We sought to evaluate the effetc of metformin on body mass index (BMI) and metabolic parameters in HIV-positive patients. We performed a comprehensive search through five major indexing databases, using keywords ("metformin" OR "dimethylguanylguanidine" OR "biguanide" OR "Glucophage") AND ("HIV" OR "human immunodeficiency virus" OR "AIDS" OR "Acquired immunodeficiency syndrome"), and all possible combinations until January 15, 2021. We measured standardized mean differences (SMD) and 95% confidence intervals (CI) for each outcome. We finally included 12 RCTs (577 participants, 274 in the metformin group and 303 in the comparators). Metformin did not significantly change BMI index compared to various comparators. Metformin generally improve LDL levels (SMD = 0.29, 95% CI: - 1.00 1.57, P = 0.01), HDL levels (SMD = - 0.15, 95% CI: - 0.72 0.41, P = 0.001), triglycerides values (SMD = 0.46, 95% CI: - 0.36 1.27, P < 0.00001), fasting glucose (SMD = - 0.82, 95% CI: - 1.80 0.15, P < 0.00001), insulin 120 min (SMD = - 0.82, 95% CI: - 1.59-0.04, P = 0.02), and glucose 120 min (SMD = - 1.24, 95% CI: - 2.57 0.10, P < 0.0001), but worsened total cholesterol values (SMD = 1.24, 95% CI: - 0.98 3.46, P = 0.0001). Metformin is safe for weight loss in obese people; however, this drug may not be suitable for everyone, especially those who are not overweight. Nevertheless the body of evidences may suggest that metformin had promising impacts on metabolic parameters in patients with both HIV, it is still unknown that such surrogate changes will translate to long-standing clinical advantages.

The online version contains supplementary material available at 10.1007/s40200-021-00869-1.

To assess in a cohort of Caucasian patients exposed to stavudine (d4T) the association of polymorphisms in pyrimidine pathway enzymes and HLA-B*40∶01 carriage with HIV/Highly active antiretroviral therapy (HAART)-associated lipodystrophy syndrome (HALS).

Three-hundred and thirty-six patients, 187 with HALS and 149 without HALS, and 72 uninfected subjects were recruited. The diagnosis of HALS was performed following the criteria of the Lipodystrophy Severity Grading Scale. Polymorphisms in the thymidylate synthase (TS) and methylene-tetrahydrofolate reductase (MTHFR) genes were determined by direct sequencing, HLA-B genotyping by PCR-SSOr Luminex Technology, and intracellular levels of stavudine triphosphate (d4T-TP) by a LC-MS/MS assay method.

HALS was associated with the presence of a low expression TS genotype polymorphism (64.7% vs. 42.9%, OR = 2.43; 95%CI: 1.53-3.88, P<0.0001). MTHFR gene polymorphisms and HLA-B*40∶01 carriage were not associated with HALS or d4T-TP intracellular levels. Low and high expression TS polymorphisms had different d4T-TP intracellular levels (25.60 vs. 13.60 fmol/10(6) cells, P<0.0001). Independent factors associated with HALS were(OR [95%CI]: (a) Combined TS and MTHFR genotypes (p = 0.006, reference category (ref.): 'A+A'; OR for 'A+B' vs. ref.: 1.39 [0.69-2.80]; OR for 'B+A' vs. ref.: 2.16 [1.22-3.83]; OR for 'B+B' vs. ref.: 3.13, 95%CI: 1.54-6.35), (b) maximum viral load ≥5 log10 (OR: 2.55, 95%CI: 1.56-4.14, P = 0.001), (c) use of EFV (1.10 [1.00-1.21], P = 0.008, per year of use).

HALS is associated with combined low-expression TS and MTHFR associated with high activity polymorphisms but not with HLA-B*40∶01 carriage in Caucasian patients with long-term exposure to stavudine.

