Efficacy and safety of dolutegravir plus emtricitabine versus standard ART for the maintenance of HIV-1 suppression: 48-week results of the factorial, randomized, non-inferiority SIMPL’HIV trial

Background Dolutegravir (DTG)–based dual therapy is becoming a new paradigm for both the initiation and maintenance of HIV treatment. The SIMPL’HIV study investigated the outcomes of virologically suppressed patients on standard combination antiretroviral therapy (cART) switching to DTG + emtricitabine (FTC). We present the 48-week efficacy and safety data on DTG + FTC versus cART. Methods and findings SIMPL’HIV was a multicenter, open-label, non-inferiority randomized trial with a factorial design among treatment-experienced people with HIV in Switzerland. Participants were enrolled between 12 May 2017 and 30 May 2018. Patients virologically suppressed for at least 24 weeks on standard cART were randomized 1:1 to switching to DTG + FTC or to continuing cART, and 1:1 to simplified patient-centered monitoring versus standard monitoring. The primary endpoint was the proportion of patients virologically suppressed with <100 copies/ml through 48 weeks. The secondary endpoints included virological suppression at 48 weeks according to the US Food and Drug Administration (FDA) snapshot analysis. Non-inferiority of DTG + FTC versus cART for viral suppression was assessed using a stratified Mantel–Haenszel risk difference, with non-inferiority declared if the lower bound of the 95% confidence interval was greater than −12%. Adverse events were monitored to assess safety. Quality of life was evaluated using the PROQOL-HIV questionnaire. Ninety-three participants were randomized to DTG + FTC, and 94 individuals to cART. Median nadir CD4 count was 246 cells/mm3; median age was 48 years; 17% of participants were female. DTG + FTC was non-inferior to cART. The proportion of patients with viral suppression (<100 copies/ml) through 48 weeks was 93.5% in the DTG + FTC arm and 94.7% in the cART arm in the intention-to-treat population (risk difference −1.2%; 95% CI −7.8% to 5.6%). Per-protocol analysis showed similar results, with viral suppression in 96.5% of patients in both arms (risk difference 0.0%; 95% CI −5.6% to 5.5%). There was no relevant interaction between the type of treatment and monitoring (interaction ratio 0.98; 95% CI 0.85 to 1.13; p = 0.81). Using the FDA snapshot algorithm, 84/93 (90.3%) participants in the DTG + FTC arm had an HIV-1 RNA viral load of <50 copies/ml compared to 86/94 (91.5%) participants on standard cART (risk difference −1.1%; 95% CI −9.3% to 7.1%; p = 0.791). The overall proportion of patients with adverse events and discontinuations did not differ by randomization arm. The proportion of patients with serious adverse events was higher in the cART arm (16%) compared to the DTG + FTC arm (6.5%) (p = 0.041), but none was considered to be related to the study medication. Quality of life improved more between baseline and week 48 in the DTG + FTC compared to the cART arm (adjusted difference +2.6; 95% CI +0.4 to +4.7). The study’s main limitations included a rather small proportion of women included, the open label design, and its short duration. Conclusions In this study, DTG + FTC as maintenance therapy was non-inferior to cART in terms of efficacy, with a similar safety profile and a greater improvement in quality of life, thus expanding the offer of 2-drug simplification options among virologically suppressed individuals. Trial registration ClinicalTrials.gov NCT03160105.


Study category and Rationale
A -Dolutegravir 50 mg (DTG, Tivicay®) is used as a dual therapy in this protocol, i.e. in association with other antiretroviral agents as indicated in the product information.

Clinical Phase:
Phase IV

Background and Rationale:
At present, HIV treatment guidelines recommend a combination of three drugs for the initiation and maintenance of antiretroviral therapy (cART). Simplification of treatment and care is considered critical to further scaleup treatment, support retention in care, and reduce costs. Current simplified maintenance regimens are mainly based on boosted protease inhibitor-based mono and dual therapies. However, many HIV-infected individuals are still excluded from this niche, either due to suboptimal virological control or a lack of the necessary infrastructure to monitor such a regimen as is the case in resource-limited settings.
Dolutegravir (DTG) is a once-daily integrase inhibitor that shows very good tolerability, high potency, very few drug-drug interactions and a distinctive resistance profile in combination therapy. These characteristics suggest that DTG could be an acceptable and efficient alternative to protease inhibitors in simplified maintenance therapy when given together with a nucleoside reverse transcriptase inhibitor (NRTI).
The efficacy of a dual therapy of DTG with 3TC (lamivudine) was demonstrated in a large, fully powered, randomized clinical trial of ARTnaïve individuals. A single arm, open label pilot study of 90 patients tested the association of DTG with 3TC as a de-escalation strategy and showed no alarming signal. In addition, a large randomized trial conducted by ViiV pharmaceutical has shown that a dual therapy combining rilpivirine (RIL) and DTG was non inferior to standard cART. In our trial, we chose to study a novel, soon generically available, dual maintenance therapy including DTG and emtricitabine (FTC).
Simplification also includes optimized monitoring, such as simplified laboratory monitoring, task-shifting of ART management from doctors to nurses or decentralization of care. To our knowledge, these strategies have only been tested in resource-limited settings.
We aim to demonstrate, in a multicentre, non-inferiority, open-label, randomized controlled trial that maintenance therapy could be safely simplified to DTG-based dual therapy in association with FTC and to patient-centered monitoring once virological suppression is achieved.

Objective(s):
The trial will address two primary objectives: 1. To assess the efficacy of DTG-based maintenance therapy in virologically suppressed HIV-infected individuals who are switched from standard therapy (cART) to DTG + FTC dual therapy.
2. To assess the costs of a patient-centered ART monitoring which offers participants alternative options for venipuncture and blood analysis/drug delivery/study visits and omits CD4 cell counts and safety blood tests during follow-up.

Outcome(s):
1. The first primary outcome will be the maintenance of HIV-RNA <100 copies/ml through the 48-week study duration.
2. Secondary outcomes will include the maintenance of HIV-RNA <50 copies/ml through 48 weeks of follow-up (classical proportion and by FDA snapshot), loss of future drug options, change in CD4 cell count, DTG and FTC plasma levels, safety, treatment satisfaction, monitoring satisfaction, health-related quality of life, study satisfaction, and costs.The second primary outcome will be to assess the direct costs of patient-centered monitoring.
Secondary outcomes will include acceptability, safety, satisfaction and cost-effectiveness of monitoring arms.

Study design:
This is a pragmatic multicentre, 2x2 factorial randomized controlled trial with 1:1:1:1 randomization to switching to DTG-based maintenance dual therapy in association with FTC or continuation of cART, and to patientcentered monitoring or continuation of standard monitoring.
The randomized comparisons will examine whether DTG + FTC dual therapy is non-inferior in terms of viral suppression compared to standard therapy, and whether patient-centered monitoring is cost-saving and acceptable compared to standard monitoring.
Patients will be followed during 48 weeks.
A sample size of 92 patients in each group (DTG + FTC dual therapy and standard cART) will be required to demonstrate non-inferiority with a noninferiority (NI) margin of 12%.

Inclusion / Exclusion criteria:
Inclusion criteria: Patients enrolled in other interventional studies are not elibible. After the other interventional study termination, they will have to wait at least 3 months before the Simpl'HIV screening.

Measurements and procedures:
Intervention: DTG 50mg 1x / day + FTC 200 mg 1x / day Clinical procedures: participants will be screened up to 4 weeks prior to the baseline visit and, if eligible, will be seen at the baseline visit, at week 6 and week 12, and twelve-weekly afterwards (weeks -4, 0, 6, 12, 24, 36 and week 48). During each of these visits starting from the baseline visit, adherence to study drug will be assessed, concomitant medications and adverse events will be evaluated.  Genotypic resistance in case of virological failure (defined as two HIV-RNA measurements ≥ 100 copies/ml 2 weeks apart);  Pharmacogenetics analysis in case of virological failure (defined as two HIV-RNA measurements ≥ 100 copies/ml 2 weeks apart);  Plasma samples will be stored at each study visit and used for dolutegravir and emtricitabine plasma concentration measurement, genotypic testing and pharmacogenetics analysis in patients with virological failure.
For patients in the standard monitoring arm, additional laboratory assessments will be performed as per SHCS regular assessments:  Weeks 12, 24, 36: CD4 count, full blood count, safety serum chemistry, glucose and lipid profile.
Questionnaires: health-related quality of life and patient's monitoring satisfaction questionnaires will be performed for all patients at baseline and weeks 12 and 48.

Study Product / Intervention:
Dual therapy arm: patients randomized to this arm will be switched to DTG + FTC dual maintenance therapy. DTG 50 mg will be administered together with FTC 200 mg once daily as dual therapy for a duration of 48 weeks.
Patient-centered monitoring arm: patients randomized to this arm will have immunological and safety blood analyses (CD4 cell count, lipids and glucose, renal and hepatic function tests, creatine kinase) performed at screening and at week 48. Additional safety blood tests will be performed only in case of signs of symptoms as indicated by physician.
In addition, patients will be offered alternative options for the conduction of study visits, of venipunctures and blood analyses and of drugs delivery at weeks 6, 12 and 36. Participants will be asked to select at least one of the three following strategies:  Venipuncture for blood analyses: decentralised venipuncture, i.e. at peripheral laboratory near patient's home or place of work, or with general practitioner, versus at their affiliated SHCS site;  Drug delivery: delivery of ARV drugs/prescription by mail or at a chosen pharmacy versus at their affiliated SHCS site; Assessment and clinical interview (adherence, side effects, concomitant medications): phone call with study nurse/physician versus face-to-face at their affiliated SHCS site.

Control Intervention
Standard-of-care arm: patients randomized to this arm will continue their current standard ART regimen (cART).
Standard monitoring arm: patients randomized to this arm will continue a standard 3-monthly routine safety biological monitoring (including CD4 cell count, lipids and glucose, renal and hepatic function tests, creatine kinase) at their SHCS site.

Post-study follow-up
At week 48 visit, participants will give their informed consent to participate in the post-study period including a follow-up up to week 144 with an annual visit.
Outcomes will include proportion of patients maintaining HIV suppression, proportion of patients experiencing loss of future drug options, time to loss of virological response (TLOVR), assessment of predictors of virological failure, the change in several laboratory in CD4 cell count, safety, quality of life, ART and monitoring changes during post-study, patient's treatment and monitoring satisfaction, adherence to treatment.
Week 96 and 144 visits include clinical procedures (ART changes and  reasons for changes; monitoring changes; current treatment and  monitoring satisfaction; number, date and value of HIV-RNA performed; number, date and results of genotypes resistance testing performed; grade 3 or 4 AE and SAE occurrence; guality of life; adherence questionnaire; patient's weight and blood pressure) and laboratory procedures (HIV-1 RNA in plasma; CD4 count; full blood count; safety serum chemistry inluding creatinine, ASAT/ALAT, alkaline phosphatases, glucose and lipid profile).

Number of Participants with Rationale:
Total number of participants: 184 Number in each group: 92 A sample size of 92 patients in each group (DTG + FTC dual therapy and standard cART) will be required to demonstrate non-inferiority with a noninferiority (NI) margin of 12%. DTG + FTC dual therapy is expected to be non-inferior to standard-ofcare using a 12% non-inferiority margin assuming that 92% of patients are virologically suppressed at week 48 in the two comparison arms.
We will evaluate the proportion of patients with viral suppression at week 48 in each arm, and compute a Mantel-Haenszel risk difference (DTG+FTC minus cART) stratified by monitoring type with a two-sided 95% confidence interval. If the lower confidence limit is higher than -12% we will conclude non-inferiority. If the lower confidence limit is below -12% we will conclude that DTG + FTC is potentially inferior to cART. Per protocol (PP) and intention-to-treat (ITT) analyses will be performed. Exclusion criteria for PP will be: patients who discontinue treatment prematurely for reasons other than death, patients with a treatment adherence of less than 80%, or those who do not have HIV-1 RNA results available at week 48. For ITT analysis, all randomized patients will be analysed in the allocated group regardless of any protocol violations.

