The aim of this study was to compare 4 different ARV regimens in a clinical cohort in Brazil, with regard to the virologic and immunologic responses, clinical failure and reasons for changing. To compare the virologic response and clinical failure between groups we used the Cox and Kaplan Meier proportional hazard models. To analyze the immunologic outcome, we used multilevel GLLAMM and mixed effect linear regression models. To compare regimen change outcomes we used the Pearson's chi-square test. We included 840 participants distributed across the groups according to the initial ART regimen. The mean follow-up period was 27.8 months. Almost half the sample initiated ART with AIDS-related signs/symptoms. Virologic response was effective in 79.6% of participants within 12 months. The tenofovir/lamivudine/efavirenz group presented a higher proportion of virologic response (VL<50 at 6 months) when compared to the zidovudine/lamivudine/efavirenz group. There was no difference between the regimens regarding the immunologic response. A total of 17.3% of individuals changed regimen because of failure and 46.5% due to adverse events. Changes due to adverse events were more frequent in the group using zidovudine/lamivudine/efavirenz. The proportion of hospitalizations at 1 year was higher in the zidovudine/lamivudine/efavirenz group when compared to the tenofovir/lamivudine/efavirenz group. The effectiveness outcomes between the regimens were similar. Some differences may be due to the individual characteristics of patients, toxicity and acceptability of drugs. Studies are needed that compare similarly effective regimens and their respective treatment costs and financial impacts on SUS . Antiretroviral therapy (ART) has changed the prognosis of AIDS, and has increased longevity and decreased mortality and morbidity –3. The dFrom 2013, based on the perspective of reducing HIV transmissibility, Brazil was the third country worldwide to encourage the initiation of ART regardless of the T-CD4 lymphocyte count, considering the motivation of the patient . Thus, tIn this study, we evaluated the effectiveness of different initial antiretroviral regimens, comparing groups for virologic response, immunologic response, clinical failure, and reasons for regimen changes in a cohort with PLWHIV, monitored at two outpatient services in Recife, Brazil.This was a bidirectional clinical cohort followed at the Hospital Universitário Oswaldo Cruz and Hospital Correia Picanço, in Recife/PE, Brazil. Together, the two hospitals take in around half the adult HIV/AIDS cases in the state of Pernambuco, in outpatient follow-up and also provide beds for hospitalization, including intensive care.The patient universe registered at SICLOM  from the start of collection  made up the prospective phase of the study. Of the 626 registrations, 519 patients were eligible for the study. The sample for the retrospective component was obtained from a simple random draw of the records in the logistic drug control system of the two health services for a number of participants proportional to that of the prospective component. The filter for eligibility of registrations was to be over 18 years old and to start antiretroviral therapy with any of the four regimens that would be studied. The number “six” was randomly drawn and every six number records, one was selected to compose the sample. Of the 2196 eligible participants, 472 were drawn . We inclThe ART regimens compared were: tenofovir/lamivudine/efavirenz; zidovudine/lamivudine/efavirenz; tenofovir/lamivudine/atazanavir/ritonavir and tenofovir/lamivudine/lopinavir/ritonavir. We considered losses participants whose medical records did not allow follow-up . Women who changed ART in the first year due pregnancy were accounted in the “losses”, and followed up at other health services. The total loss was 151 patients, thereby resulting in a total of 840 participants.Participants were monitored from the moment that ART had been introduced, through a review of outpatient records and from access systems for drug dispensing and examinations. Data for the CD4 and viral load counts were retrieved from medical records and databases from SISCEL (the laboratory examination control system). In order to investigate genotyping and access the confirmation reports for cases of resistance mutations, in addition to the medical records, we also consulted SISGENO (the system and information for the genotyping network). Information on hospitalization and death from any cause was taken from the Hospitalization Information System (SIH) and from the Mortality Information System (SIM), both from the Brazilian Ministry of Health. Between Jan/2011 and May/2017, we searched the SIH database to identify individuals, date of hospitalization, diagnostic hypothesis and hospital discharge. In SIM, we identified the individuals and the date of death. We used SICLOM to identify people who were initiating ART for prospective follow-up.Virologic response: a) Viral suppression  at 6 and 12 months after initiating ART; b) time until viral suppression ; c) virologic treatment failure when participants presented at least two consecutive tests of viral load (VL) >50copies/mm3 after 6 months on ART, with an interval of less than 6 months between them, or a level of VL>1,000copies/mm³.2 2) Immunologic response: a) an increase of at least 50 cells in the CD4 count in up to 12 months in comparison to when treatment was initiated5; b) average monthly increase in the CD4 cell count. 3) Clinical failure: proportion of individuals who evolved to hospitalization and death. 4) Regimen change: proportion of individuals who changed or modified at least one component of the ART regimen .In order to measure the effectiveness, the participants' records were investigated for at least 12 months after initiating ART in the following outcome variables: 1) 2The reasons for modifying the ART regimen were classified as they were recorded in medical records, characterized as: adverse events from drugs, virologic failure and other reasons, including non-adherence, antiretroviral unavailable at the pharmacy, patient request, medical decision, and drug interaction. The measure used to suggest adherence to therapy was assiduity in dispensing at the pharmacy enabled by the SICLOM system, in addition to information described in the medical records during consultations. Participants were considered as assiduous when they were registered at SICLOM as having collected their monthly, bimonthly or quarterly ART according to the justification described in the system. Treatment abandonment was considered as failing to collect ART from the pharmacy within 100 days after the previously planned dispensation date.Characterization of clinical conditions when initiating ART followed the Rio de Janeiro/Caracas, BRAZIL, 1998 score. Data were collected and gathered on standardized forms by trained staff.The database was built with double entry and was later compared and corrected. We used Stata 12 for the analysis.3 were calculated during the first 6 months of treatment, and only those who had repeated viral load tests during this period were considered. The groups were compared using the Pearson's chi-square test. For the incidence ratio and in the person-time observation stage, the time was calculated between the ART initiation date and the date on which the first VL measurement was below 50 copies/mm3. We used the Cox proportional hazard calculation to estimate the association between the exposure  and the outcome (virologic response). The Kaplan Meier curve was used to analyze the time until viral suppression and for the clinical outcome related to hospitalization, considering the time of study follow-up. Individuals who changed regimens before completing 28 days of treatment were excluded. We considered this time criteria, because it was the habitual period they returned to the health service to receive their medication. Follow-up was discontinued for those who changed to ART regimens other than those in the study groups, while those who changed to one of the studied regimens were considered as new exposure and the outcomes were independently observed. Cases confirmed as lost to follow-up were censored on the date of the last follow-up recorded in the medical records.To analyze the virologic response, the frequency of individuals with a VL<50 copies/mm3), the multilevel generalized linear latent and mixed model (GLLAMM) was used since it is a sample with repeated measures and with varying time intervals between the tests in the period up to 15 months. We used the multilevel linear mixed-effect regression model to compare the mean increase in CD4/month by comparing antiretroviral regimens. To minimize the effect of observation dependence, the odds ratios confidence intervals and incidence of immune response were adjusted by the random effect. For the multivariate analysis, variables were included with p <0.10 to verify association with immune response.To assess the immunologic response, participants with at least two CD4 cell count tests were considered eligible, the first count being <90 days before or up to 30 days after initiating ART. The immunologic response was observed for up to 15 months after exposure. Participants were excluded if the first CD4 tests after initiating ART was after 12 