Introduction: Extensive use of antiretroviral therapy has remarkably improved the survival rates of people living with HIV. Doravirine (DOR) is a newly-approved antiretroviral belonging to the class of non-nucleoside reverse transcriptase inhibitors. Here, we compared the efficacy and safety of DOR + tenofovir dipivoxil fumarate (TDF)+Lamivudine (3TC)/Emtritabine (FTC) with traditional triple therapies in treatment-naïve HIV-1-positive adults. Methods: Randomized controlled trials involving treatment-naïve HIV-1-positive adults that met inclusion criteria were systematically retrieved and data on the following outcomes extracted: virological suppression, adverse events, severe adverse events, and drug-related adverse events. A Bayesian network meta-analysis was then performed on the data. Results: This study included a total of 39 randomized controlled trials involving 26 antiretroviral therapies and 21,110 HIV1-positive patients. At week 48, relative to the other 25 regimens included in the network of virological suppression, DOR + TDF+3TC/FTC exhibited superiority to some efavirenz, nevirapine, atazanavir, or lopinavir-based regimens, including efavirenz + abacavir+3TC [Odd Ratio (OR) = 0.52, 95% confidence interval (CrI) = 0.35-0.77]. At week 48, the performance of DOR + TDF+3TC/FTC was relatively similar to all other analyzed regimens in terms of adverse events. The DOR + TDF+3TC/FTC regimen performed better in terms of severe adverse events and drug-related adverse events. Conclusion: The network meta-analysis showed that DOR + TDF+3TC/FTC has good efficacy and safety at 48 weeks. Systematic Review Registration: Open Science Framework, https://osf.io/6ybp7.
In this study, we aim to explore the effects on lipids of integrase strand transfer inhibitors (INSTIs) in naïve and switch randomised controlled trials, and compare them with protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). We reviewed phase 3/4 randomised clinical trials in the Cochrane and PubMed databases that compare an INSTI with a boosted PI, an NNRTI, or another INSTI plus one or two nucleoside/nucleotide reverse transcriptase inhibitors (NtRTIs) in naïve patients and switching strategies in HIV-infected patients. We reported the baseline plasma concentration of total cholesterol (TC), low and high-density lipoprotein cholesterol (LDL-c, HDL-c), triglycerides (TG), and the TC/HDL-c ratio, as well as the change at weeks 48 and 96, when available. In naïve HIV-infected patients, raltegravir (RAL) and dolutegravir (DTG) have a more favourable lipid profile compared with NNRTI and boosted PI. Elvitegravir (EVG/c) has a superior lipid profile compared with efavirenz and is similar to that observed with ritonavir-boosted atazanavir except in TG, which increases less with EVG/c. In naïve patients, RAL, DTG, and bictegravir (BIC) produce a similar, slight increase in lipids. In switching trials, the regimen change based on a boosted PI or efavirenz to RAL, DTG, or BIC is associated with clinically significant decreases in lipids that are minor when the change is executed on EVG/c. No changes were observed in lipids by switching trials between INSTIs. In summary, RAL, DTG, and BIC have superior lipid profiles compared with boosted-PI, efavirenz, and EVG/c, in studies conducted in naïve participants, and they are associated with a clinically significant decrease in lipoproteins by switching studies.
Introduction: The extensive utilisation of antiretroviral therapy has greatly improved the survival rates of those infected with human immunodeficiency virus (HIV). The objective of this study was to compare 3-drug regimens containing non-nucleoside reverse transcriptase inhibitor with 3-drug regimens containing integrase inhibitor (INI) regarding efficacy and safety in treatment-naive HIV-1-infected adults at 48 and 96 weeks, respectively. Methods: This study was a network meta-analysis using a Bayesian methodology. On January 8, 2020, we searched databases and other sources for randomized controlled trials conducted in treatment-naive HIV-1 adults and compared multiple 3-drug antiretroviral regimens containing INI, efavirenz (EFV), or rilpivirine (RPV). We extracted data on the following outcomes: virologic suppression, CD4+ cell recovery, discontinuations, deaths, adverse events, serious adverse events, deaths related to study drugs, and drug-related adverse events. We conducted calculations within a Bayesian framework using R software. Results: The network contained 15 randomized controlled trials including 9,745 patients. For efficacy outcomes, regimens containing INI, especially dolutegravir (DTG), were generally superior to other regimens. For virologic suppression at 48 weeks, odds ratios (95% credible intervals) were 0.6 (0.43, 0.82) for EFV+ tenofovir disoproxil fumarate (TDF)+emtricitabine (FTC) versus DTG+ abacavir+ lamivudine (3TC) and 0.52 (0.36, 0.75) for EFV+TDF+FTC vs. DTG+TDF+FTC/3TC. For safety outcomes, regimens containing INI tended to be safer relative to regimens without INI. Outcomes associated with death were unsuitable for network meta-analysis due to low event rates. Conclusion: 3-drug regimens containing INI demonstrate better efficacy and safety than those containing RPV or EFV.