GCP Statement:
This study will be conducted in compliance with the protocol, the current version of the Declaration of Helsinki, the ICH-GCP or ISO EN 14155 (as far as applicable) as well as all national legal and regulatory requirements. Avec un suivi étendu à 144 semaines, nous espérons répondre à la question de l'efficacité du dolutégravir et de l'emtricitabine en bithérapie avec une puissance suffisante pour nous approcher du contexte de la vie réelle.
Con un follow-up della durata di 144 settimane, speriamo rispondere alla domanda relativa all'efficacità di dolutegravir ed emtricitabina in biterapia con una potenza sufficiente per avvicinarci al contesto della vita reale. The Sponsor-investigator will oversee all activities within this protocol in regular meetings with the trial team, the trial coordinators and the sites (teleconferences, physical meetings and email). The Sponsor-investigator will setup contracts with the participating sites to determine the sites' and the sponsor's role in the study (i.e. data collection, reporting and reimbursement). Major tasks such as protocol writing, site monitoring visits, data management, statistical analysis, interpretation of the data, writing of the report will be conducted in collaboration with the trial team and the Sponsor's delegates.

Abbreviations
Contracts will be setup with the Clinical Trial Units where necessary. All participating sites will be using their local laboratories for virology, immunology, haematology and chemistry assessments. The laboratories' postal addresses, certifications and normal values will be filed in the investigator files of the respective sites.

Monitoring institution
Clinical Research Unit (CTU) of Geneva University Hospitals will be responsible for developing a central monitoring plan that will be followed in the seven study sites.

Data Safety Monitoring Committee
An independent Data Safety and Monitoring Board (DSMB) will be set up to monitor the safety and efficacy of the study interventions in participants enrolled in the trial. The DSMB will be chaired by Jose Ramon Arribas Lopez, and will include Yasdan Yasdanpanah (

clinical epidemiology, pharmacoeconomics), Valérie Journot (statistician), Bart Rijnders (clinical medicine) and Samia Hurst (bioethics).
A conflict of interest statement will be completed by all members. Frequency of data reporting to the DSMB, frequency of DSMB meetings and stopping rules are described in section 11.3.

1.7
Any other relevant Committee, Person, Organization, Institution External persons might be invited to join the Study Scientific Committee meeting.

Trial Team Coordinators at the coordinating centre Geneva
The study will be coordinated under the direct supervision of the sponsor-investigator by the following study physicians and clinical research associates at the research team of the HIV unit at Geneva

ETHICAL AND REGULATORY ASPECTS
The decision of the CEC concerning the conduct of the study will be made in writing to the Sponsor-Investigator before commencement of this study. The clinical study can only begin once approval from all required authorities has been received. Any additional requirements imposed by the authorities shall be implemented.

Study registration
The study will be registered in the www.clinicaltrials.gov registry and in the Swiss Federal Complementary Database.

Categorisation of study
This study is a category A study because the interventional product is used as a dual therapy in combination with FTC in this protocol, i.e. in association with other antiretroviral agents as indicated in the product information.

Competent Ethics Committee (CEC)
The responsible investigator ensures that approval from an appropriately constituted Competent Ethics Committee (CEC) is sought for the clinical study. The Sponsor-Investigator asks to the Ethics Committee document needed for this aim and make tham available to the related study site.
It is the investigators duty to report all changes in the research activity and all unanticipated problems involving risks to humans; including in case of planned or premature study end and the final report to the ethics committee within the required time frames. Reporting time frames for adverse events are mentioned in chapter 10 of this protocol.
No changes are made to the protocol without prior Sponsor and CEC approval, except where necessary to eliminate apparent immediate hazards to study participants.
Premature study end or interruption of the study is reported within 15 days. The regular end of the study is reported to the CEC within 90 days, the final study report shall be submitted within one year after study end. Amendments are reported according to chapter 2.10.

Competent Authorities (CA)
The study is a category A study. Therefore, approval from the competent authority (Swissmedic) is not necessary before the start of the clinical trial.

Ethical Conduct of the Study
The study will be carried out in accordance to the protocol and with principles enunciated in the current version of the Declaration of Helsinki, the guidelines of Good Clinical Practice (GCP) issued by ICH, the Swiss Law and Swiss regulatory authority's requirements. The CEC will receive annual safety and interim reports and be informed about study stop/end in agreement with local requirements.

Declaration of interest
The Sponsor-investigator has received financial support from the Swiss National Fund for Science for the present study; the sponsor-investigator, all investigators and authors of the final manuscript will have no financial relationships with any organisations that might have an interest in the present study; no other relationships or activities that could appear to influence the results of the study.

Patient Information and Informed Consent
The investigators will explain to each participant the nature of the study, its purpose, the procedures involved, the expected duration, the potential risks and benefits and any discomfort it may entail. Each participant will be informed that the participation in the study is voluntary and that he/she may withdraw from the study at any time and that withdrawal of consent will not affect his/her subsequent medical assistance and treatment.
The participant must be informed that his/her medical records may be examined by authorised individuals other than their treating physician.
All participants for the study will be provided a participant information sheet and a consent form describing the study and providing sufficient information for participant to make an informed decision about their participation in the study. A time frame of preferably 24 hours will be given to the participant to decide whether to participate or not.
The patient information and consent form (appendix 1) will be submitted to the CEC to be reviewed and approved. The formal consent of a participant, using the approved consent form, must be obtained before the participant is submitted to any study procedure.
The participant should read and consider the statement before signing and dating the informed consent form, and should be given a copy of the signed document. The consent form must also be signed and dated by the medical investigator and it will be retained as part of the study records. Medical investigator can delegate the signature of the consent form to a study nurse via the delegation log. In this case the medical investigator must countersign the consent form before the randomisation during the baseline visit.

Participant privacy and confidentiality
The investigator affirms and upholds the principle of the participant's right to privacy and that they shall comply with applicable privacy laws. Especially, anonymity of the participants shall be guaranteed when presenting the data at scientific meetings or publishing them in scientific journals.
Individual subject medical information obtained as a result of this study is considered confidential and disclosure to third parties is prohibited. Subject confidentiality will be further ensured by utilising subject identification code numbers to correspond to treatment data in the computer files.
For data verification purposes, authorised representatives of the Sponsor-Investigator, a competent authority (e.g. Swissmedic), or an ethics committee may require direct access to parts of the medical records relevant to the study, including participants' medical history.

Early termination of the study
The Sponsor-Investigator may terminate the study prematurely according to certain circumstances, for example:  ethical concerns,  insufficient participant recruitment,  when the safety of the participants is doubtful or at risk, respectively,  alterations in accepted clinical practice that make the continuation of a clinical trial unwise,  early evidence of benefit or harm of the experimental intervention.

Protocol amendments
Substantial amendments are only implemented after approval of the CEC respectively.
Under emergency circumstances, deviations from the protocol to protect the rights, safety and wellbeing of human subjects may proceed without prior approval of the sponsor and the CEC. Such deviations shall be documented and reported to the sponsor and the CEC as relevant according to the procedure described in the related Standard Operating Procedure. All Non-substantial amendments are communicated to the CEC within the Annual Safety Report (ASR).

Background and Rationale
Current European HIV treatment (EACS) guidelines recommend a combination of three active drugs for the initiation and maintenance of ART. Combinations usually include two nucleoside reverse transcriptase inhibitors (NRTIs) plus a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor (PI), or an integrase inhibitor (INSTI). The cost of a full standard triple treatment (drugs only) in Switzerland ranges from CHF 14,000 to CHF 22,000 per year (1) .
Simplified maintenance therapy in patients on suppressive ART aims to limit toxicities, support retention in care, and reduce costs to the healthcare system (2, 3) ( Figure 1). Current simplified maintenance regimens are NRTI-sparing regimens, mainly boosted PI-based mono and dual therapies (4)(5)(6). Eleven years after the first boosted PI monotherapy trial (7), revisiting this strategy is critical. In 2015, a PI-based mono-maintenance regimen has still not been widely adopted due to suboptimal virological control, or the lack of the necessary infrastructure to monitor such regimens in resource-limited settings (2). The PROTEA trial also showed less efficacy of PI monotherapy in patients with nadir CD4 less than 200 cells/µl (8). Other possible maintenance regimen includes cabotegravir plus rilpivirine dual therapy as a phase II, industry-sponsored trial showed excellent antiviral activity compared to efavirenz plus dual-NRTIs until the end of week 96 (9). The very good tolerability, high convenience, lack of drug-drug interactions, high potency, and distinctive resistance profile suggest that INSTI-based therapy could be an acceptable and efficient alternative to PIs in simplified maintenance therapy as a bitherapy (2).

Dolutegravir efficacy data in antiretroviral drug combinations
The SINGLE, FLAMINGO and SPRING 2 randomized controlled trials showed the superiority of DTG at week 48 compared to efavirenz (88% of patients achieving undetectable viral load compared to 81% respectively, p=0.003) or ritonavir boosted darunavir (90% vs. 83%, p=0.025), and its noninferiority to raltegravir (RAL) (88% vs. 85%) in antiretroviral drug combinations among ART-naïve HIV-infected patients (10)(11)(12). In these trials, no patient developed mutations associated with resistance to integrase inhibitors or accompanying NRTIs. This absence of development of resistance has never been seen in past trials assessing the efficacy of first line ART regimens with NNRTIs or PIs (13). The DTG resistance pattern is driven by the R263K mutation which also confers a loss in viral fitness, potentially explaining the absence of detectable mutations by conventional assays in ARTnaïve patients receiving DTG (14).
DTG was found superior to raltegravir among treatment-experienced patients with resistance to at least 2 classes of antiretroviral drugs, excluding integrase inhibitors, with 71% patients on DTG achieving viral suppression at week 48 compared to 64% in the raltegravir arm (15). In patients with raltegravir or elvitegravir resistant HIV infection, DTG may retain antiviral activity at the dose of 50 mg twice daily (16,17) as DTG resistance patterns are different to resistance patterns to raltegravir or elvitegravir (14). However, cross-resistance mutations such as the combination of Q148H/R/K with G140S/A may decrease dolutegravir susceptibility (18).

HIV DNA reservoirs
A challenge in HIV treatment is the existence of a HIV-DNA reservoir made of latently infected CD4 Tcells circulating in the peripheral blood or disseminated in lymphoid organs and associated tissues (19,20). Sub-optimal drug penetration in tissues such as the genital tract or the brain may allow for ongoing replication in body compartments even with undetectable plasma viral load (21). The HIV-DNA reservoir establishes itself very early in the course of HIV infection (22), and is a strong predictor of HIV disease progression(23) as well as a risk factor for neurocognitive disorders (24). High level of HIV-DNA was predictive of virological rebound during ART interruptions (25). Some studies found that RAL decreased the HIV-DNA reservoir in latently infected peripheral T-cells when used in an intensification ART strategy (26) or when part of a conventional triple ART regimen (27).
The reservoir is measured by the total cell-associated HIV-DNA as the frequency of infected cells per million in peripheral blood mononuclear cells (PBMC) (20). Boulassel et al demonstrated that the CD4 cell nadir independently predicted the size of the HIV reservoir after prolonged therapy (28). In the current trial we will measure proviral DNA from PBMCs by using a novel digital droplet PCR based assay as developed in the laboratory of H. Günthard / K. Metzner at the University Hospital Zurich for the HIV.X project "Deciphering Host-Virus Interactions to Cure HIV" (29). We will also assess if proviral DNA, and nadir CD4 count, could predict virological failure.
Simlified maintenance therapy has the advantage to reduce common NRTI and NNRTI associated side-effects, such as renal and central nervous system toxicities mainly due to tenofovir and efavirenz respectively(30), which in turn will reduce costs to the healthcare system (31). Regimen simplification is also considered critical to further scale-up of treatment, particularly in low-and middle-income settings, and to support retention in care (3). The World Health Organization favours a simple regimen with the following characteristics: minimal risk of failure; efficacy and tolerability; robustness and forgiveness; no overlapping resistance in treatment sequencing; and convenience (3). Simplified DTGbased therapy seems to meet these criteria. Our primary objective is to assess the efficacy of simplified maintenance DTG-based dual therapy, together with FTC, in patients followed within the community research network of the Swiss HIV Cohort Study (SHCS).

