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Frontiers in Pharmacology 2021Protease inhibitors (PIs) are believed to affect insulin sensitivity. We aimed to analyze the effect of PIs on insulin sensitivity and the onset of diabetes mellitus... (Review)
Review
Protease inhibitors (PIs) are believed to affect insulin sensitivity. We aimed to analyze the effect of PIs on insulin sensitivity and the onset of diabetes mellitus (DM) in patients with HIV. We searched PubMed, Google Scholar, ClinicalTrals.gov, and the WHO International Clinical Trials Registry Platform till November 2020 for randomized controlled trials (RCTs) that studied the effects of PIs on insulin sensitivity and DM in patients with HIV. We followed the PRISMA and PICOS frameworks to develop the search strategy. We used the random-effects meta-analysis model to estimate the mean difference (MD), standardized mean difference (SMD), and risk ratios for our outcomes, using Stata 14 software. We included nine RCTs that enrolled 1,000 participants, with their ages ranging from 18 to 69 years. The parameters and investigations used in the studies to determine insulin sensitivity were glucose disposal rates, hyperglycemia, and mean glucose uptake. The majority of results showed an association between PIs and insulin sensitivity. The pooled analysis showed no statistically significant difference in insulin sensitivity with atazanavir, whether the study was performed on healthy individuals for a short term or long term in combination with other drugs like tenofovir or emtricitabine [SMD = 0.375, 95% CI (0.035, 0.714)]. The analysis showed reduced glucose disposal rates and hence reduced insulin sensitivity with lopinavir (heterogeneity chi-squared = 0.68, I-squared [variation in SMD attributable to heterogeneity] = 0.0%, = 0.031). The heterogeneity with chi-squared was substantial (61-80%), while with I-squared was not significant (0-40%), = 0.031). Less adverse events were observed with atazanavir than with lopinavir [RR = 0.987, 95% CI (0.849, 1.124)]. Darunavir and indinavir did not demonstrate any significant changes in insulin sensitivity. Most of the studies were found to have a low risk of bias. There are significant variations in the effects of PIs on insulin sensitivity and onsets of DM. Atazanavir, fosamprenavir, and darunavir did not demonstrate any significant changes in insulin sensitivity, compared to the rest of the group. There is a need to assess the benefits of PIs against the long-term risk of impaired insulin sensitivity. All patients newly diagnosed with HIV should have DM investigations before the start of ARVs and routinely. RCTs should focus on sub-Saharan Africa as the region is worst affected by HIV, but limited studies have been documented.
PubMed: 34790115
DOI: 10.3389/fphar.2021.635089 -
Nutrients Jan 2022Because pharmacokinetic changes in antiretroviral drugs (ARV), due to their concurrent administration with food or nutritional products, have become a clinical... (Meta-Analysis)
Meta-Analysis Review
Because pharmacokinetic changes in antiretroviral drugs (ARV), due to their concurrent administration with food or nutritional products, have become a clinical challenge, it is necessary to monitor the therapeutic efficacy of ARV in people living with the human immunodeficiency virus (PLWH). A systematic review and meta-analysis were conducted to clarify the pharmacokinetic outcomes of the interaction between supplements such as food, dietary supplements, and nutrients, and ARV. Twenty-four articles in both healthy subjects and PLWH were included in the qualitative analysis, of which five studies were included in the meta-analysis. Food−drug coadministration significantly increased the time to reach maximum concentration (tmax) (p < 0.00001) of ARV including abacavir, amprenavir, darunavir, emtricitabine, lamivudine, zidovudine, ritonavir, and tenofovir alafenamide. In addition, the increased maximum plasma concentration (Cmax) of ARV, such as darunavir, under fed conditions was observed. Area under the curve and terminal half-life were not significantly affected. Evaluating the pharmacokinetic aspects, it is vital to clinically investigate ARV and particular supplement interaction in PLWH. Educating patients about any potential interactions would be one of the effective recommendations during this HIV epidemic.
Topics: Anti-Retroviral Agents; Darunavir; Dietary Supplements; Drug Interactions; Emtricitabine; Humans
PubMed: 35276881
DOI: 10.3390/nu14030520 -
Bioorganic Chemistry Jan 2021Since the beginning of the novel coronavirus (SARS-CoV-2) disease outbreak, there has been an increasing interest in finding a potential therapeutic agent for the...
