Efficacy and safety of the regimens containing tenofovir alafenamide versus tenofovir disoproxil fumarate in fixed-dose single-tablet regimens for initial treatment of HIV-1 infection: A meta-analysis of randomized controlled trials

Journal Pre-proof Efficacy and safety of the regimens containing tenofovir alafenamide versus tenofovir disoproxil fumarate in fixed-dose single-tablet regimens for initial treatment of HIV-1 infection: A meta-analysis of randomized controlled trials Xingbao Tao, Yanqiu Lu, Yihong Zhou, Lvlang Zhang, Yaokai Chen

PII:

S1201-9712(20)30037-0

DOI:

https://doi.org/10.1016/j.ijid.2020.01.035

Reference:

IJID 3926

To appear in:

International Journal of Infectious Diseases

Received Date:

2 November 2019

Revised Date:

15 January 2020

Accepted Date:

20 January 2020

Please cite this article as: Tao X, Lu Y, Zhou Y, Zhang L, Chen Y, Efficacy and safety of the regimens containing tenofovir alafenamide versus tenofovir disoproxil fumarate in fixed-dose single-tablet regimens for initial treatment of HIV-1 infection: A meta-analysis of randomized controlled trials, International Journal of Infectious Diseases (2020), doi: https://doi.org/10.1016/j.ijid.2020.01.035

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.

Efficacy and safety of the regimens containing tenofovir alafenamide versus tenofovir disoproxil fumarate in fixeddose single-tablet regimens for initial treatment of HIV-1 infection: A meta-analysis of randomized controlled trials

1

ro of

Xingbao Tao1,2, Yanqiu Lu2, Yihong Zhou2, Lvlang Zhang2, Yaokai Chen1,2*

National Key Laboratory for Infectious Diseases Prevention and Treatment with

Traditional Chinese Medicine, Chongqing Public Health Medical Center, Chongqing,

2

-p

China, 400036

Department of Infection Diseases, Chongqing Public Health Medical Center,

re

Chongqing, China, 400036 *

Corresponding author: Yaokai Chen, Department of Infection Diseases, Chongqing

lP

Public Health Medical Center, Chongqing, China, No. 109, Baoyu Road, Shapingba District, Chongqing, 400036, China. Tel and Fax: +86-026-65231256, e-mail address:

Jo

ur

na

[email protected].

1

Highlights 

Two regimens were non-inferior in maintaining viral suppression.



TAF-containing regimens significantly smaller reductions in hip and spine.



TAF-containing regimens significantly less increases in renal events. TAF would be an alternative substitute for TDF in HIV-infected patients.

ro of



Abstract:

Background: Tenofovir disoproxil fumarate (TDF) can cause renal and bone toxicity,

-p

which is associated with high plasma tenofovir concentrations in antiretroviral

treatment of HIV-1 infected patients.. Tenofovir alafenamide (TAF) is a novel tenofovir

re

prodrug with a 90% reduction in plasma tenofovir concentrations. We aimed to assess the non-inferiority of a TAF-containing combination regimen versus a TDF-containing

lP

fixed-dose single-tablet regimen in the antiretroviral-treatment-naive, HIV-1-infected patients.

na

Methods: We searched PubMed, Embase, Web of Science, and the Cochrane Trial Registry, from January 2001 to July 2019, using relevant keywords. Available data were

ur

extracted from eligible randomized trials (RCTs) and pooled as risk ratios (RRs) or

Jo

standardized mean differences (SMDs) in a meta-analysis model using Stata/SE. Results: We included seven eligible randomized controlled trials (RCTs) with a total of 6269 participants. Patients who were antiretroviral-naive adults with HIV-1 on both the TAF-containing regimens and the TDF-containing regimens had similar virologic suppression effects (RR, 1.02; 95% CI, 1.00-1.04; p > 0.05) at week 24 (93.99% vs. 94.20%,), week 48 (90.71% vs. 89.54%), and week 96 (86.16% vs. 84.80%). Both 2

groups had no significant improvements in CD4 cell count for the naive patients during 48 weeks of therapy (SMD, 0.09; 95% CI, 0.01 to 0.16; p < 0.05). Both treatments were safe and well-tolerated, and most adverse events were similar as mild to moderate in severity. Moreover, compared with the TDF-containing regimens, the TAF-containing regimens in patients had significantly smaller reductions in both hip (RR, 0.33; 95CI, 0.29-0.39; p < 0.05) and spine (RR, 0.58; 95CI, 0.51-0.65; p < 0.05). Additionally, the TAF-containing regimens in patients had significantly fewer increases for renal events

ro of

than those of the TDF-containing regimens through 48 weeks (0.31; 95% CI, 0.18-0.55; p < 0.05).

Conclusions: Our meta-analysis indicated that efficacy, safety, and tolerability of TAF-

-p

containing regimens were non-inferior in fixed-dose single-tablet regimens for initial treatment of HIV-1 infection. Furthermore, compared with those receiving the TDF-

re

containing regimens, patients on the TAF-containing regimens had significant

lP

advantages in renal function, bone parameters, and lipid profile for the naive patients. Keywords: HIV-1, tenofovir alafenamide (TAF), tenofovir disoproxil fumarate (TDF),

Jo

ur

na

antiretroviral regimens, meta-analysis

3

Introduction Combined antiretroviral therapy (cART) had significantly improved the survival rate, and it increased life expectancy in the HIV-1 infected population. Still, it contributed to the development of various metabolic complications (Jeong et al., 2013). With the development of non-AIDS complications, it was increasingly critical to choose a

ro of

balanced antiviral drug regimen (Rathbun et al., 2006). Currently, the treatment approaches for HIV-1 infection are commonly based on the use of a combination of

nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) along with a non-

-p

nucleoside reverse transcriptase inhibitor (NNRTI), ritonavir boosted-protease inhibitor

