Phenotype and predictors of insulin independence in adults presenting with diabetic ketoacidosis: a prospective cohort study.

AIMS/HYPOTHESIS: The aim of this work was to describe the phenotype of adults presenting with a first episode of diabetic ketoacidosis (DKA) in Cape Town, South Africa, and identify predictors of insulin independence at 12 and 60 months after presentation. METHODS: A prospective, descriptive cohort study of all individuals, 18 years or older, presenting for the first time with DKA to four public-sector hospitals of the Groote Schuur Academic Health Complex was performed. Clinical, biochemical and laboratory data including GAD antibody and C-peptide status were collected at baseline. Insulin was systematically weaned and stopped in individuals who achieved normoglycaemia within the months after DKA. Individuals were followed for 12 months and then annually until 5 years after initial presentation with ketoacidosis. RESULTS: Eighty-eight individuals newly diagnosed with diabetes when presenting with DKA were included and followed for 5 years. The mean ± SD age was 35±10 years and the median (IQR) BMI at diagnosis was 28.5 (23.3-33.4) kg/m2. Overall, 46% were insulin independent 12 months after diagnosis and 26% remained insulin independent 5 years after presentation. Forty-one participants (47%) tested negative for anti-GAD and anti-IA-2 antibodies and had C-peptide levels >0.3 nmol/l; in this group, 68% were insulin independent at 12 months and 37% at 5 years after diagnosis. The presence of acanthosis nigricans was strongly associated with insulin independence (OR 27.1 [95% CI 7.2, 102.2]; p<0.001); a positive antibody status was associated with a lower likelihood of insulin independence at 12 months (OR 0.10 [95% CI 0.03, 0.36]; p<0.001). On multivariable analysis only acanthosis (OR 11.5 [95% CI 2.5, 53.2]; p=0.004) was predictive of insulin independence 5 years after diagnosis. CONCLUSIONS/INTERPRETATION: The predominant phenotype of adults presenting with a first episode of DKA in Cape Town, South Africa, was that of ketosis-prone type 2 diabetes. These individuals presented with obesity, acanthosis nigricans, negative antibodies and normal C-peptide and could potentially be weaned off insulin at follow-up. Classic type 1 diabetes (lower weight, antibody positivity, low or unrecordable C-peptide levels and long-term insulin dependence) was less common. The simple clinical sign of acanthosis nigricans is a strong predictor of insulin independence at 12 months and 5 years after initial presentation.

Transfers between health facilities of people living with diabetes attending primary health care services in the Western Cape Province of South Africa: A retrospective cohort study.

OBJECTIVES: Transfers between health facilities of people living with HIV attending primary health care (PHC) including hospital to PHC facility, PHC facility to hospital and PHC facility to PHC facility transfers occur frequently, affect health service planning, and are associated with disengagement from care and viraemia. Data on transfers among people living with diabetes attending PHC, particularly transfers between PHC facilities, are few. We assessed the transfer incidence rate of people living with diabetes attending PHC, and the association between transfers between PHC facilities and subsequent HbA1c values. METHODS: We analysed data on HbA1c tests at public sector facilities in the Western Cape Province (2016-March 2020). Individuals with an HbA1c in 2016-2017 were followed-up for 27 months and included in the analysis if ≥18 years at first included HbA1c, ≥2 HbA1cs during follow-up and ≥1 HbA1c at a PHC facility. A visit interval was the duration between two consecutive HbA1cs. Successive HbA1cs at different facilities of any type indicated any transfer, and HbA1cs at different PHC facilities indicated a transfer between PHC facilities. Mixed effects logistic regression adjusted for sex, age, rural/urban facility attended at the start of the visit interval, disengagement (visit interval >14 months) and a hospital visit during follow-up assessed the association between transfers between PHC facilities and HbA1c >8%. RESULTS: Among 102,813 participants, 22.6% had ≥1 transfer of any type. Including repeat transfers, there were 29,994 transfers (14.4 transfers per 100 person-years, 95% confidence interval [CI] 14.3-14.6). A total of 6996 (30.1%) of those who transferred had a transfer between PHC facilities. Visit intervals with a transfer between PHC facilities were longer (349 days, interquartile range [IQR] 211-503) than those without any transfer (330 days, IQR 182-422). The adjusted relative odds of an HbA1c ≥8% after a transfer between PHC facilities versus no transfer were 1.20 (95% CI 1.05-1.37). CONCLUSION: The volume of transfers involving PHC facilities requires consideration when planning services. Individuals who transfer between PHC facilities require additional monitoring and support.