BACKGROUND
Since the beginning of the novel coronavirus (SARS-CoV-2) disease outbreak, there has been an increasing interest in finding a potential therapeutic agent for the disease. Considering the matter of time, the computational methods of drug repurposing offer the best chance of selecting one drug from a list of approved drugs for the life-threatening condition of COVID-19. The present systematic review aims to provide an overview of studies that have used computational methods for drug repurposing in COVID-19.
METHODS
We undertook a systematic search in five databases and included original articles in English that applied computational methods for drug repurposing in COVID-19.
RESULTS
Twenty-one original articles utilizing computational drug methods for COVID-19 drug repurposing were included in the systematic review. Regarding the quality of eligible studies, high-quality items including the use of two or more approved drug databases, analysis of molecular dynamic simulation, multi-target assessment, the use of crystal structure for the generation of the target sequence, and the use of AutoDock Vina combined with other docking tools occurred in about 52%, 38%, 24%, 48%, and 19% of included studies. Studies included repurposed drugs mainly against non-structural proteins of SARS-CoV2: the main 3C-like protease (Lopinavir, Ritonavir, Indinavir, Atazanavir, Nelfinavir, and Clocortolone), RNA-dependent RNA polymerase (Remdesivir and Ribavirin), and the papain-like protease (Mycophenolic acid, Telaprevir, Boceprevir, Grazoprevir, Darunavir, Chloroquine, and Formoterol). The review revealed the best-documented multi-target drugs repurposed by computational methods for COVID-19 therapy as follows: antiviral drugs commonly used to treat AIDS/HIV (Atazanavir, Efavirenz, and Dolutegravir Ritonavir, Raltegravir, and Darunavir, Lopinavir, Saquinavir, Nelfinavir, and Indinavir), HCV (Grazoprevir, Lomibuvir, Asunaprevir, Ribavirin, and Simeprevir), HBV (Entecavir), HSV (Penciclovir), CMV (Ganciclovir), and Ebola (Remdesivir), anticoagulant drug (Dabigatran), and an antifungal drug (Itraconazole).
CONCLUSIONS
The present systematic review provides a list of existing drugs that have the potential to influence SARS-CoV2 through different mechanisms of action. For the majority of these drugs, direct clinical evidence on their efficacy for the treatment of COVID-19 is lacking. Future clinical studies examining these drugs might come to conclude, which can be more useful to inhibit COVID-19 progression.
Topics: Animals; Antiviral Agents; Cell Line, Tumor; Computational Chemistry; Drug Discovery; Drug Repositioning; Humans; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33261845
DOI: 10.1016/j.bioorg.2020.104490 -
Infectious Diseases and Therapy Dec 2016Patients with human immunodeficiency virus (HIV) infection have an increased risk of cardiovascular disease (CVD). While viral suppression with antiretroviral therapy... (Review)
Review
INTRODUCTION
Patients with human immunodeficiency virus (HIV) infection have an increased risk of cardiovascular disease (CVD). While viral suppression with antiretroviral therapy decreases CVD risk overall, several studies have suggested that certain antiretrovirals, particularly certain protease inhibitors, may be associated with an increased relative risk of CVD. In AIDS Clinical Trials Group 5260 s, ritonavir-boosted atazanavir (ATV) was associated with slower atherosclerosis progression compared to ritonavir-boosted darunavir and raltegravir, potentially due to hyperbilirubinemia. Although hyperbilirubinemia may lead to increased rates of treatment discontinuation, it may also contribute to a favorable cardiovascular (CV) profile for ATV. To fully elucidate the effect of ATV on CVD risk among HIV-infected patients, a systematic review of the literature was performed.
METHODS
A systematic search of the PubMed and Embase databases was conducted on August 26, 2015, using terms to identify papers that discuss ATV, HIV, and CVD. Articles were limited to English-language publications of randomized-controlled or observational studies investigating adult humans. The primary outcome was the incidence of CVD. Articles describing surrogate markers of CVD were also included.
