Use of Combined Antiretroviral Therapy to Determine Sites of Persistent HIV Infection
| Status: | Completed |
|---|---|
| Conditions: | Infectious Disease, HIV / AIDS, HIV / AIDS |
| Therapuetic Areas: | Immunology / Infectious Diseases |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 4/21/2016 |
| Start Date: | March 1997 |
| End Date: | February 2010 |
Use of Combination Antiviral Therapy to Delineate the Identity and Longevity of Persistent Reservoirs of HIV-1 Infection and Replication
This study will try to define how and where HIV infection persists in the body by
determining: 1) if there are cells where HIV can live for long periods of time without being
seen and destroyed by the immune system; 2) if there are sites where anti-HIV drugs cannot
penetrate enough to stop new HIV replication; and 3) if HIV in certain lymph nodes can
remain infectious for prolonged periods of time. It will also explore whether immune system
damage caused by HIV can be repaired after new virus replication is stopped with treatment.
HIV-infected patients 18 years of age and older may be eligible for this study, which will
include three groups as follows. Candidates will be screened with a medical history,
physical examination, blood and urine tests and possibly chest X-ray and electrocardiogram.
Participants will be divided into three groups according to CD4 count levels: > 500
cells/microliter of blood; between 300 and 500 cells/microliter, and < 300 cells/microliter
of blood. All participants will be treated with a combination of four antiretroviral drugs:
indinavir, zidovudine, lamivudine and nevirapine. (Exceptions to this regimen may be made in
certain circumstances for patients who cannot tolerate one of the four drugs.) In addition,
they will undergo the following procedures:
Blood tests - Blood tests will be done at screening and at study entry to evaluate the
patient's health status and measure CD4 T cell count and plasma HIV levels; at the beginning
of treatment to look for drug-related side effects; and during the course of the study to
evaluate drug effectiveness in inhibiting HIV replication; CD4 T cell levels and function.
Lymph node biopsy - Lymph node biopsies are done under local anesthesia. A small incision is
made, the node is removed, and the incision is closed with stitches. Up to two nodes may be
removed during each procedure. Patients with CD4 counts greater than 500 cells/microliter of
blood and those with counts less than 300 cells/microliter will have three lymph node
biopsies in order to 1) assess the effectiveness of therapy in inhibiting HIV replication in
the nodes (the major site of replication); 2) determine how long HIV-infected cells may
persist in the nodes after new replication is stopped by therapy; and 3) determine if immune
damage caused by HIV can be repaired when virus replication is stopped. Lymph node biopsy in
patients with counts between 300 and 500 cells/microliter of blood is required only at
baseline, although follow-up biopsies are encouraged.
Leukapheresis - In this procedure, whole blood is collected through a needle placed in an
arm vein. The blood circulates through a cell separator machine where the white cells are
removed and collected. The rest of the blood is returned to the body, either through the
same needle used to draw the blood or through a second needle placed in the other arm. The
collected white cells are used for special studies of the level and function of T cells
before and after drug treatment. Patients with CD4 counts > 500 cells/microliter and < 300
cells/microliter will undergo leukapheresis up to four times - at study entry and about 2, 6
and 12 months after starting antiretroviral therapy. Patients with CD4 counts between 300
and 500 cells/microliter will have this procedure either at study entry and 6 and 12 weeks
after initiation therapy, or on the same schedule as the other patients.
determining: 1) if there are cells where HIV can live for long periods of time without being
seen and destroyed by the immune system; 2) if there are sites where anti-HIV drugs cannot
penetrate enough to stop new HIV replication; and 3) if HIV in certain lymph nodes can
remain infectious for prolonged periods of time. It will also explore whether immune system
damage caused by HIV can be repaired after new virus replication is stopped with treatment.
HIV-infected patients 18 years of age and older may be eligible for this study, which will
include three groups as follows. Candidates will be screened with a medical history,
physical examination, blood and urine tests and possibly chest X-ray and electrocardiogram.
Participants will be divided into three groups according to CD4 count levels: > 500
cells/microliter of blood; between 300 and 500 cells/microliter, and < 300 cells/microliter
of blood. All participants will be treated with a combination of four antiretroviral drugs:
indinavir, zidovudine, lamivudine and nevirapine. (Exceptions to this regimen may be made in
certain circumstances for patients who cannot tolerate one of the four drugs.) In addition,
they will undergo the following procedures:
Blood tests - Blood tests will be done at screening and at study entry to evaluate the
patient's health status and measure CD4 T cell count and plasma HIV levels; at the beginning
of treatment to look for drug-related side effects; and during the course of the study to
evaluate drug effectiveness in inhibiting HIV replication; CD4 T cell levels and function.
Lymph node biopsy - Lymph node biopsies are done under local anesthesia. A small incision is
made, the node is removed, and the incision is closed with stitches. Up to two nodes may be
removed during each procedure. Patients with CD4 counts greater than 500 cells/microliter of
blood and those with counts less than 300 cells/microliter will have three lymph node
biopsies in order to 1) assess the effectiveness of therapy in inhibiting HIV replication in
the nodes (the major site of replication); 2) determine how long HIV-infected cells may
persist in the nodes after new replication is stopped by therapy; and 3) determine if immune
damage caused by HIV can be repaired when virus replication is stopped. Lymph node biopsy in
patients with counts between 300 and 500 cells/microliter of blood is required only at
baseline, although follow-up biopsies are encouraged.
