Concerns regarding potential toxicity and drug-drug interactions during long-term treatment with three-drug active antiretroviral therapy (ART) regimens have been attracting increasing attention. We aimed to evaluate the efficacy and safety of dolutegravir (DTG) plus lamivudine (3TC) in ART-naive adults in China.This prospective observational cohort study enrolled HIV-naive inpatients treated with DTG + 3TC (2DR arm) or efavirenz (EFV) plus tenofovir disoproxil fumarate (TDF) and 3TC (3DR arm). There were no limits on baseline viral load. Inflammatory biomarkers were also investigated in the 2DR arm.Between September 2019 and January 2020, 27 patients treated with DTG + 3TC and 28 patients treated with EFV + TDF + 3TC were enrolled in the study. At week 12, the proportion of patients with viral loads < 50 copies/mL in the 2DR arm was 81.5% (22/27) compared with 53.6% (15/28) in the 3DR arm (p < 0.01). At week 24, the proportion of patients with viral loads < 50 copies/mL in the 2DR arm was 100% (26/26) compared with 83.3% (20/24) in the 3DR arm (p < 0.05). Mean changes in CD4 cell counts from baseline at week 12 were 125.46 cells/µL in the 2DR arm and 41.20 cells/µL in the 3DR arm (p < 0.05). Mean changes in CD4 cell counts from baseline at week 24 were 209.68 cells/µL in the 2DR arm and 73.28 cells/µL in the 3DR arm (p < 0.05).DTG + 3TC achieved virologic suppression more rapidly than EFV + TDF + 3TC after 12 and 24 weeks. DTG + 3TC could represent an optimal regimen for advanced patients.Clinical Trial Registration ChiCTR1900027640 (22/November/2019). There has been a sustained decrease in the mortality and morbidity of patients with human immunodeficiency virus type 1 (HIV-1) infection since the introduction of highly active antiretroviral therapy (HAART) . HoweverTwo-drug regimens (2DRs) have been investigated as a means to improve the quality of life of patients with HIV-1 by reducing adverse drug reactions, saving costs, and improving HAART compliance –7. DolutIn the GEMINI trials, the antiviral activity of DTG + 3TC was similar to that of DTG + TDF/emtricitabine (FTC) in ART-naive individuals with baseline viral loads below 500,000 copies/mL; furthermore, no resistance was reported for up to 96 weeks . AntivirCurrently, international guidelines recommend DTG + 3TC as the first-line regimen for ART-naive individuals with HIV-1 infection and viral loads < 500,000 copies/mL. However, this regimen has not been evaluated in individuals with no limitations on viral loads and especially in individuals with baseline viral loads > 500,000 copies/mL. In addition, there is limited experience with DTG + 3TC in China.Several potential mechanisms to explain the relationship between inflammation and HIV-1 replication have been proposed –17.One pIn this prospective cohort study, we aimed to evaluate the efficacy and safety of DTG + 3TC compared with a first line 3DR (EFV + TDF + 3TC) for treatment of HIV-1 infection in ART-naive adults in China with no limitations on baseline viral load.This ongoing observational single-center prospective observational cohort study enrolled ART-naive individuals with HIV-1 infection referred to our hospital from September 2019 to January 2020. Data were collected from September 2019 to July 2021. No CD4 count restrictions nor limitations on baseline viral loads were imposed.Exclusion criteria included pre-existing major viral resistance mutations to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, or protease inhibitors; active hepatitis B virus infection; anticipated hepatitis C treatment during the study period; unstable or severe hepatic impairment; alcohol or drug abuse; pre-existing mental disorders; and pregnancy.The study was approved by the Research Ethics Committee of the Fifth Affiliated Hospital of Sun Yat-sen University . Written informed consent was obtained from each participant prior to the initiation of study procedures. All study procedures were performed in accordance with relevant local guidelines and regulations. The study was registered in the Chinese Clinical Trial Registry: ChiCTR1900027640 (22/November/2019).HAART regimens were selected according to Chinese guidelines and patient requirements. For all patients, HAART regimens were selected on clinical grounds either because of concomitant diseases, the results of laboratory tests, financial reasons, AEs, or risk of DDIs.Study visits were scheduled at baseline and weeks 2, 4, 8, 12, 24, 36, and 48 following HAART initiation. Renal function, liver enzymes, lipid profiles, blood counts, and bone mineral density were assessed at all study visits. Plasma HIV-1 RNA viral load was tested at weeks 12, 24, and 48 . CD4 cell counts were determined at weeks 4, 12, 24, and 48. Levels of inflammatory biomarkers in individuals in the 2DR arm were assessed at baseline and at weeks 2, 4, and 12.Safety, including AEs and serious AEs (SAEs), was assessed at each study visit. Events were graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, version 2.0 . All SAEThe primary efficacy endpoint was the proportion of participants with virologic success, defined as HIV-1 RNA viral load < 50 copies/mL. The secondary endpoints included evaluating the efficacy, safety, and tolerability of HAART regimens, assessing changes from baseline in CD4 + cell counts, and assessing changes from baseline in the CD4 + /CD8 + cell ratio. Inflammatory biomarkers were exploratory outcomes in the 2DR arm.2 and Fisher’s exact tests were used to assess differences between categorical variables. The student’s t-test or Wilcoxon’s signed-rank test were used to assess differences between continuous variables. Statistical analyses were performed using SPSS 22.0  and GraphPad Prism 6.0 . Values of P < 0.05 were considered statistically significant. Multivariate logistic regression analysis was used to identify factors influencing the viral suppression rate at week 12.