Optimization of clinical and biological treatment monitoring
Maintenance therapy does not only refer to drug optimization. Costs are mainly shared among the direct drug costs, biological monitoring, and medical (and paramedical) consultations (32). We consider that with newer more potent antiretroviral drugs, which are also better tolerated, there is room for resource optimization. The use of routine, frequent CD4 cell measurements in the monitoring of HIVinfected patients on treatment is an excellent example. This raises the issue as to whether regular and frequent CD4+ cell counts measurements are still of benefit for monitoring treatment success in these patients when access to HIV-RNA measurement is guaranteed. Thus, while a CD4 cell count at baseline continues to be important for initial clinical management decisions, once ART is initiated and patients have stabilized on treatment, the additional value of CD4 testing is questionable. Indeed, a recent meta-analysis and literature review supported the reduction in the frequency or stopping routine CD4 monitoring for patients who are immunologically stable on ART in settings where routine viral load monitoring is provided (33,34). Based on previous randomized trials among adults and children (35,36), we anticipate that routine lipid, renal, and complete blood count testing may not be helpful in the management of patients on long-term therapy.
To our knowledge, optimized monitoring strategies have only been tested in resource-limited settings where human and financial resources are scarce compared to the growing number of HIV patients in care. Several strategies have demonstrated positive results. The STRATALL trial demonstrated that the clinical follow-up of HIV patients commencing cART was non-inferior to biological monitoring with 6-monthly CD4 count and HIV viral load measurements, at a time when generic HIV viral load assays were not available (37,38). A Cochrane systematic review of 10 studies, all conducted in Africa and including randomized controlled trials (39,40), showed that task-shifting of ART management from doctors to trained and supported nurses did not reduce the quality of care and potentially decreased the number of patients lost to follow-up. Ahn et al have shown that annual CD4 monitoring was sufficient in virologically suppressed patients with higher baseline CD4 count ≥250 cells/mm 3 in the Asia-Pacific region (41).
Seventy percent of HIV-infected patients in Switzerland are integrated into the work force and most are able to work full time (42). In this situation, a patient-centered monitoring may be more suitable in the long-term. As a second objective, we propose to assess if a patient-centered monitoring that offers alternative options for the delivery of study visits, laboratory tests and drugs is cost-saving (first goal) and acceptable (second goal) , without jeopardizing safety, compared to routine monitoring.

Investigational Product (treatment) and Indication
DTG is a second-generation INSTI that can be administered once daily without the need for pharmacokinetic boosting, irrespective of food intake, and with very few drug-drug interactions. Following a dose of 50 mg, it has a plasma concentration 24 hours after that is 19 times higher than the in vitro protein-adjusted IC90 (concentration inhibiting 90% of in vitro viral replication) of 64 ng/ml, thus providing a significant buffer in the case of reduced concentrations due to late or missed doses, reduced absorption, or drug interactions (10,43). In vivo trough concentration values are 25 times higher than the in vitro threshold and its long half-life of 12 hours also contributes to the higher efficacy observed with DTG (43). However, plasma concentrations of antiretroviral drugs may be influenced by drug-metabolizing enzymes or drug transporters, leading either to insufficient levels of the drugs with the risk of virological failure, either to higher plasma levels associated with side effects (44). For example, large interindividuel variation in plasma concentration of raltegravir was reported (45) and raltegravir was found to be a substrate of efflux transporters expressed in the intestines (46,47). Efflux transporters with altered function could also potentially impact dolutegravir plasma concentration.
Prolonged and more stable binding to the integrase-DNA complex compared to first generation integrase inhibitors, raltegravir or elvitegravir, with a longer dissociative half-life (71 hours compared with 8.8 hours for raltegravir and 2.7 hours for elvitegravir) is thought to add to its higher barrier to resistance (48). The DTG resistance pattern is driven by the mutation R263K, which confers low-grade resistance to the drug, and defers from the three genetic pathways involving integrase residues Q148, N155, and Y143 to the first-generation INSTI (43). When associated with H51Y and/or G118R mutations, the mutation R263K decreases viral replication capacity and impairs the emergence of resistance against reverse transcriptase inhibitors (13,14). This loss in viral fitness may explain the absence of detectable mutations by conventional assays in naïve patients receiving DTG (14). Single initial mutations to DTG in salvage trials do not result in high-level resistance to the drug, suggesting a high genetic barrier at least similar to the one of boosted PI (13). However, recent data from the SAILING trial and an observational DTG monotherapy maintenance study have shown the development of INSTI mutations including N155H or Q148R pathways (15,49,50). Cross-resistance mutations such as the combination of Q148H/R/K with G140S/A may also decrease dolutegravir susceptibility in patients failing raltegravir salvage regimens (18).
DTG is well tolerated with only 2% to 3% of patients discontinuing the drug for adverse events in phase III trials. Frequent side-effects include sleep disturbance, gastro-intestinal complaints, headache, and respiratory tract complaints; most were grades 1 or 2 in clinical trials (13,14). No life threathening adverse events were observed. Rates of psychiatric adverse events, i.e. insomnia, anxiety, depression or suicidality, were low in treatment-naïve phase III/IIb trials of DTG with frequency of withdrawal as low as 5% (51). However, observational studies have reported higher rates of central nervous system side effects (up to 20%) in treatment-naïve or -experienced patients receiving DTG (52, 53) with discontinuation rates due to central nervous system adverse events from 0.6% to 3.4% (52,(54)(55)(56). A retrospective cohort study in the Netherlands reported up to 13.7% of discontinuation rate due to adverse event on DTG (57) and another in Germany found that women and older patients were more at risk of discontinuating DTG for neuropsychiatric side effects (58). DTG is also lipid neutral with fewer elevations of low-density lipoprotein of grade 2 or higher compared to efavirenz or boosted darunavir in the SINGLE and FLAMINGO trials (12,59). However, there are no data on the effect of DTG on body fat composition and the associated cardiovascular risk or bone mass density, which are growing concerns in our aging HIV population.
Drug interactions are very few (43), another advantage of the compound. DTG is a substrate of UGT1A1, CYP3A4, UGT1A3, and UGT1A9. Only 1% of potential drug-drug interactions are considered to be at risk (Figure 2). DTG should be used at the dose of 50mg twice daily with rifampicin, a potent inducer of UGT1A1 and CYP3A4. Co-administration with other inducers of UGT1A1 and CYP3A4 such as carbamazepin, oxcarbamazepin, phenytoin, phenobarbital and St. John's wort should be avoided. As DTG inhibits the renal transporter OCT2, it is contraindicated with the antiarrhythmic dofetelide (which is not authorized in Switzerland) and caution is needed when coadministered with metformin. DTG should be taken with food when administered with calcium or iron supplementation or vitamins intake as well as with magnesium or aluminium-containing antiacids (14).   (60). The calculated DTG area under the concentration versus time curve (AUC) was 25-30% lower in the 2 nd and 3 rd trimesters compared to paired postpartum data but these differences were not statistically significant and the AUC was similar to historical adult controls (60). One maternal adverse event of increased hepatic tests was reported and possibly related to DTG. Four infants were born with congenital abnormalities but no relationship to ARV exposure during first trimester was reported (60). Post-marketing surveillance up to January 16, 2016 reported a total of 74 pregnancies on DTG. Pregnancy outcomes were as followed: 18 live enfant with no apparent congenital anomaly, 2 live enfant with congenital anomaly, 13 spontanerous abortion with no apparent congenital anomaly, 1 spontaneous abortion with congenital anomaly, 1 still birth with no apparent congenital anomaly and 39 outcomes were ongoing or unknown (61). Based on results shown in July 2017 in 845 pregnant women in Botzwana (62), dolutegravir-based triple antiretroviral regimen was accepted in the 9.0 EACS guideline also during pregnancy (63), and dolutegravir was announced as part of first line regimen in various low-income countries regardless of the childbearing potential (64). However, on May 18, 2018, the WHO, the FDA, and the EMA diffused an advertisement regarding a safety signal on the use of dolutegravir in early pregnancy with a risk of neural tube defect in infant born to women using dolutegravir in early pregnancy. This advertisement was based on a non planned analysis of data from pregnant women using dolutegravir in pregnancy in Botswana: 4/426 women gave birth to infants with neural tube defects(65-67). Despite the safety signal regarding the use of DTG in early pregnancy, dolutegrvir is considered safe when used in late pregnancy(68).
Emtricitabine is a nucleoside reverse transcriptase inhibitor that has activity against both HIV and hepatitis B virus. It is very similar to lamivudine (3TC) with respect to activity, convenience, safety and resistance profile (69). However, a randomized trial of FTC versus 3TC short-term monotherapy showed a longer plasma half-life activity and a superior antiviral activity of FTC 200 mg once a day compared to 3TC (70). Finally, FTC is a pregnancy category B drug and therefore an acceptable medication to use during pregnancy (69).

Preclinical Evidence
Based on exhaustive OMS literature review (71), even if FTC is currently considered equivalent to 3TC, some pharmacological differences could be important in the clinical context of dual therapy. FTC has a longer half-life and a greater potency against HIV-1 compared to 3TC. FTC has superior inhibition of viral replication when combined with tenofovir (TDF) compared to 3TC+TDF combination and has a higher binding affinity for reverse transcriptase and lower affinity for mitochondrial DNA polymerase compared to 3TC. Moreover, the development of the M184V/I mutation, which is the most common NRTI mutation, is associated to a greater extent with the use of a 3TC-rather than a FTCcontaining regimen.

Dolutegravir efficacy data in maintenance monotherapy
DTG monotherapy as maintenance treatment in an ART experienced population was proved to be feasible, with a high rate of effectiveness over 24 weeks in three observational studies (49,72,73 However, an academic-driven randomized controlled trial of DTG mono-maintenance therapy (the DOMONO trial -NCT02401828) in which 104 HIV virologically suppressed patients were enrolled to an immediate or delayed (at week 24) switch to DTG monotherapy and followed throughout 48 weeks from the date of switch, was prematurely stopped because of virological failure in 10% of patients (74,75). While DTG monotherapy was non-inferior to cART at week 24, most of virological failures occurred after week 24 and led to INSTI-associated resistance mutations in three patients.
In addition, the Data Safety Monitoring Board of the DOLAM study, an open-label randomized controlled trial (EudrCT number 2015-000274-35) which enrolled HIV-1-infected adults on stable triple antiretroviral therapy to receive cART, DTG + 3TC or DTG monotherapy, decided to interrupt the DTG monotherapy arm because of the occurrence of two virological failures in this arm (76).
Finally, the REDOMO study showed that the percentage of virological failures in three large clinical cohorts of individualy switching to a DTG-monotherapy maintenance strategy was 9%. The selection of genotypic resistance mutations in individuals failing to DTG-monotherapy was rapid and high. The mutations selected on virological failures to DTG-monotherapy involves different pathways of resistance to INSTI (92Q, 118R, 148X and 155H) (77).

Dolutegravir efficacy data in dual therapy (either in ART-naive or experienced patients)
The PADDLE study, a single-arm pilot trial for patients with HIV-RNA<100,000/ml copies at screening, demonstrated an overall efficacy of DTG-3TC of 90% as first-line treatment. One patient with virologic failure had an entry HIV RNA >100,000 copies and was suppressed initially, but developed low-level viremia from week 36-48; no resistance was detected (78

Dose Rationale
This trial will be using the dose of DTG 50mg in combination with FTC 200 mg oral per day, which corresponds to the doses recommended by the manufacturers. -PI monotherapy (simplified regimen already).

