Predictors of Virologic and Clinical Outcomes in HIV-1–Infected Patients Receiving Concurrent Treatment with Indinavir, Zidovudine, and Lamivudine: AIDS Clinical Trials Group Protocol 320

Demeter, Lisa M.; Hughes, Michael D.; Coombs, Robert W.; Jackson, J. Brooks; Grimes, Janet M.; Bosch, Ronald J.; Fiscus, Susan A.; Spector, Stephen A.; Squires, Kathleen; Fischl, Margaret A.; Hammer, Scott M.

doi:10.7326/0003-4819-135-11-200112040-00007

Cited by 60 publications

(31 citation statements)

References 20 publications

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“…ACTG 320 was a phase III trial of subjects with Ͼ3 months of prior experience with zidovudine and CD4 cell counts of Յ200 cells/mm 3 , and it demonstrated that treatment with the combination of indinavir, zidovudine, and lamivudine (indinavir arm) was superior to treatment with zidovudine and lamivudine (dual-nucleoside arm) in delaying clinical progression (9). A total of 1,178 subjects had been randomized by 21 February 1997, the date that the study was terminated and the subjects were unblinded, following an interim review that demonstrated an improved clinical outcome in the indinavir arm of the study.…”

Section: Methodsmentioning

confidence: 99%

“…If either of these measurements was outside the assay's range of quantification, then an imputed value was used: if a value of Ͻ500 copies/ml was obtained (which occurred in 1% of subjects), then a value of 500 copies was used, and if a value of Ͼ750,000 copies/ml was obtained (which occurred in 9% of subjects), then a value of 750,000 copies was used. The baseline CD4 cell count was defined as the mean of the preentry and entry measurements and excluded the screening value, which had to be Յ200 cells/mm 3 . Analyses were based on subjects with available data, regardless of whether they discontinued their randomized treatment.…”

Section: Methodsmentioning

confidence: 99%

“…The mean baseline CD4 cell count was 83 cells/mm 3 ; the baseline plasma HIV-1 RNA concentration was 4.95 log 10 copies/ml. The baseline characteristics of subjects assigned to each of the two treatment arms were similar, with the exception of a lower mean Karnofsky score for subjects in the indinavir arm (89.4 versus 91.9, P ϭ 0.026, Wilcoxon rank sum test).…”

Section: Patient Populationmentioning

confidence: 99%

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Detection of Replication-Competent Human Immunodeficiency Virus Type 1 (HIV-1) in Cultures from Patients with Levels of HIV-1 RNA in Plasma Suppressed to Less Than 500 or 50 Copies Per Milliliter

et al. 2002

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We determined the frequency with which human immunodeficiency virus (HIV) peripheral blood mononuclear cell cultures convert from positive to negative in subjects enrolled in a substudy of AIDS Clinical Trials Group (ACTG) 320, which compared the efficacy of treatment with a combination of indinavir, zidovudine, and lamivudine (indinavir arm) to that of a combination of zidovudine and lamivudine (dual-nucleoside arm). All subjects included for study had positive baseline HIV cultures. Cultures were performed in real time with 10 7 fresh patient peripheral blood mononuclear cells, using the ACTG consensus method. We found lower rates of positive HIV cultures in the indinavir treatment arm than in the dual-nucleoside treatment arm (64 versus 96% at week 24, P < 0.001). Within the indinavir arm of the study, we found that positive cultures were less likely to occur in samples with a plasma HIV type 1 (HIV-1) RNA level of <500 copies/ml than in those with a level of >500 copies/ml (44 versus 90%, P < 0.001). In addition, HIV cultures from samples with HIV-1 RNA levels of >500 copies/ml turned positive 8.5 days earlier, on average, than those from samples with levels of <500 copies/ml (P < 0.001). However, 38% of samples with plasma RNA levels of <50 copies/ml still were positive for HIV by culture. Thus, the rates of HIV isolation by standard culture procedures decrease as the plasma viral load decreases below 1,000 copies/ml; however, HIV isolates were still obtained from a substantial proportion of subjects with RNA levels of <50 copies/ml. The delay in the time required for HIV cultures to turn positive should be considered when attempting to obtain an HIV isolate from patients with suppression of plasma viral load.Currently available combination antiretroviral regimens can suppress human immunodeficiency virus type 1 (HIV-1) viral load in plasma to below the limits of detection in a significant proportion of patients (8,9,15). Initial reports of the inability, with standard culture techniques, to culture HIV-1 from patients with viral load suppression raised the question of whether circulating peripheral reservoirs of replication-competent HIV-1 could be eradicated (13,14,16,17). Subsequent studies demonstrated that HIV-1 could be cultured from HIVinfected patients with viral load suppression by using more sensitive, labor-intensive techniques that included CD8 cell depletion (2, 5, 13, 17). We performed real-time peripheral blood mononuclear cell (PBMC) cultures using the AIDS Clinical Trials Group (ACTG) consensus method in a subset of subjects enrolled in a phase III clinical trial of indinavir, zidovudine, and lamivudine. We found that this method, which does not utilize CD8 depletion, resulted in the isolation of HIV-1 in 38% of samples with plasma HIV-1 RNA levels that were Ͻ50 copies/ml. We have studied the impact of viral load on the yield of HIV-1 cultures and have explored the ability of a positive HIV culture to predict the subsequent viral load responses. MATERIALS AND METHODSStudy designs of ACTG 32...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Patient Populationmentioning

