Dolutegravir (DTG)–based dual therapy is becoming a new paradigm for both the initiation and maintenance of HIV treatment. The SIMPL’HIV study investigated the outcomes of virologically suppressed patients on standard combination antiretroviral therapy (cART) switching to DTG + emtricitabine (FTC). We present the 48-week efficacy and safety data on DTG + FTC versus cART.3; median age was 48 years; 17% of participants were female. DTG + FTC was non-inferior to cART. The proportion of patients with viral suppression (<100 copies/ml) through 48 weeks was 93.5% in the DTG + FTC arm and 94.7% in the cART arm in the intention-to-treat population . Per-protocol analysis showed similar results, with viral suppression in 96.5% of patients in both arms . There was no relevant interaction between the type of treatment and monitoring . Using the FDA snapshot algorithm, 84/93 (90.3%) participants in the DTG + FTC arm had an HIV-1 RNA viral load of <50 copies/ml compared to 86/94 (91.5%) participants on standard cART . The overall proportion of patients with adverse events and discontinuations did not differ by randomization arm. The proportion of patients with serious adverse events was higher in the cART arm (16%) compared to the DTG + FTC arm (6.5%) (p = 0.041), but none was considered to be related to the study medication. Quality of life improved more between baseline and week 48 in the DTG + FTC compared to the cART arm . The study’s main limitations included a rather small proportion of women included, the open label design, and its short duration.SIMPL’HIV was a multicenter, open-label, non-inferiority randomized trial with a factorial design among treatment-experienced people with HIV in Switzerland. Participants were enrolled between 12 May 2017 and 30 May 2018. Patients virologically suppressed for at least 24 weeks on standard cART were randomized 1:1 to switching to DTG + FTC or to continuing cART, and 1:1 to simplified patient-centered monitoring versus standard monitoring. The primary endpoint was the proportion of patients virologically suppressed with <100 copies/ml through 48 weeks. The secondary endpoints included virological suppression at 48 weeks according to the US Food and Drug Administration (FDA) snapshot analysis. Non-inferiority of DTG + FTC versus cART for viral suppression was assessed using a stratified Mantel–Haenszel risk difference, with non-inferiority declared if the lower bound of the 95% confidence interval was greater than −12%. Adverse events were monitored to assess safety. Quality of life was evaluated using the PROQOL-HIV questionnaire. Ninety-three participants were randomized to DTG + FTC, and 94 individuals to cART. Median nadir CD4 count was 246 cells/mmIn this study, DTG + FTC as maintenance therapy was non-inferior to cART in terms of efficacy, with a similar safety profile and a greater improvement in quality of life, thus expanding the offer of 2-drug simplification options among virologically suppressed individuals.NCT03160105.ClinicalTrials.gov  Delphine Sculier and co-workers study switching to dual antiretroviral therapy including dolutegravir in virologically-suppressed patients with HIV infection. Treatment simplification among people with HIV has been tested worldwide and includes reducing the number and/or dosage of antiretroviral drugs, and simplifying monitoring, but without compromising adherence and quality of life.We evaluated the combination of dolutegravir (DTG) + emtricitabine (FTC) as an alternative to standard therapy combinations in an HIV population highly representative of routine clinical conditions.Simplified patient-centered monitoring was also evaluated, to allow patients to receive care outside the hospital as is usual in Switzerland.We conducted the SIMPL’HIV study, a randomized trial with a factorial design, to permit patients with a suppressed viral load to receive a simplified treatment of DTG + FTC and/or simplified patient-centered monitoring.Efficacy of the DTG + FTC regimen was defined as keeping the patient’s HIV viral load below 100 copies/ml through 48 weeks of study duration.The combination of DTG with FTC had a similar efficacy in maintaining viral suppression through 48 weeks of treatment as standard combined antiretroviral therapy, without jeopardizing safety, and it improved patient quality of life.These results provide further evidence on the efficacy of 2-drug DTG-based regimens as a simplified switch option for patients whose viral load is well controlled on standard treatment, including those with a low CD4 nadir, and expands the currently existing options for dual maintenance therapy.Our efficacy definition allowed us to observe the occurrence of HIV viral load blips, irrespective of the treatment arm, without any consequences for HIV management.The quality of life of the participants was already very satisfactory at the start of the study and further increased over time with the simplified DTG + FTC treatment. Treatment optimization has been at the forefront of innovative HIV-1 care management. Dual-therapy regimens are already considered appropriate alternatives to standard combination antiretroviral therapy (cART) as they have been approved by the US Food and Drug Administration (FDA) and the European AIDS Clinical Society (EACS) guidelines for both initial and maintenance therapy .Dual therapy may also be associated with reduced toxicity and costs and improved tolerability, adherence, and quality of life (QoL) .In recent years, there has been a focus on dolutegravir (DTG)–based simplification therapy. DTG is a potent second-generation integrase strand transfer inhibitor (InSTI) with a high genetic barrier to resistance, rare severe side effects, and very few drug–drug interactions . While DWe aimed to investigate the efficacy and safety of DTG plus emtricitabine (FTC) dual therapy, which has not yet been examined to our knowledge. FTC is similar to 3TC with respect to the convenience, safety, and resistance profile, but it has a longer intracellular half-life activity and shows greater in vitro potency, results that contributed to the selection of FTC for subsequently developed triple antiretroviral fixed dose combinations . We aimeSIMPL’HIV was a multicenter, non-inferiority, open-label, randomized, factorial trial conducted in Switzerland. The primary objective of SIMPL’HIV was to assess the 48-week efficacy and safety of DTG + FTC dual maintenance therapy in virologically suppressed PWHIV compared with standard cART. As a co-primary objective, the study aimed to compare a patient-centered monitoring (PCM) approach with standard 3-monthly routine surveillance (standard monitoring [SM]). Here we focus on the comparison between DTG + FTC and cART in terms of efficacy, safety, and QoL; costs and other outcomes for the comparison of the monitoring options are not reported in this paper.SIMPL’HIV was performed in the 7 main Swiss HIV Cohort Study (SHCS) sites  with parParticipants were randomly assigned 1:1 to switch to DTG + FTC dual maintenance therapy or continue their cART, and 1:1 to PCM or SM . An indePatients were randomized to receive a once-daily 2-drug regimen of DTG 50 mg plus FTC 200 mg or to continue their standard cART, as well as to PCM or SM. Allocation to SM consisted of 3-monthly routine immunological and blood safety tests including CD4 cell count, lipid profile, glucose level, renal and hepatic function tests, and creatinine kinase, with all visits and laboratory analyses conducted at the affiliated SHCS sites. Participants allocated to the PCM arm had a restricted immunological and blood safety monitoring at weeks 0 and 48. In addition, participants were offered the choice to complete some of the study visits by a telephone call with a study nurse, to have their drugs delivered to a specified address, or to have their blood tests performed at alternative locations, including certified private laboratories.All participants had HIV-1 RNA measurements performed at all study visits, which were scheduled every 6 weeks between baseline and week 12, and every 12 weeks thereafter until the study ended. We quantified HIV-1 RNA levels using PCR assays with a limit of detection of 20 copies/ml or less at local virology laboratories. Patients with HIV-1 RNA between 20 and 99 copies/ml were retested after 6 weeks (±5 days). Patients with HIV-1 RNA ≥ 100 copies/ml were retested after 14 days (±5 days), received additional adherence sessions, had their concomitant medications reviewed, and had drug plasma concentration measurements performed. In patients with virological failure, defined as 2 consecutive plasma HIV-1 RNA values ≥ 100 copies/ml, genotypic resistance testing was performed as part of routine care by 4 laboratories in Switzerland authorized by the Federal Office of Public Health. All laboratories performed population-based sequencing. Drug resistance was defined using the French National Agency for AIDS Research version 29 algorithm –17.We recorded adverse events, concomitant medications, and adherence checks and performed symptom-directed physical examinations at all study visits. We graded adverse events by severity on a scale from 1 to 4 using the categories in the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use E2A guidelines . SeriousThe primary outcome for the comparison between DTG + FTC and cART was the maintenance of HIV-1 RNA < 100 copies/ml through the 48-week duration of the study. A single blip, defined as HIV-1 RNA between 100 and 199 copies/ml at any time during the study period, was allowed as long as this measurement was followed by an HIV-1 RNA result of <50 copies/ml. Secondary endpoints included the proportion of patients with HIV-1 RNA < 50 copies/ml at week 48 according to the FDA snapshot algorithm ,21 from Safety endpoints included the incidence, type, and seriousness of adverse events, as well as the discontinuation of treatment. Renal function, lipids, Framingham cardiovascular risk score, glucose, and weight were monitored by assessing changes from baseline to week 48.The co-primary outcome, for the comparison between PSM and SM, was the direct costs