Dolutegravir based antiretroviral therapy compared to other combined antiretroviral regimens for the treatment of HIV-infected naive patients: A systematic review and meta-analysis.

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.

Introduction

The advent of antiretroviral therapy (ART) has made human immunodeficiency virus (HIV) infection a chronic manageable disease for many patients [1]. Individuals taking ART have now a wide range of therapeutic options and good prospects for long term survival. The current standard of care for HIV treatment is a three-drug regimen containing a nonnucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI), or an integrase strand transfer inhibitor (INSTI) plus two nucleoside/tide reverse transcriptase inhibitors (NRTIs), usually abacavir/lamivudine (ABC/3TC) or either tenofovir alafenamide/emtricitabine (TAF/FTC) or tenofovir disoproxil fumarate (TDF/FTC) [2]. Despite the undeniable success of antiretroviral therapy, limitations to safety and efficacy still persist. Moreover, in patients with baseline viral loads of greater than 100,000 copies/mL a slower rate of achieving viral suppression has been observed [2, 3].

Due to their favorable side effect profile, limited drug-drug interactions, and virologic potency, INSTI-based regimens are now among the recommended and preferred first-line ART for the treatment of HIV-1 infection in ART-naïve patients (a person with HIV who has never taken ART). Dolutegravir is a new-generation INSTI with distinct advantages compared with other available antiretroviral agents [4-7]. On the basis of data from in vitro studies and clinical trials in ART-naive patients, it is anticipated that, like dolutegravir, bictegravir has a high barrier to resistance. However, clinical data and experience with bictegravir are relatively limited at this time [2].

To assess the efficacy and safety of the combined ARTcontaining dolutegravir relative to other ART regimens not containing dolutegravir in naïve patients, we have conducted a systematic review and meta-analysis

Material and methods

This review has been conducted according to the PRISMA statement for the reporting of systematic reviews and meta-analyses [8]. A protocol has been registered in PROSPERO, the prospective register of systematic reviews (Available from: http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018104938).

Search

The PubMed/MEDLINE, Embase, and Cochrane databases were systematically searched (up to April 2019) to identify randomized controlled trials (RCTs) evaluating efficacy and/or safety of DTG, EVG/c, RAL,BIC, ATV/r, DRV/r, EFV or RPV in treatment-naive HIV-1 patients. PubMed and EMBASE search terms were ‘‘HIV-1 [mesh] OR HIV infections [mesh] AND ((dolutegravir OR GSK1349572) OR (efavirenz OR Sustiva OR Stocrin OR DMP-266) OR (raltegravir OR Isentress OR MK-0518) OR (elvitegravir OR GS-9137 OR JTK-303) OR (bictegravir OR GS-9883) OR (rilpivirine OR Edurant OR TMC 278) OR (darunavir OR Prezista OR TMC-114) OR (atazanavir OR Reyataz OR BMS-232632) OR (Atripla OR Quad OR Stribild OR Eviplera OR Complera))

We also searched reference lists of identified studies and major reviews, abstracts of conference proceedings, scientific meetings and clinical trials registries(www.clinicaltrials.gov).

Types of study included

Randomized clinical trials (RCTs) conducted in adults HIV-infected naïve patients (> 18 years old) comparing antiretroviral regimen containing dolutegravir plus two NRTIs to regimens not containing dolutegravir (eg, NNRTI, PI, or other INSTI plus two NRTIs).

Virologic outcome: rates of patients with viral load (VL) below 50 copies/ml at 48 weeks and/or at 96 weeks

Overall rate of discontinuation and/or switching for any cause (virologic failure, clinical failure, adverse events).

Rate of patients with any adverse event.

Rates of adverse events requiring treatment interruption and/or switching.

Occurrence of AIDS-defining illness

Death (all cause)

Change from baseline in CD4 count

Data extraction

The two authors independently extracted data from the selected trials using standardized data extraction form. Agreement on the final assessment for each criterion was achieved by discussion. The following data were extracted: details of participants (number, setting, baseline characteristics by group), details of the study (study design; type and duration of follow up), details of ART regimen used, primary and secondary outcome descriptions and outcomes measures, number of withdrawals in each group with reasons. Data at 48 and 96 weeks were considered.

Assessment of risk of bias and heterogeneity

We explored clinical heterogeneity (eg study setting, characteristics of participants) and assessed statistical heterogeneity using Tau2, Cochran’s Q and estimated this using the I2 statistic, which examines the percentage of total variation across studies that is due to heterogeneity rather than to chance (I2 ≤25 suggest low heterogeneity; I2 >50, high heterogeneity) [9]. The risk of bias of each included study is assessed following the domain-based evaluation described in the Cochrane Handbook for Systematic Reviews of Interventions [10]. The Cochrane ‘Risk of bias’ tool addresses six specific domains: sequence generation, allocation concealment, blinding, incomplete data, selective outcome reporting, and other issues relating to bias. We have presented our assessment of risk of bias using two ‘Risk of bias’ summary figures: 1) a summary of bias for each item across all studies; and 2) a cross-tabulation of each trial by all of the ‘Risk of bias’ item.

We used the principles of the GRADE (The Grading of Recommendations Assessment, Development and Evaluation) system to assess the quality of the body of evidence associated with specific outcomes, and constructed a ‘Summary of findings’ table using the software Review Manager, version 5.3 (available at https://community.cochrane.org/help/tools-and-software/revman-5/revman-5-download). The certainty of a body of evidence involves consideration of within-trial risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates, and risk of publication bias. To inspect for publication bias visually we generated graphical funnel plots [10, 11].

