Chapter 3: Result
3.3 Quality assessment
Overall, the risk of bias for all studies was generally low, with the exception of the unclear
mentioned of allocation concealment, and blinding of participants and personnel because
of the nature of open-label design. The objective analysis of the efficacy and viral load
measurement were not likely to be disrupted by blinding or not, but the process of
blinding may have been important for assessment of subjective analysis, for examples,
drug-related adverse events. Three studies26-28 assessed with unclear risk on reporting bias,
because those published as an abstract on posters or reports on AIDS conferences with
preliminary or simplistic results. No study assessed the attrition bias for incomplete
outcome data because of high rate of loss to follow-up (Figure 2a, 2b).
We summarized the certainty of evidence findings for three HIV-positive populations;
virally suppressed (Table 3), treatment-naive with stratification of ARV mechanism
(Table 4,5,6) and treatment-experienced (Table 7) by GRADE approach. For the
virological suppression outcomes at 48 weeks, the certainty of evidence was high for
treatment-naive patients when compared to EFV-based regimen, PI-based regimen and
experienced patients. There was moderate quality evidence that both
treatment-naive patients using DTG-based compared to InSTI-based regimen and virally suppressed
patients switched to DTG-based, both did not reached significantly different, contributed
by four and six trials separately. Evidence quality was mainly downgraded for imprecision
because of few clinical events in several studies14-16,25. For tolerability outcomes, the
certainty of evidence was low for most scenarios, mainly downgraded by potential
performance bias because limited by open-label design and imprecise estimates for
limited number of events and wide confidence intervals reported. In contrast, evidence
quality were upgraded one level because of large magnitude of estimated effect with no
plausible confounders while DTG-based compared to EFV-based and PI-based regimen
in treatment-naive patients group.
Chapter 4: Discussion
Although the aspect of cost-benefit considerations and the global health burden
endorsed by international agencies, especially the WHO, there had been more LMICs
large-scale initiative to implement DTG transition programme, switching DTG-based as
the first-line regimen, which is still an importance issues on how likely to perform within
HIV-positive patients. In this meta-analysis, we provided a more comprehensive view of
relative efficacy and tolerability between DTG-based regimen and others combination
ART in three independent scenarios of HIV-positive populations. Our results
demonstrated that HIV virally suppressed patients who was no significant difference rate
of both viral suppression and discontinuation due to any adverse events. For efficacy,
among three studies12,15,16 showed virological benefit were trend toward others
ART-based regimen. Patients in DOLAM15 and ASPIRE16 who were assigned to control group
for non-switching regimen but remained current ART (cART), among patients in
DOLAM mostly with NNRTI-based regimen (71%) at baseline. Patients in NEAT02212
control group were assigned to continue using ritonavir-boosted PI regimen, primarily
ritonavir-boosted darunavir (51%), with TDF/FTC backbone (65%) at baseline. Results
of efficacy demonstrated a robust and well homogeneity, supported by stratification
factors of different follow-up durations. For tolerability, the estimated risk ratios showed
a large effect and higher proportion of discontinuation of study drug related to adverse
events after switched to DTG-based regimen, among three DTG-switch trials12,13,17
shown a well-tolerated aspect on another ART regimen, even there was no significant
difference between both groups at the endpoint. Nevertheless, the particularly notable risk
ratio of discontinuation due to any AEs reported within the DTG-switch arm was
expectable while compared with remaining on a stable baseline regimen that patients have
been well-tolerating from a long period of time. Based on the results that we did not
support a proactive practice to switch the current ART to DTG-based regimen while the
patients were reaching virological suppression, since the risk of switching could outweigh
the benefits. But for specific long-term safety, patients who switched from tenofovir
disoproxil fumarate (TDF) combination to DTG-based regimens was associated with
reduced bone mineral density31 and improved bone turnover markers.17 Moreover, DTG
is likely to be a good substitute therapeutic ART class to LPV/r for HIV patients due to
less likely to dyslipidemia. Patients with those comorbidities that may derive benefit from
being switched to DTG-based regimen. However, in some LMICs had been already
completed the DTG transition programme by amended their national guidelines and prior
preferred standard EFV were no longer available, that is necessary for national healthcare
and provider take caution the emergence of ART discontinuation while patients switching
regimen to DTG-based.