months. To analyze the cumulative incidence and factors associated with the immunologic response . For the outcome of death, the cases were described with absolute numbers and proportions amongst the users of the regimens in the different groups. Regimen changes were described in simple frequencies and compared using the Pearson's chi-square test or Fisher's exact test.tenofovir/lamivudine/efavirenz and tenofovir/lamivudine/lopinavir/ritonavir regimens, 29 months for the tenofovir/lamivudine/atazanavir/ritonavir and 31 months for the zidovudine/lamivudine/efavirenz. In terms of education, 48.9% of the participants in the sample had attended school for more than 9 years and 4.2% had never attended. Most individuals (87%) came from the city of Recife or metropolitan region. With regard to sexual orientation, 55.7% of the sample identified themselves as heterosexual. The main reason recorded for HIV testing amongst participants was the presence of symptoms possibly associated with opportunistic diseases (48.5%) followed by a positive diagnosis of a partner or former partner (24.7%). The mean time from HIV diagnosis to initiating antiretroviral treatment was 21 months (± 36.4), with 19 months for participants in the prospective stage and 23 months for those in the retrospective group.From a cohort of 840 HIV-infected patients who had initiated antiretroviral treatment, comprising a total of 898 observations, 65.1% of whom were male (N = 547). The mean follow-up period was 27.8 months, with a minimum of 28 days and a maximum of 78 months. Through differentiating the regimens, the mean follow-up time in the study was 26 months for the On initiating ART, 22.3% presented with a diagnosis of some other sexually transmitted disease besides HIV, of which syphilis was the most frequent (15.1%), and 23.3% presented with other diagnoses, whereby hypertension was the most common (34%).3, a median of 296.5 . At the beginning of the regimen, 52% (n = 437) presented with some type of AIDS-defining symptom or disease.During the follow-up period, 43 (5.1%) individuals abandoned treatment and there were 15 deaths (1.8%), with no difference between groups. The most commonly used regimens for initiating treatment were two NRTI (Nucleoside Reverse Transcriptase Inhibitors) drugs and one NNRTI (Non Nucleoside Reverse Transcriptase Inhibitors), which corresponded to the majority of the sample (88.6%). The mean age was 38 years (18 to 74 years). The age group with the largest number of participants (50%) was 25 to 39 years old. In terms of the immunologic status on initiating ART, 30.2% (n = 254) of all participants initiated treatment with severe immunodeficiency (CD4 <200 and/or manifestations of opportunistic disease). The average initial CD4 count was 324 cells/mm3) at 12 months was 14.61 per 100 people treated-month (95%CI:13.58–15.73). The frequency of this response was 79.6% (n = 715) in the first year of ART. Of the 451 participants who repeated a viral load test at 6 months, 366 (81.5%) presented a virologic response within the first 6 months of treatment. Amongst those who initiated ART with the tenofovir/lamivudine/efavirenz regimen, 88.4% presented a virologic response within one year, followed by the tenofovir/lamivudine/lopinavir/ritonavir regimen with 86.1%, the tenofovir/lamivudine/atazanavir/ritonavir regimen with 81.6% and the zidovudine/lamivudine/efavirenz regimen with 76%. There was a difference when comparing the proportions between the groups with NNRTIs, with a better virologic response in the group using tenofovir/lamivudine/efavirenz (p = 0.004), which did not occur amongst participants using the Protease Inhibitor (PI) based regimen.The overall incidence rate of virologic response  within up to 15 months of treatment. Most were male (62.8%), with a mean age of 39.2 years (± 10.6), who had attended school for more than 9 years (65.7%), and 23.4% presented with comorbidities and other sexually transmitted infections. More than half of the participants (52.9%) presented some symptoms suggestive of AIDS on initiating ART. The median CD4 count before initiating ART was 281.5  with an average of 305.2 cells. Most individuals (57.6%) initiated ART with an initial CD4 cell count below 350, 18.3% were between 350 and 500 and 20.7% with a CD4> 500. At the end of follow-up, 227 participants (42.4%) presented CD4 counts >500. Treatment adherence failure was recorded in 17.8% of the participants.To analyze the immunologic response, the sample consisted of 535 participants, out of a total of 555 observations. Of the total participants, 82.5% presented immunologic response . Thehe incidence of hospitalization among those with CD4 < 200 was significantly higher compared to those with Cd4 count > = 200 (p< 0.001).With regard to hospitalization, there was no difference between the groups using PI-based regimens (16.8%) when compared to those using NNRTIs (15.4%). When comparing those using NNRTI regimens, the group using zidovudine/lamivudine/ efavirenz presented a higher frequency of hospitalizations at 1 year (21.3%) with a significant difference compared to the tenofovir/lamivudine/efavirenz regimen , with p = 0.032. There was no difference amongst those using PIs (p = 0.317).Of the 15 deaths that occurred during the cohort follow-up, 11 were male. The proportion of users from the tenofovir/lamivudine/lopinavir/ritonavir regimen was 4.3% (2/47), followed by the tenofovir/lamivudine/atazanavir/ritonavir regimen with 1.7% (1/57), the tenofovir/lamivudine/efavirenz with 1.7% (10/518) and the zidovudinar/lamivudine/efavirenz with 1.3% (2/158). The median initial CD4 cell count on initiating ART in cases of death was 202 . The main causes involved opportunistic diseases such as AIDS complications (11/15), followed by lung, colon and liver cancer (4/15).Regimens were changed in 28.1% (0.25–0.31) of the observations (n = 254) and 63.8% (n = 162) of the changes were due to virologic failure and adverse events. The regimen with the lowest rate of change for any cause was tenofovir/lamivudine/efavirenz (16.7%). When compared at 1 year of ART treatment, the regimen with the highest proportion of change for any reason was the zidovudine/lamivudine/efavirenz when compared to the tenofovir/lamivudine/efavirenz (p<0.001). Adverse events were the reason for change in 46.5% (0.40–0.53), and were the main reason for regimen changes in the cohort. Amongst the groups, considering the first 6 months of treatment, that group taking zidovudine/lamivudine/efavirenz changed regimen to a greater extent by adverse events when compared to tenofovir/lamivudine/efavirenz (p = 0.04). There was no difference between IP users.Of the participants who changed regimens, 17.3% (0.13–0.22) did so because of virologic failure (n = 44). The mean time between detecting virologic failure and changing the regimen was 4.8 months. The least changed regimen was tenofovir/lamivudine/efavirenz (16.7%). In the first year of ART, there was no regimen change because of virologic failure in the groups using protease inhibitors, and no difference was observed between the groups that changed due to virologic failure. Participants with a pre-treatment CD4<200 changed the initial regimen more frequently (37.2%) than those with a CD4>200 (23.4%) (p<0.001).We compared the effectiveness of four ART regimens at two referral hospital services in the state of Pernambuco/Brazil in a bidirectional cohort. The proportion of participants with a virologic response within the first 6 months of taking ART was higher in the tenofovir/lamivudine/efavirenz group when compared to the zidovudine/lamivudine/efavirenz group, but did not differ from the others. There was no difference between the regimens in relation to the time until viral suppression and virologic failure. There was no difference between the groups regarding immune response and the mean monthly increase in the CD4 count. Regimen changes for any reason was more frequent in the zidovudine/lamivudine/efavirenz group. The proportion of hospitalizations was also higher in the zidovudine/lamivudine/efavirenz group when compared to the tenofovir/lamivudine/efavirenz group. In general, adverse events were the main reason for changing regimens. Amongst the NNRTI users, the zidovudine/ lamivudine/efavirenz group presented a higher chance of changing regimens for this reason. Participants who did not change the ART regimen during follow-up demonstrated a better virologic response, as did females, those living with partners or relatives, asymptomatic individuals initiating ART, and those who initiated treatment with a CD4>200. A better immune response outcome was observed in younger people, those with no adherence failure, and CD4<500. Our sample is similar to other cohorts with PLWHIV regarding general sociodemographic characteristics, whereby the cases were mostly concentrated in heterosexual males with more than 9 years of schooling .In order to assess the effectiveness of antiretroviral regimens, virologic response has been used as the most practical and earliest outcome . In the In the multivariate analysis of our data, females presented a higher chance of virologic response, thereby corroborating an observational cohort conducted in Uganda from 2004 to 2011 with 4537 participants . AdherenLiving with a partner or family member was associated