(PI/r) or integrase strand transfer inhibitor ((INSTI) (Akanbi et al., 2012). Although the

re

combination of these drugs had a strong antiviral effect, these effective treatment

lP

options might still lead to reduced safety, tolerance and compliance, and various nonAIDS complications. Therefore, optimal antiretroviral regimens should be considered to reduce the toxicity, improve tolerability, and simplify adherence, or to adjust to

na

allow for concomitant medication or comorbid conditions (DeJesus et al., 2017). Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir, was approved by the

ur

Food and Drug Administration (FDA) in 2001 and the European Medical Agency

Jo

(EMA) in 2008 as a recommended first-line drug for HIV treatment. Although strong clinical efficacy and generally well-tolerated, TDF can lead to severe renal toxic effects, especially in patients with risk factors for kidney disease or who were receiving concomitant ritonavir boosted-protease inhibitors (Mocroft et al., 2010, Morlat et al., 2013). Besides, TDF is related to bone mineral density (BMD), which has a more significant decrease in BMD than other ART drugs, and the fall in TDF was most 4

pronounced after the initiation of all NRTI-containing treatments (McComsey et al., 2011). Tenofovir alafenamide fumarate (TAF), a novel prodrug of the antiretroviral tenofovir (TFV), was approved by the FDA in 2016 and EMA in 2017 as a nucleotide reverse transcriptase inhibitor (NRTI). After treatment with TAF, TAF was converted intracellularly to TFV both for treatment-naive patients and treatment-experienced patients. As a result, TAF demonstrated superior antiviral potency, higher peripheral blood mononuclear cell (PBMC) intracellular tenofovir diphosphate (TFVpp) levels

ro of

and lower plasma tenofovir concentrations as compared to TDF. Because of TAF’s reduced dose and the improved stability, plasma exposure of tenofovir is 90% lower

with TAF than with TDF, which is thought to reduce the risk of renal and bone toxicity

-p

(Van Rompay et al., 2008). Current guidelines recommend that patients begin ART earlier and stay on it continuously (Panel on Antiretroviral Guidelines for Adults and

re

Adolescents, 2014), so the contribution of specific antiretroviral agents to long term

lP

morbidity and mortality is increasingly significant. In regimens of comparable efficacy, pill burden, dose frequency, safety, and tolerability are substantial factors affecting maximal adherence over the long term (Aldir et al., 2014, Escobar et al., 2003,

na

Sterrantino et al., 2012).

ur

To date, despite multiple RCTs had shown that the efficacy and safety in the TAFcontaining regimens for initial treatment of HIV-1 infected patients, such as it could

Jo

effectively improve the renal and bone safety comparable with those of the TDFcontaining regimens especially in BMD with a minimum effect. However, whether TAF would be an alternative substitute for TDF in anti-HIV therapy remains to deserve further analysis and verification (Sax et al., 2015b, Sterrantino et al., 2012, Tao et al., 2019). The efficacy and safety of TAF-containing regimens have been mostly evaluated 5

in the context of the coformulation of elvitegravir (E), cobicistat (C), emtricitabine (F), darunavir (D), and TAF. Though included these RCTs can provide the highest level of evidence, single studies still have insufficient statistical power. Therefore, in this metaanalysis, based on different drug combinations, we aimed to investigate a definite conclusion by further comprehensively assessing the clinical efficacy, safety, tolerability of the regimens containing TAF versus TDF in fix-dose single-tablet

ro of

regimens for initial treatment of HIV-1 infection. Methods

This meta-analysis was performed following the PRISMA statement and the

-p

recommendations of the Cochrane Collaboration. The protocol was registered in

Literature Search Strategy

re

PROSPERO (registration number: CRD 42018089828).

We searched Pubmed, Embase, Web of Science and the Cochrane Trial Registry, from

lP

January 2001 to July 2018, using the search terms “Tenofovir alafenamide (TAF) AND Tenofovir disoproxil fumarate (TDF) AND HIV”. Additionally, a manual search of

na

original studies and review studies was performed to identify articles potentially missed by the database searches. Only randomized trials published in peer-reviewed journals

ur

were considered qualified in this meta-analysis; observational studies, abstracts, case

Jo

series, and case reports were not included. We also searched for relevant citations in identified literature. No language restrictions were enforced. Eligibility Criteria and Study Selection Two reviewers (XBT, YHZ) evaluated all articles by using this search strategy to determine if these articles were potentially eligible for inclusion in this meta-analysis. The following inclusion criteria were used to determine whether the included studies 6

were available for this meta-analysis: (1) randomized, controlled trials (RCTs); (2) HIV1 infected patients who were treatment-naive participants in antiretroviral regimens (aged ≥ 18 years); (3) experimental group was given the regimens containing TAF and control group was carried the regimens containing TDF. The following non-compliant studies were excluded: (1) non-randomized, observational, cohort, case-control, and non-blinded clinical studies; (2) patients who were infected with positive hepatitis B surface antigen or hepatitis C antibody or previously received antiviral therapy; (3)

ro of

patient who were defined with a new AIDS condition or pregnant within 30 days after screening; (4) Studies did not show any efficacy measures and safety measures; (5) experimental group did not include the TAF-containing regimens and control group did

Data Extraction and Quality Assessment

-p

not include the TDF-containing regimens, synchronously.

re

The titles and abstracts of all included studies were reviewed and identified in the first

lP

search. Studies data were collected in an EXCEL form, including general information of the recruited patients, reasonable outcomes indicators, along with other favourable indicators. All included studies were assessed using the Cochrane collaboration tool.

na

The methodological domains were considered to perform as follow: sequence generation, allocation sequence concealment, blinding of participants, personnel and

ur

outcome assessors, incomplete outcome data, selective outcome reporting, and other

Jo

potential threats to validity. We carefully judged each of the domains as having a low risk, high risk, or unclear risk of bias according to the Cochrane handbook. For which unclear risks of bias were determined to be due to lack of enough information or uncertainty factors over the potential of bias. Each study outcome was shown by a single dot with a central regression line through the forest plot. On the y-axis, the logtransformed effect size divided by the SE (z score) was represented, and on the x-axis, 7

the inverse of the SE was represented. Heterogeneity Test and Subgroup Analysis Heterogeneity was assessed (differences in reported estimates among studies) by I2 test and p statistic values. According to the Cochrane review guidelines, the high heterogeneity was defined as (I2 test > 50% or P-value of < 0.1) among the studies; Otherwise, it was considered that there was no heterogeneity (I2 test < 50% or P-value of > 0.1). If there was a high heterogeneity, we conducted an appropriate method to

ro of

investigate the potential covariates that might have substantial impacts on betweenstudy heterogeneity. Meanwhile, the subgroup analysis was also carried out according to the type of study design.