from the healthcare system perspective of the 2 monitoring options. Secondary outcomes for the comparison of monitoring arms included cost-effectiveness; the number of extra visits during the study period; in the PSM arm, participants’ monitoring satisfaction and the proportion of participants expressing willingness to change monitoring options during the study; and all participants’ satisfaction with treatment, monitoring, and study participation. Primary and secondary outcomes related to the comparison of the monitoring options will not be presented in this paper.We determined the target sample size for the non-inferiority comparison between DTG + FTC and cART on the primary outcome, assuming that there was no interaction between the treatment and monitoring strategy. The targeted sample size of 184 patients  was based on 80% power, a 2.5% 1-sided alpha level, expected proportions of HIV-1 RNA < 100 copies/ml through 48 weeks of 94% and 97% in the DTG + FTC and cART arm, respectively, and a non-inferiority margin of −12%, as used in previous non-inferiority HIV trials –29.p-value using the Mantel–Haenszel test of homogeneity in order to exclude that the treatment effect on viral suppression was different depending on the type of monitoring.We primarily analyzed the trial as a stratified 2-arm trial comparing DTG + FTC with cART, with monitoring type (PCM versus SM) being the stratification factor. The primary outcome was assessed in both the intention-to-treat (ITT) and per-protocol (PP) populations, as recommended by the FDA guidance for non-inferiority trials . PP exclWe summarized baseline characteristics and adverse events using descriptive statistics. We evaluated the primary outcome using the Mantel–Haenszel risk difference stratified by the monitoring type , declariNCT03160105). This report was written according to the CONSORT statement for non-inferiority trials; the CONSORT checklist is available in An independent data monitoring committee reviewed descriptive safety data after the first 100 participants had completed the week 24 study visit. SIMPL’HIV is registered on ClinicalTrials.gov , discontinuation due to an adverse event (n = 2), change to previous cART for a reason other than virological failure (n = 1), and low adherence (n = 1).Of 873 individuals screened for eligibility, 188 were randomly assigned either to switch to DTG + FTC dual therapy or to continue their cART . One ran3 (IQR 103–330) in the DTG + FTC arm, and 253 cells/mm3 (IQR 174–367) in the cART arm. Standard cART at inclusion comprised an association of 2 NRTIs with an InSTI for two-thirds of participants. DTG was the InSTI received before study entry for one-half of all participants.Key demographic and baseline characteristics were well balanced between the treatment arms in the ITT population . Particip = 0.81). We did not observe any difference in efficacy by monitoring arm  participants in the DTG + FTC dual therapy arm and 89/94 (94.7%) in the cART arm achieved HIV-1 RNA < 100 copies/ml throughout 48 weeks in the ITT population  ; Fig 2A.ring arm . One patp = 0.791) (p = 0.671).Using the FDA snapshot algorithm, 84/93 (90.3%) participants in the DTG + FTC arm had HIV-1 RNA < 50 copies/ml at week 48, compared to 86/94 (91.5%) in the standard cART arm  . Two pat= 0.791) . AdherenWe did not observe any new occurrence of resistance, and thus no loss of future drug options, among patients who virologically failed according to the primary or secondary outcome. Of note, we did not detect DTG plasma levels for the patient who experienced virological failure according to the primary outcome. Still, 41L and 69D thymidine analogue mutations were present at the time of virological failure. These mutations were transmitted as they were observed in the genotyping performed at the time of HIV diagnosis, before any exposure to HIV treatment. Overall, no patient required a change of therapy, although 1 patient in the DTG + FTC arm requested to switch back to standard cART due to low-level viremia occurring before week 48. As we only observed 1 virological failure, we were not able to explore risk factors for this outcome.p = 0.041). None of the serious adverse events was considered to be related to the study medication. There was no difference in the proportion of participants with serious adverse events by monitoring arm  (The most commonly reported adverse events across both treatment arms were upper respiratory infection (20.9%), headache (10.2%), diarrhea (7%), and insomnia (4.3%) . The pro= 0.781) . One par2; 95% CI −7.3 to −1.3; p = 0.006). We observed a slight increase in weight in both arms, but without a statistically significant difference between the arms. Changes between baseline and week 48 in safety endpoints are presented in We observed no difference in the change in CD4 count or lipid profile from baseline to week 48 between the treatment arms. Creatinine clearance was significantly lower in the DTG + FTC arm compared to the cART arm (adjusted difference −4.3 ml/min/1.73 mp = 0.023) (p = 0.166).Mean scores for QoL at baseline and week 48 were high in both treatment arms as measured by the PROQOL-HIV questionnaire. The PROQOL score was rated above 80/100 points for all participants at week 48. Change in QoL between baseline and week 48 with this measure was statistically superior in the DTG + FTC arm (+2.9 points) compared to the cART arm (+0.3 points)  . We obseAt study termination, patients were offered the choice of remaining on their allocated treatment or switching to another regimen; 85.6% of patients in the dual therapy arm decided to stay on the dual combination of DTG + FTC, whereas 32.2% of participants in the cART decided to initiate DTG + FTC.SIMPL’HIV, a nationwide randomized trial in Switzerland, tested FTC in combination with DTG as a 2-drug regimen. Switching HIV-1-infected virologically suppressed participants to DTG + FTC was non-inferior in terms of efficacy compared to maintaining standard cART through a duration of 48 weeks. ITT analysis showed that the percentage of patients maintaining viral suppression (<100 copies/ml) through 48 weeks was 93.5% in the DTG + FTC arm and 94.7% in the cART arm, thus confirming non-inferiority of the 2-drug arm. We demonstrated a good safety profile of the dual therapy, with few serious adverse events, 6.5% of patients in the DTG + FTC arm and 16% in the cART arm. None was drug-related. QoL improved more between baseline and week 48 in the DTG + FTC arm compared to the cART arm, while there was no difference in QoL over time in the PCM arm compared to the SM one. The lack of improvement in QoL whatever the monitoring arm might reflect the already facilitated access to care in Switzerland and the high level of trust by patients in the healthcare system.3 [IQR 147–340]), thus reflecting routine urban HIV care.The FDA snapshot virological outcome, with 90.3% of patients having virological suppression in the DTG + FTC arm versus 91.5% in the cART arm, also met the non-inferiority criterion. Our results are similar to those of the TANGO trial, in which 93.2% of patients had virological suppression in the DTG/3TC arm versus 93% in the standard ART arm , and theThe safety profile of DTG + FTC was consistent with the safety profiles of DTG/3TC and DTG/rilpivirine in the TANGO and SWORD trials, respectively. We observed a significantly lower estimated creatinine clearance in the DTG + FTC compared to the cART arm. DTG is known to increase serum creatinine and reduce creatinine clearance by inhibiting the tubular secretion of creatinine . HoweverOur novel viral suppression outcome, defined as HIV-1 RNA < 100 copies/ml through 48 weeks’ duration, allowed us to observe the occurrence of blips in both treatment arms, with no consequences for HIV management. However, we did not assess inflammatory parameters, which may be affected in the context of continuous antigen exposure. SIMPL’HIV addressed treatment optimization not only by assessing a 2-drug maintenance regimen, but also by simplifying HIV-1 monitoring through reducing the frequency of immunological and safety measurements and providing patient-friendly approaches for follow-up. Treatment optimization cannot only be driven by changes or modulations of antiretroviral drugs; drug and care delivery, including the frequency of laboratory tests, contribute to patient satisfaction and cost control. To our knowledge, no study has assessed such management optimization in a high-income country.Our study has some limitations. First, despite our efforts to include women in a similar proportion to our national prospective SHCS cohort, i.e., 28%, we failed to reach this target. A qualitative study is planned to understand barriers—a possible implicit sex bias in research both from the researcher side and from the participant side—to the participation of women in clinical trials in Switzerland. Second, the open-label design may have introduced bias regarding the reporting of adverse events. Such bias may explain the lower number of serious adverse events observed in the DTG + FTC arm, because all participants were stable on standard cART for nearly a decade before the start of the study, and such a difference was not expected. Finally, our study duration of 48 weeks was short, and a longer follow-up is needed to document the durability of DTG + FTC dual therapy in terms of efficacy and safety. All study participants will be followed over an extended 3-year period to assess these issues.The only virological failure occurred in a patient who had transmitted thymidine analogue mutations at the time of HIV-1 diagnosis, before any exposure to antiretroviral drugs. Thus, the results from resistance tests, as well as a detailed medical history, should be considered before switching to a simplified therapy. Of note, this patient was randomized to cART, and we did not detect any drug plasma concentration at the time of virological failure. Importantly, no patient lost drug options during the course of the study.In conclusion, this study provides evidence that the combination of DTG + FTC expands the possibility of offering 2-drug simplification in maintenance treatment, especially as both drugs are available as generic formulations. The combination demonstrated non-inferiority in efficacy and safety, as well as a greater improvement in QoL over time compared to standard regimens. An ongoing assessment of data from the SIMPL’HIV study regarding healthcare-related costs and patient choices and satisfaction will provide additional insights into potential advantages of dual therapy and PCM.S1 Fig(TIF)Click here for additional data file.S1 TableITT analysis.