with a better virologic response, probably because social bonding has a strong influence over not feeling lonely or depressed, and adhering and responding better to medication . Onoya eIn terms of the immunologic response, we observed no difference between the groups in the first year of treatment, nor regarding the mean monthly increase in the CD4 count. When adjusted for confounders, an increase in the CD4 was higher in younger people, thereby corroborating other studies , 21. In Participants with initial CD4<200 had a higher chance of immunologic response with the criterion of a minimum increase of 50 cells after 6 months of treatment. However, it is known that individuals with a severe immunologic condition may either take longer or indeed never manage to reach a CD4 immune recovery threshold at normal levels, even maintaining virologic suppression . It is pIn our study, initiating ART with a lower CD4 count was more often associated with changes in the initial regimen and with a greater need for hospitalization. Initiating ART in the first 6 months after infection is considered early . A studySeveral authors state that the pretreatment CD4 count acts as a prognostic indicator for the effectiveness outcome , 24, 29.The group with the highest ART regimen change rate for any reason during follow-up was the group on zidovudine/lamivudine/efavirenz. A significant part of these changes (31.3%) was to simplify the regimen. During the follow-up period, the Ministry of Health advocated changing this regimen to tenofovir/lamivudine/efavirenz in a fixed-dose combination in individuals with controlled viremia.In this cohort, adverse events were the main cause for changing the regimen, which is often the most common reason for regimen change , and is There was no difference between the regimens with regard to change because of failure. In our findings, during the first year, there were no changes due to failure amongst the groups using PI-based regimens. This reinforces the safety of these drugs in terms of potency , 34. ForIn terms of clinical failure, when comparing the groups, we observed no differences in the proportion of hospitalizations at 1 year amongst PI-based regimen users. A higher frequency of hospitalizations was observed amongst the NNRTI users, in the zidovudine/lamivudine/efavirenz group, when compared to the tenofovir/lamivudine/efavirenz group.Investigating effectiveness in a clinical cohort portrays the “real” situation of the exposed population and the inclusion criteria are less “restrictive” than in randomized trials, thereby allowing for different information on treatment response in populations that may not be well represented in clinical trials. One possible limitation of this study was collecting information from secondary sources . In order to minimize information gaps and losses, we complemented data collection with national information systems on laboratory data, drug supplies, hospitalizations and mortality. The field team used a single instrument, standardized after pilot testing and training for data capture. All inpatient data were collected from the Hospitalization Information System, and no access was made to private services or generated through other instances, but Hospitalization in private services must have been an exception in our cohort. To minimize the possibility of underestimating hospitalization data, the hospital records of participants who were not registered in the SIH were reviewed.In this study we observed few differences between the compared regimens with regard to the main outcomes. Virologic response in the sample was achieved in almost 80% within the first year of treatment. All the regimens seemed to be effective in the comparison groups. Differences in outcomes may be due more to individual characteristics of the participant, toxicity of certain medications, acceptability, and dosage rather than to drug potency. In order to identify the most appropriate regimens for initiating ART, several factors, including treatment costs, need to be taken into consideration, and we suggest further studies to compare regimens with similar effectiveness, their respective costs and financial impacts on the Brazilian Integrated Healthcare System. 9 Mar 2020PONE-D-20-00907Effectiveness analysis of virological response, immune response, regimen change, and clinical failure of four different antiretroviral regimens for treating people living with HIV: an observational cohortPLOS ONEDear Mrs Cavalcanti,Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.We would appreciate receiving your revised manuscript by Apr 23 2020 11:59PM. When you are ready to submit your revision, log on to If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocolsTo enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: Please include the following items when submitting your revised manuscript:A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.We look forward to receiving your revised manuscript.Kind regards,Marcel Yotebieng, M.D., MPH, Ph.DAcademic EditorPLOS ONEJournal Requirements:When submitting your revision, we need you to address these additional requirements:http://www.plosone.org/attachments/PLOSOne_formatting_sample_main_body.pdf and http://www.plosone.org/attachments/PLOSOne_formatting_sample_title_authors_affiliations.pd1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at 2. We note that you have reported significance probabilities of 0 in places. Since p=0 is not strictly possible, please correct this to a more appropriate limit, eg 'p<0.0001'.3. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide.4. Please amend either the title on the online submission form (via Edit Submission) or the title in the manuscript so that they are identical.[Note: HTML markup is below. Please do not edit.]Reviewers' comments:Reviewer's Responses to QuestionsComments to the Author1. Is the manuscript technically sound, and do the data support the conclusions?The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: YesReviewer #2: Yes**********2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: YesReviewer #2: Yes**********3. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.The Reviewer #1: YesReviewer #2: Yes**********4. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: YesReviewer #2: No**********5. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: This is a very comprehensive and interesting manuscript.I have few minor commentsWhy the authors decided to sample from the retrospective cohort, and not use all the available data?It is not clear if the women who changed ART in the first year due to pregnancy are accounted in the "losses". "Women were excluded who had modified", revise languageIt is not clear what the 898 observations are as opposed to the number of patients (840)Figure 3 a and b: give more details in the text about the differenceReviewer #2: This paper has very useful and important information. Authors explored multiple outcomes from observation cohort study among people living with HIV. Each section of the manuscript has been explored rigorously. The only concern is the English. The manuscript needs language revision.General comment:The paper will benefit language revision specifically in the way results were presented.Check for consistencies of decimals in the tablesAvoid some medical terminologies where possibleCheck for type errors**********what does this mean?). If published, this will include your full peer review and any attached files.6. PLOS authors have the option to publish the peer review history of their article  digital diagnostic tool, AttachmentComments.docxSubmitted filename: Click here for additional data file. 30 Jul 2020Response to ReviewersReviewer #1: This is a very comprehensive and interesting manuscript.Why the authors decided to sample from the retrospective cohort, and not use all the available data?The retrospective component is justified by the possibility of a longer follow-up of patients, allowing the study of outcomes that occur less early.It is not clear if the women who changed ART in the first year due to pregnancy are accounted in the "losses". "Women were excluded who had modified", revise language.RevisedIt is not clear what the 898 observations are as opposed to the number of patients (840).Second paragraph of Method- data analysis:“ Follow-up was discontinued for those who changed to ART regimens other than those in the study groups, while those who changed to one of the studied regimens were considered as new exposure and the outcomes were independently observed.”Figure 3 a and b: give more details in the text about the difference.When comparing regimens in the group of participants who remained on the same regimen during the follow-up, there was no differences between the survival curves for virological response by regimens . The same we did found for those group who changed their regimen during the follow-up. . When comparing the survival curves of the virological response between these two groups of participants, we observed differences in their survival curves (p<0.001) .Reviewer #2: This paper has very useful and important information. Authors explored multiple outcomes from observation cohort study among people living with HIV. Each section of the manuscript has been explored rigorously. The only concern is the