Search

Aims: To assess the potential direct effects of the integrase strand-transfer inhibitors (INsTIs) dolutegravir, bictegravir, and raltegravir, drugs used as treatment for people living with human immunodeficiency virus (PLWH), on human adipose cells., Main Methods: Drugs were added to the differentiation medium of human Simpson-Golabi-Behmel syndrome (SGBS) adipose cells and morphological adipogenesis was monitored for 10 days. Also, adipocytes were exposed to drugs following differentiation (day 14). The gene expression levels of selected adipogenesis markers, adipocyte metabolism markers, adipokines, and cytokines were determined by quantitative-reverse transcription polymerase-chain reaction. The release of adiponectin and leptin into the culture medium was measured using specific enzyme-linked immunosorbent assay, and release of interleukin-6 and chemokine (CC motif) ligand-2 using Multiplex assays., Key Findings: Overall morphological adipogenesis was unaltered by INsTIs. The expression of adipogenesis marker genes (peroxisome proliferator-activated receptor-Ɣ and lipoprotein lipase) was slightly reduced in dolutegravir-treated differentiating adipocytes. Bictegravir repressed gene expression and the release of pro-inflammatory cytokines in differentiating adipocytes. Dolutegravir and raltegravir increased interleukin-6 gene expression, but only dolutegravir increased interleukin-6 release. Dolutegravir repressed adiponectin expression and release in differentiating adipocytes and had a similar but milder effect on leptin. Drug treatment of mature adipocytes reduced adiponectin gene expression in response to dolutegravir., Significance: The INsTIs studied do not have a significant effect on human adipose cell differentiation but exert distinct effects on gene expression and secretion of adipokines and cytokines. These findings will help understand and manage the effects of INsTI-containing treatments on body weight and metabolic dysregulation in PLWH., Competing Interests: Declaration of competing interest Dr. Pere Domingo reported receiving honoraria from Merck Sharp & Dohme, Gilead Sciences, ViiV Healthcare, Janssen, Cilag, Thera technologies, and Roche. All the other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this manuscript. The authors guarantee that they have the authority to publish the work and that the manuscript and confirm that neither the manuscript nor any parts of its content are currently under consideration or published in another journal., (Copyright © 2022. Published by Elsevier Inc.)

Objective: People living with HIV (PLWH) have an increased cardiovascular risk (CVR) owing to dyslipidemia, insulin resistance, metabolic syndrome, and HIV/combination antiretroviral therapy (cART)-associated lipodystrophy (HALS). Atherosclerosis and inflammation are related to growth differentiation factor-15 (GDF15). The relationship between metabolic disturbances, HALS, and CVR with GDF15 in PLWH is not known., Research Design and Methods: Circulating GDF15 levels in 152 PLWH (with HALS = 60, without HALS = 43, cART-naïve = 49) and 34 healthy controls were assessed in a cross-sectional study. Correlations with lipids, glucose homeostasis, fat distribution, and CVR were explored., Results: PLWH had increased circulating GDF15 levels relative to controls. The increase was the largest in cART-treated PLWH. Age, homeostatic model assessment of insulin resistance 1 (HOMA1-IR), HALS, dyslipidemia, C-reactive protein, and CVR estimated with the Framingham score correlated with GDF15 levels. The GDF15-Framingham correlation was lost after age adjustment. No correlation was found between GDF15 and the D:A:D Data Collection on Adverse Effects of Anti-HIV Drugs (D:A:D) score estimated CVR. CVR independent predictors were patient group (naïve, HALS-, and HALS+) and cumulated protease inhibitor or nucleoside reverse transcriptase inhibitor exposure., Conclusions: PLWH, especially when cART-treated, has increased GDF15 levels-this increase is associated with dyslipidemia, insulin resistance, metabolic syndrome, HALS, and inflammation-related parameters. GDF15 is unassociated with CVR when age-adjusted.