(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 TableITT analysis.(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S1 Text(DOC)Click here for additional data file.S2 Text(PDF)Click here for additional data file. 13 Mar 2020Dear Dr Sculier, Thank you for submitting your manuscript entitled "Efficacy and safety of dolutegravir plus emtricitabine versus standard ART for the maintenance of HIV-1 suppression: 48-week results of the factorial, randomized, non-inferiority SIMPL-HIV trial" for consideration at PLOS Medicine.Your manuscript has now been evaluated by the PLOS Medicine editorial staff, as well as by an academic editor with relevant expertise, and I am writing to let you know that we would like to send your submission out for external review.However, before we can send your manuscript to reviewers, we need you to complete your submission by providing the metadata that is required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire.Please re-submit your manuscript within two working days, i.e. by .https://www.editorialmanager.com/pmedicineLogin to Editorial Manager here: Once your full submission is complete, your paper will undergo a series of checks in preparation for peer review. Once your manuscript has passed all checks it will be sent out for review. plosmedicine@plos.org if you have any queries relating to your submission.Feel free to email us at Kind regards,Richard Turner, PhDSenior editor, PLOS Medicinerturner@plos.org 25 Aug 2020Dear Dr. Sculier,Thank you very much for submitting your manuscript "Efficacy and safety of dolutegravir plus emtricitabine versus standard ART for the maintenance of HIV-1 suppression: 48-week results of the factorial, randomized, non-inferiority SIMPL-HIV trial" (PMEDICINE-D-20-00718R1) for consideration at PLOS Medicine. We do apologize for the delay in sending you a decision. Your paper was evaluated by an academic editor with relevant expertise and sent to independent reviewers, including a statistical reviewer. 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For instructions see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it. Please ensure that the paper adheres to the PLOS Data Availability Policy .Please convert reference call-outs to the following style throughout the text: "... maintenance therapy ." (noting the missing full point at line 113). The details for some references seem incomplete, e.g., reference 16.Please remove all instances of "[Internet]" from the reference list, and convert French text to English. Please include a completed CONSORT checklist as a supplementary file, referred to in the Methods section . In the checklist, please refer to individual items by section  and paragraph number rather than by line or page numbers, as the latter generally change in the event of publication. Comments from the reviewers:*** Reviewer #1: Statistical reviewThis paper reports a randomised controlled trial comparing continuing cART with switching to dual DTG+FTC therapy in HIV patients who are virally supressed. A secondary randomisation is between a simplified monitoring strategy and normal monitoring. The authors show the DTG+FTC therapy is non-inferior to continuing cART, with some QoL advantages. Generally the paper used appropriate statistical methods. I have some minor comments on the reporting:1. Abstract "patients were randomized 1:1:1:1…" I would recommend rewriting this sentence to emphasise that patients were randomised 1:1 between continuing cART and switching, and 1:1 between PCM and SM.2. Abstract line 92/93 - I would recommend putting the non-inferiority margin earlier in the abstract and giving a p-value for non-inferiority in addition to the CI for risk difference.3. Methods - there is no mention of blinding. the study was not double-blinded, but was there any blinding (e.g. rater-blinding?).4. Methods, outcomes - I would recommend all secondary outcomes listed on the clinicaltrials.gov registration are mentioned in the main body of the paper (even if they are not reported in the paper).5. Methods, sample size calculation - "We primarily analyzed the trial as a stratified two-arm trial" - I would mention the stratification factor in this sentence (i.e. the monitoring type).6. Methods, sample size calculation - was the sample size chosen to find a difference in monitoring types, if it existed? I see in the protocol this is based on cost differences, which are not reported in this paper - I would suggest it might be informativ to add this to the sample size calculation and say that these outcomes are not reported in this paper.7. Results line 287 - I didn't follow what a randomisation occurring by mistake meant - was the patient ineligible? 8. Results - I would recommend all secondary endpoints are reported in a table in the main body of the paper, as opposed to in supplementary material.9. Line 394 - I recommend adding 'significant' between 'no' and 'difference'.James Wason*** Reviewer #2: Overall a well-designed and conducted study demonstrating the non-inferiority of DTG/FTC to standard cART in maintaining virologic suppression in treated patients. Minor comments: 1. More needs to be explicitly said regarding the relatively low number of female participants recruited to the study, in comparison to the gender proportions of the Swiss HIV cohort as a whole. 2. In general, the authors can consider making more explicit the rationale for the entire study - it is not immediately clear why the combination of DTG/FTC is required given that the evidence for DTG/3TC is fairly well-established, and FTC and 3TC are essentially clinically equivalent. A statement on this would clarify their position, as well as situate the study in the context of antiretroviral choices available to patients and prescribers. 3. It is somewhat surprising that there was no significant difference in the QOL indices between participants undergoing SCM and PCM. What are some of the postulated reasons for this? Otherwise, no other issues and would recommend acceptance. *** Reviewer #3: Overall, this is a well-executed trial with appropriate study design. The biggest aspect that needs to be addressed in this study is why it was conducted, how it will supplement the data already available, and in what patient scenarios would this data be applicable. Additionally, one of the secondary outcomes is quality of life, with this trial being an open-label design you allow for bias while assessing subjective matters. Generally, I felt the article verbiage flowed well and there were few grammatical errors. I did feel that the difference between the patient-centered simplified monitoring (PCM) and the standard monitoring (SM) could have been elaborated on further. Global Recommendations: 1. Instead of "HIV-1 infected adults" use "people living with HIV (PLWH)"Abstract: 1. On page 4, they define virologic suppression as having < 100 copies/mL. Later on page 7, under the methods section, they state that they "define virological suppression as HIV-11 RNA of < 50 copies/mL"Introduction:1. Need more convincing of why this research was conducted? The pill burden would be increasing for the patient which could lead to decreased adherence and worse clinical outcomes. Why would you ever make this switch in clinical practice when there is dolutegravir/lamivudine? 2. On page 7, in the introduction section, there is a statement that says "As a second primary objective, the study aimed to compare the costs of the patient-centered monitoring (PCM) approach with standard 3-monthly routine surveillance" - within the primary outcome section, there is no mention of the results of this objective. It is never addressed.Methods: 1. On page 4, they define virologic suppression as having < 100 copies/mL. Later on page 7, under the methods section, they state that they "define virological suppression as HIV-11 RNA of < 50 copies/mL" Results:1. Table 1, the demographic between the study group and they cART group. Based on the patient information on the table, the DTG+FTC group appears to be more compromised than the cART group, The DTG+FTC patient's median CD4 baseline is low, while the medical viral load was higher. Additionally, the DTG+FTC group had been receiving ART longer than the cART group, on average. 2. An aspect I found interesting was that if you look at table 3 on page 17, there appear to be substantially more serious adverse effects from the cART group compared to the DTG+FTC group. This was not highlighted in the article. 3. On page 17, they point out that the CrCl for the DTG+FTC group is significantly lower than the cART patients. The authors do not offer any explanation of why they believe this to be happening.***Any attachments provided with reviews can be seen via the following link:[LINK] 17 Sep 2020AttachmentResponses_to_reviewers.docxSubmitted filename: Click here for additional data file. 25 Sep 2020Dear Dr. Sculier,Thank you very much for re-submitting your manuscript "Efficacy and safety of dolutegravir plus emtricitabine versus standard ART for the maintenance of HIV-1 suppression: 48-week results of the factorial, randomized, non-inferiority SIMPL-HIV trial" (PMEDICINE-D-20-00718R2) for consideration at PLOS Medicine.I have discussed the paper with editorial colleagues and our academic editor, and I am pleased to tell you that, provided the remaining editorial and production issues are fully dealt with, we expect to be able to accept the paper for publication in the journal.The issues that need to be addressed are listed at the end of this email. 