BASTA Study on STI in HIV Infected Patients
Condition: HIV Infection
MeSH terms: HIV Infections
Study type: Interventional
Phase: Phase 3

Summary: 
      This is a single center, independent study. 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.
      Evaluation will be based on clinical, immunological and virological response.

      Patients will be randomized in a ratio 1:2 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 < 400 cells/mcL. 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
      > 800 cells/mcL and their HIV-RNA will drop below the detection limit of 50 copies/ml. 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 The study is powered to evaluate equivalence between the two strategies
      under the assumption of a failure proportion in the control arm at each time point not
      greater than 5% and a maximum allowed difference of 15%.
    

Detailed description: 
      Study objectives

      Primary objective of the study is:

      To compare efficacy (clinical and immunological) and safety of continuing a conventional
      HAART in chronically infected HIV patients with a therapeutic strategy based on long term,
      immunologically driven treatment interruptions. To verify the risk of developing viral
      resistance

      Secondary objectives are:

      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 To verify costs connected to the strategy

      Inclusion and exclusion criteria

      a. Inclusion i. Age > 17 years ii. Informed consent signed iii. 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.

      iv. Current CD4 cell count above 800 cells/mcL b. Exclusion i. Childbearing or breastfeeding.
      Women of childbearing potential will be asked to adopt effective contraceptive methods or
      behaviors ii. 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.

      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 randomized, controlled, open, comparative study. The trial will have a follow-up of
      4 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. 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 locally
           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 as well as to comply with new indications from
      international guidelines. 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 AT analysis In the STI arm, patients will stay off
      therapy until their CD4 count drop < 400 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 (unless judged as no more of choice according to new international
      guidelines) and will continue HAART until their CD4 count raises > 800 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 100 patients will be allocated in the STI arm and
      30 patients in the control arm.

      End points and evaluation criteria

      The primary end-points for the evaluation of the main objective of the study can be divided
      in short term end points and long term end points:

      The primary short term outcome measure will be the proportion of subjects maintaining at each
      time-point (every 4 months) a CD4 + cell count above 400 cells/mcL. The trial power is
      calculated on this end point.

      On the long term, the primary outcome measure will be based on the occurrence of clinical
      end-points including: disease progression defined as the occurrence of any AIDS defining
      event and death. The occurrence of grade 4 (WHO) adverse events limiting the possibility to
      maintain the patient in the randomized arm will also be considered in AT analysis.

      Virologic failure with the selection of resistance conferring mutations is the second
      long-term primary end-point. Genotypic tests will be performed in the case of HIV-RNA > 1000
      copies/ml while on therapy for at least 6 months (in either group).

      The secondary objectives of the study will be evaluated on the basis of:

      Mean variation of blood cholesterol and triglycerides from baseline values. For these
      parameters the proportion of subjects with a value above grade 2 (AHA) will be also used as
      evaluation criteria.

      Development of lipodystrophy or modification of a pre-existing lipodystrophy Time off therapy
      Economic evaluation 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 4 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.

      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) i. Informed consent and treatment randomization ii. Biochemical
      analysis: ALT, AST, total cholesterol and HDL, triglycerides iii. CD4 count, CD8 count iv.
      Plasma HIV-RNA v. 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) i. CD4 count, CD8 count, HIV-RNA

        2. months after each STI (only STI group) i. Biochemical analysis: ALT, AST, cholesterol
           (total and HDL), triglycerides ii. CD4 count, CD8 count iii. Plasma HIV-RNA, Genotype
           iv. Clinical evaluation: disease progression, lipodystrophy assessment Every 2 months
           thereafter (STI group and control group) i. Biochemical analysis: ALT, AST, cholesterol
           (total and HDL), triglycerides ii. CD4 count, CD8 count iii. Plasma HIV-RNA iv. Clinical
           evaluation: disease progression, lipodystrophy assessment Additional tests

      Additional tests will be requested in specific cases:

      i. 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
      ii. 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) > 5
      months.

      Statistical considerations

      The study is powered to evaluate equivalence between the two strategies under the assumption
      of a failure proportion in the control arm at each time point not greater than 5% and a
      maximum allowed difference of 15%. Equivalence will be defined on the basis of the 95%
      confidence interval.

      According to this hypothesis with alfa = 5% and 1-beta = 80% a minimum of 70 patients will be
      needed. 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. The primary outcome measure
      (the proportion of patients with CD4 + cell counts above 400 cells/mcL) will be analyzed by
      means of Chi-square or Fisher's exact test that will be used to analyze all other categorical
      variables, too. 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 Mann-Whitney U tests will be used. Logistic regression analyses (forward
      stepwise model) will be used to evaluate the relationship between variables and outcome.
      Comparisons between pairs of groups will bee performed only in the case of a multiple test
      yielding a statistically significant result.

      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 10.0.

      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 purposes only. The analysis will be performed yearly. 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. All participants will
      be acknowledged as members of the study group.
    

Intervention name(s): STI (structured Treatment Interruption)
Intervention type(s): Procedure
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: CD4-guided STI; Keywords:; HAART; Clinical outcome; Resistance; Costs; Prognostic factors; pulse therapy; treatment experienced; treatment interruption