Development and feasibility testing of a time-restricted eating intervention for women living with overweight/obesity and HIV in a resource-limited setting of South Africa.

BACKGROUND: Human Immunodeficiency Virus (HIV) and type 2 diabetes (T2D) are amongst the leading causes of death in South Africa. The preferred first-line anti-retroviral treatment contains dolutegravir (DTG), shown to increase body weight, may compound the already high rates of obesity and associated risk for T2D. South Africa has widespread food insecurity, making traditional dietary strategies difficult to implement. Time-restricted eating (TRE) may be an appropriate intervention in resource-limited communities. METHODS: This article outlines the development and feasibility testing of a TRE intervention to inform the design of a TRE randomised controlled trial in women (20-45 years old) living with overweight/obesity and HIV, receiving DTG-based treatment from a resource-limited community in Cape Town, South Africa. Factors influencing TRE adoption were identified using the Capability, Opportunity, Motivation - Behaviour model and the Theoretical Domains Framework, combining in-depth interviews (IDIs) and focus group discussions. Participants from the IDIs went on to participate in a single arm 4-week TRE pilot trial where feasibility was explored in terms of reach, acceptability, applicability, and implementation integrity. An iterative, thematic analysis approach was employed to analyse the qualitative data. RESULTS: Participants included 33 isiXhosa-speaking women (mean age 37.1 years, mean BMI 35.9 kg/m2). Thematic analysis identified psychological capability (knowledge of fasting), social influences (cultural preferences, family support), and reflective motivation (awareness of weight, health impact, motivation for TRE) as key factors influencing adoption of TRE for weight management. In a 4-week TRE pilot trial (n = 12), retention was 100%. Positive outcomes perceived included improved energy, appetite control and weight loss. TRE was perceived as acceptable, easy, and enjoyable. Family support facilitated adherence, while habitual and social eating and drinking practices were barriers. Compliance was high, aided by self-selected eating times, reminders, and weekly calls. Recommendations included the incorporation of dietary education sessions and text messages to provide additional support and reminders. CONCLUSIONS: This study indicates that TRE is a feasible weight management strategy in women living with overweight/obesity and HIV, receiving DTG-based treatment in a resource-limited community. These findings will ensure that the forthcoming TRE randomised controlled trial is adapted and optimised to the local South African context.

Clinical features and outcomes of COVID-19 admissions in a population with a high prevalence of HIV and tuberculosis: a multicentre cohort study.

BACKGROUND: There is still a paucity of evidence on the outcomes of coronavirus disease 2019 (COVID-19) among people living with human immunodeficiency virus (PWH) and those co-infected with tuberculosis (TB), particularly in areas where these conditions are common. We describe the clinical features, laboratory findings and outcome of hospitalised PWH and human immunodeficiency virus (HIV)-uninfected COVID-19 patients as well as those co-infected with tuberculosis (TB). METHODS: We conducted a multicentre cohort study across three hospitals in Cape Town, South Africa. All adults requiring hospitalisation with confirmed COVID-19 pneumonia from March to July 2020 were analysed. RESULTS: PWH comprised 270 (19%) of 1434 admissions. There were 47 patients with active tuberculosis (3.3%), of whom 29 (62%) were PWH. Three-hundred and seventy-three patients (26%) died. The mortality in PWH (n = 71, 26%) and HIV-uninfected patients (n = 296, 25%) was comparable. In patients with TB, PWH had a higher mortality than HIV-uninfected patients (n = 11, 38% vs n = 3, 20%; p = 0.001). In multivariable survival analysis a higher risk of death was associated with older age (Adjusted Hazard Ratio (AHR) 1.03 95%CI 1.02-1.03, p < 0.001), male sex (AHR1.38 (95%CI 1.12-1.72, p = 0.003) and being "overweight or obese" (AHR 1.30 95%CI 1.03-1.61 p = 0.024). HIV (AHR 1.28 95%CI 0.95-1.72, p 0.11) and active TB (AHR 1.50 95%CI 0.84-2.67, p = 0.17) were not independently associated with increased risk of COVID-19 death. Risk factors for inpatient mortality in PWH included CD4 cell count < 200 cells/mm3, higher admission oxygen requirements, absolute white cell counts, neutrophil/lymphocyte ratios, C-reactive protein, and creatinine levels. CONCLUSION: In a population with high prevalence of HIV and TB, being overweight/obese was associated with increased risk of mortality in COVID-19 hospital admissions, emphasising the need for public health interventions in this patient population.