English. The manuscript needs language revision.RevisedThe paper will benefit language revision specifically in the way results were presented.RevisedCheck for consistencies of decimals in the tablesRevisedAvoid some medical terminologies where possibleRevisedCheck for type errorsRevisedAuthors stated that “Individuals who changed regimens before completing 28 days of treatment were excluded” What was the criteria for the 28 days?We considered this time criteria, because it was the habitual period they returned to the health service to receive their medication.Virological response“When comparing participants who changed regimens during follow-up withthose who remained on the same regimen, we observed different survival curves . There was no difference in the virologic response between the groups.There was a difference when we compared the participants who changed the regimenduring follow-up period with those who did not (p <0.001) .”This paragraph makes it difficult to follow: The way it is written it is not exactly what these graphs were demonstrating.3a: compared differences of regimens among those who did not change treatment3b. compared differences of regimens among those who changed treatment3c. Compared survival between those who changed and those who did not change treatment. This section needs to be re-writtenRevisedTables: (IC 95%), can this be written as 95% CI, this is standardRevisedCheck for typo error  to 3.40, since you are doing 2 decimals through out.RevisedFor this paragrapgh “After the multivariate analysis, the characteristics associated with a virologic response were: being female; living with a family member/partner; being asymptomatic when initiating ART; not report of adherence failure and initiating ART with a CD4 mm3 count of between 200-350 cells/”RevisedWould it be better to express those factors that were associated with increased or decreased likeli-hood of viral response separately?We chose to present the multivariate analysis separately to facilitate the exposure of the data in more detail.Legend for table 3, authors reported gross odd ratio, it would be better to just state an adjusted instead of grossRevisedBelow information is also found in the results section. This information should be in the analysis section“For the multivariate analysis, the following variables were included in themodel: age group, adherence failure and initial CD4 cell count, with p <0.10 in themultivariate analysis to verify association with immune response”RevisedClinical failure.Incidence proportion should not be incidence rateRevisedBelow information can be better presented“Amongst the participants who initiated ART with a CD4 count <200, 29.9% werehospitalized during follow-up, whereas in those with higher counts, the proportion was 18.4%, with a significant difference for 1 year”This can be written as if one says “the incidence of hospitalization among those with CD4 < 200 c/ml was significantly higher compared to those with Cd4 count >= 200. (p< 0.001)”. something like that  should be 13.9%RevisedDiscussionTerminologies such as “myelotoxicity” Would avoid medical terminology and make it easier bone marrow suppressionRevisedFigures:Needs to be improved. Groups compared are hardly visualized, poor quality. Can customize analytical codes and produce high quality figuresRevisedAttachmentResponse to Reviewers.docxSubmitted filename: Click here for additional data file. 9 Sep 2020Effectiveness of four antiretroviral regimens for treating people living with HIVPONE-D-20-00907R1Dear Dr. Cavalcanti,We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at onepress@plos.org.If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact Kind regards,Marcel Yotebieng, M.D., MPH, Ph.DAcademic EditorPLOS ONEAdditional Editor Comments :Reviewers' comments:Reviewer's Responses to QuestionsComments to the Author1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.Reviewer #1: All comments have been addressed**********2. Is the manuscript technically sound, and do the data support the conclusions?The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes**********3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes**********4. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.The Reviewer #1: Yes**********5. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: Yes**********6. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: (No Response)**********what does this mean?). If published, this will include your full peer review and any attached files.7. PLOS authors have the option to publish the peer review history of their article (If you choose “no”, your identity will remain anonymous but your review may still be made public.Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.Reviewer #1: No 16 Sep 2020PONE-D-20-00907R1 Effectiveness of four antiretroviral regimens for treating people living with HIV Dear Dr. Cavalcanti:I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. onepress@plos.org.If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact plosone@plos.org. If we can help with anything else, please email us at Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staffon behalf ofDr. Marcel Yotebieng Academic EditorPLOS ONE


Currently recommended boosted protease-inhibitor (bPI) regimens may be associated with increased risk of cardiovascular or chronic kidney diseases; in addition, boosted regimens are particularly associated with drug-drug interactions. Since both cardiovascular and renal disease, and polypharmacy, are common in ageing people with HIV, there is a need for alternative efficacious regimens. bPI-based regimens are often the treatment of choice for individuals with pre-treatment or treatment-acquired resistance but it is plausible that carefully selected HIV-positive individuals with drug resistance, who are virologically suppressed on their current bPI regimen, could maintain virological efficacy when switched to bictegravir, emtricitabine and tenofovir alafenamide (B/F/TAF) fixed dose combination (FDC).A phase IV, investigator-initiated, multicentre, open label pilot, randomised two-arm study to assess the safety and efficacy of switching from bPI regimen to B/F/TAF single tablet regimen in integrase inhibitor-naïve, virologically suppressed adults with HIV-1 infection harbouring drug resistance mutations. Eligible individuals will either continue on their bPI regimen or switch to B/F/TAF FDC. After 24 weeks, all participants in the bPI arm will be switched to B/F/TAF and followed for a further 24 weeks and all participants will be followed for 48 weeks. The primary efficacy endpoint is the proportion of participants with HIV-1 RNA < 50 copies/mL at week 24 using pure virologic response whilst the secondary efficacy endpoint is the proportion of participants with HIV-1 RNA < 50 copies/mL at Week 48. Other secondary outcome measures include between arm comparisons of drug resistance at virological failure, safety and tolerability and patient-reported outcome measures.We aim to provide preliminary evidence of the efficacy of switching to B/F/TAF in patients with virological suppression on a bPI-based regimen who harbour select drug resistance mutations.ISRCTN 44453201, registered 19 June 2019 and EudraCT 2018–004732-30. Boosted darunavir and atazanavir are recommended as preferred boosted protease inhibitors (bPI) in the British HIV Association treatment guidelines. However, boosted darunavir was associated with increased cardiovascular risk in a large prospective observational study . AlthougThere is evidence from clinical trials that switching from virologically suppressive bPI-based antiretroviral therapy (ART) to regimens based on the newer strand transfer integrase inhibitors, bictegravir  and doluHowever, evidence indicates that second-generation INSTIs, including bictegravir and dolutegravir, have an improved barrier to resistance relative to first-generation compounds and may overcome both PDR and limited treatment-associated drug resistance. In the DAWNING study, a second line switch to a regimen comprising the INSTI dolutegravir plus 2 NRTIs, where at least one NRTI was predicted to be fully active based on resistance analysis at the time screening, was superior to a bPI plus 2 NRTIs at 24 weeks in patients failing first line ART . DAWNINGIt should be noted that in virologically suppressed patients it is often possible to recover proviral sequences from cellular reservoirs in peripheral blood . The preTaken together these studies suggest that B/F/TAF may be effective in maintaining virological suppression in patients with historical evidence of drug resistance mutations. In light of this, we hypothesize that switching HIV-positive patients who harbour selected drug resistance mutations and are virologically suppressed on bPI regimen to B/F/TAF will maintain virological efficacy over 24 weeks.The PIBIK trial is a phase IV, investigator-initiated, prospective, multicentre, open label pilot, randomised two arm study to assess the safety and efficacy of switching from a bPI-based regimen to B/F/TAF single tablet regimen in INSTI-naïve, virologically suppressed HIV-1 Infected adults harbouring drug resistance mutations. The allocation ratio is 1:1 , Brighton, UK. Other NHS Trust within the Sussex HIV network will be able to refer potentially eligible participants to BSUH for