With widespread access to effective antiretroviral therapy, a majority of HIV-infected patients can nowadays achieve sustained viral suppression . However, antiretroviral therapy should be indefinitely taken and the associated risk of long-term chronic toxicities and/or negative impact on aging comorbidities increases with exposure. In fact, these reasons are now the most common ones leading to changes in antiretroviral therapy in developed countries .
Because of suboptimal efficacy and limited number, antiretroviral drugs were usually approved at the maximum tolerated dose rather than the minimum effective dose . There is a clear relationship between plasma levels of some antiretroviral drugs such as efavirenz (EFV)  or tenofovir  and their potential for developing drug-related toxicities. Reducing the daily dose of EFV from 600 to 400 mg in antiretroviral-naïve patients [6,7] and using tenofovir alafenamide (TAF) instead of tenofovir disoproxil fumarate (TDF) [8,9] are strategies decreasing exposure to EFV and tenofovir, respectively, that have shown noninferior efficacy and better safety profile.
Antiretroviral therapy has evolved to a larger number of families available and drugs with more convenient dosing schemes and better overall tolerability. The construction of fixed-drug combinations with half-lives long enough to allow for once-daily dosing established the basis for preferred antiretroviral regimens in the last decade. Atripla, a fixed-drug combination of EFV 600 mg/emtricitabine 200 mg/TDF 300 mg, was the first once-daily single-tablet combination, approved more than 10 years ago. The drugs contained in the Atripla pill are among the ones with longer half-lives, allowing for sustained viral suppression despite suboptimal adherence [10–13]. Although triple regimens based on integrase inhibitors are currently recommended as first options in most developed countries, the combination EFV with lamivudine or emtricitabine with tenofovir disoproxil fumarate remains as preferred first-line regimen according to the World Health Organization  and a substantial number of patients are expected to use it in low-income and middle-income countries in the next years [15,16].
Previous small randomized controlled trials have shown that short-cycle 5 days on/2 days off intermittent treatment with either EFV/FTC/TDF  or a three-drug combination therapy including EFV with two nucleoside reverse transcriptase inhibitors [18,19] resulted in noninferior efficacy and improved safety profile relative to standard continuous antiretroviral therapy. These studies helped putting the rationale of our work into context and provided a strong support to test the 3-day-per-week Atripla scheme. However, those studies were not performed with either Atripla or the drugs contained in the Atripla pill, they were based on a 5 days on/2 days off schedule instead of a the 3-day-per-week schedule, and did not assess potential benefits on subclinical disease or in-depth changes in immunological and virological parameters. We hypothesized that simplifying the fixed-dose single-tablet combination EFV/FTC/TDF (Atripla) from standard once-daily dosing to a 3-day-per-week schedule would be feasible, able to maintain viral suppression and less toxic.
Study design and participants
The A-TRI-WEEK study is an open-label, pilot, unicentre, randomized clinical trial. Consecutive stable and asymptomatic HIV-infected adults (≥18 years) on Atripla once daily were invited to participate if they had plasma HIV-1 RNA less than 37 copies/ml for at least the previous 2 years and CD4+ cell counts greater than 350 cells/μl at the time of consideration for the study (Fig. 1). In addition, participants were required not to have any of the following: prior virological failure to any antiretroviral regimen or documented resistance mutations to EFV, tenofovir, or emtricitabine; any diagnosis of psychiatric illness, evidence of alcohol abuse or illicit drug consumption (based on their past medical history and specific questions at the time of recruitment) or any other condition at the doctor's discretion that did not allow ensuring a correct adherence. For women of childbearing age, a negative pregnancy test at the time of consideration for the study and use of anticonceptive measures were also required. Patients who meet all inclusion criteria, none of exclusion criteria, and agreed to participate were randomized 1 : 1 to maintain their once-daily regimen (OD arm) or to reduce it to 3 days (Mondays, Wednesdays, and Fridays) a week (3W arm). We took into consideration time and cost for estimating a realistic sample size. Assuming less than 15% therapeutic failure (10% viral failure with 5% attrition) as a plausible target for the experimental treatment arm, with 30 patients per group we could be 68% confident that our estimate was accurate within 5% points, 90% confident that it was accurate within 8% points, and 95% confident that it was accurate within 9% points . The Institutional Review Board of Hospital Clínic approved the study and all participants signed informed consent prior to inclusion. The study was registered at ClinicalTrials.gov: NCT01778413.
