Treatment Success and Failure in HIV-Infected Subjects Receiving Indinavir in Combination With Nucleoside Analogs: A Rollover Study for ACTG 320

Trial end date:
Target enrollment:
Participant gender:
Group A: To compare the time to confirmed virologic failure (2 consecutive plasma HIV-RNA concentrations of 500 copies/ml or more) between the treatment arms: abacavir (ABC) or placebo in combination with zidovudine (ZDV), lamivudine (3TC), and indinavir (IDV). To evaluate the safety and tolerability of these treatment arms. [AS PER AMENDMENT 06/16/99: To compare the time to confirmed treatment failure, permanent discontinuation of treatment, or death between the treatment arms.] [AS PER AMENDMENT 12/27/01: Groups B, C, and D completed follow-up on March 4, 1999. Therefore, only information pertinent to Group A is applicable.] Group B: To compare the proportion of patients who achieve plasma HIV-1 RNA concentrations below 500 copies/ml, as assessed by the standard Roche Amplicor assay at Week 16, or to compare the absolute changes in plasma HIV-1 RNA concentrations at Week 16 across the treatment arms: ABC or approved nucleoside analogs and nelfinavir (NFV) or placebo in combination with efavirenz (EFV) and adefovir dipivoxil. To compare the safety and tolerability of these treatment arms. Group C: To monitor plasma HIV-1 RNA trajectory over time and determine the time to a confirmed plasma HIV-1 RNA concentration above 2,000 copies/ml on 2 consecutive determinations for patients treated with ZDV or stavudine (d4T) plus 3TC and IDV. Group D: To evaluate plasma HIV-1 RNA responses at Weeks 16 and 48. To evaluate the safety and tolerability of the treatment arms: ABC, EFV, adefovir dipivoxil, and NFV. This study explores new treatment options for ACTG 320 enrollees (and, if needed, a limited number of non-ACTG 320 volunteers) who have been receiving ZDV (or d4T) plus 3TC and IDV and are currently exhibiting a range of virologic responses. By dividing the study into the corresponding, nonsequential cohorts (Groups A, B, C, D), different approaches to evaluating virologic success, i.e., undetectable plasma HIV-1 RNA levels, and virologic failure, i.e., plasma HIV-1 RNA levels of 500 copies/ml or more [AS PER AMENDMENT 12/27/01: 200 copies/ml or more], are explored while maintaining long-term follow-up of ACTG 320 patients. [AS PER AMENDMENT 12/27/01: Groups B, C, and D completed follow-up on March 4, 1999. Therefore, only information pertinent to Group A is applicable. This study will examine the question of whether intensification of therapy can prolong the virologic benefit in individuals whose plasma HIV-1 RNA concentrations have been below the limits of assay detection on ZDV (or d4T) plus 3TC plus IDV.]
Phase 2
Accepts Healthy Volunteers?
Lead Sponsor:
National Institute of Allergy and Infectious Diseases (NIAID)
Adefovir dipivoxil
Inclusion Criteria

Concurrent Medication:


- Chemoprophylaxis for Pneumocystis carinii pneumonia for all patients with a CD4 cell
count of 200 cells/mm3 or less.


- Treatment, maintenance, or chemoprophylaxis, including topical and/or oral antifungal
agents unless otherwise excluded by the protocol.

- All antibiotics as clinically indicated, unless otherwise excluded in the protocol.

- Systemic corticosteroid use for 21 days or less for acute problems as medically
indicated. Chronic corticosteroid use is not permitted, unless it is within
physiologic replacement levels. Study team must be contacted in these instances.

- rEPO and G-CSF as medically indicated.

- Regularly prescribed medications such as [AS PER AMENDMENT 06/29/98: alternative,
FDA-approved antiretrovirals not supplied by the study] [AS PER AMENDMENT 12/27/01: or
unapproved antiretrovirals available by expanded access (when permanently discontinued
from randomized study treatment)], antipyretics, analgesics, allergy medications,
antidepressants, sleep medications, oral contraceptives, megestrol acetate,
testosterone, or any other medications not otherwise excluded by the protocol, as
medically indicated.