-p

Statistical Analysis

Statistical analysis was performed by using Stata/SE software (Stata Corp, Collegmodel

re

with weighted standardized mean differences (SMD) or risk ratios (RR) within 95%

lP

confidence intervals for each included outcome estimate. Moreover, independent t-test has performed the comparisons of continuous variables by SPSS 25. All P-values were

Results

na

2-tailed, and a probability level < 0.05 was considered statistically significant.

Study Characteristics

ur

In this meta-analysis, we included 7 RCTs, including one-phase 1/2 trial (Markowitz et

Jo

al., 2014), two-phase 2 trials (Mills et al., 2015, Sax et al., 2014) and four-phase 3 trials (Eron et al., 2018, Orkin et al., 2019, Sax et al., 2015b, Wohl et al., 2016). The flow diagram of the study selection process for the meta-analysis was listed in Figure 1. We initially identified 332 potentially studies through electronic database searching. After deduplicating, 185 remaining papers were screened by title and abstract of publications. Then, 142 irrelevant records were excluded, and 43 records were assessed for eligibility 8

in full articles. Eventually, by careful full-text screening, we excluded some articles that did not meet the following criteria: (1) had no specific direction with the efficacy and safety of the regimens containing TAF versus TDF in antiretroviral regimens for the treatment of HIV-1 infection (n=31); (2) were reviews or meta-analysis (n=3); (3) the comparable regimens containing TAF or TDF versus other regimens (n=4). As a result, the remaining five independent RCTs met the inclusion criteria. These five RCTs were published between 2014 and 2018, and altogether 2811 patients were recruited. Among

ro of

these patients, 1463 were treated with the TAF-containing regimens, and the other 1348 were given the TDF-containing regimens. The general characteristics of the included

studies were summarized in Table 1. Study subjects recruited who came from different

-p

countries and races were given the TAF-containing regimens and the TDF-containing

Risk of Publication Bias Assessment

re

regimens in fixed-dose single-tablet regimens for initial treatment of HIV-1 infection.

lP

All included studies achieved adequate random sequence generation, and there was a low risk of bias in terms of allocation concealment. ‘‘Incomplete outcome data’’ and “selective reporting’’ domains were of low risks in all included studies (except for these

na

studies by (Markowitz et al., 2014, Mills et al., 2015, Orkin et al., 2019, Wohl et al., 2016); in which did not report on the complete outcome data). All studies were

ur

randomized controlled trials (RCTs), ‘‘blinding of participants and personnel’’ and

Jo

‘‘blinding of outcome assessment’’ were deemed at low risks of bias in all included trials (Figure 2). Efficacy Outcomes Virologic Suppression We selected six eligible RCTs (Eron et al., 2018, Mills et al., 2015, Orkin et al., 2019, Sax et al., 2015a, Sax et al., 2014, Wohl et al., 2016) to investigate the virologic suppression (defined as a viral load less than 50 copies per mL) 9

for the Treatment-naive patients covering a total of 5239 adult patients evaluated (two RCTs (Mills et al., 2015, Sax et al., 2014) with 24 weeks of follow-up, four RCTs (Eron et al., 2018, Mills et al., 2015, Sax et al., 2015a, Sax et al., 2014) with 48 weeks of follow-up, and two RCTs (Orkin et al., 2019, Wohl et al., 2016) with 96 weeks of follow-up). In the intention-to-treat (ITT) analysis, there was no statistically significant difference in the combined virologic response between the regimens containing TAF versus TDF for the treatment-naive patients (RR, 1.02; 95% CI, 1.00-1.04; p > 0.05)

ro of

(Figure 3, A). In the subgroup analysis, a high degree of heterogeneity was found between the RR estimates from the drug combination regimens (D/C/F/TAF vs.

D/C/F/TDF) at week 48 (heterogeneity test I2= 54.3%, p = 0.139). Furthermore, in the

-p

per-protocol (PP) analysis, for the treatment-naive patients, the combined virologic response in the TAF-containing regimens had also no significant difference compared

re

with the TDF-containing regimens at weeks 24 and 96 (RR, 1.01; 95% CI, 0.99-1.02;

lP

p > 0.05) (Figure 3, B).

CD4+ Cell Count Five RCTs (Eron et al., 2018, Markowitz et al., 2014, Mills et al., 2015, Sax et al., 2015a, Sax et al., 2014) measured CD4 cell count (absolute, cells/mL)

na

that enrolled 2685 participants contributed to the calculation of this outcome from baseline to week 48. The combined standardized mean difference (SMD) did not show

ur

a significant improvement in CD4+ cell count by comparing the regimens containing

Jo

TAF with TDF for the antiretroviral-naive patients (SMD, 0.05; 95% CI, -0.08 to 0.19; p > 0.05) (Figure 3, C). Virologic Failure Six RCTs (Eron et al., 2018, Mills et al., 2015, Orkin et al., 2019, Sax et al., 2015a, Sax et al., 2014, Wohl et al., 2016) reported the virologic failure with resistance, of which 2.38% of patients participated in the TAF-containing regimens, and 1.71% of patients participated in the TDF-containing regimens. For the summary effect 10

size of virologic failure, no significant difference was observed in the treatment-naive patients between the two groups during weeks 48 and 96 of therapy (RR, 1.25; 95% CI, 0.85-1.84; p > 0.05) (Figure 3, D). Adherence To the end of weeks 24, 48, and 96, expressed as the median cumulative adherence change in the treatment-naive patients from baseline as measured by pill count was 91.61% in the TAF-containing regimens and 88.22% in the TDF-containing regimens. Four RCTs (Eron et al., 2018, Mills et al., 2015, Orkin et al., 2019, Sax et al.,

ro of

2014) reported the median adherence to study treatment, and there was no significant difference for the Treatment-naive patients between the two groups (RR, 1.01; 95CI, 0.99-1.03; p > 0.05) (Figure 3, E),