χBetween September 2, 2019 and January 26, 2020, 73 participants were screened and 69 were enrolled in this study. Genotypic tests were performed by the Chinese Center for Disease Control prior to HAART administration; none of the participants harbored viruses bearing mutations conferring resistance to INSTIs or NRTIs. In the 2DR group, two participants discontinued study follow-up prior to week 36 and were lost to follow-up. In the 3DR group, twelve participants discontinued study follow-up prior to week 8 for the following reasons: moved out of the area (n = 2), drug withdrawal (n = 3), lost to follow-up (n = 5), and change in HAART regimen (n = 2) . The mean baseline CD4/CD8 ratio was 0.25 in the 2DR arm and 0.36 in the 3DR arm p = 0.031)   through 48 weeks of treatment. Multivariate logistic regression analysis indicated that none of age, opportunistic infections, CD4 cell counts, and HIV-1 viral loads > 100,000 copies/mL were independently associated with treatment outcome. Importantly, the more rapid reduction in viral load at week 12 in the 2DR demonstrated that DTG + 3TC was statistically superior to the 3DR. In addition, increases in CD4 cell counts from baseline to week 12 and week 24 were more rapid in the 2DR arm than in the 3DR arm. The rapid reduction in viral load may be responsible for the immune reconstitution observed in the 2DR arm.Data from the SINGLE study demonstrated the superior efficacy and better tolerability of DTG + abacavir + 3TC compared with EFV + TDF + FTC . The GEMStrikingly, both mean CD4 cell counts and CD4/CD8 ratios were lower in the 2DR arm compared with the 3DR arm at baseline. Low CD4 cell counts are strongly correlated with high HIV-1 RNA levels –24. Low There are continuing challenges in managing HIV-1 infection, particularly in older patients who often experience age-related comorbidities resulting in complex polypharmacy and increased risks of DDIs . DTG hasIncreases in CD4 cell counts from baseline to week 12 and week 24 occurred more rapidly in the 2DR arm than in the 3DR arm. The recovery of CD4 cell counts reflects immune reconstitution. INSTIs, especially DTG and EVG, are associated with a higher probability of development of immune reconstitution inflammatory syndrome (IRIS) . InflammHigher frequencies of drug-related AEs were observed in the 3DR arm than in the 2DR arm in this study, especially grade 1 or grade 2 dizziness. This finding was consistent with the toxicity profile of EFV, which includes neuropsychiatric AEs such as abnormal dreams, sleep disturbances, anxiety, depression, and dizziness , 34. DTGDrug induced liver injury (DILI) is a common and challenging AE in patients receiving EFV-based HAART regimens . A totalcreatinine and moderate reductions in eGFR without changes in the iohexol-measured glomerular filtration rate . In thisThere were several limitations to our study. This was an observational study with a limited sample size, which could lead to bias. In addition, the study enrolled predominantly men with a median age of 31 years. Because of the limited study duration, a roll-over study with 96-week and 144-week follow-up is ongoing to show the durable efficacy and safety of DTG + 3TC.Administration of DTG + 3TC achieved virologic suppression rapidly and with good immune reconstitution at weeks 12 and 24 in HAART-naive individuals, regardless of baseline viral load and with no CD4 cell count restrictions. DTG + 3TC could represent an optimal regimen for ART-naïve patients with advanced HIV-1 infection, especially those who require complex treatment plans or wish to minimize potential drug toxicity or DDIs.


Raltegravir (RAL) has favorable tolerability and safety profile, with few and manageable drug interactions. The use of RAL 1200 mg once daily (qd) for first-line therapy is well established. We assessed efficacy and safety of RAL 1200 mg qd, as part of triple combined antiretroviral therapy (cART), for maintenance strategy.The QDISS trial (NCT03195452) was a 48-week multicenter, single-arm, open-label study designed to evaluate the ability of 2 NRTIs + RAL 1200 mg qd to maintain virological suppression in HIV-1 infected subjects on a stable cART with 2 NRTIs and a third agent for at least 6 months. The primary endpoint was the proportion of participants with HIV-1 RNA < 50 copies/mL at week 24, by the FDA snapshot algorithm.p = 0.023) and LDL-cholesterol (p = 0.009) decreased, lifestyle and ease subscale significantly improved (p = 0.04). The quality of life and Patients Reported Outcomes (PROs) also improved at W12 (p = 0.007).Of 100 participants 91% maintained viral suppression (95% CI: 83.6–95.8) at week 24 and 89% (81.2–94.4) at week 48. At week 24, there was one virological failure, without emergence of resistance-associated mutation and 10 participants had discontinued, 4 because of adverse events (AEs). Over 48 weeks, 7 AEs of grade 3–4 were reported, one possibly study-drug related (spontaneous abortion). BMI remained stable regardless of previous therapy or baseline BMI category. Over 48 weeks, total cholesterol (RAL 1200 mg qd as part of a maintenance triple therapy showed a high efficacy in virologically suppressed HIV-1 infected subjects, with good safety profile and improved lipid profile and patient reported outcomes.Trial registration: Clinical trials.gov NCT03195452 and EudraCT 2016-003702-13. As viral suppression is achieved in most people living with HIV (PLWHIV) with currently recommended regimens, HIV treatment goals has shifted towards a durable viral suppression and an optimal long-term tolerability of cART with regimens that are life-style compatible rd agent, or management of drug-drug interaction, or for patient’s request to simplify or to improve regimen convenience. Patients with chronic hepatitis B infection were allowed in the study if their treatment included TDF or TAF.QDISS study was a 48 weeks open-label, single-arm, prospective study, conducted in 17 clinical sites in France, designed to evaluate the ability of 2 NRTIs in association with RAL qd to maintain virological suppression in HIV-1 infected adults receiving a stable therapy with 2 NRTIs (tenofovir disoproxil fumarate (TDF)/ /lamivudine (3TC), tenofovir alafenamide (TAF)/emtricitabine (FTC) or abacavir (ABC)/3TC) and a third agent , for at least 6 months. Adults aged 18 years or older were eligible if they had plasma HIV-1 RNA < 50 copies/mL for at least 6 months with no more than one blip (between 50 and 200 copies/mL) and no prior virological failure on INSTI or non-nucleoside reverse transcriptase inhibitor- based cART or on NRTI(s) only-therapy. Additional inclusion criteria included absence of resistance to any antiretroviral drug except E138A/G/K/Q/R/S or V179D in blood HIV-RNA or DNA, aspartate and alanine aminotransferase concentration below five times the upper limit of normal, haemoglobin > 8 g/dl, platelet count > 50 000/mm3, estimated glomerular filtration