Background: Simplified antiretroviral therapy (ART) regimens are desirable for people with HIV. We investigated the efficacy and safety of switching from triple ART to dual dolutegravir plus lamivudine therapy., Methods: DOLAM is a phase 4, randomised, open-label, non-inferiority trial, done at six HIV clinics in Catalonia, Spain. Adults with HIV-1 receiving a triple ART regimen, aged 18 years or older, with virological suppression, a CD4 nadir of at least 200 cells per μL, who were HBsAg-negative, and without previous viral failure or resistance mutations to study drugs were eligible. Participants underwent computer-generated randomisation, stratified by the class of the third drug, and were assigned (1:1) to switch to oral dolutegravir 50 mg and lamivudine 300 mg once daily or to continue triple ART for 48 weeks. The primary endpoint was the proportion of people with an HIV RNA value of at least 50 copies per mL at week 48 (US Food and Drug Administration snapshot algorithm, 8% non-inferiority margin). Both the primary and safety outcomes were evaluated in the intention-to-treat exposed population. The study is completed and was registered with EudraCT 201500027435., Findings: Between July 7, 2015, and Oct 31, 2018, 265 participants were randomly assigned to switch to dolutegravir plus lamivudine (n=131) or to maintain triple ART (n=134) and all received at least one dose. Nine (7%) participants in the dual therapy group and ten (7%) in the triple therapy group were excluded before 48 weeks, mostly due to treatment discontinuations or virological failure. Participants were predominantly male (116 [87%] of 134 in the triple ART group and 111 [85%] of 131 in the dolutegravir plus lamivudine group). The difference in the proportion of participants with HIV RNA values of at least 50 copies per mL at 48 weeks between the dual therapy group (three [2%] of 131) and triple therapy group (two [1%] of 134) was 0·8 percentage points (95% CI -3·3 to 5·2), showing non-inferiority of dolutegravir plus lamivudine dual therapy compared with triple ART. 73 (56%) of 131 participants allocated to dual therapy had 150 adverse effects, compared with 78 (58%) of 134 participants allocated to triple therapy who also had 150 adverse events (p=0·68). Drug discontinuation due to adverse effects occurred in four people in the triple therapy group and three people in the dual therapy group., Interpretation: Our findings show the efficacy and safety of dolutegravir plus lamivudine as a simplified therapy switch option for selected people with HIV with virological suppression on triple ART., Funding: Instituto de Salud Carlos III, Red de Investigación en Sida, and ViiV Healthcare., Competing Interests: Declaration of interests PD reports grants and personal fees from Gilead Sciences, ViiV Healthcare, and Janssen & Cilag, and personal fees from Merck, Sharp & Dohme and Theratechnologies, outside the submitted work. JT reports personal fees from Gilead Sciences, ViiV Healthcare, Merck, Sharp & Dohme, and Janssen, outside the submitted work. ER reports personal fees from Merck, Sharp & Dohme, Gilead Sciences, Janssen, and ViiV Healthcare, outside the submitted work. DP reports research grants and honoraria for advisory boards and conferences from Viiv Healthcare, Pfizer, Bristol Myers Squibb, Gilead Sciences, Janssen, and Merck, Sharp & Dohme, outside the submitted work. RP reports grants from ViiV Healthcare during the conduct of the study, and grants and personal fees from Merck, Sharp & Dohme and Gilead Sciences, outside the submitted work. JMG is currently a full employee at ViiV Healthcare, reports grants from ViiV Healthcare during the conduct of the study, and personal fees from ViiV Healthcare, outside the submitted work. JLB reports grants, personal fees, and non-financial support from ViiV Healthcare and Janssen, and personal fees and non-financial support from Merck, Sharp & Dohme, Gilead Sciences, and Theratechnologies, outside the submitted work. EM reports grants from Instituto de Salud Carlos III and ViiV Healthcare during the conduct of the study, grants and personal fees from Merck, Sharp & Dohme and ViiV Healthcare, and personal fees from Gilead Sciences and Janssen, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: When coronavirus infectious disease-2019 (COVID-19) blew up, ill-fated auguries on the collision between COVID-19 and the human immunodeficiency virus (HIV) epidemics loomed., Areas Covered: Data from observational studies suggest similar incidence attacks of SARS-CoV-2 infection in people living with HIV (PLWH) and HIV-uninfected populations. The mortality rate of COVID-19 is similar in both populations too. The authors discuss the role of combination antiretroviral therapy (cART) in preventing infection or reducing COVID-19 severity. They also discuss the pharmacological interventions for COVID-19 in PLWH., Expert Opinion: Management of COVID-19 in PLWH is no different from the general population. It should be based on careful supportive care, emphasizing lung-protective ventilation, and wise pharmacological interventions. The antiviral drug remdesivir and dexamethasone are the only pharmacological interventions with clinical benefit for COVID-19, whereas anticoagulation may prevent thrombotic complications. The experience with using these drugs in PLWH is limited, which prevents from rendering well-founded conclusions. Until more data on COVID-19 in PLWH become available, the best weapons within our reach are sound supportive care and sensible use of RDV and dexamethasone, bearing in mind the potential for drug-drug interactions of most corticosteroids and antiretroviral drugs.

Introduction : Drug-drug interactions (DDI) between antiretroviral drugs and drugs for the treatment of metabolic disturbances in people living with human immunodeficiency virus (HIV) (PLWH) have represented a problem of paramount importance in the recent times. The problem has been mainly driven by sharing common metabolizing pathways. This problem has classically been worsened by the frequent use of pharmacokinetic boosters to enhance protease inhibitors and some integrase inhibitors plasma levels. Areas covered : This article focuses on the interactions between antiretroviral drugs and those drugs used to treat metabolic disturbances which frequently appear in PLWH. These include dyslipidemia, diabetes mellitus, hyperuricemia, and finally, drugs for the treatment of overweight and clinical obesity. References from PubMed, Embase, or Web of Science, among others, were reviewed. Expert opinion : The advent of safer drugs, in terms of DDI, in the antiretroviral and the metabolic field,such as non-boosted antiretrovirals and drugs with divergent metabolizing paths. Besides, learning by the caregivers on how to decrease and manage DDI, together with the extensive use of online updated DDI databases, has undoubtedly minimized the problem. The foreseeable increase in the burden of HIV-associated comorbidities and their associated treatments anticipates further complexities in the management of DDI in PLWH.

Introduction: The massive implementation of combination antiretroviral therapy (cART) has forever changed the landscape of HIV infection. This unprecedented success has turned HIV infection into a manageable chronic disease. The increased survival of people living with HIV is, however, shadowed by a high burden of aging-related comorbidities. The pathogenic basis underlying this excess of co-morbid conditions is most likely a persistent inflammatory and immune activation state, despite an optimal control of HIV replication, which in turn has largely been attributed to bacterial or bacterial products translocation from the gut. Area covered: This review is focused on the relationship between cART and the chronic inflammatory and immune activation status in otherwise virologically well-controlled people living with HIV (PLWH). Particular focus will be placed on the differences, if any, between distinct cART modalities, with emphasis on less-drug cART regimens, and especially on dual therapies. Expert opinion: Research to address the increased inflammatory and immune activation status of cART-treated, HIV-infected patients, should focus on adjuvant means of therapy, rather than on the cART regime itself. With current antiretrovirals, no difference between dual and triple regimens has been demonstrated, provided that virological and immunological outcomes be non-inferior.