BACKGROUND: We conducted a systematic review and meta-analysis (CRD#42017070552) to quantify the impact of oral TDF/FTC on bone mineral density (BMD), and the risk of osteoporosis, low bone mass, and fractures, among people taking it as PrEP, HIV treatment and hepatitis B (HBV) treatment.
METHODS: We searched MEDLINE and EMBASE for randomized controlled trials published 1997-2018 reporting BMD, osteoporosis, low bone mass, and/or fractures in treatment-naïve patients taking compared to not taking TDF for 48±4 weeks. We pooled outcomes using DerSimonian random-effects models.
RESULTS: Our search yielded 5178 abstracts, representing 3865 articles, with 25 meeting the inclusion criteria. TDF was associated with greater BMD decline when taken as PrEP (lumbar spine: mean difference, MD=-0.82%, 95%CI=-1.28,-0.37%, I2=38%; total hip: MD=-0.81%, 95%CI=-1.22,-0.40%, I2=48%) and HIV treatment (lumbar spine: MD=-1.62%, 95%CI=-2.30,-0.95%, I2=93%; total hip: MD=-1.75%, 95%CI=-2.08,-1.42%, I2=83%; femoral neck: MD=-1.26%, 95%CI=-2.15,-0.38%, I2=43%) in comparison to those not taking TDF. Eight studies reported on incident osteoporosis or low bone mass, with variable results. Pooled results from five PrEP studies showed that TDF was not associated with increased fractures compared to no PrEP (RR=1.12, 95%CI=0.752,1.74, I2=26%).
CONCLUSIONS: TDF caused greater decreases in BMD than did comparators when used for all three indications, and the magnitude of this decrease was larger for HIV treatment compared to PrEP. Fractures were not increased among PrEP patients. The clinically-significant BMD decline caused by TDF and current expansion of PrEP use suggest attention to the adverse bone effects of TDF will increase in importance.
Integrase strand transfer inhibitors (INSTIs) are the most recent class of antiretroviral drugs with potent and durable antiviral activity used to treat human immunodeficiency virus type 1 (HIV-1) infection. However, the development of drug resistance increases the risk of treatment failure, disease progression and mortality. A better understanding of drug efficacy and resistance against INSTIs is crucial for their efficient use and the development of new antiretrovirals. We performed meta-analyses of studies reporting efficacy and resistance data on INSTI use in HIV-infected patients. Odds ratios (ORs) of efficacy outcome data favoring INSTI use in different clinical settings demonstrated that compared with drugs of other classes, INSTIs have higher efficacy. For combination antiretroviral treatment (cART)-naïve patients and viral suppressed patients that switched to INSTI-based therapy, the ORs were 1.484 (95% CI, 1.229-1.790) and 1.341 (95% CI, 0.913-1.971), respectively. ORs of resistance data indicated decreased treatment-emergent resistance development to dolutegravir (DTG) upon virologic failure than to non-INSTIs (OR = 0.081, 95% CI, 0.004-1.849), whereas the opposite was observed for raltegravir (RAL; OR = 3.137, 95% CI, 1.827-5.385) and elvitegravir (EVG; OR = 1.886, 95% CI, 0.569-6.252). Pooled analysis of resistance data indicated that development of resistance to DTG and bictegravir (BIC) was rare, while EVG and RAL had low genetic barriers to resistance and that the intensive cross-resistance between them limits INSTI efficiency. Efficient means of monitoring emergence of resistance to INSTIs and development of drugs with high genetic barriers are clear paths for future research.
BACKGROUND: Numerous randomized clinical trials (RCTs) were conducted to evaluate dolutegravir based triple antiretroviral therapy (ART) compared to other triple antiretroviral regimens in naïve patients, and a summary of the available evidence is required to shed more light on safety and effectiveness issues.