-p

Safety Outcomes

Adverse Events The 48-week and 96-week safety profile of TAF-containing regimens

re

in the treatment-naive patients were generally similar to those of TDF-containing

lP

regimens, with 67.26% vs. 66.61% patients from 5 RCTs reporting any treatmentemergent adverse events (AEs) (Eron et al., 2018, Mills et al., 2015, Orkin et al., 2019, Sax et al., 2014, Wohl et al., 2016). No significant difference was found between the

na

two groups (RR, 1.00; 95CI, 0.96-1.04; p > 0.05) (Figure 4, A). The common adverse events include nausea, diarrhoea, upper respiratory tract infection, fatigue, sinusitis,

ur

bronchitis, nasopharyngitis, back pain, headache, insomnia, cough, influenza,

Jo

pharyngitis, pain in extremity, and anogenital warts. Among these main adverse events, there were no significant differences in most adverse events by comparing TAFcontaining regimens with those of TDF-containing regimens for the Treatment-naive patients through 48 weeks (Supplementary Figure 1 and Supplementary Figure 1 (continued)). Both treatments were well tolerated, with most adverse events reported as mild or moderate in severity. 11

Discontinuation due to Adverse Events After 48 and 96 weeks of treatment, six RCTs reported the discontinuations because of adverse events (Eron et al., 2018, Mills et al., 2015, Orkin et al., 2019, Sax et al., 2015a, Sax et al., 2014, Wohl et al., 2016). Of these, 1.54% of patients received the TAF-containing regimens, 2.66% of patients received the TDF-containing regimens. The TAF-containing regimens showed that the prevalence of discontinuation due to adverse events was significantly lower than those of the TDF-containing regimens (RR, 0.55; 95CI, 0.37-0.82; p < 0.05) (Figure 4, B).

ro of

Meanwhile, in the subgroup analysis, the naive patients on the drug combination D/C/F/TAF regimen also showed a significantly lower incidence compared to E/C/F/TDF regimen through week 48 (RR, 0.45; 95CI, 0.20-0.99; p < 0.05).

-p

Grade 3 or 4 Adverse Events Six RCTs (Eron et al., 2018, Mills et al., 2015, Orkin et

al., 2019, Sax et al., 2015a, Sax et al., 2014, Wohl et al., 2016) revealed the information

re

of grade 3 or 4 AEs between 48 weeks and 96 weeks of follow-up, the occurrence of

lP

rates was similar (18.49% vs. 17.64%), and there was no significant difference between the TAF-containing regimens and the TDF-containing regimens (RR, 1.07; 95CI, 0.961.20; p > 0.05) (Figure 4, C).

na

Fractures Five RCTs reported fractures (Eron et al., 2018, Mills et al., 2015, Sax et al., 2015a, Sax et al., 2014, Wohl et al., 2016), including 0.35% patients received the TAF-

ur

containing regimens and 0.82% patients received the TDF-containing regimens, which

Jo

had no significant difference between the two groups at weeks 48 and 96 (RR, 0.48; 95CI, 0.12-2.00; p > 0.05) (Figure 4, D). Thus, we believed that all fractures are related to trauma rather than osteoporosis caused by drug conversion. A combined high degree of heterogeneity occurred at two-drug combination regimens between week 48 and week 96 (heterogeneity test I2= 54.1%, p = 0.113) Bone Outcomes Bone outcomes was observed from five RCTs in bone mineral density 12

(BMD) changes at the hip and spine from baseline to week 48 (Eron et al., 2018, Mills et al., 2015, Orkin et al., 2019, Sax et al., 2015a, Sax et al., 2014). The median percentage change in BMD decreases of > 3% were 15.82% (TAF-containing regimens) vs. 47.42% (TDF-containing regimens) at the hip, and 26.93% (TAF-containing regimens) vs. 46.20% (TDF-containing regimens) at the spine, respectively. The TDFcontaining regimens had significantly more declines in BMD than those of the TAFcontaining regimens in both the hip (RR, 0.33; 95CI, 0.29-0.39; p < 0.05, Figure 5, A)

ro of

and spine (RR, 0.58; 95CI, 0.51-0.65; p < 0.05, Figure 5, B) through 48 weeks. As shown in Supporting Table 1, bone parameters change in the treatment-naive patients were expressed from baseline to week 96. The independent t-test was

-p

performed using SPSS 25 for the comparisons of continuous data between TAF-

containing regimens and TDF-containing regimens in the treatment-naive patients. The

re

mean BMD parameters changes were significantly smaller decrease in the TAF-

lP

containing regimens at both the hip (-0.51 vs. -2.95, p < 0.05) and spine (-1.17 vs. -3.01, p < 0.05) as compared to the TDF-containing regimens from baseline to week 48. Furthermore, we also observed changes in the markers of bone turnover, procollagen

na

Type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide (CTx) between the two groups. During 48 weeks of therapy, the bone formation marker P1NP in the TAF-

ur

containing regimens had significantly increased than in the TDF-containing regimens

