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HIV Expression in Patients With Viral Loads Suppressed on HAART


N/A
18 Years
N/A
Open (Enrolling)
Both
HIV Infections

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Trial Information

HIV Expression in Patients With Viral Loads Suppressed on HAART


This protocol is an exploratory study of HIV expression in patients who are receiving highly
active antiviral therapy and who have low viral loads below or near the current limit of
detection (50 copies/ml plasma). Recent studies have suggested that patients with
suppressed viral loads in this low range have continued HIV expression, but the amount and
the origin of this virus remains unknown. The amount of virus expression in plasma is
uncertain because the current viral load assays are imprecise in the cutoff range of 50-75
copies/ml plasma. The origin of the HIV found at low viral loads detected is unknown as
well; two possible sources of virus include expression from long-lived reservoirs of
infected cells, and low level spreading infection to uninfected cells. Determining the
origin of HIV expression has clinical importance; currently available HIV drug therapy will
have little effect on HIV expression from established reservoirs, but more potent HIV
therapy could potentially inhibit a spreading HIV infection.

In this study we plan two principal objectives. First, we will investigate the level of HIV
expression in plasma samples at low viral loads using a new HIV load assay with enhanced
sensitivity and precision in the viral load range of 1-100 copies. If data from the survey
confirms acceptable performance characteristics for this assay we will proceed with stage II
of the protocol. In stage II we plan to determine, in several short-term intensification
approaches to investigate whether the incorporation of an additional antiretroviral to
suppressive HAART regimens ("intensification HAART") will further suppress plasma virus. In
a small pilot study, we will plan to intensify regimens for 30 days in a nonrandomized
fashion. Secondly, we plan to study patients who are switching medications for preference
or mild toxicity. In these patients we will intensify their regimens for 30 days in an
overlap fashion, adding the new drug instead of switching medications. After 30 days of
drug overlap, we will continue the new drug and discontinue the identified antiretroviral.
These initial studies will assist in obtaining initial data and confirming the estimated
sample size of a larger, randomized study to rigorously investigate the virologic effects of
drug intensification. If these initial proof-of-concept experiments suggest that HIV may be
suppressed by intensification HAART, then we plan to expand the study in a larger controlled
trial to determine the degree of suppression possible with intensification therapy.

As a secondary objective we will investigate whether it is feasible to study HIV genetic
variation in samples from patients with suppressed viral loads using molecular techniques
developed to study HIV variation in patients with viral loads greater than 1000 copies/ml
plasma (protocol 00-I-0110).

We plan to enroll up to 70 patients in a viral load survey cohort of HIV viral loads, and
analyze a series of samples from completed trials of antiretroviral therapy.

Inclusion 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):

- less than 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, M97-720, AACTG 5201 SAMPLES (no inclusion/exclusion):

-Samples from patients enrolled in the completed M98-863, M97-720 or AACTG 5201 study.

INCLUSION CRITERIA: PILOT 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/ micro liter and CD4% greater than 14% and not requiring
prophylaxis for opportunistic infections

- Therapy with accept 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 0.38 copies RNA/ml plasma by SCA assay or positive in the
adapted Amplicor assay

- Current HAART with DHHS-approved regimen NRTI+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

- For patients starting raltegravir, no prior history of rhabdomyolysis and no
co-administration of agents which, in the opinion of the investigators, would cause
rhabodomyolysis or myopathy.

- Patient must have primary care outside this protocol.

- Patients must practice accepted barrier methods to prevent pregnancy.

- For patients enrolled in piolt study of suppression after development of resistance,
patient must have documented evidence of prior drug resistance either: Prior
resisteance testing with the presence of resisnce mutations or documents evidence of
viral RNA levels greater than 100 copies/ml plasma for greater than 6 months despite
antiretroviral thereapy. Patients with prior therapy on monotherapy or suboptimal
combination therapy ARE eligible for this study.

INCLUSION CRITERIA: RANDOMIZED INTENSIFICATION COHORT (NIH, University of Pittsburgh):

- 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/ micro liter 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 0.38 copies RNA/ml plasma by SCA assay or
positive in the adapted Amplicor assay

- Current HAART with DHHS-approved regimen NRTI+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:

- 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 PI therapy or NNRTI therapy is not permitted unless the previous PI-containing
therapy was switched because of patient preference. If the patient has 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 baseline ALT liver function assays greater than 2 fold greater than upper
limit of normal

- Known history of liver disease or Child-Pugh score greater than 5.

- 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, statin class of drugs, gemfibrozil,
cyclosporine, ergonavine, ergotamine, methylergonavine, dihydroergotamine,
dofetilide, flecanide, quinidine, fusidic acid, methadone, demerol, midazolam,
triazolam, phenytoin, dilantin, pimozide, sirolimus, tacrolimus, propafenone,
quinupristin, terfenadine, theophylline, rifampin, rifapentene, or rifabutin 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.

INCLUSION CRITERIA - DRUG OVERLAP COHORT:

- HIV-1 infection documented by HIV ELISA and WB

- Age greater than or equal to18 years old

- Hgb greater than or equal to 12 mg/dl

- CD4 greater than 200 cells/ micro liter 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 0.38 copies RNA/ml plasma by SCA assay or positive in the
adapted Amplicor assay

- Current HAART with DHHS-approved regimen NRTI+PI, NRTI alone, NRTI+NNRTI

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

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

- For patients to start efavirenz, 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:

- 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 PI therapy or NNRTI therapy is not permitted unless the previous PI-containing
therapy was switched because of patient preference. If the patient has 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 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 protease addition, baseline elevated triglycerides greater than 400 mg/dl without
lipid lowering agents

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

- Known history of liver disease or Child-Pugh score greater than 5.

- History of pancreatitis requiring hospitalization

- For patients who are adding ritonavir or efavirenz, concomitant use with drugs that
are highly dependent on cytochrome P 450 for clearance, which, in the opinion of the
investigators, may lead to the unexpected changes in their concentrations occurring
after the new drug is added. Examples include but are not limited to: wafarin-like
anticoagulation , amiodarone, astemizole, cisapride, statin class of drugs,
gemfibrozil, cyclosporine, ergonavine, ergotamine, methylergonavine,
dihydroergotamine, dofetilide, flecanide, quinidine, fusidic acid, methadone,
demerol, midazolam, triazolam, phenytoin, dilantin, pimozide, sirolimus, tacrolimus,
propafenone, quinupristin, terfenadine, theophylline, rifampin, rifapentene, or
rifabutin 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

Type of Study:

Observational

Study Design:

N/A

Principal Investigator

Frank Maldarelli, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

020232

NCT ID:

NCT00043641

Start Date:

July 2002

Completion Date:

Related Keywords:

  • HIV Infections
  • RT PCR
  • Antiretrovial Therapy
  • Drug Intensification
  • Ultra-low
  • Sequence
  • HIV
  • Treatment Experienced
  • HIV Infections
  • Acquired Immunodeficiency Syndrome

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892