Pilot Study on the Effect of Adding Raltegravir +/- a Second Drug on HIV Levels in the Gut

A Prospective Longitudinal Pilot Study to Measure the Effect of Intensification With Raltegravir +/- a Protease Inhibitor (PI) or Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) on HIV-1 Levels in the Gut

The "PLUS" study is a pilot study to measure the effect of therapy intensification (with raltegravir and optional second agent) on HIV levels in the gut and blood in patients on antiretroviral therapy (ART) with viral load < 50 copies/mL (herein referred to as "suppressed"). We hypothesize that there is ongoing replication in the gut despite suppressive ART and that this replication can be inhibited by the addition of one or two new antiretroviral drugs whose activity affects a distinct part of the viral life cycle. All study participants will have upper and lower endoscopy at baseline (before intensification) and after intensification. These endoscopies will be used to obtain gut tissue and single cells (for CD4+ cells) .

The "PLUS" study is a prospective, longitudinal pilot study to measure the effect of therapy intensification (with raltegravir and possible addition of a study PI or NNRTI-Non-Nucleoside Reverse Transcriptase Inhibitor) on HIV-1 DNA/RNA levels in the gut-associated lymphoid tissue (GALT) and blood in patients on ART with viral load (VL) < 50 copies/mL (herein referred to as "suppressed"). We hypothesize that there is ongoing replication in the GALT despite suppressive ART and that this replication can be inhibited by the addition of one or two new antiretroviral drugs whose activity affects a distinct part of the viral life cycle. All study participants will have a colonoscopy and esophagogastroduodenoscopy (EGD) at baseline (before intensification) and a second colonoscopy with EGD 12 weeks after intensification. These endoscopies will be used to obtain GALT mononuclear cells (for CD4+ lymphocytes) as well as tissue for in situ hybridization and immunohistochemical studies.

Inclusion Criteria:

1. Age 18 to 65 years
2. Infection with HIV-1, as documented by a licensed ELISA and confirmed by a Western blot or HIV-1 RNA at any time prior to study entry
3. On ART for at least 12 months prior to study entry with a regimen that includes at least two NRTIs and either an NNRTI or PI
4. No change in ART for at least 3 months prior to study entry.
5. CD4+ T cell count of 200 or greater within 30 days prior to study entry.
6. HIV-1 RNA level consistently below the limit of detection of commercial ultrasensitive assays (<50 copies/mL) for at least 6 months before study entry.
7. Women of reproductive potential (those who have not undergone surgical sterilization via hysterectomy, bilateral oophorectomy, or tubal ligation and who have had menses in the preceding 24 months) must have a negative urine or serum pregnancy test within 48 hours prior to study entry.
8. All subjects must agree not to participate in the process of conception (such as active attempts to impregnate or become pregnant, sperm or egg donation, in vitro fertilization) while receiving study drugs and for 6 weeks after stopping study drugs. If participating in sexual activity that could lead to pregnancy, the subject and/or partner should use at least two reliable methods of contraception, including oral contraceptive pills, an intrauterine device (IUD), condoms, and a diaphragm or cervical cap with spermicide.
9. Ability and willingness to provide informed consent.

Exclusion Criteria:

1. Any condition that, in the opinion of the GI specialist, would either be a contraindication to endoscopy or would increase the risk from sedation, endoscopy, or mucosal biopsies. These conditions may include, but are not limited to:

   • Significant complication (such as perforation) from prior endoscopy
   • Known bleeding diathesis
   • Platelet count < 100,000 per microliter
   • INR > 1.6
   • Current use of antiplatelet agents (aspirin, other NSAIDS, clopidogrel (Plavix), other antiplatelet agents) or anticoagulants (heparin, low molecular weight heparin, warfarin, lepirudin, or other anticoagulants) and inability to temporarily hold such medications for endoscopy.
   • Active angina, unstable angina, or MI within 2 months prior to study entry
   • Decompensated CHF
   • Respiratory insufficiency with FEV1 < 1L, resting hemoglobin saturation of <92%, or need for oxygen supplementation
   • OSA requiring CPAP
   • Ongoing substance abuse
   • Peripheral glucose > 350 mg/dL

2. Prior use of raltegravir

3. Any condition that, in the opinion of the infectious disease (ID) specialist, would be a contraindication to raltegravir. These conditions may include, but are not limited to: unstable clinical condition (such as recent hospitalization, cancer with need for chemotherapy or radiation); severe hepatic insufficiency; need for contraindicated medicines; breastfeeding; or high risk for myopathy or rhabdomyolysis.

4. Calculated creatinine clearance (CrCl) < 50 mL/min, as estimated by the Cockcroft-Gault equation

5. AST (SGOT), ALT (SGPT), alkaline phosphatase, or bilirubin > 3x the upper limit of normal (ULN).

6. LDL > 200 mg/dL or TG > 400 mg/dL in fasting lipids, as measured within three months prior to screening or at the time of screening

7. Plan to change the background ART within 16 weeks after study entry

8. Receipt of any HIV vaccine

9. Receipt of a non-HIV vaccine within 30 days prior to study entry

10. An opportunistic infection within 60 days prior to study entry

11. Use of significant immunosuppressive medications (such as systemic corticosteroids, tacrolimus, sirolimus, mycophenolate, azathioprine, interferon, and cancer chemotherapy) within 60 days prior to study entry.

12. Active drug or alcohol abuse that, in the opinion of the investigator, would interfere with adherence to the requirements of the study