RESULTS
Ten studies were included in this qualitative analysis: six reported CVD outcomes, two reported data on atherosclerosis as assessed by carotid intima-media thickness (cIMT), and two reported outcomes related to endothelial function. The studies reporting the incidence of myocardial infarction (MI) among HIV-infected patients showed that ATV (boosted and unboosted) was not associated with an increased risk of acute MI. Other CV endpoints were similarly unaffected by treatment with ATV. Compared with non-ATV-based regimens, ATV had beneficial effects on cIMT progression in the publications identified, with no apparent impact on endothelial function.
CONCLUSIONS
This analysis showed that there was no increased risk or occurrence of adverse CV events among HIV-infected patients receiving ATV. Markers of atherosclerosis were improved, suggesting a possible antioxidant effect of ATV, and endothelial function was not affected.
FUNDING
Bristol-Myers Squibb (article processing charges and medical writing support).
PubMed: 27677263
DOI: 10.1007/s40121-016-0132-z -
Frontiers in Pediatrics 2022Atazanavir/ritonavir is recommended as a preferred second-line antiretroviral regimen in children older than 3 months, alternatively to lopinavir/ritonavir. We performed...
BACKGROUND
Atazanavir/ritonavir is recommended as a preferred second-line antiretroviral regimen in children older than 3 months, alternatively to lopinavir/ritonavir. We performed a systematic review to assess safety and effectiveness of atazanavir use in children and adolescents.
METHODS
We searched observational studies and clinical trials on Web of Science, Embase and Cochrane CENTRAL database between 2009/01/01 and 2020/10/01; as well as grey literature. We extracted safety (adverse events, grade 3 or 4 adverse events, treatment discontinuation) and effectiveness (CD4 cell counts and HIV viral load) outcomes. We estimated weighted summary pooled incidence with corresponding 95% confidence intervals.
RESULTS
Out of the 1,085 records screened, we included five studies (one comparative cohort, three single phase 2-3 trial arms, one retrospective cohort) reporting 975 children and adolescents, of whom 56% (544) received atazanavir. Three studies reported all-cause treatment discontinuation rates, yielding a pooled incidence of 19% [15-22] at 12 months. The comparative cohort compared atazanavir to darunavir, with few grade 3-4 adverse events, except transient hyperbilirubinemia, occurring in half (92/188) of the atazanavir patients. No death occurred (two studies reporting). Four studies described increased CD4 cell counts and decreased HIV viral load at 6 or 12 months.
CONCLUSION
Few safety and effectiveness data were available for children and adolescents exposed to atazanavir. Transient grade 3-4 hyperbilirubinemia was the main adverse outcome reported. Immune and viral responses were descriptive. The use of atazanavir/ritonavir in children and adolescents needs further investigation, but remains a suitable option for a preferred second-line antiretroviral regimen.
PROSPERO NUMBER
CRD42022309230.
PubMed: 35676899
DOI: 10.3389/fped.2022.913105 -
AIDS and Behavior May 2023Multiple factors may affect combined antiretroviral therapy (cART). We investigated the impact of food, beverages, dietary supplements, and alcohol on the... (Meta-Analysis)
Meta-Analysis Review
Multiple factors may affect combined antiretroviral therapy (cART). We investigated the impact of food, beverages, dietary supplements, and alcohol on the pharmacokinetic and pharmacodynamic parameters of 33 antiretroviral drugs. Systematic review in adherence to PRISMA guidelines was performed, with 109 reports of 120 studies included. For each drug, meta-analyses or qualitative analyses were conducted. We have found clinically significant interactions with food for more than half of antiretroviral agents. The following drugs should be taken with or immediately after the meal: tenofovir disoproxil, etravirine, rilpivirine, dolutegravir, elvitegravir, atazanavir, darunavir, lopinavir, nelfinavir, ritonavir, saquinavir. Didanosine, zalcitabine, zidovudine, efavirenz, amprenavir, fosamprenavir, and indinavir should be taken on an empty stomach for maximum patient benefit. Antiretroviral agents not mentioned above can be administered regardless of food. There is insufficient evidence available to make recommendations about consuming juice or alcohol with antiretroviral drugs. Resolving drug-food interactions may contribute to maximized cART effectiveness and safety.
