Randomized, Double-Blind Study Comparing Dexelvucitabine (DFC) to Lamivudine (3TC) in Subjects With Resistance to NRTIs, PIs, and NNRTIs (DECLARE)

Inclusion Criteria:

• a) Male (at birth) subjects, between 16 years (or the legal age of consent, whichever is older) and 75 years of age, utilizing adequate contraceptive methods.
• b) Female (at birth) subjects between 16 years (or the legal age of consent, whichever is older) and 75 years of age.

• Women of childbearing potential may be enrolled following a negative serum pregnancy test. If participating in activity that could lead to pregnancy, women shall agree to use TWO forms of contraception as listed in # 1-4 below (at least one must be a barrier method) while receiving protocol-specified medication and for 2 months after stopping the medication.

  1. Condom (male or female) with or without a spermicidal agent
  2. Diaphragm or cervical cap with spermicide
  3. IUD
  4. Hormonal-based contraception
• Women who are not of reproductive potential (documented to be surgically sterile or postmenopausal [defined as amenorrhea >1 year and follicle stimulating hormone {FSH} >30 mU/mL]) are eligible to be enrolled without a serum pregnancy test and will not be required to use contraception.
• Subjects treated with a HAART regimen(s), including a minimum of 3 drugs, for at least 3 months and who have been on a stable HAART regimen for a minimum of 8 weeks prior to the Screening visit. The HAART regimen must also remain stable from the Screening visit until randomization on Day 0 in order for the subject to qualify for enrollment.

• Demonstrate evidence of failure of at least 3 drug classes, defined as #s 1-3 below:

  1. Prior NRTI use and presence of one or more NRTI-resistance-conferring mutations, including mutations at RT amino acids 41L, 65R, 67N, 70R, 74V or 74I, 184V or 184I, 210W, 215Y or 215F, and/or 219Q or 219E.
  2. Presence of one or more NNRTI-resistance conferring mutations, including mutations at RT amino acids 100I, 101E or 101P, 103N, 106A or 106M, 188L, and/or 190A or 190S or 190E at Screening or documented to be present on a prior genotype OR documented evidence of prior NNRTI use of at least 2 months duration with viral load ≥1000 copies/mL after at least 2 months of treatment.
  3. Prior ritonavir-boosted PI use AND presence of one or more PI-resistance-conferring mutations, including mutations at protease amino acids 33F, 46I or 46L, 50V, 82A or 82F or 82T or 82S, 84V, and/or 90M.
• Demonstrate a Screening plasma HIV RNA concentration of ³1000 copies/mL (Roche Amplicor HIV-1 Monitor® Test, v1.5 - Quantitative assay) and, in the expert judgment of the investigator, be failing the current regimen.
• Be able and willing to provide written informed consent.
• Be able and willing to comply, in the opinion of the investigator, with the requirements of this study.

Exclusion Criteria:

• Current or recent (<30 days) opportunistic infection (Category C according to the Centers for Disease Control (CDC) Classification System for HIV-1 Infection, 1993 Revised Version) that is not being controlled by medication in the judgment of the investigator.
• Subjects who are, in the opinion of the investigator, unable to comply with the dosing schedule and protocol evaluations.
• Pregnant women or women who are breastfeeding
• Current alcohol or drug use, which in the expert judgment of the investigator, will interfere with the subject's ability to comply with the protocol requirements.
• Subjects treated with dexelvucitabine (formerly known as Reverset) in a prior investigational drug protocol.
• Subjects with a history of acute or chronic pancreatitis.
• Subjects with acute hepatitis B and/or C infection.
• Subjects with unstable chronic hepatitis.
• Subjects with chronic renal failure requiring dialysis.
• Subjects currently receiving 3TC or FTC as part of a regimen for treatment of stable, chronic HBV infection. Subjects with stable chronic HBV infection who are being treated with entecavir, adefovir, or tenofovir are eligible to enroll.

• Subjects with the following laboratory parameters within 35 days prior to first dose of study medication:

  • Hemoglobin <9.0 g/dL (males) or <8.0 g/dL (females)
  • Absolute neutrophil count (ANC) <750/mm3
  • Platelet count <75 000/mm3
  • Aspartate aminotransaminase (AST [SGOT]) or alanine aminotransaminase (ALT [SGPT]) >5 X upper limit of normal (ULN)
  • Serum lipase >1.5 X ULN
  • Serum creatinine > 3.0 x ULN
• Subjects who have received an HIV prophylactic or corrective vaccination within 6 months prior to the first dose of study medication.
• Subjects who have received radiation therapy or cytotoxic chemotherapeutic agents and have not recovered from side effects prior to the first dose of study medication.
• Subjects with RT mutations Q151M or T69SS on Screening genotype.