Recent data on the role of antiretroviral therapy in weight gain and obesity in persons living with HIV.

PURPOSE OF REVIEW: Antiretroviral therapy (ART) has long been implicated in fat alterations and weight variations leading to cardiometabolic consequences. Recent largely prescribed antiretrovirals (ARVs) from the integrase-strand-transfer-inhibitor (INSTI) class have been associated with excessive weight gain/obesity in a minority of persons with HIV (PWH). As well, in the nucleoside reverse transcriptase inhibitors (NRTI) class, tenofovir-alafenamide (TAF), often replacing tenofovir-disoproxil-fumarate (TDF), has been associated with weight gain, a worrying concern in the present worldwide obesogenic environment. The respective role of the different ARV, the risk factors and the mechanisms remain questionable. RECENT FINDINGS: The INSTIs dolutegravir (DTG) and bictegravir (BIC) and TAF have a proper effect on weight gain, while efavirenz (EFV) and TDF inhibit it. These effects are reported in ART-naïve PWH, in addition to weight gain resulting from the return to health process, and in ART-controlled PWH. Also, INSTIs induce weight gain in adolescents and excessive weight gain during pregnancy. The effects of INSTIs and TAF are additive. Their trajectory differs. Most of the weight gain is observed during the initial 12-month period.The main risk factors are low CD4+ and high viral load (VL) in ART-naïve PWH, Black race or originating from some African countries and female gender. The role of age and BMI differs between studies. The reversibility of the effect of INSTI and TAF appears limited.Regarding the mechanisms, the INSTIs can directly alter adipose tissue in particular through inhibition of fat beiging, resulting in fat fibrosis and hypertrophy. Macrophage infiltration is decreased. The mechanisms explaining the opposite effects of TDF and TAF remain elusive. SUMMARY: The specific impact of DTG, BIC and TAF on weight gain/obesity in PWH is confirmed in different populations independently of the weight limiting effect of EFV and TDF. ART-linked excessive weight gain is uncommon. African origin and female sex are risk factors that need to be considered. The mechanisms are better understood for INSTIs but unknown for TDF/TAF. The reversibility of weight gain/obesity when stopping INSTI or TAF remains limited.

HIV and adipose tissue: A long history linked to therapeutic classes of antiretrovirals.

HIV infection has been controlled only since the introduction of triple therapy in 1996, combining, as antiretroviral agents, two nucleoside reverse transcriptase inhibitors (NRTIs) and one protease inhibitor (PI). However, among the NRTIs, the thymidine analogues stavudine and zidovudine led to lipoatrophy, either generalized or associated with visceral fat hypertrophy and buffalo hump. These molecules also increased insulin resistance and the prevalence of diabetes. They were replaced by other NRTIs or non-NRTIs (NNRTIs) that were considered to be free of adipose tissue (AT) toxicity. More recently, the NRTI tenofovir disoproxyfumarate (TDF) and the NNRTI efavirenz have been associated with inhibition of fat gain but not with clear lipoatrophy. Otherwise, the use of PIs led to a phenotype of trunk fat hypertrophy associated with cardiometabolic complications. To avoid their adverse effects, PIs have recently been replaced by a new class of antiretrovirals, the integrase inhibitors (INSTIs), which are well tolerated and effective in controlling HIV. However, this class has been associated with global weight gain, which may be important and concerning for some people living with HIV (PWH). Also, in the NRTI class, TDF has often been replaced by tenofovir alafenamide (TAF) due to bone and renal toxicities, and TAF has been associated with global fat gain. The cardiometabolic consequences of INTIs and TAF are primarily related to the associated weight gain. In the global obesogenic worldwide context, PWH are gaining weight as well in relation to poor health life conditions. Taking in charge obesity uses the same strategies as those used in the general population.

Pink adipose tissue: A paradigm of adipose tissue plasticity.

Adipose tissue is highly plastic, as illustrated mainly by the transdifferentiation of white adipocytes into beige adipocytes, depending on environmental conditions. However, during gestation and lactation in rodent, there is an amazing phenomenon of transformation of subcutaneous adipose tissue into mammary glandular tissue, known as pink adipose tissue, capable of synthesizing and secreting milk. Recent work using transgenic lineage-tracing experiments, mainly carried out in Saverio Cinti's team, has demonstrated very convincingly that this process does indeed correspond to a transdifferentiation of white adipocytes into mammary alveolar cells (pink adipocytes) during gestation and lactation. This phenomenon is reversible, since during the post-lactation phase, pink adipocytes revert to the white adipocyte phenotype. The molecular mechanisms underlying this reversible transdifferentiation remain poorly understood.

Major depletion of insulin sensitivity-associated taxa in the gut microbiome of persons living with HIV controlled by antiretroviral drugs.

BACKGROUND: Persons living with HIV (PWH) harbor an altered gut microbiome (higher abundance of Prevotella and lower abundance of Bacillota and Ruminococcus lineages) compared to non-infected individuals. Some of these alterations are linked to sexual preference and others to the HIV infection. The relationship between these lineages and metabolic alterations, often present in aging PWH, has been poorly investigated. METHODS: In this study, we compared fecal metagenomes of 25 antiretroviral-treatment (ART)-controlled PWH to three independent control groups of 25 non-infected matched individuals by means of univariate analyses and machine learning methods. Moreover, we used two external datasets to validate predictive models of PWH classification. Next, we searched for associations between clinical and biological metabolic parameters with taxonomic and functional microbiome profiles. Finally, we compare the gut microbiome in 7 PWH after a 17-week ART switch to raltegravir/maraviroc. RESULTS: Three major enterotypes (Prevotella, Bacteroides and Ruminococcaceae) were present in all groups. The first Prevotella enterotype was enriched in PWH, with several of characteristic lineages associated with poor metabolic profiles (low HDL and adiponectin, high insulin resistance (HOMA-IR)). Conversely butyrate-producing lineages were markedly depleted in PWH independently of sexual preference and were associated with a better metabolic profile (higher HDL and adiponectin and lower HOMA-IR). Accordingly with the worst metabolic status of PWH, butyrate production and amino-acid degradation modules were associated with high HDL and adiponectin and low HOMA-IR. Random Forest models trained to classify PWH vs. control on taxonomic abundances displayed high generalization performance on two external holdout datasets (ROC AUC of 80-82%). Finally, no significant alterations in microbiome composition were observed after switching to raltegravir/maraviroc. CONCLUSION: High resolution metagenomic analyses revealed major differences in the gut microbiome of ART-controlled PWH when compared with three independent matched cohorts of controls. The observed marked insulin resistance could result both from enrichment in Prevotella lineages, and from the depletion in species producing butyrate and involved into amino-acid degradation, which depletion is linked with the HIV infection.