Jo

(4.63 vs. 48.70, p < 0.05). In contrast, the bone resorption marker CTx in TAFcontaining regimens remained unchanged as compared to the TDF-containing regimens (14.07 vs. 50.87, p < 0.05). Renal Outcomes In all included clinical trials, six RCTs (Eron et al., 2018, Mills et al., 2015, Orkin et al., 2019, Sax et al., 2015a, Sax et al., 2014, Wohl et al., 2016) reported the renal 13

adverse events, including 14 (0.52%) of 2671 participants in the TAF-containing regimens and 49 (1.90%) of 2568 participants in the TDF-containing regimens. The renal events with the use of the TAF-containing regimens were significantly lower than the TDF-containing regimens after 48 weeks of therapy (RR, 0.31; 95% CI, 0.18-0.55; p < 0.05, Figure 5, C). Renal parameters were expressed as serum creatinine (Cr), estimated creatinine clearance by Cockcroft–Gault (eGFR-CG), urine protein to Cr, urine albumin to Cr, retinol-binding protein to creatinine (RBP/Cr), β2-microglobulin

ro of

to creatinine ratio (β-2M /Cr). The renal parameters median changes were presented in Supporting Table 2 for the treatment-naive patients from baseline to week 96. After 48 and 96 weeks of therapy, there was no statistically significant differences were observed

-p

(p > 0.05 for all) despite it had significant reductions from baseline for both groups, Lipid Profile

re

The fasting lipid profile changes in the treatment-naive patients was presented in

lP

Supporting Table 3. Six RCTs with 4144 adult participants were used to analyze the lipid profile from baseline to week 96 (Eron et al., 2018, Mills et al., 2015, Orkin et al., 2019, Sax et al., 2015a, Sax et al., 2014, Wohl et al., 2016). There were significant

na

differences in the median changes between the TAF-containing regimens and the TDFcontaining regimens, which included total cholesterol (30.87 vs. 11.63, p < 0.05), low-

ur

density lipoprotein (LDL) cholesterol (17.47 vs. 5.40, p < 0.05), high density

Jo

lipoprotein (HDL) cholesterol (6.12 vs. 2.67, p < 0.05) and triglycerides (22.86 vs. 7.48, p < 0.05), whereas total cholesterol/HDL cholesterol ratio remained unchanged (median increases 0.14 vs. 0.03, p > 0.05) for the treatment-naive patients at week 48. Among these RCTs, 2.62% of subjects participated in the TAF-containing regimens and 3.47% of subjects participated in the TDF-containing regimens initialled lipid-lowering medications during the treatment period, and no significant difference was observed 14

between two groups (RR, 0.74; 95%CI, 0.52-1.04; p > 0.05, Figure 5, D). Discussion According to the currently used guidelines, TDF or TAF can be utilized for the firstline antiretroviral therapy (Williams et al., 2012). However, the TDF-containing regimens may be associated with renal toxicity; previous comparative studies had demonstrated those TDF-containing regimens treatments were linked to a more significant loss in bone mineral density as compared with other NRTI options

ro of

(McComsey et al., 2011, Stellbrink et al., 2010). Given the prolonged survival of patients with HIV with effective therapy, and the need for indefinite treatment, TAFcontaining regimens provide superior antiviral activity comparable with TDF-

-p

containing regimens with an improved safety profile (Sax et al., 2014).

In our meta-analysis, the virologic response was expressed as virologic

re

suppression and virologic failure. For the naive patients, we demonstrated similar viral

lP

suppression effects in both groups by the ITT analysis (88.05% vs. 87.07%, p < 0.05) and PP analysis (96.43% vs. 95.32%, p < 0.05). Also, our results indicated that the TAFcontaining regimens did not effectively improve the immunological outcome during 48

na

weeks of therapy. Virologic failure (HIV RNA < 50 copies/mL) did not demonstrate any significant differences between the TAF-containing regimens and the TDF-

ur

containing regimens from baseline to weeks 48 and 96. Although the resistance to study

Jo

treatment occupied a small proportion in both groups, a small percentage of patients (< 1% in both groups) developed resistance to both ART regimens, most commonly Met184Val, a nucleoside reverse transcriptase inhibitor selected by emtricitabine (Sax et al., 2015b). Both treatments were generally safe and well-tolerated with equivalent AEs and few discontinuations due to AEs or laboratory toxicities. As a result, laboratory 15

abnormalities were usually mild to moderate in severity and resolved without study drug disruption. Treatments with TDF-containing regimens were consistently associated with less increase in lipids profile compared to TAF-containing regimens in the treatment-naive patients. However, median plasma lipid changes (including total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides) were significantly increased in the TAF-containing regimen. In contrast, there was no significant difference in total cholesterol/HDL ratio compared to TDF-containing regimens. The

ro of

lower concentrations of tenofovir in plasma from TAF as compared with TDF, the lipidlowering effect of TFV might explain the statistically significant increases in total

cholesterol in the TAF-containing regimens compared with the TDF-containing

-p

regimens (Behrens et al., 2012). Differences in lipid profiles were likely due to the loss of the lipid-lowering effect of TDF rather than an adverse effect of TAF or any other of

re

the components on lipids (Sax et al., 2015b). Despite the differences in fasting lipid

lP

parameters, a similar proportion of participants compared TAF vs. TDF group (2.62% vs. 3.47%, p > 0.05) initiated a lipid-lowering drug within 96 weeks of treatment. HIV-1 infected patients have a lower BMD than age-matched HIV-uninfected

na

controls, and they also experience higher fracture rates (Capeau, 2011, Guaraldi et al., 2011). The decrease in BMD revealed an increased prevalence of osteopenia and

ur

osteoporosis in patients with HIV infection (Brown and Qaqish, 2006). The cause is

Jo

multifactorial, with both HIV disease-specific and treatment-specific effects observed. Commonly, initiation of antiretroviral therapy leads to a reduction in bone mineral density (Grund et al., 2009), possibly related to immune reconstitution (Grant et al., 2013). However, in the meta-analysis, we noted that as bone density decreased in TAFcontaining regimens group, CD4 increased at week 48, accordingly. This result cited that the decrease in BMD might be associated with immune reconstitution. Presently, 16

about the mechanism of TDF-related reductions in bone mineral density was poorly understood but might include osteomalacia because of increased urinary phosphate loss (Mateo et al., 2016). Of note, in our analysis, the BMD in TAF-containing regimens was significantly less reduction than in the continuous TDF regimens at both the hip and spine over 48 weeks; therefore, it could be considered as a potential beneficial marker for preventing bone disease when switching from the TAF-containing regimens to the TDF-containing regimens.