Antiretroviral drugs have been associated with several toxicities that limit their success. Of the chronic toxicities, the lipodystrophy syndrome is of special concern due to the metabolic alterations that can accompany it. Why some patients treated with a particular antiretroviral regimen develop lipodystrophy, while others do not, is a medical mystery, but it has been suggested that individuals may (or may not) have a genetically conditioned predisposition. Pharmacogenetics is the science that studies how the genetic composition of individuals can give rise to interindividual variations in response to drugs and drug toxicity.

This article reviews the published investigations on the association between host genetic determinants in treated HIV-infected patients and the presence of lipodystrophy. Studies were identified through a PubMed database search. Case-control and longitudinal studies into pharmacogenetic association were selected. Areas covered include the data on the genetic variants of mitochondrial parameters, cytokines, adipokines, proteins involved in adipocyte biology and proteins involved in stavudine metabolism.

Most studies provide inconsistent data due to partial genetic evaluation, different assessment of lipodystrophy and low number of patients evaluated. The pharmacogenetics of lipodystrophy in HIV-infected patients treated with antiretroviral drugs still belongs in the research laboratory.

Human immunodeficiency virus type 1 (HIV)-associated lipodystrophy syndrome compromises body composition and produces metabolic alterations, such as dyslipidemia and insulin resistance. This study aims to determine whether energy expenditure and substrate oxidation are altered due to human HIV-associated lipodystrophy syndrome.

We compared energy expenditure and substrate oxidation in 10 HIV-infected men with lipodystrophy syndrome (HIV+LIPO+), 22 HIV-infected men without lipodystrophy syndrome (HIV+LIPO-), and 12 healthy controls. Energy expenditure and substrate oxidation were assessed by indirect calorimetry, and body composition was assessed by dual-energy X-ray absorptiometry. The substrate oxidation assessments were performed during fasting and 30 min after eucaloric breakfast consumption (300 kcal).

The resting energy expenditure adjusted for lean body mass was significantly higher in the HIV+LIPO+ group than in the healthy controls (P = 0.02). HIV-infected patients had increased carbohydrate oxidation and lower lipid oxidation when compared to the control group (P < 0.05) during fasting conditions. After the consumption of a eucaloric breakfast, there was a significant increase in carbohydrate oxidation only in the HIV+LIPO- and control groups (P < 0.05), but there was no increase in the HIV+LIPO+ group.

Hypermetabolism and alteration in substrate oxidation were observed in the HIV+LIPO+ group.

Treated HIV-1-infected patients with lipodystrophy often develop insulin resistance and proatherogenic dyslipidaemia. Zinc alpha-2 glycoprotein (ZAG) is a recently characterized adipokine which has been shown to be involved in the development of obesity and metabolic syndrome in uninfected subjects. We assessed the relationship between circulating ZAG levels and metabolic derangements in HIV-1-infected patients receiving antiretroviral drugs.

Plasma ZAG levels were assessed in 222 individuals: 166 HIV-1-infected patients treated with antiretroviral drugs (77 with lipodystrophy and 89 without lipodystrophy) and 56 uninfected controls. Plasma ZAG levels were assessed by enzyme-linked immunosorbent assay (ELISA) and were correlated with fat distribution abnormalities and metabolic parameters.

HIV-1-infected patients had lower plasma ZAG levels compared with uninfected controls (P < 0.001). No differences were found in ZAG plasma levels according to the presence of lipodystrophy, components of the metabolic syndrome or type of antiretroviral treatment regimen. Circulating ZAG levels were strongly determined by high-density lipoprotein cholesterol (HDLc) in men (B = 0.644; P < 0.001) and showed a positive correlation with total cholesterol (r = 0.312; P < 0.001) and HDLc (r = 0.216; P = 0.005).

HIV-1-infected patients have lower plasma ZAG levels than uninfected controls. In infected patients, plasma ZAG levels are in close relationship with total cholesterol and HDLc.