screening and if enrolled will be followed up at BSUHBarts Health NHS Trust, Royal London Hospital, London, UKThe Mortimer Market Centre, Central and North West London NHS Foundation TrustChelsea and Westminster Hospital NHS Foundation Trust, London, UKRoyal Free London NHS Foundation Trust, UKKings College Hospital NHS Foundation Trust, London, UKGuy’s and St Thomas’ NHS Foundation Trust, London, UKSubjects will be enrolled from seven sexual health clinics in England. These are:Clinical staff in the HIV department will identify potential participants by any of the following methods: review of a clinic records/database, pre-identification of patients attending for routine care, review of notes during routine clinical follow up and posters/advertisements in the clinics to inform patients of the study.Clinical staff identifying patients will be members of the direct care team or research nurses or doctors working within the same HIV multidisciplinary team. A medically qualified doctor on the study delegation log will confirm eligibility.Anonymised information on participants who are not randomised / registered for CONSORT (16)reporting will include the reason, if they are not eligible for trial participation, or if they are eligible but declined.Potentially eligible participants will be invited to attend for an appointment, having been provided with a participant information sheet (PIS). Adequate time will be allowed for questions and to consider the study before agreeing to participate. The investigator or designee will provide adequate explanation of the aims, methods, objectives and potential hazards of the study. It will also be explained to the individual that they are free to refuse or withdraw from the study for any reason without detriment to their future care or treatment. The investigator can decide to withdraw a subject from the study for urgent medical reasons or repeated non- compliance with the study protocol. Once randomised, withdrawn subjects may be replaced if considered necessary by the chief investigator.18 years and aboveOn a bPI-based ART regimen with documented HIV-1 RNA < 50 copies/mL for at least 6 months on current regimen and at screening (A switch from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF), lamivudine (3TC) to emtricitabine (FTC), or splitting co-formulated tablets to their individual component or vice versa will not be considered true regimen changes)Must have a historical genotypeo M184V/I with or without any NRTI-associated mutation o M184V/I alone (maximum of 20 participants with isolated M184V/I mutation with or without NNRTI mutations)o Up to 2 TAMs  with or without M184V/Io Any of the above with or without NNRTI mutationsEligible drug resistance mutations in historical genotype include at least one of the following:No previous use of any approved or experimental INSTINo known INSTI mutationsEstimated GFR ≥ 50 mL/min (Cockcroft-Gault formula)Have the following laboratory values at screening within 30 days prior to baseline:Alkaline phosphatase ≤3.0 x upper limit of normal (ULN)AST and ALT ≤5.0 x ULNHaemoglobin ≥9.0 g/dL  or ≥ 10.0 g/dL .Provides written, informed consent to participateIs willing to comply with the protocol requirementso Must be using effective birth control methods, that is has an expected failure rate of < 1% per year and willing to continue practicing these birth control measures during the trial and for at least 30 days after the end of the trial. Effective methods include IUD, combined pill, contraceptive injection, implant, IUS, contraceptive vaginal ring, contraceptive patches etc.o Must be truly abstinent from penile-vaginal intercourse from 2 weeks prior to administration of study drug, throughout the study, and for at least 30 days after the end of the trial  .Women who are postmenopausal for least 2 years, women with a total hysterectomy, and women who have a tubal ligation are considered of non-childbearing potential.If male, and sexually-active with female partners of child bearing potential, is using effective barrier contraception, and willing to continue using this during the trial and for at least 30 days after the end of the trial.If a woman and of childbearing potential and are willing to continue practicing one of the following:A single repeat of a laboratory screening test will be allowed for test results that are unexpected based on documented prior laboratory results.o Presence of any of the following mutations: K65R/N/Eo Presence of multidrug resistance mutations: T69ins, Q151M with or without A62V, V75I, F77L, F116Yo Three or more TAMs Exclusion based on drug resistance mutations includeIndividuals experiencing decompensated cirrhosis An opportunistic illness within the 30 days prior to screeningActive tuberculosis infectionHave been treated with immunosuppressant therapies or chemotherapeutic agents within 3 months of study screening, or expected to receive these agents or systemic steroids during the study Current alcohol or substance use judged by the Investigator to potentially interfere with patients’ adherence to study procedure.A history of malignancy of less than 5 years or ongoing malignancy (including untreated carcinoma in-situ) other than cutaneous Kaposi’s sarcoma (KS), basal cell carcinoma, or resected, non-invasive cutaneous squamous carcinoma. Individuals with biopsy-confirmed cutaneous KS are eligible but must not have received any systemic therapy for KS within 30 days of Day 1 and are not anticipated to require systemic therapy during the study.Active, serious infections (other than HIV 1 infection) requiring parenteral antibiotic or antifungal therapy within 30 days prior to Day 1 Any other clinical condition or prior therapy that will, in the opinion of the investigator, make the patient ineligibleAny known allergies to the excipients of B/F/TAF FDCFemales who are pregnant (as confirmed by positive urine pregnancy test)Women who are breastfeedingWomen of childbearing age not using any reliable form of contraception Acute hepatitis in the 30 days prior to study entry, anyone with hepatitis C (HCV) who is likely to need direct acting antivirals in studyAny concomitant medications that cannot be administered with TAF (i.e strong inducers of p-glycoprotein) or bictegravir The investigational medicinal product in this trial is Biktarvy® comprising FDC of B/F/TAF. Each film-coated tablet contains bictegravir sodium equivalent to 50 mg of bictegravir, 200 mg of emtricitabine, and tenofovir alafenamide fumarate equivalent to 25 mg of tenofovir alafenamide.Eligible individuals will either continue on their bPI regimen arm 1) or switch to B/F/TAF FDC (arm 2). After 24 weeks, all participants in the bPI arm will be switched to B/F/TAF arm and will be followed up for a further 24 weeks whilst those immediately switched to B/F/TAF at baseline will be followed up for 48 weeks as illustrated in Fig.  or switcA participant is free to withdraw from the study at any time. In addition, the investigator may decide, for reasons of medical prudence, to withdraw a participant. If a participant discontinues study medication dosing, every attempt would be made to keep the participant in the study and continue to perform the required study-related procedures and follow-up procedures. If this is not possible or acceptable to the subject or investigator, the participant may be withdrawn from the study.If the participant withdraws his/her consent.If the investigator considers in the interest of the subject  that it is best for them to withdraw their consent.The participant fails to comply with the protocol requirements or fails to cooperate with the investigator.Pregnancy during the course of the study.Study medication may also be discontinued in the following instances:The date and reasons for the withdrawal will be clearly stated on the participant’s eCRF and source document. Every attempt should be made to arrange follow up visits for participants who are withdrawn from the trial .Pill counting at each visit by a research team member and recording of the number of pills returnedSelf-report using a visual analogue scale (VAS)Participant adherence B/F/TAF and bPI will be assessed through:Participants will bring in all pill bottles at each study visit. The total number of pills remaining at each visit will be counted and, then returned to the participant to take until the bottle is finished. The percentage of compliance for each participant will be calculated.Participants will also be asked be asked to self-report their level of adherence at each visit using the VAS in which they would be asked to indicate their level of adherence in the previous 30 days on a scale ranging from 0 to 100% in which 0 represents no pill taken and 100 represents every single dose had been taken. Where adherence is < 80%, this will lead to likely withdrawal from the study although this will be at the discretion of the investigator.The primary endpoint is the proportion of participants with HIV-1 RNA < 50 copies/mL at Week 24 using pure virologic response (PVR).On study treatmento HIV RNA ≥ 50 copies/mL on 2 consecutive visitso HIV-1 RNA ≥ 50 copies/mL during study followed by premature discontinuationNo confirmed virologic rebound defined as:Discontinuation prior to week 24 for reasons other than virologic rebound (i.e. no data in window and last HIV RNA < 50 copies/mL) are considered PVRPure virologic response is defined as follows:Proportion of patients with HIV RNA < 50 copies/mL at week 48 using PVRProportion of patients with HIV-1 RNA < 50 copies/mL at weeks 24 and 48 using PVR in those with any archived resistance detected in proviral DNAEmergence of new resistance mutations in participants with two consecutive viral load ≥50 copies/mL measured 2–3 weeks apartSafety and tolerability of B/F/TAF FDC in participants switching from bPI-based regimens at 48 weeks based on clinical presentation and laboratory resultsHIV Symptom Distress Module (HIV-SI) and the Pittsburgh Sleep Quality Index (PSQI) questionnaires.Change from baseline in patient reported outcomes at weeks 24 and 48 measured using the Change from baseline in serum lipid concentrations at weeks 24 and 48Change from baseline in HBA1c in blood weeks 24 and 48Change from baseline in weight and BMI at weeks 24 and 48Secondary outcome measures include the following:We considered a number of sample size scenarios bearing in mind the pilot nature of the study Table . We willFor the study to continue beyond 24 weeks, we need 90% (45/50) of the individuals randomised to the B/F/TAF arm to be suppressed with the lower limit of the confidence interval to just lie above 80%. Recruiting 50 participants per arm would achieve this at the 90% confidence level. The sample size required decreases as the level of confidence in our estimates decreases.We have allowed 12 months to recruit 100 participants over the seven sites involved in the trial. This requires recruitment of 1–2 participants per month per site which is deemed feasible. Each site has been allocated a target of 14–15 subjects. In the case of slow enrolment, additional sites will be offered participation in the study.The web-based Sealed Envelope™ system will be used to allocate individuals randomly to Arm 1 and Arm 2. The statistician will provide the randomisation list. Each study site will be provided with a randomisation guide. The Sealed Envelope™ system will randomise subjects within 8 strata as shown in Table The bPI used in the subject’s baseline regimen (Atazanavir or Darunavir)Use of lipid lowering therapy at study day 1 (yes/no)Number baseline mutations of the NRTI class (< 2 vs. ≥2)The purpose of the stratification is to balance the treatment arms on important prognostic factors such as:Investigators randomise patients by completing an on-screen form with patient details, stratification factors, inclusion and exclusion criteria. Investigators are immediately shown the treatment allocation. Trial managers have real-time access to recruitment statistics and are notified by email of every new randomisation. The randomisation application conforms to the requirements of FDA 21 CFR part 11, Electronic Records; Electronic Signatures and ICH GCP. No-one can delete records from the randomisation database, so that all randomisations have to be accounted for. Audit log files detailing all activity on the randomisation system are available to the trial manager. Neither the investigators nor the participants will be blinded to the treatment allocation.The presence of resistance mutations will be determined using historical genotype results obtained in local laboratories in those eligible according to the inclusion and exclusion criteria. We would obtain more information on resistance mutations by sequencing cell-associated HIV-1 DNA in peripheral blood mononuclear cells prior to commencing B/F/TAF. The results of proviral DNA sequence will not be available in real time and will not be used to inform treatment decisions but will further the understanding of the clinical importance of archived resistance mutations, if any, in individuals developing virological failure.The baseline visit will not exceed 30 days after the screening visit. Follow up of participants will continue until all participants have accrued 48 weeks from their baseline visits. Individuals who have completed Week 48 visit will be followed up 30 days post cessation of trial treatment via a telephone call or a standard of care clinical appointment for performance of the following assessments; adverse events and symptoms review, HIV associated conditions, concomitant medications and for women of child bearing potential (WOCBP), confirmation that contraception has been used in the previous 30 days.Study procedures, screening, randomisation and safety monitoring will be according to attached visit schedule in Table Individuals with virological failure defined as a rebound in HIV-1 RNA ≥ 50 copies/mL, which is subsequently confirmed at the following scheduled or unscheduled visit. Following the initial detection of virological rebound, subjects will be asked to return to the clinic for a scheduled or unscheduled blood draw (2 to 3 weeks after the date of the first measured rebound) for repeat viral load testing. If virological rebound is confirmed and the HIV-1 RNA is ≥200 copies/mL, the blood sample from the confirmation visit will be the primary sample used for HIV-1 genotypic testing. After a participant’s first post-baseline resistance test, additional testing will be conducted on a case-by-case basis. Any participant may be discontinued at the investigator’s discretion or per local treatment guidelines. If no resistance is detected from the genotype, the participant may remain on study drugs and a repeat HIV-1 RNA measurement should be performed (2 to 3 weeks after date of test with HIV-1 RNA ≥ 50 copies/mL). Investigators should carefully evaluate the benefits and risks of remaining on study drug for each individual participant and document this assessment in the on-site medical record.Data on patient reported outcome measures will be collected using the HIV-SI and the PSQI. The HIV-SI is a validated, self-administered 20-item health-state questionnaire for use in clinical care and research amongst people living with HIV (PLHIV)in order to identify and address common and bothersome symptoms associated with HIV treatment and disease . The insThe Pittsburgh Sleep Quality Index (PSQI) is a self-rated questionnaire which assesses sleep quality and disturbances over a 30-day recall period . NineteeParticipants with early study termination from whatever cause will undergo the assessments outlined in Table A source data worksheet will be created to capture all the relevant information and will be filed as source documentation in the participants’ notes. Questionnaires and self-report VAS scores will also be completed by the patients. A source data agreement will be completed prior to recruitment commencing to ensure all parties are aware which documents constitute source data.Data from the source will be entered onto the electronic case report form (eCRF) on the web-based MACRO™ electronic data capture system. Data entered will be checked by the Data Manager in accordance with the Data Management Plan  and querDirect access will be granted to authorised representatives from the sponsor, host institution and the regulatory authorities when appropriate to permit trial-related monitoring, audits and inspections.Archiving will be the responsibility of the sponsor and all documentation will be archived for 25 years, with the exception of the health records which will be kept in accordance with UK law and local policy. The sponsor named archivist will be responsible for ensuring the documentation is prepared in line with the relevant sponsor standard operating procedures.All randomised patients who received at least one dose of the study medication will be included in the analysis.Summary statistics will be presented by trial arm using median with interquartile ranges for continuous variables with skewed distributions or mean with standard deviations for normally distributed variables. Categorical variables will be summarised using frequencies and proportions.Non-inferiority for the futility analyses will be concluded if the lower bound of a two-sided 90% CI for the difference in proportions (B/F/TAF minus boosted PI) of patients with plasma HIV-1 RNA < 50 copies/mL at week 24 is greater than − 13%.Proportions of individuals with HIV RNA < 50 copies/mL at 24 weeks will be estimated using PVR.The percentage of participants with PVR for HIV-1 RNA cut-off at 50 copies/mL at Week 24 will be summarized.Differences between trial arms will be estimated together with 95% confidence intervals.Proportions of individuals with HIV RNA < 50 copies/mL at 48 weeks will be estimated using PVR.The percentage of participants with PVR for HIV-1 RNA cut-off at 50 copies/mL at Week 48 will be summarized.Differences between trial arms will be estimated, together with 95% confidence intervals. The proportion of patients with HIV-1 RNA < 50 copies/mL at weeks 24 and 48 using PVR in those with any archived resistance detected in proviral DNA will be estimated.The proportion of patients with any emergent drug resistance following virological rebound will be estimated.Mean total Cholesterol, LDL, HDL and triglycerides will be estimated.Mean HBA1cMean weight and BMILaboratory and clinical adverse events will be described and summarised using percentages.The analysis of the following secondary safety outcomes will be presented as the estimated difference and 95% confidence interval between arms from baseline to 24 and 48 