Although the hypothesis of the study was based on consistent data to support its potential feasibility, we planned prior to the initiation of the study that development of virological failure in more than 10% of the patients in the 3W arm would be unacceptable and should lead to stopping the trial. Following the request of the Institutional Review Board that approved the study, if the 24-week trial proved to be successful an extension phase was planned in which patients in the 3W would remain with such schedule and patients in the OD arm would be invited to switch to the 3W schedule; in this extension phase, all patients would have a follow-up long enough (e.g. at least 3 years) with the 3W dosing schedule to better guarantee the efficacy and safety of the new schedule. Again, development of virological failure in more than 10% of the patients in the 3W arm would be unacceptable and should lead to stopping the extension phase. The extension phase is currently ongoing and will not be reported here.
After inclusion, all patients had three medical visits: baseline, 12, and 24 weeks. At baseline, patients’ characteristics including age, sex, ethnicity, suspected route of HIV transmission, and Centers for Disease Control (CDC) stage at the time of HIV diagnosis were collected. At baseline, 12 and 24 weeks, participants had a complete physical examination done and blood drawn for CD4+ and CD8+ cell counts and standard plasma HIV-1 RNA (Siemens VERSANT HIV-1 RNA 1.5 Assay, limit of detection 37 copies/ml). Patients allocated to the 3W arm had blood drawn also at 1, 2, 4, 6, and 8 weeks for standard plasma HIV-1 RNA to detect potential early viral failure. In the 3W arm, blood was drawn on Mondays following the longest period off therapy. At each follow-up visit, information on adverse events and use of drugs other than antiretroviral therapy was collected, and a simplified adherence questionnaire  and a pregnancy test for women of childbearing age were performed.
At baseline and at 24 weeks: weight and height were measured; the Spanish-validated version of the Pittsburg Sleep Quality Index (PSQI)  was self-assessed; blood was drawn after at least a 8-h fasting period to measure blood cells and chemistry including total and HDL cholesterol, triglycerides, creatinine, 25-OH vitamin D, and EFV plasma levels; urine was collected to measure protein/creatinine, albumin/creatinine, and beta-2-microglobulin; and a dual X-absorptiometry (DXA) to measure lumbar and femur bone mineral density was performed. The PSQI is an effective instrument used to measure the quality and patterns of sleep in adults in both clinical and research settings . It differentiates ‘poor’ from ‘good’ sleep quality by measuring seven sleep characteristics: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction over the last month. A total score of ‘5’ or greater is indicative of poor sleep quality. BMI was calculated from weight and height. Estimated glomerular filtration rate (CKD-EPI) was calculated from plasma creatinine following a standard formula . Assessment of these variables was chosen because they would reveal any potential impact of reducing the exposure of Atripla components on their subclinical toxicity profiles. EFV plasma concentrations were categorized as suboptimal (<1 μg/ml), normal (1–4 μg/ml ) or high (>4 μg/ml) .
In addition, at baseline and at 24 weeks, plasma and peripheral blood mononuclear cells (PBMC) samples were collected and stored at −80 °C until deferred measurement of ultrasensitive plasma HIV-1 RNA (limit of detection 2 copies/ml), total and integrated HIV-1 DNA in CD4+ cells, and immunophenotyping (the last two not reported here). Ultrasensitive plasma HIV-1 RNA was measured according to Palmer et al.. Assessment of these variables was chosen because they could provide additional evidence on the potential efficacy of the 3W arm.
