Vitamin D status, nutrition and growth in HIV-infected mothers and HIV-exposed infants and children in Botswana.

BACKGROUND: Poor vitamin D status is a global health problem and common in patients with human immunodeficiency virus (HIV) in high-income countries. There is less evidence on prevalence of vitamin D deficiency and nutrition and growth in HIV-infected and -exposed children in low- and middle-income countries. OBJECTIVES: To determine the vitamin D status in Batswana HIV-infected mothers and their children, differences among HIV-infected mothers and between HIV-exposed and -infected infants and children, and associations between vitamin D and disease-related outcomes, nutrition, and growth. METHODS: This was a cross-sectional study of HIV+ mothers and HIV-exposed infants and unrelated children (1-7.9 years). Serum 25-hydroxyvitamin D (25(OH)D) was measured, among other nutritional indicators, for mothers, infants and children. Vitamin D status for HIV-infected mothers and children, and an immune panel was assessed. History of HIV anti-retroviral medications and breastfeeding were obtained. Data were collected prior to universal combination antiretroviral therapy in pregnancy. RESULTS: Mothers (n = 36) had a mean serum 25(OH)D of 37.2±12.4ng/mL; 11% had insufficient (<20ng/mL), 17% moderately low (20.0-29.9ng/mL) and 72% sufficient (≥30ng/mL) concentrations. No infants (n = 36) or children (n = 48) were vitamin D insufficient; 22% of HIV- and no HIV+ infants had moderately low concentrations and 78% of HIV- and 100% of HIV+ infants had sufficient status, 8% of HIV- and no HIV+ children had moderately low concentrations and 92% of HIV- and 100% HIV+ children had sufficient concentrations. HIV+ children had significantly lower length/height Z scores compared to HIV- children. Length/height Z score was positively correlated with serum 25(OH)D in all children (r = 0.33, p = 0.023), with a stronger correlation in the HIV+ children (r = 0.47 p = 0.021). In mothers, serum 25(OH)D was positively associated with CD4% (r = 0.40, p = 0.016). CONCLUSIONS: Results showed a low prevalence of vitamin D insufficiency in Botswana. Growth was positively correlated with vitamin D status in HIV-exposed children, and HIV+ children had poorer linear growth than HIV- children.

Risk Factors for Measles in HIV-infected Children and Adolescents in Botswana.

We conducted a matched case-control study of 566 HIV-infected children in Botswana during a 2009-2010 measles outbreak to identify the risk factors for measles. Children in the oldest age quartile (≥13.1 years) were 4-fold more likely to acquire measles than those in the youngest quartile (<7.1 years). HIV-infected older children and adolescents may benefit from additional measles vaccination.

Vitamin D3supplementation in Batswana children and adults with HIV: a pilot double blind randomized controlled trial.

OBJECTIVES: Since vitamin D insufficiency is common worldwide in people with HIV, we explored safety and efficacy of high dose cholecalciferol (D3) in Botswana, and evaluated potential modifiers of serum 25 hydroxy vitamin D change (Δ25D). DESIGN: Prospective randomized double-blind 12-week pilot trial of subjects ages 5.0-50.9 years. METHODS: Sixty subjects randomized within five age groups to either 4000 or 7000 IU per day of D3 and evaluated for vitamin D, parathyroid hormone, HIV, safety and growth status. Efficacy was defined as serum 25 hydroxy vitamin D (25D) ≥32 ng/mL, and safety as no simultaneous elevation of serum calcium and 25D. Also assessed were HIV plasma viral RNA viral load (VL), CD4%, anti-retroviral therapy (ART) regime, and height-adjusted (HAZ), weight-adjusted (WAZ) and Body Mass Index (BMIZ) Z scores. RESULTS: Subjects were 50% male, age (mean±SD) 19.5±11.8 years, CD4% 31.8±10.4, with baseline VL log10 range of <1.4 to 3.8 and VL detectable (>1.4) in 22%. From baseline to 12 weeks, 25D increased from 36±9 ng/ml to 56±18 ng/ml (p<0.0001) and 68% and 90% had 25D ≥32 ng/ml, respectively (p = 0.02). Δ25D was similar by dose. No subjects had simultaneously increased serum calcium and 25D. WAZ and BMIZ improved by 12 weeks (p<0.04). HAZ and CD4% increased and VL decreased in the 7000 IU/d group (p<0.04). Younger (5-13y) and older (30-50y) subjects had greater Δ25D than those 14-29y (26±17 and 28±12 vs. 11±11 ng/ml, respectively, p≤0.001). Δ25D was higher with efavirenz or nevirapine compared to protease inhibitor based treatment (22±12, 27±17, vs. 13±10, respectively, p≤0.03). CONCLUSIONS: In a pilot study in Botswana, 12-week high dose D3 supplementation was safe and improved vitamin D, growth and HIV status; age and ART regimen were significant effect modifiers. TRIAL REGISTRATION: ClinicalTrials.gov NCT02189902.