Factors that influence patient empowerment in inpatient chronic care: early thoughts on a diabetes care intervention in South Africa.

BACKGROUND: The burden of non-communicable diseases is growing rapidly in low- and middle-income countries. Research suggests that health interventions that aim to improve patient self-management and empower patients to care actively for their disease will improve health outcomes over the long-term. There is, however, a gap in the literature about the potential role of the inpatient setting in supporting chronic care. This is particularly important in low-and-middle income countries where hospitals may be a rare prolonged point of contact between patient and health provider. The aim of this small scale, exploratory study was to understand what factors within the inpatient setting may affect patients' feelings of empowerment in relation to their chronic disease care and provides recommendations for future inpatient-based interventions to support self-management of disease. METHODS: This study was based in a public, academic hospital in South Africa. Eighteen qualitative, semi-structured interviews were conducted with multiple participants with experience of diabetes care: inpatients and health professionals such as nurses, endocrinologists, and dieticians. Findings were analysed using a broad, exploratory, thematic approach, guided by self-management and chronic care literature. RESULTS: Interviews with both patients and providers suggest that patients living in low socio-economic contexts are likely to struggle to access appropriate healthcare information and services, and may often have financial and emotional priorities that take precedence over their chronic illness. Younger people may also be more dependent on their family and community, giving them less ability to take control of their disease care and lifestyle. In addition, hospital care remains bound by an acute care model; and the inpatient setting of focus is characterised by perceived staff shortages and ineffective communication that undermine the implementation of patient empowerment-focused interventions. CONCLUSIONS: Patient and provider contexts are likely to make supporting patient engagement in long-term chronic care difficult in lower income settings. However, knowledge of these factors can be harnessed to improve chronic care interventions in South Africa and other similar countries.

Evolution of sensory neuropathy after initiation of antiretroviral therapy.

INTRODUCTION: We studied the evolution of sensory neuropathy after antiretroviral therapy (ART) in human immunodeficiency virus-infected South Africans. METHODS: Enrolment commenced before ART with 6-monthly follow-ups for 24 months. Symptomatic distal sensory polyneuropathy (SDSP) was defined as one symptom and sign. Symptom/sign scores were compared between visits. RESULTS: We enrolled 184 participants. Pre-ART, 16% had SDSP. After 18 months of ART, pain prevalence decreased in those with pre-ART SDSP (odds ratio [OR], 0.09; 95% confidence interval [95%CI], 0.03-0.29). Symptoms improved in 50% ever experiencing pain (mean improvement = 4.5 on 11-point scale). Participants SDSP-free pre-ART developed SDSP at a rate of 18 per 100 person-years. After 24 months (n = 102), 18% had SDSP. Stavudine (60% of cohort) did not predict incident SDSP, but associated with increased prevalence of reduced/absent reflexes at 18 months (OR, 2.24; 95% CI, 1.08-4.65). DISCUSSION: Painful symptoms improved during ART. Evolving sensory neuropathy was due to increasing small and large fiber dysfunction. Muscle Nerve 57: 371-379, 2018.

Pharmacogenetics of plasma efavirenz exposure in HIV-infected adults and children in South Africa.

AIMS: Genetic factors, notably CYP2B6 516G→T [rs3745274] and 983T→C [rs28399499], explain much of the interindividual variability in efavirenz pharmacokinetics, but data from Africa are limited. We characterized relationships between genetic polymorphisms and plasma efavirenz concentrations in HIV-infected Black South African adults and children. METHODS: Steady-state mid-dosing interval efavirenz concentrations were measured. We genotyped 241 polymorphisms in genes potentially relevant to efavirenz metabolism and transport, including ABCB1, CYP2A6, CYP2B6, CYP3A4, CYP3A5, NR1I2 and NR1I3. RESULTS: Among 113 participants (59 adults and 54 children), minor allele frequencies for CYP2B6 516G→T, 983T→C, and 15582C→T [rs4803419] were 0.36, 0.07, and 0.09, respectively. Based on composite CYP2B6 15582/516/983 genotype, there were 33 extensive metabolizer, 62 intermediate metabolizer and 18 slow metabolizer genotypes. Median (IQR) mid-dose efavirenz concentrations were 1.44 (1.21-1.93) µg ml(-1), 2.08 (1.68-2.94) µg ml(-1) and 7.26 (4.82-8.34) µg ml(-1) for extensive, intermediate and slow metabolizers, respectively. In univariate analyses, a model that included composite genotype best predicted efavirenz concentrations (ß = 0.28, 95% CI 0.21, 0.35, P = 2.4 × 10(-11)). Among individual CYP2B6 polymorphisms, 516G→T best predicted efavirenz concentrations (ß = 0.22, 95% CI 0.13, 0.30, P = 1.27 × 10(-6)). There was also associations with 983T→C (ß = 0.27, 95% CI 0.10, 0.44, P = 0.002) and 15582C→T (ß = 0.11, 95% CI 0.01, 0.22, P = 0.04). Associations were consistent in adults and children. No other polymorphisms were independently associated with efavirenz concentrations. CONCLUSIONS: Composite CYP2B6 genotype based on CYP2B6 516G→T, 983T→C, and 15582C→T best described efavirenz exposure in HIV-infected Black South African adults and children.