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Limited data are available on the effect of antiretroviral treatment (ART) or Tenofovir disoproxil fumarate (TDF) on renal function in Ethiopians. We aimed to assess factors associated with renal function changes during the first year of ART with special focus on TDF.HIV positive persons who were ≥ 18 years of age and eligible for ART initiation were recruited. Creatinine measurement to estimate glomerular filtration rate (eGFR) and spot urine analyses were performed at baseline and after 3, 6 and 12 months of ART. Univariate and multivariate linear regression and univariate logistic regression were used to determine factors associated with eGFR as continuous and categorical variable respectively. A linear mixed model was used to assess 12 month eGFR difference in TDF and non-TDF based regimen.2. About 41 and 26.9% of HIV patients had a drop of greater than 3 and 10 mL/min/1.73 m2 in eGFR at 12 month, respectively. However, none of the HIV patients declined to < 60 ml/min/1.73m2 within 12 months. Moreover, none of the HIV patients had persistent proteinuria or glycosuria. Older HIV patients especially age > 45 years and those with unsuppressed viral load at 6 month of ART had a significantly lower eGFR at 12 months of ART initiation. However, there was no difference in 12 month eGFR between HIV patients initiated on TDF based regimen and non-TDF based regimen.Of 340 ART-naïve HIV patients with baseline renal function tests, 82.3% (279/339) were initiated on a TDF based ART regimen. All patients were on non-nucleoside reverse transcriptase inhibitors (NNRTI) based ART regimen. The median (IQR) change in eGFR with 12 months of ART was 0.8  ml/min/1.73mRenal function remained stable with no difference between HIV patients treated with TDF or non-TDF NNRTI based ART regimen over 12 months. However, older HIV patients and those with unsuppressed viral load deserve special focus on renal monitoring. Data on long-term safety of TDF (> 1 year) is still warranted in this population. Chronic kidney disease incidence has increased worldwide in HIV positive people , and renART is the treatment for HIV associated nephropathies (HIVAN)  and earlA number of studies conducted to look at the renal safety of TDF in sub-Saharan Africa and provides variable results. Most reported TDF use was associated with decline renal function  and someEthiopia introduced TDF as first line drug in national ART guideline in 2008  but limi3, ii) CD4 count <350cells/mm3 and WHO stage 3 or 4 disease, or iii) WHO stage 4 disease regardless of CD4 count. ART was provided for HIV patients for free. The available first-line nucleoside reverse transcriptase inhibitors (NRTI) were TDF, zidovudine (AZT), stavudine (d4T), lamivudine (3TC) and abacavir and the available non-nucleoside reverse transcriptase inhibitors (NNRTI) were efavirenz (EFV) and nevirapine (NVP). The preferred first line antiretroviral regimens in Ethiopia guideline during the study period were TDF/3TC/EFV, AZT/3TC/NVP or AZT/3TC/EFV  and fat mass index (FMI) was calculated as [FM (kg)/height (m)2]  .The study laboratory personnel collected 10 ml of fasting venous blood in an EDTA tube, and 10 ml in a plain tube. CD4+ T cells were enumerated using the Facscount® . Spot urine samples were also collected, and urine dipstick analyses were performed to check for proteinuria and glycosuria at baseline, 3, 6, and 12 months.Creatinine was measured at baseline, 3, 6 and 12 months using a colorimetric kinetic assay (HORIBA ABX A11A01933) for Pentra 400 . The glomerular filtration rate was estimated using the “Chronic Kidney Disease Epidemiology Collaboration” (CKD-EPI)  equationHIV-1 RNA load was quantified using a commercial PCR assay  at baseline and at 6 months using an automated extraction system . Immunochromatographic rapid test was used for qualitative detection of HCV antibody and Hepatitis B surface antigen (HBsAg) in serum at baseline .P-value < 0.1 were included in multivariate linear regression analysis. Linear mixed model was used to evaluate 12-month eGFR difference in TDF and non-TDF based regimen. Univariate and multivariate linear regression models were used to assess how baseline characteristics and changes in viral load and body composition after 6 months of intervention  affected 12-month eGFR; only variables with a P-value < 0.1 in the univariate analysis were included in multivariate analysis. We also further analyzed by categorizing change in eGFR (12 month –baseline) in to < − 3, − 3 to 3, > 3 and < − 10, − 10 to 10 and > 10 and assessed factors associated with each group eGFR change with univariate logistic regression. Stata version 14.0  was used for all analyses.Data were described with frequencies, medians (interquartile ranges [IQR]) and mean (±Standard deviation (SD)). Demographic and clinical characteristics were compared between patients initiated on TDF and non-TDF based ART regimen using Wilcoxon rank-sum test or Pearson chi square test, as appropriate. Age, sex, hypertension, WHO stage, tuberculosis treatment, HCV, HBsAg and viral load suppression at 6 months were used as categorical variable. All anthropometric, body composition and other laboratory data  were used as continuous variables. Univariate and multivariate linear regression analysis were used to determine factors associated with baseline eGFR. Sociodemographic, anthropometric, body composition and clinical parameters were included in univariate linear regression analysis and variables that were associated with eGFR with a A total of 340 HIV positive adults had baseline renal function tests performed and 339 were initiated on ART. Of these, 279 (82.3%) were initiated on a TDF based regimen Fig. . More spn = 3) of the HIV positive adults reported history of hypertension and 2.6% (n = 9) reported history of cigarette smoking. Only 1.8% (n = 6) had hypertension (systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg). Two of these participants had both systolic and diastolic hypertension and four of them had only diastolic hypertension. All the six participants were on TDF based regimen. Hepatitis C virus antibody was positive in 0.6% (n = 2) of participants and both participants were on TDF based regimens.None of the HIV positive adults had known history of diabetes mellitus and chronic kidney disease, 0.9% (There was no difference in baseline eGFR in HIV positive adults initiated on TDF and non-TDF based regimen Table .Table 1P < 0.05). A large proportion of females  were younger than 35 years whereas only 50.9% (n = 57) of males were younger than 35 years. However, when formally testing, no interaction was found between age and sex (P = 0.2).In univariate linear regression analysis, lower baseline eGFR was significantly associated with older age, male gender, higher CRP, higher weight and presence of hypertension. Older age and high CRP level remained after adjustment for other variables in multivariate analysis Table . Being an = 9) or from EFV to NVP (n = 10) due to toxicity, new tuberculosis treatment or pregnancy. Two patients had NRTI substitutions; one from d4T to AZT and the other from AZT to TDF due to toxicity. Patient whose ART changed from AZT to TDF at third month was excluded from follow up analysis comparing TDF based vs non-TDF based ART. However, no patients were changed from TDF to other NRTI’s.Renal function data were available for 79% (n=269) of HIV positive adults at 12 months after ART initiation; 80% (n=225) for patients in TDF regimen and 73% (n=44) for patients in non-TDF based regimen  ml/min/1.73m2 respectively. None of the HIV positive adults had decline to < 60 ml/min/1.73m2. From four HIV positive adults that had eGFR < 60 ml/min/1.73m2 at the baseline, three of them had eGFR of > 90 ml/min/1.73m2 at 12 months and one had lost follow up after the baseline. There was no difference in change of creatinine and eGFR from baseline to 12 months between patients starting TDF based regimen and non-TDF based regimen (Table P = 0.19). Except in one patient at baseline and 1 patient at 12 month, all reported proteinuria was in participants taking TDF based regimen. However, except the four participants with proteinuria on urine dipstick at 12 month, all participants with proteinuria had at least two urine dipstick results and none of the participants had proteinuria in two consecutive urine samples. Glycosuria was detected in 2 patients on TDF based regimen at 3 months but was not persistent and in 2 other patients on non-TDF based regimen at 12 months.The median (IQR) and mean (± SD) change in eGFR with 12 months of ART was 0.8  ml/min/1.73mOlder HIV positive adults and those with unsuppressed viral load at 6 month of ART had lower eGFR at 12 months of ART initiation. Moreover, patients with a higher baseline eGFR had also higher eGFR at 12 months Table . However2 per year and increased mortality and morbidity [2, “stable” if change in eGFR remained between − 3 and 3 mL/min/1.73 m2 and “riser” if there were an increase in eGFR of > 3 mL/min/1.73 m2. Of 268 patients who had 12 months renal function data, 41, 14.6 and 44.4% were “decliner”, “stable” and “riser”, respectively. About 40.9, 14.7, and 44.4% in TDF group and 41.9, 14, and 44.1% in non-TDF group were “decliner”, “stable” and “riser” respectively. We found no difference in baseline characteristics  between these three groups (P > 0.05). In univariate logistic regression, there was no significant associations between “decliners” or “risers” compared with “stable” eGFR; “decliner” compared with “riser”; and “decliner” compared with the combined group of “stable” and “riser” and any baseline characteristics, 6 month changes and type of ART regimen (TDF and non-TDF based). The only exception was baseline eGFR for all comparisons. HIV positive adults with higher baseline eGFR were more likely to be “decliner” than “stable” or “riser” and were more likely to be “stable” compared to “riser”. We also found similar results when using cut-offs of − 10 and 10 ml/min/1.73 m2, and there were no significant differences between TDF and non-TDF based regimen (P > 0.05). About 26.9, 48.5 and 24.6% in the whole participants with ART; 