METHODS: Systematic review and meta-analysis of RCTs comparing dolutegravir-containing ART to non-dolutegravir containing ART in HIV-infected naive patients. Primary outcomes: % of patients with viral load<50 copies/mL at 48 weeks, stratified according to baseline viral load levels (< or >100.000 copies/mL); overall rate of discontinuation and/or switching for any cause (virologic failure, clinical failure, adverse events). Measure of treatment effect: Risk Difference (RD) with 95% confidence intervals (CIs). The GRADE system was used to assess the certainty of the body of evidence.
RESULTS: We included 7 RCTs (13 reports, 6407patients) comparing dolutegravir containing to non-dolutegravir containing ART, both in combination with 2 NRTIs. Controls were raltegravir or bictegravir (3 RCTs), boosted atazanavir or darunavir (2 RCTs) or efavirenz (2 RCTs). Rates of patients with VL <50 copies/ml were higher in dolutegravir recipients compared to controls at 48 weeks (RD, 0.05; 95% CIs, 0.03/0.08, p = 0.0002) and 96 weeks (RD, 0.06; 95% CIs, 0.03/0.10, p<0.0001); the average benefit of using dolutegravir was particularly evident at 48 weeks in the subgroup of patients with high baseline viral load (RD, 0.10; 95% CIs, 0.05/0.15; p< 0.0001; GRADE assessment: "high certainty of evidence"). Overall rate of discontinuation were lower in dolutegravir compared to controls (RD,-0.03, 95% CIs -0.05/-0.01; p = 0.007). No significant differences were observed in rates of discontinuation due to adverse events (RD, -0.02; 95% CIs, -0.05/0.00), virologic failure (RD, -0.01; 95% CIs, -0.02/0.01), and most common adverse events (GRADE assessment: from "very-low" to "moderate certainty of evidence").
CONCLUSION: Starting treatment in naive patients with dolutegravir containing ART has an increased likelihood of achieving viral suppression in the comparison with non-dolutegravir containing ART. The average benefit is particularly evident in those with high baseline viral load.
OBJECTIVE: Compare the efficacy and safety of the 2-drug antiretroviral therapy (ART) regimen dolutegravir + lamivudine (DTG+3TC) with traditional 3-drug regimens in treatment-naïve patients with HIV-1.
DESIGN: Data from double-blind, randomized controlled trials (RCTs) of ≥48 weeks' duration in treatment-naïve patients with HIV-1 identified by systematic review were evaluated using a Bayesian network meta-analysis (NMA) methodology.
METHODS: The primary outcome was virologic suppression (VS) at Week 48 for 3-drug regimens versus DTG+3TC (also analyzed in patient subgroup with baseline viral load (VL) > 100,000 RNA copies/mL). Secondary outcomes included CD4+ cell count change from baseline and safety (adverse events [AEs], serious AEs, and drug-related AEs) at Week 48.
RESULTS: The network contains 14 unique regimens from 14 RCTs based on data from 10,043 patients. The proportional difference for viral suppression at 48 weeks for Dolutegravir + Lamivudine (DTG+3TC) versus the other 13 regimens included in the network ranged from -2.7% (-11.0%, 5.6%) vs DTG + tenofovir alafenamide (TAF)/FTC to 7.3% (0.6%, 13.8%) vs efavirenz + tenofovir disoproxil fumarate/emtricitabine (EFV+TDF/FTC). DTG+3TC was found to be significantly better than EFV+TDF/FTC and similar to all other regimens analysed in terms of viral suppression at 48 weeks. With regards to other outcomes (CD4, AE, SAE, DRAE) at 48 weeks, DTG+3TC was broadly similar to all regimens analysed.
CONCLUSIONS: This NMA demonstrates similar efficacy and safety outcomes over 48 weeks with DTG+3TC compared with traditional 3-drug ART regimens.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0.
BACKGROUND: Network meta-analyses (NMAs) provide comparative treatment effects estimates in the absence of head-to-head randomized controlled trials (RCTs). This NMA compared the efficacy and safety of dolutegravir (DTG) with other recommended or commonly used core antiretroviral agents.
METHODS: A systematic review identified phase 3/4 RCTs in treatment-naïve patients with HIV-1 receiving core agents: ritonavir-boosted protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), or integrase strand inhibitors (INSTIs). Efficacy (virologic suppression [VS], CD4+ cell count change from baseline) and safety (adverse events [AEs], discontinuations, discontinuation due to AEs, lipid changes) were analyzed at Week 48 using Bayesian NMA methodology, which allowed calculation of probabilistic results. Subgroup analyses were conducted for VS (baseline viral load [VL] ≤/> 100,000copies/mL, ≤/> 500,000copies/mL; baseline CD4+ ≤/>200cells/μL). Results were adjusted for the nucleoside/nucleotide reverse transcriptase inhibitors (NRTI) combined with the core agent (except subgroup analyses).
