Evolution of L74V or K65R Mutations in VIremic Subjects on Tenofovir Disoproxil Fumarate (TDF) or Abacavir (ABC) (EVITA)

This is a multicenter, open-label, non-randomized, dual-arm pilot study to investigate the prevalence of the RT resistance mutations, K65R/x or L74V/x, in HIV-1 plasma from subjects experiencing confirmed first-time incomplete virologic suppression during treatment with an initial ARV regimen consisting of at least 12 weeks of TDF or ABC + FTC or 3TC + NNRTI or PI. Subjects will be followed until substantial loss of virologic or immunologic control requires a treatment switch. Confirmed first-time incomplete virologic suppression is defined as an initial plasma HIV-1 RNA response < 400 copies/mL, and subsequent virologic rebound > 400 copies/mL measured at two consecutive times.

Subjects will have screening genotype to establish adherence to their non-suppressive TDF- or ABC-containing regimen by the presence of M184V (or other treatment-related primary) mutation and to demonstrate that the evolution of treatment-emergent RT mutations can be characterized.

Twenty subjects (maximum 10 per arm) will be enrolled at 10-20 U.S. sites. If fewer than 20 subjects can be enrolled, the study may be discontinued early by the sponsor. Equal numbers of subjects on Arm A vs. Arm B will be a goal.

Inclusion criteria

• Confirmed first-time incomplete virologic suppression during treatment with at least 12 weeks of an ARV regimen consisting of TDF or ABC + FTC or 3TC + NNRTI or PI (TDF as Truvada or individually with FTC, and ABC as Epzicom or individually with 3TC). Confirmed first-time incomplete virologic suppression is defined as an initial plasma HIV-1 RNA response < 400 copies/mL, and subsequent virologic rebound > 400 copies/mL measured at two consecutive times.
• Screening HIV-1 RNA < 20,000 copies/mL obtained within 30 days prior to study entry.
• Screening CD4 cell count ≥ 200 cells/mL.
• Screening HIV-1 genotype with M184V or at least one treatment-related primary mutation.
• Routine labs as demonstrated by last available lab panel to be:

• Hemoglobin > 8.0 g/dL;
• Platelet count > 50,000/mm3;
• AST (SGOT) < 210 U/L;
• ALT (SGPT) < 240 U/L;
• Alkaline phosphatase < 625 U/L;
• Total bilirubin < 3.25 mg/dL; and
• Calculated creatinine clearance ≥ 50 as estimated by the Cockcroft-Gault equation.
• If participating in sexual activity that could lead to pregnancy, female study subjects must use two forms of contraception, one of which must be a barrier method.
• Men and women aged ≥ 18 years.
• Ability and willingness of subjects to give written informed consent.

Exclusion criteria

• Subjects with screening HIV-1 genotype that is wild-type or contains the resistance mutations K65R/x or L74V/x.
• Prior or current treatment with ARV regimen consisting of only nucleoside reverse transcriptase inhibitors (NRTIs), zidovudine (ZDV) or stavudine (d4T), more than 2 NRTIs, ritonavir-boosted or dual PI regimen.
• Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 30 days prior to study entry. Chronic treatment with prednisone at a daily dose of 10 mg or less is permitted. For non-serious illnesses, treatment of less than 21 days with larger doses of corticosteroids is permitted.
• Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
• Serious illness requiring systemic treatment and/or hospitalization until subject either completes therapy or is clinically stable on therapy, in the opinion of the site investigator, for at least 7 days prior to study entry. NOTE: Oral candidiasis, vaginal candidiasis, mucocutaneous herpes simplex, and other minor illnesses (as judged by the site investigator) have no restrictions.
• Unable to discontinue contraindicated current medications.

Inclusion criteria

• Confirmed first-time incomplete virologic suppression during treatment with at least 12 weeks of an ARV regimen consisting of TDF or ABC + FTC or 3TC + NNRTI or PI (TDF as Truvada or individually with FTC, and ABC as Epzicom or individually with 3TC). Confirmed first-time incomplete virologic suppression is defined as an initial plasma HIV-1 RNA response < 400 copies/mL, and subsequent virologic rebound > 400 copies/mL measured at two consecutive times.
• Screening HIV-1 RNA < 20,000 copies/mL obtained within 30 days prior to study entry.
• Screening CD4 cell count ≥ 200 cells/mL.
• Screening HIV-1 genotype with M184V or at least one treatment-related primary mutation.
• Routine labs as demonstrated by last available lab panel to be:

• Hemoglobin > 8.0 g/dL;
• Platelet count > 50,000/mm3;
• AST (SGOT) < 210 U/L;
• ALT (SGPT) < 240 U/L;
• Alkaline phosphatase < 625 U/L;
• Total bilirubin < 3.25 mg/dL; and
• Calculated creatinine clearance ≥ 50 as estimated by the Cockcroft-Gault equation.
• If participating in sexual activity that could lead to pregnancy, female study subjects must use two forms of contraception, one of which must be a barrier method.
• Men and women aged ≥ 18 years.
• Ability and willingness of subjects to give written informed consent.

Exclusion criteria

• Subjects with screening HIV-1 genotype that is wild-type or contains the resistance mutations K65R/x or L74V/x.
• Prior or current treatment with ARV regimen consisting of only NRTIs, ZDV or d4T, more than 2 NRTIs, ritonavir-boosted or dual PI regimen.
• Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 30 days prior to study entry. Chronic treatment with prednisone at a daily dose of 10 mg or less is permitted. For non-serious illnesses, treatment of less than 21 days with larger doses of corticosteroids is permitted.
• Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
• Serious illness requiring systemic treatment and/or hospitalization until subject either completes therapy or is clinically stable on therapy, in the opinion of the site investigator, for at least 7 days prior to study entry. NOTE: Oral candidiasis, vaginal candidiasis, mucocutaneous herpes simplex, and other minor illnesses (as judged by the site investigator) have no restrictions.
• Unable to discontinue contraindicated current medications.