Protease Inhibitor Monotherapy Versus Ongoing Triple-therapy in the Long Term Management of HIV Infection (PIVOT)

Study Overview
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Brief Summary
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The PIVOT trial aims to determine whether a strategy of switching to PI monotherapy is non-inferior to continuing triple-therapy, in terms of the proportion of patients who maintain all the drug treatment options that were available to them at baseline after at least 3 years of follow-up, and to compare clinical events, safety, toxicity and health economic parameters between the two strategies.

Official Title
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A Randomised Controlled Trial of a Strategy of Switching to Boosted PI Monotherapy Versus Continuing Combination ART for the Long-term Management of HIV-1 Infected Patients Who Have Achieved Sustained Virological Suppression on HAART

Conditions
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HIV Infection, Acquired Immunodeficiency Syndrome

Intervention / Treatment
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* Drug: Protease Inhibitor
* Drug: Standard-of-care Antiretroviral therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Vl < 50 for 24 weeks prior to screening CD4 > 100 at screening Exclusion Criteria: Known major protease resistance mutation(s) documented on prior resistance testing if performed (prior resistance testing is not mandatory for trial participation). Previous change in ART drug regimen for reasons of unsatisfactory virological response (patients who have changed regimen for prevention or management of toxicity or to improve regimen convenience are permitted to enter the trial). Previous allergic reaction to a PI. Patient currently using or likely to require use of concomitant medication with known interaction with PIs. Patient requiring treatment with radiotherapy, cytotoxic chemotherapy, or is anticipated to need these during the trial period. Treatment for acute opportunistic infection within 3 months prior to trial screening. Pregnant or trying to become pregnant at the time of trial entry. History of active substance abuse or psychiatric illness that, in the opinion of the investigator, would preclude compliance with the protocol, dosing schedule or assessments. History of HIV encephalopathy with current deficit >1 in any domain of the Neuropsychiatric AIDS Rating Scale (see Appendix 7). Past or current history of cardiovascular disease, or 10 year absolute coronary heart disease risk of >30%, or risk of >20% if the patient has diabetes or a family history of premature ischaemic heart disease or stroke. History of insulin-dependent diabetes mellitus. Patient currently receiving interferon therapy for Hepatitis C virus infection or planning to start treatment for Hepatitis C at the time of trial entry. Co-infection with hepatitis B, defined as Hepatitis BsAg positive at screening or at any time since HIV diagnosis, unless the patient has had a documented Hepatitis B DNA measurement of less than 1000 copies/ml taken whilst off Hepatitis B active drugs. Any other active clinically significant condition, or findings during screening medical history or examination, or abnormality on screening laboratory blood tests that would, in the opinion of the investigator, compromise the patient's safety or outcome in the trial. Fasting plasma glucose >7.0mmol/L at trial screening.

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Protease Inhibitor Monotherapy<br>Ritonavir-boosted protease inhibitor | Drug: Protease Inhibitor<br>* Switch to a regimen comprising a single ritonavir-boosted Protease Inhibitor<br>|
| Active Comparator: Control<br>Standard-of-care triple-therapy regimen | Drug: Standard-of-care Antiretroviral therapy<br>* Regimen should consist of 3 drugs: 2 nucleoside reverse transcriptase inhibitors with either a non-nucleoside reverse transcriptase inhibitor or a protease inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Loss of future drug options | The first occurrence of intermediate to high level resistance to any one or more of the standard antiretroviral drugs (limited to licensed drugs in contemporary use) to which the patient's virus was considered to be sensitive at trial entry (i.e. excluding drug resistance that was known to be present on previous resistance testing). | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death from any cause |  | Up to 5 years | 
| Serious AIDS-defining illness |  | Up to 5 years | 
| Serious non-AIDS defining illness |  | Up to 5 years | 
| Adverse events |  | Up to 5 years | 
| Confirmed Virological rebound |  | Up to 5 years | 
| CD4+ count change |  | Up to 5 years | 
| Health-related Quality of Life change |  | Up to 5 years | 
| Neurocognitive function change |  | Up to 5 years | 
| Cardiovascular risk change |  | Up to 5 years | 
| Health care costs |  | Up to 5 years | 
| HIV VL in Genital Secretions | In a sub-set of participants (n=73):- Compare prevalence of detectable VL and magnitude of viral replication in genital secretions in patients taking PI monotherapy and triple therapy; to test if PI monotherapy is non-inferior to triple therapy. Compare drug levels in genital secretions and plasma. Describe the profile of drug resistance (if any) in patients with detectable VL in genital secretions and to compare this with any previous or subsequent resistance profile in plasma. (Genital Secretions substudy REC # 09/H0305/58) | Week 96 | 
| HIV VL in CSF | In a subset of participants on PI monotherapy (n=40). Estimate the proportion of patients who have detectable HIV viral load in CSF after 48 weeks on PI monotherapy, and to refute the hypothesis that this proportion is greater than 20%. Assess whether CSF markers of CNS immune activation, inflammation and neuronal degeneration are elevated after 48 weeks on PI monotherapy. Assess whether CSF HIV viral load and markers of immune activation, inflammation and neuronal degeneration are elevated in patients with symptomatic CNS disease. (CNS substudy REC # 09/H0305/58). | Week 96 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Protease Inhibitors, RNA virus infections, Virus diseases, Sexually Transmitted Diseases viral, Immune system diseases, Anti-infective Agents, Drug resistance