Strategy for data synthesis

We used aggregate data. The analysis was conducted on an "intention to treat" approach. Quantitative synthesis was used if the included studies were sufficiently homogenous.

When I values were = 0, studies were pooled using a fixed-effect model. Where values of I are greater than zero, both fixed and random effects analyses were performed and any differences in estimates of treatment effect considered. The fixed effect model was also considered as a sensitivity analysis for evaluating the possible bias effects of smaller studies. Potential sources of heterogeneity were explored by pre-specified subgroup analysis. We used risk difference as measure of effect. Review Manager 5.3 was used to analyze the data.

Analysis of subgroups or subsets

We anticipated clinical heterogeneity in the effect of the intervention and we conducted, where possible, the following sub-group analyses:

Virologic efficacy of dolutegravir and comparators analyzed according to baseline VL (eg, < 100,000 copies/ml or >100,000 copies/ml)

Efficacy and safety data of dolutegravir analyzed according to the control intervention (eg, vs PI, vs NNRTI, or vs other INSTI).

When sufficient trials were identified, we conducted a sensitivity analysis comparing the results using all trials as follow:

those RCTs with high methodological quality (studies classified as having a 'low risk of bias' versus those identified as having a 'high risk of bias');

Those RCTs that performed intention-to treat versus per-protocol analyses.

Results

Electronic searches yielded 842 potentially relevant studies (Fig 1). 779 articles were excluded after preliminary screen and 63 were deemed potentially eligible and the full-text assessed.

Fig 1

Study flow diagram.

Twenty-five studies were then excluded because they were not randomized. Of the 34 RCTs, 13 reports (corresponding to 7 studies) comparing dolutegravir-containing regimens to non-dolutegravir-containing regimens were conducted in naïve patients and were included in the qualitative and quantitative synthesis [12-24]. The main features of the included studies are summarized in Table 1. Controls were INSTI (raltegravir or bictegravir, 3 studies, 6 reports) [14, 15, 18, 21, 23, 24], boosted PI (atazanavir or darunavir, 2 studies, 3 reports)[12, 13, 19] or NNRTI (efavirenz, 2 RCTs, 4 reports) [16, 17, 20, 22].

Table 1

Main characteristic of included studies.

Study name	Methods	Interventions	Outcomes data extracted	Notes
ARIA [12]	Multicenter, RCT, open-label, non-inferiority phase 3b study	DTG+ ABC and 3TC OD or ATV/r + coformulated TDF and FTC, OD	HIV-1 RNA <50 cps/mL at week 48. Adverse events, adverse events requiring discontinuation, overall rate of discontinuation. Virologic failure. Death	ITT analysis according to the FDA snapshot algorithm.
FLAMINGO [13. 19]	Multicenter, RCT, open-label, non-inferiority phase 3b study	DTG or DRV/r, with TDF/FTC or ABC/3TC, OD.	HIV-1 RNA <50 cps/mL at week 48 and 96. Adverse events, adverse events requiring discontinuation, overall rate of discontinuation. Virologic failure. Death	ITT analysis according to the FDA snapshot algorithmData at 96 wks reported in a separate report19
GS 1489 [14, 24]	double-blind, multicenter, RCT non-inferiority trial	BIC + FTC and TAF, or coformulated DTG/ABC/3TC with matching placebo, OD for 144 weeks.	HIV-1 RNA <50 cps/mL at week 48 and 96. Adverse events, adverse events requiring discontinuation, overall rate of discontinuation. Virologic failure. Death	ITT analysis according to the FDA snapshot algorithm
GS 1490 [15, 23]	double-blind, multicenter, RCT non-inferiority trial	BIC + FTC and TAF, or DTG+ FTC and TAF, with matching placebo, OD for 144 weeks.	HIV-1 RNA <50 cps/mL at week 48 and 96. Adverse events, adverse events requiring discontinuation, overall rate of discontinuation. Virologic failure. Death	ITT analysis according to the FDA snapshot algorithm
SINGLE [16, 22]	Double-blind, RCT, phase 3 trial	DTG + ABC and 3TC or combination therapy with EFV/TDF/FTC	HIV-1 RNA <50 cps/mL at wks 48 and 96/144. Adverse events, adverse events requiring discontinuation, overall rate of discontinuation. Virologic failure. Death	ITT analysis according to the FDA snapshot algorithm. Data at 96 and 144 wks reported in a separate report22
SPRING-1 [17, 20]	RCT, dose ranging, phase 2 study	DTG 10, 25 or 50 mg or 600 mg efavirenz, with either TDF/FTC or ABC/3TC	HIV RNA <50 cps at wks 48 and 96. Adverse events, adverse events requiring discontinuation, overall rate of discontinuation. Virologic failure	ITT analysis using the FDA TLOVR approach. Dose but not drug allocation was masked. Data at 96 wks reported in a separate report.20
SPRING-2 [18, 2]	Double-blind, RCT, phase 3 study	DTG or RTG 400 bid + coformulated TDF/FTC or ABC/3TC	HIV RNA <50 cps at wks 48 and 96. Adverse events, adverse events requiring discontinuation, overall rate of discontinuation. Virologic failure. Death	ITT analysis according to the FDA snapshot algorithm Data at 96 wks reported in a separate report.21