28, 45.8, and 26.2% in TDF group; and 20.9, 62.8, and 16.3% in non-TDF group had eGFR drop greater than 10 mL/min/1.73 m2, change between − 10 to 10 mL/min/1.73 m2 and increase greater than > 10 mL/min/1.73 m2 at 12 month from the baseline eGFR, respectively.Based on previous studies which described an association between a drop in eGFR > 3 mL/min/1.73 morbidity , 36, we We further compared the baseline characteristics of HIV positive persons who completed 12 months follow up and had eGFR data with those who did not have 12 month eGFR data. We did not find any difference in age, sex and other baseline characteristics like fat mass and fat free mass, CD4 count, Viral load, presence of HBV and TB infection and baseline eGFR. However, HIV positive persons that had no data at 12 months had higher baseline CRP, lower weight and BMI at baseline and more patients were in WHO Stage III than stage I compared to patients who completed follow up and had 12 month data.As ART is a lifelong treatment, it is important to understand the potential adverse effects of treatment among various populations. We studied HIV treatment effect on the renal function determining eGFR, serum phosphate and urine dipstick test in HIV patients during the first year on ART. We did not find any significant negative effect on renal function associated with neither TDF use nor other antiretroviral drugs. We found that older individuals and HIV positive adults with high CRP had lower eGFR at ART initiation. Moreover, older and HIV positive adults with unsuppressed viral load at 6 months experienced declines in eGFR after 12 months of ART.Most HIV positive adults were initiated on fixed dose combination drugs either TDF/3TC/EFV, which was recommended as preferred first line regimen in all treatment naïve HIV patients without contraindication, or AZT/3TC/NVP, which was recommended in women of child bearing age without usage of reliable contraceptive measures . This isMost studies have shown that lower CD4 count and advanced HIV disease are associated with lower eGFR in ART naïve HIV patients , 37. HowWe found that a higher CRP was associated with lower eGFR in ART naïve HIV positive adults. However, in a previous paper we showed that CRP was not associated with serum creatinine . The ass2 at 12 month, respectively and none of the patients had decline to < 60 ml/min/1.73m2. However, we did not find general difference in eGFR in HIV patients before ART and after 12 months of ART. This may be because most of the HIV positive adults in our cohort had normal renal function at the initiation of ART. The absence of APOL1 genetic variants in people of Ethiopian ancestry which makes Ethiopians less susceptibility to HIVAN may be the contributing factor for relatively normal kidney function at initiation of ART [ART has been reported to improve renal function –45; and n of ART , 27. It n of ART . We founOur data also showed no difference in serum creatinine and eGFR in patients who were on TDF based and non-TDF based regimen after 12 months of ART. Moreover, no persistent proteinuria or glycosuria as markers of tubular dysfunction was observed in the study population. Additionally, as opposed to TDF nephrotoxicity, the serum phosphate level was higher in TDF based regimen compared to non-TDF based regimen after 12 months of ART. Although larger retrospective cohort studies reported decline in kidney function with TDF use in Africa –23, therThese results on TDF/non-TDF and eGFR remained in adjusted linear regression model including all variables associated in univariate linear regression model Table . HoweverOur study monitored the renal function of a cohort of HIV patients that were followed at regular interval with repeated measurements of serum creatinine and urine dipstick during the first 12 months of ART. Though the sex and age distribution of our cohort of HIV patients well represents the HIV prevalence in Ethiopia and the epidemiology in sub-Saharan Africa, we had limited HIV patients with concomitant traditional risk factors for kidney disease and also the hepatitis B and C co-infection rate was lower than previous report in Ethiopia  . Also dWe found no significant difference in kidney function in HIV positive adults treated with TDF or non-TDF NNRTI based ART regimen for 12 months. However, older HIV positive persons especially those above 45 years and those with unsuppressed viral load while on ART seem at higher risk of developing renal impairment and deserve special focus on renal monitoring. Moreover, data in larger cohort on longer term safety and slowly accumulating adverse events of TDF (> 1 year) are still warranted in this population.Additional file 1.


Indonesia antiretroviral therapy guideline suggests the use of Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI)-based regiments as first line of HIV treatment and Protease Inhibitor to replace NNRTI when treatment failure occurred. This case-control study was aimed to study factors predicting first-line ART treatment failure among HIV positive patients aged >15 years, non-pregnant, and registered in our institution, Indonesia.Diagnosis of HIV treatment failure was made according to the standard WHO criteria. Demographic and outcome variables were recorded. The association between variables were analyzed by Chi-square test with odds ratios (OR) and 95% confidence intervals (95% CI), followed by multivariate analysis using logistic regression test.p = 0.007) and 6.7–folds  higher risk for treatment failure, respectively.Twenty-six index cases and 26 age- and sex-matched control cases were included in the study with a mean age of 32.27 ± 8.7 years and 32.88 ± 8.15 years, respectively. Median time for switching to second-line  was 46.32 ± 30.21 months. Patients presented with tuberculosis and treated by nevirapine as the first-line treatment were 26.6-folds (95% CI: 2.41–293.81, The presence of tuberculosis and the use of nevirapine in first-line treatment were strong predictors for first-line ARV treatment failure, suggesting for closer clinical monitoring for patients with those conditions. A further and larger prospective cohort study is needed to confirm the findings in this study. •Tuberculosis and the use of nevirapine are significant predictors for ARV treatment failure•Closer clinical monitoring for patients with TB-HIV coinfection is necessary•Consideration of not using Nevirapine to initiate antiretroviral therapy for patients with HIV who accompanied by TB co-infection Until the end of 2018, it is noted that there were approximately 750,000 HIV infected individuals with 103,000 patients were currently on antiretroviral therapy (ART) .Concomitant tuberculosis treatment could induce the metabolism of nevirapine, thus reducing its plasma concentration from the third weeks to the end of tuberculosis therapy ,8. Low nTsegaya in 2016 reported the risk factors for developing second-line ART treatment failure in adult HIV-infected patients in Ethiopia which revealed that a high rate of failure was found in the first 2 years of ART therapy . In our In our study, patients with Nevirapine (NVP) as first-line ART were 7.8 times as likely to fail compared to those initiated with Efavirenz (EFV). A retrospective cohort study conducted to children age 6 months up to 18 years old in Kampala, Uganda, also showed treatment failure was related to the use of an NVP-based regimen, in addition to less adherence to ART, and prior use of single-dose NVP . A studyOur study found that presence of Tuberculosis co-infection alone, but not Tuberculosis plus other opportunistic infections, as predictors of first-line treatment failure. A retrospective 5-years cohort conducted in India, however, revealed that the presence of opportunistic infection, lower BMI, and low CD4 count at ART initiation were predictors of first-line ART failure with a failure rate of 7.69% and incidence of first-line ART failure 2.09 per 1000 person-years . At the In a high TB-burden country, the result of this study could be used to provide information on the rationale for wiser administration of TB drugs and choice of ART. Instead of being the alternative treatment, our study suggest that Nevirapine still can be the drug of choice if all other first-line ART treatment were contraindicated.There are several limitations of our study, including small number of case and controls, and only involved one center in Indonesia, that might not represent the whole country.5Our case-control study is the first to report predicting factors of treatment failure of the first-line ART in Indonesia. Presence of tuberculosis and the use of nevirapine as the first-line treatment were strong predictors for ARV treatment failure, suggesting for closer clinical monitoring for patients with TB-HIV coinfection and wiser drug selection to initiate antiretroviral therapy. A further and larger prospective cohort study is needed to confirm the findings in this study.Written informed consent was obtained from the patients for join the study. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.Not commissioned, externally peer reviewed.Universitas Gadjah Mada Research and Publication Quality Improvement Program.This study is funded by the Ethical clearance from the Medical and Health Research Ethics Committee (MHREC) of the Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada/Dr. Sardjito Hospital, states that the research protocol meets the ethical principle outlined in the Declaration of Helsinki 2013 .YWS, NAK, ASA, and PDS brainstormed this study.NAK,ASA,PDS prepared the manuscript draft and YWS critically revised the manuscript for important intellectual content.NAK,ASA,PDS and YWS facilitated all project-related tasks. All authors read and approved the final manuscript.Name of the registry: Research Registry.Unique Identifying number or registration ID: 5866.https://www.researchregistry.com/browse-the-registry#home/registrationdetails/5f28f38504f3590017191696/.Hyperlink to your specific registration (must be publicly accessible and will be checked): Yanri Wijayanti Subronto.The authors declared no potential conflicts of interest.