Primary end-point was the proportion of patients free of treatment failure (noncompleter = failure) at 24 weeks. Treatment failure was defined as any of the following possibilities occurring within the 24-week study framework: virological failure (confirmed plasma viral load ≥37 copies/ml), discontinuation of the antiretroviral therapy schedule irrespective of the reason, consent withdrawal, lost to follow-up, pregnancy, inability to comply with the study or any other reason that could make the doctor in charge consider the cessation of the study.
Secondary outcomes were 24-week changes in plasma lipids, 25-OH vitamin D, CD4+ cells, CD4+/CD8+ ratio, ultrasensitive HIV-1 RNA in plasma, PSQI score, lumbar and femur T-score, estimated glomerular filtration rate, and urine protein/creatinine, albumin/creatinine, and beta-2 microglobulin.
Patients were followed for the entire trial period regardless of whether they prematurely discontinued assigned study medication. All randomized patients were included in the analysis. Statistical analysis was performed with the use of Stata (release 14) software (StataCorp., College Station, Texas, USA). Chi-squared or Fisher's exact tests were used to compare proportions between treatment groups. Mann−Witney or ANOVA tests were used for comparisons of continuous variables between groups. For comparing efficacy of the 3W arm relative to the OD arm, 95% confidence intervals were calculated by Newcombe's method . Simple comparisons were made with use of a two-sided alpha level of 0.05.
Between 3 June 2013 and 30 May 2014, 68 patients were assessed for eligibility, 61 underwent randomization and received at least one dose of study drugs. Seven patients were excluded because of refusal to participate (lack of time, n = 4; lack of interest, n = 1; fear of viral failure, n = 1) or evidence of illicit drug consumption (n = 1). Out of 61 patients randomized, 30 were allocated at the 3W arm and 31 were allocated at the OD arm. Baseline epidemiological characteristics are shown in Table 1. Most participants were men (n = 54, 89%), of Caucasian ethnicity (n = 40, 66%), and infected with HIV through homosexual sex (n = 45, 75%). Their median age was 48 years. Although most participants in this study had a CDC stage A (n = 48, 80%), there was a trend to more patients with CDC stages B or C in the 3W arm than in the OD arm. Median (interquartile range) pretreatment HIV-1 RNA was 5.2 (4.7–5.6) log copies/ml in the OD arm and 5.2 (4.8–5.7) log copies/ml in the 3W arm (P = 0.826). HIV-1 RNA had been maintained below detection level for a median (interquartile range) of 61 (35–86) months before randomization.
Table 2 shows median (interquartile range) values of plasma and urine chemistry, plasma 25-OH vitamin D, immunology, ultrasensitive HIV-1 RNA in plasma, efavirenz plasma concentration, PSQI, and bone mineral density (lumbar and femur T-scores) at baseline. In general, most chemistry values and PSQI score were within normal values. CD4+ cells and CD4+/CD8+ ratio were well preserved. As it often occurs, plasma 25-OH vitamin D values were usually lower than normal. Median lumbar and femur T-scores were indicative of mild osteopenia. A substantial number of patients (n = 41, 72%) had ultrasensitive plasma HIV-1 RNA below detection threshold at baseline. At baseline, efavirenz plasma concentrations were: suboptimal (<1 μg/ml) in four (13%) OD patients and two (7%) 3W patients; normal (1–4 μg/ml) in 26 (84%) OD patients and 27 (90%) 3W patients; and high (>4 μg/ml) in one (3%) OD patient and one (3%) 3W patient.
At 24 weeks, 30 out of 30 (100%) patients in the 3W arm and 31 out of 31 (100%) patients in the OD arm completed the study and remained free of treatment failure (estimated difference 0%; 95% confidence interval −14.1 to 14.1). Out of 333 plasma samples for standard HIV-1 RNA measurement during the study, none had at least 37 copies/ml.