Topics: Humans; HIV Infections; Ritonavir; Ethanol; Anti-Retroviral Agents; Beverages; Dietary Supplements; Anti-HIV Agents
PubMed: 36318429
DOI: 10.1007/s10461-022-03880-6 -
PloS One 2014A network meta-analysis can provide estimates of relative efficacy for treatments not directly studied in head-to-head randomized controlled trials. We estimated the... (Meta-Analysis)
Meta-Analysis Review
48-week efficacy and safety of dolutegravir relative to commonly used third agents in treatment-naive HIV-1-infected patients: a systematic review and network meta-analysis.
BACKGROUND
A network meta-analysis can provide estimates of relative efficacy for treatments not directly studied in head-to-head randomized controlled trials. We estimated the relative efficacy and safety of dolutegravir (DTG) versus third agents currently recommended by guidelines, including ritonavir-boosted atazanavir (ATV/r), ritonavir-boosted darunavir (DRV/r), efavirenz (EFV), cobicistat-boosted elvitegravir (EVG/c), ritonavir-boosted lopinavir (LPV/r), raltegravir (RAL), and rilpivirine (RPV), in treatment-naive HIV-1-infected patients.
METHODS
A systematic review of published literature was conducted to identify phase 3/4 randomized controlled clinical trials (up to August 2013) including at least one third agent of interest in combination with a backbone nucleoside reverse transcriptase inhibitor (NRTI) regimen. Bayesian fixed-effect network meta-analysis models adjusting for the type of nucleoside reverse transcriptase inhibitor backbone (tenofovir disoproxil fumarate/emtricitabine [TDF/FTC] or abacavir/lamivudine [ABC/3TC]) were used to evaluate week 48 efficacy (HIV-RNA suppression to <50 copies/mL and change in CD4+ cells/µL) and safety (lipid changes, adverse events, and discontinuations due to adverse events) of DTG relative to all other treatments. Sensitivity analyses assessing the impact of NRTI treatment adjustment and random-effects models were performed.
RESULTS
Thirty-one studies including 17,000 patients were combined in the analysis. Adjusting for the effect of NRTI backbone, treatment with DTG resulted in significantly higher odds of virologic suppression (HIV RNA<50 copies/mL) and increase in CD4+ cells/µL versus ATV/r, DRV/r, EFV, LPV/r, and RPV. Dolutegravir had better or equivalent changes in total cholesterol, LDL, triglycerides, and lower odds of adverse events and discontinuation due to adverse events compared to all treatments. Random-effects and unadjusted models resulted in similar conclusions.
CONCLUSION
Three clinical trials of DTG have demonstrated comparable or superior efficacy and safety to DRV, RAL, and EFV in HIV-1-infected treatment-naive patients. This network meta-analysis suggests DTG is also favorable or comparable to other commonly used third agents (ATV/r, LPV/r, RPV, and EVG/c).
Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Deoxycytidine; Dideoxynucleosides; Drug Combinations; Emtricitabine; HIV Infections; HIV-1; Heterocyclic Compounds, 3-Ring; Humans; Lamivudine; Lipids; Lopinavir; Nitriles; Organophosphonates; Oxazines; Piperazines; Pyridones; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic; Rilpivirine; Ritonavir; Tenofovir; Time Factors; Treatment Outcome; Viral Load
PubMed: 25188312
DOI: 10.1371/journal.pone.0105653 -
BMC Infectious Diseases Feb 2021The objective of this study was to assess the durability of response of dolutegravir (DTG) as an antiretroviral core agent by comparing its efficacy and safety with...
Comparative efficacy, safety and durability of dolutegravir relative to common core agents in treatment-naïve patients infected with HIV-1: an update on a systematic review and network meta-analysis.
BACKGROUND
The objective of this study was to assess the durability of response of dolutegravir (DTG) as an antiretroviral core agent by comparing its efficacy and safety with other recommended or commonly used core agents up to 96-weeks (W96).
