Nigel J. Crowther

Metabolic function and the prevalence of lipodystrophy in a population of HIV-infected African subjects receiving highly active antiretroviral therapy.

Objective:This study measured the prevalence of lipodystrophy and the metabolic effects of highly active antiretroviral therapy (HAART) in HIV-infected African subjects. Methods:Prevalence was measured in 571 Rwandans receiving HAART for ≥6 months. Metabolic variables were measured in 100 HIV-positive adults with lipodystrophy, 50 HIV-positive nonlipodystrophic adults, and 50 HIV-negative controls. Results:A HAART regimen of stavudine, lamivudine, and nevirapine was used by 81.6% of subjects; none received protease inhibitors. Lipodystrophy was observed in 34% (48.5% in urban groups and 17.3% in rural groups) of subjects, with a prevalence of 69.6% in those receiving HAART for >72 weeks. Peripheral lipoatrophy combined with abdominal lipohypertrophy was observed in 72% of lipodystrophic subjects. HIV-positive adults with lipodystrophy had a significantly higher waist-to-hip ratio (WHR; 0.99 ± 0.05 vs. 0.84 ± 0.03: P < 0.0005) than HIV-positive nonlipodystrophic adults. Total cholesterol concentrations (median [interquartile range], mmol/L) were significantly higher in the HIV-positive adults with lipodystrophy (3.60 [1.38]) than in HIV-positive nonlipodystrophic adults (3.19 [0.65]; P < 0.005) and control (3.13 [0.70]; P < 0.0005) groups. Impaired fasting glucose was observed in 18% of HIV-positive adults with lipodystrophy, 16% of HIV-positive nonlipodystrophic adults, and 2% of controls, but insulin levels did not differ. Conclusions:African subjects with lipodystrophy have increased WHR, glucose, and cholesterol levels. Glucose concentrations are also elevated in nonlipodystrophic HIV-positive subjects. Therefore, factors other than body fat redistribution contribute to the glucose intolerance.

Association of HIV and ART with cardiometabolic traits in sub-Saharan Africa: a systematic review and meta-analysis

Background Sub-Saharan Africa (SSA) has the highest burden of HIV in the world and a rising prevalence of cardiometabolic disease; however, the interrelationship between HIV, antiretroviral therapy (ART) and cardiometabolic traits is not well described in SSA populations. Methods We conducted a systematic review and meta-analysis through MEDLINE and EMBASE (up to January 2012), as well as direct author contact. Eligible studies provided summary or individual-level data on one or more of the following traits in HIV+ and HIV-, or ART+ and ART- subgroups in SSA: body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TGs) and fasting blood glucose (FBG) or glycated hemoglobin (HbA1c). Information was synthesized under a random-effects model and the primary outcomes were the standardized mean differences (SMD) of the specified traits between subgroups of participants. Results Data were obtained from 49 published and 3 unpublished studies which reported on 29 755 individuals. HIV infection was associated with higher TGs [SMD, 0.26; 95% confidence interval (CI), 0.08 to 0.44] and lower HDL (SMD, −0.59; 95% CI, −0.86 to −0.31), BMI (SMD, −0.32; 95% CI, −0.45 to −0.18), SBP (SMD, −0.40; 95% CI, −0.55 to −0.25) and DBP (SMD, −0.34; 95% CI, −0.51 to −0.17). Among HIV+ individuals, ART use was associated with higher LDL (SMD, 0.43; 95% CI, 0.14 to 0.72) and HDL (SMD, 0.39; 95% CI, 0.11 to 0.66), and lower HbA1c (SMD, −0.34; 95% CI, −0.62 to −0.06). Fully adjusted estimates from analyses of individual participant data were consistent with meta-analysis of summary estimates for most traits. Conclusions Broadly consistent with results from populations of European descent, these results suggest differences in cardiometabolic traits between HIV-infected and uninfected individuals in SSA, which might be modified by ART use. In a region with the highest burden of HIV, it will be important to clarify these findings to reliably assess the need for monitoring and managing cardiometabolic risk in HIV-infected populations in SSA.