Figure 2 shows plasma ultrasensitive HIV-1 RNA at baseline and at 24 weeks in both arms. The number of patients with ultrasensitive plasma HIV-1 RNA below detection threshold at 24 weeks was roughly similar to that at baseline and it showed no difference between arms (70% in the 3W arm vs. 71% in the OD arm, P = 0.933). In the OD arm, three (15%) patients went from less than 2 copies/ml at baseline to at least 2 copies/ml at 24 weeks and four (40%) patients from at least 2 copies/ml at baseline to less than 2 copies/ml at 24 weeks; in the 3W arm, three (14%) patients went from less than 2 copies/ml at baseline to at least 2 copies/ml at 24 weeks and one (17%) patient from at least 2 copies/ml at baseline to less than 2 copies/ml at 24 weeks.
Eleven (36%) patients in the OD arm and 13 (43%) in the 3W arm reported at least one adverse effect (P = 0.530). All adverse effects reported were grade 1 or 2 and none of them was considered to be drug-related. No patient discontinued therapy because of adverse effects. Adherence in both arms was excellent; two (6%) patients in the OD arm and no patient in the 3W arm missed at least one dose during the study period. Patients allocated to the 3W arm overwhelmingly reported that they were more comfortable with this schedule than with the daily one.
Ten (33%) patients in the 3W arm and 12 (39%) patients in the OD arm used new drugs other antiretroviral therapy at some time being the most common ones nonsteroid anti-inflammatory agents and antibiotics. No patient used psychotropic drugs during the study.
Table 3 shows the 24-week minus baseline changes in plasma lipids, 25-OH vitamin D, CD4+ cells, CD4+/CD8+ ratio, PSQI score, lumbar and femur T-scores, and urine parameters. In the 3W arm, total cholesterol significantly increased whereas PSQI score significantly decreased, femur T-score significantly increased, and both urine albumin/creatinin ratio and urine β-2-microglobulin significantly decreased relative to the OD arm.
Although EFV plasma levels remained relatively stable in the OD arm [median (interquartile range) 24-week minus baseline absolute change 0.2 μg/ml (−0.1; 0.5), P = 0.051], there was a significant decrease in the 3W arm [median (interquartile range) 24-week minus baseline absolute change −1.3 μg/ml (−1.8; −0.6), P < 0.005]. At week 24, EFV plasma concentrations were: suboptimal (<1 μg/ml) in two (7%) OD patients and 17 (63%) 3W patients; normal (1–4 μg/ml) in 28 (90%) OD patients and 10 (37%) 3W patients; and high (>4 μg/ml) in one (3%) OD patient and no (0%) 3W patients.
This pilot study is a proof of concept confirming the feasibility of a 3-day-per-week Atripla schedule. In otherwise healthy HIV-infected adults with sustained viral suppression, 3-day-per-week Atripla was able to maintain efficacy and to improve subclinical toxicity parameters. Despite Atripla being dosed as just one pill a day, patients were enthusiastic on the prospect of decreasing the burden of their chronic medication to three pills a week. Patients allocated to the 3W arm were specifically asked on their follow-up visits on how they managed to comply with their new nonstandard regimen. We did not design any special intervention to facilitate adherence in the 3W arm. At the beginning, some patients in the 3W arm confessed having developed reminders on their smartphones or wall calendars to help them to comply with the new nonstandard dosing schedule, but after a few weeks, the new regimen became their routine regimen and they felt comfortable and managed excellently with it. We were unable to find a single patient showing adherence problems with the new 3-day-per-week regimen. Despite having no neuropsychiatric complaints and showing normal kidney function and mild osteopenia, patients allocated to the 3W schedule had improvements on markers of subclinical toxicities associated with both EFV and tenofovir. These improvements were evident despite the relatively short study period and were presumably because of decreased drug exposure. It is difficult to extrapolate these significant subclinical changes into clinical meaningful long-term benefits. Nevertheless, we should acknowledge that these changes were not for worse. Moreover, some of these 24-week changes show comparable favourable trends as those seen after 96 weeks with the reduction of EFV daily dose from 600 to 400 mg or the use of TAF instead of TDF. Reduction in the exposure to some antiretroviral drugs such as EFV or tenofovir to decrease toxicity while preserving efficacy is a strategy actively investigated. EFV 400 mg once-daily has been approved by the 2015 World Health Organization (WHO) Guidelines following the results of ENCORE1 Study [6,7] and, where available, TAF is being increasingly used instead of TDF to decrease the risk of tenofovir-related kidney and bone toxicities [28–30]. As it was not preplanned, we did not include any economic analysis in our study. Nevertheless, it is obvious that reducing the Atripla dose from 7 days a week to 3 days a week has a 57% reduction effect in direct antiretroviral therapy cost and this may have important implications in resource-limited settings .