Risk of bias in selected studies

Summary graphs of methodological quality items are presented in Figs 2 and 3. All the included studies were judged at low risk of selection, attrition and reporting bias. Three of the included studies were open-label, and we judged this domain as "high risk" of bias for these studies (ARIA, Flamingo, SPRING-1) [12, 13, 17, 19, 20]; however, masking probably has limited importance for more objective outcomes (as the virologic outcomes), because the risk of ascertainment bias is limited. We made a judgment of "low risk of bias" for the remaining studies defined as double-blind. We judged the masking of outcome assessor to treatment allocation at "low risk" of bias for 4 studies in which the assessment was performed by someone not involved in the study (GS 1489, GS1490, SINGLE, SPRING-2) [14–16, 18, 21–24], and at unclear risk of bias for the remaining 3 studies where it was unclear if adequate measures were taken to ensure that the assessors were unaware of treatment allocation. Although all the included studies were sponsored by pharmaceutical companies, our evaluation showed that they were of high methodological quality and also excluded the presence of other biases that cannot be explained by standard ‘Risk of bias’ assessments (eg, deficiencies in the definition of patient-relevant endpoints, selection of suitable substances for the control arm, evidence of publication bias); moreover, the protocol of these studies were registered on international registers of clinical trials (clinicalTrials.gov) and results publicly available. Therefore we made a judgment of “low risk of bias” for the domain “other bias.

Fig 2

Risk of bias graph: Review authors’ judgment about each risk of bias item presented as percentage across all included studies.

Fig 3

Risk of bias summary: Review authors’ judgment about each risk of bias item for each included included study.

Funnel plots were not performed because when the number of studies is small (e.g., <10) the plot may not detect publication. [10]

Effects of interventions

Table 2 summarizes the pooled outcome data and grade assessment for the outcomes in overall analyses and subgroup analyses. We evaluated virologic outcomes, overall rate of discontinuation and/or switching for any cause, adverse events requiring discontinuation of treatment, occurrence of any adverse events, most common adverse events, virologic failure, and death. No AIDS defining conditions were reported across the studies.

Table 2

Summary of the pooled outcome data.

Results are provided for all possible comparisons, and for subgroups analyses.

Outcome or subgroup	Studies (no. pts)	No. with event /Total no. pts: DTG & control	Effect Estimate (RD and 95% CI)	P value	Grades of evidence
VL <50 cps/ml, 48 wks
DTG vs all comparators	7(4113)	1880/2110 & 1679/2003	0.05 (0.03/0.08)	0.0002	High
- High baseline VL	7 (1019)	440/515 & 382/504	0.10 (0.05/0.15)	<0.0001	High
- Low baseline VL	7 (3094)	1441/1595 & 1297/1499	0.03 (0.01/0.06)	0.01	High
DTG vs INTI	3(2096)	958/1051 & 924/1045	0.03 (0.00/0.05)	0.04	High
-High baseline VL	3(453)	190/218 & 188/235	0.08 (0.01/0.14)	0.03	High
- Low baseline VL	3(1643)	768/833 & 736/810	0.01 (-0.01/0.04)	0.33	Moderate*
DTG vs PI	2 (979)	420/490 & 376/489	0.11 (0.02/0.20)	0.02	High
-High baseline VL	2 (257)	112/130 & 85/127	0.20 (0.10/0.30)	<0.0001	High
-Low baseline VL	2 (722)	308/360 & 291/362	0.05 (-0.02/0.12)	0.19	Moderate*
DTG vs NNRTI (efavirenz)	2 (1038)	503/569 & 379/469	0.07 (0.03/0.12)	0.001	High
-High baseline VL	2 (247)	138/167 & 109/142	0.06 (-0.03/0.15)	0.21	Moderate*
-Low baseline VL	2 (729)	365/402 & 270/327	0.08 (0.03/0.13)	0.002	High
VL <50 cps/ml, 96 wks
DTG vs all comparators	6(3624)	1559/1862 & 1357/1762	0.06 (0.03/0.10)	0.0001	Moderate**
VL <50 cps/ml, 48 wks, per protocol analysis
DTG vs all comparators	6(3689)	1717/1853 & 1615/1836	0.04 (-0.00/0.09)	0.06	Low***
VL <50 cps/ml, 48 wks, according to baseline CD4 count (</> 200 cells/ml)
<200 CD4	6 (530)	221/265 & 207/265	0.06 (0.00/0.11)	0.05	Moderate*
>200 CD4	6 (3478)	1515/1690 & 1434/1688	0.04 (0.01/0.07)	0.009	Moderate**
VL <50 cps/ml, 48 wks, according to NRTI backbone
DTG vs controls, ABC/3TC as backbone	3 (652)	255/310 & 288/360	-0.1 (-0.06/0.05	0.82	Moderate*
DTG vs controls, TDF/FTC as backbone	3 (869)	446/509 & 299/360	0.05 (0.00/0.10	0.04	High
DTG combined to ABC/3TC	3 (310)	255/310	-0.06/0.00	0.06	Moderate*
DTG combined to TDF/FTC	3 (509)	446/509
Overall rate of discontinuation
DTG vs all comparators	7 (4118)	188/2111 & 257/2007	-0.03 (-0.05/-0.01)	0.0007	High
Adverse events requiring discontinuation
DTG vs all comparators	7 (4117)	40/2111 & 85/2006	-0.02 (-0.05/0.00)	0.10	Low**
Any Adverse Events
All studies	7 (4117	1273/2111 & 1221/2006	-0.01 (-0.07/0.06	0.84	Very Low§
Double blind studies only	4 (2301)	615/1205 & 508/1096	0.03 (-0.06/0.12)	0.46	Low***
Most common adverse events
-Nausea
All studies	7 (4113)	250/2110 & 190/2003	0.03 (-0.01/0.06(	0.19	Very Low§
Double blind studies only	4 (2301)	179/1206 & 113/1095	0.05 (-0.00/0.11)	0.07	Very Low§
-Diarrhoea
All studies	7 (4122)	225/2110 & 246/2012	-0.01 (-0.04/0.02)	0.46	Low***
Double blind studies only	4 (2310)	139/1206 & 127/1104	0.00 (-0.02/0.03)	0.72	Moderate*
-Insomnia
All studies	7 (3933)	103/1930 & 91/2003	0.01 (-0.01/0.03)	0.46	Very Low §
Double blind studies only	4 (2121)	58/1026 & 51/1095	0.01 (-0.03/0.06)	0.61	Low***
-Psychiatric disorders
All studies	4 (2629)	114/1315 & 115/1314	-0.00 (-0.04/0.04	0.95	Very Low§
Double blind studies only	1 (822)	34/411 & 33/411	0.00 (-0.03/0.04)	0.90	Low***
Virologic failure (Protocol-defined)	7 (4119)	53/2115 & 68/2004	-0.01 (-0.02/0.01)	0.39	Low**
Death	7 (4117)	5/2111 & 5/2006	-0.00 (-0.00/0.00)	0.81	Low§§