Risks / Benefits
The main risk in this trial is virological failure on DTG + FTC dual therapy. In the ART Cohort Collaboration of 18 cohorts from Europe and North America including about 17900 patients, low level viremia measured between 50 and 199 copies/ml was weakly associated with virological failure (aHR 1.38, 95%CI 0.96-2.00) (85). We will measure HIV-1 RNA level in the plasma on a regular basis to monitor for low level viremia. Any patient with HIV-1 RNA ≥100 copies/ml will undergo an additional HIV-1 RNA measurement 14 days later (± 5 days), as well as additional adherence session and review of concomitant medications and dolutegravir and emtricitabine plasma concentration measurements.
We will define virological failure as plasma HIV-1 RNA ≥100 copies/ml on two consecutive measurements. Any patient reaching virological failure will be assessed for genotypic resistance and pharmacogenetic analyses. This latest analysis will be only done in patients who are included in the SHCS and have also signed a consent form for genetic studies. In case of virological failure, the patient will undergo an additional medical visit with review of adherence, concomitant medications, discussion of results of DTG + FTC plasma concentration. Patients randomised in the DTG + FTC dual therapy arm will be switched to a standard cART regimen while waiting for results of genotypic resistance. Patients randomised in the continuing cART arm will await results of the genotypic results. In both cases, treatment will be adjusted according to genotypic resistance results. All failing patients will complete study procedures until week 48. Figure 3 presents the algorithm for the management of virological failure.
Any patient with HIV-RNA between 20 and 99 copies at any time of scheduled visits will have an additional HIV-RNA measurement after 6 weeks (+/-5 days). Other risks associated with the trial consist of the occurrence of DTG-related side effects as observed in phase III trials and observational studies, and described in section 3.2. Side effects were relatively uncommon, with the exception of CNS adverse events in observational studies. These CNS side effects led to few discontinuation of the drug. However, patients randomised in the DTG + FTC dual therapy arm and "new" to DTG will be evaluated for CNS symptoms using a standardised questionnaire at week 2 (by phone call by the study nurse/physician) and at week 6. Emtricitabine is a well tolerated drug with little toxicity: in trials of patients with HIV or HBV infection, adverse events occurring with at least 10% frequency include gastro-intestinal symptoms with 14% to 18% of nausea and 9% to 24% of diarrhea, asthenia (10%-16%) and headache (12%18%) (69). Very few of the adverse events were categorized as serious.
Potential benefits to participants may include a simplification of antiretroviral therapy and a decrease in potential side effects related to other antiretroviral drugs.

Justification of choice of study population
This maintenance trial will enroll HIV-positive individuals on first-line or maintenance antiretroviral therapy who are virologically suppressed and included in the SHCS or getting care from a medical doctor of the SHCS network. The SHCS is highly representative of the HIV epidemic in Switzerland with an estimated coverage of 75% of HIV-infected individuals, 69% of all patients with AIDS in Switzerland, and 72% of all ART-treated individuals. Patients will be recruited during routine consultations in the outpatient clinics of the participating sites of the SHCS network. The study does not foresee inclusion of vulnerable participants or enrolment in emergency situations.

Overall Objective
The purpose of this study is to evaluate whether maintenance antiretroviral therapy could be simplified to DTG + FTC dual therapy and/or patient-centered monitoring once virological suppression is achieved. Using a factorial design, the study aims to assess the efficacy of DTG + FTC dual therapy to maintain virological suppression through 48 weeks of follow-up as well as the costs of a patientcentered ART laboratory monitoring. The study will also describe the safety and acceptability of the different study arms.

Primary Objective
The study seeks primarily to assess: -The efficacy of DTG + FTC dual therapy to maintain virological suppression throughout 48 weeks in virologically suppressed HIV-infected individuals who are switched from standard therapy to DTG + FTC dual therapy. -The costs from the perspective of the health care provider of a patient-centered ART monitoring strategy which offers alternative options for the conduction of study visits, venipunctures, drugs delivery, and which omits CD4 cell count, lipid and glucose measurements, and safety blood tests (CK, renal, liver and full blood count) during follow-up.

Secondary Objectives
Secondary objectives are to assess: -Loss of future drug options in patients with virological failure, predictors of virological failure, time to loss of virological response (TLOVR), change in CD4 cell count, change in HIV-DNA blood reservoir, adherence, DTG and FTC plasma concentration, safety, treatment satisfaction, acceptability, health-related quality of life, costs of treatment arms; -Acceptability, safety, cost-effectiveness, and health-related quality of life of monitoring arms.

Safety Objectives
The study aims to assess the safety of DTG + FTC dual therapy and simplified ART monitoring throughout 48 weeks by evaluating the following parameters: -Loss of future drug options in case of virological failure defined as new intermediate or highlevel resistance to one or more drugs to which the patient's virus was considered sensitive at trial entry; -Change in CD4 cell count, total cholesterol, low density lipoprotein-cholesterol, Framinghamcalculated cardiovascular risk, and glomerular function rate; -Occurence of adverse events; -Occurence of serious adverse events; -Occurrence of CNS adverse events in patients new to DTG.

Primary Outcomes
The first primary outcome for the comparison between DTG + FTC dual therapy and standard cART is the proportion of patients maintaining HIV suppression defined as HIV-RNA <100 copies/ml throughout 48 weeks (+/-21 days). A single blip defined as HIV-RNA <200 copies/ml during the study period is allowed as long as this value is followed by HIV-RNA <50 copies/ml.
The second primary outcome for the comparison between patient-centered and standard monitoring is the direct costs of the two study arms from the health care system perspective at week 48.

Secondary Outcomes
5. Change in glomerular function rate from baseline to week 48; 6. Proportion of patients with an adverse event at week 48; 7. Proportion of patients with a serious adverse event at week 48; 8. Proportion of patients with a CNS adverse event throughout 48 weeks 9. Proportion of patients new to DTG with CNS symptom at 2 and 6 weeks after starting DTG; 10. Changes in patient weight from baseline to week 48.

General study design and justification of design
This is a pragmatic multicentre, 2 x 2 factorial randomized controlled trial with 1:1:1:1 randomization to switching to DTG + FTC dual therapy or continuation of cART and to patient-centered monitoring or continuation of standard monitoring (Figure 4).

Figure 4: Schematic presentation of study design DTG + FTC dual therapy
HIV-infected patients virologically suppressed for at least 24 weeks on standard cART will be randomly allocated: -Standard-of-care arm: patients randomized in this arm will continue their current cART regimen, according to section 7.1.
-Dual therapy arm: patients randomized in this arm will be switched to DTG + FTC dual therapy. DTG 50 mg and FTC 200 mg will be administered once daily as dual therapy for a duration of 48 weeks.
For all patients, HIV-RNA measurements will be performed at screening, baseline, week 6, week 12, and every 12 weeks afterwards. Any patient with HIV-RNA between 20 and 99 copies/ml at any time of scheduled visits will have an additional HIV-RNA measurement after 6 weeks (± 5 days). Any patient with HIV-RNA > 100 copies/ml at any time of scheduled visits will have an additional HIV-RNA measurement after 2 weeks (± 5 days).

Patient-centered monitoring
Randomization will also allocate patients into the following two groups: -Standard monitoring arm: patients randomized in this arm will continue a standard 12-weekly routine immunological and safety blood monitoring, including CD4 cell count, lipids and glucose, renal and hepatic function tests, creatine kinase at their affiliated SHCS sites.
-Patient-centered monitoring arm: patients randomized in this arm will have immunological and safety blood analyses (CD4 cell count, lipids and glucose, renal and hepatic function tests, creatine kinase) performed at screening and at week 48. Additional safety blood tests will be performed in case of signs and symptons as indicated by the physician. In addition, patients will have to choose at least one of three alternative options for the conduction of study visits, venipuncture and drugs delivery at weeks 6, 12 and 36, see section 8.1.1. Patients will also have the opportunity to change or give their opinion on the alternative option(s) chosen if they find it non convenient during the study. Changes will be possible at week 24; satisfaction will be assessed at week 12, 24, 36 and 48. Importantly, all interventions or blood measurements potentially related to adherence (affecting the primary endpoint) will be identical between the study arms (see section 8.4).

Allocation sequence
Patients will be randomised 1:1:1:1 using randomly-permuted blocks of varying sizes to one of the four study arms (one computer-based randomization list stratified per study center).

Concealment mechanism
Each of the 7 centres will receive the attribution number using a central computer-based randomization system.

Implementation
One allocation sequence stratified per study center will be generated by an independent team who will not be involved in the implementation of the study on sites using a computer-generated sequentially numbered randomization list. Lists will be transferred to the electronic case report form based on a standardized process. The process ensures that lists are stored with restricted access so that only system administrators have access. Once eligibility criteria are confirmed and when the patient has provided oral written consent to participate in one of the 7 centers enrolled in the trial, the study nurse on site (or the study investigator) will register the patient in the electronic data capture system after which the allocation will be revealed.

Blinding procedures
This will be an open-label trial.

Other methods of minimising bias
The use of validated questionnaires on adherence, health related quality of life and treatment satisfaction will help minimising information biais. The following validated questionnaires will be used: -Adherence will be measured using the questionaire reported by Glass, Sterne et al. 2015 (86) and used during routine HIV consultations within the SHCS. -Health related quality of life will be measured using the PROQOL-HIV questionnaire (87,88) together with a visual analog scale. -Central nervous system symptoms will be assessed using the depression module PHQ-9 recommended by the WHO (89, 90).

Unblinding Procedures (Code break)
Not applicable. This is an open-label trial.

STUDY POPULATION
HIV-1 positive individuals included in the SHCS or getting care from a medical doctor of the SHCS network will be enrolled in this maintenance trial. All SHCS centres will participate in the study. Patients relocating within Switzerland can be followed in any of the participating SHCS centres.

Eligibility criteria
Participants fulfilling all of the following inclusion criteria are eligible for the study: 1. Informed consent as documented by signature 2. Documented HIV-1 infection; 3. Enrolled in the SHCS or receiving care from a medical doctor of the SHCS network; 4. ≥ 18 years of age; 5. HIV-RNA <50 copies/mL at screening and for at least 24 weeks before screening on effective suppressive cART, one blip with less than 200 copies/mL allowed during this period if followed by at least 2 results < 50 copies/mL; 6. On standard cART at the time of inclusion, i.e.: -2 NRTIs + either 1 NNRTI, 1 boosted PI or 1 INSTI; -NRTI-sparing triple ARV regimen (e.g. 1 NRTI + 1 NNRTI + 1 InSTI); -Dual therapy with protease inhibitor.
Every effort will be made to include women (91) in the same proportion as in the prospective SHCS (28% of HIV-infected individuals included into the SHCS are female; SHCS website demographic data, accessed 20 December 2017).
The presence of any of the following exclusion criteria will lead to exclusion of the participant: 1. HIV-2 infection; 2. Previous ART change for unsatisfactory virological response, i.e. slow initial virological suppression, incomplete suppression or rebound; change for convenience or toxic effect prevention or management allowed. Note: patients with documented genotype(s) presenting only a M184V mutation remain eligible; 3. Creatinine clearance <50 ml/min; 4. ASAT or ALAT > 2.5x upper limit of the norm; 5. Known hypersensitivity, intolerance or allergy to DTG or FTC; 6. Known or suspected non-adherence (defined as <80% adherence, i.e. missed dose > 1x/week), to current treatment in the last 24 weeks; 7. Concomitant use of drugs that decrease dolutegravir blood concentrations including carbamazepine, oxcarbamazepine, phenytoin, phenobarbital, St John's wort and rifampicin; 8. Women who are pregnant or breast-feeding; 9. a. Presence of any InSTI-resistance. (92).
b. Non availability of previous routine resistance test, at least for reverse transcriptase and protease genes. Patients enrolled in other interventional studies are not eligible. After the other interventional study termination, they will have to wait at least 3 months before the Simpl'HIV screening.

Recruitment strategies
Patients will be recruited using the SHCS database. According to the database, it is estimated that >2500 individuals followed at the participating centres in 2014 (out of 8900 participants) are potentially eligible. However, the genotype is not available to screen patients solely on the basis of the SHCS database and the potential number of candidates will be therefore downgraded to 1200. If 15% of the patients agree to participate, the recruitment will be completed within a year.
Possible candidates will be contacted by their attending physician or delegates (e.g.study nurse, study coordinator) and will undergo screening procedures according to the protocol after giving written consent. No advertising is intended at this stage other than information about the protocol (flyer in appendix 2) in the study centers and local HIV/AIDS associations. Participants will not receive financial compensation for participation. Recruitment will continue until the target sample size is reached. In the event of slow or insufficient recruitment, study sites visits will be conducted and human resources allocated. In addition, an international collaboration could be sought in case a rapid recruitment is needed.

Feasibility of recruitment
The prospective research cohort (SHCS) has been already used successfully to plan randomized controlled trials and other clinical trials in the field of HIV in Switzerland, including SNF grants (SNF grant 32003B_135745). As the SHCS is highly representative of the HIV care and treatment network in Switzerland, with over 75% of all HIV-infected individuals included this cohort in Switzerland (93), we consider that we have an excellent tool to estimate patient recruitment.
All participating SHCS sites agree to recruit patients according to the following table:

Allocation sequence
Patients will be randomised 1:1:1:1 using randomly-permuted blocks of varying sizes to one of the four study arms (one computer-based randomization list stratified per study center).

Concealment mechanism
Each of the 7 centres will receive the attribution number using a central computer-based randomization system.