Changes in blood pressure, glucose levels, insulin secretion and anthropometry after long term exposure to antiretroviral therapy in South African women.

BACKGROUND: A number of metabolic abnormalities, such as dysglycaemia, insulin resistance, lipodystrophy and dyslipidaemia, are associated with the use of antiretroviral drugs. We aimed to assess the effects of long-term antiretroviral exposure on blood pressure, glycaemia, insulin secretion and anthropometric measures in black South African women. METHODS: A convenience sample of HIV-infected women on first-line ART for a median of 16 months at baseline, had the following evaluations twice, at baseline and after approximately 5 years: anthropometry, including skin fold thicknesses, blood pressure, oral glucose test, and insulin. Insulin sensitivity and secretion (HOMA-IR, IGI and DIo) were estimated. RESULTS: At baseline more than half the 103 women were using stavudine and efavirenz. The median interval between baseline and follow-up evaluation was 66 months. Weight, waist circumference, and waist-hip ratio increased over time, while limb skinfold thickness decreased over time. Systolic and diastolic blood pressure increased significantly and the proportion of participants with hypertension increased from 3.9 to 15.5% (p < 0.001). There were increases from baseline in plasma glucose concentrations at 30 and 120 min; insulin concentrations at 0 and 30 min; and IGI and DIo. The proportion of participants with diabetes increased from 1 to 7.5% (p = 0.070). CONCLUSION: In black South African women with long-term exposure to ART, increases in hypertension and possibly diabetes were observed. Participants experienced an increase in central fat and a decrease in peripheral fat distribution. Early identification and management of these metabolic changes are important, especially in a region with the highest HIV-infected population in the world.

Sensory neuropathy and metabolic risk factors in human immune deficiency virus infected South Africans receiving protease inhibitors.

BACKGROUND: Protease inhibitors (PI)s have been associated with distal sensory polyneuropathy (DSP) and metabolic complications in high-income countries. No data exist in Africans where second-line antiretroviral therapy (ART) often include PIs. METHOD: We performed a cross-sectional study to assess the DSP frequency and metabolic risk factors in community-based South Africans taking ritonavir-boosted lopinavir as PI. Examination findings categorized subjects as having DSP (≥1 neuropathic sign) or symptomatic DSP [DSP with symptom(s)]. Fasting-state glucose and lipid profiles were assessed. We compared the ritonavir/lopinavir-group to a nested group on first-line ART [dideoxy-nucleoside reverse transcriptase inhibitors (d-drugs)] selected from a dataset collected at the same time and matched for d-drug exposure. RESULTS: The ritonavir/lopinavir-group (n = 86) consisted predominantly of women (84 %) with a median age of 36 years (IQR 32-41). The median current CD4+ count was 489 cells/µL (IQR 291-665). The median exposure time to ritonavir/lopinavir was 18 months (IQR 10-26) and to d-drugs, 24 months (IQR 16-38). DSP was present in 78 % and symptomatic DSP in 48 %; symptoms were most frequently of moderate intensity. Only age independently associated with DSP and symptomatic DSP (p = 0.08 and p = 0.04, respectively). None of the metabolic syndrome components showed associations with DSP or symptomatic DSP despite a trend towards hypertriglyceridemia overall. The ritonavir/lopinavir-group had less DSP compared to the d-drug only group (p = 0.002) but the frequency of symptomatic DSP was similar (p = 0.49). CONCLUSION: Ritonavir-boosted lopinavir did not add additional risk to developing DSP in this community-based African cohort after a median of 18 months on second-line ART.

The development of simple anthropometric measures to diagnose antiretroviral therapy-associated lipodystrophy in resource limited settings.

