Study of Anti-HIV Therapy Intensification

ACTG 315 and its follow-up study, ACTG 375, were designed to examine the immunologic and virologic consequences of highly active antiretroviral therapy (HAART) in patients with moderately advanced HIV-1 disease. At the conclusion of ACTG 375, patients eligible for participation in ACTG A5136 will have received over 5 years of antiretroviral therapy. Despite long-term therapy and long-term maximal viral suppression in most patients, significant immune defects such as impaired response to antigens, including HIV, abnormally low CD4 cell counts, abnormally high immune activation, and decreased expression of CD28 persist. It is uncertain whether these defects persist as a result of irreversible damage inflicted by HIV infection or ongoing immune perturbation resulting from continuous low-level HIV replication. Cellular reservoirs of HIV that persist (despite undetectable plasma viral load) may contribute to persistent immune activation and impaired immune function. A great deal of information on the relationship between low-level viral replication and persistent immune impairment may be gained by investigating these patients before and after intensification of their antiretroviral therapy regimens.

Patients continue to receive their ACTG 375 antiretroviral therapy until they register to A5136. Following entry evaluations, patients replace the protease inhibitors (PIs) in their ACTG 375 regimen with lopinavir/ritonavir (LPV/r), add tenofovir disoproxil fumarate (TDF) to their regimen, and maintain the rest of their ACTG 375 regimen for 48 weeks. Patients have clinic visits at entry and at Weeks 4, 12, and 16. After 24 weeks, patients have clinic visits every 12 weeks. Blood is drawn at these visits for viral load, immune response, and other routine tests. A skin test, a urine sample collection, and a pregnancy test (for women of reproductive potential) are also performed at entry. Patients also receive immunizations. At Weeks 12 and 16, a lyme vaccine, polyvalent is administered. At Week 36, lyme vaccine, polyvalent; pneumococcal vaccine, polyvalent; and haemophilus b conjugate (HIB) vaccine are administered [AS PER AMENDMENT 05/14/02: Lyme disease vaccine has been removed from the study due to unavailability]. At Week 48, skin tests are performed. Week 52 is the final clinic visit, at which blood is drawn and a urine sample is taken.

Patients who participate in substudy A5140s undergo 2 lymph node aspirates, at entry and at Week 48. Patients participating in substudy A5155s have blood drawn at screening and Week 48.

Inclusion criteria

Patients may be eligible for this study if they:

• Have completed ACTG 375 within 2 weeks of finishing Week 230.
• Have a viral load less than 400 copies/ml within 90 days prior to study entry.
• Agree not to become pregnant or to impregnate during the study. The female patient/male partner must use acceptable methods of contraception while receiving study drugs and for 1 month after stopping the drugs. Women and men who cannot have children are eligible without requiring the use of contraception, but they must provide acceptable documentation of menopause, sterilization, or lack of sperm cells.

Exclusion criteria

Patients may not be eligible for this study if they:

• Need to use certain drugs within 30 days of study entry.
• Have taken any immunomodulatory therapies within 30 days prior to study entry unless approved by the protocol chairs.
• Have a history of serious kidney problems.
• Are allergic or sensitive to the study drugs.
• Are pregnant or breast-feeding.
• Have an alcohol or drug dependency that, in the opinion of the investigator, would interfere with the study.