rate by MDRD equation > 50 mL/min. Women of childbearing potential had to have a negative pregnancy test at screening and to accept the use of contraceptive methods during the study. All participants had an indication to change their current triple cART for intolerance or prevention of toxicity, or presence of comorbidity justifying change of the 3The study was conducted according to Good Clinical Practice. The protocol was approved by the Ethics Committee of Est III (17.04.06), and authorized by the French National Agency for the Safety of Medicines (ANSM 170133A-41). All participants gave written informed consent. The study was registered with ClinicalTrial.gov (NCT03195452).http://www.hivfrenchresistance.org). Adherence was assessed by visual scale, at day 0, weeks 24 and 48. Treatment satisfaction was assessed using two versions of the revised HIV Treatment Satisfaction Questionnaire (HIVTSQ): the HIVTSQs (status version) at baseline, week 24 and 48 and the HIVTSQc (change version) at week 24 After enrolment, participants switched to RAL 1200 mg qd, while maintaining the same background 2 NRTIs. Participants were evaluated at baseline, weeks 4, 12, 24, 36, and 48. At all study visits, assessments were done for symptom-directed physical examinations, weight, adverse events and concomitant medications, and symptom-directed physical examinations were done. Laboratory tests included haematological analysis, serum chemistry and measures of plasma HIV-1 RNA at each visit, fasting glucose and lipid parameters and CD4 and CD8 cell counts at baseline, weeks 36 and 48. Protocol-defined virological failure (PDVF) was occurrence of 2 consecutive HIV-1 RNA ≥ 50 copies/mL, the second specimen being taken within 1 to 4 weeks. Genotypic resistance testing was performed in case of PDVF on the confirmatory sample and interpreted following the ANRS algorithm for drug resistance-associated mutations, version 27 .A sample size of 94 patients was required to give a 85% probability of rejecting a baseline response rate of 80% with an exact 5% one-sided significance test when the true response rate is 90%. To take into account patients with consent withdrawal or lost to follow-up (5%), 100 patients had to be enrolled. All patients who received at least one dose of study medication were included in the analysis. No data imputation was performed for secondary endpoint analysis. Baseline variables were described, for all patients, by numbers and percentages for categorical variables and means and standard deviation (sd) for quantitative variables. The proportion of patients with plasma HIV-1 RNA < 50 copies/mL, by the US FDA snapshot algorithm, at week 24 was estimated with 95% exact confidence interval. Changes in biological parameters or questionnaire scores were analysed using paired Student's tests. All analyses were conducted with software R v3.6.0 .From November 2017 to April 2019, 100 subjects were enrolled out of 122 screened individuals, in 17 centers  regardless of previous therapy (RAL or ARV therapy without RAL) or baseline BMI category. Mean total cholesterol and LDL-cholesterol significantly decreased at W48 (− 0.21 mmol/L (± 0.84), p = 0.023; and − 0.19 mmol/l (± 0.66) p = 0.009, respectively). There were no significant changes in triglycerides, HDL-cholesterol and glycaemia at week 48 (mean change: − 0.08 (± 0.67), p = 0.3; 0.01 (± 0.26), p = 0.61, and 0.22 (± 1.03), p = 0.081, respectively). Renal parameters were unchanged. Median increase in CD4 cell count at week 48 was 50 cells/mm p < 0.001).During the total 48 weeks follow-up, a total of 7 adverse events of grade 3–4 were reported, one possibly related to study drug (spontaneous miscarriage at week 8); 4 of these 7 events were classified as serious (acute HCV infection (1), traumatic bone fracture (1), hematemesis (1), miscarriage (1)). Most frequent AEs, occurring in > 10% of participants, were gastrointestinal, musculoskeletal, neuropsychiatric disorders, infections and infestations, and respiratory disorders. Reasons for discontinuation because of treatment-related adverse events were gastro-intestinal side effects , gastrointestinal disorder and headache , insomnia, nightmare and arthralgias . BMI remained stable (mean change at W48: 0.15 (± 1.23) p = 0.42). The lifestyle and ease subscale significantly improved between baseline and week 48 (mean change = 0.88 ± 3.86); p = 0.04. Participants mostly preferred the new regimen, with a total satisfaction change score (HIVTSQc) of 21.3 (± 11.79) at week 24. The quality of life and PROs, improved from baseline to week 12 with total score of 47/100 (± 15.10) and 50/100 (± 14.46) respectively (p = 0.007). There was also improvement in the body change dimension (p = 0.034), and the treatment impact dimension (p = 0.001). No significant difference was observed for other PROs, and between baseline and week 48, for any PRO.Adherence to cART was high (97% intake) and stable throughout the 48 weeks follow-up. At baseline, patient global satisfaction  was high and remained unchanged until week 48 (mean change = 0.81 ± 9.06) Our study showed the high efficacy and safety of switching to a triple therapy based on 2 NRTIs plus RAL 1200 mg qd in virologically suppressed patients. At both weeks 24 and 48, maintenance of HIV-1 RNA < 50 copies/mL by FDA snapshot analysis was around 90% with the lower margin of 95% CI above the predefined 80% value. RAL 1200 mg qd demonstrated non-inferiority to RAL 400 mg bid, each combined with emtricitabine and tenofovir disoproxil fumarate in previously untreated HIV-1 patients Our study have some limitations, including the absence of a control group, which in terms of impact on metabolic parameters  may limit the interpretation of the observed changes over time. Although absence of a comparator group precludes any formal conclusion, efficacy rate of 89% is at the same level as for other INSTIs as maintenance switch strategy. Second, the magnitude of patients’ satisfaction might have been biased by the open label design of the study and by the request for a change of cART by patients themselves in 52% of cases. Also, because of the diversity of prior cART regimen, we could not assess changes in PROs according to previous regimen.In conclusion, results of our study position RAL 1200 mg qd as an alternative option to bictegravir or dolutegravir as INSTI plus 2 NRTIs switch in virologically suppressed patients.