weeksTreatment differences for patient reported outcomes using the HIV-SI module and the PSQI will be compared by using the prevalence of symptoms reported by each method and presented with 95% confidence intervals. Consistent with prior analyses on HIV-SI , 20 we wIn the event of missing data, only available data will be included in the analyses and missing data will be quantified but not imputed. For missing data relating to primary and secondary efficacy endpoints, using the principle of PVR, the last known measured viral loads will be carried forward if data is missing at the 24 and 48 week time points.A three-member independent data safety monitoring board (DSMB) has been established comprising specialists in clinical infectious diseases, HIV medicine and a clinical trial statistician. The role of the DSMB will be to safeguard the interest of the trial participants, assess safety and efficacy of the intervention and to monitor the overall conduct of the trial. The DSMB should receive and review the progress and accruing data of the trial and provide advice on the conduct of the trial to the Trial Steering Committee (TSC). The DSMB would perform an interim review of the trial’s progress including updated figures on recruitment, data quality, main outcomes and safety data and will have responsibility on the decision whether to stop or continue the trial. The DSMB will meet six-monthly but the frequency of meetings may depend on recruitment rates or other trial events. Further details on the DSMB charter can be found in the Information on all adverse events (AEs), adverse reactions (ARs), serious adverse reactions (SARs), suspected unexpected serious adverse reactions (SUSARs) and serious adverse events (SAEs) will be documented in the case report forms. AEs, SAEs, ARs, SARs and SUSARs may be directly observed, reported spontaneously by the participant or by questioning the participant at each study visit. These will be followed up until they are resolved or the participant’s participation in the study ends . Any untoward event that may occur subsequent to the reporting period that the investigator assesses as related to the study drug medication will also be reported as an adverse event. The adverse event reporting period will be from consent until the participant’s final study visit. After informed consent, but prior to initiation of study treatment, all SAEs and adverse events related to protocol-mandated procedures would be reported on the CRFs. Following initiation of study treatment, all AEs, regardless of cause or relationship until 30 days post cessation of trial treatment would be reported on the CRFs. In addition, all serious adverse events assessed by the investigator as related to the investigational medication would continue to be followed even after participation in the study is over. Such events would be followed until resolution, or until no further change can reasonably be expected.This study is registered with the International Standard Randomised Controlled Trials Number registry (44453201) and with the European Union Drug Regulating Authorities Clinical Trials Database (2018–004732-30). The main study findings will be reported in accordance the Consolidated Standards of Reporting Trials (CONSORT) statement . The stuAll investigators and trial site staff will comply with the requirements of the General Data Protection Regulation 2018 (GDPR)  with regIt is plausible that carefully selected HIV-positive individuals with pre-treatment or treatment-acquired resistance who are virologically suppressed on their current PI-based regimen could maintain virological efficacy when switched to B/F/TAF FDC.The hypothesis is based on a consideration of each component of B/F/TAF. TAF, like the earlier version tenofovir disoproxil fumarate (TDF), is a prodrug of tenofovir. However, TAF yields 5-fold higher intracellular concentrations of the active moiety tenofovir diphosphate (TFV-DP) in HIV target cells than TDF, despite much lower plasma drug concentration .. Since HIV-1 strains harbouring the M184V/I mutation, which causes high-level resistance to 3TC and FTC, display increased or restored susceptibility to tenofovir . M184V/IBictegravir has potent in vitro activity against laboratory strains and clinical isolates of HIV-1, a higher genetic barrier to resistance development than raltegravir (RAL) and elvitegravir (EVG), and a statistically improved resistance profile compared to RAL, EVG, and DTG against a set of patient derived INSTI-resistant viral isolates . In the We do not foresee a challenge to recruiting the 100 participants required for this trial, however recruitment will be monitored closely and if sluggish, we would activate additional sites for participation in the study. Since all sites will be utilising standardised study documents and procedures, the number of study sites should not affect data quality. Furthermore, all sites will be closely monitored for compliance with the study protocol.The trial started enrolling participants on 16 September 2019 and it is anticipated that enrolment will continue until September 2020.Additional file 1.


Prior to the availability of rilpivirine (RPV), patients who could not tolerate efavirenz and nevirapine (NVP) were treated with protease inhibitor (PI)‐based antiretroviral therapy (ART). Dyslipidaemia and other metabolic complications are commonly associated with PI use. This study aimed to compare the efficacy and adverse events between switching from PI‐based to RPV‐based regimen, versus continuing PI‐based regimens in HIV‐positive individuals with complete viral suppression.A randomized controlled trial was conducted in HIV‐positive individuals receiving PI‐based regimens with undetectable HIV RNA and without prior HIV drug resistance. Patients were enrolled between July and December 2017 in a university medical centre in Bangkok, Thailand. They were randomized to switch from PIs to RPV (switch group) or continue ritonavir‐boosted PI (control group). Primary endpoint was the proportion of patients with undetectable HIV RNA at 48 weeks. Changes in CD4 cell counts, lipid profiles and adverse events were also analysed.3 in switch and control groups respectively (p = 0.632). Mean changes in lipid profiles (switch vs. control groups) were: total cholesterol, −12.5 versus + 12.2 (p = 0.024); LDL, −3.4 versus + 6.2 (p = 0.040); HDL, +1.6 versus + 1.9 (p = 0.887); and triglycerides, −82.6 versus − 24.4 mg/dL (p = 0.031). The mean changes of glucose and eGFR were similar (p > 0.05) between the two groups. The mean change of ALT was significantly greater in switch group . One patient in switch group had anorexia and elevated ALT at 14 weeks and completely recovered after RPV discontinuation.A total of 84 patients were enrolled, 42 in each group. Mean age was 47.7 years and 53.6% were males. At 48 weeks, 95.2% of patients in the switch group and 92.9% of control group had maintained undetectable HIV RNA . Means of CD4 cell counts were 611 and 641 cells/mmSwitching PIs to RPV, in patients with complete viral suppression and without prior HIV drug resistance, sustains viral suppression and yields better lipid profiles. This finding supports its use as switching therapy in patients receiving PI‐based regimens due to intolerance to efavirenz and NVP and previous alternatives limited to PI in resource‐limited settings. HIV RNA was performed using Amplicor HIV‐1 Monitor Test version 1.5 .The primary outcome was the proportion of patients with undetectable HIV RNA (<40 copies/mL) at 48 weeks. The secondary outcomes were the mean changes of CD4 cell count and lipid levels including TC, LDL, high‐density lipoprotein cholesterol (HDL) and triglycerides (TG) and adverse events between the two groups during the study. Virologic failure was determined when HIV RNA was ≥200 copies/mL based on two consecutive measurements. We classified patients with missing HIV RNA measurements as having virologic failure at each time point for which a value was not available (“missing = failure”). Adverse events were defined as any undesirable experience associated with the use of antiretroviral drugs included rash, gastrointestinal symptoms , neurological symptoms and psychiatric events. Serious adverse events included any untoward medical occurrence that resulted in death, life‐threatening conditions, hospitalization or prolongation of existing hospitalization, or persistent or significant disability.t test or Mann‐Whitney U test for continuous variables and chi square or Fisher’s exact tests for categorical variables. All analyses were performed using an electronic database organized in SPSS version 18.0. A p < 0.05 was considered statistically significant.From our infectious disease clinic of approximately a two thousand HIV‐positive population, 75% of persons receiving PI‐based regimens have complete viral suppression at 48 weeks of ART. Sample size was calculated from the proportional response rates from a previous trial , 15. A p33. Baseline characteristics including age, gender, body weight, duration of ART, distribution of NRTIs and PIs used, CD4 cell count, lipid profiles, glucose, ALT and estimated glomerular filtration rate (eGFR) between the two groups were similar, as summarized in Table Of the 86 patients screened, 84 fulfilled inclusion and exclusion criteria and were enrolled, 