Implementation
One allocation sequence stratified per study center will be generated by an independent team who will not be involved in the implementation of the study on sites using a computer-generated sequentially numbered randomization list. Lists will be transferred to the electronic case report form based on a standardized process. The process ensures that lists are stored with restricted access so that only system administrators have access. Once eligibility criteria are confirmed and when the patient has provided oral written consent to participate in one of the 7 centers enrolled in the trial, the study nurse on site (or the study investigator) will register the patient in the electronic data capture system after which the allocation will be revealed.

Criteria for withdrawal / discontinuation of participants
Participants will be withdrawn from the trial if: 1. The subject withdraws consent; in this case the patient will continue the antiretroviral treatment with a standard-of-care treatment (cART) and will continue regular follow-up with his/her treating physician; 2. Clinical reasons believed to be life-threatening by the physician, even if not addressed in the toxicity management protocol; 3. Subject is judged by the investigator to be at significant risk of failing to comply with the provisions of the protocol so as to cause harm to self or seriously interfere with the validity of the study result. 4. Study routine procedure must be stopped due to safety concerns.
Withdrawn participants will not be replaced.
Participants in the DTG + FTC dual therapy maintenance arm will discontinue study drugs if (non exhaustive list): -diagnosed with virological failure defined as plasma HIV-RNA ≥100 copies/ml on two consecutive occasions; -become pregnant -start breastfeeding; -requiring to use prohibited concomitant medications such as carbamazepine, oxcarbamazepine, phenytoin, phenobarbital, rifampicin or St John's Wort; -presenting serious adverse events that necessite to stop dolutegravir and/or emtricitabine; -reasons related to conceiving and DTG potentially safety issue.
They will still be included in the study, continue their antiretroviral treatment with a standard cART. They can be switched to their previous ARV regimen or to a different one according to the genotypic resistance testing, drug-drug interactions profile and/or clinical evolution, and will complete study procedures until week 48. If the new regimen still fulfills the eligibility criteria the subject can continue the study, otherwise the subject will be withdrawn from the trial. In case of a pregnancy the viral load measurement will be performed once per month accordingly to the EACS guidelines.

Experimental Intervention (treatment)
Dolutegravir 50 mg (Tivicay®) is manufactured by ViiV Health Care. It is a round pale yellow tablet to be taken orally once daily with or without food. DTG 50 mg will be administered once daily in combination with FTC for a duration of 48 weeks.
Emtricitabine 200 mg (Emtriva®) is manufactured by Gilead Sciences. It is blue and white capsule to be taken orally once daily with or without food. FTC 200mg will be administered once daily in combination with DTG for a duration of 48 weeks.
Patient-centered monitoring will include reduced immunological and safety blood analyses (CD4 cell count, lipids and glucose, creatine kinase, renal and hepatic function tests) performed at screening and at week 48. In addition, patients will be offered alternative options for the conduction of study visits, venipuncture and drugs delivery at weeks 6, 12 and 36. Participants will be asked to select at least one of the three following strategies:  Venipuncture for blood analyses: decentralised venipuncture, e.g. at peripheral laboratory near patient's home or place of work, or with general practitioner, versus at their affiliated SHCS site;  Drug delivery: delivery of ARV drugs/prescription by mail or at a chosen pharmacy versus at their affiliated SHCS site;  Assessment and clinical interview: phone call with study nurse/physician versus face-to-face at their affiliated SHCS site. These options will be organized at study site discretion. Table 1 summarises the differences between the monitoring arms and Table 2 lists the different options chosen by each study site.  Patients will also have the opportunity to change or give their opinion on the alternative option chosen if they find it non convenient during the study. Changes will be possible at week 24; satisfaction will be assessed at week 12, 36 and 48.

Control Intervention (standard/routine/comparator treatment)
Patients in the control intervention will be on fully suppressive antiretroviral regimen.
Within-class antiretroviral switch (such as switch from TDF to TAF) are accepted during the study period only for patients randomized in the continuing cART arm. Other antiretroviral switch are discouraged and sponsor agreement is needed before the switch.
The following regimens will be excluded: - -PI monotherapy (simplified regimen already).
Standard monitoring includes a standard 12-weekly routine immunological and safety blood monitoring, including CD4 cell count, lipids and glucose, creatine kinase, renal and hepatic function tests, at affiliated SHCS sites.

Packaging, Labelling and Supply (re-supply)
The commercial product of Dolutegravir (Tivicay®), Emtricitabine (Emtriva®) and other antiretroviral drugs will be administered in this study (without deviation, i.e. only commercial product will be administered). The ARV drugs will be distributed to the participants according to usual local practice at the study centers. Each study centre distributing ARV will be resupplied using the hospital's routine order system. The study drugs (Tivicay® and Emtriva® and cART drugs) will be labelled with the following information in the local language: Short title of the study, Protocol CCER number, patient ID number, name of sponsor-investigator and/or principal investigator. Additional information such as date of IMP/prescription distribution can be added at site's discretion.

Storage Conditions
The investigational product will be stored securely at the study centers distributing ARV with limited access and under the recommended storage conditions. ARV drugs must be stored at maximum 30°C. Study centre distributing ARV will be equiped with a temperature monitoring system and document storage temparatures in the investigator site file.
Temperature deviations of >30°C must be reported to the sponsor-investigator.

Administration of experimental and control interventions 8.2.1 Experimental Intervention
Dolutegravir 50 mg and Emtricitabine 200 mg will be administered per os once daily as dual therapy for a duration of 48 weeks. Participants will be requested to take the IMPs at approximately the same time each day (+/-1 hour) with or without food. Dolutegravir and emtricitabine will be dispensed from study site or local pharmacy according to site practice at each scheduled visit. Study drug dispensing and return information will be recorded on the CRFs and drug accountability logs.
At the end of the study, all patients will be offered the possibility to continue their treatment with either a standard ART regimen or DTG + FTC dual therapy. This will be decided at treating physician discretion after discussion with the patient and depending on the efficacy of the strategy during the study period. Subsequent follow-up will be made at the discretion of the treating physicians.
Participants in the patient-centered monitoring arm will be asked to select at least one of the three different options:  Venipuncture for blood analyses: decentralised venipuncture, i.e. at peripheral laboratory nearer to their home or place of work, or with general practitioner, versus at their affiliated SHCS site;  Drug delivery: delivery of ARV drugs/prescription by mail or at chosen pharmacy versus at their affiliated SHCS site;  Assessment and clinical interview: phone call with study nurse/physician versus fa-to-face at their affiliated SHCS site.
At the end of the study, patients will continue regular monitoring as per SHCS requirements.

Control Intervention
Participants randomised in the continuing cART arm will continue to take their standard fully suppressive antiretroviral therapy as previously, once or twice daily according to their antiretroviral regimen, at approximatively the same time (+/-1 hour) with or without food. All recommended American and European regimens are administered per os.
Patients randomized in the standard monitoring arm will continue a standard 12-weekly routine immunological and safety blood monitoring, including CD4 cell count, creatine kinase, lipids and glucose, renal and hepatic function tests, at their affiliated SHCS sites.

Dose modifications
The dose of emtricitabine must be adapted according to kidney function. The dose of 200 mg once a day is the dose for a creatinine clearance of ≥ 50ml/min. As participants will be excluded if creatinine clearance is < 50 ml/min, there is no need for dose modification at enrolment. However, if creatinine clearance decreases during the study period, dose modification of emtricitabine will be made according to European guidelines, i.e. 200 mg every 96 hours creatinine clearance <10 ml/min or haemodialysis (calculation preferably according to the CKD-EPI).

Compliance with study intervention
Since non-adherence is one reason for simplified maintenance failure, special care will be given to optimize adherence. Patients known or suspected to be non-adherent will not be eligible for the study. All centres will apply standard specific interventions to promote patient adherence.
-Adherence will be documented at each visit, being face-to-face or through phone call, as participants will answer specific questions, identical to the questions used at the routine visits of the SHCS (86); -Patients will be asked to fill in a diary with daily documentation of the date and time of drug intake, concomitant health conditions and medications at least in the case of any deviation from usual practice; -Pill count will be performed at each visit, being face-to-face or through phone call.
Patient's adherence will be calculated as a percentage. Patients should have taken at least 80% of treatment pills during the study period to be considered in the per protocol analysis.
Patients with HIV-RNA ≥100 copies/ml at any time during the study will also benefit from DTG + FTC plasma concentration measurement.

Retention
Participant retention will be promoted using different strategies: -Participants will be reminded of the critical importance of drug intake during visits, either faceto-face or through phone call; -SMS reminders will be sent to patients 1 day prior to each scheduled study visit where feasible; -Efforts will be made to adjust the timing of the study visits to the schedule of the patient whilst respecting the protocol given visit windows.

Data Collection and Follow-up for withdrawn participants
Participants who withdraw from the study will be asked to come in for a close-out visit (named study discontinuation visit) where all assessments planned at week 48 will be done.

Trial specific preventive measures
Concomitant medication(s) will be reviewed at baseline, at each visit thereafter and in case HIV-RNA is measured ≥ 100 copies/ml. Patients receiving anti-epileptic drugs such as carbamazepine, oxcarbamazepine, phenytoin, phenobarbital, St John's wort, or receiving the antibiotics rifampicin will not be eligible for the study. The concomitant administration of these drugs with dolutegravir decreases the plasma concentration of dolutegravir, and thus increasing the risk of virological failure. Patients on anti-tuberculosis treatment may be eligible at completion of anti-TB drugs. The use of these drugs is part of the exclusion criteria to the study and will be recorded in the screening CRF.
Pregnant women or breastfeeding mothers will not be eligible for the study as triple antiretroviral therapy is standard of care for these conditions. Pregnancy and breastfeeding are part of the exclusion criteria and will be recorded in the CRF.
Women of child-bearing potential will be screened for pregnancy at the screening visit of the study. Those who are found to be pregnant will be excluded from study participation (i.e. screening failure) and referred to an appropriate medical service.
Women of child-bearing potential included into the trial will further undergo urine pregnancy test once every 6 months (i.e. at week 24 and 48 visits). Results of screening and follow-up urine pregnancy tests will be recorded in the study CRF.
Women who become pregnant or start breasfeeding after randomisation will be switched to standard triple cART not containing dolutegravir and will continue the study. They will continue to be monitored for the development of adverse events (AE) or serious adverse events (SAE), and for pregnancy outcome.
After May 23, 2018, women of child-bearing potential and on dolutegrvir are quickly identified by Sponsor-investigator and Study Sites and these women are all informed about the safety signal concerning DTG use in early pregnancy and risk of neural tube defect in infants born to women using DTG in early pregnancy. As communicated on May 25, 2018 to the leading Ethics Committee and to the DSMB (see appendix n° 7 and n° 8 respectively), these women are all asked to sign an information sheet explaining this risk. In case of willingness of pregnancy, they are switched to DTGfree regimen, at study investigator's discretion. In case of non-willingness of a pregnancy, the use of an effective contraceptive method (oral, injectable, implantable contraceptive and intrauterine contraceptive device are considered effective contraceptive methods as well as condom in stable couple and sexual abstinence) is proposed, if not already used by the women. Women of child-bearing potential, on dolutegravir, without willingness of a pregnancy, and refusing to use an effective contraceptive method are proposed to change their ART to a DTG-free regimen. If any of the above procedure is not respected, the sponsor will decide to withdraw the concerned patient from the study.

Concomitant Interventions (treatments)
Co-administration of the anti-diabetic drug metformine with dolutegravir increases the plasma concentration of metformine; a dose adjustment of metformine is needed with limiting total daily dose to 1000 mg. As metformin is eliminated renally, patients with moderate renal impairment may be at increased risk for lactic acidosis due to increased metformin concentrations. Thefore, blood glucose and kidney function will be screened in diabetic patients under metformine at the start and during coadministration with dolutegravir + emtricitabine dual therapy, i.e. week 6, 12, 24 and 36. If creatinine clearance falls below 45ml/min, metformine will be stopped as per Swiss endocrinology and diabetology guidelines (94) and a switch to another oral antidiabetic drug will be made and documented in the study CRF.
Participants receiving magnesium-, aluminium-or calcium-containing anti-acids or vitamin supplements with calcium, iron, or magnesium will take dolutegravir 2 hours before or 6 hours after coadministered drugs.
Concurrent participation in non-interventional clinical trials is allowed as long as there is no impact on the objectives of this trial.