Notes:

Abbreviations: DTG, dolutegravir; ABC, abacavir;: 3TC, lamivudine; FTC, emtricitabine; TDF, tenofovir disoproxil fumarate; NNRI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor, INTI, integrase strand transfer inhibitor; cps, copies; VL, Viral Load; wks, weeks

*Downgraded once for imprecision (95% CI includes line of no effect)

** Downgraded once for heterogeneity

*** Downgraded twice for imprecision and heterogeneity

§ Downgraded for imprecision, heterogeneity and risk of bias (performance and detection bias) in open label studies

§§ downgraded for imprecision and indirectness

Virologic outcomes

For most of the virologic outcomes, the GRADE assessment showed high quality of evidence (Tables 2 and 3).Rates of patients with VL <50 copies/ml at 48 weeks were higher in dolutegravir group compared to the alternative agents in the overall comparison (RD, 0.05; 95% CIs, 0.03/0.08, p = 0.0002), in the subgroups of patients with high baseline VL (RD, 0.10; 95% CIs, 0.05/0.15; p< 0.0001), and in the subgroup of patients with low baseline VL (RD, 0.03; 95% CIs, 0.01/0.06; p< 0.01) (Fig 4, Tables 2 and 3).

Table 3

Summary of findings table.

ART with DTG compared with ART with other core agents for HIV-1 infected naive patients.

Patient or population: treatment-naive patients with HIV infectionSettings: outpatientsIntervention: DTG in combination with 2 NRTIComparison: PI (boosted DRV, ATV), or NNRTI (EFV), or INSTI (RAL, BIC) in combination with 2 NRTI
Outcomes	Illustrative comparative risks * (95% CI)		Relative effect:(95% CI)	No of Participants(studies)	Quality of the evidence(GRADE)**	Comments
	Assumed risk	Corresponding risk
	CONTROLS (ALL)	DTG
Virologic Outcomes: % pts with VL <50 cps/ml at 48 wks
all pts, regardless to baseline VL	83.8% (1679/2003)	89.2% (86.3–90.5%)	RD, 0.05 (0.03/0.08)	4113 (7)	⊕⊕⊕⊕ high ***	Starting treatment with DTG containing ART has an increased likelihood of achieving VL <50 cps/ml at 48 wks compared to the alternative treatments
baseline VL >100.000 cps/ml	75.7% (382/504)	83.2% (79.4–87.0%)	RD, 0.10 (0.05/0.15)	1019 (7)	⊕⊕⊕⊕ high	The average benefit is particularly evident in those with high baseline VL (+10%, CIs +5/+15%)
baseline VL <100.000 cps/ml	86.5% (1297/1499)	89.0% (87.3–91.7%)	RD, 0.03 (0.01/0.06)	3094 (7)	⊕⊕⊕⊕ high	The benefit includes also pts with low screening VL
	INSTI (BIC, RAL)	DTG
all pts, regardless to baseline VL	88.4% (924/1045)	91.0% (88.4–92.8%)	RD 0.03 (0.00/0.05)	2096 (3)	⊕⊕⊕⊕ high	Starting treatment with DTG containing ART has an increased likelihood of achieving VL <50 cps/ml at 48 wks compared to other INSTI
baseline VL >100.000 cps/ml	80.0%(188/235)	86.4% (80.8/91.2%)	RD 0.08 (0.01/0.14)	453 (3)	⊕⊕⊕⊕ high	The average benefit is particularly evident in those with high baseline VL (+8%, CIs +1/+14)
baseline VL <100.000 cps/ml	90.8% (736/810)	91.7% (89.9–94.4%)	RD 0.01 (-0.01/0.04)	1643 (3)	⊕⊕⊕⊝§ moderate	On average, it is unclear whether or not use of DTG compared to other INSTI increases rates of pts with undetectable VL.
	NNRTI (EFV)	DTG
all pts, regardless to baseline VL	80.8% (379/469)	86.4% (83.2–90.4%)	RD 0.07 (0.03/0.12)	1038 (2)	⊕⊕⊕⊕ high	starting treatment with DTG containing ART has an increased likelihood of achieving VL <50 cps/ml at 48 wks compared to EFV
baseline VL >100.000 cps/ml	76.7% (109/142)	81.3% (74.4/88.2%)	RD 0.06 (-0.03/0.15)	247 (2)	⊕⊕⊕⊝§ moderate	On average, it is unclear whether or not use of DTG compared to EFV increases rates of pts with undetectable VL in subgroup of pts with high baseline VL
baseline VL <100.000 cps/ml	82.5% 8270/327)	89.1 (84.9–93.2%)	RD 0.08 (0.03/0.13)	729 (2)	⊕⊕⊕⊕ high	starting treatment with DTG containing ART has an increased likelihood of achieving VL <50 cps/ml compared to EFV in subgroup of pts with low baseline VL
	PI (DRV, ATV)	DTG
all pts, regardless to baseline VL	76.8% (376/489)	85.2% (78.3–92.1%)	RD 0.11 (0.02/0.20)	979 (2)	⊕⊕⊕⊕ high	starting treatment with DTG containing ART has an increased likelihood of achieving VL <50 cps/ml at 48 wks compared to PI
baseline VL >100.000 cps/ml	66.9% (85/127)	77.2% (73.5–86.9)	RD 0.20 (0.10/0.30)	257 (2)	⊕⊕⊕⊕ high	The average benefit is particularly evident in those with high baseline VL (+20%, 95 CIs +10/+30)
baseline VL <100.000 cps/m	80.3% (291/362)	84.3% (78.7/89.9%)	RD 0.05 (-0.02/0.12)	722 (2)	⊕⊕⊕⊝§ moderate	On average, it is unclear whether or not use of DTG compared to PIs increases rates of pts with undetectable VL in subgroup of pts with low baseline VL
Overall rate of discontinuation of treatment in DTG recipients and controls (INSTI, PI, EFV) at 48 wks.
All pts.	12.8% (257/2007)	9.8% (7.8/11.8%)	RD -0.03 (-0.05/-0.01)	4118 (7)	⊕⊕⊕⊕ high	Rates of interruption of treatment for any reason (virologic failure, clinical failure, adverse events) were significantly lower in DTG recipients compared to controls

