on eczema symptoms were completed by adolescents 13 to 14 years old and by parents of children 6 to 7 years old. Current eczema was defined as an itchy flexural rash in the past 12 months and was considered severe eczema if associated with 1 or more nights per week of sleep disturbance. RESULTS: For the age group 6 to 7 years, data on 385,853 participants from 143 centers in 60 countries showed that the prevalence of current eczema ranged from 0.9% in India to 22.5% in Ecuador, with new data showing high values in Asia and Latin America. For the age group 13 to 14 years, data on 663,256 participants from 230 centers in 96 countries showed prevalence values ranging from 0.2% in China to 24.6% in Columbia with the highest values in Africa and Latin America. Current eczema was lower for boys than girls (odds ratio, 0.94 and 0.72 at ages 6 to 7 years and 13 to 14 years, respectively). CONCLUSION: ISAAC Phase Three provides comprehensive global data on the prevalence of eczema symptoms that is essential for public health planning. New data reveal that eczema is a disease of developing as well as developed countries.

The role for government health centers in provision of same-day voluntary HIV counseling and testing in Kenya.

OBJECTIVE: To explore the role of primary health centers in provision of voluntary counseling and testing (VCT) in Kenya. DESIGN AND SETTING: Prospective service evaluation at 3 (1 urban and 2 rural) government health centers. SUBJECTS: Consecutive adult clients. MAIN OUTCOME MEASURES: Uptake of services, user characteristics, quality of service. RESULTS: Counseling services received 2315 new clients over 26 months. The last quarter averaged 101 clients per clinic. More than 80% of clients lived locally. Overall 93% opted to test, 91% receiving results, 82% on the same day. Most clients tested HIV negative (81%). Youth and men were well represented. Few couples (10%) attended. Seventeen percent of women were pregnant. Self-referral was common and illness was an uncommon reason for testing (<20%). Thirty-one percent of clients were referred from VCT to other health center services. Counseling was perceived as high quality by users and providers. Validation of the test algorithm showed a sensitivity of 98.0% and specificity of 98.7%. CONCLUSION: Government health centers in Kenya can be appropriate providers of VCT. This pilot helped initiate a new strategy of health center-based VCT in Kenya and this has facilitated rapid expansion and more equitable provision for Kenyans.

Comparison of PCR with the routine procedure for diagnosis of tuberculosis in a population with high prevalences of tuberculosis and human immunodeficiency virus.

Direct smear examination with Ziehl-Neelsen (ZN) staining for the diagnosis of tuberculosis (TB) as employed in most low-income countries is cheap and easy to use, but its low sensitivity is a major drawback. The low specificity of chest X-rays, used for the diagnosis of smear-negative TB, risks high levels of overdiagnosis. Major advances in molecular techniques, which rapidly identify mycobacterial DNA in sputa, may overcome these obstacles. In this study, the AMPLICOR PCR system was used to diagnose pulmonary TB in a developing country with high prevalences of both TB and human immunodeficiency virus (HIV). The sensitivity and specificity of this technique were compared to those of the usual diagnostic techniques. Sputum specimens were collected from 1,396 TB suspects attending the Rhodes Chest Clinic, Nairobi, Kenya. The specimens were analyzed for the presence of Mycobacterium tuberculosis by PCR; culture on Löwenstein-Jensen medium was used as the "gold standard." All culture-positive samples were genotyped to identify the mycobacterial species. The sensitivity and specificity of PCR were 93 and 84%, respectively. HIV status did not affect the sensitivity of PCR. A total of 99.7% of the true smear-positive and 82.1% of the true smear-negative TB patients were correctly identified by PCR. PCR detected M. tuberculosis in 11.7% of the culture-negative suspects, 60% of which had one or two PCR-positive sputum specimens. Of the 490 positive cultures, 486 were identified as M. tuberculosis. The high sensitivity of Amplicor PCR merits usage in a clinical setting with high TB and HIV burdens. Thus, PCR can be considered as an alternative to ZN staining in combination with chest X-ray for diagnosis of TB; however, cost-effectiveness studies and operational studies are required to support an evidence-based decision of introducing PCR for TB control in high-burden environments.

Mortality and burden of disease in a cohort of HIV-seropositive adults in Nairobi, Kenya.

The purposes of this study were to measure incidence and determine risk factors associated with opportunistic infections (OIs) and mortality among an HIV-infected cohort in Nairobi, Kenya. Three hundred and eighty-one seropositive ambulatory adults in Nairobi, Kenya were followed from 1997 to 2000 with participants visiting the clinic every two months and when acutely ill. Acute bronchitis was the most frequent diagnosis, followed by sexually transmitted infections, candida vaginitis (among women), fever, diarrhoea, pneumonia, HIV-associated skin rash, oral candidiasis and urinary tract infection. Associations between the frequency of these diagnoses including survival and sociodemographic factors and initial CD4 count were assessed. A CD4 count <200 cells/mL at recruitment was strongly associated with decreased survival (adjusted odds ratio=3.0, 95% confidence interval 1.7-5.1). These findings may help to target high-risk populations and guide OI prevention and treatment strategies including decisions regarding initiation of antiretroviral therapy in sub-Saharan Africa.

Risk factors for pneumonia in urban-dwelling HIV-infected women: a case-control study in Nairobi, Kenya.