Efficacy of the 3W arm was demonstrated in this intensive study, with frequent plasma HIV RNA monitoring particularly at the beginning of the study. Not only no patient had any viral failure but also there were no blips detected either. In addition, results from ultrasensitive plasma viral load measurements further confirmed the efficacy of the 3W arm. Safety of the 3W arm was excellent. Participants were already taking Atripla at standard OD dosing and the 3W arm only decreased drug exposure without further changes in therapy. This reason may explain in great part the excellent tolerability of the 3W arm. In addition to proving efficacy, any therapy simplification strategy has to offer additional advantages . In the A-TRI-WEEK study, reduction of drug exposure had a significant positive impact on parameters reflecting toxicities related with efavirenz or tenofovir such as sleep quality, bone mineral density, and proteinuria. It should be also noted that there was an increase in total cholesterol in patients allocated to the 3W arm; as tenofovir has a cholesterol-lowering effect , the decrease in total cholesterol may be related to less exposure to tenofovir. These changes, despite being significant, were of small magnitude and they occurred in stable patients, with no evidence of clinical disease, and as previously said its real clinical importance is unknown. Nevertheless, because toxicity of antiretroviral agents is directly associated with the duration of exposure, it is reasonable to assume that the long-term impact of those small changes may have clinical relevance. As expected, EFV plasma levels were reduced in the 3W arm at 24 weeks. Therapeutic concentrations of EFV have been reported between 1 and 4 μg/ml . In the 3W arm, 63% of the patients had less than 1 μg/ml at 24 weeks. However, despite this decrease in EFV plasma concentration, no patient in the 3W arm experienced viral failure not only as defined by detectable standard plasma viral load but also considering ultrasensitive viral load results. Some studies assessing pharmacokinetics of EFV in patients taking rifampin, an inducer of EFV metabolism, have shown that a proportion of patients taking both drugs may have EFV trough levels below 1 μg/ml yet not developing viral failure [34,35]. In addition, a novel method to assess antiretroviral target trough concentrations using in-vitro susceptibility data estimated that the protein-bound 95% inhibitory concentration of EFV was 126 ng/ml , which is well below the average Ctrough of 1.800 ng/ml in patients receiving 600 mg once daily and below the proposed EFV lower concentration threshold (1.000 ng/ml) .
This study had several limitations. There were few patients and the follow-up was short. However, this was a convenient way for planning such an intensive pilot study on a new therapeutic strategy. To compensate for these limitations, intensive virological and immunological studies were done (total and integrated HIV-1 DNA in CD4+ cells and immunophenotyping have been reported elsewhere ) and the results obtained are confirmatory of the ones reported here. In addition, a 3-year extension phase is currently ongoing. All participants agreed participating in the extension phase of the A-TRI-WEEK study and so far after more than 2 years of follow-up, no patient has discontinued therapy or been lost, and there have not been any viral failure or any other major incidences obliging to stop it. Another limitation is that, by design, all participants came from a stable standard regimen consisting of Atripla. Therefore, the conclusions of the A-TRI-WEEK study cannot be generalized to HIV-infected patients taking antiretroviral regimens other than Atripla.
In conclusion, 3-day-per-week Atripla in patients with sustained viral suppression was a feasible option that maintained efficacy and improved subclinical toxicity parameters after 24 weeks of follow-up. A 3-year extension phase to support the long-term efficacy and safety of the new schedule is currently ongoing. The A-TRI-WEEK study represents a proof of concept for the feasibility of 3-day-per-week Atripla maintenance that should be further confirmed in a larger, adequately powered clinical trial.