Footnotes:

*The assumed risk is the mean control group risk of having VL <50 cps/ml at 48 wks across studies; the corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

** GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect.

Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Very low quality: We are very uncertain about the estimate.

***Despite the fact that 3 of the included studies were judged at high risk of performance bias (open label), we judged this as high-certainty evidence because masking has limited importance for the virologic outcomes, because the risk of ascertainment bias is limited.

§ Downgraded once for imprecision (95%CI includes line of no effect)

Abbreviations: pts, patients; VL, viral load; cps, copies; wks, weeks; PI, protease inhibitors; INSTI, integrase strand transfer inhibitors; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; EFV, efavirenz; DTG, dolutegravir; BIC, bictegravir; RAL, raltegravir; DRV, darunavir; ATV, atazanavir. CI, Confidence interval; RD, Risk Difference.

Fig 4

Forest plot of comparison.

Doultegravir vs comparators, outcome: VL<50 copies at 48 weeks.

The results of subgroups analyses according to comparators (other INSTI, PI, efavirenz) are summarized in Table 2 and supplemental Figs 1–4 (S1–S4 Figs). Of note, in the comparison with efavirenz, the effect size was mostly driven mostly by one of the included studies.[16]

At 96 weeks (Table 2, S5 Fig), data from 6 reports (2 versus efavirenz, one versus darunavir, 2 versus bictegravir and one versus raltegravir) show that, compared to controls, an higher proportions of dolutegravir recipients had undetectable viremia (RD 0.06; 95% CI, 0.03/0.10) [19-24].

Analyses according to baseline CD4 values show a significant higher proportions of undetectability in dolutegravir compared to controls in the subgroup of patients with baseline CD4 levels >200 cells/mmc (RD 0.04; 95% CI, 0.01/0.07); in the subgroup of patients with <200 cells/mmc at baseline there was still a higher proportions of undetectability, of borderline significance (RD 0.06; 95% CI, 0.00/0.11; p = 0.05), in dolutegravir compared to controls, (Table 2, S6 Fig). Virologic outcomes from 3 studies reporting results according to the NRTI backbone used are summarized on Table 2 [13, 17, 18].

Protocol- defined virologic failure (generally defined as two consecutive HIV-1 RNA values of at least 50 copies/mL) occurred rarely both in dolutegravir and controls groups (2.5 and 3.3%, respectively) (Table 2). No geno-phenotypic mutation were recorded among dolutegravir recipients; in the control groups, few NNRTI and/or NRTI mutations were recorded in 3 studies [12, 16, 18]. Notably, in the SPRING-2 study one patient in the raltegravir group with baseline plasma HIV-1 RNA of more than 3 million copies/ mL developed both integrase-resistant and NRTI-resistant mutations; phenotype resistance at virologic failure showed a raltegravir fold-change of 34 and a dolutegravir fold-change of 2 [18].

Other outcomes

Overall rate of discontinuation and/or switching for any cause (virologic failure, clinical failure, adverse events) was lower in dolutegravir recipients compared to controls (RD, -0.03, 95% Cis, -0.05/-0.01; p = 0.0007; “high certainty of evidence) (Fig 5, Tables 2 and 3). The occurrence of any adverse events and of adverse events requiring discontinuation of treatment was not significantly different in dolutegravir compared to controls (p = 0.84 and p = 0.10, respectively). Most common adverse events related to study treatment were nausea, diarrhea, insomnia and psychiatric disorders, not significantly different between dolutegravir recipients and controls, both in the whole analyses and in subgroup analyses of double blind studies (Table 2, S7 Fig). The certainty of evidence for adverse events outcomes was low or very low in the majority of comparisons (downgraded for imprecision, heterogeneity and/or performance and detection bias).

Fig 5

Forest plot of comparison.

Dolutegravir vs comparators, outcome: Overall rate of discontinuation.