The prevalence and determinants of short stature in HIV-infected children.

BACKGROUND: Children with HIV infection are often reported to be short. The aim of this study was to assess the prevalence of HIV-associated short stature in HIV endemic setting. METHODS: Data were obtained by retrospective review of the electronic medical records. Patients were grouped into various clinical categories. For each category, the proportion of patients with height-for-age Z score of less than -2 standard deviation [SD] and of less than -3 SD was determined. RESULTS: The prevalence of short stature (less than -2 SD) was 28.4%. Severe short stature (less than -3 SD) is more likely with percentage of CD4 <15% (odds ratio [OR]: 3.30, confidence interval [CI]: 1.51-7.09, P = .002) and with males (OR: 1.49, CI: 1.19-1.87, P = .001). Severe short stature is more likely with viral load >400 copies/mL (OR 2.64, CI 1.27-5.38, P = .008) and poor adherence (<95%; OR 1.72, CI 1.03-2.05, P = .037). CONCLUSION: In Botswana, short stature affects a quarter of HIV-infected children and severe short stature is associated with poor adherence to antiretroviral treatment, severe immunosuppression, and virologic failure.

Delivering pediatric HIV care in resource-limited settings: cost considerations in an expanded response.

If children are to be protected from HIV, the expansion of PMTCT programs must be complemented by increased provision of paediatric treatment. This is expensive, yet there are humanitarian, equity and children's rights arguments to justify the prioritization of treating HIV-infected children. In the context of limited budgets, inefficiencies cost lives, either through lower coverage or less effective services. With the goal of informing the design and expansion of efficient paediatric treatment programs able to utilize to greatest effect the available resources allocated to the treatment of HIV-infected children, this article reviews what is known about cost drivers in paediatric HIV interventions, and makes suggestions for improving efficiency in paediatric HIV programming. High-impact interventions known to deliver disproportional returns on investment are highlighted and targeted for immediate scale-up. Progress will carry a cost - increased funding, as well as additional data on intervention costs and outcomes, will be required if universal access of HIV-infected children to treatment is to be achieved and sustained.

Protease genotypes in patients failing protease inhibitor-based antiretroviral therapy at a pediatric center in Botswana.

With increasing use of protease inhibitors (PI) in Botswana, a large proportion of HIV-infected children are now exposed to PI-based regimens. There is limited protease genotype data from African children and adolescents who have failed PI-based antiretroviral therapy. We describe a cohort of pediatric HIV-infected patients experiencing virologic failure at time of second-line or salvage PI-based regimens and analyze associated PI mutations.

Adaptation of a general primary care package for HIV-infected adults to an HIV centre setting in Gaborone, Botswana.

BACKGROUND: As life expectancy of HIV-infected patients improves due to antiretroviral treatment (ART) and the importance of associated co-morbidities and chronic diseases increases, preventive care will become increasingly important. Adaptation of existing preventive guidelines to local environments will become a priority for HIV treatment programmes. METHODS: Guidance from the World Health Organization, a focused evidenced-based literature review, Botswana national guidelines, Botswana-specific morbidity and mortality data and centre-specific data were used to adapt a published general primary care package for limited-resource areas to our centre's specific setting. RESULTS: The preventive care package contains recommendations on tuberculosis prevention, malnutrition, depression, cervical and breast cancer, hepatitis B coinfection, cardiovascular risk factors, external injury prevention, domestic violence screening, tobacco and substance-abuse counselling, contraception and screening and treatment of sexually transmitted infections. CONCLUSION: This preventive care package addresses the comprehensive health needs of HIV-infected adults in the FMC in an evidence-based manner. The process of combining clinic-specific prevalence data, national guidelines, regional literature and assessment of public-sector resources to adapt an existing general package could be utilised to develop similar guidelines in other resource-limited locales.