Funding: «Instituto de Salud Carlos III (PI12/01217) and «Fondo Europeo de Desarrollo Regional (FEDER). Unión Europea. Una manera de hacer Europa».
Conflicts of interest
None of the authors had conflicts of interes twith this study.
1. O’Connor J, Smith C, Lampe FC, Johnson MA, Chadwick DR, Nelson M, et al. UK Collaborative HIV Cohort (CHIC) StudyDurability of viral suppression with first-line antiretroviral therapy in patients with HIV in the UK: an observational study
. Lancet HIV
2. Di Biagio A, Cozzi-Lepri A, Prinapori R, Angarano G, Gori A, Quirino T, et al. Treatment discontinuation in HIV-1-infected individuals starting their first-line HAART after 2008: data from the ICONA Foundation Study Cohort
. J Int AIDS Soc
2014; 17 (suppl 3):19825.
3. Vozza L, D’Incalci M. How medicines are born: the imperfect science of drugs
. 1st ed.Singapore: World Scientific Europe Ltd; 2017.
4. Gutierrez F, Navarro A, Padilla S, Antón R, Masiá M, Borrás J, Martín-Hidalgo A. Prediction of neuropsychiatric adverse events associated with long-term efavirenz therapy, using plasma drug level monitoring
. Clin Infect Dis
5. Baxi SM, Greenblatt RM, Bacchetti P, Scherzer R, Minkoff H, Huang Y. Common clinical conditions –age, low BMI, ritonavir use, mild renal impairment- affect tenofovir pharmacokinetics in a large cohort of HIV-infected women
6. ENCORE1 Study GroupEfficacy of 400 mg efavirenz versus standard 600 mg dose in HIV-infected, antiretroviral-naive adults (ENCORE1): a randomised, double-blind, placebo-controlled, noninferiority trial
7. ENCORE1 Study GroupEfficacy and safety of efavirenz 400 mg daily versus 600 mg daily: 96-week data from the randomised, double-blind, placebo-controlled, noninferiority ENCORE1 study
. Lancet Infect Dis
8. Sax PE, Zolopa A, Brar I, Elion R, Ortiz R, Post F, et al. Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study
. J Acquir Immune Defic Syndr
9. Mills A, Crofoot G Jr, McDonald C, Shalit P, Flamm JA, Gathe J Jr< ET-AL>. Tenofovir alafenamide versus tenofovir disoproxil fumarate in the first protease inhibitor-based single-tablet regimen for initial HIV-1 therapy: a randomized phase 2 study
. J Acquir Immune Defic Syndr
10. Wang L, Begley J, St Claire RL 3rd, Harris J, Wakeford C, Rousseau FS. Pharmacokinetic and pharmacodynamic characteristics of emtricitabine support its once daily dosing for the treatment of HIV infection
. AIDS Res Hum Retroviruses
11. Hawkins T, Veikley W, St Claire RL 3rd, Guyer B, Clark N, Kearney BP. Intracellular pharmacokinetics of tenofovir diphosphate, carbovir triphosphate, and lamivudine triphosphate in patients receiving triple-nucleoside regimens
. J Acquir Immune Defic Syndr
12. Back D, Burger DM, Flexner CW, Gerber JG. The pharmacology of antiretroviral nucleoside and nucleotide reverse transcriptase inhibitors: implications for once-daily dosing
. J Acquir Immune Defic Syndr
2005; 39 (suppl 1):S1–S23.
13. Mathias AA, Hinkle J, Menning M, Hui J, Kaul S, Kearney BP. Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate Single-Tablet Regimen Development TeamBioequivalence of efavirenz/emtricitabine/tenofovir disoproxil fumarate single-tablet regimen
. J Acquir Immune Defic Syndr
15. Gupta A, Juneja S, Vitoria M, Habiyambere V, Nguimfack BD, Doherty M, Low-Beer D. Projected uptake of new antiretroviral (ARV) medicines in adults in low- and middle-income countries: a forecast analysis 2015-2025
. PLoS One
17. Cohen C, Colson A, Pierone G, et al. The FOTO study: the 48 week extension to assess durability of the strategy of taking efavirenz, tenofovir and emtricitabine five days on, two days off (FOTO) each week in virologically suppressed patients [Abstract MOPE B063]
. 5th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention
; Cape Town, South Africa; July 19–22, 2009. Abstr MOPE B063.