Background: Hypertriglyceridemia is common in HIV-infected patients. Polyunsaturated fatty acids reduce fasting serum triglyceride (TG) levels in HIV-infected patients. It is not known whether docosahexanoic acid (DHA) supplementation can reduce hypertriglyceridemia and modify fat distribution in HIV-infected patients., Methods: We conducted a randomized, double-blind, placebo-controlled trial with 84 antiretroviral-treated patients who had fasting TG levels from 2.26 to 5.65 mmol/l and were randomized to receive DHA or placebo for 48 weeks. TG levels were assessed at baseline, week 4 and every 12 weeks. Body composition was assessed at baseline and at week 48. Registered under ClinicalTrials.gov Identifier no. NCT02005900., Results: Patients receiving DHA had a 43.9% median decline in fasting TG levels at week 4 (IQR: -31% to -56%), compared with -2.9% (-18.6% to 16.5%) in the placebo group (P < 0.0001). DHA levels and decrease in TG at week 4 in the DHA arm correlated significantly (r = 0.7110, P < 0.0001). The median reduction in TG levels in the DHA arm was -43.7% (-32.4% to -57.5%), and in the placebo arm +2.9% (-21.3% to +30.1%) at week 12. The difference remained statistically significant at week 48 (P = 0.0253). LDL cholesterol levels significantly increased at week 4 by 7.1% (IQR: -4.8% to +35.3%) in the DHA arm but not in the placebo group. No significant changes were observed in HDL cholesterol, insulin, and HOMA-IR during the study. Limb fat significantly increased in both arms, without statistically significant differences between groups (P = 0.3889). DHA was well tolerated; only 3 patients experienced treatment-limiting toxicity., Conclusions: Supplementation with DHA reduced fasting TG levels in antiretroviral-treated HIV-infected patients with mild hypertriglyceridemia. DHA was well tolerated with minor GI symptoms. Peripheral fat significantly increased in the DHA group but did not increase significantly compared with placebo., (Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Omega-3 fatty acids have the potential to decrease inflammation and modify gene transcription. Whether docosahexanoic acid (DHA) supplementation can modify systemic inflammatory and subcutaneous adipose tissue (SAT) gene expression in HIV-infected patients is unknown., Methods: A randomized, double-blind, placebo-controlled trial that enrolled 84 antiretroviral-treated patients who had fasting TG levels from 2.26 to 5.65 mmol/l and received DHA or placebo for 48 weeks was performed (ClinicalTrials.gov, NCT02005900). Systemic inflammatory and SAT gene expression was assessed at baseline and at week 48 in 39 patients., Results: Patients receiving DHA had a 43.9% median decline in fasting TG levels at week 4 (IQR: -31% to -56%), compared with -2.9% (-18.6% to 16.5%) in the placebo group (P < 0.0001). High sensitivity C reactive protein (hsCRP) and arachidonic acid levels significantly decreased in the DHA group. Adipogenesis-related and mitochondrial-related gene expression did not experience significant changes. Mitochondrial DNA (mtDNA) significantly decreased in the placebo group. SAT inflammation-related gene expression (Tumor necrosis factor alpha [TNF-α], and monocyte chemoattractant protein-1 [MCP-1]) significantly decreased in the DHA group., Conclusions: DHA supplementation down-regulated inflammatory gene expression in SAT. DHA impact on markers of systemic inflammation was restricted to hsCRP and arachidonic acid., (Copyright © 2018. Published by Elsevier Ltd.)

The advent of protease inhibitors (PI) in the mid-nineties and its use as part of triple combinations revolutionized the management of HIV infection. Since then, progression to AIDS and AIDS-related deaths can be prevented. However, antiretroviral therapy based on PI has been discouraged for a while given its lower tolerability compared to alternative options; and only recent improvements in pharmacotherapy have renewed the interest for the newest agents within this class. First, the tolerability of the latest PI darunavir (DRV) and atazanavir is much better than for older PI, such as indinavir or lopinavir. Second, metabolic abnormalities and/or drug interactions associated to ritonavir boosting have been ameliorated using cobicistat. Third, adding safer accompanying nucleos(t)ides, such as tenofovir alafenamide (TAF), have minimized further toxicity concerns of PI. Finally, the unique barrier to resistance and new single-tablet regimen (STR) presentation makes DRV, especially attractive for long-term therapy. The recent coformulation of DRV, cobicistat, TAF, and emtricitabine (DRV/c/TAF/FTC) within a single pill to be given once daily (Symtuza ® ) has positioned PI again at the frontline of HIV therapeutics. In this review, we discuss the results of studies that have assessed the efficacy and safety of the newest STR. In view of the current data, it seems worthy expanding the consideration of Symtuza® for a wider range of clinical scenarios, beyond the treatment of antiretroviral failures including first-line therapy and switching of otherwise virologically suppressed patients. The good tolerability and robust resistance profile should reward Symtuza ® and position it among the preferred contemporary STRs., (Copyright: © 2018 Permanyer.)