METHODS
A previously published systematic review was updated to identify phase 3/4 randomised controlled trials (RCTs) of core agents in treatment-naïve HIV-1 patients. Efficacy [virologic suppression (VS), CD4 cell change from baseline] and safety [adverse events [AEs], discontinuations, drug-related AEs [DRAEs]] were analysed at W96 using Bayesian network meta-analysis (NMA) adjusting for nucleoside/nucleotide reverse transcriptase inhibitors' (NRTIs') backbone. Subgroups of patients with VL > 100,000 copies/mL or CD4 ≤ 200 cells/μL at baseline were analysed separately.
RESULTS
The NMA included 20 studies reporting data at W96. A higher proportion of patients receiving DTG achieved VS compared to those on protease inhibitors [PI:Range:8.7%(CrI:3.1,16.0)-19.9%(10.8,30.5)], efavirenz [EFV:6.9%(1.3,10.8)] and cobicistat-boosted elvitegravir [EVG/c:8.2%(0.2,17.4)], and similar but numerically higher compared to rilpivirine [RPV:5.0%(- 2.8,12.5)], raltegravir [RAL:2.9%(- 1.6,7.7)] and bictegravir [BIC:2.7%(- 2.7,10.6)]. The probability that more patients on DTG would achieve VS at W96 compared to any other core agent was greater than 80%. A higher proportion of patients on DTG achieved VS compared to PI/rs [Range:33.1%(13.6,50.4)-45.3%(24.1,61.6)] and RAL [16.7%(3.3,31.2)] in patients with VL > 100,000 copies/mL at baseline, and similar VS was achieved in patients with CD4 ≤ 200 cells/μL at baseline. DTG also achieved greater increase in CD4 cells from baseline compared to EFV [32.6(10.7,54.7)], ritonavir-boosted darunavir [DRV/r:25.7(3.6,48.1)] and BIC [24.7(1.5,47.7)]. Patients receiving DTG had lower odds of discontinuing therapy by W96 compared to PI/rs, EFV, RAL and EVG/c. Patients on DTG had lower odds of experiencing an adverse event (AE) compared to patients on EFV [odds ratio:0.6(0.3,0.9)], ATV/r [0.4(0.3,0.6)] and LPV/r [0.3(0.2,0.5)]. For patients on DTG, the odds of experiencing a drug-related AE were lower than the odds for patients on EFV [0.3(0.2,0.4)], comparable to patients on RAL [1.1(0.8,1.4)] and higher than those on BIC [1.5(1.1,2.0)].
CONCLUSION
Un-boosted integrase inhibitors had better efficacy and similar safety compared to PI/rs at W96 in treatment-naïve patients with HIV-1, with DTG being among the most efficacious core agent, particularly in patients with baseline VL > 100,000 copies/mL or ≤ 200 CD4 cells/μL, who can be difficult to treat.
Topics: Adult; Anti-HIV Agents; Female; HIV Infections; HIV Integrase Inhibitors; HIV-1; Heterocyclic Compounds, 3-Ring; Humans; Male; Network Meta-Analysis; Oxazines; Piperazines; Pyridones; Treatment Outcome
PubMed: 33637050
DOI: 10.1186/s12879-021-05850-0 -
Clinical Pharmacokinetics Nov 2014Maternal-to-fetal transfer of antiretroviral drugs contributes to prevention of vertical transmission of HIV. (Review)
Review
BACKGROUND
Maternal-to-fetal transfer of antiretroviral drugs contributes to prevention of vertical transmission of HIV.
OBJECTIVE
This systematic review discusses published studies containing data pertaining to the pharmacokinetics of placental transfer of antiretrovirals in humans, including paired cord and maternal plasma samples collected at the time of delivery as well as ex vivo placental perfusion models.
METHODS
Articles pertaining to placental transfer of antiretrovirals were identified from PubMed, from references of included articles, and from US Department of Health and Human Services Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission guidelines. Articles from non-human animal models or that had no original maternal-to-fetal transfer data were excluded. PRISMA guidelines were followed.
RESULTS
A total of 103 published studies were identified. Data across studies appeared relatively consistent for the nucleoside reverse transcriptase inhibitors (NRTIs) and the non-nucleotide reverse transcriptase inhibitors (NNRTIs), with cord to maternal ratios approaching 1 for many of these agents. The protease inhibitors atazanavir and lopinavir exhibited consistent maternal-to-fetal transfer across studies, although the transfer may be influenced by variations in drug-binding proteins. The protease inhibitors indinavir, nelfinavir, and saquinavir exhibited unreliable placental transport, with cord blood concentrations that were frequently undetectable. Limited data, primarily from case reports, indicate that darunavir and raltegravir provide detectable placental transfer.