18. Reynolds SJ, Kityo C, Hallahan CW, Kabuye G, Atwiine D, Mbamanya F < ET-AL>. A randomized, controlled, trial of short cycle intermittent compared to continuous antiretroviral therapy for the treatment of HIV infection in Uganda
. PLoS One
19. BREATHER (PENTA 16) Trial GroupWeekends-off efavirenz-based antiretroviral therapy in HIV-infected children, adolescents, and young adults (BREATHER): a randomised, open-label, noninferiority, phase 2/3 trial
. Lancet HIV
20. Hertzog MA. Considerations in determining sample size for pilot studies
. Res Nurs Health
21. Knobel H, Alonso J, Casado JL, Collazos J, González J, Ruiz I, et al. Validation of a simplified medication adherence questionnaire in a large cohort of HIV-infected patients: the GEEMA Study
22. Royuela A, Macías JA. Propiedades clinimétricas de la versión castellana del cuestionario de Pittsburgh
23. Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research
. Psychiatry Res
24. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate
. Ann Intern Med
25. Marzolini C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients
26. Palmer S, Wiegand AP, Maldarelli F, Bazmi H, Mican JM, Polis M, et al. New real-time reverse transcriptase-initiated PCR assay with single-copy sensitivity for human immunodeficiency virus type 1 RNA in plasma
. J Clin Microbiol
27. Newcombe RG. Interval estimation for the difference between independent proportions: comparison of eleven methods
. Stat Med
28. Wang H, Lu X, Yang X, Xu N. The efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate in antiretroviral regimens for HIV-1 therapy: Meta-analysis
. Medicine (Baltimore)
29. Gallant JE, Daar ES, Raffi F, Brinson C, Ruane P, DeJesus E, et al. Efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate given as fixed-dose combinations containing emtricitabine as backbones for treatment of HIV-1 infection in virologically suppressed adults: a randomised, double-blind, active-controlled phase 3 trial
. Lancet HIV
30. Raffi F, Orkin C, Clarke A, Slama L, Gallant J, Daar E, et al. Long-term (96-week) efficacy and safety after switching from tenofovir disoproxil fumarate to tenofovir alafenamide in HIV-infected, virologically suppressed adults
. J Acquir Immune Defic Syndr
31. Menzies NA, Berruti AA, Blandford JM. The determinants of HIV treatment costs in resource limited settings
. PLoS One
32. Carr A, Hoy J, Pozniak A. The ethics of switch/simplify in antiretroviral trials: noninferior or just inferior?
. PLoS Med
33. Santos JR, Saumoy M, Curran A, Bravo I, Llibre JM, Navarro J, et al. Tenofovir/emtricitabine inflUence on LIPid metabolism (TULIP) Study GroupThe lipid-lowering effect of tenofovir/emtricitabine: a randomized, crossover, double-blind, placebo-controlled trial
. Clin Infect Dis
34. Lopez-Cortes LF, Ruiz-Valderas R, Ruiz-Morales J, Leon E, de Campos AV, Marin-Niebla A, et al. Efavirenz trough levels are not associated with virological failure throughout therapy with 800 mg daily and a rifampicin-containing antituberculosis regimen
. J Antimicrob Chemother
35. Borand L, Madec Y, Laureillard D, Chou M, Marcy O, Pheng P, et al. Plasma concentrations, efficacy and safety of efavirenz in HIV-infected adults treated for tuberculosis in Cambodia (ANRS 1295-CIPRA KH001 CAMELIA trial)
. PLoS ONE
36. Acosta EP, Limoli KL, Trinh L, Parkin NT, King JR, Weidler JM, et al. Novel method to assess antiretroviral target trough concentrations using in vitro susceptibility data
. Antimicrob Agents Chemother