Elvitegravir is a recently developed integrase inhibitor used for antiretroviral treatment of HIV infection. Secondary effects, including disturbances in lipid metabolism and, ultimately, in adipose tissue distribution and function, are common concerns associated with antiretroviral treatments. Here, we provide the first study of the effects of elvitegravir (in comparison with efavirenz, a non-nucleoside analog inhibitor of reverse transcriptase; and raltegravir, another integrase inhibitor) on human adipocyte differentiation, gene expression and secretion of adipokines and cytokines. Elvitegravir impaired adipogenesis and adipocyte metabolism in human SGBS adipocytes in a concentration-dependent manner (delaying acquisition of adipocyte morphology and reducing the expression of adipogenesis marker genes such as PPARγ, glucose transporter GLUT4, lipoprotein lipase, and the adipokines adiponectin and leptin). Compared with efavirenz, the effects of elvitegravir were similar but tended to occur at higher concentrations than those elicited by efavirenz, or were somewhat less intense than those caused by efavirenz at similar concentration. Elvitegravir tended to cause a more moderate induction of pro-inflammatory cytokines than efavirenz. Efavirenz induced a marked concentration-dependent increase in interleukin-8 expression and release whereas elvitregravir had little effect. Raltegravir had totally neutral actions of adipogenesis, adipocyte metabolism-related gene expression and release of adipokines and cytokines. In conclusion, elvitegravir alters adipocyte differentiation and function and promotes induction of pro-inflammatory cytokines similarly to efavirenz, but several effects were less intense. Further assessment of lipid metabolism and adipose tissue function in patients administered elvitegravir-based regimes is advisable considering that totally neutral effects of elvitegravir on lipid homeostasis cannot be anticipated from the current study in vitro., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Highly active antiretroviral therapy has remarkably improved quality of life of HIV-1-infected patients. However, this treatment has been associated with the so-called lipodystrophic syndrome, which conveys a number of adverse metabolic effects and morphological alterations. Among them, lipoatrophy of subcutaneous fat in certain anatomical areas and hypertrophy of visceral depots are the most common. Less frequently, lipomatous enlargements of subcutaneous fat at distinct anatomic areas occur. Lipomatous adipose tissue in the dorso-cervical area ("buffalo hump") has been associated with a partial white-to-brown phenotype transition and with increased cell proliferation, but, to date, lipomatous enlargements arising in other parts of the body have not been characterized. In order to establish the main molecular events associated with the appearance of lipomatosis in HIV-1 patients, we analyzed biopsies of lipomatous tissue from "buffalo hump" and from other anatomical areas in patients, in comparison with healthy subcutaneous adipose tissue, using a marker gene expression approach. Both buffalo-hump and non-buffalo-hump lipomatous adipose tissues exhibited similar patterns of non-compromised adipogenesis, unaltered inflammation, non-fibrotic phenotype and proliferative activity. Shorter telomere length, prelamin A accumulation and SA-β-Gal induction, reminiscent of adipocyte senescence, were also common to both types of lipomatous tissues. Buffalo hump biopsies showed expression of marker genes of brown adipose tissue (e.g. UCP1) and, specifically, of "classical" brown adipocytes (e.g. ZIC1) but not of beige/brite adipocytes. No such brown fat-related gene expression occurred in lipomatous tissues at other anatomical sites. In conclusion, buffalo hump and other subcutaneous adipose tissue enlargements from HIV-1-infected patients share a similar lipomatous character. However, a distorted induction of white-to-"classical brown adipocyte" phenotype appears unique of dorso-cervical lipomatosis. Thus, the insults caused by HIV-1 viral infection and/or antiretroviral therapy leading to lipomatosis are acting in a location- and adipocyte lineage-dependent manner.

Initiation of family planning at the time of birth is opportune, since few women in low-resource settings who give birth in a facility return for further care. Postpartum family planning (PPFP) and postpartum intrauterine device (PPIUD) services were integrated into maternal care in six low- and middle-income countries, applying an insertion technique developed in Paraguay. Facilities with high delivery volume were selected to integrate PPFP/PPIUD services into routine care. Effective PPFP/PPIUD integration requires training and mentoring those providers assisting women at the time of birth. Ongoing monitoring generated data for advocacy. The percentages of PPIUD acceptors ranged from 2.3% of women counseled in Pakistan to 5.8% in the Philippines. Rates of complications among women returning for follow-up were low. Expulsion rates were 3.7% in Pakistan, 3.6% in Ethiopia, and 1.7% in Guinea and the Philippines. Infection rates did not exceed 1.3%, and three countries recorded no cases. Offering PPFP/PPIUD at birth improves access to contraception., (Copyright © 2015. Published by Elsevier Ireland Ltd.)