In sub-Saharan Africa, respiratory tract infections (RTI) are the leading cause of serious morbidity and mortality in HIV-infected persons. This study sought to investigate demographic, socioeconomic, and environmental risk factors for pneumonia in a cohort of HIV-infected women. The authors performed a nested case-control study in a cohort of HIV-1-infected adults followed in Nairobi, Kenya. Thirty-nine women who developed pneumonia during the follow-up period were selected as cases, and 66 women who did not develop pneumonia were randomly chosen to serve as control subjects. A questionnaire was administered in subjects' homes that assessed demographics, home environment, and socioeconomic status. Women were followed in the cohort for a median of 36.8 months (range, 27.3-39.3). Adjusting for length of follow-up period, factors associated with lower socioeconomic status (lower monthly spending [OR = 3.2; 95% CI, 1.2-8.4 per 10,000 Kenyan shilling decrease], having no savings [OR = 4.1; 95% CI, 1.4-11.9], less sturdy home construction material such as mud or cement walls [OR = 2.6; 95% CI, 1.1-5.9] or dirt floors [OR = 2.8; 95% CI, 1.0-7.6], and lack of a window in the home [OR = 5.5; 95% CI, 0.9-32.2]) and being widowed (OR = 4.3; 95% CI, 1.2-15.1) or single (OR = 3.3; 95% CI, 1.0-11.2) were associated with an increased risk of pneumonia. In multivariate analysis, widowed (AOR = 5.9; 95% CI, 1.3-26.3), single (AOR = 7.7; 95% CI, 1.6-36.4), and divorced (AOR = 4.5; 95% CI, 1.0-20.1) women, those without savings (AOR = 3.7; 95% CI, 1.2-11.7), and those living in more crowded and contagious conditions (AOR = 1.5; 95% CI, 1.1-2.1) remained at increased risk of pneumonia. If confirmed by prospective investigation, these findings could help identify persons and subpopulations of HIV-infected women with the greatest risk of pneumonia.

Assessing the cost and willingness to pay for voluntary HIV counselling and testing in Kenya.

OBJECTIVE: Voluntary counselling and testing (VCT) should be an important component in a country's HIV/AIDS prevention and care strategy. However, the high cost of VCT raises concerns about the affordability of VCT in low-income countries. This study was designed to assess the costs of VCT and to identify potential ways of introducing VCT more affordably. METHODOLOGY: An economic evaluation was performed of VCT services in two rural health centres in Thika District and an urban health centre in Nairobi, Kenya. A contingent valuation study was also performed among VCT clients. Estimates were developed regarding the national cost of offering VCT services in Kenya. RESULTS: VCT added US dollars 6800 per year to the average cost of providing services at each of these three health centres. The evaluation revealed that the incremental cost, from the government's perspective, of adding VCT is approximately 16 dollars per client. The estimated incremental cost per client is significantly less than a previous cost estimate in Kenya which estimated a cost per client of 26 dollars. The difference in cost estimates is in part attributable to the emphasis of this project on integrating VCT services into existing health centres, rather than creating stand-alone sites. The cost of VCT services might be further reduced to as little as 8 dollars per client if a government health worker could perform the counselling. A contingent valuation study indicated that most VCT clients would be willing to pay at least 2 dollars for the service. However, if the full cost of the service were charged to the client, less than 5% of clients indicated they were willing and able to pay for the service. CONCLUSIONS: Integrating services into existing health centres can significantly reduce the cost of VCT. Additional cost reductions may be feasible if health centre staff are hired to perform the counselling. Furthermore, it appears that some level of cost recovery from VCT clients is feasible and can contribute to sustainability, although it is very unlikely that the full cost of the service could be recovered from the clients. The national provision of VCT in all Kenyan health centres is likely to be an affordable option, although additional operational research is required to determine the most appropriate way of scaling up VCT services throughout the country.

Atopy, asthma, and antibodies to Ascaris among rural and urban children in Kenya.

OBJECTIVE: The purpose of this study was to evaluate differences in the relationship between asthma and immune responses to allergens in children living in rural and urban areas of Kenya. STUDY DESIGN: Children (mean age, 11 years) from Kabati (n = 136), a rural village, and Thika (n = 129), a small town, were studied by skin testing and serum immunoglobulin E (IgE) and immunoglobulin G (IgG) antibody measurement. Asthma was evaluated by symptoms, as well as spirometry before and after vigorous exercise to test for exercised-induced bronchospasm (EIB). School children from a study performed in Atlanta, Georgia, were used for comparison of anthropometric and immunologic results. RESULTS: Compared with the urban area of Kenya, children living in the rural area had a lower percentage of body fat, smaller and fewer skin test responses to allergens, a higher prevalence of IgE antibodies to Ascaris (67% vs 26%) and 10-fold higher total IgE. In the urban area of Kenya, there was a strong correlation between EIB and atopy determined both by IgE antibodies (P =.02) and skin tests (P =.002). By contrast, in the rural area, none of the 13 children with EIB were skin-test positive (vs 13/109 of children without EIB). CONCLUSIONS: Among the rural children, there was no association between immune responses to allergens and airway-related symptoms or reactivity. The association between asthma and atopy seen in the town of Thika may represent an important step in the increase in asthma seen both in urban Africa and in the West.