Leukapheresis - In this procedure, whole blood is collected through a needle placed in an
arm vein. The blood circulates through a cell separator machine where the white cells are
removed and collected. The rest of the blood is returned to the body, either through the
same needle used to draw the blood or through a second needle placed in the other arm. The
collected white cells are used for special studies of the level and function of T cells
before and after drug treatment. Patients with CD4 counts > 500 cells/microliter and < 300
cells/microliter will undergo leukapheresis up to four times - at study entry and about 2, 6
and 12 months after starting antiretroviral therapy. Patients with CD4 counts between 300
and 500 cells/microliter will have this procedure either at study entry and 6 and 12 weeks
after initiation therapy, or on the same schedule as the other patients.
The reservoirs of HIV-1 infection that permit maintenance of persistent virus infection
(even when virus replication cannot be detected using sensitive assays to quantify plasma
HIV-1 RNA levels) are currently unknown. Potential sites for persistent HIV-1 infection
include cells with chronic or latent infections, cells present in locations within the body
where antiviral drugs may not penetrate in levels sufficient to prevent additional cycles of
de novo virus infection (e.g., the central nervous system), the presence of susceptible
target cells for virus infection that may not metabolize certain antiviral drugs to their
active inhibitory forms (e.g., macrophages), or extracellular (possible infectious) virus
that may be retained on the surface of follicular dendritic cells within lymphoid organs. In
an attempt to determine which, if any, of these potential reservoirs contribute to
persistent HIV-1 infection, HIV-1-infected persons in two groups categorized by CD4+ T cell
levels will be treated with concomitant administration of 4 antiviral drugs (zidovudine,
lamivudine, indinavir and nevirapine) to accomplish maximal achievable suppression of virus
replication. The rates of decay of virus and virus-infected cells following initiation of
antiviral (and steroid) therapy will be monitored with sensitive, quantitative assays, and
the identity and longevity of persistent sites of infection will be determined. This study
may also illuminate to what extent HIV-1-induced immune system damage manifest as decreased
CD4 T cell responses, a constricted repertoire of T cell antigen recognition, or as
structural compromise of lymphoid tissue architecture can be reversed upon cessation of
active HIV-1 replication by combinations of potent antiviral drugs.
(even when virus replication cannot be detected using sensitive assays to quantify plasma
HIV-1 RNA levels) are currently unknown. Potential sites for persistent HIV-1 infection
include cells with chronic or latent infections, cells present in locations within the body
where antiviral drugs may not penetrate in levels sufficient to prevent additional cycles of
de novo virus infection (e.g., the central nervous system), the presence of susceptible
target cells for virus infection that may not metabolize certain antiviral drugs to their
active inhibitory forms (e.g., macrophages), or extracellular (possible infectious) virus
that may be retained on the surface of follicular dendritic cells within lymphoid organs. In
an attempt to determine which, if any, of these potential reservoirs contribute to
persistent HIV-1 infection, HIV-1-infected persons in two groups categorized by CD4+ T cell
levels will be treated with concomitant administration of 4 antiviral drugs (zidovudine,
lamivudine, indinavir and nevirapine) to accomplish maximal achievable suppression of virus
replication. The rates of decay of virus and virus-infected cells following initiation of
antiviral (and steroid) therapy will be monitored with sensitive, quantitative assays, and
the identity and longevity of persistent sites of infection will be determined. This study
may also illuminate to what extent HIV-1-induced immune system damage manifest as decreased
CD4 T cell responses, a constricted repertoire of T cell antigen recognition, or as
structural compromise of lymphoid tissue architecture can be reversed upon cessation of
active HIV-1 replication by combinations of potent antiviral drugs.
- INCLUSION CRITERIA:
Greater than or equal to 18 years old.
Ability to sign informed consent and willingness to comply with study requirements and
clinic policies.
For women of child-bearing potential, negative result on pregnancy test within one week
prior to initiating therapy.
No medical contraindication to lymph node biopsy.
HIV infection confirmed by ELISA and Western blot.
Two CD4+ T cell counts less than 300/microliters within 3 months of beginning the
protocol, with one of the two counts obtained at a screening history and physical
examination performed 2 weeks prior to initiating therapy.
Plasma HIV-1 RNA levels greater than 8000/ml.
For participants with CD4 T cell counts greater than or equal to 300/microliter,
asymptomatic for significant HIV-related illnesses. For participants with CD4 T cell
counts less than or equal to 300/microliter no active opportunistic infections.
For participants with greater than or equal to 300 CD4 cells/ microliter, no prior receipt
of antiretroviral therapy. For participants with less than or equal to 300 CD4
cells/microliter, no prior use of lamivudine, nevirapine or protease inhibitors.
Three or more palpable lymph nodes.
Willingness to allow storage of samples for future research.
Willingness to allow HLA testing.
EXCLUSION CRITERIA:
Platelet count less than 100,000 platelets/mm(3).
PT or PTT (in the absence of documented anti-cardiolipin antibody) prolonged by greater
than 2 seconds.
Known underlying bleeding disorder.
Pregnancy or breastfeeding.
Psychiatric illness that might interfere with study compliance.
Active substance abuse or history of prior substance abuse that may interfere with
protocol compliance or compromise patient safety.
Creatinine greater than 2.
Liver function tests greater than 1.5 times the normal laboratory values.
Significant cardiac, pulmonary, kidney, rheumatologic, gastrointestinal, or CNS disease as
detectable on routine history, physical examination, or screening laboratory studies.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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