ro of

Fractures occurred infrequently and were not different between TAF-containing regimens group and TDF-containing regimens group, with a remarkable high

heterogeneity was found in two separate drug combinations (0.35% vs. 0.67%,

-p

I2=73.8%, p = 0.050). We note that the heterogeneity might be caused by different drug combinations occurring in fewer populations. In one observational study, these

re

investigators noted that TDF exposure was associated with an increased rate of fractures

lP

(Bedimo et al., 2012). Although generally well-tolerated as initial treatment, findings of several studies have shown an association between ART regimens and kidney disease. In the analysis, after switched to the TAF-containing regimens, we noted that a

na

significant advantage was demonstrated in improving renal function, which occurred significantly decline in eGFR-CG as compared with patients who continued previous

ur

TDF-containing regimens for more than 48 weeks. Despite the exact mechanism of this

Jo

difference remains unclear but may be related to lower plasma TFV. TFV in plasma via organic anion enters proximal tubular transporter (OAT) 1 and OAT 3, but TAF is not a substrate for these transporters (Bam et al., 2014). It has been suspected that high doses of TFV cause TDF-related renal dysfunction through mitochondrial toxicity of their proximal tubular cells. Also, the excretion of a higher urinary protein was associated with an increased risk of death of HIV-infected patients (Choi et al., 2010, Wyatt et al., 17

2010). Therefore, we propose to improve the renal function by switching to the TAF regimen, which might aggravate renal damage. Furthermore, we found that only one study followed up to 96 weeks regarding clinical safety when switching TDFcontaining regimens to TAF-containing regimens; therefore, more long-term follow-up data are required to assess the clinical safety further. Overall, our week-24, week-48, and week-96 objective analysis demonstrated that the TAF-containing regimens was non-inferior to the TDF-containing regimens in fixed-dose single-tablet antiviral

ro of

therapy, which met statistical superiority for maintenance of viral suppression, the led to lower occurrence of AEs and smaller BMD decrease, and improvement of renal

function in the treatment-naive patients with HIV-1. Based on our findings, we believed

-p

that TAF was likely to be an alternative substitute for TDF in the initial anti-HIV therapy. Strengths and Limitations

re

The limitations of this meta-analysis included the use of different drug combinations in

lP

the study, the varying of drug doses, the extended time of the latest research considered, and the inclusion of only English publications. The differences in treatment regimens and medication doses in HIV infected patients among included studies might affect the

na

consistency of overall results. Additionally, a relatively small amount population with incomplete clinical indicators in clinical studies between phase 1/2 and 3 (Markowitz

ur

et al., 2014, Wohl et al., 2016), which might lead to increases of the risk of publication

Jo

bias. Furthermore, this analysis only analyzed the naive patients but neglected the patients who had experienced ART treatment, which might have led to a single result in guiding clinical rational drug use. Besides, in this analysis, we only calculated clinical studies during the follow-up period of 96 weeks, thereby longer-term followup is required to evaluate further the clinical significance linked to the advantages in renal, bone, and lipid effects of TAF-containing regimens. 18

Conclusions In conclusions, our findings lead us to argue that TAF would be an alternative substitute for TDF in the prevention of HIV initial infection. Our meta-analysis indicated that efficacy, safety, and tolerability of TAF-containing regimens were non-inferior in fixeddose single-tablet regimens for initial treatment of HIV-1. Furthermore, compared with those receiving the TDF-containing regimens, patients on the TAF-containing regimens had significant advantages in renal function, bone parameters, and lipid profile for the

ro of

naive patients. Author Contributions

XBT wrote the main manuscript text, XBT and YHZ searched the library and reviewed

-p

all articles, XBT and YQL conducted all meta-analysis, YHZ and LLZ prepared all figures, and YKC wrote part of the manuscript. All authors reviewed the manuscript.

re

Funding Source

lP

This work was supported by grants from National Major Scientific and Technological Special Project during the Thirteenth Five-year Plan Period (No. 2018ZX10302104), and the Chongqing Municipal Health and Family Planning Commission Medical

na

Research Projects (ZY201702045, ZY201702047, and ZY201702049). Conflict of Interest Statement

ur

The authors declare that there were no commercial or financial relationships in the

Jo

research that could be interpreted as a potential conflict of interest. Ethical Approval Not required.

19

References Akanbi MO, Scarci K, Taiwo B, Murphy RL. Combination Nucleoside/Nucleotide Reverse Transcriptase Inhibitors for Treatment of HIV Infection. Expert Opin Pharmaco 2012;13(1):65-79.

ro of

Aldir I, Horta A, Serrado M. Single-tablet regimens in HIV: does it really make a difference? Curr Med Res Opin 2014;30(1):89-97.

Bam RA, Yant SR, Cihlar T. Tenofovir alafenamide is not a substrate for renal organic anion transporters (OATs) and does not exhibit OAT-dependent cytotoxicity. Antivir Ther 2014;19(7):687-92.

Bedimo R, Maalouf NM, Zhang S, Drechsler H, Tebas P. Osteoporotic fracture risk associated with

-p

cumulative exposure to tenofovir and other antiretroviral agents. Aids 2012;26(7):825-31.

Behrens G, Maserati R, Rieger A, Domingo P, Abel F, Wang H, et al. Switching to tenofovir/emtricitabine from abacavir/lamivudine in HIV-infected adults with raised cholesterol: effect on lipid profiles. Antivir

re

Ther 2012;17(6):1011-20.

Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a metaanalytic review. Aids 2006;20(17):2165-74.

lP

Capeau J. Premature Aging and Premature Age-Related Comorbidities in HIV-Infected Patients: Facts and Hypotheses. Clinical Infectious Diseases 2011;53(11):1127-9. Choi AI, Li YM, Deeks SG, Grunfeld C, Volberding PA, Shlipak MG. Association Between Kidney Function and Albuminuria With Cardiovascular Events in HIV-Infected Persons. Circulation

na

2010;121(5):651-8.

