Protocol Number: 02-I-0232

Title:

HIV Expression in Patients with Viral Loads Suppressed on HAART

Number:

02-I-0232

Summary:

This study will investigate low-level viral loads in HIV-infected patients taking highly active antiretroviral therapy (HAART). Although HAART reduces viral levels and restores immune function to some degree, it does not cure HIV infection. The virus persists even at levels below that which it can be detected. This study will examine where this residual virus comes from in order to better understand the infection and the effectiveness of therapies. In addition, the study will 1) evaluate the ability of a new test to detect the virus at low levels; and 2) determine whether adding the protease inhibitor Kaletra to the HAART treatment regimen for patients with a low viral load will further decrease their viral load.

HIV-infected patients 18 years of age and older may be eligible for this study. Patients involved in the viral load test will be recruited from an NIAID HIV study in which they are already participating. Three groups of patients will be enrolled: those with a viral load of less than 50 copies/ml plasma, those with 51-500 copies/ml, and those with 501-5000 copies/ml. Patients involved in the Kaletra trial must have been taking HAART for 6 months or more and have less than 50 viral copies/ml plasma. They will be screened for this study with a history, physical examination, and routine laboratory tests.

Participants in the viral load test evaluation will donate 70 ml of blood up to four times. No more than one sample will be collected per day.

Participants in the Kaletra trial will have blood samples drawn on two successive days and will then be randomly assigned to one of two treatment groups. One group will begin Kaletra therapy (four capsules two times a day) immediately; the other will undergo observation for 4 weeks before starting Kaletra. Depending on what group they are in, patients will provide blood samples for viral load measurements and clinical samples according to the following schedule:

Immediate Kaletra

One sample each during weeks 1, 2, and 3, of therapy and two samples during week 4.

Delayed Kaletra

One sample each during weeks 1, 2, and 3 of observation and two samples during week 4. After starting therapy, one sample will be collected each week during weeks 1, 2, and 3 of therapy and two samples during week 4.

In both groups, after the last dose of medicine on day 28, Kaletra therapy will be complete. At the end of therapy, additional blood will be collected for viral sampling as follows: one sample each during weeks 1, 2, and 3, and two samples during week 4 after Kaletra therapy.

Sponsoring Institute:

National Institute of Allergy and Infectious Diseases (NIAID)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

Inclusion Criteria: Viral survey cohort

-HIV-1 infection documented by HIV ELISA and WB

-Age greater than or equal to 18 years old

-Hemoglobin greater than or equal to 12 mg/dl within the last six weeks

-On HAART according to current DHHS guidelines.

-Most recent viral load (within the last 12 weeks):

--<50 by bDNA or RT-PCR (65 patients)

--50-500 by bDNA or RT-PCR (3 patients )

--501 - 10,000 by bDNA or RT-PCR (2 patients)

Exclusion criteria:

-Any febrile illness (T greater than 38.0 degrees C) in the 3 weeks prior to blood draw

-Viral Survey Cohort- M98-863 samples (no inclusion/exclusion )

-Samples from patients enrolled in the completed M98-863 study.

Inclusion Criteria: Intensification Cohort

-HIV-1 infection documented by HIV ELISA and WB

-Age greater than or equal to 18 years old

-Hgb greater than or equal to 12 mg/dl

-CD4 greater than 200 cells/ µ (Micro)l and CD4%greater than 14% and not requiring prophylaxis for opportunistic infections

-Therapy with accepted HAART regimen for greater than or equal to 6 months.

-Viral load less than 50 copies RNA /ml plasma by RT-PCR for at least four months.

-Viral load greater than or equal to 5 copies RNA/ml plasma by SCA assay or positive in the adapted Amplicor assay

-Current HAART with: DHHS approved regimenNRTI+PI, NRTI alone, NRTI+NNRTI.

-Willingness to take an additional antiretroviral to current regimen for 30 days.

-For patients to start lopinavir/ritonavir, willingness to reduce the dose of sildenafil and other co-administered medicines that may be affected by the addition of lopinavir/ritonavir during the course of therapy with lopinavir/ritonavir

-For patients to start efavirenz arm, willingness to take efavirenz and adjust other medications or supplements as necessary, and to be aware that efavirenz is contraindicated in pregnancy and that may result in false positive urine tests for THC

-Patient must have primary care outside this protocol.

-Patients must practice accepted barrier methods to prevent pregnancy.