Early outcomes of darunavir- and/or raltegravir-based antiretroviral therapy in children with multidrug-resistant HIV at a pediatric center in Botswana.

BACKGROUND: Data on the use of ritonavir-boosted darunavir (DRV/r) and/or raltegravir (RAL) in resource-limited settings are rare and there is currently no published data regarding their use among African children. Botswana has recently made DRV/r and RAL available for patients failing second-line antiretroviral therapy (ART). METHODS: Retrospective chart review of 4 multidrug-resistant pediatric patients on DRV/r- and/or RAL-based regimens. Viral load, CD4 count, adherence by pill count, and World Health Organization (WHO) clinical stage prior to and after switch to DRV/r- and/or RAL-based regimen were assessed. Antiretroviral therapy history, duration of virologic failure, and time to viral suppression were also noted. Genotypic resistance assays reviewed for mutations present prior to switch. RESULTS: All patients achieved viral suppression, showed improved/stable CD4 counts, and obtained or maintained WHO clinical treatment stage I, even after long-standing virologic/immunologic failure. CONCLUSIONS: Well tolerated by and effective in our patients, DRV/r and RAL provide potentially lifesaving ART options for children and adolescents in resource-limited settings failing ART due to ritonavir-boosted lopinavir (LPV/r) resistance.

Evaluation of the effectiveness of an outreach clinical mentoring programme in support of paediatric HIV care scale-up in Botswana.

Clinical mentoring by providers skilled in HIV management has been identified as a cornerstone of scaling-up antiretroviral treatment in Africa, particularly in settings where expertise is limited. However, little data exist on its effectiveness and impact on improving the quality-of-care and clinical outcomes, especially for HIV-infected children. Since 2008, the Botswana-Baylor Children's Clinical Centre of Excellence (COE) has operated an outreach mentoring programme at clinical sites around Botswana. This study is a retrospective review of 374 paediatric charts at four outreach mentoring sites (Mochudi, Phutadikobo, Molepolole and Thamaga) evaluating the effectiveness of the programme as reflected in a number of clinically-relevant areas. Charts from one visit prior to initiation of mentoring and from one visit after approximately one year of mentoring were assessed for statistically-significant differences (p<0.05) in the documentation of clinically-relevant indicators. Mochudi showed notable improvements in all indicators analysed, with particular improvements in documentation of pill count, viral load (VL) results, correct laboratory monitoring and correct antiretroviral therapy (ART) dosing (p<0.0001, p<0.0001, p<0.0001 and p<0.0001, respectively). Broad and substantial improvements were also seen in Molepolole, with the most improvement in disclosure documentation of all four sites. At Thamaga, improvements were restricted to CD4 documentation (p<0.001), recent VL and documented pill count (p<0.05 and p<0.05, respectively). Phuthadikobo showed the least amount of improvement across indicators, with only VL documentation and correct ART dosing showing statistically-significant improvements (p<0.05 and p<0.0001, respectively). These findings suggest that clinical mentoring may assist improvements in a number of important areas, including ART dosing and monitoring; adherence assessment and assurance; and disclosure. Clinical mentoring may be a valuable tool in scale-up of quality paediatric HIV care-and-treatment outside specialised centres. Further study will help refine approaches to clinical mentoring, including assuring mentoring translates into improved clinical outcomes for HIV-infected children.

Reverse transcriptase genotypes in pediatric patients failing initial antiretroviral therapy in Gaborone, Botswana.