Exercise Training Reduces Central Adiposity and Improves Metabolic Indices in HAART-Treated HIV-Positive Subjects in Rwanda: A Randomized Controlled Trial

As HAART becomes more accessible in sub-Saharan Africa, metabolic syndromes, body fat redistribution (BFR), and cardiovascular disease may become more prevalent. We conducted a 6-month, randomized controlled trial to test whether cardiorespiratory exercise training (CET), improves metabolic, body composition and cardiorespiratory fitness parameters in HAART-treated HIV(+) African subjects with BFR. Six months of CET reduced waist circumference (-7.13 +/- 4.4 cm, p < 0.0001), WHR (-0.10 +/- 0.1, p < 0.0001), sum skinfold thickness (-6.15 +/- 8.2 mm, p < 0.0001) and % body fat mass (-1.5 +/- 3.3, p < 0.0001) in HIV(+)BFR(+)EXS. Hip circumference was unchanged in non-exercise control groups. CET reduced fasting total cholesterol (-0.03 +/- 1.11 mM, p < 0.05), triglycerides (-0.22 +/-0.48 mM, p < 0.05) and glucose levels (-0.21 +/- 0.71 mM, p < 0.05) (p < 0.0001). HDL-, LDL-cholesterol and HOMA values were unchanged after CET. Interestingly, HIV(+) subjects randomized to non-exercising groups experienced increases in fasting plasma glucose levels, whereas HIV seronegative controls did not (p < 0.001). Predicted VO(2) peak increased more in the HIV(+)BFR(+)EXS than in all other groups (4.7 +/- 3.9 ml/kg/min, p < 0.0001). Exercise training positively modulated body composition and metabolic profiles, and improved cardiorespiratory fitness in HAART-treated HIV(+) Africans. These beneficial adaptations imply that exercise training is a safe, inexpensive, practical, and effective treatment for evolving metabolic and cardiovascular syndromes associated with HIV and HAART exposure in resource-limited sub-Saharan countries, where treatment is improving, morbidity and mortality rates are declining, but where minimal resources are available to manage HIVand HAART-associated cardiovascular and metabolic syndromes.

The current waist circumference cut point used for the diagnosis of metabolic syndrome in sub-Saharan African women is not appropriate.

The waist circumference cut point for diagnosing the metabolic syndrome in sub-Saharan African subjects is based on that obtained from studies in European populations. The aim of this study was to measure the prevalence of obesity and related metabolic disorders in an urban population of African females, a group at high risk for such diseases, and to determine the appropriate waist cut point for diagnosing the metabolic syndrome. Anthropometry and fasting lipid, glucose and insulin levels were measured in a cohort of 1251 African females participating in the Birth to Twenty cohort study in Soweto, Johannesburg. The waist circumference cut points for diagnosing metabolic syndrome (as defined using the new harmonised guidelines), insulin resistance, dysglycaemia, hypertension and dyslipidaemia were obtained using receiver operator characteristic curve analysis. The prevalence of obesity, type 2 diabetes and metabolic syndrome were 50.1%, 14.3% and 42.1%, respectively. The appropriate waist cut point for diagnosing metabolic syndrome was found to be 91.5 cm and was similar to the cuts points obtained for detecting increased risk of insulin resistance (89.0 cm), dysglycaemia (88.4 cm), hypertension (90.1 cm), hypo-high density lipoproteinaemia (87.6 cm) and hyper-low density lipoproteinaemia (90.5 cm). The present data demonstrates that urban, African females have a high prevalence of obesity and related disorders and the waist cut point currently recommended for the diagnosis of the metabolic syndrome (80.0 cm) in this population should be increased to 91.5 cm. This latter finding demonstrates a clear ethnic difference in the relationship between abdominal adiposity and metabolic disease risk. The similar waist cut points identified for the detection of the individual components of the metabolic syndrome and related cardiovascular risk factors demonstrates that the risk for different metabolic diseases increases at the same level of abdominal adiposity suggesting a common aetiological pathway.