RESULTS: The NMA included 36 studies; 2 additional studies were included in subgroup analyses only. Odds of achieving VS with DTG were statistically superior to PIs (odds ratios [ORs] 1.78-2.59) and NNRTIs (ORs 1.51-1.86), and similar but numerically higher than other INSTIs. CD4+ count increase was significantly greater with DTG than PIs (difference: 23.63-31.47 cells/μL) and efavirenz (difference: 34.54 cells/μL), and similar to other core agents. INSTIs were more likely to result in patients achieving VS versus PIs (probability: 76-100%) and NNRTIs (probability: 50-100%), and a greater CD4+ count increase versus PIs (probability: 72-100%) and NNRTIs (probability: 60-100%). DTG was more likely to result in patients achieving VS (probability: 94-100%), and a greater CD4+ count increase (probability: 53-100%) versus other core agents, including INSTIs (probability: 94-97% and 53-93%, respectively). Safety outcomes with DTG were generally similar to other core agents. In patients with baseline VL > 100,000copies/mL or ≤ 200 CD4+cells/μL (18 studies), odds of achieving VS with DTG were superior or similar to other core agents.
CONCLUSION: INSTI core agents had superior efficacy and similar safety to PIs and NNRTIs at Week 48 in treatment-naïve patients with HIV-1, with DTG being among the most efficacious, including in patients with baseline VL > 100,000copies/mL or ≤ 200 CD4+cells/μL, who can be difficult to treat.
Currently, combinations of typical types of antiretroviral agents have been adopted as chemotherapy for human immunodeficiency virus (HIV) infection, comprising two nucleoside analogue reverse transcriptase inhibitors plus one of a non-nucleoside reverse transcriptase inhibitor, an integrase strand-transfer inhibitor, and a protease inhibitor. Although several meta-analyses have been conducted to determine first-line combination antiretroviral therapy, this has yet to be confirmed due to the technical limitation associated. In the present study, we applied a model-based meta-analysis (MBMA) approach, because it allows integration of information from clinical trials with varying dosing, duration, and sampling time points, resulting in enlargement of available data sources. We performed a bibliographic search to identify clinical trials involving dolutegravir (DTG)-based and efavirenz (EFV)-based regimens in HIV-infected, antiretroviral therapy-naïve adults, and then identified 30 independent trial data. The time course of drug effect was described by a consecutive first-order kinetic model and analyzed using the nonlinear mixed effect modeling approach. The developed model suggests that the DTG-based regimen provides a faster-acting and more sustainable drug effect than the EFV-based regimen. Moreover, the drug effect tends to appear more slowly and decay faster in severe patients having higher viral load or smaller baseline CD4 count.
Introduction: Extensive use of antiretroviral therapy has remarkably improved the survival rates of people living with HIV. Doravirine (DOR) is a newly-approved antiretroviral belonging to the class of non-nucleoside reverse transcriptase inhibitors. Here, we compared the efficacy and safety of DOR + tenofovir dipivoxil fumarate (TDF)+Lamivudine (3TC)/Emtritabine (FTC) with traditional triple therapies in treatment-naïve HIV-1-positive adults. Methods: Randomized controlled trials involving treatment-naïve HIV-1-positive adults that met inclusion criteria were systematically retrieved and data on the following outcomes extracted: virological suppression, adverse events, severe adverse events, and drug-related adverse events. A Bayesian network meta-analysis was then performed on the data. Results: This study included a total of 39 randomized controlled trials involving 26 antiretroviral therapies and 21,110 HIV1-positive patients. At week 48, relative to the other 25 regimens included in the network of virological suppression, DOR + TDF+3TC/FTC exhibited superiority to some efavirenz, nevirapine, atazanavir, or lopinavir-based regimens, including efavirenz + abacavir+3TC [Odd Ratio (OR) = 0.52, 95% confidence interval (CrI) = 0.35-0.77]. At week 48, the performance of DOR + TDF+3TC/FTC was relatively similar to all other analyzed regimens in terms of adverse events. The DOR + TDF+3TC/FTC regimen performed better in terms of severe adverse events and drug-related adverse events. Conclusion: The network meta-analysis showed that DOR + TDF+3TC/FTC has good efficacy and safety at 48 weeks. Systematic Review Registration: Open Science Framework, https://osf.io/6ybp7.