42 in each group Figure . The mea3 in the switch and control groups respectively (p = 0.632). The mean changes in lipid profiles (switch vs. control groups) were: TC, −12.5 versus +12.2 (p = 0.024); LDL, −3.4 versus +6.2 (p = 0.040); HDL, +1.6 versus +1.9 (p = 0.887); and TG, −82.6 versus −24.4 mg/dL (p = 0.031) . The mean change of ALT was significantly greater in the switch group compared to the control group . A female patient in the switch group had anorexia and an elevated ALT of 65 U/L at 14 weeks after switching and completely recovered to be within normal range within two weeks after RPV discontinuation. The total and direct bilirubin were within normal ranges. An ultrasonography of the upper abdomen was performed and the result was unremarkable. The investigations for hepatitis A virus, hepatitis B virus, hepatitis C virus and hepatitis E virus were all negative. She had no history of alcohol or herbal medicine consumption.At 48 weeks, 95.2% of patients in the switch group and 92.9% of the control group had maintained undetectable HIV RNA . This met the prespecified noninferiority criterion. The proportions of patients who maintained viral suppression at 24 and 48 weeks are shown in Figure PLHIV may have benefits from switching from a PI‐based regimen to an RPV‐based regimen, even when they have complete viral suppression. These include managing or preventing short‐term or long‐term adverse effects, high pill burden, problematic drug interactions or costs. , 18. AltThe present study has demonstrated that in HIV‐positive individuals taking a PI‐based ART with complete viral suppression and without prior HIV drug resistance, switching to an RPV regimen was not inferior to continuing a PI‐based ART, in term of maintained viral suppression at 48 weeks. The rates of sustained viral suppression in both treatment groups were also quite high. One of the key success factors was the fact that we enrolled only patients without a history of HIV drug resistance. This is important because the majority of patients taking a PI‐based ART in resource‐limited settings have failed their first‐line NNRTI‐based regimen. Those patients were not eligible for this study because RPV has significant cross‐resistance to EFV and NVP , 20. TheImmunological response in patients switching PIs to RPV was also similar between the two treatment groups. In this study, all patients at entry had complete viral suppression with a median duration of their first‐line ART of nine years and high CD4 cell counts. This reflects the good adherence on ART among these study patients. It has been established that good adherence on ART is associated with long‐term viral suppression and immune recovery , 22. AltIn addition to sustained viral suppression and immune recovery, our study demonstrated that switching from PIs to RPV was associated with statistically significant improvement of TC, LDL and TG at 48 weeks. Improvement of TC and TG occurred significantly starting at the 24 week follow‐up. In a large Asian cohort, the development of fatal and nonfatal cardiovascular events was associated with high TC and TG . This swTo the best of our knowledge, this is the first randomized controlled trial regarding switching ART from first‐line PI‐based regimens to an RPV‐based regimen in patients with complete viral suppression and without history of HIV drug resistance. The strength of our study was the study design of a randomized control trial that RPV was the only antiretroviral agent in the regimen that was switched. Therefore, the efficacy of RPV as a switch therapy has been demonstrated. However, there were some limitations. The study was not blinded to investigators and participants. Therefore, the open‐label design may actually be more reflective of true adherence to each particular regimen. This is instrumental to efficacy because PI‐based and RPV‐based regimens have great differences in pill burden, drug and food interactions, as well as directions for taking. These differences directly impact the ease of adherence and in turn may affect efficacy. In addition, a long‐term follow‐up study may be needed to demonstrate whether the benefit of lipid profile changes will translate into benefits for cardiovascular disease.4Switching PIs to RPV, in patients with complete viral suppression and without prior HIV drug resistance, sustains viral suppression and yields better lipid profiles. This finding supports its use as switching therapy in patients receiving PI‐based regimens due to intolerance to efavirenz and NVP and previous alternatives limited to PIs in resource‐limited settings. Although uncommon, elevation of liver enzymes leading to RPV discontinuation may occur. Close monitoring of liver function after switching is recommended.All authors declare no competing interests related to this work.KP and SS performed the research and oversaw the participants. SS designed the research study. SS performed all statistical analysis. KP and SS wrote the paper. All authors critically reviewed and approved the final draft of manuscript.


In Malawi, 236 participants from the Advancing Cryptococcal Meningitis Treatment for Africa trial were followed for 12 months. The trial outcomes reported at 10 weeks were sustained to 1 year. One-week amphotericin B plus flucytosine was associated with the lowest 1 year mortality . Mortality from cryptococcal meningitis (CM) remains unacceptably high in sub-Saharan Africa . The mosACTA was a large, open-label, phase 3, randomized, noninferiority, multicenter trial in which 721 patients with human immunodeficiency virus (HIV)–associated CM from centers in Malawi, Zambia, Tanzania, and Cameroon were randomized to 3 strategies: oral FLU+5FC for 2 weeks, 1 week AmB, and standard 2 weeks AmB. Those in the AmB arms were further randomized to 5FC or FLU in a 1:1 ratio, as the partner drug given with AmB. Outcomes at 10 weeks of antifungal therapy have been reported . In thisTrained study personnel (nurse or clinician) collected data using a structured questionnaire and record review. Face-to-face interviews were conducted at 6 and 12 months posttrial entry. If face-to-face interviews were not possible, patients were followed up by telephone  was used for statistical analyses. All-cause mortality at 10 weeks, 6 months, and 1 year was compared between the treatment groups using log-rank tests. Kaplan-Meier plots were constructed, and Cox regression models with treatment as a predictor were used to derive hazard ratios (HRs) and 95% confidence intervals (CIs). The analyses were also adjusted for the following prespecified baseline covariates: site, age, sex, Glasgow coma scale, CD4+ cell count, cerebrospinal fluid fungal count, and antiretroviral therapy (ART) status. Analyses were performed on both intention-to-treat (ITT) and per-protocol populations, as in the main trial analyses [The London School of Hygiene and Tropical Medicine Research Ethics Committee and the national ethics and regulatory bodies in each country approved the ACTA trial protocol . EthicalFrom January 2013 to November 2016, 236 patients were randomized, 186 patients in Lilongwe and 50 in Zomba . Of thesBaseline characteristics were consistent with those of the trial as a whole , and 5. Mortality at 10 weeks followed the main trial results. Overall mortality was 35.7% at 10 weeks , 41.1% at 6 months , and 45.1% at 1 year . Thus, of those who survived to 10 weeks, 85% (123/144) survived to 1 year. Results at 10 weeks were sustained to 6 and 12 months. In particular, results for the 5 treatment arms are shown in These HRs are similar to those for this comparison in the trial as a whole at 10 weeks . ResultP value, 0.02; Comparing AmB partner drugs, the hazard of death was significantly lower for participants administered 5FC compared to those taking FLU at all time points  and unexposed participants  evident in the 1-week AmB+5FC arm. This substudy, with complete follow-up of 224 participants to 1 year post-induction therapy, extends the results seen at 10 weeks in the ACTA trial overall. The long-term benefit seen with 1 week AmB+5FC supports updated World Health Organization (WHO) guidelines that recommend this regimen as first-line induction therapy and underlines the need for rapid wide access to 5FC , 9.The results also confirm that after 10 weeks, mortality rates decrease, with a general flattening out of survival curves in the context of effective antifungal therapy and appropriately timed ART . The few long-term follow-up data that are available in the context of timely ART initiation for all patients are consistent with our study in this regard . The lonNo differences in long-term survival were detected between participants previously exposed to ART and ART-unexposed participants. Further work is needed to separate out, within the ART exposed group, those with unmasking CM-IRIS and those who failed ART due to adherence or resistance issues. Our results underline that all these patients can have a good long-term prognosis if they survive meningitis. Thus, continued efforts are needed to target and support patients with advanced HIV disease, as recently emphasized by WHO and others , 9. LastClinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.Supplementary materials are available at ciz454_suppl_Supplementary_AppendixClick here for additional data file.