BACKGROUND: Lipohypertrophy does not appear to be an adverse ART reaction while lipoatrophy is clearly associated with the use of stavudine (d4T) and zidovudine (AZT). In low and middle income countries d4T has only recently been phased out and AZT is still widely being used. Several case definitions have been developed to diagnose lipodystrophy, but none of them are generalizable to sub-Saharan Africa where black women have less visceral adipose tissue and more subcutaneous adipose tissue than white women. We aimed to develop a simple, objective measure to define lipoatrophy and lipohypertrophy by comparing patient report to anthropometric and dual-energy X-ray absorptiometry (DXA) -derived variables. METHODS: DXA and anthropometric measures were obtained in a cross sectional sample of black HIV-infected South African men (n = 116) and women (n = 434) on ART. Self-reported information on fat gain or fat loss was collected using a standard questionnaire. Receiver operating characteristic (ROC) curves were used to describe the performance of anthropometric and DXA-derived variables using patient reported lipoatrophy and lipohypertrophy as the reference standard. RESULTS: Lipoatrophy and lipohypertrophy were more common in women (25% and 33% respectively) than in men (10% and 13% respectively). There were insufficient numbers of men with DXA scans for meaningful analysis. The best predictors of lipoatrophy in women were the anthropometric variables tricep (AUC = 0.725) and thigh skinfold (AUC =0.720) thicknesses; and the DXA-derived variables percentage lower limb fat (AUC = 0.705) and percentage lower limb fat/height (AUC = 0.713). The best predictors of lipohypertrophy in women were the anthropometric variable waist/hip ratio (AUC = 0.645) and the DXA-derived variable percentage trunk fat/percentage limb fat (AUC = 0.647). CONCLUSIONS: We were able to develop simple, anthropometric measures for defining lipoatrophy and lipohypertrophy, using a sample of black HIV-infected South African women with DXA scans. This is of particular relevance in resource limited settings, where health professionals need simple and inexpensive methods of diagnosing patients with lipoatrophy and lipohypertrophy.

High Molecular Weight (HMW): total adiponectin ratio is low in hiv-infected women receiving protease inhibitors.

BACKGROUND: At the time of the study, the HIV-treatment policy in South Africa included highly active antiretroviral therapy (HAART) regimens 1 (nucleotide reverse transcriptase inhibitors (NRTIs) only), and 2 (protease inhibitors (PI) and NRTIs). HAART is associated with the lipodystrophy syndrome, insulin resistance and reduced total adiponectin (TA) levels. The high molecular weight (HMW):TA ratio is a superior marker of insulin resistance. The aim of this study was to establish whether HMW:TA ratios are low in patients on PIs and whether they correlate with insulin resistance. METHODS: This was a cross-sectional study undertaken in an antiretroviral clinic at a tertiary hospital. The participants were 66 HIV-infected females: 22 were on regimen 2 (PI group), 22 on regimen 1 (non-PI) and 22 treatment naïve (TN), matched for BMI and age. Patients with a history of diabetes or impaired glucose tolerance were excluded. Serum adiponectin multimers were analysed using the AlpcoTM Adiponectin (Multimeric) enzyme immunoassay. Waist hip ratios (WHR), glucose and insulin levels were assessed, and HOMA-IR and QUICKI calculated. Data were analysed non-parametrically and multivariate analysis was performed. RESULTS: TA and HMW levels were lower in the treatment groups than in the TN group. HMW:TA was lower in the PI than in the non-PI and TN groups, and in the non-PI than in the TN groups. HMW:TA correlated negatively with waist, insulin and HOMA-IR, independently of BMI and duration of therapy. HOMA-IR and QUICKI did not differ among the groups. CONCLUSION: HMW:TA is significantly decreased with HAART (particularly with PIs, but also with non-PIs) and may be a more sensitive marker of insulin resistance in these patients than conventional markers or HMW and total adiponectin individually.

Quality of life in individuals living with HIV/AIDS attending a public sector antiretroviral service in Cape Town, South Africa.