A single-tablet regimen (STR) has been associated with better drug adherence. However, the durability of different STRs was unknown in the real-world settings. Our aim was to investigate the durability of different initial STR regimens in antiretroviral-naive patients starting STR in southern Taiwan.This was a retrospective study of antiretroviral-naive patients that initiated first-line antiretroviral regimens with STRs between May 2016 and December 2017. The primary endpoint was time to virological failure. Secondary endpoints were STR discontinuation due to toxicity/intolerance. Durability was defined as time from the initiation until discontinuation/modification. Kaplan- Meier curves were plotted assessing time to virological suppression, treatment failure and discontinuation for the three STRs and Cox proportional hazards model was used to analyze the factors associated with time to viral suppression, treatment failure or discontinuation.Two hundred and twenty-three patients were included: The median follow-up duration (IQR) was 73.9 (48–101.6) weeks, 25 patients (11%) experienced virological failure; the 48 weeks probability of treatment failure was 22.9% (16/70) for Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF), 24.1% (13/54) for Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate (FTC/RPV/TDF) and 24.2% (24/99) for Abacavir/Dolutegravir/Lamivudine (ABC/DTG/3TC) (p=0.16). Fifty-six patients (25%) discontinued their STRs owing to toxicity/intolerance. When compared to EFV/FTC/TDF, treatment with FTC/RPV/TDF  and ABC/DTG/3TC  were more likely to have treatment failure. The predictors for treatment failure included age ≦ 30 years old , switch between different STR  and free of active syphilis infection . The risk factor for treatment discontinuation included younger age ≦ 30 years old , treatment with EFV/FTC/TDF  and free of active syphilis infection .Younger age was associated with treatment failure and drug discontinuation. Active syphilis infection s/p treatment was associated with free from treatment failure and discontinuation. This probably driven by the more frequently sexual health education and counseling when patients had syphilis infection. Treatment with ABC/DTG/3TC was associated with higher risk of treatment failure. The STR durability was dependent on the drug toxicity/intolerance, age and syphilis infection. Single tablet regimen (STR) has been associated with better drug compliance , improveThere are cohort studies dealing with ARV regimen durability in HIV infected treatment-naïve patients in the real-world settings. In a retrospective cohort study at eight UK centers, Lewis et al. found that the rilpivirine based STR (FTC/RPV/TDF) had a significantly lower discontinuation rate than another STR (EFV/FTC/TDF) and other third agents . In anotThe results with contemporary STRs in registrational studies in treatment-naïve HIV infected individuals showed that the efficacy was about 88–93%, rate of virological failure was 0.8–4.4% and rate of discontinuation due to severe adverse effects were around 0–1.9% . Real- wThe objectives of this study were to investigate the durability of different initial regimens in patients starting ART with single tablet regimen in southern Taiwan.This was a retrospective cohort study conducted at Kaohsiung Veterans General Hospital; a 1500-bed medical center in southern Taiwan. The study period was from May 2016 to Dec 2017. In Taiwan, all of the HIV infected patients were mandatory to enroll into the case management program sponsored by Taiwan Center for Disease Control (CDC) since 2008. The data of social, demographic, pharmacologic, laboratory, and concurrent infections were collected through electronic medical records. We included treatment-naïve patients with age more than 20 years old, initiating STR  between May, 2016 and December, 2017 in this retrospective cohort. This cohort study was conducted in parallel with the introduction of second and third STRs (FTC/RPV/TDF and ABC/DTG/3TC) into Taiwan in June 2016. Before June 2016, the only available STR was EFV/FTC/TDF which was used as the second line ARVs in those patients unable to tolerance to zidovudine (AZT)/3TC/EFV or HIV/HBV coinfection. After June 2016, any one of the three STRs  was recommended as the first line therapy in those HIV-1 infected, treatment-naïve patients in Taiwan.The laboratory tests for patients diagnosed with HIV infection included CD4 cell count, plasma viral load, serological markers for syphilis, hepatitis, cryptococcus, toxoplasmosis, cytomegalovirus, amoebiasis, liver and renal function. HIV-1 genotype resistance testing (GRT) for treatment-naive patients was not routinely performed in our country due to limited budget. Standard follow-up of the HIV-infected patients consisted of out-patient visits every 3 months. Testing for CD4 cell count, plasma viral load, haematology, and biochemistry were conducted every 6 months for viral suppressed patients. HIV Genotypic drug resistance testing for the protease and reverse transcriptase region was done by the commercial kit Viroseq version 2.8  . For intDurability was defined as the number of weeks from the STR regimen initiation until discontinuation or modification. Viral suppression was defined as viral load (VL) < 20 copies/ml. Virologic failure was defined if at least one of the following occurred: (1) failure to achieve viral suppression by 48 weeks or (2) after achieving viral suppression, having a detectable VL on two consecutive occasions at least 14 days apart or a single VL ≥ 200 copies/ml. Treatment failure was a composite endpoint defined as virological failure or discontinuation/switch of STR for any reason or death. Active syphilis was defined as a new positive rapid plasma regain (RPR) and the Treponema pallidum particle agglutination test (TPPA) . In thosp < 0.05 was considered statistically significant. Statistical calculations were performed using the SPSS program version 12.0 .Categorical data were analyzed using Chi-square test or Fisher’s exact tests as appropriate, and continuous variables, expressed as median and interquartile range, were compared using the Manne-Whitney U or Kruskal-Wallis test. Kaplan-Meier curves were plotted assessing time to virological suppression, treatment failure and discontinuation for the three STRs. The median duration for durability was reported in weeks and compared across stratified STRs using the log-rank test. In treatment failure analysis, patients were censored if they were lost to follow-up, discontinuation/switch of STR for any reason or death. Association of various demographic characteristics with time to viral suppression, treatment failure or regimen modification/ discontinuation were evaluated using Cox proportional hazards model to estimate crude and adjusted hazard ratios (HRs), and the associated 95% confidence intervals (CIs) were estimated by multivariable regression models. The following clinically important variables were included: age, sex, HIV transmission risk factor, CD4 count, viral load, concurrent infection with hepatitis A, B, C and syphilis and individual STR. Variables that were significant in univariate analysis were considered for the multivariable model. A stepwise selection was used to select the covariates to be included in the final model using a p-value of 0.2 to enter the model and a p-value of 0.10 to remain in the model. We also examined all variables for correlation and interaction and excluded the