The clinical relevance of low‐level viraemia (LLV) and virological outcomes among children living with HIV (CLHIV) remains controversial. This study aimed to determine the impact of LLV on virological failure (VF) among Asian CLHIV on first‐line combination antiretroviral therapy (cART).CLHIV aged <18 years, who were on first‐line cART for ≥12 months, and had virological suppression  were included. Those who started treatment with mono/dual antiretroviral therapy, had a history of treatment interruption >14 days, or received treatment and care at sites with a pVL lower limit of detection >50 copies/mL were excluded. LLV was defined as a pVL 50 to 1000 copies/mL, and VF as a single pVL >1000 copies/mL. Baseline was the time of the second pVL < 50 copies/mL. Cox proportional hazards models were performed to assess the association between LLV and VF.p < 0.001). In multivariable analyses, ever experiencing LLV was associated with increased risk of subsequent VF .From January 2008 to September 2016, 508 CLHIV  were eligible for the study. At baseline, the median age was 9.6 (IQR: 7.0 to 12.3) years, cART duration was 1.4 (IQR: 1.3 to 1.8) years, 97% of CLHIV were on non‐nucleoside reverse transcriptase inhibitor‐based regimens, and the median CD4 was 25% (IQR: 20% to 30%). Over a median follow‐up time of 6.0 (IQR: 3.1 to 8.9) years from baseline, 86 CLHIV (17%) had ever experienced LLV, of whom 32 (37%) had multiple LLV episodes. Female sex, living in Malaysia (compared to Cambodia), having family members other than biological parents/grandparents as a primary caregiver, and baseline CD4 < 25% increased risk of LLV. Overall, 115 children (23%) developed VF, corresponding to a rate of 4.0 (95%CI: 3.4 to 4.9) per 100 person‐years of follow‐up (PYFU). VF was greater among children who had ever experienced LLV compared with those who maintained virological suppression throughout the study period (8.9 vs. 3.3 per 100 PYFU; LLV increased the risk of subsequent VF among Asian CLHIV who had previously been suppressed on first‐line cART. Adherence interventions and additional targeted pVL monitoring may be warranted among children with LLV to facilitate early detection of VF. One of the primary aims of combination antiretroviral therapy (cART) is to achieve and maintain pVL below the lower level of detection , 2, 3. HDuring the course of cART, people living with HIV may experience small increases in pVL (pVL 50 to 1000 copies/mL) that do not reach the threshold for viral failure, known as low‐level viraemia (LLV). LLV can be transient, which is characterized by a brief increase in pVL followed by subsequent virological suppression, or persistent, which is a sustained increase in pVL over time. Transient LLV has been found in approximately 11% to 34% of adults living with HIV (ALHIV) in the United States, Canada, Spain and Switzerland on stable cART regimens , 7, and The clinical consequences of LLV among patients on previously suppressive cART have been controversial. Some previous studies among ALHIV have found no association between transient LLV and adverse virological and immunological outcomes , 16, whe22.1The TREAT Asia Pediatric HIV Observational Database (TApHOD) is a multinational, multicentre, prospective observational cohort of CLHIV in the Asia‐Pacific region, established in 2008. TREAT Asia/amfAR  is the study coordinating centre, and the Kirby Institute, University of New South Wales  is the data management and statistical analysis centre for the cohort, which contributes to the International Epidemiology Databases to Evaluate AIDS (IeDEA) global consortium. The details of data collection have previously been published . In Sept2.2The study population consisted of Asian CLHIV followed in the cohort during January 2008 to September 2016. Eligible participants were CLHIV aged <18 years, and (1) who had perinatally acquired HIV infection; (2) whose first cART regimen was a combination of two nucleoside reverse transcriptase inhibitors (NRTI) with either a non‐nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor‐boosted with ritonavir (PI/r), which was continued for ≥12 months and (3) who had a documented history of virological suppression, defined as having pVL < 50 copies/mL on two consecutive occasions over a period of at least six months after cART initiation. CLHIV who (1) were started treatment with mono or dual antiretroviral therapy, (2) had history of treatment interruption for >14 days or (3) received HIV treatment and care at sites with pVL lower level of detection >50 copies/mL were excluded from this study.2.3Demographic and HIV‐related characteristics of eligible CLHIV were abstracted from the TApHOD database for this retrospective cohort analysis. Weight and height were based on the available recorded data closest to, but not more than 90 days before or 30 days after the date of interest. Weight (WAZ) and height for age z‐scores (HAZ) were calculated according to the 1977 National Center for Health Statistics/World Health Organization (WHO) reference , and the2.4In this study, LLV was described as an at least one pVL level between 50 and 1000 copies/mL without a change of treatment regimen. This definition was applied because this level of viraemia would be considered an indicator of the risk of subsequent VF among CLHIV in our cohort on first‐line NNRTIs, given the low genetic barrier to resistance of these regimens. During the study follow‐up, CLHIV who had had at least one LLV episode after achieving virological suppression were classified as ever experiencing LLV. Those having more than one documented LLV event were classified as having multiple episodes of LLV. CLHIV who maintained virological suppression (pVL < 50 copies/mL) throughout the study period were classified as children sustaining virological suppression.2.5Virological failure (VF) was defined as having a single pVL > 1000 copies/mL among CLHIV who had previously attained virological suppression on their first‐line cART. For CLHIV who had ever experienced LLV, VF must occur after their first episode of LLV. Loss to follow‐up was described as not presenting to the clinic for more than 12 months without documentation of transfer to another clinic or death.2.6Demographic and HIV‐related characteristics of CLHIV were summarized with number (n) and percentage (%) for categorical variables, and median and interquartile range (IQR) for continuous variables. The incidence rate of LLV was calculated by dividing the number of CLHIV with LLV by the total number of patient‐years of follow‐up (PYFU). The comparison of characteristics between children ever experiencing LLV versus children sustaining virological suppression were performed using Pearson’s Chi‐square or Fisher’s exact test, as appropriate, for categorical data, and Wilcoxon rank sum test for continuous data. Possible predictors of LLV were assessed using Poisson regression analysis. The associations between predictors and LLV were presented as incidence rate ratios (IRR).In this study, baseline was defined as the visit date of the second pVL < 50 copies/mL for CLHIV with sustained virological suppression. For children ever experiencing LLV, the baseline was set at the time of the first LLV episode in order to prevent immortal time bias – the time during which the outcome of interest (e.g. VF) could not occur. All CLHIV were entered into the survival analysis at their baseline visit and were followed until having the study outcome (VF) or the end of study follow‐up. Children were censored at the time of the event or at the most recent visit for which a pVL was measured. The incidence rate of VF was calculated by dividing the number of CLHIV with VF by the total number of PYFU. Kaplan–Meier estimates and log‐rank test were performed to compare the cumulative probability of VF between those ever experiencing LLV versus sustaining virological suppression. Cox proportional hazards analysis was conducted to identify the predictors of VF. The associations between predictors and VF were summarized as hazard ratio (HR). Schoenfeld residuals were used to assess the statistical models for violations of the proportional hazards assumption and the models were accepted only after no violations were shown to occur.p < 0.10 in univariable models were included in the multivariable models. Statistical significance was identified as a two‐sided p < 0.05. All statistical analyses were performed with SAS statistical software, version 9.4  and Stata statistical software, version 14.1 .Covariates for the Poisson and Cox proportional hazard models which demonstrated a 33.110 copies/mL. At baseline, the median age was 9.6 (IQR: 7.0 to 12.3) years, WAZ was −1.3 (IQR: −1.9 to −0.4) and HAZ was −1.6 (IQR: −2.5 to −0.8). Almost all (97%) were on NNRTI‐based cART regimens, and the median duration of cART