BACKGROUND: Health related quality of life (HRQoL) is an important outcome helping to understand the impact of antiretroviral therapy (ART). We examined and compared the HRQoL in relation to ART status among HIV-infected patients in a public sector service in Cape Town, South Africa. In addition, we aimed to examine the relationship between ART status and HRQoL according to CD4 count strata. METHODS: A cross sectional study sample of 903 HIV-infected patients who were categorized as not receiving ART (ART-naïve) or receiving first-line ART for > 6 months (ART). HRQoL outcomes were compared in the two groups. HRQoL was assessed using the EQ-5D (five domains) and Visual Analogue Scale (EQ-5D VAS). RESULTS: Of the total sample, 435 were categorised as ART naïve (76% women) and 468 were on ART (78% women). There were no significant associations between groups for most of the EQ-5D domains, however ART-naïve experienced a significantly greater problem with mobility than the ART group. Being ART-naïve (adjusted odds ratio (aOR) 3.08 95% confidence interval (CI) 1.63- 7.89) and obese 2.78 (95% CI 1.24- 6.22) were identified as predictors for increased mobility problems in multivariate analysis. In addition, receiving ART (5.61 difference; 95% CI 2.50 - 8.72) and having some source of income (4.76; 95% CI 1.63 -7.89) were identified as predictors for a higher EQ-5D VAS score. When grouped according to CD4 count strata, there were no significant difference between groups for most of the EQ-5D domains, however the ART-naïve group indicated having significantly greater problems under the CD4 count of >500 cells/µL in the anxiety/depression domain (22.4% vs 8.8%, p = 0.018) and significantly lower EQ-5D VAS scores under the CD4 counts of ≤ 200 cells/µL (median 80 (IQR 60-90) vs 90 (IQR 80-100), p = 0.0003) and 201-350 cells/µL (median 80 (IQR 70-90) vs 90 (80-100), p = 0.0004) compared to ART group. CONCLUSIONS: HRQoL (self-rated health state) was improved with ART use, including those with immunocompromised status, which may be relevant to the public sector ART program in South Africa.

Routine health data describe adherence and persistence patterns for oral diabetes medication for a virtual cohort in the Khayelitsha sub-district of Cape Town, South Africa.

Type 2 diabetes mellitus (T2DM) is managed with combined lifestyle modifications and antidiabetic drugs, but people on treatment often fail to reach glycaemic control. Adherence is important for achieving optimal glycaemic control, and management of diabetes with drugs is a lifelong process, so understanding adherence through analysis of longitudinal medications data is important. Using retrospective routine health data and metformin dispensing records as a proxy for medication use, we describe longitudinal persistence and adherence to oral diabetes medication in a virtual cohort of 10541 people with diabetes (PLWD) in Khayelitsha subdistrict, Cape Town. Adherence was measured in 120-day sliding windows over two years and used to estimate metformin adherence trajectories. Multinomial logistic regression identified factors influencing these trajectories. Analysis of pharmacy dispensing records showed varying medication refill patterns: while some PLWD refilled prescriptions consistently, others had treatment gaps with periods of non-persistence and multiple treatment episodes-from one to five per individual across two years. There was a general trend of decreasing adherence over time across all sliding windows in the two-year period, with only 25% of the study population achieved medication adherence (> = 80% adherence) after two years. Four adherence trajectories; 'low adherence gradual decline (A), 'high adherence rapid decline' (B), 'low adherence gradual increase (C) and 'adherent' (D) were identified. Only trajectory D represented participants who were adherent at treatment start and remained adherent after two years. Taking HIV antiretroviral treatment before or concurrently with diabetes treatment and taking metformin in combination with sulphonylurea and/or insulin were associated with the long-term adherence (trajectory D). Routine data shows real life medication implementation patterns which might not be seen under controlled study conditions. This study illustrates the utility of these data in describing longitudinal adherence patterns at both an individual and population level.

Management of Type 2 Diabetes Mellitus and Kidney Failure in People with HIV-Infection in Africa: Current Status and a Call to Action.

There is an increasing global burden of diabetes mellitus (DM) and chronic kidney disease (CKD), coupled with a high burden of people with HIV (PWH). Due to an increased lifespan on ART, PWH are now at risk of developing non-communicable diseases, including DM. Africa has the greatest burden of HIV infection and will experience the greatest increase in prevalence of DM over the next two decades. In addition, there is a rising number of people with CKD and progression to kidney failure. Therefore, there is an urgent need for the early identification and management of all 3 diseases to prevent disease progression and complications. This is particularly important in Africa for people with CKD where there is restricted or no access to dialysis and/or transplantation. This review focuses on the epidemiology and pathophysiology of the interaction between HIV infection and DM and the impact that these diseases have on the development and progression of CKD. Finally, it also aims to review the data on the management, which stems from the growing burden of all three diseases.

Association of lopinavir concentrations with plasma lipid or glucose concentrations in HIV-infected South Africans: a cross sectional study.