Evidence for insulin resistance in black women from South Africa

OBJECTIVE: The rate of glucose disposal was determined in 10 black and 10 white obese nondiabetic urban women from South Africa to assess insulin resistance.DESIGN AND METHODS: Euglycemic hyperinsulinemic clamp and body composition analysis.RESULTS: Age, body mass index (BMI), anthropometric measurements and body composition were similar in both groups of women. A five-level computed tomography (CT) scan showed a similar mean subcutaneous fat mass in both groups of women (black obese women 555±9.0 vs white obese women 532±6.0 cm2), but less visceral fat in black obese women (90±3.0 vs 121±3.1 cm2; P<0.05). Black obese women had higher fasting free fatty acid (997±69 vs 678±93 μmol/l; P<0.05) and lactate concentrations (1462±94 vs 1038±39 μmol/l; P<0.05), but lower fasting insulin levels (87±12 vs 155±9 pmol/l; P<0.001). Black obese women also had a more favorable HDL: total cholesterol ratio (30.5% vs 23.0%; P<0.04). The mean glucose disposal rate (M) and disposal expressed as glucose sensitivity index (M/I) were reduced in the black obese women vs white obese women (M: 7.1±0.8 vs 13.7±1.0 mmol/kg·min−1×100; P<0.01, and M/I: 0.12±0.01 vs 0.24±0.02 mmol/kg·min−1/pmol/l×1000; P<0.01). Only black obese women showed a significant decrease in C-peptide levels during the clamp (2.9±0.22 vs 1.2±0.12 nmol/l; P<0.001). During the euglycemic period, the black obese women had higher lactate levels at all time points, but only the white obese women had increased lactate levels (918±66 to 1300±53 μmol/l; P<0.05).CONCLUSION: Black obese women demonstrate a higher degree of insulin resistance, despite less visceral fat and a higher HDL: total-cholesterol ratio. In addition, endogenous β-cell secretory function in black obese women appears to be more sensitive to the suppressive effect of exogenous insulin administration. The significant increase in lactate levels in white obese women confirms that they are more insulin sensitive.

Relation between weight gain and beta-cell secretory activity and non-esterified fatty acid production in 7-year-old African children: results from the Birth to Ten study.

Aims/hypothesis. This study aimed to assess the effects of fetal and childhood growth on beta-cell activity and insulin sensitivity in 7-year-old children. Methods. Insulin, des-31,32 proinsulin, proinsulin, non-esterified fatty acids and glucose concentrations were measured in oral glucose tolerance tests in 152 South African children for whom longitudinal weight data was available. Results. Children with low weights at birth and 7 years (low–low) had relatively low beta-cell activity whereas children with low birth weight and high weight at 7 years (low–high) had relatively high beta-cell activity. The low–low group had higher 30-min glucose concentrations than children with high birth weights. When each insulin-related peptide was expressed as a percentage of all these peptides the low–low children had the highest percentage of insulin but the lowest of the prohormones. The low–high children had the lowest percentage of insulin but the highest of the prohormones. Non-esterified fatty acid concentrations were lowest and their suppression post-glucose load highest in the low–high group. Conclusion/interpretation. Poor fetal and neonatal growth give rise to low beta-cell numbers compensated for by increased efficiency of proinsulin processing to insulin. Poor fetal followed by higher postnatal growth results in low beta-cell numbers and reduced whole-body glucose uptake which leads to reduced efficiency in the processing of proinsulin. Growth in utero and postnatally therefore have profound effects on beta-cell activity and insulin sensitivity with poor fetal coupled with high postnatal growth being detrimental to these processes but not detrimental to the suppression of lipolysis. [Diabetologia (2000) 43: 978–985]

The interrelationship between bone and fat: from cellular see-saw to endocrine reciprocity

The number of mature osteoblasts and marrow adipocytes in bone is influenced by the differentiation of the common mesenchymal progenitor cell towards one phenotype and away from the other. Consequently, factors which promote adipogenesis not only lead to fatty marrow but also inhibit osteoblastogenesis, resulting in decreased osteoblast numbers, diminished bone formation and, potentially, inadequate bone mass and osteoporosis. In addition to osteoblast and bone adipocyte numbers being influenced by this skewing of progenitor cell differentiation towards one phenotype, mature osteoblasts and adipocytes secrete factors which may evoke changes in the cell fate and function of each other. This review examines the endogenous factors, such as PPAR-γ2, Wnt, IGF-1, GH, FGF-2, oestrogen, the GP130 signalling cytokines, vitamin D and glucocorticoids, which regulate the selection between osteoblastogenesis and adipogenesis and the interrelationship between fat and bone. The role of adipokines on bone, such as adiponectin and leptin, as well as adipose-derived oestrogen, is reviewed and the role of bone as an energy regulating endocrine organ is discussed.