Objectives: Maximizing ART efficiency is of growing interest. This study assessed the efficacy, safety, pharmacokinetics and economics of a darunavir dose-reduction strategy., Methods: This was a multicentre, randomized, open-label clinical trial in HIV-infected patients with plasma HIV-1 RNA <50 copies/mL while receiving triple ART including 800 mg of darunavir once daily. Participants were randomized to continue 800 mg of darunavir (DRV800) or to 600 mg of darunavir (DRV600), both once daily. Treatment failure was defined as two consecutive HIV-1 RNA determinations >50 copies/mL or discontinuation of study treatment by week 48. The study was registered at https://www.clinicaltrialsregister.eu (trial number 2011-006272-39)., Results: Fifty participants were allocated to each arm. The mean (SD) CD4+ T cell count at baseline was 562 (303) cells/mm(3) and HIV-1 RNA had been <50 copies/mL for a median (IQR) of 106.9 (43.4-227.9) weeks before enrolment. At week 48 no treatment failure had occurred in 45/50 (90%) DRV600 patients and in 47/50 (94%) DRV800 patients (difference -4%; 95% CI lower limit, -12.9%). When only patients with virological data were considered, that endpoint was met by 45/48 (94%) in the DRV600 arm and 47/49 (96%) in the DRV800 arm (difference -2.2%; 95% CI lower limit, -9.6%). Darunavir exposure was similar in the two arms. The average reduction in annual cost per successfully treated DRV600-arm patient was US$7273., Conclusions: The efficacy of a darunavir daily dose of 600 mg seemed to be similar to the efficacy of the standard 800 mg dose in virologically suppressed HIV-infected patients on triple ART. This strategy can potentially translate to substantial savings in the cost of care of HIV-infected patients., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Dyslipidaemia, insulin resistance, metabolic syndrome and HIV/HAART-associated lipodystrophy syndrome (HALS) are common comorbidities in HIV-1-infected patients, which may increase cardiovascular risk. Fibroblast growth factor 23 (FGF23) is a bone-derived hormone with effects on metabolism and phosphate homeostasis. The aim of this study was to determine the relationship between FGF23 levels, metabolic alterations, fat distribution and cardiovascular risk., Methods: This was a cross-sectional study. Serum FGF23 levels were analysed in 152 patients and 34 healthy control individuals. Patients belonged to three groups: HIV-1-infected, antiretroviral-treated patients who have developed HALS (n = 60); HIV-1-infected, antiretroviral-treated patients without HALS (n = 43); and untreated (naive) HIV-1-infected patients (n = 49). Serum FGF23 levels were compared with lipid and glucose homeostasis parameters, fat distribution and cardiovascular risk., Results: Serum FGF23 levels were increased in HIV-1-infected patients, but the increase was most marked in those with HALS. FGF23 levels showed a strong positive correlation with age, indicators of dyslipidaemia (LDL cholesterol, polyunsaturated fatty acids and monounsaturated fatty acids), HALS parameters (trunk/appendicular fat ratio), insulin resistance (fasting insulin and homeostasis model assessment of insulin resistance) and C-reactive protein. FGF23 levels correlated with cardiovascular risk but correlation was lost after age adjustment., Conclusions: FGF23 levels are increased in HIV-1-infected patients, especially in those with HALS, and this increase is associated with dyslipidaemia, insulin resistance, metabolic syndrome, fat distribution and parameters of inflammation. FGF23 is not associated with cardiovascular risk when age is taken into account., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Conflicting reports on the effects of efavirenz (EFV) and lopinavir/ritonavir (LPV/r) on subcutaneous adipose tissue (SAT) have been described., Objective: The aim was to assess the 48-week molecular and clinical effects of LPV/r and EFV, combined with tenofovir/emtricitabine (TDF/FTC), on SAT of HIV-infected, antiretroviral-naive patients., Methods: Forty-four adults were started on LPV/r or EFV combined with TDF/FTC. Fasting metabolic tests, HIV RNA, CD4 cell count, and fat measured by dual x-ray absorptiometry scans were obtained at study entry and week 48. Mitochondrial DNA (mtDNA) and transcripts for mtDNA-encoded proteins and genes involved in inflammation, adipocyte differentiation, and metabolism were assessed in paired SAT biopsies., Results: Whole-body fat and limb fat mass increased in the LPV/r and EFV groups. MtDNA and cytochrome oxidase subunit II did not change, and cytochrome b increased significantly in EFV-treated patients. Tumor necrosis factor alpha and monocyte chemotactic protein-1 gene expression did not change in the LPV/r group, but these significantly increased in the EFV group. Interleukin 18 decreased in the LPV/r group, whereas it increased in the EFV group., Conclusions: Starting TDF/FTC plus EFV was associated with an increased expression of genes encoding for inflammatory cytokines in SAT in naive patients. Therapy with TDF/FTC plus LPV/r or EFV was associated with an increase in subcutaneous fat mass.

Introduction: With the introduction of combination antiretroviral therapy (ART) for HIV infection in the mid-1990s, descriptions of morphological changes and metabolic disturbances in treated patients began to emerge. HIV-1/highly active ART-associated lipodystrophy syndrome (HALS) involves metabolic abnormalities and diverse forms of anomalous fat distribution. The current review focuses on the pathophysiological basis and the clinical evidence for the use of several medical strategies in the management of HALS., Areas Covered: We have covered the most relevant studies related to the pharmacological strategies in the treatment of HALS, with attention to the current and novel antiretroviral agents., Expert Opinion: The most commonly used strategies for HALS reversion have included modification of host-dependent factors, including those related to HIV-1 infection and those associated with ART. Preventive and medical strategies have been associated with moderate success. The only intervention that offers an immediate aesthetical improvement for patients with HALS so far has been plastic surgery.

Introduction: HIV-1 integrase strand transfer inhibitors (INSTIs) are a novel class of antiretroviral drugs with a good safety profile. Several INSTIs have been developed clinically., Areas Covered: The purpose of this review is to examine the safety data of the three FDA-approved INSTIs: Raltegravir (RAL), Elvitegravir (EVG) and Dolutegravir (DTG). The most relevant papers related to the safety profile of integrase inhibitors were selected and summarized., Expert Opinion: INSTIs have demonstrated a favorable safety profile in Phase II and III trials. The most common clinical adverse events reported were diarrhea, nausea and headache. DTG and cobicistat, a component of Stribild(™), increase serum creatinine and decrease estimated creatinine clearance due to inhibition of active tubular secretion of creatinine without affecting renal glomerular function. INSTIs intrinsic potency, together with an outstanding safety profile, preludes an important role for these drugs to build up highly active antiretroviral treatment (HAART) in the near future.