Study Drug Accountability
Study centre distributing ARV will order its own study drugs using the hospital's supply route. The ARV drug bottles will be labelled with study specific labels. Participants will be asked to return ARV drug bottles (full, partially empty and completely empty) to the study nurse at each visit occurring at the SHCS center. The study sites will maintain adequate documentation of the ARV drug distribution. Sample documentation will be provided by the Sponsor-Investigator. This applies to the interventional product as well as the comparators.

Return of Study Drug
Returned drugs bottles (full, partially empty and completely empty) will be registered in individual patient's files.

STUDY ASSESSMENTS
Full blood count*

Assessments of outcomes 9.2.1 Assessment of Primary Outcomes
-Viral load in plasma: HIV-1 RNA level in the plasma will be measured at every study-visit. HIV-1 RNA levels will be quantified using PCR with a limit of detection of 20 copies/ml or less at local virology laboratories. The same assays are being used for and recognised by the SHCS.
-Costs: costs will be measured starting from the baseline visit for the complete study period and from the perspective of the health care provider. Costs will be obtained from health-care insurance of the participants and from trial accounting and collected at week 48. We will consider the following costs:  Costs related to the study;  Other costs.

Assessment of Secondary Outcomes
-Proportion of patientswith HIV-RNA <50 cp/ml at week 48 by FDA snapshot. The following assumptions will be done: a. Success is considered as HIV-RNA < 50 cp/ml in the shanpshot time window; b. Failures will be defined as one of the following categories, i.e.: i. HIV-RNA ≥ 50 cp/ml; ii. Change of therapy iii. Discontinuation of therapy due to lack of efficacy; c. No virological data will be defined as one of the following categories, i.e.: i. Discontinued due to adverse event or death; ii. Discontionuation of therapy due to consent withdrawal or loss to follow-up or other reason; iii. Patients that are on study but have missing data in shapshot time window; d. Shapshot time window is 48 wkks after the baseline visit +/-3 weeks (i.e. window size is half of the duration of the time between study visits); -Loss of future drug options will be assessed in patients failing treatment, i.e. patients who will have 2 consecutive HIV RNA measurements ≥100 copies/ml. For these patients, genotype resistance testing will be performed at the SHCS center according to their usual practice. Plasma samples will be collected at each visit, processed and stored at -80°C at local virology laboratories. The same processing and storage conditions will be used as for SHCS samples. Genotype resistance interpretation will be centrally repeated by the Laboratory of Virology at HUG at the end of the study.
-CD4 cell count change: measurement of the CD4/CD8 fraction at local immunology or virology laboratories.
-HIV-DNA level change: HIV-DNA level will be measured in batch by a digital droplet PCR (ddPCR) assay using the RAINDANCE system. PBMC samples will be stored at randomization and at week 48 visit and the assay will be performed retrospectively in the Division of Infectious Diseases and Hospital Epidemiology, University hospital Zurich -Lipidic profile changes: measurement of total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides at local chemistry laboratories.
-Glocose level changes: measurement of glucose at local laboratories.
-Framingham-calculated cardiovascular risk changes: calculation using the Framingham 10 year CHD risk calculator by MDCalc: http://www.mdcalc.com. A printout of the result should be filed with the source documents.
-Glomerular function rate changes: measurement of plasma creatinine at the sites' local chemistry laboratories and calculation according to the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation using the following online calculator: http://www.qxmd.com/calculateonline/nephrology/ckd-epi-egfr. A printout of the result should be filed with the source documents.
-Occurence of adverse events: documentation in the electronic CRF by the study nurse or other (e.g. study coordinator, research associate).
-Occurence of serious adverse events (SAE): documentation in the electronic CRF by the study nurse or other (e.g. study coordinator, research associate).
-Occurence of CNS adverse events: documentation in the electronic CRF (log AE) by the study nurse or other (e.g. study coordinator, research associate).
-Presence of CNS symptoms: documentation in the electronic CRF (week 2 and 6 CNS questionnaire) by the study nurse or other (e.g. study coordinator, research associate).
-Weight changes: documentation in the electronic CRF by the study nurse or other (e.g. study coordinator, research associate).
-Health-related quality of life: assessment using the PROQOL-HIV instrument (87,88) and a visual analog scale. These assessments will be performed at baseline, week 12 and week 48 by the study nurse/physician. The PROQOL-HIV questionnaire can be filled-in directly by the patient. Documentation on paper source document and transfer into the electronic CFR by the study nurse or other (e.g. study coordinator, research associate). -Study satisfaction: assessment using 7 questions discussed at week 48.

Assessment of other Outcomes of Interest
-Adherence will be assessed at each study visit by questionnaire and pill count as described in section 8.4 for all patients. Adherence will also be assessed via a DTG + FTC plasma concentration at weel 48 (performed retrospectively) for patient on an ARV regimen containing at least DTG + FTC.
-DTG and FTC drug plasma concentration levels will be determined by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). This method is available at the Laboratory of clinical pharmacology at CHUV, Lausanne, Switzerland.
-DTG pharmacogenetic analysis will be performed at the Laboratory of clinical pharmacology at CHUV, Lausanne, Switzerland, only for patients included in the SHCS and who have signed a consent form for genetical analysis within the SHCS.
-Extra-visits outside scheduled study visits will be recorded in the electronic CRF by the study nurse or other (e.g. study coordinator, research associate) with the date and reason of consultation. Extra visits are all medical and non-medical visits reimboursed by the patient's health insurance.
-Study-related data, such as study drug distribution and return, randomization will be collected by the study nurse or other (e.g. study coordinator, research associate) as per protocol and recorded on study source documents and entered into the electronic CRF.
-Demographic data will be retrieved from the SHCS or the patient's medical file and will include: age, sex, ethnicity and level of education.
-HIV related data and medical history data will be retrieved from the SHCS or the patient's medical file and will include: date of HIV-1 infection (first documented positive HIV-1 serology), duration of viral suppression, nadir CD4 count, previous genotype, prior AIDS events (CDC C events), co-infection with hepatitis B or C, other ongoing medical conditions at baseline (i.e. diabetes mellitus, hypertension, etc.).

Adverse Events
At every study visit starting from the randomization in the trial, i.e. from the baseline visit, we will record adverse event information (i.e. type of event, date of onset, duration, final outcome, action to be taken, assessment of severity, relationship with study drug(s) and/or procedure). For the definition and procedures, we are reffering to section 10. CNS side effects will be recorded using a standardized questionnaire at week 2 (by phone call) and week 6 among patients new to DTG drug and reported as adverse events as well. Assessment of adverse events will be standardized in the CRF.

Laboratory parameters
Efficacy laboratory such as HIV-1 RNA level will be quantified at every visit using PCR with a limit of detection of 20 copies/ml or less at the sites' virology laboratories. Plasma samples will also be collected at every visit, processed and stored at -80°C as per SHCS samples. In case of HIV-RNA measurement ≥ 100 copies/ml, stored plasma sample will be sent to the Laboratory of clinical pharmacology of the CHUV for DTG and FTC plasma concentration. In case of virological failure, stored plasma will be used for genotypic resistance testing. Otherwise, cells and plasma samples are stored at least until the publication of the final manuscript. Detailed instructions for sample collection, storage and shipment will be provided by the sponsor in the written standard operating procedure.
Safety laboratory (i.e. creatinine, CK, ASAT, ALAT, gamma-GT, alkaline phosphatases, glucose and lipid profile), full blood count and CD4/CD8 cell count will be measured at the local clinical chemistry, haematology and immunology/virology laboratories. Certificates and normal value ranges will be available at each study site in the investigator file. Laboratory abnormalities that are listed in the Adverse Event list should be graded accordingly (see details in the section 10).

Vital signs
Blood pressure and heart rate will be measured after 10 minutes resting in a sitting position. Temperature will be collected and recorded in the CRF. Physical examination will include anthropometric measurements (weight and height), assessement of the cardiovascular, respiratory and gastrointestinal systems, as well as skin and central nervous systems as deemed necessary by the study physician.

Assessments in participants who prematurely stop the study
Participants who prematurely stop the study will be asked to come in and complete the study procedures of the week 48 visit. Procedures are described in section 10.

Screening, visit 1 and informed consent (Week -4 to week-1) at SHCS center
Participants must give their written consent by signing the informed consent form prior to any study specific procedure. Results from a blood test performed before the screening visit is accepted for the Simpl'HIV trial if a patient is included in the SHCS and if the time window of -7 to -28 days to the baseline visit is respected. In such cases data should be entered in the database as part of the screening visit.
Screening visit can be done by the study nurse only (the presence of a medical doctor is not obligatory).

Clinical assessments:
-Demographics related data.
Eligibility criteria will be checked by the study physician following the results of the screening visit. If some of the laboratory assessments are not done at the screening visit and this does not impact patient's eligibility, these assessments should be performed at baseline visit. In such cases the results will be entered in the database as part of the screening visit.

Baseline, visit 2 (Day 0) at SHCS center
All assessments made at the screening visit must be reviewed and the eligibility criteria check-list completed by the study physician in order to randomise the patient. The randomisation will be performed by sending a completed electronic randomisation request from the study site in secuTrial. Details will be provided by the sponsor in the Standard Operating Procedure.
The randomisation confirmation will be filed in the study documents. The participant's assigned treatment groups and corresponding randomisation numbers will be recorded in the CRF.

Clinical assessments:
-Eligibility check; -Questionnaires completion by the patient: visual analog scale, patient's monitoring satisfaction; -Adherence check; -Medical history including diagnosis, diseases and concomitant medications. Any ongoing conditions that could be recorded as adverse events during the course of the study should be recorded; -Physical examination and vital signs; -Start DTG+FTC dual maintenance therapy OR remain on standard cART; -Start patient-centered monitoring OR remain on standard monitoring; -Documentation of alternative option(s) chosen for patient-centered monitoring if randomised in patient-centered monitoring; -Study drug distribution and documentation (DTG + FTC or standard cART).

Laboratory assessments:
-HIV-1 RNA in plasma. If the baseline visit is performed within 7 days from the HIV-RNA measurement used for the screening visit, it is not mandatory to repeat the HIV-RNA measurement at the baseline visit. In such cases, HIV-RNA result used for the screening visit will be entered as well for the baseline visit in the database. -Sample plasma and cells sample storage. If a venipuncture is planned at the baseline visit only for storages and the patient is included into the SHCS, plasma and cell sample storage can be drown at the screening visit. -HIV-1 DNA from PBMCs by ddPCR (performed retrospectively) -DTG-related pharmacogenetics host profile will be performed for all patients on DTG. This analysis will be performed retrospectively according to funding availability and only for patients included in the SHCS and who have signed a consent form for genetic studies.

Week 2 (± 3 days)
Clinical assessments: -CNS adverse event questionnaire for patients new to DTG (phone call with study nurse/physician for all subjects, regarless of the monitoring arm after randomisation).

Week 6 (± 7 days)
Clinical assessments: -Adherence check by the study nurse/physician (face-to-face visit or by phone call); -Recording/update of concomitant medications (face-to-face visit or by phone call); -Adverse events recording (face-to-face visit or by phone call); -CNS adverse event questionnaire for patients new to DTG (face-to-face visit or by phone call); -Study drug distribution (DTG + FTC or standard cART) at study center, chosen pharmacy or by mail depending of study arm and option(s) chosen by the patient.

Laboratory assessments (at SHCS center or peripheral laboratory):
- For patients randomised in the patient-centered monitoring arm, study drug distribution and laboratory assessments can be done before clinical assessments but within the time window of the visit.

Weeks 12 and 36 (± 7 days)
Clinical assessments: -Adherence check by the study nurse/physician (face-to-face visit or by phone call); -Recording/update of concomitant medications (face-to-face visit or by phone call); -Adverse events recording (face-to-face visit or by phone call); -Questionnaires completion: visual analog scale, PROQOL-HIV, (face-to-face visit or by phone call); -Study drug distribution (DTG + FTC or standard cART) at study center, chosen pharmacy or by mail depending of study arm and option(s) chosen by the patient; -Patient's monitoring satisfaction.

