Evaluation of a Simplified Strategy for the Long-term Management of HIV Infection (Simpl'HIV)

Study Overview
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Brief Summary
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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 patient-centered ART laboratory monitoring.

Detailed Description
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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 patient-centered monitoring or continuation of standard monitoring. Patients will be followed during 48 weeks.

Official Title
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Evaluation of a Simplified Strategy for the Long-term Management of HIV Infection: a Non-inferiority, Randomized, Controlled, Open-label Clinical Trial

Conditions
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HIV-1-infection, Antiretroviral Therapy, Maintenance Therapy

Intervention / Treatment
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* Drug: Switch to DTG + FTC
* Other: Patient-centered monitoring


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent as documented by signature; Documented HIV-1 infection; Enrolled in the Swiss HIV Cohorte Study (SHCS) or receiving care from a medical doctor of the SHCS network; ≥ 18 years of age; 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 being allowed during this period if followed by at least 2 results < 50 copies/mL. 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. Exclusion Criteria: HIV-2 infection; Previous ART change for unsatisfactory virological response, i.e. slow initial virological suppression, incomplete suppression or rebound. Change of drug or drug class for convenience or toxic effect prevention or management is allowed. Note: patients with documented genotype(s) presenting only a M184V mutation remain eligible; Creatinine clearance < 50ml/min; ASAT or ALAT >2.5x upper limit of the norm; Known hypersensitivity, intolerance or allergy to DTG or FTC; Known or suspected non-adherence (defined as <80% adherence, i.e. missed doses > 1x/week) to current treatment in the last 6 months; Concomitant use of drugs that decrease DTG blood concentrations including carbamazepine, oxcarbamazepine, phenytoin, phenobarbital, St John's wort and rifampicin; Women who are pregnant or breast-feeding; a. Presence of any INSTI-resistance. Non-availability of INSTI resistance testing is NOT an exclusion criteria. b. Non availability of previous routine resistance test, at least for reverse transcriptase and protease genes. Note: Subjects remain eligible in the absence of any previous resistance test only if they are on their first-line antiretroviral regimen; Evidence of acute or chronic hepatitis B virus infection based on results of serology testing.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: This is a pragmatic multicentre, 2x2 factorial randomized controlled trial with 1:1:1:1 randomization. A sample size of 92 patients in each group will be required to demonstrate non-inferiority with a non-inferiority (NI) margin of 12%.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Continuing cART + Standard monitoring<br>Patients randomized to this arm will continue their current standard ART regimen (cART) and will continue a standard 3-monthly routine safety biological monitoring (including CD4 cell count, fasting lipids and glucose, renal and hepatic function tests) at their SHCS site. | |
| Experimental: Continuing cART + Patient-centered monitoring<br>Patients randomized to this arm will continue their current cART and will have immunological and safety blood examinations performed once per year and at least one options (decentralised venipuncture and blood tests, delivery of ARV drugs by mail and interview by phone or skype call) for weeks 6, 12 and 36 | Other: Patient-centered monitoring<br>* Immunological and safety blood examinations performed only once per year at least one options (decentralised venipuncture and blood tests, delivery of ARV drugs by mail and interview by phone or skype call) for weeks 6, 12 and 36<br>|
| Experimental: Switch to DTG+FTC + Standard monitoring<br>Patients randomized to this arm will be switched to DTG + FTC dual maintenance therapy and will have immunological and safety blood examinations performed once per year and at least one options (decentralised venipuncture and blood tests, delivery of ARV drugs by mail and interview by phone or skype call) for weeks 6, 12 and 36 | Drug: Switch to DTG + FTC<br>* Switch from standard cART to DTG + FTC dual maintenance therapy.<br>|
| Experimental: Switch to DTG+FTC + Patient-centered monitoring<br>Patients randomized to this arm will be switched to DTG + FTC dual maintenance therapy and will have immunological and safety blood examinations performed at screening and at week 48. In addition, patients will be ask to choose at least one of the following alternative options for weeks 6, 12 and 36: decentralised venipuncture and blood tests, delivery of ARV drugs by mail and Assessment and clinical interview by phone or skype call | Drug: Switch to DTG + FTC<br>* Switch from standard cART to DTG + FTC dual maintenance therapy.<br>Other: Patient-centered monitoring<br>* Immunological and safety blood examinations performed only once per year at least one options (decentralised venipuncture and blood tests, delivery of ARV drugs by mail and interview by phone or skype call) for weeks 6, 12 and 36<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of DTG-based maintenance therapy (< 100 copies/ml) | Proportion of patients maintaining HIV-RNA <100 copies/ml throughout 48 weeks | 48 weeks | 
| Costs of a patient-centered ART monitoring | Direct costs of the two study arms from the health care system perspective at week 48 | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of DTG-based maintenance therapy (<50 copies/ml) | Proportion of patients maintaining HIV-RNA <50 copies/ml throughout 48 weeks | 48 weeks | 
| Efficacy of DTG-based therapy (<50 copies/ml) by FDA snapshot analysis | Proportion of patients with HIV-RNA < 50 cp/ml at week 48 | 48 weeks | 
| HIV-RNA >100 copies/ml as time to loss of virological response (TLOVR) | defined as the first of the two-confirmed HIV-RNA >100 copies/ml (at least two weeks apart) | 48 weeks | 
| Change in CD4 cell count | from baseline to week 48 | 48 weeks | 
| Change in HIV-DNA | from baseline to week 48 | 48 weeks | 
| Change in lipidic profile | from baseline to week 48 | 48 weeks | 
| Change in glucose profile | from baseline to week 48 | 48 weeks | 
| Change in Framingham-calculated cardiovascular risk | from baseline to week 48 | 48 weeks | 
| Change in glomerular function rate | from baseline to week 48 | 48 weeks | 
| Proportion of patients with an adverse event | throughout week 48 | 48 weeks | 
| Proportion of patients with a severe adverse event | throughout week 48 | 48 weeks | 
| Proportion of patients with CNS adverse event | throughout week 48 | 48 weeks | 
| Proportion of patients new to DTG with CNS symptoms | at 2 and 6 week | 6 weeks | 
| PROQOL questionnaire | from baseline to weeks 12 and 48 | 48 weeks | 
| Patient's monitoring satisfaction for pts in the patient-centered monitoring arm | from baseline to weeks 24 and 48 | 48 weeks | 
| Global satisfaction of the monitoring | at week 48 | 48 weeks | 
| Proportion of patients in the patient-centered monitoring arm expressing willingness to change monitoring options | Monitoring satisfaction throughout 48 weeks | 48 weeks | 
| Patient's treatment satisfaction at week 48 | at week 48 | 48 weeks | 
| ARV treatment in the post study | ART decided to be used in the post study period | 48 weeks | 
| Study satisfaction | at week 48 | 48 weeks | 
| Cost-effectiveness of study arms | at week 48 | 48 weeks | 
| Change in patient weight | from baseline to week 48 | 48 weeks | 
| Adherence questions | Patient adherence to treatment throughout 48 weeks of follow-up | 48 weeks | 
| Number of study-related extra clinical visits | performed outside trial scheduled throughout 48 weeks | 48 weeks |