Pilot Study of a Raltegravir Based NRTI Sparing Regimen

This pilot study will provide data on the safety and efficacy of the combination of Raltegravir (RAL) 400mg BID + Atazanavir (ATV) 300 mg BID in Antiretroviral (ARV)-experienced subjects that have a suppressed HIV viral load on a Ritonavir (RTV) boosted Protease Inhibitor (PI) based regimen who are then switched to a regimen of RAL 400mg BID +ATV 300mg BID.

The purpose of this pilot study is to compare the virological efficacy, as measured by the proportion of patients with plasma HIV-RNA below the limit of detection (<50 copies/mL), of two ARV regimens; patients are randomized to remain on regimens containing N(t)RTI(s) + PI/r or switch to Raltegravir + ATV but without N(t)RTI(s).

Study Arms:

1. N(t)RTI(s) based backbone + PI/r
2. Raltegravir (RAL) 400mg BID + atazanavir (ATV) 300 mg BID

Antiretroviral (ARV) treatment guidelines currently recommend ARV regimens containing a Nucleos(t)ide Reverse Transcriptase Inhibitors [N(t)RTI(s)] based backbone with a Non Nucleoside Reverse Transcriptase Inhibitor (NNRTI) or ritonavir boosted Protease Inhibitor (PI/r).(1) However, significant toxicity has been associated with N(t)RTI(s) and PI/r containing regimens. N(t)RTI(s) can cause lipoatrophy, lipid elevations, renal toxicity, neuropathy and lactic acidosis.(1) These toxicities have required clinicians and HIV-infected individuals to use alternative ARV regimens that do not use N(t)RTI(s). PIs are known to cause gastrointestinal side effects, dyslipidemia, and fat maldistribution (lipodystrophy).(1) The DHHS HIV treatment guidelines recommend that PIs should be given with a low dose of ritonavir (RTV). RTV is a PI that has an inhibitory effect on cytochrome P-450 3A4 isoenzyme which metabolizes most PIs. The addition of RTV serves as a pharmacokinetic "booster" by increasing PI drug concentrations.(1) However, RTV is known to increase PI side effects, elevate lipid levels and has significant drug-drug interactions with many medications given to HIV+ individuals.(1) These RTV drug interactions can complicate the medical care of an HIV-infected individual.

Raltegravir (RAL) is a recently FDA approved antiretroviral agent that inhibits HIV replication by blocking the integration of HIV proviral DNA into the host cell chromosomal DNA. RAL does not exhibit cross resistance to other ARV classes and thus has been initially used in HIV-infected individuals that are infected with drug resistant HIV strains. Recently published data on the use of RAL(2,3)in HIV-infected subjects with known ARV drug resistance or those without ARV drug resistance4 demonstrates that RAL is a potent agent, suppressing HIV viral loads in the majority of subjects and having excellent CD4 cell responses.(2-4) RAL is metabolized through glucuronidation by the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) enzyme pathway.(5)ATV is a known inhibitor of this enzyme pathway. ATV will increase RAL levels,(5) however, the current DHHS HIV treatment guidelines do not recommend a change in the dose of RAL if given with ATV as persons receiving ATV and RAL have demonstrated good tolerability of the combination and low side effect profiles.(1-3,5)

The availability of RAL provides an opportunity to examine alternative ARV strategies that may be equally efficacious and less toxic than those currently recommended in HIV treatment guidelines. Such combinations might include RAL+ATV regimen without a concomitant N(t)RTI(s) based backbone and/or the inclusion of RTV. However, there is little data available to date regarding such a combination. HIV care providers have already begun to use the combination of RAL+ unboosted ATV as the patients they care for are intolerant of RTV or have had major side effects/toxicity with N(t)NRTIs. More investigation is required to determine if RAL+ATV is an efficacious and safe alternative to RTV boosted PI based ARV strategies. Before a RAL based strategy that does not include N(t)RTIs or RTV can be compared to other ARV class strategies for long-term efficacy outcomes, preliminary data on a RAL+ATV based regimen is needed. This pilot study will provide data on the safety and efficacy of the combination of RAL 400mg BID + ATV 300 mg BID in ARV-experienced subjects that have a suppressed HIV viral load on a RTV boosted PI based regimen who are then switched to a regimen of RAL 400mg BID +ATV 300mg BID.

• Acquired Immune Deficiency Syndrome
• AIDS
• Human Immunodeficiency Virus
• HIV Infections

• Drug: Raltegravir
  400 mg BID
  Other Name: Isentress
• Drug: Atazanavir
  300 mg BID
  Other Name: Reyataz
• Other: Standard treatment regimen
  N(t)RTI(s) based backbone plus ritonavir boosted PI

• Active Comparator: a.
  N(t)RTI(s) based backbone & PI/r
  Intervention: Other: Standard treatment regimen
• Experimental: b.
  Raltegravir (RAL) 400mg BID + atazanavir (ATV) 300 mg BID
  Interventions:

  • Drug: Raltegravir
  • Drug: Atazanavir

Inclusion Criteria:

• HIV-1 positive
• On stable ARV-therapy for a minimum of 4 months with a HIV viral load of < 50 copies
• Currently on a N(t)RTI(s) based backbone + PI/r
• No prior history of PI drug resistance (by historical genotype or phenotype)
• Aged > 18 years of age
• Written informed consent
• Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the last dose of investigational product, in such a manner that the risk of pregnancy is minimized.

Exclusion Criteria:

• Prior exposure to Raltegravir or Elvitegravir
• A detectable HIV viral load >50 copies within the last 4 months
• An ARV change within the last 4 months
• History of PI drug resistance
• Prior virologic failure on an ATV containing regimen
• Prior history of intolerance to ATV
• Pregnant or nursing mothers
• Pre-existing grade 3 or above laboratory toxicity except for lipids:
• Absolute neutrophil count (ANC) < 750 cells/mL.
• Hemoglobin < 8.0 g/dL.
• Platelet count < 50 000 cells/mL.
• AST, ALT and alkaline phosphatase > 5 x ULN.
• Serum bilirubin > 5 x ULN.
• calculated creatinine clearance of <50mL/min/1.73m2
• Patients with chronic active hepatitis B infection defined by positive serum Hbs antigen
• Use of any prohibited medications and/or the use of proton pump inhibitors in ATV plus RAL containing regimens)
• Patients with current alcohol or illicit substance use that in judgment of investigator makes study adherence unlikely

• Bristol-Myers Squibb
• Merck