was 1.4 (IQR: 1.3 to 1.8) years. The median CD4 T‐cell percentage was 25% (IQR: 20 to 30%), and 51% had a CD4 T‐cell percentage ≥25%. The median frequency of pVL measurement was 1.2 (IQR: 0.8 to 1.5) time/year throughout the study period.Of 5668 CLHIV in the cohort who had initiated cART as of September 2016, 508 were eligible for this study , a higher proportion had pVL > 10 000 copies/mL at cART initiation , and they had more frequent pVL measurements . In the multivariable analysis, female sex (adjusted IRR (aIRR): 1.80; 95% confidence interval (95% CI): 1.29 to 2.52), living in Malaysia , having family members other than biological parents/grandparents as a primary caregiver  and having baseline CD4 T‐cell percentage <25%  were independently associated with an increased risk of LLV (Table Over a median follow‐up time of 6.0 IQR: 3.1 to 8.9) years from baseline, 86 CLHIV (17%) had ever experienced post‐suppression LLV, corresponding to an incidence rate of LLV of 2.8 (95% CI: 2.3 to 3.5) per 100 PYFU. Fifty‐four CLHIV (63%) had a single LLV episode, and 32 (37%) had multiple LLV episodes . Of children with a single LLV episode , 89% of the events were low magnitude LLV (50 to <400 copies/mL), and among children with multiple episodes of LLV , 84% were low magnitude LLV. The comparison of demographic and HIV‐related characteristics at the time of cART initiation and at baseline between CLHIV ever experiencing LLV versus children with sustaining virological suppression are summarized in Table  to 8.9 y3.2p log‐rank test <0.001). Kaplan–Meier estimates of unadjusted cumulative probability for VF by LLV experiences during the study follow‐up are illustrated in Figure Over the study follow‐up, 115 CLHIV 23%) developed VF after achieving virological suppression, corresponding to an overall incidence rate of 4.0 (95% CI: 3.4 to 4.9) events per 100 PYFU. VF was detected in 34 children (40%) who had experienced LLV, corresponding to an incidence rate of 8.9 (95% CI: 6.3 to 12.5) events per 100 PYFU; whereas VF was observed in 81 children (19%) who had previously sustained virological suppression, corresponding to an incidence rate of 3.3 (95% CI: 2.6 to 4.1) events per 100 PYFU (3% develop < 0.001). There were 30 CLHIV (6%) lost to follow‐up, of whom five ever experienced LLV and 25 had sustained virological suppression; there were no deaths during the study period.In a sub‐analysis comparing the incidence of VF among CLHIV who had ever experienced high magnitude LLV (pVL 400 to 1000 copies/mL) and those who had low magnitude LLV (pVL 50 to <400 copies/mL), we noted that 13 out of 15 children with high magnitude LLV (87%) and 21 out of 71 children with low magnitude LLV (30%) developed a subsequent VF during the study follow‐up  log10 copies/mL. Among 34 CLHIV who had experienced LLV and subsequently developed VF, 21 (62%) had had a single LLV episode, whereas 13 (39%) had had multiple LLV episodes  during the study period. The median duration from baseline to VF was 1.4 (IQR: 0.5 to 4.0) years, and the median duration from the last LLV to VF was 0.5 (IQR: 0.4 to 0.9) years. Comparing children who had ever experienced LLV with children who had previously sustained virological suppression, the clinical characteristics at the time of VF were not significantly different (p > 0.05), except for their current pVL  and the duration from baseline to VF , which were higher among children in the latter group  were female. Overall, at the time of VF, 95% were on NNRTI‐based cART regimens. The median age of CLHIV was 14.8 (IQR: 11.9 to 18.2) years, current CD4 T‐cell count was 469 IQR: 317 to 624) cells/mm17 to 6243.4In the multivariable analysis, ever experiencing LLV during study follow‐up (adjusted hazard ratio (aHR): 3.01; 95% CI: 1.97 to 4.60), older age  and baseline CD4 T‐cell percentage <25%  increased the risk of subsequent VF . We also observed a short duration from the last LLV episode to VF in this study which might be attributed to an early pVL measurement in children experiencing LLV due to a high suspicion of subsequent VF.We noted that 17% of children in our cohort ever experienced at least one LLV episode following virological suppression after their first‐line cART initiation. Our prevalence of LLV is consistent with a previously published adult study in South Africa which noted that the prevalence of LLV (at least one pVL 51 to 999 copies/mL) was 23% among ALHIV receiving suppressive first‐line cART . CompariThe underlying mechanisms of LLV remain controversial. Plausible explanations include intermittent bursts of viral particles from latently infected reservoirs , low drup < 0.001). This finding suggests that high magnitude LLV may be useful as an indicator for subsequent VF risk in this population. Due to the non‐uniformity of LLV definitions used across paediatric studies, it is difficult to directly compare our findings. Nevertheless, the results from this study provide evidence that experiencing at least one LLV increases the risk of subsequent VF. This may help guide clinicians to more proactively implement interventions like intensive adherence monitoring and additional targeted pVL testing in children with LLV in order to prevent and detect early VF.Our study demonstrated that ever experiencing LLV was linked to subsequent VF among treatment‐stable children on first‐line cART. This is supported by a study in a large multicentre rural‐urban South African cohort among adults receiving a suppressive first‐line cART, where LLV (pVL 51 to 999 copies/mL) significantly increased the risk of subsequent VF (pVL > 1000 copies/mL)  . AdditioThis study contains several limitations. Since we included only those sites in our network with pVL testing at a lower level of detection of <50 copies/mL to prevent chronological and misclassification biases, this led to the exclusion of a number of children with more limited pVL access and those with pVL testing using a less sensitive assay. This additionally reduced our ability to observe clear associations with single or multiple episodes of LLV and VF. We acknowledge that there are potential misclassification biases in this study . First, 5This study demonstrated the prevalence of LLV within our cohort, and how it increased the risk of subsequent VF among Asian CLHIV who were on stable first‐line suppressive cART. In resource‐limited settings, more intensive adherence interventions and potentially additional targeted pVL monitoring should be considered among children having LLV to prevent and detect early VF.AHS has received unrelated travel and project funding to her institution from ViiV Healthcare. Other authors declare no conflict of interest related to this study.TS developed the conception of research, designed the study, and developed the protocol. TS, KL, NK, MSF, RH, TB, LPS and RAN performed the data collection. ST, AK and TS designed and conducted the statistical analyses. TS contributed to the interpretation of study results. TS wrote the first draft and revised the manuscript. TS, AHS and VS provided critical revisions. All authors reviewed and approved the final version.ALHIV, adults living with HIV; aHR, adjusted hazard ratio; aIRR, adjusted incidence rate ratio; cART, combination antiretroviral treatment; CHIPS, the UK and Ireland Collaborative HIV Paediatric Study; CLHIV, children living with HIV; HAZ, height for age z‐score; HR, hazard ratio; IeDEA, the International Epidemiology Databases to Evaluate AIDS; IQR, interquartile range; IRR, crude incidence rate ratio; LLV, low‐level viraemia; NNRTI, non‐nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI/r, protease inhibitor‐boosted with ritonavir; pVL, plasma viral load; PYFU, patient‐years of follow‐up; TApHOD, the TREAT Asia Pediatric HIV Observational Database; VF, virological failure; WAZ, weight for age z‐score; WHO, World Health Organization; 95% CI, 95% confidence interval.The TREAT Asia Pediatric HIV Observational Database is an initiative of TREAT Asia, a programme of amfAR, The Foundation for AIDS Research, with support from the U.S. National Institutes of Health’s National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Cancer Institute, National Institute of Mental Health, National Institute on Drug Abuse, the National Heart, Lung, and Blood Institute, the National Institute on Alcohol Abuse and Alcoholism, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Fogarty International Center, as part of the International Epidemiology Databases to Evaluate AIDS . The Kirby Institute is funded by the Australian Government Department of Health and Ageing, and is affiliated with the Faculty of Medicine, UNSW Australia.The views expressed are those of the authors and does not necessarily represent the official views of any of the governments or institutions mentioned in the Funding Sources.