CONCLUSION
These findings appear consistent with current guidelines of using two NRTIs plus an NNRTI, atazanavir/ritonavir, or lopinavir/ritonavir to maximize placental transfer as well as to optimally suppress maternal viral load. Darunavir/ritonavir and raltegravir may reasonably serve as second-line agents.
Topics: Animals; Anti-HIV Agents; Female; Fetus; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; Humans; Infectious Disease Transmission, Vertical; Maternal-Fetal Exchange; Placenta; Pregnancy; Pregnancy Complications, Infectious; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ritonavir; United States
PubMed: 25223699
DOI: 10.1007/s40262-014-0185-7 -
EClinicalMedicine Apr 2022The World Health Organization recommends protease inhibitor (PI)-based antiretroviral therapy (ART) as second-line and third-line regimens in pregnant women living with...
BACKGROUND
The World Health Organization recommends protease inhibitor (PI)-based antiretroviral therapy (ART) as second-line and third-line regimens in pregnant women living with HIV (WLHIV). US, European, and UK guidelines include PI-based ART as first-line regimens, but advise against the use of lopinavir/ritonavir (LPV/r)-based ART, citing an increased risk of preterm birth (PTB). We aimed to assess the risk of adverse perinatal outcomes in WLHIV receiving PI-ART and the comparative risks associated with different PI-ART regimens.
METHODS
We conducted a systematic literature review by searching PubMed, CINAHL, Global Health, and EMBASE for studies published between Jan 1, 1980, and April 20, 2020. Two investigators independently selected studies and extracted data from studies reporting on the association of pregnant WLHIV receiving PI-ART with 11 perinatal outcomes: PTB, very PTB (VPTB), spontaneous PTB (sPTB), low birth weight (LBW), very LBW (VLBW), term LBW, preterm LBW, small for gestational age (SGA), very SGA (VSGA), stillbirth, and neonatal death. Pairwise random-effects meta-analyses examined the risk of each adverse perinatal outcome in WLHIV receiving PI-ART compared to non-PI-based ART (non-PI-ART), and comparisons of different PI-ART regimens. Quality assessments of studies were performed, subgroup and sensitivity analyses were conducted based on country income status and study quality, heterogeneity assessed, and the effect of adjustment for confounding factors assessed. The protocol is registered with PROSPERO, CRD42021248987.
FINDINGS
Of 94,594 studies identified, 34 cohort studies including 57,546 women met the inclusion criteria. Random-effects meta-analyses showed that PI-ART was associated with a significantly increased risk of SGA (Relative Risk [RR] 1.24, 95% CI 1.08-1.43; =66.7%) and VSGA (RR 1.40, 1.09-1.81; =0.0%), but not PTB (RR 1.09, 0.95-1.24; =68.3%), VPTB (RR 1.30, 0.78-2.18; =43.0%), sPTB (RR 1.91, 0.61-5.99; =95.7%), LBW (RR 1.04, 0.85-1.27; =63.9%), VLBW (RR 0.72, 0.37-1.43; =37.9%), term LBW (RR 0.94, 0.30-3.02; =0.0%), stillbirth (RR 1.04, 0.60-1.79; =0.0%), and neonatal death (RR 1.82, 0.97-3.40; =0.0%), compared to non-PI-ART. We found no significant differences in perinatal outcomes between ART regimens containing LPV/r, atazanavir/ritonavir (ATV/r), and darunavir/ritonavir (DRV/r), which are the most commonly used PIs.
INTERPRETATION
PI-ART is associated with an increased risk of SGA and VSGA, but not PTB or other perinatal outcomes. No significant differences in perinatal outcomes were found between LPV/r, ATV/r, and DRV/r. These findings should inform clinical guidelines, and further efforts should be made to improve perinatal outcomes among pregnant WLHIV.
FUNDING
None.
PubMed: 35521067
DOI: 10.1016/j.eclinm.2022.101368