Purpose: 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)., Methods: 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., Results: 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)., Conclusion: 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.

Introduction: Stavudine extended release (d4T XR) was a formulation which tried to solve the two main problems associated with the use of stavudine immediate release (d4T IR). These were twice daily dosing schema at a time when most formulations were long-life allowing once daily dosing; and that the use of d4T IR was associated with long-term toxicity through mitochondrial toxicity clinically expressed as peripheral neuropathy, pancreatitis and above all, lipodystrophy. The link between stavudine exposure and lipodystrophy had a great negative impact on its use in clinical practice., Areas Covered: The authors cover the most relevant papers related to the efficacy and safety of d4T XR-based antiretroviral therapy., Expert Opinion: The development of d4T XR has only been partially successful with regard to its objectives. Improved pharmacokinetic properties allow its once daily dosing, and although it exhibits less mitochondrial toxicity it is still hampered by its development in a significant proportion of patients. This has caused its use to be almost residual in industrialised countries. As of now, d4T XR has not been made available in developing countries, despite the extended use of the immediate-release formulation. Currently, if there is no other chance of starting combination antiretroviral therapy, d4T XR could play a role in the treatment of HIV infection.

Background: Low expression thymidylate synthase (TS) polymorphism has been associated with increased stavudine triphosphate intracellular (d4T-TP) levels and the lipodystrophy syndrome. The use of d4T has been associated with acute pancreatitis and peripheral neuropathy. However, no relationship has ever been proved between TS polymorphisms and pancreatitis and/or peripheral neuropathy., Methods: We performed a case-control study to assess the relationship of TS and methylene-tetrahydrofolate reductase (MTHFR) gene polymorphisms with acute pancreatitis and/or peripheral neuropathy in patients exposed to d4T. Student's t test, Pearson's correlations, one-way ANOVA with Bonferroni correction and stepwise logistic regression analyses were done., Results: Forty-three cases and 129 controls were studied. Eight patients (18.6%) had acute pancreatitis, and 35 (81.4%) had peripheral neuropathy. Prior AIDS was more frequent in cases than in controls (OR = 2.36; 95%CI 1.10-5.07, P = 0.0247). L7ow expression TS and MTHFR genotype associated with increased activity were more frequent in patients with acute pancreatitis and/or peripheral neuropathy than in controls (72.1% vs. 46.5%, OR = 2.97; 95%CI: 1.33-6.90, P = 0.0062, and 79.1% vs. 56.6%, OR = 2.90, 95%CI: 1.23-7.41, P = 0.0142, respectively). Independent positive or negative predictors for the development of d4T-associated pancreatitis and/or peripheral neuropathy were: combined TS and MTHFR genotypes (reference: A+A; P = 0.002; ORA+B = 0.34 [95%CI: 0.08 to 1.44], ORB+A = 3.38 [95%CI: 1.33 to 8.57], ORB+B = 1.13 [95%CI: 0.34 to 3.71]), nadir CD4 cell count >200 cells/mm(3) (OR = 0.38; 95%CI: 0.17-0.86, P = 0.021), and HALS (OR = 0.39 95%CI: 0.18-0.85, P = 0.018)., Conclusions: Low expression TS plus a MTHFR genotype associated with increased activity is associated with the development of peripheral neuropathy in d4T-exposed patients.

Objectives: The aim of the study was to assess the separate contributions of smoking, diabetes and hypertension to acute coronary syndrome (ACS) in HIV-infected adults relative to uninfected adults., Methods: Two parallel case-control studies were carried out. In the first study, HIV-positive adults diagnosed with ACS between 1997 and 2009 (HIV+/ACS) were matched for age, gender and known duration of HIV infection with HIV-positive adults without ACS (HIV+/noACS), each individual in the HIV+/ACS group being matched with three individuals in the HIV+/noACS group. In the second study, each individual in the HIV+/ACS group in the first study was matched for age, gender and calendar date of ACS diagnosis with three HIV-negative individuals diagnosed with ACS between 1997 and 2009 (HIV-/ACS). Each individual in the HIV-/ACS group was then matched for age and gender with an HIV-negative adult without ACS (HIV-/noACS). After matching, the ratio of numbers of individuals in the HIV+/ACS, HIV+/noACS, HIV-/ACS and HIV-/noACS groups was therefore 1 : 3 : 3 : 3, respectively. We performed logistic regression analyses to identify risk factors for ACS in each case-control study and calculated population attributable risks (PARs) for smoking, diabetes and hypertension in HIV-positive and HIV-negative individuals., Results: There were 57 subjects in the HIV+/ACS group, 173 in the HIV+/noACS group, 168 in the HIV-/ACS group, and 171 in the HIV-/noACS group. Independent risk factors for ACS were smoking [odds ratio (OR) 4.091; 95% confidence interval (CI) 2.086-8.438; P < 0.0001] and a family history of cardiovascular disease (OR 7.676; 95% CI 1.976-32.168; P = 0.0003) in HIV-positive subjects, and smoking (OR 4.310; 95% CI 2.425-7.853; P < 0.0001), diabetes (OR 5.778; 95% CI 2.393-15.422; P = 0.0002) and hypertension (OR 6.589; 95% CI 3.554-12.700; P < 0.0001) in HIV-negative subjects. PARs for smoking, diabetes and hypertension were 54.35 and 30.58, 6.57 and 17.24, and 9.07 and 38.81% in HIV-positive and HIV-negative individuals, respectively., Conclusions: The contribution of smoking to ACS in HIV-positive adults was generally greater than the contributions of diabetes and hypertension, and was almost twice as high as that in HIV-negative adults. Development of effective smoking cessation strategies should be prioritized to prevent cardiovascular disease in HIV-positive adults., (© 2012 British HIV Association.)