- [AS PER AMENDMENT 12/27/01: Supplemental and] alternative therapies such as vitamins,
acupuncture, and visualization techniques.

Recommended as an alternative agent for chemoprophylaxis against Mycobacterium avium
complex for patients randomized to EFV in Group B or D:

- clarithromycin or azithromycin.

Patients must have:

- HIV-1 infection as documented by any licensed ELISA test kit and confirmed by either a
Western Blot, HIV culture, HIV antigen, plasma HIV-1 RNA, or a second antibody test by
a method other than ELISA at any time prior to study entry.

Non-ACTG patients:

- Documented CD4 cell count of 200 cells/mm3 or less at the time of initiation of ZDV
(or d4T) plus 3TC plus IDV.

- Signed, informed consent from a parent or legal guardian for patients under 18 years
of age.

Prior Medication:


Non-ACTG 320 patients:

- At least 3 months prior therapy with ZDV (or d4T) plus 3TC plus IDV and continued
receipt of ZDV (or d4T) plus 3TC plus IDV until enrollment. IDV and 3TC must have been
initiated concurrently.

ACTG patients:

- Randomization to the ZDV (or d4T) plus 3TC plus IDV combination arm or receipt of
open-label prior to unblinding and maintenance of that treatment as participation in
ACTG 320.

Group D:

- Prior NNRTI-exposure.

Exclusion Criteria

Co-existing Condition:

Patients with the following conditions and symptoms are excluded:

- Unexplained temperature above 38.5 C for any 7 days or chronic diarrhea, defined as
more than 3 liquid stools per day persisting for 15 days, within 30 days prior to
study treatment.

- AIDS-related malignancy, other than minimal Kaposi's sarcoma that requires systemic
chemotherapy. Minimal Kaposi's sarcoma is defined as 5 or fewer cutaneous lesions and
no visceral disease or tumor-associated edema that does not require systemic therapy.

- Documented or suspected acute hepatitis within 30 days prior to study entry,
irrespective of laboratory values.

Concurrent Medication:


- All antiretroviral therapies other than study [AS PER AMENDMENT 06/16/99: provided]
medications, [AS PER AMENDMENT 06/16/99: unless approved by the protocol chairs] [AS
PER AMENDMENT 12/27/01: while on original randomized treatment.]

- Rifabutin and rifampin.

- Investigational agents without specific approval from the protocol chair.

- Systemic cytotoxic chemotherapy.

- Oral ketoconazole and itraconazole. NOTE: Itraconazole may be permitted for Group B
and Group D patients if fluconazole is not an option.

- Terfenadine, astemizole, cisapride, triazolam, midazolam, amiodarone, quinine, ergot
derivatives, isotretinoin, [AS PER AMENDMENT 12/27/01: pimozide, St.John's Wort, and
milk thistle.]

- [AS PER AMENDMENT 12/27/01: Concomitant use of lovastatin or simvastatin is not
recommended because of potential drug interactions. Pravastatin or atorvastatin may be
used after consultation with the Study Team.]

To be avoided:

- Herbal medications.

Prior Medication:


- Any prior protease inhibitor therapy other than indinavir.

- Interferons, interleukins, or HIV vaccines within 30 days prior to study entry.

- Any experimental therapy within 30 days prior to study entry.

- Rifampin, rifabutin, ketoconazole, or itraconazole within 14 days of study entry.

Non-ACTG patients:

- Acute therapy for an infection or other medical illness within 14 days prior to study

- NNRTI therapy prior to study entry (with the exception of Group D).

- Recombinant erythropoietin (rEPO), granulocyte colony-stimulating factor (G-CSF,
filgrastim), or granulocyte-macrophage colony-stimulating factor (GM-CSF,
sargramostim) within 30 days prior to study entry.

Caution should be taken in the consumption of alcoholic beverages with study medications.