DeJesus E, Ramgopal M, Crofoot G, Ruane P, LaMarca A, Mills A, et al. Switching from efavirenz, emtricitabine, and tenofovir disoproxil fumarate to tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with HIV-1 infection: a randomised, double-blind,

ur

multicentre, phase 3b, non-inferiority study. Lancet Hiv 2017;4(5):E205-E13. Eron JJ, Orkin C, Gallant J, Molina JM, Negredo E, Antinori A, et al. A week-48 randomized phase-3

Jo

trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients. Aids 2018;32(11):1431-42. Escobar I, Campo M, Martin J, Fernandez-Shaw C, Pulido F, Rubio R. Factors affecting patient adherence to highly active antiretroviral therapy. Ann Pharmacother 2003;37(6):775-81. Grant PM, Kitch D, McComsey GA, Dube MP, Haubrich R, Huang J, et al. Low Baseline CD4(+) Count Is Associated With Greater Bone Mineral Density Loss After Antiretroviral Therapy Initiation. Clinical Infectious Diseases 2013;57(10):1483-8. Grund B, Peng G, Gibert CL, Hoy JF, Isaksson RL, Shlay JC, et al. Continuous antiretroviral therapy decreases bone mineral density. Aids 2009;23(12):1519-29. Guaraldi G, Orlando G, Zona S, Menozzi M, Carli F, Garlassi E, et al. Premature Age-Related Comorbidities Among HIV-Infected Persons Compared With the General Population. Clinical Infectious 20

Diseases 2011;53(11):1120-6. Jeong SJ, Song JE, Kim SB, Kim HW, Ku NS, Han SH, et al. Plasma Klotho Levels Were Inversely Associated with Subclinical Carotid Atherosclerosis in HIV-Infected Patients Receiving Combined Antiretroviral Therapy. Aids Res Hum Retrov 2013;29(12):1575-81. Markowitz M, Zolopa A, Squires K, Ruane P, Coakley D, Kearney B, et al. Phase I/II study of the pharmacokinetics, safety and antiretroviral activity of tenofovir alafenamide, a new prodrug of the HIV reverse transcriptase inhibitor tenofovir, in HIV-infected adults. J Antimicrob Chemoth 2014;69(5):13629. Mateo L, Holgado S, Marinoso ML, Perez-Andres R, Bonjoch A, Romeu J, et al. Hypophosphatemic osteomalacia induced by tenofovir in HIV-infected patients. Clin Rheumatol 2016;35(5):1271-9. McComsey GA, Kitch D, Daar ES, Tierney C, Jahed NC, Tebas P, et al. Bone Mineral Density and Fractures in Antiretroviral-Naive Persons Randomized to Receive Abacavir-Lamivudine or Tenofovir Disoproxil Fumarate-Emtricitabine Along With Efavirenz or Atazanavir-Ritonavir: AIDS Clinical Trials

ro of

Group A5224s, a Substudy of ACTG A5202. J Infect Dis 2011;203(12):1791-801.

Mills A, Crofoot G, Jr., McDonald C, Shalit P, Flamm JA, Gathe J, Jr., et al. Tenofovir Alafenamide Versus Tenofovir Disoproxil Fumarate in the First Protease Inhibitor-Based Single-Tablet Regimen for

Initial HIV-1 Therapy: A Randomized Phase 2 Study. J Acquir Immune Defic Syndr 2015;69(4):439-45. Mocroft A, Kirk O, Reiss P, De Wit S, Sedlacek D, Beniowski M, et al. Estimated glomerular filtration

-p

rate, chronic kidney disease and antiretroviral drug use in HIV-positive patients. Aids 2010;24(11):166778.

Morlat P, Vivot A, Vandenhende MA, Dauchy FA, Asselineau J, Deti E, et al. Role of Traditional Risk

re

Factors and Antiretroviral Drugs in the Incidence of Chronic Kidney Disease, ANRS CO3 Aquitaine Cohort, France, 2004-2012. Plos One 2013;8(6).

Orkin C, Eron JJ, Rockstroh J, Podzamczer D, Esser S, Vandekerckhove L, et al. Week 96 results of a

lP

phase 3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients. Aids 2019.

Rathbun RC, Lockhart SM, Stephens JR. Current HIV treatment guidelines--an overview. Curr Pharm Des 2006;12(9):1045-63.

na

Sax PE, Wohl D, Yin MT, Post F, DeJesus E, Saag M, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1

infection:

two

randomised,

double-blind,

phase

3,

non-inferiority

trials.

Lancet

ur

2015a;385(9987):2606-15.

Sax PE, Wohl D, Yin MT, Post F, DeJesus E, Saag M, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of infection:

two

randomised,

double-blind,

phase

3,

non-inferiority

trials.

Lancet

Jo

HIV-1

2015b;385(9987):2606-15. Sax PE, Zolopa A, Brar I, Elion R, Ortiz R, Post F, et al. Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study. J Acquir Immune Defic Syndr 2014;67(1):52-8. Stellbrink HJ, Orkin C, Arribas JR, Compston J, Gerstoft J, Van Wijngaerden E, et al. Comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIVinfected adults: 48-week results from the ASSERT study. Clin Infect Dis 2010;51(8):963-72. Sterrantino G, Santoro L, Trotta M, Antinori A, Bartolozzi D, Zaccarelli M. Self-reported adherence supports patient preference for the single tablet regimen (STR) in the current cART era. J Int Aids Soc 21

2012;15:33-4. Tao XB, Lu YQ, Zhou YH, Huang YQ, Chen YK. Virologically suppressed HIV-infected patients on TDF-containing regimens significantly benefit from switching to TAF-containing regimens: A metaanalysis of randomized controlled trials. Int J Infect Dis 2019;87:43-53. Van Rompay KKA, Durand-Gasselin L, Brignolo LL, Ray AS, Abel K, Cihlar T, et al. Chronic administration of tenofovir to rhesus macaques from infancy through adulthood and pregnancy: Summary of pharmacokinetics and biological and virological effects. Antimicrob Agents Ch 2008;52(9):3144-60. Williams I, Churchill D, Anderson J, Boffito M, Bower M, Cairns G, et al. British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012. Hiv Med 2012;13:1-85. Wohl D, Oka S, Clumeck N, Clarke A, Brinson C, Stephens J, et al. A Randomized, Double-Blind Comparison of Tenofovir Alafenamide Versus Tenofovir Disoproxil Fumarate, Each Coformulated With

ro of

Elvitegravir, Cobicistat, and Emtricitabine for Initial HIV-1 Treatment: Week 96 Results. Jaids-J Acq Imm Def 2016;72(1):58-64.