Discussion

For the treatment of HIV infected naive patients current guidelines endorse an ARV regimen generally consisting of two NRTI administered in combination with a third active ARV drug from one of three drug classes: INSTI, NNRTI, or boosted PI [2, 25]. For most patients, initial therapy should be with two NRTIs combined with an INSTI; in some individuals, a combination of an NNRTI or boosted PI should be considered. Basing on recent guidelines for the use of antiretroviral agents in adults and adolescents with HIV, “the choice between an INSTI, PI, or NNRTI as the third drug in an initial ARV regimen should be guided by the regimen’s efficacy, barrier to resistance, adverse effects profile, convenience, comorbidities, concomitant medications, and the potential for drug-drug interactions” [2]. Dolutegravir in combination with NRTIs is one of the recommended regimens in antiretroviral therapy-naïve patients, but others INSTI, such as raltegravir and, more recently, bictegravir, can be considered [2, 25]. In clinical trials, these INSTI-containing regimens were highly effective and have relatively infrequent adverse effects and few drug interactions. In several head-to-head comparisons between boosted PI-containing regimens and INSTI-containing regimens, the INSTI was better tolerated and caused fewer treatment discontinuations [13, 26]. On the basis of data from in vitro studies and clinical trials in ART-naive patients, it is anticipated that, like dolutegravir, bictegravir has a high barrier to resistance. However, clinical data and experience with bictegravir are relatively limited right now [2]. Although the success of ART is beyond question, several issues related to safety and efficacy still persist. Pre-treatment viral load level is an important factor in the selection of an initial antiretroviral regimen because several antiretroviral drug regimens have been associated with poorer responses and slower rate of achieving viral suppression in patients with high baseline VL [2, 3]..

Numerous RCTs were conducted to evaluate dolutegravir containing ART compared to other ART regimens in naïve patients, and these have been the objectives of systematic reviews [7, 27–30]. Since then, however, new evidence is accumulating, and a new review is required to shed more light on safety and effectiveness issues related to ART regimens containing or not dolutegravir.

In this systematic review we have included seven primary studies, corresponding to 13 reports, evaluating the efficacy and safety of ART regimens containing dolutegravir or others core agents (PIs, NNRTI or other INSTI), both in combination with a dual nucleoside backbone (TDF/FTC, TAF/FTC or ABC/3TC) in naïve patients. Bias assessment using Cochrane methodology showed that the studies analyzed had few methodological limitations. Only four of the seven included studies were blind. However, the primary outcome of the analysis and its measurement (viral load) is not likely to be influenced by lack of blinding; on the other hand, blinding could have been important for assessment of subjective outcomes such as adverse events.

The primary endpoint of the included studies was the proportion of patients with HIV-1 RNA concentration lower than 50 copies/ ml. Our systematic review and meta-analysis demonstrate convincing evidence that starting ART with dolutegravir in naïve patients has important clinical implications. Actually, we observe an increased likelihood (+5%; 95% CIs, +3/+8%) of achieving VL<50 copies/ml at 48 weeks compared to the alternative agents (boosted atazanavir or darunavir, efavirenz, raltegravir or bictegravir). The average benefit is particularly evident (+10%; 95%CIs, +5%/+15%) in the subgroup of patients with high baseline VL: in this subgroup of patients the superior activity of dolutegravir is consistent for the comparison with other INSTI (+8%; 95% CIs, +1/+14%) and with boosted PIs (+20%; 95% CIs, +10/+30%). Basing on GRADE assessment, all these comparisons were graded as "high certainty of evidence". An assessment of high-certainty evidence means that further research is very unlikely to change our confidence in the estimates of the effect. At 96 weeks dolutegravir recipients still had higher proportion of undetectable viremia (+ 6%; 95% CIs, +3/+10%) compared to controls (efavirenz, darunavir, bictegravir or raltegravir) (moderate certainty of evidence due to heterogeneity).Overall rate of discontinuation and/or switching for any cause (virologic failure, clinical failure, adverse events) at 48 weeks were lower in dolutegravir group compared to controls (-3%; 95% CIs, -5/-1%) (high certainty of evidence).

Data on adverse events (any adverse events, adverse events requiring discontinuation, most common adverse events) produced low or very low certainty evidence, due to imprecision, heterogeneity and/or risk of bias in open label studies. An assessment of low-certainty evidence means that our confidence in the effect estimate is limited, and the true effect may be substantially different from the estimate of the effect. There were no statistically significant differences in the occurrence of any adverse events, adverse events requiring discontinuation and most common adverse events in dolutegravir group compared to controls, in the overall analysis and in the analysis of double-blind studies only. Most common adverse events reported in both groups were nausea, diarrhea, insomnia and psychiatric disorders.

Protocol- defined virologic failure occurred rarely both in dolutegravir and controls groups. Notably, in trials included in the current review no geno-phenotypic mutations and mutations that confer dolutegravir resistance have been recorded, which suggests that dolutegravir, like bictegravir, has a higher barrier to resistance than raltegravir and elvitegravir. Resistance to dolutegravir and bictegravir has not been reported in clinical trials when these drugs are used as part of initial triple-drug ART, and only rarely in treatment-experienced patients receiving a dolutegravir-containing regimen [13, 15, 16, 18, 31–33]. Combinations of INSTI resistance mutations selected by prolonged exposure to raltegravir or elvitegravir in the setting of treatment failure can, however, result in cross-resistance to dolutegravir and bictegravir [34-36].

In all the included studies, the experimental intervention was compared to an established standard-of-care treatment, as endorsed by current guidelines. Dolutegravir and comparators were administered with fixed-dose combination of TDF/FTC, or TAF/FTC, or ABC/3TC Screening for hypersensitivity reaction was performed in all the studies included in the current review, with the exception of one study where TAF/FTC was the only NRTI combination administered [15].