Laboratory assessments (at SHCS center or peripheral laboratory):
-HIV-1 RNA in plasma -Plasma sample storage; -Dolutegravir and emtricitabine plasma concentration if HIV-1 RNA measurement ≥ 100 copies/ml in plasma; -Genotypic resistance test if 2 consecutive HIV-1 RNA measurements ≥ 100 copies/ml in plasma; -Pharmacogenetic analyses if 2 consecutive HIV-1 RNA measurements ≥ 100 copies/ml in plasma only for patients included in the SHCS and who have signed a consent form for genetic studies; -CD4 count, full blood count, safety serum chemistry (CK, creatinine, ASAT/ALAT, gamma-GT, alkaline phosphatases, glucose and lipids) if patient randomised in standard monitoring arm; -Glucose, and creatinine if patient under DTG and metformine and patient-centered monitoring arm.
For patients randomised in the patient-centered monitoring arm, study drug distribution and laboratory assessments can be done before clinical assessments but within the time window of the visit.

Week 24 (± 7 days) at SHCS center Clinical assessments:
-Adherence session by the study nurse; -Recording/update of concomitant medications; -Adverse event recording; -Physical examination and vital signs; -Study drug distribution and return (DTG + FTC or standard cART) according to site standard practice; -Patient's monitoring satisfaction (possibility to change patient-centered monitoring options).

Laboratory assessments:
-HIV-1 RNA in plasma; -Plasma sample storage; -Dolutgeravir and emtricitabine plasma concentration if HIV-1 RNA measurement ≥ 100 copies/ml in plasma -Genotypic resistance test if 2 consecutive HIV-1 RNA measurements ≥ 100 copies/ml in plasma; -Pharmacogenetic analyses if 2 consecutive HIV-1 RNA measurements ≥ 100 copies/ml in plasma only for patients included in the SHCS and who have signed a consent form for genetic studies; -CD4 count, full blood count, safety serum chemistry (CK, creatinine, ASAT/ALAT, gamma-GT, alkaline phosphatases, glucose and lipids) if patient randomised in standard monitoring arm; -Glucose, and creatinine if patient under DTG and metformine and patient-centered monitoring arm. -Urinary β-HCG in women of childbearing potential.

Drug studies
The Sponsor's SOPs provide more detail on safety reporting.
During the entire duration of the study, adverse events (AE) and serious adverse events (SAEs) are collected, fully investigated and documented in source documents and case report forms (CRF). Study duration encompassed the time from when the participant has been randomized in one study arm, i.e. starting from the baseline visit until the last protocol-specific procedure has been completed, including a safety follow-up period when needed.

Definition and assessment of (Serious) Adverse Events and other safety related events
An Adverse Event (AE) is any untoward medical occurrence in a patient or a clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with the study procedure. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
Adverse Events that need to be reported in this study are listed in the Adverse Event list (see Appendix 6). This list will be used starting from the baseline visit to confirming the absence or presence of any listed adverse event. Spontaneous, non-serious Adverse Events that are not listed in the Appendix 6 list will be collected in the patient's medical file according to local usual practice but will not be reported into the study-related document. Laboratory abnormalities listed in the Adverse Event list, will be reported as Adverse Events if they are at least a grade 3 and if they appear after randomization in the study (i.e. starting from the baseline visit). In case of laboratory abnormality already present befor the randomisation, this will be considered as an adverse event only in case of worsening.
A Serious Adverse Event (SAE) is classified as any untoward medical occurrence that:  results in death,  is life-threatening,  requires in-patient hospitalization or prolongation of existing hospitalisation,  results in persistent or significant disability/incapacity,  results in a congenital anomaly/birth defect, or  is an important medical events that may not be immediately life-threatening or result in death, or require hospitalisation, but may jeopardise the patient or may require intervention to prevent one of the other outcomes listed above should also usually be considered serious. Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation, or development of drug dependency or drug abuse.
SAEs should be followed until resolution or stabilisation. See details in section 10.1.3.

Assessment of Causality of (Serious) Adverse Events and other safety related events
The Study Investigator makes a causality assessment of the event to the study drug and study procedure using the categories based on the ICH E2A guidelines: In case of an Adverse Event at least possibily related to the study drug, DTF and FTC plasma concentration measurement can be performed at trating fisician discretion as standard of care.

Unexpected Adverse Drug Reaction
An unexpected adverse drug reaction is an adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g. Investigator's Brochure for drugs that are not yet approved and Product Information for approved drugs, respectively).

Suspected Unexpected Serious Adverse Reactions (SUSARs)
A SUSAR is an unexpected adverse drug reaction that is at least possibly related to the IMP or the study procedure. The Sponsor-Investigator receives the SAE evaluation about seriousness and causality from the Study Investigator. The Sponsor-Investigator evaluates any SAE that has been reported regarding expectedness. If the event is at least possibly related to the investigational product and is both serious and unexpected, it is classified as a SUSAR.

Assessment of Severity of (Serious) Adverse Events and other safety related events
Assessment of severity of events will be performed on the basis of the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse events (version 2.0, November 2014) (95).
hours. The course and outcome of the pregnancy will be followed up carefully, and any abnormal outcome regarding the mother or the child will be documented and reported to the Sponsor-Investigator. Pregnancies and their outcomes should be followed until resolution or stabilisation. Participants with ongoing pregnancy at week 48 or study discontinuation visit will be further followed up until pregnancy resolution. In case of newborn health problem, the duration of the follow-up can be extended.

Periodic reporting of safety
An annual safety report will be submitted once a year to the leading Ethics Committee by the Sponsor-Investigator. This annual safety report will contain information from all study sites. The Sponsor-Investigator will prepare the annual safety report and distribute it to the participating Investigators.

Follow up of (Serious) Adverse Events and other safety related events
Participants with ongoing AE, SAEs, SUSARs or pregnancy at week 48 or at study discontinuation visit will be further followed until either final outcome or 6 weeks (+/-5 days) after the last patient last visit. Ongoing pregnancies at 48 week visit or at study discontinuation visit will be further followed-up until pregnancy resolution. Extension of this duration can be proposed for event of particular interest for the study. Follow up may include but is not limited to physical examination, laboratory tests, vital signs, telephone calls. Outcomes and resolution of events will be recorded in the Case Report Forms.
In case of lost to follow up, efforts will be made to contact the patient or to ascertain the vital status of the participant.

Hypotheses
-HA1: DTG + FTC maintenance dual therapy is non-inferior to cART in maintaining plasma HIV viral load <100 copies/ml throughout 48 weeks in virologically suppressed patients. -HO1 (tested): DTG + FTC maintenance dual therapy is inferior to cART by 12% in maintaining plasma HIV viral load <100 copies/ml throughout 48 weeks in virologically suppressed patients.
-HA2: Patient-centered monitoring reduces health-costs compared to standard monitoring.
-HO2 (tested): Patient-centered monitoring does not reduce health-costs compared to standard monitoring.

Determination of Sample Size
The first sample size calculation was based on the primary outcome for the comparison between DTG + FTC dual therapy and standard cART, i.e. the comparison between the proportions of patients in the two arms maintaining virologic suppression, using a two-sample proportion test (96). The following assumptions were made:  Power 80%  Significance level 0.025 (one-sided Z test of non-inferiority)  97% of patients with conventional cART will be virologically suppressed at week 48 (<100 copies/ml)  94% of patients on DTG + FTC dual therapy will be virologically suppressed at week 48 (<100 copies/ml)  Non-inferiority margin of 12% (as in previous non-inferiority trials) (97)(98)(99)(100)(101)(102)(103)(104). We chose 12% noninferiority margin because there is no difference in terms of resistance acquisition between 10% and 22% virological failure.
Sample size of 83 patients in each group (total sample size, 166 patients) to achieve 80% power to detect a non-inferiority margin difference between the group proportions of -0.12 was calculated. The power was computed for the case when the actual cART group proportion is 97% and the actual DTG + FTC dual therapy group proportion is 94%. To allow for at least 10% loss to follow-up and also for the randomisation in two steps in this 1:1:1:1 trial, we will aim to recruit a total of 184 patients.
The second sample size calculation was based on the primary outcome for the comparison between simplified monitoring and standard monitoring, i.e. the comparison between mean direct costs in the two arms (105). The following assumptions were made:  Significance level 0.05 (two-sided t-test)  Direct costs are CHF 25,000 per year (standard deviation (SD) CHF 8,000) with conventional monitoring  SDs are equal in the two groups (CHF 8,000) With sample sizes of 92 patients in each group, we will have approximately 55% power to detect a 10% difference in costs, and 99% power to detect a 25% difference in costs. We will also have substantial power to detect small-to-moderate differences in many of the secondary outcomes, e.g. changes in CD4 cell counts or health-related quality of life. The exceptions are rare outcomes such as adverse events, resistance or clinical complications for which the statistical power to detect differences will be low.

Statistical criteria of termination of trial
This is an open label study. The laboratory results that define treatment failure (HIV-RNA) of all participants included will be available within a week to the investigators. A detailed report including a summary of Serious Adverse Events, grade 3/4 Adverse Events, laboratory toxicities as well as virological failures, pregnancies and safety signals will be sent to the DSMB on a 6-monthly basis.
To protect the safety of the study participants, a safety interim analysis on the first 100 patients randomized will be done once reached the end of the time window for their 24 weeks study visit. The following data will be reviewed: Safety data: -Participant recruitment, accrual, retention and withdrawal information -Adverse events (AEs) and serious adverse events (SAEs) -Pregnancies -Laboratory values -Additional virological tests performed outside study schedule -Any other safety-supporting data requested by the DSMB Efficacy data: -HIV-RNA data (primary endpoint measure) -Genotype resistance test data (secondary endpoint) We will also convene the DSMB in the following situations: (1) if > 2 patients experienced virological failure and a new resistances on DTG + FTC dual therapy before the planned interim safety analysis is done; (2) if new published or unpublished data show any major inconvenience of testing a DTG + FTC dual therapy arm.
The DSMB will then give recommendations regarding the continuation, modification or termination of the trial.
Stopping rules: The DSMB may recommend stopping the trial for the following reasons: -The data show a significantly increased risk of serious adverse events in one of the study groups; -On the basis of a positive efficacy result only when the data are truly compelling and the risk of a false positive conclusion is acceptably low. The trial will only be stopped for positive efficacy if a strong statistically and clinically significant difference in virological success is seen between treatment arms; -If interim data suggest that the simplified treatment/monitoring arm under study is of no benefit (trend indicating clear inferiority of the simplified treatment/monitoring arm), or that accrual rates are too low and/or that noncompliance is too great to provide adequate power for identifying the specified benefit, the DSMB may consider whether continuation of the study is futile and may recommend termination on this basis; -It becomes clear that successful completion of the study is not feasible (e.g. there is an excess of patient dropout, missing data, lack of recruitment etc).

Datasets to be Analysed, Analysis Populations
As recommended by the CONSORT statement (106), two analysis sets will be performed: per-protocol (PP) and intention-to-treat (ITT).
For PP analysis, we will exclude patients for the following reasons: patients who discontinue treatment prematurely (< 47 weeks), unless virological failure occurred before, patients with a treatment adherence of less than 80% while on treatment, those who do not have HIV-1 RNA results at week 48 (+/-21 days), unless virological failure occurred before, or patients with major protocol deviation(s) (i.e. any failure to obtain informed consent, violation of any inclusion criteria, not receiving the allocated treatment or monitoring). Per-protocol and intention-to-treat analyses should reach the same conclusion to consider DTG + FTC as non-inferior to standard treatment.
For ITT analysis, all randomized patients will be analysed in the allocated group regardless of any protocol violations.
All drop outs will be described and reasons for their discontinuation will be given where possible.