Background: To determine the role of fibroblast growth factor (FGF)-19 and FGF21 and the endocrine FGFs receptor system in the metabolic alterations that manifest in HIV-1-infected patients undergoing highly active antiretroviral treatment (HAART)., Methods: Serum FGF19 and FGF21 levels were determined in 4 groups of individuals as follows: (1) HIV-1-infected HAART patients with lipodystrophy (n = 38); or (2) without lipodystrophy (n = 34); (3) untreated (naive) HIV-1-infected patients (n = 34); and (4) healthy controls (n = 31). Serum FGF19 levels were correlated with anthropometric, metabolic, HIV-1 infection-related, and HAART-related parameters and with FGF21 levels. The gene expression of FGF receptor 1 and the coreceptor β-Klotho was analyzed in adipose tissue from 10 individuals from each group., Results: Serum FGF19 levels were significantly reduced in all groups of HIV-1-infected patients, whereas FGF21 levels were increased. FGF19 levels were negatively correlated with insulin resistance and insulin levels and positively correlated with high-density lipoprotein cholesterol. FGF19 was inversely correlated with cumulative exposure to nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor drugs. The expression of FGF receptor 1 and coreceptor β-Klotho was reduced in adipose tissue from all groups of HIV-infected patients., Conclusions: FGF19 levels are reduced in HIV-1-infected patients, in contrast with FGF21 levels. Impaired expression of the corresponding receptor and coreceptor, which mediate the actions of endocrine FGFs in adipose tissue, suggests a resistance to the metabolic effects of FGF19 and FGF21 in HIV-1-infected patients. Considering the beneficial effects of endocrine FGFs on metabolism, the observed reduction in FGF19 levels and decreased sensitivity to endocrine FGFs in adipose tissue may contribute to metabolic alterations in HIV-1-infected patients.

Rilpivirine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) recently developed as a drug of choice for initial antiretroviral treatment of HIV-1 infection. Disturbances in lipid metabolism and, ultimately, in adipose tissue distribution and function are common concerns as secondary effects of antiretroviral treatment. Efavirenz, the most commonly used NNRTI, causes mild dyslipidemic effects in patients and strongly impaired adipocyte differentiation in vitro. In this study, we provide the first demonstration of the effects of rilpivirine on human adipocyte differentiation, gene expression, and release of regulatory proteins (adipokines and cytokines) and compare them with those caused by efavirenz. Rilpivirine caused a repression of adipocyte differentiation that was associated with impaired expression of the master adipogenesis regulators peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT enhancer binding protein alpha (C/EBPα), and sterol regulatory element binding transcription factor 1 (SREBP-1) and their target genes encoding lipoprotein lipase and the adipokines leptin and adiponectin. Rilpivirine also repressed adiponectin release by adipocytes, but only at high concentrations, and did not alter leptin release. Rilpivirine induced the release of proinflammatory cytokines (interleukin-6 and -8, monocyte chemoattractant protein 1 [MCP-1], plasminogen activator inhibitor type 1 [PAI-1]) only at very high concentrations (10 μM). A comparison of the effects of rilpivirine and efavirenz at the same concentration (4 μM) or even at lower concentrations of efavirenz (2 μM) showed that rilpivirine-induced impairment of adipogenesis and induction of proinflammatory cytokine expression and release were systematically milder than those of efavirenz. It is concluded that rilpivirine causes an antiadipogenic and proinflammatory response pattern, but only at high concentrations, whereas efavirenz causes similar effects at lower concentrations.

Polymorphisms of the ITPA gene have been associated with anemia during combination therapy in hepatitis C virus (HCV)-monoinfected patients. Our aim was to confirm this association in HIV/HCV-coinfected patients. In this prospective, observational study, 73 HIV/HCV-coinfected patients treated with pegylated interferon plus ribavirin (RBV) were enrolled. Two single nucleotide polymorphisms within or adjacent to the ITPA gene (rs1127354 and rs7270101) were genotyped. The associations between the ITPA genotype and anemia or treatment outcome were examined. Fifty-nine patients (80.8%) had CC at rs1127354, whereas 14 (19.2%) had a CA/AA ITPA genotype. Percent decreases from baseline hemoglobin level were significantly greater in patients with the CC genotype than in those with the CA/AA genotype at week 4 (P = 0.0003), week 12 (P < 0.0001), and week 36 (P = 0.0102) but not at the end of treatment. RBV dose reduction was more often needed in patients with the CC genotype than in those with the CA/AA genotype (odds ratio [OR] = 11.81; 95% confidence interval [CI] = 1.45 to 256.17; P = 0.0039), as was erythropoietin therapy (OR = 8.28; 95% CI = 1.04 to 371.12; P = 0.0057). Risk factors independently associated with percent hemoglobin nadir decrease were RBV dose reduction (OR = 11.72; 95% CI = 6.82 to 16.63; P < 0.001), baseline hemoglobin (OR = 1.69; 95% CI = 0.23 to 3.15; P = 0.024), and body mass index (OR = -0.7; 95% CI = -1.43 to 0.03; P = 0.061). ITPA polymorphism was not an independent predictor of sustained virological response. Polymorphisms at rs1127354 in the ITPA gene influence hemoglobin levels during combination HCV therapy and the need for RBV dose reduction and erythropoietin use in HIV/HCV-coinfected patients.