BACKGROUND: Dyslipidaemia and dysglycaemia have been associated with exposure to ritonavir-boosted protease inhibitors. Lopinavir/ritonavir, the most commonly used protease inhibitor in resource-limited settings, often causes dyslipidaemia. There are contradictory data regarding the association between lopinavir concentrations and changes in lipids. AIM: To investigate associations between plasma lopinavir concentrations and lipid and glucose concentrations in HIV-infected South African adults. METHODS: Participants stable on lopinavir-based antiretroviral therapy were enrolled into a cross-sectional study. After an overnight fast, total cholesterol, triglycerides, and lopinavir concentrations were measured and an oral glucose tolerance test was performed. Regression analyses were used to determine associations between plasma lopinavir concentrations and fasting and 2 hour plasma glucose, fasting cholesterol, and triglycerides concentrations. RESULTS: There were 84 participants (72 women) with a median age of 36 years. The median blood pressure, body mass index and waist: hip ratio were 108/72 mmHg, 26 kg/m2 and 0.89 respectively. The median CD4 count was 478 cells/mm3. Median duration on lopinavir was 18.5 months. The median (interquartile range) lopinavir concentration was 8.0 (5.2 to 12.8) µg/mL. Regression analyses showed no significant association between lopinavir pre-dose concentrations and fasting cholesterol (ß-coefficient -0.04 (95% CI -0.07 to 0.00)), triglycerides (ß-coefficient -0.01 (95% CI -0.04 to 0.02)), fasting glucose (ß-coefficient -0.01 (95% CI -0.04 to 0.02)), or 2-hour glucose concentrations (ß-coefficient -0.02 (95% CI -0.09 to 0.06)). Lopinavir concentrations above the median were not associated with presence of dyslipidaemia or dysglycaemia. CONCLUSIONS: There was no association between lopinavir plasma concentrations and plasma lipid and glucose concentrations.

Tumor-induced osteomalacia: a case report.

BACKGROUND: Tumor-induced osteomalacia is a rare, acquired paraneoplastic syndrome, including hypophosphatemia, high serum alkaline phosphatase, reduced active vitamin D, suboptimal bone mineral density, bone pain, fragility fractures, and muscle weakness. CASE PRESENTATION: We report a case of 74-year-old male of mixed ancestry with hypophosphatemia resistant to treatment despite optimal compliance, associated with profound reduction of bone mineral density and multiple nontraumatic fractures, including bilateral rib fractures, lower-thoracic (T11, T12) vertebrae, and two fractures involving the surgical and anatomical neck of the right humerus. We discuss an approach to identifying the underlying cause of hypophosphatemia associated with fragility fractures, and options for management of this rare condition. CONCLUSION: Although rare, tumor-induced osteomalacia can be diagnosed if a logical stepwise approach is implemented. Surgery could be curative if the tumor is properly located and is resectable.

Reference intervals for biochemical analytes in transgender individuals on hormone therapy.

BACKGROUND: Hormone therapy in transgender individuals may impact processes that lead to changes in biochemical analytes, and therefore reference intervals. Currently, few reference interval studies are available for the transgender population. We determined biochemical reference intervals for transgender individuals receiving hormone therapy. METHODS: Our retrospective, laboratory-based, observational study included healthy transgender males (N = 24) and transgender females (N = 84) on hormone therapy. Various biochemical reference intervals were established for each cohort and compared to their cisgender counterparts. RESULTS: We detected significant differences in reference intervals for sodium, 139-142 mmol/L vs. 136-145 mmol/L when comparing transgender males (TM) with cisgender males (CM). The following significant changes in upper reference limits (URL) for TM versus CM were detected, ALP (URL: 96 U/L vs. 128 U/L), GGT (URL: 27 U/L vs. 67 U/L) and testosterone (URL: 46.7 nmol/L vs. 29.0 nmol/L), respectively. Moreover, when comparing transgender female (TF) to cisgender female (CF), significant differences in creatinine (URL: 117 µmol/L vs. 90 µmol/L), albumin (lower reference limit: 41 g/L, vs. 35 g/L), AST (URL: 50 U/L vs. 35 U/L), ALP (URL: 118 U/L vs. 98 U/L) and oestradiol (URL: 934 pmol/L vs. 213 pmol/L) were noted, respectively. Significantly higher LDL-C was observed for TM on hormone treatment, compared to baseline (2.9 mmol/L vs. 2.2 mmol/L, p <0.01). CONCLUSIONS: Biochemical results for TM and TF receiving hormone therapy can be evaluated against our transgender-specific reference intervals for some analytes, while others can be compared to their identified gender reference intervals.

Depot- and ethnic-specific differences in the relationship between adipose tissue inflammation and insulin sensitivity.

