A Randomized, Prospective Study of the Efficacy, Safety and Tolerability of Two Doses of GW433908Ritonavir Given With Abacavir/Lamivudine Fixed Dose Combination

The optimal long-term management of HIV-1 infection necessitates the chronic use of highly effective, well-tolerated antiretroviral (ARV) combination therapy, which ideally can preserve future treatment options. Current preferred standard treatment for HIV consists of a regimen composed of a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs). A recent trend that may contribute to improving rates of treatment response is to use regimens with fewer pills and once daily dosing. This study is designed to assess two PI options that consist of four or five pills taken once daily - these options may also offer advantages in terms of metabolic consequences.

The primary objective of this multi-center, open-label, randomized, two-arm, pilot study is to evaluate the antiretroviral efficacy, safety, and tolerability (adverse events and metabolic profile) of fos-amprenavir (fAPV) boosted with either of two doses of ritonavir (RTV) when administered in combination with ABC/3TC (abacavir/lamivudine, Epzicom®) FDC (fixed dose combination) in a once-daily regimen over 48 weeks in ART-naïve, HIV-infected adults. Approximately 100 subjects will be enrolled from about 10 sites in the United States. Subjects must be >18 years of age, be ART-naïve (<7 days of prior therapy with any licensed or investigational ARV drugs) and have a plasma HIV-1 RNA>1,000 copies/mL. A CD4+ cell count >50 cells/mm3 was initially required for eligibility. Amendment 1 has dropped this as a requirement. Subjects will be stratified at entry according to their screening plasma HIV-1 RNA level (<100,000 copies/mL or >100,000 copies/mL). Eligible subjects will be randomized (1:1) to one of the following two treatment arms for 96 weeks; fAPV 1400 mg/RTV 100 mg QD plus ABC 600 mg/3TC 300 mg FDC QD (Treatment Arm A) or fAPV 1400 mg/RTV 200 mg QD plus ABC 600 mg/3TC 300 mg FDC QD (Treatment Arm B).

Inclusion criteria

• HIV-1 infection
• Male or Female 18 years of age or older
• Has plasma HIV-1 RNA (viral load) 1,000 or more copies/mL at screening
• Subject is antiretroviral-naïve ( less than 7 days of prior therapy with any agent
• Competency
• Not pregnant and willing to use effective birth control if applicable.

Exclusion criteria

• Inability to comply due to pre-existing mental, physical, or substance abuse disorder or other reason.
• Has active/acute CDC Clinical Category C event at screening.
• Has history of inflammatory bowel disease, gastrointestinal malignancy, intestinal ischemia, malabsorption or other gastrointestinal dysfunction.
• Females who are pregnant or breastfeeding.
• Has a serious medical condition, such as diabetes, congestive heart failure, cardiomyopathy or other cardiac dysfunction, which in the opinion of the investigator would compromise the safety of the subject.
• Has ongoing clinically relevant pancreatitis or clinically relevant hepatitis at screening.
• Requires treatment with foscarnet, hydroxyurea or other agents with documented activity against HIV-1 in vitro within 28 days of study drug administration.
• Has an acute laboratory abnormality at screening that, in the opinion of the investigator, should preclude the subject's participation in the study. Any Grade 4 laboratory result would exclude a subject from study participation.
• Has required treatment with radiation therapy or cytotoxic chemotherapeutic agents within 28 days prior to screening, or has an anticipated need for such a treatment within the study period.
• Requires treatment with immunomodulating agents (such as systemic corticosteroids, interleukins, vaccines, or interferons) within 28 days prior to screening or subject has received an HIV-1 immunotherapeutic vaccine within 90 days prior to screening.
• Has a history of allergy to any of the study drugs or any excipients therein.
• Is enrolled or plans to enroll in one or more investigational drug protocols, which may impact HIV RNA suppression.
• Requiring treatment with pharmacological agents for diabetes, or elevated triglycerides/cholesterol.
• Has an AST or ALT >5 times the upper limit of normal (ULN).
• Has an estimated creatinine clearance <50 mL/min via the Cockcroft-Gault method
• Subject requires treatment with any of the following medications within 28 days prior to study drug administration, or the anticipated need during the study: amiodarone, astemizole, bepridil, cisapride, dihydroergotamine, ergonovine, ergotamine, flecainide, halofantrine, lidocaine, lovastatin, methylergonovine, midazolam, pimozide, propafenone, quinidine, simvastatin, terfenadine, and triazolam, carbamazepine, dexamethasone, phenobarbital, phenytoin, primidone, rifampin, and St. John's Wort (hypericum perforatum)