Primary analysis
As a first step in this factorial trial, we will test for an interaction between the type of drug treatment and the monitoring type in order to assess if treatment effect is different depending on the type of monitoring. If the test is non-significant we will combine the two types of monitoring for the drug therapy comparison and the two drug therapies for the monitoring comparison. Otherwise, the trial will be analysed as a four-arm trial with a hierarchical testing approach.
For the primary comparison of the primary outcome between the two treatment arms, we will obtain the proportion of patients with viral suppression for 48 weeks in each arm, and compute a Mantel-Haenszel risk difference (DTG+FTC -cART) stratified for the monitoring type with a two-sided 95% confidence interval (107). If the lower confidence limit is higher than -12% we will conclude noninferiority. If the lower confidence limit is below -12% we will conclude that DTG + FTC is potentially inferior to cART.
For the secondary comparison of the primary outcome between the two monitoring arms, we will calculate a Mantel-Haenszel test statistics and Mantel-Haenszel risk difference (DTG+FTC -cART) stratified for the type of treatment.
Secondary categorical outcomes (proportions of virological suppression <50 copies/mL both as a standard proportion and as FDA snapshot, of loss of future treatment options, of adverse events, of serious adverse events, of CSN adverse events, of CNS symptoms) between the DTG+FTC and cART groups, and between the patient-centered and standard monitoring groups will also be analysed using the Mantel-Haenszel test statistics and Mantel-Haenszel risk difference (DTG+FTC -cART) stratified for the type of monitoring and type of treatment, respectively.
For continuous outcome variables (CD4 count, HIV-DNA level, total cholesterol, high-density lipoproteine, triglycérides, low density lipoprotein-cholesterol, glucose, Framingham-calculated cardiovascular risk, glomerular function rate, weight, health-related quality of life, treatment satisfaction), we will compare the mean values at 48 months between the DTG+FTC and cART treatment groups and between the patient-centered and standard monitoring groups using linear regression adjusted for the type of monitoring and type of treatment, respectively.
Time to loss of virological response (TLOVR) will be graphically depicted by Kaplan-Meier curves, and evaluated by a univariable and multivariate Cox proportional Hazard model, adjusted for stratified for the type of monitoring and type of treatment.
Predictors of virological failure (nadir CD4 count, baseline HIV-DNA, zenith HIV-RNA, years since HIV infection, years of viral suppression, CD4/CD8 ratio, age, DTG and FTC plasma concentrations, pharmacogenetic analysis, any other relevant clinical or laboratory parameters) will be assessed using forward stepwise multiple logistic regression.
Economic analyses will be performed from the health provider perspective. A multiple linear regression model will be performed to compare the mean direct costs between the two monitoring strategies after adjustment for the treatment arm.
All analyses will be performed in the PP dataset and in the ITT dataset.

Secondary analysis
For categorical outcomes, we will additionally calculate relative risk differences between groups. We will calculate odds ratios from multiple logistic regression models adjusting for the type of monitoring and type of treatment as appropriate. For repeatedly measured categorical outcome variables (virological suppression <50 copies/mL), we will consider a mixed effects logistic regression with a random intercept on the subject to account for within-patient correlations.
For repeatedly measured continuous outcome variables, we will also consider all measurements in a linear mixed effects regression model to account for within-patient correlations. Finally, we will analyse development over time by exploring the functional relationship between outcome and time using fractional polynomials and a treatment-by-time interaction term.
Moreover, we will evaluate all outcomes in crude analyses not adjusting for type of monitoring or type of treatment. Binary outcomes will be compared by the Chi-squared or Fisher's exact test, continuous outcomes by the Student t-test.
Cost-effectiveness of treatment arms (incremental cost-effectiveness ratio) will be calculated by taking the difference in mean costs between patient-centered arm and standard monitoring arm, and between DTG + FTC dual therapy arm and cART arm, and dividing them by the difference in time to loss of virological response (TLOVR) between the study arms. Difference in TLOVR will be assessed by comparing the area under the patient-centered and standard monitoring Kaplan-Meier curves, and under the DTG+FTC and cART Kaplan-Meier curves. Generalised lo-rank test will be used to compare times between groups.

Interim analyses
The DSMB will meet for a single interim safety analysis on the first 100 patients randomized once the end of the time window for their 24 weeks study visit is reached. The Sponsor-Investigator and all Study investigators will receive the related DSMB advice blinded to study arm. In addition to the scheduled meetings, extraordinary meetings may be requested by DSMB members, the Sponsor-Investigator, or the Study Scientific Committee at any time. The DSMB will review the safety data and may make recommendations about the conduct of the trial (study interruption) should any safety concerns be identified. The interim analysis will be prepared by an independent, unblinded statistician.

Safety analysis
The proportion of serious adverse events across the different study time-points will be compared between the two treatment arms by mixed logistic regression model with a random effect on the subject after adjustment for the monitoring strategy.
The proportion of drug-related events across the different study time-points will be compared between the two treatment arms by mixed logistic regression model with a random effect on the subject after adjustment for the monitoring strategy.
The proportion of patients experiencing loss of future drug options defined as new intermediate or high-level resistance to one or more drugs to which the patient's virus was considered sensitive at trial entry will be compared between the two treatment arms by a multiple logistic regression model adjusted for the monitoring strategy.

Deviation(s) from the original statistical plan
A statistical analysis plan will be written before the end of the first year of participants enrolment. It will describe in details the statistical analyses answering the primary research question but also answering secondary research questions. It will detail how data will be described depending on their format. Once data will be available, the statistician in charge of the statistical analyses will apply the statistical analysis plan. Any deviations from the planned analyses will be at least described and justified.

Handling of missing data and drop-outs
The following strategies will be used to replace missing values at the final study timepoint. If HIV-RNA is available at week 36, the value at time 36 will be considered (last observation carried forward). If no data is available at weeks 36 and 48, we will consider these patients as failures. The same approach will be considered for secondary outcomes. For continuous outcomes, we will exclude patients from the analysis if no data is available at weeks 36 and 48. In the snapshot analysis, patients with missing outcome in the time snapshot window will be considered as failures. Sensitivity analyses will be performed to determine whether the conclusions are sensitive to assumptions about the missing-data mechanism. We will compare patient characteristics between the two groups having or not missing data in order to assess their similarity. If differences are outlined, missing data would be considered not at random and some bias in the estimation of treatment effect would be suspected. If not, we will consider the complete case analysis as valid to estimate the noninferiority of DTG+FTC compared to standard treatment.

Case Report Forms
All study data will be entered in an Electronic Data Capture (EDC) system by the study nurse or study coordinator or investigator or the local data manager with no double data entry.
CRFs will be kept current to reflect subject status at each phase during the course of the study. Studyrelated data of the patient will be collected in a coded manner. The names of the patients will not be disclosed. A code (unique) will be attributed to each patient registered.
Persons authorized by the sponsor-investigator to perform data entry or data review will be communicated to the data manager who will provide individual access codes according to the function assigned. CRF data entry authorization will be documented on each delegation log and a list of all authorized persons and their function stored with the data manager.

Source data
Source data must be available at each site to document the existence of the study participants. Source data must include the medical history and treatment of the participant as well as the original documents relating to the study: worksheets (as paper CRF) for screening, baseline, week2, week6, week 12, week24, week 36, week 48 visits and extra visit, study drug discontinuation visit and study discontinuation visit); logs (adherence log, drug accountability log, adverse event log, concomitant medication log); patient diary; cost-related letter from the patient's health insurance company.
The following data will be considered as source documents: patient questionnaires, demographic data, visit dates, participation in study and Informed Consent Forms, SAEs, AEs, adherence log, drug accountability log and concomitant medication log. All other data must be available in the participant's hospital chart.

Analysis and Record keeping / archiving
At interim safety analysis and final analysis, data files will be extracted from the database into statistical packages to be analyzed. The status of the database at this time is recorded in special archive tables.
The study database with all archive tables will be securely stored by the CTU, University of Bern. Essential documents, the trial master file as well as the investigator file for Geneva will be stored at the HIV unit, infectious diseases consultation at the HUG. Investigator files of other Swiss sites will be stored at each site separately. All study data must be archived for a minimum of 10 years after study termination or premature termination of the clinical trial.

Data Management System
The CRFs in this trial are implemented electronically using a dedicated electronic data capturing (EDC) system (secuTrial). The EDC system is activated for the trial only after successfully passing a formal test procedure. All data entered in the CRFs are stored on a Linux server in a dedicated Oracle database.
Responsibility for hosting the EDC system and the database lies with CTU, University of Bern.

Confidentiality, Data Protection (Data security, access and back-up)
The server hosting the EDC system and the database is kept in a locked server-room. Only the system administrators have direct access to the server. A role concept with personal passwords (site investigator, statistician, monitor, administrator etc.) regulates permission for each user to use the system and database as he/she requires.
All data entered into the CRFs are transferred to the database using Secure Sockets Layer (SSL) encryption. Each data point has attributes attached to it identifying the user who entered it with the exact time and date. Retrospective alterations of data in the database are recorded in an audit table.  Time, table, data field and altered value, and the person are recorded (audit trail). A multi-level backup system is implemented.

Electronic and Central Data Validation
Data is checked by the EDC system for completeness and plausibility. Furthermore, selected data points are cross-checked for plausibility with previously entered data for that participant. In addition, central data reviews will be performed on a regular basis to ensure completeness of the data collected and accuracy of the primary outcome data.
Before database lock the PI will validate the collected data with his signature.

Monitoring
For quality control of the study conduct and data retrieval, all study sites will be visited on-site by appropriately trained and qualified monitors. Any findings and comments will be documented in site visit reports and communicated to the local Investigator and to the Sponsor as applicable.
Investigators at the participating study sites will support the Monitor in his/her activities. Prior to study start (first participant enrolled) a plan detailing all monitoring-related procedures will be developed. All source data and relevant documents will be accessible to Monitors and questions of Monitors are answered during site visits.

Audits and Inspections
No audits are foreseen by the sponsor-investigator. The study documentation and the source data/documents are accessible to auditors/inspectors (also CEC and CA) and questions are answered during inspections. All involved parties must keep the participant data strictly confidential.

Confidentiality, Data Protection
Direct access to source documents will be permitted for the purposes of monitoring, audits and inspections. Both ethics committee members and employees must also understand the confidentiality requirements for any information divulged to them. The data generated by this study will be considered confidential by the investigators, except to the extent that it is included in a publication as agreed in the publication policy of this protocol.
All data will be collected without any names and identifying information will not be recorded in transcription of tapes.
The protocol will be accessible to the trial team and all investigators and delegates during and after the course of the study. The dataset will be accessible only to the data manager, the principal investigators, sponsor-investigator and the statistician.

Storage of biological material and related health data
Plasma samples will be stored until at least the publication of the final manuscript

POST-STUDY
The study period ends at the week 48 visit or at the study discontinuation visit.

Antiretroviral treatment and monitoring after the end of the study period
At week 48 or study discontinuation visit, all patients will be offered the possibility to continue their treatment with DTG + FTC dual therapy, or previous-to-study cART regimen, or current cART regimen, or another regimen. This will be decided at the end of study by treating physician in collaboration with the patient. We suggest planning a viral load follow-up 6 weeks after an ARV de-escalating switch or a switch to a different regimen from the previous-to-study cART.
At week 48 or study discontinuation visit, all patients will be offered the possibility to continue their follow-up as standard monitoring or with one or more options from the patient-centered monitoring, according to local possibilities.
The treating physician will schedule follow-up after the end of the study period in any case, frot he following cases: -HIV-RNA ≥ 20 cp/ml, for which the procedure descriped at point 3.6 applies.

Post-study visits
All subjects having concluded the week 48 study visit will give their informed consent to extend the study follow-up to 3 years with one visit per year (i.e. week 96 and 144 visits) coinciding with a standard-of-care follow-up visit. -Adherence questionnaire*; -Patient's weight and blood pressure*.
* Data will be extracted from the SHCS database whenever possible.

Funding
This trial has received funding from the Swiss National Science Foundation. The funding application, review and approval documents as well as the approved budget are stored online (on mysnf.ch) and a copy filed in the trial master file.
Any potential additional funding from SHCS or other institution will be notified to the leading Ethic Committee.

Other Support
The study will be performed within the SHCS network using the local infrastructure of all participating sites.
Nested sub-studies are possible. In such cases the leading Ethics Committee will be notified.

INSURANCE
Insurance will be provided by the Geneva University Hospitals. A copy of the insurance confirmation will be filed in each investigator site file and the trial master file. The insurance certificate is filed at the legal office of the HUG.

STUDY AGREEMENT
The present Protocol acts as an Agreement between all participating Study Sites and the Sponsor. Confidential (see e-mail by Esteban Martinez on 9.2.2017): 2 VF in monoT arm at the end of phase A (90 pts, 24W follow-up). According to DSMB advise (called according to protocol safety rules "DSMB will review the data if the proportion of confirmed virological failure in any of the experimental arms reaches ≥5%"), the Steering Commitee has decided to interrupt the DTG arm and to continue the DOLAM study with two arms: CONTROL