A longitudinal study of stavudine-associated toxicities in a large cohort of South African HIV infected subjects

BackgroundThere has been major improvement in the survival of HIV-1 infected individuals since the South African Government introduced highly active anti-retroviral therapy (HAART) in the public sector in 2004. This has brought new challenges which include the effects of stavudine-related toxicities.MethodsProspective analysis of a cohort of 9040 HIV-infected adults who were initiated on HAART at the Themba Lethu Clinic (TLC) in Johannesburg between April 1, 2004 to December 31, 2007, and followed up until June 30, 2008.ResultsAmongst the 9040 study subjects, 8497(94%) were on stavudine based therapy and 5962 (66%) were women. The median baseline CD4 count was 81 cells/mm3 (IQR 29-149). Median follow up on HAART was 19 months (IQR: 9.1-31.6). The proportion of HAART-related side effects for stavudine compared to non-stavudine containing regimens were, respectively: peripheral neuropathy,17.1% vs. 11.2% (p < 0.001); symptomatic hyperlactataemia, 5.7% vs. 2.2% (p < 0.0005); lactic acidosis, 2.5 vs. 1.3% (p = 0.072); lipoatrophy, 7.3% vs. 4.6% (p < 0.05). Among those on stavudine-based regimens, incidence rates for peripheral neuropathy were 12.1 cases/100 person-years (95%CI 7.0-19.5), symptomatic hyperlactataemia 3.6 cases/100 person-years (95%CI 1.2-7.5), lactic acidosis 1.6 cases/100 person-years (95%CI 0.4-5.2) and lipoatrophy 4.6 cases/100 person-years (95%CI 2.1-9.6). Females experienced more toxicity when compared to males in terms of symptomatic hyperlactataemia (p < 0.0001), lactic acidosis (p < 0.0001), lipoatrophy (p < 0.0001) and hypertension (p < 0.05).ConclusionsWe demonstrate significant morbidity associated with stavudine. These data support the latest WHO guidelines, and provide additional evidence for other resource limited HAART rollout programs considering the implementation of non-stavudine based regimens as first line therapy.

Free fatty acids and insulin levels—relationship to leptin levels and body composition in various patient groups from South Africa

OBJECTIVE: To investigate the relationship between leptin concentrations, various metabolic indices and body composition in six different groups.DESIGN AND MEASUREMENTS: Anthropometric measurements, fasting plasma glucose, serum insulin, C-peptide, FFA and leptin levels were performed. In the obese and diabetic subjects, body composition was analysed with bio-impedance equipment and as a 5 level CT scan.SUBJECTS: Five lipoatrophic diabetes mellitus (LDM) patients, five normal subjects (N), nine white and nine black obese women (WW, BW), and nine white and nine black diabetic women (DWW, DBW) were investigated after an overnight fast.RESULTS: In both ethnic groups there was a positive correlation between leptin and BMI (black group: r=0.8; P<0.0001, white group: r=0.7, P<0.002) and leptin and SC fat mass (black group: r=0.6; P<0.005, white group: r=0.6; P<0.004).CONCLUSIONS: Across the groups, there were positive linear correlations between leptin concentrations, BMI, SC fat mass and FFA levels. Leptin and FFA concentrations are higher and insulin levels lower in both groups of black women compared to the two groups of white women, despite a similar BMI and body fat mass. In the DBW the large increase in visceral fat mass may be indicative of a more complex relationship between compensatory insulin resistance, elevated FFA levels and leptin secretion.

A Longitudinal Study of the Changes in Body Fat and Metabolic Parameters in a South African Population of HIV-Positive Patients Receiving an Antiretroviral Therapeutic Regimen Containing Stavudine

The aim of this study was to determine the patterns of change in body fat and metabolic parameters in a South African cohort on a first line ART regimen containing stavudine. Fasting lipogram, blood glucose and insulin levels, CD4 cell count, viral load, BMI, waist-to-hip ratio (WHR), and skinfold thickness at the triceps, scapula, and iliac crest were measured before starting ART in 42 (27 female) subjects. Repeat measurements were performed at four monthly intervals for 2 years. Lipodystrophy was diagnosed using patient perception and assessment by a physician. At baseline, subjects who went on to develop lipodystrophy (LD group) were fatter and had higher skinfold thickness at all three sites and higher insulin levels than subjects who never developed lipodystrophy (NLD group). The WHR increased to a greater extent while hip circumference and tricep skinfolds fell more significantly in the LD than NLD group. Triglyceride and cholesterol levels increased significantly in both groups while lactate and glucose levels increased more and insulin levels increased less in the LD than the NLD group. Neither viral load nor CD4 count differed between the groups during the study. Viral load correlated positively with insulin levels at baseline. Thus, lipodystrophy in the South African population is characterized by a higher BMI before initiation of ART and lipoatrophy of the arms and hips, lipohypertrophy of the waist, and increased lactate production. When compared to the NLD group, the LD subjects display attenuated insulin secretory output in response to a higher weight gain.