variables that were highly correlated. Validity of the proportional hazards assumption was evaluated using Schoenfeld residuals. A two-sided A total of 345 HIV-1 infected, treatment-naïve patients were eligible for the study between May 2016 to Dec 2017. Among them, 122 patients were not enrolled due to no ARV use during the study period, use of multiple tablet regimen, or incomplete clinical data, received with less than 60 days of STRs, transferred out or went to jail  discontinued their STRs due to drug adverse effects (p < 0.0001). The most common cause for discontinuing EFV/FTC/TDF was neuropsychiatric adverse effects . The most frequent symptoms included insomnia and sleep disturbances as well as dizziness and dreaminess. For ABC/DTG/3TC, it was skin pruritis and rash . A similar but nonsignificant result was also seen in EFV/FTC/TDF , log rank test p < 0.001; Fig. The risk of treatment failure was also different in 3 STRs , switch between different STR  and active syphilis infection , treatment with EFV/FTC/TDF  and active syphilis infection  of the patients discontinued their STRs due to toxicity/intolerance. Treatment with ABC/DTG/3TC and FTC/RPV/TDF were associated with treatment failure. However, when the risk of treatment failure was compared between two different STRs, treatment with FTC/RPV/TDF was not found to have higher risk of treatment failure when compared to EFV/FTC/TDF. Treatment discontinuation was common in the EFV/FTC/TDF group. Younger age ≦ 30 years old was associated with treatment failure and drug discontinuation. However, active syphilis received treatment was not associated with treatment failure and drug discontinuation.The finding of a higher treatment failure rate in the ABC/DTG/3TC group was interesting and the result of a higher drug discontinuation rate in the EFV/FTC/TDF group was quite similar to that reported in the literature .In a retrospective study from Maple Leaf Medical Clinic in Canada, researchers enrolled 780 patients between January 2006 and June 2016 to investigate the virologic durability of first-line INSTI, NNRTI, or PI -based antiretroviral regimens. No information on the percentage of STR uses were lack. They found that being on an INSTI or NNRTI-based regimens versus PI regimen, frequent VL testing and longer duration on of ART were associated with better durability [3) and high viral load (> 5 log10 copies/ml) who started first line ART with boosted protease inhibitors (bPIs), NNRTIs or INSTIs to analyze the durability of their different regimen. They concluded that starting ART with NNRTIs versus starting with bPIs; and starting ART with InSTIs versus starting with NNRTIs were less likely to be associated with treatment failure. Therefore, the durability of InSTIs-based regimen was longer than that of NNRTI- and bPI-based regimens [In an Italian ICONA cohort, they prospectively followed up patients with low CD4 count  in USA, they integrated data from eight Centers for AIDS Research (CFARs), focusing on HIV infected patients initiating ART between 2007 and 2014. In that study, 59% of patients starting their ART with STRs (EFV/FTC/TDF (n = 2173) 40%, Elvitegravir/Cobicistat/FTC/TDF (n = 571) 11%, FTC/RPV/TDF (n = 336) 6% and ABC/DTG/3TC (n = 106) 2%)). The initial regimen was modified in 43% (2285/5373) of patients. The median durability for all regimens was 48.6 months. Female sex, intravenous drug use, and CD4 cell count less than 200 cells/µl were significantly associated with regimen modification. NNRTI and INSTI-based ART were most durable in this study .The possible explanation for the higher treatment failure rate in the ABC/DTG/3TC group in this study might be related to the high rates with drug discontinuation and loss of follow up. Clinicians may tend to prescribe high genetic barrier STR in those patients with suspicious poor drug adherence and severe diseases. Among the 24 patients suffered from virological failure, 8 loss of follow up, 11 patients reattained viral suppression at the end of our follow-up and 5 had persistent viremia. Only 2 patients had genotypic drug resistance testing, none had INSTI resistance-associated mutations and one of them had resistance to NRTI and NNRTI. In addition, the median follow-up times were short in our cohort, at around 1.5 years. This raises the possibility that, for some ART regimens such as ABC/DTG/3TC, the lost follow-up rate may be higher in the first year of therapy due to drug adverse effects but reduced to a lower rate (for those remaining on therapy) for subsequent years on treatment. The low STR discontinuation in the FTC/RPV/TDF group was similar to the study from UK. In a retrospective cohort study at eight UK centers conducted between 2012 and 2015 with only 2 STRs in their centers, Lewis et al. [Active syphilis received treatment was associated with less treatment failure and drug discontinuation. Our study result was different from that from the France  and simiIn this study, younger age (≤ 30 years) was associated with treatment failure and drug discontinuation. Several large cohort studies also report that older age was associated with better treatment outcomes , 20, andNo data about the level of adherence was available in this study due to the retrospective cohort design. However, all of the patients were educated about their adherence and cared by the case management nurses, suggesting that other issues than adherence can explain their treatment failure and drug discontinuation , 22.The reasons why the median time (IQR) to discontinue STRs were longer in the EFV/FTC/TDF group compared to FTC/RPV/TDF and ABC/DTG/3TC groups were unclear. This was probably due to the neuropsychiatric adverse effects for EFV/FTC/TDF were well known by the doctors, care management nurses and patients themselves, and patients were well educated about the adverse effects before the EFV/FTC/TDF was prescribing.Our study had some limitations. First, there was always the risk of bias due to unmeasured confounding, such as drug adherence levels, not reporting adverse effects and missing data, when using retrospective cohort data. Secondly, reasons for regimen selection were not reported, patients with presumed poorer adherence, loss to follow-up in the initial phase of treatment and higher viral load were more likely to be prescribed ABC/DTG/3TC (INSTI-based) and could impact our analysis. Another caveat was that we censored patients who were lost to follow-up. Such censoring could have led to bias in increasing rate of treatment failure. Finally, our study results could not be applied to those health care systems whom did not have HIV case management program and free STR available.In conclusion, younger age was associated with treatment failure and drug discontinuation. Active syphilis infection was not associated with an increase risk of treatment failure and discontinuation. Treatment with ABC/DTG/3TC was associated with more treatment failure. The STR durability was dependent on the drug toxicity/intolerance, age and syphilis infection regardless of genetic barrier of antiretroviral regimen.Younger age was associated with treatment failure and drug discontinuation. Active syphilis infection s/p treatment was associated with free from treatment failure and discontinuation. This probably driven by the more frequently sexual health education and counseling when patients had syphilis infection. The STR durability was dependent on the drug toxicity/intolerance, age and syphilis infection.


