Metabolic syndrome is a cluster of clinical features comprising obesity, dyslipidaemia, hypertension, and impaired glucose tolerance. It has been defined by the International Diabetes Federation as having central obesity plus any two of the following: (1) raised triglycerides, (2) reduced high-density lipoprotein (HDL) cholesterol or on lipid lowering therapy, (3) hypertension, and (4) raised fasting plasma glucose or diagnosis of type 2 diabetes (1) (See Table 1). The mechanism of development is not fully understood, but has been linked to genetic predisposition, chronic inflammation, neurohormonal activation, and insulin resistance (2, 3). Visceral adiposity has been shown to be a significant trigger to activate pathways of metabolic syndrome development (2, 4).

There has been a suggestion that metabolic syndrome may be more prevalent in people living with HIV (PLWH) in a meta-analysis conducted in Sub Saharan Africa, with a prevalence of 21.5% in PLWH compared to 12% in uninfected populations (5). The global prevalence has been estimated to be between 16.7% and 31.3% among PLWH in another study (6).

It has been widely reported that metabolic syndrome predisposes to development of cardiovascular disease and type II diabetes, with an estimated two and five-fold increased risk respectively, compared to those without the syndrome (1). It has also been linked to co-morbidities including cancer development, polycystic ovarian syndrome (7), obstructive sleep apnoea (8), chronic kidney disease (9), and non-alcoholic fatty liver disease (10, 11).

Previously, protease inhibitors used to treat HIV were associated with metabolic syndrome development (12). However, there is now a significant body of evidence associating weight gain and obesity with integrase inhibitors (INSTI) (13, 14), which are recommended as the preferred first line antiretroviral in the WHO guidelines for treatment of HIV-1 infection (15). Tenofovir alafenamide, often used in combination with INSTIs, has also been implicated in weight gain and obesity (13, 16). Weight gain associated with both INSTIs +/− TAF, has been greater in Black ethnicity, and females (13, 16). As one of the main risk factors for metabolic syndrome, growing rates of obesity within this patient population may drive metabolic syndrome development.

The NAMSAL-ANRS-12313 (NAMSAL) trial is a phase 3 open-label randomised trial which compared the efficacy of TDF/3TC + DTG to TDF/3TC + EFV (17). The trial recruited adults with HIV-1 infection who had not received antiretroviral therapy from three hospitals in Cameroon. The ADVANCE trial is a phase 3 randomised controlled open-label trial which evaluated the efficacy and safety of TAF/FTC + DTG and TDF/FTC + DTG, as compared with TDF/FTC/EFV (18). The trial recruited participants from routine HIV testing sites, based in Johannesburg, South Africa.

The ADVANCE and NAMSAL trials have both reported substantial levels of clinical obesity (17, 18). Weight gain has been more pronounced on the DTG arms of both trials, disproportionally affecting females, and particularly those on the TAF/FTC backbone on the ADVANCE trial (17, 18). This study aims to evaluate the risk of metabolic syndrome in the ADVANCE and NAMSAL trials.

In the ADVANCE trial there were a total of 1,053 randomised participants (TAF/FTC + DTG = 351, TDF/FTC + DTG = 351, TDF/FTC + EFV = 351). The median age of participants was 32 in the TAF/FTC + DTG and TDF/FTC + DTG arms and 33 in the TDF/FTC + EFV arm. Females comprised 61% of participants in the TAF/FTC + DTG arm, 59% in the TDF/FTC + DTG arm and 57% in the TDF/FTC + EFV arm. The median weight of participants was 66.4 kg, 66.3 kg and 66.4 kg in the TAF/FTC + DTG, TDF/FTC + DTG and TDF/FTC + EFV arms respectively. In the NAMSAL trial there were a total of 616 randomised participants (TDF/3TC + DTG = 310, TDF/3TC + EFV = 303). The median age of participants was 38 in the TDF/3TC + DTG arm and 36 in the TDF/3TC + EFV arm. 63.5% of participants in the TDF/3TC + DTG arm and 68.3% in the TDF/3TC + EFV arm were females. The median weight of participants was 64 kg in both arms. Further details on baseline characteristics of participants in ADVANCE and NAMSAL are presented in Tables 2A,B.

In ADVANCE, across all study visits to week 192, treatment-emergent metabolic syndrome was present in 15% (TAF/FTC + DTG), 10% (TDF/FTC + DTG) and 7% (TDF/FTC/EFV) of participants. In NAMSAL the incidence of treatment-emergent metabolic syndrome was 14% (TDF/3TC + DTG) and 5% (TDF/3TC + EFV) at any time up to week 192. We highlight treatment-emergent metabolic syndrome associated with dolutegravir, likely driven by obesity. There is some evidence of metabolic syndrome associated with INSTI use in other trials. However, there is limited data coming from other randomised trials.

In a Zambian cross-sectional study, a DTG-based regimen was associated with metabolic syndrome (OR: 2.10, 95% CI: 1.05–4.20) (19). The ACTG A5001 and A5322 trials observed changes in weight gain to correspond with lower levels of HDL, and higher levels of LDL cholesterol, total cholesterol, triglyceride levels and fasting glucose (20). Similarly, 10% weight gain in NAMSAL was associated with a rise in cholesterol levels (21).

By contrast, in the REPRIEVE cohort study, despite being associated with a significant higher odds of developing obesity, INSTI use was not associated with metabolic syndrome, or differences in glucose, LDL, or hypertension (22). A randomised switch study from TDF/FTC/NNRTI to ABC/3TC/DTG saw significant weight gain in the DTG arm, but no associated reduced insulin sensitivity or treatment-emergent metabolic syndrome (23). Similarly, in the ATHENA cohort, weight gain of ≥10% was observed following switch to INSTI and/or TAF, without significant changes in metabolic parameters (24). In the TANGO trial, switching from a 3-/4-drug TAF based regimen to DTG/3TC, resulted in improvements in metabolic parameters (25). No significant differences in odds of metabolic syndrome were seen between the treatment groups in this trial (25).

Case reports have described incidences of hyperglycaemia associated with INSTI use (26, 27, 28, 29). In some of these cases, the hyperglycaemia was independent of weight gain, and associated with ketoacidosis, suggestive that the mechanism of dysglycaemia may not be associated with obesity. Another study showed cases of hyperglycaemia in pre-treated patients independent of weight gain and associated with ketoacidosis (30). There is mixed evidence relating INSTIs to insulin resistance. Some studies have shown association with insulin resistance (31, 32) and small rises in glycated haemoglobin (33, 34). A recent analysis of the FDA Adverse Event Reporting System linked INSTIs to greater odds of hyperglycaemia or new onset diabetes (ROR: 2.16, CI: 1.96–2.38) (35). However, there is also evidence opposing the association of INSTIs to insulin resistance and diabetes (36, 37).

Previous analyses of the ADVANCE trial looking at 10-year risk of developing diabetes using the QDiabetes equation, a risk equation validated in populations of Black ethnicity, have shown that TAF/FTC + DTG was associated with greater risk of developing diabetes (38).

INSTIs have been associated with increases in fat gain and body circumference (39, 40, 41, 42, 43). In the ADVANCE trial, DTG, combined with TAF was associated with increases in both mass and volume of VAT compared with the TDF/FTC/DTG and the TDF/FTC + EFV arms (16). They have generally been found to be lipid neutral (44, 45, 46, 47).

In two observational studies, dolutegravir was not associated with a significant change in glucose metabolism (48, 49). However, both studies were based on follow-up to 48 weeks. Such short-term studies may not be able to demonstrate metabolic syndrome.