Efficacy and Safety of 2 Raltegravir Doses in Naive HIV-1-infected Patients Receiving Rifampin for Active Tuberculosis

• Proportion of patients with virologic response with the following definitions: - Plasma HIV RNA <50 copies/ml at week 24 - Rate of strategy discontinuation and treatment changes - Proportion of death - Proportion of patients loss to follow-up [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
• Proportion of patients with virologic response with the following definitions: o Plasma HIV RNA <50 copies/ml o Plasma HIV RNA <400 copies/ml [ Time Frame: 24 and 48 weeks ] [ Designated as safety issue: No ]
• Evolution in HIV RNA and HIV DNA (total and 2 LTR circular) from baseline to week 48 [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
• Rate of viral resistance mutations in the plasma at the time of virologic failure and in comparison with HIV-RNA mutations at W0 [ Time Frame: At the time of virologic failure ] [ Designated as safety issue: No ]
• Evolution of CD4 cell counts from baseline to week 48 [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
• Frequency, type and time to a new AIDS-defining event or death [ Time Frame: Through out the trial ] [ Designated as safety issue: Yes ]
• Frequency, type, time to grade 3 or 4 adverse event [ Time Frame: Through out the trial ] [ Designated as safety issue: Yes ]
• Rate of success of TB treatment [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
• Anti-TB resistance rate [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
• Evolution of raltegravir and efavirenz trough concentration [ Time Frame: Through out the trial ] [ Designated as safety issue: No ]

Raltegravir is a potent antiretroviral agent that could be used as an alternative to efavirenz in HIV-1 infected patients with tuberculosis. However due to pharmacokinetic interactions, the optimal dose of raltegravir to be used in combination with rifampin is currently unknown.

This phase II open-label randomized multicenter trial is designed to estimate the antiviral efficacy of two doses of raltegravir and one dose of efavirenz at week 24, in HIV-1 naive patients co-infected with active tuberculosis (TB) treated with rifampin.

• HIV Infections
• Tuberculosis

• Drug: efavirenz
  tenofovir 245 mg / lamivudine 300 mg / efavirenz 600 mg
• Drug: raltegravir
  tenofovir 245 mg / lamivudine 300 mg / raltegravir 400 mg
• Drug: raltegravir
  tenofovir 245 mg / lamivudine 300 mg / raltegravir 800 mg

• Active Comparator: 1
  efavirenz
  Intervention: Drug: efavirenz
• Experimental: 2
  raltegravir 400 mg
  Intervention: Drug: raltegravir
• Experimental: 3
  raltegravir 800 mg
  Intervention: Drug: raltegravir

Inclusion Criteria:

• Adult patients (at least 18 years old)
• Plasma HIV RNA > 1000 copies/ml
• HIV-1-infection confirmed by ELISA and Western blot or Immunofluorescence
• ART naïve patients or
• ART for less than 3 months and more than 6 months ago ; an HIV resistance genotype at baseline showing no mutation to NNRTI and TDF or 3TC will be required
• For women of childbearing age, negative urinary test for pregnancy and to accept contraceptive methods: condom use and intra-uterine device when possible or declare no wish of pregnancy in the coming year.
• Confirmed or probable TB
• TB treatment including rifampin started since 2 to 8 weeks before randomisation
• Signed informed consent form
• For French patients, to be affiliated to the National Health Care System

Exclusion Criteria:

• HIV-2 infection (single or with HIV-1)
• Woman who is pregnant or likely to become so, is breastfeeding or refuses to use contraception
• ALT>2.5N, Hb <7g/dl, neutrophils < 750/mm3, platelet<50 000/mm3, bilirubin >5N, lipase >3N
• Creatinine clearance <60ml/min as assessed by the Cockcroft method
• Ongoing psychiatric pathology or any condition (including, but not limited to, the consumption of alcohol or drugs) which might, in the investigator's opinion, compromise the safety of treatment and/or patient compliance with the protocol
• Concomitant treatments including phenytoin or phenobarbital (compounds interacting with UGT1A1)
• Prior TB with a Mycobacterium tuberculosis strain resistant to rifampin
• TB treatment started for more than 8 weeks before randomisation

• Gilead Sciences
• Merck