Monitoring the population‐level emergence and transmission of HIV drug resistance (HIVDR) is necessary for supporting public health programmes. This study provides a nationally representative prevalence estimate of HIVDR in people initiating antiretroviral therapy (ART) and estimates of acquired HIVDR and viral load (VL) suppression in people who have received it for 12 or ≥48 months in Vietnam.The study was conducted between September 2017 and March 2018 following World Health Organization guidance. Thirty ART clinics were randomly sampled using probability proportional to size sampling from a total of 367 ART clinics in the country.In total, 409 patients initiating ART were enrolled into the survey of pre‐treatment HIVDR. The prevalence of any pre‐treatment HIVDR was 5.8% (95% CI 3.4–9.5%), and the prevalence of non‐nucleoside reverse transcriptase inhibitor resistance was 3.4% (95% CI 1.8–6.2%). Four hundred twenty‐nine patients on ART for 12±3 months and 723 patients on ART for ≥48 months were enrolled into the surveys of acquired HIVDR. The prevalence of VL suppression (defined as <1000 copies/ml) in patients on ART for 12±3 and ≥48 months was 95.5% (95% CI 91.3–97.8%) and 96.1% (95% CI 93.2–97.8%), respectively. Among individuals with viral non‐suppression, any HIVDR was detected in 11/14  of those on ART for 12±3 months and in 24/27  of those receiving ART for ≥48 months.This nationally representative study of HIVDR found high levels of VL suppression among those on ART for 12 and ≥48 months. Overall, high levels of VL suppression at both time points suggested good adherence among patients receiving ART and quality of treatment services in Vietnam.Not applicable As of December 2020, there was an estimated 215,000 people living with HIV in Vietnam and about 70% of them were receiving ART . The preIn 2019, WHO reported HIV drug resistance (HIVDR) data from 44 nationally representative HIVDR surveys from 24 low‐ and middle‐income countries, including Vietnam. In this work, we report prevalence estimates of pre‐treatment HIV drug resistance (PDR) among people starting ART and the prevalence of VL suppression and ADR among those taking ART.22.1We conducted a nationally representative cross‐sectional study of PDR and ADR in adults receiving ART for 12±3 months (ADR12) and ≥48 months (ADR48+). At the end of 2016, Vietnam had a total of 367 ART outpatient clinics (OPCs) providing ART to 105,938 adults. Of the 263 OPCs in operation for ≥48 months , 25 were sampled to contribute to the PDR, ADR12 and ADR48+ month surveys. Of the remaining 104 OPCs in operation for <48 months, five OPCs were sampled to contribute to the PDR and ADR12 months study. This sampling approach maximized overlap in sites contributing to each of the three time points [2.2The PDR survey included people living with HIV (PLHV) presenting to sampled clinics for ART initiation for the first time or re‐initiation of ART if they were on it for less than 1 month and had stopped it for more than 3 months. For ADR surveys, PLHV who have been receiving ART for 12 (±3) months (ADR12) or for ≥48 months were enrolled. All participants in PDR and ADR surveys were 18 years of age or older and provided written informed consent.2.3Sample size calculation followed procedures described by WHO for two‐stage cluster sampling for combined PDR and ADR surveys , 5. The 2.4All participating OPCs consecutively enrolled eligible patients until reaching the target site‐specific sample size or passing 6 months of the study start date, whichever came first.Whole blood specimens were collected for plasma VL measurement in both PDR and ADR survey populations. Collecting and processing of specimens followed WHO laboratory guidance . Specime2.5Data were double entered using Epi Data 3.0  and statistical analysis was performed using STATA version 14  following WHO methods. The prevalence of VL suppression and HIVDR were estimated using STATA's survey (SVY) commands . Data we2.6The study was reviewed and approved by the Institutional Review Board in Biomedical Research, National Institute of Hygiene and Epidemiology, Hanoi, Vietnam .3Thirty randomly sampled OPCs enrolled patients from September 2017 to March 2018 across 18 of 63 provinces in Vietnam. During the 6 months of the study, the number of eligible patients presenting to OPCs were 1150 across 30 OPCs in the PDR group, 1829 across 30 OPCs in the ADR12 group and 12,199 across 25 OPCs in the ADR48+ group. A total of 1561 patients were enrolled in the survey: 409 patients in the PDR survey, 429 patients in the ADR12 survey and 723 patients in the ADR48+ survey.Among the 409 people enrolled in the PDR survey, VL was detectable in 393 (96.1%) with 375/409 (91.7%) having VLs >1000 copies/ml. The genotyping success rate was 340/375 (90.7%). A total of 340 genotypes are available from the PDR survey. HIV‐1 subtype CRF01_AE was the predominant subtype and identified in 328/340 (97.1%) patients. Other subtypes included: subtypes B , subtype C  and CRF07_BC and CRF25_cp (each of 1% or 0.1%).In the ADR survey, genotyping was performed only for patients with non‐suppressed VLs (VL >1000 copies/ml). Viral non‐suppression was documented in 18/429 patients (4.2%) receiving ART for 12 months and 32/723 patients (4.4%) receiving ≥48 months.3.1p = 0.013).We enrolled 409 patients who presented to OPC for ARV drugs. Participant characteristics are summarized in Table Estimates of PDR are summarized in Table p = 0.02).In specimens with any HIVDR, non‐nucleoside reverse transcriptase inhibitor (NNRTI) resistance was predicted in 15/22 (68.2%); one had NVP resistance, and 14 had NVP and EFV resistance. NRTI resistance was predicted in 13/22 (59.1%), and 6/22 (27.3%) had resistance to both NNRTI and NRTI. The nationally representative prevalence of PDR to the NNRTI drug class was 3.4% (95% CI 1.8–6.2%)  patients with successful genotyping, 11 had any HIVDR . The prevalence of any HIVDR among those on ART12±3 months was 3.0% (95% CI 1.6–5.7%). All 11 patients with any HIVDR had NNRTI resistance and nine had NRTI resistance. No PI resistance was observed.3.3A total of 723 patients from 25 clinics were included in the ADR48+ survey Table .The VL suppression and ADR outcomes are summarized in Table p = 0.39 by Fisher's exact test)  was similar to that observed in people receiving ART for at least 48 months (3.4%) , which was seen in 2014 among people on