A second sub-population analysis was performed to compare efficacy and tolerability
in treatment-naive patients using DTG-based regimen, could had a significantly better
efficacy up to week 48, either included the study of pregnant women and HIV-associated
TB coinfected patients or not. Sensitivity analyses all showed treatment differences in
favour of the DTG-based regimen and subgroup analysis revealed DTG-based regimen
versus EFV- and PI-based regimen, was associated with a greater proportion of patients
being virally suppressed; versus others InSTI-based regimen with marginally
significantly better, at week 48 after ART initiation, which was partly consistent with the
pooled result by George;32 included two original DTG versus EFV RCTs with
HIV-positive treatment-naive populations. However, we cannot directly contrast the result with
Junjun’s study33, since the misclassification subgroup analysis. There was moderate to
high quality evidences of achieved viral suppression for DTG-based relative to others
mechanisms-based ART in treatment-naive patients. For tolerability, the superior
responses were also driven by a reduction risk to discontinue ART due to any adverse
events in the DTG-based regimen than EFV-based and PI-based regimen, both evidences
was upgraded to high and moderate quality separately, based on the large magnitude of
effect that was observed. Although the comparison to others InSTI-based regimen was no
statistically significant, which was correspond to the large prospective cohort study,34 but
with low quality evidences nevertheless. Overall, our results consistently supported the
WHO 2018 latest guideline suggestion; recommended DTG-based as the preferred
first-line regimen for people living with HIV initiating ART with conditional recommendation.
For DTG-based used in treatment-experienced patients, despite insufficient number of
RCTs included, we found that DTG-based regimen was associated with a significantly
greater proportion of treatment-experienced patients achieving virological suppression,
at the end of 48 weeks after initiated second-line regimen. Our results provided the
efficacy related quality evidence was high certainty; which showed that DTG-based was
an effective ART regimen for second-line among adults for whom a NNRTI- or PI- based
first-line regimen had failed. For tolerability, results also supported DTG-based as an
alternative regimen based on patients in the DTG-based regimen were almost a half times
the risk less likely to discontinue their ART due to any adverse events. On the overall of
our findings, DTG in combination with an optimized backbone was a superior regimen
for treatment-experienced patients with HIV.
Our meta-analysis was included all adequate RCTs and introduced new scenario which
contributed to a consolidated view for DTG-based efficacy and tolerability profile.
However, there were few limitations existed. First, the predominant of the study
characteristics, which may not be fully represented to the global HIV epidemic, since the
mainly completed by white and male adults in developed country settings, typically
limiting the evidences for pregnant women, people with HIV-associated TB and people
with advanced HIV infection. Recent studies also did not consider the integral
circumstances, the people who lived in resource-limited LMICS, where an increasing rate
of NRTI- and NNRTI-transmitted resistance and local people without sufficient medium
of healthcare services,35 for example: HIV viral load monitoring, drug mutation or
resistance testing. Second, tolerability outcome was analyzed considering ART
discontinuations due to any adverse events, but study drug-related adverse events were
not independently reported on each included RCT, thus it may leading to an
overestimation of ART discontinuations rate. Nonetheless, there are several ongoing
RCTs will enable to fit the evidence gaps in the forthcoming year, using DTG-based
regimen with assessment of virologic efficacy and safety of HIV-positive pregnant
women and their infants; VESTED (NCT03048422) and DolPHIN2 (NCT03249181),
switching to DTG-based regimen with dual regimen simplification; DUALIS
(NCT02486133), the more detailed data highlight the HIV-positive patients from LMICs
who failing the first-line regimen; D2EFT (NCT03017872).
In summary, our meta-analyses show that the DTG-based regimens have superior
efficacy and tolerability to EFV- and PI- based regimens for patients who are
treatment-naive, and treatment-experienced patients with virological failure. Conversely, for those
who already achieved virological suppression under other regimens, switch to
DTG-based regimen did not yield a better virological suppression rate by 24-48 weeks.
Furthermore, for this group of patients, switch from a stable regimens to DTG-based
regimens is associated with an inferior tolerability.
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Table 1: PubMed and Embase search strategy, which was modified and adapted as needed for use in the other databases.
Search PubMed query
#3 Search #1 AND #2
#2 HIV Integrase Inhibitors[mh] OR HIV Infections/drug therapy[mh] OR reverse transcriptase inhibitors[mh] OR Antiretroviral Therapy, Highly Active[mh] OR Anti-Retroviral Agents[mh] OR integrase inhibitor*[tw]
OR integrase strand transfer inhibitor*[tw] OR INSTI[tw] OR antiretroviral[tw] OR retroviral[tw] OR HIV*[tw] OR anti-AIDS[tw]
#1 dolutegravir[tw] OR DTG[tw] OR S/GSK1349572[tw] OR GSK-1349572[tw] OR Tivicay[tw] OR dolutegravir[Supplementary Concept]
[mh] = Medical Subject Heading (MeSH) term. [tw] = text word. [pt] = publication type.
