Strategic, Long Term, Immunologically Driven Treatment Interruptions in Patients on Effective HAART: A Controlled, Randomized Study
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- Enrollment
- 320
- Locations
- 1
- Primary Endpoint
- The primary outcome will be clinical response: Death, ADE, pathology requiring hospital admission
Study Overview
Brief Summary
LOTTI study Centers
This a multicenter, multinational study.
Clinical phase: III
Objectives
The primary objective is to compare efficacy and safety of continuing a conventional HAART in chronically infected HIV patients with a therapeutic strategy based on long term, immunologically driven treatment interruptions.
Secondary objectives are:
- To verify the risk of developing viral resistance
- To verify the effect of the two strategies on metabolic parameters
- To verify the possibility to steadily discontinue antiretroviral therapy in patients who started it with baseline immunological values higher than those currently recommended by international guidelines for HIV treatment
- To identify predictive variables of the possibility to safely discontinue antiretroviral therapy
- To verify the dynamic of CD4+ cell loss and HIV replication after treatment interruption
Number of Patients: A total of 320 patients.
Study design:
Controlled, Randomized, Open study The study will last 5 years
Treatment arms:
Patients will be randomized in a ratio 1:1 to one of the two treatment arms Control group continuing the ongoing therapy STI group performing long term CD4 guided structured treatment interruptions In the STI arm patients will stay off therapy until their CD4 count will drop < 350 cells/mcL (one measurement will be considered sufficient). At that time point patients will resume the HAART regimen they were assuming before STI and will continue HAART until they CD4 count will raise > 600 cells/mcL (at least 2 consecutive measurements 2 months apart) and their HIV-RNA will drop below the detection limit of 50 copies/ml (one measurement will be considered sufficient). When both the CD4 count and the viral load will be within these pre-set values they will stop therapy again. There is no limit to the number of interruptions and re-start cycles during the study period
End points:
The primary end-point for the evaluation of the main objective of the study will be clinical. The primary outcome measure will be based on the occurrence of a clinical end-point defined as: disease progression (occurrence of any AIDS defining event), death for any cause or the occurrence of clinical events requiring hospital admission
The secondary objectives of the study will be evaluated on the basis of:
- Mean variation of blood cholesterol and triglycerides from baseline values.
- Development of lipodystrophy or modification of a pre-existing lipodystrophy
- Time off therapy.
- Variation of CD4 counts and HIV-RNA levels
- Genotypic tests to be performed in the case of HIV-RNA > 1000 copies/ml while on therapy for at least 4 months or one month after each treatment interruption.
Statistics:
The study is powered to evaluate equivalence between the two strategies under the assumption that, in the control arm, the primary end-point would be observed in a proportion of subjects < 7% and that the same proportion in the STI arm would not exceed 10% with a maximum allowed 95%CI of 12%. 320 patients will be needed for alfa = 5% and 1-beta = 80%. The primary analysis will be made according to the intention-to-treat approach and therefore no correction for eventual drop outs is needed. In addition, a secondary per-protocol analysis will be performed.
Detailed Description
Rationale
As the current regimens cannot eradicate HIV infection, persons living with HIV are doomed to assume chronic therapies with often very demanding daily schedules. In the long run, this may lead to reduced adherence to therapy, to incomplete suppression of viral replication and to the emergence of resistant viruses that can vanish the patients' efforts. Furthermore with continued exposure to antiretroviral drugs, patients have begun to experience new adverse effects including body fat redistribution, dislipidemia, diabetes, insulin resistance, osteopenia and the fear of unexpected complications such as cardiovascular diseases has raised. A variety of strategies has emerged to try to help the long-term management of HAART. Researchers have focused their attention on the development of simpler regimens. An alternative approach involves various types of structured treatment interruptions (STI). Several different roles have been claimed for STIs. They have been postulated to enhance specific immune response and allow control of viral replication, in the absence of continuous HAART, in seroconverters. In advanced treatment failures STIs has been suggested to favor the overgrowth of wild-type virus in the peripheral circulation and thus facilitate the "disappearance" of resistance mutations. In chronically infected patients without virologic failure STIs have been explored to boost HIV specific immune responses and, more recently, to reduce drug exposure, promote adherence and minimize drug-related morbidity .
Various strategies with fixed intervals for on and off periods, or with specific thresholds, either immunologic or virologic, for re-initiation of therapy have been explored.
To date, unanswered questions about STIs or even pulse therapy include the risk of exposing patients to differential drug levels which may enhance selection of resistant mutants, the effects of re-seeding of viral reservoirs, the real extent of the assumption that less drug is associated with less toxicity or better adherence, and the overall outcome compared to continuous HAART.
Finally STIs and pulse therapy may result strictly linked with questions raised by new treatment recommendations: what to do with individuals who began therapy at a CD4 + cell level above the currently recommended threshold, and how to manage those patients who, under HAART, have gained a CD4 cell count far above this threshold.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Age > 17 years
- •Informed consent signed
- •Effective ongoing treatment (HIV-RNA < 50 copies/ml). Treatment must be based on any triple drug therapy. Patients must be on the same steady therapy for at least 3 months.
- •Current CD4 cell count above 600 cells/mcL and nadir of CD4 cell count > 200 cells/mcL
Exclusion Criteria
- •Childbearing or breastfeeding. Women of childbearing potential will be asked to adopt effective contraceptive methods or behaviors
- •Any ongoing grade 4 (WHO) AE or laboratory abnormality with the exclusion of cholesterol, triglycerides for which a grade 3 (AHA) level will be considered an exclusion criteria.
- •Previous diagnosis of AIDS
- •Patients with HBV coinfection on active anti-HIV treatment with either lamivudine and/or tenofovir
Arms & Interventions
1
STI
Intervention: STI (Other)
2
stable HAART, Any registered regimen containing NRTIs (AZT or D4T or 3TC or TDF or DDI), NNRTIs (EFV or NVP) or PIs (RTV-boosted ATV; IDV; LPV, fosAPV, SQV; unboosted ATV or NFV)is allowed according to international guidelines
Intervention: stable HAART (Drug)
Outcomes
Primary Outcomes
The primary outcome will be clinical response: Death, ADE, pathology requiring hospital admission
Time Frame: 5 years
Secondary Outcomes
- Time off therapy, variation of CD4 counts and HIV-RNA levels(5 years)
- Mean variation of blood cholesterol and triglycerides from baseline values. Development of lipodystrophy or modification of a pre-existing lipodystrophy(5 years)
- Genotypic tests to be performed in the case of HIV-RNA > 1000 copies/ml while on therapy for at least 4 months or one month after each treatment interruption.(5 years)