CCRC: A Pilot Project of Virologic, Pharmacologic and Immunologic Correlates of Gastrointestinal-Associated Lymphoid Tissue Immune Reconstitution Following Raltegravir Therapy

• To measure the trough plasma and tissue drug levels in volunteers at the time of the upper endoscopy [ Time Frame: nine months ] [ Designated as safety issue: No ]
• To correlate the level of HIV RNA per gram of duodenal tissue versus plasma HIV load and drug regimen received [ Time Frame: nine months ] [ Designated as safety issue: No ]
• To measure the change in GALT CD4+ and CD8+T-cell subpopulations (naive versus memory) in volunteers receiving raltegravir versus NNRTI [ Time Frame: nine months ] [ Designated as safety issue: No ]
• To assess GALT immune function and activation in volunteers receiving raltegravir versus NNRTI [ Time Frame: nine months ] [ Designated as safety issue: No ]
• To explore whether the treatment regimen correlates with the changes in CD3+/CD4+ T-cell numbers [ Time Frame: nine months ] [ Designated as safety issue: No ]
• To compare the level of immune reconstitution with respect to absolute numbers of CD4+ T-cells, the relative proportion of T-cell subpopulations in the tissue, and immune activation to a cohort of normal controls [ Time Frame: nine months ] [ Designated as safety issue: No ]

This research is being done to study how the immune system in the small intestine improves after taking antiretroviral (anti-HIV) medications. The main purpose is to measure the increase in the numbers of immune cells in the intestine to see if one type of HIV medication gives different results than other types of HIV medications.

While the world-wide AIDS epidemic continues to impact millions of individuals, effective anti-HIV medications have substantially reduced morbidity and mortality for those patients able to adhere to combination regimens. Despite improved survival, durable virologic suppression, and increases in peripheral CD4+T-cell counts in patients receiving potent antiretroviral therapy (ART), immune reconstitution remains incomplete as measured by a number of additional surrogate markers. Perhaps critically important among areas of apparent incomplete immune recovery is the gastrointestinal-associated lymphoid tissue (GALT), where CD4+T-cells repopulate very slowly, if at all. Raltegravir is a new ART agent from a novel class of HIV inhibitors, integrase inhibitors, that results in rapid suppression of HIV and recovery of peripheral CD4+T-cells. This project proposes to examine whether volunteers receiving raltegravir recover GALT immune cells more completely than those taking comparator ART.

• HIV Infections
• AIDS

• Procedure: Upper Endoscopy and biopsies
  5 HIV-Negative volunteers will only undergo this single procedure - A gastroenterologist (specialist in intestinal disease) will pass a flexible endoscope tube connected to a video camera, into the stomach and small intestine, will examine these areas, and will biopsy (take small pieces of tissue--about the size of a grain of rice) these areas.
• Drug: raltegravir
  400mg tablet twice daily by mouth for nine months
  Other Name: Isentress
• Drug: efavirenz
  600mg capsule once daily by mouth without regard to food
  Other Name: Sustiva

• No Intervention: 1
  HIV Negative volunteers
  Intervention: Procedure: Upper Endoscopy and biopsies
• Active Comparator: 2
  HIV-Positive volunteers taking raltegravir in combination with two other nucleoside reverse transcriptase inhibitors (NRTI) medications
  Intervention: Drug: raltegravir
• Active Comparator: 3
  HIV-Positive volunteers taking efavirenz or any other non-nucleoside reverse transcriptase inhibitors (NNRTI) in combination with two other nucleoside reverse transcriptase inhibitor (NRTI) medications
  Intervention: Drug: efavirenz

Inclusion Criteria:

• willing to sign consent form
• no known GI pathology
• no anticipated antiretroviral therapy adjustments or changes
• males & females between the ages of 18 & 50 years
• no active opportunistic infections (OI) or therapy for OI within 30 days of entry
• can be on secondary prophylaxis with a history of AIDS defining illness
• per standard of care requirements, all females of child-bearing potential must agree to use barrier methods to prevent pregnancy or be abstinent from activity while on study

Exclusion Criteria:

• abnormal coagulation parameters (PT > or equal to 1.2 ULN)
• thrombocytopenia (platelet count < 50,000 within 6 weeks)
• contra-indications to upper endoscopy or conscious sedation
• anemia (> or equal to grade 1)
• aspirin, ibuprofen, warfarin or other agents that interfere with the coagulation cascade are prohibited within 1 week of endoscopy