ART for at least 36 months (4.6%) .Vietnam has initiated the transition to dolutegravir containing regimens as preferred first‐ and second‐line regimens since 2020 . A thirdOur report has limitations. Firstly, our results were not reported in a timely manner. However, the data were included in the global report and Vietnam has considered these results and decided to continue the first‐line ART regimen containing NNRTIs and keep improving the quality of ART service. Secondly, we were not able to evaluate the HIVDR when the VL was less than 1000 copies/ml. However, we assumed that the prevalence of HIVDR among patient with suppressed VL was low and this issue is recognized as a technical limitation in other studies .4Vietnam achieved very high level of HIV VL suppression among people on ART and maintained moderate prevalence of HIVDR in patients starting ART and low prevalence of HIVDR in patients receiving ART.The authors declare that there are no competing interests.QD, ND, MRJ, SB and VN developed study protocol, analysed data, interpreted the results and wrote the manuscript. NA, KN, NL, HT, MT, TT, QA, NP, PH, DN and NH contributed to protocol development, monitoring survey implementation and reviewed the manuscript. NA, NL, HT, TT and LQA were involved in the protocol development, performed viral load testing and genotyping and reviewed the manuscript. QD, AC, ND, MRJ and SI performed data analysis. All authors revised the manuscript and approved the final draft.This work is supported by the Global Fund to Fight AIDS, Tuberculosis and Malaria and the World Health Organization.The views expressed in this paper are those of the authors and do not necessarily represent the official position of the authors’ institutions and World Health Organization.


Antiretrovirals, including tenofovir, can suppress human immunodeficiency virus (HIV) infection but cannot completely eradicate it. Patients with HIV infection are administered antiretroviral drugs over a long term; thus, managing consequent adverse drug reactions, such as renal dysfunction and bone mineral loss, is important. Currently, highly sensitive biomarkers that can detect adverse drug reactions early have not been well studied.This single-center, prospective, observational study explored changes in the biomarkers of renal function, bone metabolism, and lipid profile before and after switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) in patients with HIV infection.p < 005 for both at 3 and 6 months). The urinary N-terminal telopeptide (NTx)/creatinine ratio decreased over the study period, and the ratios were significantly different between 3 and 6 months . Low density lipoprotein-cholesterol level significantly increased at 3 (+ 26 mg/dL) and 6 months (+ 13 mg/dL) compared with that at the baseline (p < 0.0001).All 31 enrolled patients had been treated with antiretrovirals for more than 5 years. The rate of proteinuria decreased significantly after starting TAF-containing antiretroviral regimen. The urinary liver-type fatty acid binding protein (L-FABP)/creatinine ratio was significantly decreased at 3 and 6 months after switching to TAF compared with that before switching to TAF (− 0.5 μg/g Cr at 3 months, and − 0.8 μg/g Cr at 6 months; Switching from TDF to TAF decreased the levels of renal and bone biomarkers, such as urinary L-FABP and NTx, but increased low density lipoprotein-cholesterol levels. Future studies should evaluate if these biomarkers, such as urinary L-FABP and NTx, truly detect serious adverse drug reactions early. Antiretrovirals (ARVs) have been successfully used to suppress human immunodeficiency virus (HIV) infection, and the life expectancy of the HIV-infected patients treated with ARVs has considerably increased, comparable to that of HIV-uninfected patients . HoweverLong-term therapy with ARVs can cause adverse drug effects. Tenofovir disoproxil fumarate (TDF) was used since 2001 in the world and since 2004 in Japan. TDF has recommended as a part of initial regimens for most treatment naïve patients . TenofovAlthough switching to TAF from TDF showed renal improvement with potent viral suppression, highly sensitive biomarkers that indicate these subclinical changes after switching to TAF are not well-identified.The urinary liver-type fatty acid binding protein (L-FABP) is expressed in the human proximal tubules, and its excretion via urine reflects tubulointerstitial damage . L-FABP Among the biomarkers of bone metabolism, bone-specific alkaline phosphatase (BAP) is a glycoprotein on the surface of osteoblasts that is released during bone formation. The N-terminal fragments of telopeptide (NTx) of type 1 collagen after degradation of the bone matrix is considered a resorption marker . These mIn this study, we aimed to explore the changing trends in biomarkers of renal function and bone metabolism, and lipid profile while switching from TDF- to TAF-containing regimen in HIV-infected patients.This observational study was conducted prospectively at the University of Tokyo Hospital, a 1217-bed tertiary-care teaching hospital in Tokyo, Japan. The study was approved by the research ethics committee of the Faculty of Medicine of the University of Tokyo. All the patients have provided written informed consent.HIV-infected adult (20 years old and more) patients were enrolled in the study from July 2017 to June 2018. The enrollment criteria were as follows: (1) patients who had already received TDF-containing antiretroviral regimen for at least a year, (2) patients who could visit the outpatient clinic, and undergo blood and urine tests at least once every 3 months, and (3) if the physician had determined that the patients preferred TAF over TDF to be concerned about possible adverse drug reactions such as renal dysfunction and bone mineral loss for long treatment.The study period of all the patients was for 6 months. Additional urine samples, and venous blood samples were collected for testing in a commercial laboratory during the study period.2 during the study period or previous diagnosis by their respective doctors. Body mass index was calculated as weight in kilograms divided by the square of height in meters: weight (kg)/height (m)2.The collected patient data included age, sex, body weight, height, underlying disease , chronic hepatitis C virus infection, and chronic/history of hepatitis B virus infection), a history of acquired