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CCR5 Antagonism to Decrease the Incidence of the Immune Reconstitution Inflammatory Syndrome in HIV-Infected Patients

18 Years
Open (Enrolling)
Immune Reconstitution Inflammatory Syndrome, HIV, HIV Infections

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Trial Information

CCR5 Antagonism to Decrease the Incidence of the Immune Reconstitution Inflammatory Syndrome in HIV-Infected Patients

This is a randomized, double blind, placebo-controlled, multicenter study testing the
utility of a CCR5 antagonist (Maraviroc) as an adjuvant to a standard HAART regimen to
decrease the incidence of Immune Reconstitution Inflammatory Syndrome (IRIS) in HIV-infected
patients naïve to antiretroviral treatment. The study duration will be 60 weeks, 276
subjects (138 per arm) will be recruited. The population included will be HIV-infected
patients starting antiretroviral (ARV) therapy at the participating centers in Mexico and
South Africa with a CD4 T cell count <100 cells/ul. Subjects will be randomized to receive
either Maraviroc (study drug) or placebo in addition to background ARV therapy. The
background antiretroviral regimen for all subjects will be: Efavirenz 600mg QD + Tenofovir
300 mg / Emtricitabine 200 mg QD; subjects will be randomized to one of the following arms:
Arm A: background ARV + maraviroc 600mg po BID; Arm B: background ARV + placebo po BID.
Patients will be followed for 48 weeks. The primary endpoint will be the occurrence of a
defined IRIS event by week 24 of follow up. The success of the ARV therapy will also be
evaluated by virologic and immunologic response at 24 and 48 weeks. Three immunology
sub-studies are planned: 1) Sub-study A will be conformed by a subgroup of 40 subjects (20
from Mexico and 20 from South Africa), additional blood sampling will be performed to
evaluate expression of immune activation markers; movement of central memory T cells into
cell cycle and frequencies of expandable pathogen-reactive CD4+ and CD8+ T cells in
circulation; 2) Sub-study B will be conformed by another subgroup of 60 subjects (all from
South Africa), additional blood sampling will be performed to evaluate monocyte and CD4 T
cell gene expression as related to activation-induced apoptosis and cytokine secretion.; 3)
Sub-study C will evaluate the incidence of thromboembolic disease in the study patients
along with baseline evaluation of possible bio-markers of pro-coagulant state.

Inclusion Criteria:

- HIV-1 infection, as documented by any licensed rapid test kit and confirmed by
Western blot or ELISA test kit at any time prior to study enrollment.

Plasma HIV-1 RNA is acceptable as an alternative confirmatory test.

- Men and women age > 18 years.

- Have not received any antiretroviral treatment before entering the study.

- Patients who received Single dose nevirapine or any duration of AZT for PMTC will not
be considered ARV naïve.

- CD4+ cell count of
- HIV RNA level > 1,000 copies/mL obtained within 90 days prior to study entry.

- Patients with an opportunistic or HIV-related infection may be included according to
the clinical judgment of the main investigator in each center when the patient is
ready and able to start ARV therapy.

- Laboratory values obtained within 30 days prior to study entry:

- Absolute neutrophil count (ANC) > 500/mm3.

- Hemoglobin > 8.0 g/dL.

- Platelet count > 50,000/mm3.

- AST (SGOT), ALT (SGPT), and alkaline phosphatase minor of 5 times ULN.

- Total bilirubin minor of 2.5 times ULN.

- Creatinine clearance minor of 50* mL/min as estimated by the Cockcroft-Gault
equation or Creatinine Clearance > 50ml/min as calculated by a formal creatinine
clearance measurement

- All women of reproductive potential (have not reached menopause or undergone
hysterectomy, oophorectomy, or tubal ligation) must have a negative serum or urine
b-HCG pregnancy test performed within 7 days before study entry.

- Female subjects who are not of reproductive potential (have reached menopause or
undergone hysterectomy, oophorectomy, or tubal ligation) or whose male partner has
undergone successful vasectomy with resultant azoospermia or has azoospermia for any
other reason, are eligible without requiring the use of contraception. Documentation
of menopause, sterilization (hysterectomy, oophorectomy, tubal ligation, or
vasectomy) and azoospermia by patient-reported history is acceptable.

- All subjects must agree not to participate in a conception process (i.e., active
attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization),
and if participating in sexual activity that could lead to pregnancy, the female
study volunteer/male partner must agree to use a form of contraception as specified
in the note below while receiving protocol-specified medication(s) and for one month
after stopping the medication(s).

- Ability and willingness of subject or legal guardian/representative to give written
informed consent.

Exclusion Criteria:

- Pregnancy and breast-feeding.

- Active neoplasia or previous history of neoplasia. (Except localized non visceral
Kaposi´s Sarcoma; localized squamous or basal cell carcinoma of the skin, or
intraepithelial cervical neoplasia grade III or less).

- Use of the following drugs within 180 days prior to study entry: systemic cancer
chemotherapy, systemic investigational agents, and immunomodulators (growth factors,
immune globulin, interleukins, interferons).

- Use of systemic corticosteroids in the last 2 weeks prior to randomization.

- Decompensated liver disease (defined as stage C of Child-Pugh classification) at the
beginning of the study.

- An altered mental status that in the opinion of the investigator, will compromise the
adherence to the protocol.

- Allergy/sensitivity to study drug(s) or their formulations that cannot be substituted
by another agent as described in section 5.1

- Active drug or alcohol use or dependence that, in the opinion of the investigator,
would interfere with adherence to study requirements.

- Serious illness that renders a subject unable to take the antiretroviral study

- Serious medical illness that in the opinion of the investigator compromises the
adherence and/or follow up of the protocol.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Prevention

Outcome Measure:

Time to occurrence of an IRIS event

Outcome Time Frame:

The initial 24 week period of observation

Safety Issue:


Principal Investigator

Ian Sanne, MBBCH, FCP

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of the Witwatersrand. Themba Lethu Clinic.


Mexico: Ministry of Health

Study ID:




Start Date:

December 2009

Completion Date:

April 2013

Related Keywords:

  • Immune Reconstitution Inflammatory Syndrome
  • HIV
  • HIV Infections
  • Immune reconstitution inflammatory syndrome
  • CCR5 antagonist
  • Maraviroc
  • HIV
  • treatment naive
  • HIV Infections
  • Acquired Immunodeficiency Syndrome
  • Immune Reconstitution Inflammatory Syndrome



NIH/NIAD Bethesda, Maryland  20892
Center for AIDS Research. Case Western Reserve University Cleveland, Ohio  44106
HIV-1 Immunopathogenesis Laboratory. The Wistar Institute Philadelphia, Pennsylvania  19104
Center for Clinical Epidemiology and Biostatistics. University of Pennsylvania School of Medicine Philadelphia, Pennsylvania  19104