The situation of renal impairment among HIV-infected patients treated with TDF-based antiretroviral (ARV) regimen greater than 3 years is little known when TDF use has been promptly increasing in Vietnam. 2. Multivariate regression analyses were used to explore the risk factors associated with renal impairment.  We analyse demographic and clinical data from a cross-sectional survey of 400 HIV-infected patients aged ≥18 years, who were treatment-naive or switched TDF regimen within over 3 years between November 2018 and March 2019. Serological tests for serum creatinine, ALT, and AST were performed. Renal impairment was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 and 0.8% had eGFR of 15–29 mL/min/1.73 m2, out of 34 (8.5%) of participants who had renal impairment. Multivariate analysis showed that participants who had preexposure to isoniazid (adjusted PR [aPR] = 0.35 Cl: 0.14–0.91) compared with nonexposure to isoniazid who had a BMI from 18.5 up to 25 kg/m2 (aPR = 0.31 Cl: 0.15–0.62) compared with BMI below 18.5 kg/m2 were less likely to suffer from renal impairment. Patients aged greater than 60 years  compared with those aged 20–29 years were more likely to have increased risk of renal impairment.  At the baseline, 7.8% of respondents had estimated glomerular filtration rate (eGFR) of 30–59 mL/min/1.73 m Our findings underscore the need for longitudinal studies to assess the influence of TDF on maintaining the low prevalence of renal impairment among HIV-infected patients in Vietnam. From the first HIV case detected in 1990 to June 30, 2016, there were 227,225 reported cases of HIV infection in Vietnam, of which the number of patients turned to AIDS was 85,753, and 89,210 HIV/AIDS infected cases died . Recentl3, long duration of HIV infection, WHO stage, and coinfection with hepatitis B and hepatitis C were risk factors for renal dysfunction [Until December 31, 2018, Soc Trang had 1,204 patients on antiretroviral drugs (ARV), of which 88.2% used TDF-containing regimens and 98% of new patients received ARV in 2018 with TDF + 3TC + EFV regimen . Howeverfunction . A studyThis is a cross-sectional study conducted in the department of infectious diseases, general hospital, Soc Trang Province from November 2018 to March 2019. The study protocol was reviewed and approved by the review board of the general hospital, Soc Trang Province on October 25, 2018. All participants provided written informed consent forms.2, and were treatment-naive or switched TDF regimen within over 3 years. The study was powered to obtain 80% power with a two-sided 5% significant level for estimating the overall prevalence of 50% with the desired precision of 5%, which required 384 HIV-infected patients; this was rounded up 400 to allow approximately 5% participant refusal and specimen damage rate , we filtered all patients using TDF regimen over 36 months since July first, 2018 (approximately 435 participants). Second, we recruited participants admitted to the hospital for reexamination to collect data and take blood samples based on the treatment-naive regime until we recruited enough 400 participants.The information sheet describing the purpose and method was shown to participants, and after giving informed consent, we collected baseline demographic and clinical data from medical records including sex, age, weight, height, HIV transmission, WHO stage, tested time for HIV positive, treatment time, cotrimoxazole, isoniazid, viral load, baseline CD4 count, baseline serum creatinine, ALT, AST, hepatitis B, hepatitis C, WHO stage in which treatment started, and baseline hemoglobin. Neither names nor detecting information like phone numbers or addresses were collected.3, measured by the FacsCount, Becton Dickinson), and viral load (COBAS® AmpliPrep/COBAS® TaqMan® HIV-1 Test) testing were performed at general hospital Soc Trang, Center of HIV/AIDS prevention, Can Tho Province, and Pasteur Institute Ho Chi Minh City, Vietnam, respectively, between October 2018 and March 2019.After the completed physical examination, 03 mL blood specimens were collected and stored at −20°C and transported to the Center of Testing Calibration, University of Medicine and Pharmacy at Ho Chi Minh City for serum creatinine, ALT, AST analysis by chemistry analyzer . Hemoglobin , CD4 cell count (cell/mm2. According to the guideline of CKD EPI equation [−0.329 × (0.993)Age (in year); female with serum creatinine >0.7 mg/dl: GFR = 166× (Scr (in mg/dl)/0.7)−1.209 × (0.993)Age (in year)For female with serum creatinine ≤0.7 mg/dl: GFR =166 × (Scr (in mg/dl)/0.7)−0.411 × (0.993)Age (in year); female with serum creatinine >0.9 mg/dl: GFR = 163× (Scr (in mg/dl)/0.9)−1.209 × (0.993)Age (in year)For male with serum creatinine ≤0.9 mg/dl: GFR =163 × (Scr (in mg/dl)/0.9)Measurement of weight and height: we used Health-scale weight scales and height ruler  to measure weight and height. Body mass index (BMI) was calculated as BMI = weight (in kg) ÷ (height (in m))equation  to calcu2) group including 6 stages (stage 1 (>90), stage 2 (60–89), stage 3a (45–59), stage 3b (30–44), stage 4 (15–29), and stage 5 (<15)).In this study, we used the Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney Foundation to clarify the eGFR , and all statistical analysis was implemented using Stata version 13.0 , and The patient's characteristics were described using frequency and proportion for categorical variables and mean and standard deviation or median and interquartile ranges for continuous variables.2 [P less than 0.25 or were previously known to be an important risk factor in existing literature were included in multivariate analysis. In multivariate analysis, we used Poisson multivariate regression with backward elimination to detect the final model that describes contributing variables.In this study, renal impairment was defined as eGFR less than 60 ml/min/1.73 m2 . In the A total of 400 participants were recruited in the present study. The mean (±SD) age was 39.8 (±8.8); 51.5% of respondents were male. The mean (±SD) age was 21.2 (±3.4).The majority of study participants suffered from HIV through sexuality (89.5%); up to 98.3% of respondents were found in the World Health Organization (WHO) stage 1, and fifty percent recorded WHO stage 3 for starting treatment.µmol/L, and hemoglobin (g/L) were 517 (±250), 75.7 (±18.2), and 13.5 (±1.6), respectively.The mean (±SD) time for HIV positive testing and treatment was 7.0 (±7.0); 6.5 (±2.5), respectively. Up to 93.5% and 94.7% of respondents were preexposed to isoniazid and cotrimoxazole preventive therapy. The majority of study participants had a viral load less than 20 copies per mL (93.5%), and the mean (±SD) CD4 count, serum creatinine 9.7% of study participants were with comorbidity of hepatitis B and hepatitis C (7.2%). Among study participants, approximately one-third had an AST > 37 U/L and ALT > 40 U/L, and 26.2% had an AST > 37 U/L and ALT > 40 U/L .2) was 96.0 (±24.5), 57.3% of respondents had baseline eGFR greater than 90 ml/min/1.73 m2, and none of them had had baseline eGFR less than 15 ml/min/1.73 m2, out of 34 (8.5%) of participants who had renal impairments  eGFR (ml/min/1.73 mairments .P < 0.001). Compared with KDIGO stage 1, patients who were diagnosed with KDIGO stages 2, 3, and 4 had significantly higher mean (±SD) baseline creatinine (70.1 (±12.6) vs 77.5 (±13.7), 97.2 (±18.8), 151.6 (±51.5), 167.9 (±16.9)), respectively. By contrast, compared with KDIGO stage 1, those with KDIGO stages 2, 3, and 4 had significantly lower mean (±SD) baseline eGFR, (111.9 (±18.1) vs 80.3 (±6.6), 56.4 (±3.7), 40.7 (±3.9), 21.8 (±5.5)), and mean (±SD) CD4 count (531.5 (±233.8) vs 530.7 (±404.9), 470.2 (±251.2), 526.5 (±345.8), 130.7 (±24.4)), respectively (There were significant differences between the mean (±SD) baseline creatinine, eGFR, baseline CD4 count, and KDIGO stage among study participants  compared to BMI less than 18.5 kg/m2 and who were preexposed to isoniazid (aPR = 0.35 Cl: 0.14–0.91) were less likely to suffer from renal impairment  compared with those aged 20–29 years had significantly increased risk of renal impairment. Patients who had BMI ranging from 18.5 to 25 kg/mpairment .In this study, we present findings from the renal impairment prevalence survey of semiurban HIV/AIDS patients conducted in southern Vietnam. A striking finding in this study is that participants who were preexposed to isoniazid and TDF were less likely to report renal impairment compared with those who were not preexposed to isoniazid. According to Decision No. 2495/QD-BYT dated July 18, 2012 , on issuWe also found a low prevalence of renal impairment among study participants. This finding was consistent with findings in South Africa (7.6%)  and MalaIn the current study, we also found that patients who had low BMI were significantly associated with renal impairment compared with those who had normal BMI; this result was similar to studies conducted in Vietnam and Japan , 28, 29,As shown in our study, we did not find the relationship between cotrimoxazole, hepatitis B, C virus infection, and renal impairment which was consistent with the study conducted in Vietnam ; howeverCompared with patients aged 20–29 years, patients with ages equal to and greater than 60 years were more likely to report renal impairment. This finding was in agreement with studies conducted in Ethiopia  and Mala3 was significantly associated with renal impairment, which was in line with the previous studies [In the univariate analysis, we found that baseline CD4 count less than 200 cell/mm studies , 33, 34. studies , 35.The current study was the first study to assess the risk factors among participants who were treated with ARV based TDF regimen over 3 years in Vietnam. However, there are several limitations. In this present study, we did not collect urine data for analysis so that we could not assess chronic kidney disease among participants . In a ruThis survey has important implications for the prioritized strategies for the prevention of renal impairment as TDF is still an important drug for HIV-infected patients . This stOur findings underscore the need for longitudinal studies to assess the influence of TDF to maintain the low prevalence of renal impairment among HIV-infected patients in Vietnam.