Exclusion Criteria: Intensification Cohort

-Requirement for cytotoxic agents including hydroxyurea or vaccinations during the study period

-Chronic corticosteroid therapy

-Concurrent Therapy with investigational cytokines including IL-2 or IL-12 during the course of the study. Prior administration of cytokines is not an exclusion criteria; at least 4 months from most recent cycle of IL-2 or IL-12. GCSF and erythropoietin therapy will be permitted

-History of taking a salvage regimen; i.e., patient has had clinical resistance to antiretrovirals. Changing antiviral therapy because of adverse effects is permitted

-Prior Protease Inhibitor therapy or NNRTI therapy of any duration is not permitted unless the previous PI-or NNRTI-containing therapy was switched because of patient preference and not because of resistance. If patients were previously switched because of documented resistance to NNRTI or PI containing regimen, then they will nto be eligible for the current protocol. If pt had a documented history of lipid elevations (fasting triglycerides greater than 750 mg/dl), the patient will not be eligible for PI addition.

-Any febrile illness (T greater than 38.0 degrees C) in the 3 weeks prior to enrollment

-Any vaccination in the 6 weeks prior to enrollment

-Current Pregnancy or lactation, history of pregnancy in the last 4 months

-Prior history of intolerance to the added antiretroviral

-For lopinavir/ritonavir addition, baseline elevated triglycerides greater than 400 mg/dl without lipid lowering agents elevated LDL cholesterol greater than or equal to 190mg/dl without lipid lowering agents.

-Elevated baseline ALT liver function assays greater than 2 fold greater than upper limit of normal

-History of chronic hepatitis B infection (positive HBV core antigen) or Hepatitis C infection (including positive hepatitis C viral load)

-History of pancreatitis requiring hospitalization

-Concomitant use with drugs that are highly dependent on cytochrome P450 for clearance, which, in the opinion of the investigators, may lead to the unexpected changes in their concentrations occurring after the addition of Lopinavir/ritonavir or efavirenz. Examples include but are not limited to: wafarin-like anticoagulation , amiodarone, astemizole, cisapride, certain drugs within the statin class of drugs, gemfibrozil, cyclosporine, ergonavine, ergotamine, methylergonavine, dihydroergotamine, dofetilide, flecanide, quinidine, fusidic acid (taken on the same day as the treatment), methadone, Demerol (mesperidine), prolonged administration of midazolam, triazolam, dilantin (phenytoin), pimozide, sirolimus, tacrolimus, propafenone, quinupristin, terfenadine, theophylline, Rifampin, rifapentene, or Rifabutin, vardenafil and fadafinil and illicit substances, including the recreational substance "Ecstasy" methylenedioxymethamphetamine.

-History of chronic diarrhea or inflammatory bowel disease

-History of hemophilia

-Inability to comply with the protocol

For those starting efavirenz, significant depression, which, in the opinion of the investigators, would be significantly worsened by efavirenz.

Taking a regimen containing atazanavir without also taking ritonavir.

Special Instructions: Currently Not Provided

Keywords:

RT PCR

Antiretrovial Therapy

Drug Intensification

Ultra-low

Sequence

Recruitment Keywords:

HIV

Treatment Experienced

Conditions:

HIV Infections

Investigational Drug(s):

None

Investigational Device(s):

None

Contacts:

Rosanne Burke, R.N.
National Institutes of Health
Building 10
Room 8C317
10 Center Drive
Bethesda, MD 20892
Phone: (301) 435-7937
Fax: (301) 402-1137

Electronic Address: rburke@niaid.nih.gov

Citations:

Gallego O, Ruiz L, Vallejo A, Ferrer E, Rubio A, Clotet B, Leal M, Soriano V; ERASE-3 Group. Changes in the rate of genotypic resistance to antiretroviral drugs in Spain. AIDS. 2001 Sep 28;15(14):1894-6.

Lucas GM, Chaisson RE, Moore RD. Highly active antiretroviral therapy in a large urban clinic: risk factors for virologic failure and adverse drug reactions. Ann Intern Med. 1999 Jul 20;131(2):81-7. PMID: 10419445

Adje C, High prevalence of genotypic and phenotypic HIV-1 drug-resistant strains amongpatients receiving antiretroviral therapy in Abidjan, Cote d'IvoireJ Acquir Immune Defic Syndr 2001 Apr 15;26(5):501-6PMID: 11391173

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