The strenghts of the current systematic review is that it address timely and relevant clinical question, such as that related to the virologic efficacy of ART regimens in naïve patients according to baseline VL levels, and includes studies which were not included in previously published reviews and meta analyses. The limitation is that health outcome measures of quality of life were rarely reported in the included studies, and we could not assess treatment satisfaction.

In summary, we found high quality evidence related to the higher virologic efficacy of dolutegravir-containing ART compared to other non-dolutegravir containing ART in naïve patients. For other outcomes such as occurrence of adverse events the available evidence is not conclusive. Although the randomized clinical trial setting would provide the least biased approach to assessing outcomes, blinded outcome assessment is crucial for outcomes such as adverse events, which are inherently subjective. Not all the included studies were blinded, so the risk of detection or observer bias cannot be excluded.

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 VL (eg, >100,000 copies/ml), and it is consistent in trials comparing dolutegravir to other INSTI or to boosted PIs.

PRISMA 2009 checklist.

(PDF)

Click here for additional data file.

Forest plot of comparison: DTG vs INTI, outcome: VL<50 copies/ml at 48 wks.

(EPS)

Click here for additional data file.

Forest plot of comparison: DTG vs PI, outcome: VL <50 copies/ml at 48 wks.

(EPS)

Click here for additional data file.

Forest plot of comparison: DTG vs BIC, outcome: VL < 50copies/ml at 48 wks.

(EPS)

Click here for additional data file.

Forest plot of comparison: DTG vs EFV, outcome: VL<50 copies/ml at 48 wks.

(EPS)

Click here for additional data file.

Forest plot of comparison: Dolutegravir vs comparators, outcome: VL<50 copies/ml at 96 wks.

(EPS)

Click here for additional data file.

Forest plot of comparison: DTG vs other according to baseline CD4 (cut off 200 CD4/ml), outcome: % <50 copies/ml at 48 wks.

(EPS)

Click here for additional data file.

Forest plot of comparison: Dolutegravir vs comparators, outcome: Most common adverse effects.

(EPS)

Click here for additional data file.

24 Jul 2019

PONE-D-19-17880

Dolutegravir based antiretroviral therapy compared to other combined antiretroviral regimens for the treatment of HIV-infected naive patients: a systematic review and meta-analysis.

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https://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf

https://academic.oup.com/jid/article/218/5/673/4956225

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In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed.

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MC has received honoraria as a speaker and/or advisor from  Abbott, Bayer, Cephalon, Gilead, Novartis and ViiV Healthcare, SGP  has received  research grants from Gilead Sciences, ViiV Healthcare, Abbott, MS&D, and  honoraria as a speaker from MS&D, Gilead Sciences, ViiV Healthcare, Abbvie, Janssen. These activities were not related to their work with this review

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Reviewer #1: There are several mislabeled items in the plots. Please mention if the authors performed tests for multiplicity.

Reviewer #2: The Authors performed a systematic review and meta-analysis of RCTs comparing dolutegravir-containing ART to non-dolutegravir containing ART in HIV-infected naive patients.The manuscript is well written and represents a very comprehensive analysis on this topic. The methodology is adequate and updated.

I have just one suggestion. Since the use of patients reported outcomes represent a more useful tool compared to clinician report of adverse events and they can explore outcomes such as patients' satisfaction with treatment, and considering the high virological response rates reported in some comparison between INSTI-based regimens in particular, it could be useful to include, when available, PROs as specific outcomes in the metanalysis (Whol, The Patient - Patient-Centered Outcomes Research, 2018).

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Submitted filename: PONE-D-19-17880_Comments due 23 July 2019.docx

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21 Aug 2019

Journal Requirements:

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AU: OK

2. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

AU: OK

3. We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data.

AU: as suggested, we have removed the sentence, and specified that funnel plots were not performed because the low number of studies (lines 199-200)

4. Please confirm that you have included all items recommended in the PRISMA checklist including an assessment of publication bias using graphical methods (e.g. Funnel plot) and statistical methods (e.g. Egger’s test) as appropriate; details of reasons for study exclusions in the PRISMA flowchart and number of studies excluded for each reason; and the full electronic search strategy used to identify studies with all search terms and limits for at least one database.

AU: done

5. We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed:

https://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf

https://academic.oup.com/jid/article/218/5/673/4956225

The text that needs to be addressed is in the Discussion section.

AU: The first sentence is from DHHS “the choice between an INSTI, PI, or NNRTI as the third drug in an initial ARV regimen should be guided by the regimen’s efficacy, barrier to resistance, adverse effects profile, convenience, comorbidities, concomitant medications, and the potential for drug-drug interactions” We have inserted the whole paragraph in brackets, and specified that the sentence is based on the DHHS guidelines

The second is “result in cross-resistance to dolutegravir and bictegravir. The reference you mention is now quoted (no. 36, Kuritzkes DR. Resistance to Dolutegravir—A Chink in the Armor? The Journal of Infectious Diseases, 2018, 218: 673–675)

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed.

6. Thank you for stating the following in the Competing Interests section:

MC has received honoraria as a speaker and/or advisor from Abbott, Bayer, Cephalon, Gilead, Novartis and ViiV Healthcare, SGP has received research grants from Gilead Sciences, ViiV Healthcare, Abbott, MS&D, and honoraria as a speaker from MS&D, Gilead Sciences, ViiV Healthcare, Abbvie, Janssen. These activities were not related to their work with this review

Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.

AU: we have updated this as requested

Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: There are several mislabeled items in the plots. Please mention if the authors performed tests for multiplicity.

