Long Term Treatment Interruptions
Long Term Treatment Interruptions
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.
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.

 We will conduct a controlled, prospective and randomized trial on a cohort of chronically HIV
 infected individuals on effective HAART to address most of these open questions. We will
 apply an individualized pulse therapy strategy, driven by CD4 + cell count, and will compare
 it with conventional continuous HAART.

 Study objectives

 Primary objective of the study 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
 that 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 + loss and HIV replication after treatment interruption

 As the study wants to enroll patients strictly reflecting the population of HIV infected
 individuals, previous mono or dual therapies as well as the presence of co-morbidities such
 as HBV and HCV co-infection do not constitute exclusion criteria, but will be recorded.

 Study design

 This is a multicenter, randomized, controlled, open, comparative study. The trial will have a
 follow-up of 5 years.

 Patients will be monitored according to the international and local guidelines for HIV
 infection as far as timing and type of laboratory and clinical controls. Laboratory exams
 will be decided locally and only a few key tests are required for the study. The timing of
 laboratory evaluation will be 1 and 2 months after each treatment interruption and thereafter
 every 2 months in the STI arm and every 4 months in the control group. All data will be
 stored in a computerized data-base.

 Study arms and management of the study

 Patients will be randomized in the ratio 1: 2 to one of the following treatment arms:

 1. Continuing their ongoing HAART (control)

 2. Long term treatment interruption (STI)

 Randomization will be accomplished centrally according to a pre-determined,
 computer-generated random list.

 In the control group, patients will be allowed to change therapy for virological,
 toxicological or personal reasons. All variation will be recorded. Patients changing therapy
 will be still included in the ITT analysis, but will be considered failures in the AT
 analysis. Patients stopping therapy, for any reason and not resuming it within 3 months will
 be considered as failures for both the ITT and AT analysis In the STI arm, patients will stay
 off therapy until their CD4 count drop < 350 cells/mcL (one measurement will be considered
 sufficient). At that time point patients will resume the HAART regimen they were assuming
 before the STI period and will continue HAART until their CD4 count raises > 600 cells/mcL
 and their plasma HIV-RNA drops 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 160 patients will be allocated in
 the STI arm and 80 patients in the control arm.

 End points and evaluation criteria

 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.

 Duration of the study

 Treatment will be continued for 5 years under the study conditions. Patients completing the
 study period and still responding to therapy will be kept on the same regimen.

 Statistical evaluation of the study will be performed yearly. A first interim analysis will
 be performed when the mean follow-up will reach 3 years.

 Monitoring

 Laboratory tests during the study period will be performed in he fasting state. The following
 tests and procedures are required and will be recorded in the electronic data base. It is
 also advised to perform on regular basis haemogram, renal function tests, blood glucose and
 amylase. Other test could be performed according to local needs or particular situations
 related to the specific management of single patients:

 Baseline (all patients)

 1) Informed consent and treatment randomization 2) Biochemical analysis: ALT, AST, total
 cholesterol and HDL, triglycerides 3) CD4 count, CD8 count 4) Plasma HIV-RNA 5) Clinical
 evaluation, anamnestic and demographic data: sex, age, risk factor for HIV infection, CDC
 AIDS classification, time on ART, time on current HAART, previous antiretroviral drugs,
 previous sub-optimal ARTs, current antiretroviral drugs, presence and grade of lipodystrophy,
 time with HIV-RNA below detection, nadir CD4, CD4 at start of antiretroviral therapy.

 1. month after each STI (only STI group) 1) CD4 count, CD8 count

 2. months after each STI (only STI group) 1) Biochemical analysis: ALT, AST, cholesterol
 (total and HDL), triglycerides 2) CD4 count, CD8 count 3) Plasma HIV-RNA, Genotype 4)
 Clinical evaluation: disease progression, lipodystrophy assessment

 Every 2 months thereafter (STI group) or every 4 months from baseline (control group)

 1. Biochemical analysis: ALT, AST, cholesterol (total and HDL), triglycerides

 2. CD4 count, CD8 count

 3. Plasma HIV-RNA

 4. Clinical evaluation: disease progression, lipodystrophy assessment

 Additional tests

 Additional tests will be requested in specific cases:

 1. a second genotype after 4 months from the initiation of the STI period will be performed
 in all patients showing a major mutation in the genotype performed 2 months after STI
 start

 2. a genotype will be performed in all patients either in the STI or in the control group
 showing a viral load above 1000 copies/ml after a continuous treatment period (on drugs)
 > 4 months.

 Statistical considerations

 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%. According to the model published in Controlled Clinical Trials 1982; 3:
 345-353,320 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. Chi-square or Fisher's
 exact test that will be used to analyze all categorical variables. Time to treatment failure
 will be estimated using Kaplan-Meier product-limit estimates (that will be presented
 graphically). The log-rank test will be used to assess the difference between the survival
 curves for each arm, while ANOVA test and Student's t test will be used for continuous
 variables unless the variables will not be normally distributed, in which case the
 Kruskal-Wallis and Mann-Whitney U tests will be used. Logistic regression analysis (forward
 stepwise model) will be used to evaluate the relationship between variables and outcome.

 All tests will be two-sided and a P value inferior to 0.05 will be regarded as significant.

 The analysis of data will be performed by the proposing Study Center with the SPSS
 statistical software package for Windows, version 13.0.

 Drugs

 This is a spontaneous study. It is proposed that all drugs will be dispensed according to
 standard procedures.

 Data use

 Data will be used for scientific porpoises only. The analysis will be performed yearly and
 the results will be disclosed to the major participating groups for discussion and comments.
 The type and timing of publication of data will be agreed among the participants to the
 study. The authorship of each presentation will be agreed among participants. It is
 foreseeable that no more than 10 authors will be included for each publication. The number of
 authors for each group will be proportional to the number of patients included at the site.
 All participants will be acknowledged as members of the study group. The principal
 investigator at each site will be responsible for indicating the researchers to include as
 authors.
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