Search Embase query
#3 Search #1 AND #2
#2 HIV Integrase Inhibitors OR HIV Infections therapy OR HIV drug therapy OR reverse transcriptase inhibitors OR Antiretroviral Therapy, Highly Active OR Anti-Retroviral Agents OR integrase inhibitor* OR integrase strand transfer inhibitor* OR INSTI OR antiretroviral OR anti-retroviral OR anti-HIV* OR anti-AIDS
#1 dolutegravir OR DTG OR GSK1349572 OR GSK-1349572 OR Tivicay
Table 2: Characteristics of patients included in the selected randomized control trial studies.
Study (Trial name,
publication year) Country Study
design (1) Virological Suppressed:
NEAT022, 2017a Multinational open-label 96wks 48wks 415 DTG+2NRTI PI/s+2NRTI STRIIVING, 2017 USA and
Canada open-label 24wks 24wks 553 DTG+2NRTI cART
SWORD 1+2, 2018 Multinational open-label 48wks 48wks 1024 DTG+RPV cART
ASPIRE, 2018 USA open-label 48wks 48wks 89 DTG+3TC cART
DOLAM, 2018b Spain open-label 24wks 24wks 60 DTG+3TC cART
GS-US-380-1844, 2018 Multinational double-blind 48wks 48wks 563 DTG+ABC+3TC BIC+TAF+FTC
Subtotal 2704
(2) Naive:
SPRING-1, 2012 Multinational open-label 96wks 48wks 101 DTG+2NRTI EFV+2NRTI SPRING-2, 2013 Multinational double-blind 96wks 48wks 822 DTG+2NRTI RAL+2NRTI SINGLE, 2013 Multinational double-blind 144wks 48wks 833 DTG+ABC+3TC EFV+TDF+FTC FLAMINGO, 2014 Multinational open-label 96wks 48wks 484 DTG+2NRTI DRV/r+2NRTI GS-US-380-1489, 2017 Multinational double-blind 144wks 48wks 629 DTG+ABC+3TC BIC+TAF+FTC GS-US-380-1490, 2017 Multinational double-blind 144wks 48wks 645 DTG+TAF+FTC BIC+TAF+FTC ARIA, 2017c Multinational open-label 48wks 48wks 495 DTG+ABC+3TC ATV/r+TDF+3TV
Paul, 2017 USA double-blind 48wks 48wks 98 DTG+TAF+FTC BIC+TAF+FTC
NAMSAL, 2018 Cameroon open-label 48wks 48wks 613 DTG+TDF+3TC EFV400+TDF+3TC
Table 2: Characteristics of patients included in the selected randomized control trial studies (continued)
DolPHIN-1, 2018d Africa open-label 2weeks postpartum
2weeks
postpartum 60 DTG+2NRTI EFV+2NRTI
INSPIRING, 2018e Multinational open-label 48wks 48wks 113 DTG+2NRTI EFV+2NRTI
Subtotal 4893
(1) Treatment-Experienced:
SAILING, 2013 Multinational double-blind 48wks 48wks 715 DTG+OBR RAL+OBR
DAWNING, 2019 Multinational open-label 48wks 48wks 624 DTG+OBR LPV/r+OBR
Subtotal 1339
NRTI, Nucleoside reverse transcriptase inhibitors; PI/s, ritonavir-boosted protease inhibitor; RPV, Rilpivirine; 3TC, lamivudine;
ABC, abacavir; FTC, emtricitabine; BIC, bictegravir; TAF, Tenofovir alafenamide; DRV/r, darunavir/ritonavir; ATV/r,
Atazanavir/ ritonavir; EFV, Efavirenz; EFV400, 400mg Efavirenz; RAL, raltegravir; LPV/r, lopinavir/ritonavir; cART, current ART regimen;
OBR, investigator-selected optimized backbone regimen.
a In total, 74% patients with a Framingham CVD risk score 10-year risk score more than 10%.
b This study included three different treatment arms with DTG dual- and mono-therapy.
c Eligible patients in this study were only women who aged 18 years or older, pregnant women were excluded.
d This study included Pregnant HIV positive women, initiated ART in third trimester of pregnancy, who randomised to receive DTG or EFV until two weeks postpartum.
e This study enrolled HIV-1 infected ART-naive patients with drug-sensitive tuberculosis, who allocated to DTG arm and received 50 mg twice-daily during and 2 weeks post-tuberculosis therapy, then 50 mg once-daily.
Table 3: Summary of findings: certainty of evidence for HIV virally suppressed patients
Patient or population: HIV virally suppressed patients Setting: all settings
Intervention: Dolutegravir-based
Comparison: others combination antiretroviral therapy
Outcomes
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the