immunodeficiency syndrome (AIDS), and the prescribed antiretroviral regimen by medical chart review. Chronic kidney disease was defined as eGFR < 60 mL/min/1.73 m+ lymphocyte count, plasma HIV RNA level, complete blood count, serum phosphate level, low and high density lipoprotein cholesterol levels, triglyceride (TG) level, urinalysis, and serum creatinine level. Glomerular filtration rate (GFR) was calculated with serum creatinine and cystatin C levels.The following laboratory data were reviewed using the medical charts: CD4N-acetyl-beta-d-glucosaminidase (U-NAG), cystatin-C (latex agglutination turbidimetry), urinary N-terminal telopeptide , and serum BAP (chemiluminescent enzyme immunoassay). Using this data the following creatinine ratios were calculated: U-L-FABP/creatinine (Cr), U-NAG/Cr, and U-NTx/Cr. To assess renal proximal tubular dysfunction, the rate of tubular reabsorption of phosphate  was calculated according to the following formula:In addition, serum and urine samples were tested for the following in a commercial laboratory (LSI Medience Corporation): urinary liver-type fatty acid binding protein level , urinary phosphate level, urinary Proteinuria was defined by a value of ≥ 1+ by dipstick urinalysis.The Wilcoxon signed-rank test was performed using the JMP Pro software version 14.2.0  to analyze trends of biomarkers before and after switching from TDF to TAF. The significance level of the two-tailed test was set at 0.05.Thirty-one patients were enrolled in our study. The patients’ characteristics are shown in Table + T cell count, and a rate of successful viral suppression was maintained. The median CD4+ T cell counts were 448, 385, and 442 cells/µL at 0, 3, and 6 months, respectively, after switching from TDF to TAF. The rates of HIV RNA suppression (less than 100 copies/mL) were 93.5%, 90.3%, and 100% at 0, 3, and 6 months, respectively. All patients remained on ART during the study period. No events of bone fractures, acute coronary syndrome, and renal failure occurred.There was no significant change in CD4The biomarkers of renal function such as the eGFR values calculated using creatinine, and with cystatin-C did not show any statistical change during the study period Table . The ratp = 0.0166 at 3 months, p = 0.0002 at 6 months). U-NAG/Cr ratios did not show any statistical change during the study period.U-L-FABP/Cr ratios had significantly decreased at 3 and 6 months after switching to TAF, compared to the value before switching to TAF, as shown in Fig. p = 0.026), but the rate of change in each patient was low.The value of %TRP had significantly increased at 3 months (p < 0.0001)  levels significantly increased at 3 months and 6 months compared to the baseline [+ 26 mg/dL at 3 months, and + 13 mg/dL at 6 months; BAP levels had not changed during the study period. The U-NTx/Cr ratios decreased during the study period, and there were statistical significances between all the points [− 11 nmol/mmol Cr at 3 months, − 15.2 nmol/mmol Cr at 6 months; p = 0.0069 at 3 months, p < 0.0001 at 6 months) (Fig. In this study, we reported the changes in biomarkers of renal function and bone metabolism, and lipid profile when switching from TDF to TAF in HIV-infected patients. During the study, all the patients continued the TAF-containing regimen of ARVs that showed potent viral suppression. There were no serious adverse effects in the first 6 months after switching to TAF-containing regimen.There were no noticeable changes in the eGFR calculated using creatinine levels, and cystatin-C levels during the study period. The L-FABP levels and the rate of proteinuria were significantly decreased. These results might be subclinical for majority of the participants without having CKD. However, it has been reported that the renal function in Japanese HIV-infected patients decreased depending on the duration of treatment with TDF, especially in patients with low body weight . Another+ T-cell counts, anti-hepatitis C virus antibodies, and race [+ T-cell counts by treatment including TDF on enrollment, major reason of the improvement of proteinuria might be discontinuation of TDF exposure. As Proteinuria itself is one of risk factors for CKD [Proteinuria is commonly observed in HIV-infected patients . Its risand race –18. Beca for CKD  and frag for CKD  in HIV-iBecause L-FABP was reported as a potential marker of CKD for patients without albuminuria , the det%TRP change was observed at 3 months but not at 6 months. %TRP was a marker of renal proximal tubular dysfunction and calculated as value of one minus fractional excretion of phosphate. The fractional excretion of phosphate was reported as a possible marker of end-stage renal diseases such as dialysis in moderate to advanced CKD patients . HoweverThe elevation of biomarkers of lipids such as LDL-C was observed to have significance. Previous studies have also shown the elevation in the LDL-C and TG levels, but the range of elevation depended on the observational period, and the characteristics of the participants –24. One Among the biomarkers of bone metabolism, U-NTx significantly decreased in our study. Previous study showed TDF-sparing regimen decreased the level of biomarkers of bone metabolism such as osteocalcin and bone alkaline phosphatase , and swiHere, the renal function and bone metabolism had improved within 6 months after switching to TAF. However, attention must be drawn to whether the lipid metabolism could be elevated up to the level that needs statin treatment.According to patients’ genetic background , 31 the Nevertheless, there were some limitations to our study. First, the information on the changes in lifestyle, such as new exercise habits and dietary patterns, were not collected using a questionnaire, although the treating physicians had recorded the changes in lifestyle and adherence to ARVs during each visit and no other drugs was changed. Second, the study did not have long observational period. Finally, this study was a single-centered observational study, and all except one was Japanese.The TAF-containing regimen of ARVs could be safe with potent viral suppression for 6 months after switching from a TDF-containing regimen of ARVs. Switching from TDF to TAF decreased the levels of biomarkers such as urinary L-FABP and NTx but increased LDL-C levels. Future studies should evaluate if these biomarkers truly detect serious adverse drug reactions early.