AU: as we have specified below (comments), we have made consistent legends of figures and graph. We did not perform tests for multiplicity

Reviewer #2: The Authors performed a systematic review and meta-analysis of RCTs comparing dolutegravir-containing ART to non-dolutegravir containing ART in HIV-infected naive patients.The manuscript is well written and represents a very comprehensive analysis on this topic. The methodology is adequate and updated.

I have just one suggestion. Since the use of patients reported outcomes represent a more useful tool compared to clinician report of adverse events and they can explore outcomes such as patients' satisfaction with treatment, and considering the high virological response rates reported in some comparison between INSTI-based regimens in particular, it could be useful to include, when available, PROs as specific outcomes in the metanalysis (Whol, The Patient - Patient-Centered Outcomes Research, 2018).

AU: Thank you for this interesting observation, Unfortunately, as we have now specified in lines 369-371, measures of quality of life were rarely reported in the included studies, and we could not assess treatment satisfaction.

________________________________________

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

PONE-D-19-17880

Dolutegravir based antiretroviral therapy compared to other combined antiretroviral regimens for the treatment of HIV-infected naive patients: a systematic review and meta-analysis

Comments:

Define “naïve” in the Introduction

AU: Done (lineS 64-65)

There are only two authors. Was there an adjudicator in the data extraction process in case of disagreements?

AU: as specified on lines 110-111, agreement was achieved by discussion

90 Assessment of risk of bias and Heterogeneity

Below line 90

Put here gradings of heterogeneity as in I2 = 0% indicating no heterogeneity

AU: Actually, the interpretation of I2 values is more complicated, and can be misleading; often, threshold of interpretation are: ≤25, low heterogeneity; >50, high heterogeneity (now specified in the text, line 94), but these values are completely arbitrary. So, as for other systematic reviews of our groups, we decided to use fixed effect model when I2 =0 and when values of I² are greater than zero, both fixed and random effects analyses were performed (see sentences on line 140-2 “We used the fixed-effect model when the I2 was=0,….”)

Restrict mentioning RevMan more than twice

AU: REV MAN is mentioned on line 132 and 145

Did the authors perform tests for heterogeneity?

AU: yes (see lines 118-121)

Strategy for data synthesis

104 We used aggregate data. The analysis has been conducted

Substitute the underlined with “was”

AU: done

107 random effects analyses are undertaken and any differences

Substitute the underlined with “performed”

AU: done

109 pre-specified subgroup analysis. We used risk difference as measure of effect. Review Manager 5.3 was used to analyze the data.

RevMan again?

AU: yes, for the second time

Table 2 . legend

Include RD

AU: done

203 adverse events and of adverse events requiring discontinuation of treatment was not significantly different in dolutegravir

What is the p-value for the “not significantly different “?

AU: the p values for any adverse events and adverse events requiring discontinuation have bee added to the text (line 273)

Kindly organize your Discussion so as to indicate summary of effects, clinical implications

Also mention of strengths and limitations of this study.

AU: summary effects and clinical implications are discussed (lines 321-348) and strengths and limits are now mentioned (lines 364-9)

156 Table 2 . Summary of the pooled outcome data. Results are provided for a 156 ll possible comparisons, and for

157 subgroups analyses

In column 5 of the P-values, the authors present several significant values

Did the authors correct for multiple comparisons?

AU: no, we did not.

The favours labels are opposite at the x-axis in Figures 3 and 5

Is this correct?

AU: yes, it is correct. In fig 4 thr RD is >0, which means that more people in DTG had VL<50 copies, a favourable outcome resulting in effect estimates to the right of the vertical line. In fig. 5 the RD is less than 0, which means that less people in DTG has treatment discontinuation, a favourable outcome resulting in effect estimates to the left of the vertical line

Suppl figures 1 and 2

Need to label DTG in legend

AU: we have made consistent legends of figures and graphs, using the entire words for dolutegravir and comparators

Supl Fig 4. Forest plot of comparison: DTG vs EFV, outcome: VL<50 48 wks

SINGLE 48 contributed 57.7% to the pooled RD, mention this in the text because it is an imbalance in weight contribution

AU: this is now mentioned in the text (lines 236-7)

Supl Fig 5. Forest plot of comparison: Dolutegravir vs comparators, outcome: VL<50 96 wks

The authors used random-effects here, why not fixed?

AU:because I2=31, and we chosed, starting from the protocol, to present the result of the fixed effect model when I2 =0

Supl Fig 6. Forest plot of comparison: DTG vs other according to baseline CD4 (cut off 200 CD4/ml) ,

outcome: % <50.

The authors used random-effects here even if the 9.3.1 plot is I2 = 0%. Please justify

AU: we used random effects model because in one of the subgroup there was evidence of heterogeneity; however, we performed analysis also using the fixed effect, and the results were much the same

Supl Fig 7. Forest plot of comparison: Dolutegravir vs comparators, outcome: Most common adverse

effects. Is the label favouring Dolutegravir same is DTG?

AU: as for fig 5, a RD <0 is a favourable outcome for AE. The 95 % CIs cross the vertical line for all the outcome analyzed

Submitted filename: response to reviewers.docx

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26 Aug 2019

Dolutegravir based antiretroviral therapy compared to other combined antiretroviral regimens for the treatment of HIV-infected naive patients: a systematic review and meta-analysis.

PONE-D-19-17880R1

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29 Aug 2019

PONE-D-19-17880R1

Dolutegravir based antiretroviral therapy compared to other combined antiretroviral regimens for the treatment of HIV-infected naive patients: a systematic review and meta-analysis.

Dear Dr. Cruciani:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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on behalf of

Dr. Giuseppe Vittorio De Socio

Academic Editor

PLOS ONE