BACKGROUND: Limited data are available on patterns of resistance mutations in pediatric patients in southern Africa, where HIV-1 subtype C (HIV-1C) predominates. METHODS: Retrospective chart review of pediatric patients. Nucleoside reverse transcriptase inhibitor (NRTI)- and nonnucleoside reverse transcriptase inhibitor (NNRTI)-associated resistance mutations quantified from population-based sequencing genotypic resistance assay results taken at time of first-line antiretroviral therapy (ART) failure (first-line ART = stavudine [d4T] or zidovudine [ZDV] + lamivudine [3TC] + nevirapine [NVP] or efavirenz [EFV]). RESULTS: Total number of patients with resistance assays analyzed is 45. Nucleoside reverse transcriptase inhibitor-associated mutation frequencies noted were M184V (n = 41; 91.1%); thymidine analogue mutations (TAMs; n = 20; 44.4%); >1 TAM (n = 9; 20%); TAM-2 pathway (n = 10; 22.2%); TAM-1 pathway (n = 7; 15.6%); TAM-1 and TAM-2 pathways (n = 3; 6.7%); K65R (n = 2; 4.4%); Q151M (n = 1; 2.2%); and L74V (n = 0; 0%). Nonnucleoside reverse transcriptase inhibitor-associated mutation frequencies noted were associated with notable resistance to either/both NVP and EFV (n = 40; 88.9%); K103N (n = 15; 33.3%); ≥1 mutations associated with etravirine (ETR) failure (K101E, Y181C, and G190A; n =20; 44.4%); and ≥2 notable NNRTI mutations (n = 12; 26.7%). CONCLUSIONS: In this cohort, low-genetic barrier mutations were common, as were TAMs, including more than 1 TAM. Mutations compromising nonthymidine analogue backbones were rare, suggesting that it is likely that children who fail first-line NRTI backbones containing d4T or ZDV/3TC would still respond to abacavir (ABC), didanosine (ddI), and, for adolescents, tenofovir (TDF). Our data support the empiric continuation of 3TC in second-line regimens.

Prevalence of hepatitis B and hepatitis C coinfections in an adult HIV centre population in Gaborone, Botswana.

The objective of this study was to assess the prevalence of hepatitis B and hepatitis C coinfections in human immunodeficiency virus (HIV) -infected adults at an HIV center in Gaborone, Botswana. A retrospective review was performed of charts of currently active HIV-infected adult patients in the Family Model Clinic (FMC) of the Botswana-Baylor Children's Clinical Center of Excellence (BCOE) in Gaborone, Botswana, for the results of serum hepatitis B surface antigen (HBsAg) and antihepatitis C IgG tests performed between January 1, 2005 and December 15, 2009. Of 308 active FMC patients, 266 underwent HBsAg serology testing within the period of study. The HBsAg coinfection prevalence was 5.3% (14/266); 2 of 252 patients had at least one positive antihepatitis C IgG serology, a 0.8% prevalence. Hepatitis B coinfection is relatively common in HIV-infected adults at our center in Botswana, whereas hepatitis C coinfection is rare. In this setting, where the diagnosis of hepatitis B coinfection with HIV has implications for choice of first-line antiretroviral therapy and prevention of perinatal hepatitis B transmission, broader sampling to establish the true population prevalence of hepatitis B coinfection and the desirability of adding screening to HIV management should be considered. These findings provide little justification for adding hepatitis C coinfection screening to the management of HIV infection in Botswana.

HIV management by nurse prescribers compared with doctors at a paediatric centre in Gaborone, Botswana.

OBJECTIVES: To compare compliance with national paediatric HIV treatment guidelines between nurse prescribers and doctors at a paediatric referral centre in Gaborone, Botswana. METHODS: A cross-sectional study was conducted in 2009 at the Botswana-Baylor Children's Clinical Centre of Excellence (COE), Gaborone, Botswana, comparing the performance of nurse prescribers and physicians caring for HIV-infected paediatric patients. Selected by stratified random sampling, 100 physician and 97 nurse prescriber encounters were retrospectively reviewed for successful documentation of eight separate clinically relevant variables: pill count charted; chief complaint listed; social history updated; disclosure reviewed; physical exam; laboratory testing; World Health Organization (WHO) staging documented; paediatric dosing. RESULTS: Nurse prescribers and physicians correctly documented 96.0% and 94.9% of the time, respectively. There was a trend towards a higher proportion of social history documentation by the nurses, but no significant difference in any other documentation items. CONCLUSIONS: Our findings support the continued investment in programmes employing properly trained nurses in southern Africa to provide quality care and ART services to HIV-infected children who are stable on therapy. Task shifting remains a promising strategy to scale up and sustain adult and paediatric ART more effectively, particularly where provider shortages threaten ART rollout. Policies guiding ART services in southern Africa should avoid restricting the delivery of crucial services to doctors, especially where their numbers are limited.

Evaluating a sick child after travel to developing countries.