Wyatt CM, Hoover DR, Shi QH, Seaberg E, Wei C, Tien PC, et al. Microalbuminuria Is Associated With

Jo

ur

na

lP

re

-p

All-Cause and AIDS Mortality in Women With HIV Infection. Jaids-J Acq Imm Def 2010;55(1):73-7.

22

Legends

na

lP

re

-p

Figure 2. Risk-of-bias summary for the included studies.

ro of

Figure 1. Flow diagram of the study selection process for the meta-analysis.

ur

Figure 3. Meta-analysis of efficacy outcomes of 5 RCTs with the regimen switching from TAF-containing to TDF-containing for treatment-naive patients. (A) Viral

Jo

suppression under intention-to-treat analysis. (B) Viral suppression under per-protocol analysis. (C) CD4+ cell count. (D) Virologic failure. (E) Adherence.

23

Figure 4. Meta-analysis of safety outcomes of 5 RCTs with the regimen switching from

ro of

TAF-containing to TDF-containing for the treatment-naive patients. (A) Adverse events. (B) Discontinued due to adverse events. (C) Grade 3 or 4 adverse event. (D)

na

lP

re

-p

Fractures.

Figure 5. Bone and renal adverse events compared TAF-containing regimens to TDF-

ur

containing regimens in the hip and spine at week 48. (A) BMD decreases of > 3% from baseline at the hip. (B) BMD decreases of > 3% from baseline at the spine. (C)

Jo

Renal events. (D) Initiation of lipid-lowering therapy.

24

25

Jo

NCT01497899

NA

mRCT

AMBE

AMBER

NCT02431247

X3001;

TMC114FD2HT

NCT02431247

NCT01797445

292-0111

NCT01780506/

GS-US-292-

NCT01797445

0104/ GS-US-

292-0111

0104/ GS-US-

NCT01780506/

5

3

3

3

3

2

2

96

48

96

48

48

48

E (150 mg)/C (150

TDF (300 mg )

Control group

D (800 mg)/C (300 mg) (150

lP (300 mg)

E (150 mg)/C (150

D (800 mg)/C (150

(300 mg)

(10 mg)

(300 mg)

725

1725

1733

1733

153

170

30

Patients

NA

34

34

34

33

36

34

Age (years)

ro of

mg)/F (200 mg)/TAF mg)/F (200 mg)/TDF Double-blind

D (800 mg)/C (150

(10 mg)

Double-blind

Double-blind

-p

D (800 mg)/C (150

D (800 mg)/C (150 mg)/F (200 mg)/TAF mg)/F (200 mg)/TDF

(300 mg)

mg)/F (200 mg)/ TDF

TAF (10 mg)

mg)/F (200 mg)/

E (150 mg)/C (150

Double-blind

Double-blind

Double-blind

Masking

mg)/F (200 mg)/ TDF Double-blind

re

TAF (10 mg)

mg)/F (200 mg)/

(10 mg) E (150 mg)/C (150

(300 mg) E (150 mg)/C (150

mg)/F (200 mg)/TAF mg)/F (200 mg)/TDF

D (800 mg)/C (10 mg) (150

mg)/F (200 mg)/TAF mg)/F (200 mg)/TDF

E (150 mg)/C (150

TAF (40/120 mg )

Treatment Experimental group (weeks)

*

16Countries*

16Countries

USA

USA

USA

Countries

640 (88%) 10 countries

638 (88%) 10 Countries*

(85%)

1473

(85%)

1473

(92.8%)

142

(83.3%)

194

27 (90%)

Men

American, Other

Black/African-

White,

American, Other

Black/African-

Asian White,

Hispanic or Latino,

African heritage,

White, Black or

Asian

Hispanic or Latino,

African heritage,

White, Black or

Hispanic/Latino White, Black, Other

African descent,

White, Black,

Black, Other

Races

ITT/PP

ITT/PP

ITT

ITT/PP

ITT

ITT

NA

Analytic method

10Countries*, USA, Canada, Belgium, France, Germany, Italy, Poland, Russia, Spain, UK.

16Countries*, North America, Europe, Australia, Japan, Thailand, North America, Europe, and Latin America.

10 Countries* , USA, Canada, Belgium, France, Germany, Italy, Poland, Russia, Spain, UK.

16 Countries* , North America, Europe, Australia, Japan, Thailand, North America, Europe, and Latin America

intention-to-treat; PP, per-protocol.

Data are n (%) or mean/median (as available), unless stated otherwise. NA, not available; CTG, clinicals.gov identification number;multicenter RCT; E, elvitegravir; C, cobicistat; F, emtricitabine; D, darunavir; ITT,

(2019)

Orkin et al

Eron et al (2018) mRCT

Wohl et al (2016) mRCT

Sax et al (2015) mRCT

GS-US-292-

1/2

Phase

na

ur

CTG

Mills et al (2015) mRCT GS-US-299-0102 NCT01565850

Sax et al (2014)18 mRCT

292-0102

GS-7340-02

Markowitz et al mRCT

(2014)

Study name

Type

Reference

Table 1. General characteristics of studies included in the meta-analysis.

26

ro of

-p

re

lP

na

ur

Jo