Introduction: The lamivudine (3TC) + stavudine (d4T) combination is still widely used as part of first-line therapy for HIV-1-infected patients in low-resource countries. This review is intended to assess the benefits and risks in terms of safety of d4T + 3TC-based combination antiretroviral therapy (ART) for the treatment of HIV-1 infection., Areas Covered: The most relevant papers related to the safety of d4T + 3TC-based ART were selected and summarized., Expert Opinion: In industrialized countries, the 3TC + d4T combination is not recommended for initial therapy because of long-term metabolic toxicities associated with d4T. In developing countries, it may have a role in the treatment of HIV-infected patients if there is no other chance for starting antiretroviral therapy.

The antiviral activity and toxicity of stavudine (d4T) depend on its triphosphate metabolite, stavudine triphosphate (d4T-TP). Therefore, modifications in intracellular levels of d4T-TP may change the toxicity profile of stavudine. d4T-TP intracellular levels in peripheral blood mononuclear cells were determined with a prominence liquid chromatograph connected to a triple-quadruple mass spectrometer. Polymorphisms in the thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), reduced folate carrier 1 (RFC1; SLC19A1), and cyclin D1 (CCND1) genes were determined by direct sequencing using an ABI Prism 3100 genetic analyzer or Fluidigm's Biomark system. The Mann-Whitney test, rank analysis of variance (with Bonferroni's adjusted post hoc comparisons), and logistic regression were used for the inferential analyses. Thirty-three stavudine-treated patients were enrolled in this cross-sectional study. d4T-TP intracellular levels were 11.50 fmol/10(6) cells (interquartile range [IQR] = 8.12 to 13.87 fmol/10(6) cells) in patients with a high-expression TS genotype (2/3G, 3C/3G, and 3G/3G), whereas in those with a low-expression TS genotype (2/2, 2/3C, and 3C/3C), they were 21.40 fmol/10(6) cells (IQR = 18.90 to 27.0 fmol/10(6) cells) (P < 0.0001). Polymorphisms in the MTHFR, DHFR, RFC1, and CCND1 genes did not influence the intracellular concentration of d4T-TP. d4T-TP levels were independently associated with the TS genotype (low versus high expression; odds ratio [OR] = 86.22; 95% confidence interval [CI] = 8.48 to nonestimable; P = 0.0023). The low-expression TS genotype was associated with the development of HIV/highly active antiretroviral therapy-associated lypodystrophy syndrome (HALS) (OR = 14.0; 95% CI = 2.09 to 108.0; P = 0.0032). Our preliminary data show that polymorphisms in the thymidylate synthase gene are strongly associated with d4T-TP intracellular levels and with development of HALS.

Morphologic and metabolic abnormalities remain a common problem in patients with HIV-1 infection, which contributes to poor self image and may negatively impact on patient's adherence to medication and success of therapy. In addition, these physiological and metabolic changes can lead to increased cardiovascular risk. In such patients, excess central fat could be associated with loss of subcutaneous fat. Several strategies to decrease the excess of visceral fat have been assessed. Tesamorelin, an injectable growth hormone-releasing factor analogue, has been shown to improve visceral fat adiposity with relatively little effect on subcutaneous fat with improvement in triglycerides and belly appearance distress. It is well tolerated overall without clinically significant changes in mean glucose or insulin levels. However, these benefits cease if treatment is discontinued.

The most important factor limiting the success of an antiretroviral therapy regimes is toxicity. Toxicity can depend on a number of factors; some of these are intrinsic to the host and may not only affect the latter's outward appearance, but also determine the intensity these toxic effects may reach. The former is exemplified by idiosyncratic or hypersensitivity reactions, whereas the latter is usually appreciated in metabolic disturbances or fat redistribution syndromes. Some of the determinants of antiretroviral toxicity are genetic in origin and have been the subject of intense study in recent years. Some of these are linked to a single nucleotide polymorphism (SNP), whereas others depend on a complex interaction between multiple genes variations. One of these tests (HLA B*5701) is now being applied in clinical practice and widely used to prevent the risk of hypersensitivity reactions to abacavir. Many other genetic determinants of antiretroviral drug toxicity have been suggested as an explanation for nucleoside analogue toxicity; these include lactic acidosis, peripheral neuropathy and pancreatitis, and have also been suggested as a potential basis for the non-nucleoside toxicity derived from immunogenetic factors involved in nevirapine hypersensitivity to SNPs in efavirenz enzyme metabolism, amongst other things. Metabolic toxicity, mainly due to protease inhibitors (PIs) is far more complex and depends on the interaction of various genes. The same seems to be true for fat redistribution syndromes and atherosclerosis, although a clear picture of the genetic factors operating in these syndromes is yet to emerge. The ultimate goal of pharmacogenetics is to customize antiretroviral therapy by identifying the genes that can maximize efficacy whilst helping avoid known side effects of antiretroviral drugs.