The GLUMED (Glucose metabolism changes in Ugandan PLHIV on Dolutegravir) study was a prospective cohort study at the Kisenyi Health Center IV HIV clinic in Uganda’s capital city, Kampala. This clinic has a total of 12,000 active PLHIV in care and the HIV program is supported by the Makerere University Infectious Diseases Institute with funding from the Center for Disease Control (CDC) and the U.S. President's Emergency Plan for AIDS Relief (PEPFAR).

Between January and October 2021, ART naïve PLHIV ≥ 18 years starting DTG based ART were screened for study inclusion. Pregnant women and very sick patients deemed unable to undergo a 2 h–75 g oral glucose tolerance test (2 h-OGTT) were excluded. Criteria for further exclusion during follow up included: new pregnancy and poor adherence to ART (adherence < 85% determined by pill count and self-reporting [18]). Patients with poor adherence were excluded to ascertain exposure to DTG based ART.

After consenting, patients were scheduled for review in 24–48 h after an overnight fast of 8–12 h. Baseline demographic, clinical and social data were collected which included: age, sex, CD4 count, body mass index (BMI), level of education, area of residence, blood pressure, waist circumference, tuberculosis status, smoking status, physical activity measured by the Global Physical Activity Questionnaire (GPAQ), alcohol consumption measured by the Alcohol Use Disorders Identification Test (AUDIT), serum creatine and serum lipid profiles. Fasting blood glucose (FBG) was measured after which patients were given an oral solution containing 75 g of glucose to be taken within five minutes. Blood glucose was measured at 30, 60, 90 and 120 min from the time of ingestion of the glucose solution using ACCU-CHECK™ glucometers from Roche diagnostics [29]. Patients found to have a normal 2 h-OGTT (FBG < 126 mg/dl and 2-h blood glucose (2hBG) < 200 mg/dl) were enrolled for 48-week follow up on tenofovir/lamivudine/dolutegravir (TDF/3TC/DTG) as recommended by the Uganda National HIV treatment guidelines [18]. Enrolled patients received the same adherence and positive living counselling package as the other patients in the Kisenyi HIV clinic before ART initiation.

Enrolled patients were prospectively followed up with BMI, waist circumference, adherence counselling, assessment of concurrent medications and clinical assessments at 12, 24, 36 and 48 weeks. Repeat 2 h-OGTT was performed at 12 and 36 weeks while FBG was measured at 24 and 48 weeks. ART adherence was evaluated on every clinical visit using self-reports and pill counts as recommended by the Uganda MoH guidelines [30].

The primary outcome of the study was incidence of T2DM. Secondary outcomes were: incidence of pre-DM and median changes in FBG from baseline to 48 weeks and 2hBG from baseline to 36 weeks. T2DM was defined as a FBG ≥ 126 mg/dl or 2hBG ≥ 200 mg/dl. Pre-DM was defined as a FBG of 100 mg–125 mg/dl or 2hBG between 140 and 199 mg/dl [31].

Data were collected by a clinical team including a study doctor, nurse and lab technician. Double entry of data was performed with external data quality assurance provided by the IDI study monitoring team. Data were exported for statistical analyses. CD4 cell count, age, serum creatine, serum lipids, changes in BMI and BG were reported as continuous variables and the rest of the variables as categorical data. BMI was categorized according to the WHO into: underweight (< 18.5 kg/m2), normal weight (18.5–24.9 kg/m2), overweight (25.0–29.9 kg/m2) and obesity (≥ 30 kg/m2) [32]. Waist circumference was categorized according to the WHO cut offs; Normal (≤ 94 cm) [Men (M)]; ≤ 80 cm [Women (W)], Increased risk of cardiometabolic complications [95–102 cm (M); 81–88 cm (W)] and substantially increased risk of cardiometabolic complications [> 102 cm (M); > 88 cm (W)] [33]. Blood pressure was categorized as: normal (< 120/80 mmHG), pre-hypertension (120–139/80–89 mmHG) and hypertension (≥ 140/90 mmHG) according to the Joint National Committee 8 (JNC-8) guidelines [34]. Participants were staged into HIV clinical stages 1, 2, 3 and 4 according to the WHO [35]. Physical activity was reported as meeting WHO recommendations on physical activity (≥ 600 Metabolic Equivalent of Task (MET) minutes per week) or not meeting WHO recommendations on physical activity (< 600 MET minutes per week) [36]. Virologic suppression was categorized according to the Uganda HIV treatment guidelines into suppressed viral load (VL) < 1000 copies/ml and non-suppressed (VL ≥ 1000 copies/ml) [30]. Laboratory normal ranges for serum creatine, fasting low density lipoproteins (LDL), high density lipoproteins (HDL) and total cholesterol (TC) were 0.72–1.24 mg/dl, 0–127.6 mg/dl, 34.8–56.07 mg/dl and 0–200 mg/dl respectively [37].

We compared characteristics between study participants who completed follow-up to those who did not. Categorical data were presented as proportions while continuous variables were presented as medians with their corresponding interquartile ranges (IQR). Post-baseline FBG and 2hBG was compared with the baseline using Wilcoxon signed rank test.

Multiple linear regression models were used to determine adjusted differences in blood glucose change between baseline and week 48 for FBG or baseline and week 36 for the 2hBG. Variables that had p-values < 0.1 or those with known biological plausibility and clinical significance were included in the multivariable model. Baseline BG was adjusted for in both models. Statistically significant differences were tested at a p-value of less than 0.05 and all p-values were two-sided. All analyses were done using Stata Release 17.0.