Every year, millions of children travel internationally with their families, many to developing countries. Although the vast majority experience uneventful travel and return home well, it is not uncommon for children to present as ill during or after travel. Although the majority of travel-associated illness is mild and self-limited, serious conditions regularly occur. Almost all life-threatening conditions after travel present with fever, and malaria is the most important of these to rapidly exclude. Gastrointestinal symptoms are common after travel in the developing world, and most diarrhea in child travelers has a bacterial source. Children who have a rash in association with fever or who appear ill should receive a priority work-up focused on ruling out serious conditions. Many children traveling internationally experience respiratory illness during or shortly after travel, mainly common upper respiratory infections, yet serious conditions, such as tuberculosis, may occur. Eosinophilia is common in the returned pediatric traveler, particularly those with prolonged stays in the tropics. Not all eosinophilia is caused by parasitic infection; drug reactions, asthma, and other allergic conditions are also common causes. With a focus first on ruling out life-threatening disease and subsequently on an informed and efficient path to diagnosis and treatment, clinicians may confidently provide care for this challenging group of patients.

Postexposure prophylaxis against human immunodeficiency virus.

Family physicians often encounter situations in which postexposure prophylaxis (PEP) with antiretroviral medications against human immunodeficiency virus (HIV) may be indicated. When the exposure source's HIV status is unknown and testing of the source is possible, use of a rapid HIV test kit may facilitate decision making at the point of care. When PEP is given, timing and duration are important, with data showing PEP to be most effective when initiated within 72 hours of exposure and continued for four weeks. Although two-drug PEP regimens are an option for some lower risk occupational exposures, three-drug regimens are advised for nonoccupational exposures. Sexual assault survivors should be given three-drug PEP regardless of assailant characteristics. In complicated situations, such as exposure of a pregnant woman or when a source is known to be infected with HIV, expert consultation is advised. In most cases, PEP is not indicated after an accidental needlestick in the community setting. Health care volunteers working abroad, particularly in areas of high HIV prevalence or where preferred PEP regimens may not be readily available, often choose to travel with personal supplies of PEP. Patients presenting for care after HIV exposure should have baseline testing for HIV antibodies, and follow-up HIV antibody testing at four to six weeks, three months, and six months after exposure.

A package of primary health care services for comprehensive family-centred HIV/AIDS care and treatment programs in low-income settings.

Particularly in resource-limited settings, HIV/AIDS is a family concern. Separate services for children and adults may make accessing care more difficult for families than services where family members can be cared for together. Implicit in comprehensive, family-centred approaches to care are the broader notions of longitudinal primary care and linkages to other services, including those based in communities. As highly-active antiretroviral therapy becomes more available, and the direct burden of HIV-associated morbidity diminishes, HIV-infected individuals require primary care that goes beyond exclusive management of HIV and related conditions, including preventive services and the management of common medical issues. The prevention of tuberculosis, diarrhoea, and, in endemic regions, malaria; the addressing of debilitating depression; cervical screening; and the management of chronic cardiovascular disease and its risk factors are all of benefit to patients accessing HIV/AIDS care. Packaging such services is an effective means both of standardizing care within a program and of ensuring patients receives a full roster of available interventions. As family-centred care models develop in resource-limited settings, the availability of evidence-based service packages such as presented here will help program designers prioritize available human and materiel resources toward those interventions that improve patients' global health and well being.

Mosquito-borne diseases.

Despite centuries of control efforts, mosquito-borne diseases are flourishing worldwide. With a disproportionate effect on children and adolescents, these conditions are responsible for substantial global morbidity and mortality. Malaria kills more than 1 million children annually, chiefly in sub-Saharan Africa. Dengue virus has expanded its range over the past several decades, following its principal vector, Aedes aegypti, back into regions from which it was eliminated in the mid-20th century and causing widespread epidemics of hemorrhagic fever. West Nile virus has become endemic throughout the Americas in the past 10 years, while chikungunya virus has emerged in the Indian Ocean basin and mainland Asia to affect millions. Japanese encephalitis virus, too, has expanded its range in the Indian subcontinent and Australasia, mainly affecting young children. Filariasis, on the other hand, is on the retreat, the subject of a global eradication campaign. Efforts to limit the effect of mosquito-borne diseases in endemic areas face the twin challenges of controlling mosquito populations and delivering effective public health interventions. Travelers to areas endemic for mosquito-borne diseases require special advice on mosquito avoidance, immunizations, and malaria prophylaxis.