OBJECTIVE: It is unclear whether there are differences in inflammatory gene expression between abdominal and gluteal subcutaneous adipose tissue (SAT), and between black and white women. We therefore tested the hypotheses that SAT inflammatory gene expression is greater in the abdominal compared to the gluteal depot, and SAT inflammatory gene expression is associated with differential insulin sensitivity (S(I) ) in black and white women. DESIGN AND METHODS: S(I) (frequently sampled intravenous glucose tolerance test) and abdominal SAT and gluteal SAT gene expression levels of 13 inflammatory genes were measured in normal-weight (BMI 18-25 kg/m²) and obese (BMI >30 kg/m²) black (n = 30) and white (n = 26) South African women. RESULTS: Black women had higher abdominal and gluteal SAT expression of CCL2, CD68, TNF-α and CSF-1 compared to white women (P < 0·01). Multivariate analysis showed that inflammatory gene expression in the white women explained 56·8% of the variance in S(I) (P < 0·005), compared to 20·9% in black women (P = 0·30). Gluteal SAT had lower expression of adiponectin, but higher expression of inflammatory cytokines, macrophage markers and leptin than abdominal SAT depots (P < 0·05). CONCLUSIONS: Black South African women had higher inflammatory gene expression levels than white women; however, the relationship between AT inflammation and S(I) was stronger in white compared to black women. Further research is required to explore other factors affecting S(I) in black populations. Contrary to our original hypothesis, gluteal SAT had a greater inflammatory gene expression profile than abdominal SAT depots. The protective nature of gluteo-femoral fat therefore requires further investigation.

Diabetes in a TB and HIV-endemic South African population: Analysis of a virtual cohort using routine health data.

BACKGROUND: It is widely accepted that people living with diabetes (PLWD) are at increased risk of infectious disease, yet there is a paucity of epidemiology studies on the relationship between diabetes and infectious disease in SSA. In a region with a high burden of infectious disease, this has serious consequences for PLWD. METHODS AND FINDINGS: Using routinely collected longitudinal health data, we describe the epidemiology of diabetes in a large virtual cohort of PLWD who have a high burden of HIV and TB, from the Khayelitsha subdistrict in the Western Cape Province in South Africa. We described the relationship between previous TB, newly diagnosed TB disease and HIV infection on diabetes using HbA1c results as an outcome measure. The study population was predominately female (67%), 13% had a history of active TB disease and 18% were HIV positive. The HIV positive group had diabetes ascertained at a significantly younger age (46 years c.f. 53 years respectively, p<0.001) and in general had increased HbA1c values over time after their HIV diagnosis, when compared to the HIV-negative group. There was no evidence of TB disease influencing the trajectory of glycaemic control in the long term, but diabetes patients who developed active TB had higher mortality than those without TB (12.4% vs 6.7% p-value < 0.001). HIV and diabetes are both chronic diseases whose long-term management includes drug therapy, however, only 52.8% of the study population with an HIV-diabetes comorbidity had a record of diabetes treatment. In addition, the data suggest overall poor glycaemic control in the study population with only 24.5% of the participants having an HbA1c <7% at baseline despite 85% of the study population being on diabetes treatment. CONCLUSION: The epidemiologic findings in this exploratory study highlight the need for further research into diabetes outcomes in a high TB and HIV burden setting and demonstrate that routine health data are a valuable resource for understanding disease epidemiology in the general population.

Factors Associated with Bone Mineral Density and Bone Resorption Markers in Postmenopausal HIV-Infected Women on Antiretroviral Therapy: A Prospective Cohort Study.

The study aimed to determine factors associated with changes in bone mineral density (BMD) and bone resorption markers over two years in black postmenopausal women living with human immunodeficiency virus (HIV) on antiretroviral therapy (ART). Women (n = 120) aged > 45 years were recruited from Potchefstroom, South Africa. Total lumbar spine and left femoral neck (LFN) BMD were measured with dual energy X-ray absorptiometry. Fasting serum C-Telopeptide of Type I collagen (CTx), vitamin D and parathyroid hormone were measured. Vitamin D insufficiency levels increased from 23% at baseline to 39% at follow up. In mixed linear models serum CTx showed no change from baseline to end (p = 0.363, effect size = 0.09). Total and LFN BMD increased significantly over two years, but effect sizes were small. No significant change in spine BMD over time was detected (p = 0.19, effect size = 0.02). Age was significantly positively associated with CTx over time, and negatively with total and LFN BMD. Physical activity (PA) was positively associated with LFN BMD (p = 0.008). Despite a decrease in serum vitamin D, BMD and CTx showed small or no changes over 2 years. Future studies should investigate PA interventions to maintain BMD in women living with HIV.