confidence: 99%

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Detection of Replication-Competent Human Immunodeficiency Virus Type 1 (HIV-1) in Cultures from Patients with Levels of HIV-1 RNA in Plasma Suppressed to Less Than 500 or 50 Copies Per Milliliter

et al. 2002

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“…In each case, there were 1) viral genotype and/or phenotype findings that indicated viral sensitivity to the patient's medication regimen, 2) evidence of treatment failure, as indicated by HIV-1 RNA levels of Ͼ4 log 10 copies per mL in 2 consecutive laboratory evaluations, and 3) caregiver insistence that medications were being administered regularly. The criterion and threshold for increased viral loads of Ͼ4 log 10 HIV RNA copies per mL were chosen because of 1) robust evidence in the medical literature that HAART results in an expected decrease in the viral load with time, with a decrease to Ͻ5000 (3.7 log 10 ) HIV RNA copies per mL being expected after 4 to 8 weeks of therapy 20,21 and 2) the 2002 recommendations for HAART for asymptomatic patients with viral loads of Ͼ4.7 log 10 HIV RNA copies per mL, regardless of the CD4 ϩ T cell counts. 22 All of our patients received HAART (Ն2 nucleoside analog reverse transcriptase inhibitors and Ն1 protease inhibitor or nonnucleoside reverse transcriptase inhibitor) since its availability.…”

Section: Subjectsmentioning

confidence: 99%

Nonadherence With Pediatric Human Immunodeficiency Virus Therapy as Medical Neglect

Roberts¹,

Wheeler

Tucker

et al. 2004

Pediatrics

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ABSTRACT. Objective. To examine the results of an interventionist approach applied to human immunodeficiency virus (HIV)-infected children for whom caregiver nonadherence was suspected as the cause of treatment failure.Methods. The medical records of a cohort of 16 perinatally HIV-infected children whose care was managed at the Arkansas Children's Hospital Pediatric HIV Clinic for an uninterrupted period of >3 years were reviewed through July 2003. Data collected included date of birth, dates of and explanations for clinic visits and hospitalizations, dates of laboratory evaluations, CD4 ؉ T cell percentages, plasma HIV-1 RNA levels, antiretroviral medications, viral resistance tests (eg, phenotype and genotype), and physician-initiated interventions to enhance adherence to the medication regimen. A stepwise interventionist approach was undertaken when patients continued to demonstrate high viral loads, despite documented viral sensitivity to the medication regimen and caregivers' insistence that medications were being administered regularly.Step 1 was prescribing a home health nurse referral, step 2 was administering directly observed therapy (DOT) while the patient was hospitalized for 4 days, and step 3 was submitting a physicianinitiated medical neglect report to the Arkansas Department of Human Services.Results. The results for 6 patients for whom this stepwise approach was initiated are reported. Home health nurse referrals failed to result in sustained improvements in adherence in all 6 cases. Viral load assays performed before and after DOT provided an objective measure of the effect of adherence, with 12 hospitalizations resulting in a mean ؎ SD decrease in HIV RNA levels of 1.09 ؎ 0.5 log 10 copies per mL, with a range of 0.6 to 2.1 log 10 copies per mL. Four families responded to DOT hospitalization, and sustained decreases in the respective patients' viral loads were noted. In 2 cases, medical neglect reports were submitted when DOT did not result in improved adherence. These patients were eventually placed in foster care, with subsequent improvements in their viral loads and CD4 ؉ T cell percentages.Conclusions. Nonadherence with antiretroviral therapy can be established on the basis of persistently elevated HIV RNA levels that decrease with DOT. Nonadherence poses a danger to the child that is grave and potentially irreversible. Caregivers should be offered all available resources to help them adhere to a sound treatment plan. In cases of demonstrated inability to provide needed care, it is necessary to consider seeking child protection, even for apparently healthy children. Pediatrics 2004;114:e346 -e353. URL: http://www.pediatrics.org/ cgi/content/full/114/3/e346; adherence, HIV, pediatric, neglect.

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“…The most mature and well-established markers of disease progression are CD4 T-helper cell count and RNA copy number (2,3,5,7). While these parameters are straightforwardly used for cross-sectional classification of patients with respect to clinical state, much uncertainty exists regarding evaluation and interpretation of changes in these markers over time (4).…”

mentioning

confidence: 99%

Reliability of CD4 Quantitation in Human Immunodeficiency Virus-Positive Children: Implications for Definition of Immunologic Response to Highly Active Antiretroviral Therapy

Carey

Pahwa

Weinberg

2005

Clin Vaccine Immunol

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Our objective was to develop data-based algorithms for definition of immunologic response to AIDS therapies in pediatric patients, taking account of T-cell subset measurement errors. The study design involved cross-protocol analysis of 2,148 enrollees in six completed Pediatric AIDS Clinical Trials Group trials. We used standard quantitation of T-cell subsets; linear modeling with mean-dependent measurement error variance was used to develop 95% tolerance limits for change in CD4%. For individuals with a CD4% of approximately 25%, the measurement error-based 95% tolerance interval ranges from 15% to 35%, whereas for individuals with a CD4% of approximately 5%, the tolerance interval ranges from 3% to 7%. When pairs of CD4% measures taken within a time interval of less than 30 days are averaged to estimate steady-state CD4%, tolerance interval width decreases by approximately 30%. A simple graphical tool that provides a data-based criterion for immunologic response over and above variation ascribable to T-cell measurement error is provided. Variability in CD4% due to measurement error is substantial, increases with level of CD4%, and complicates assessment of immunologic response to therapy. Replicates of CD4% measures could be used to improve precision of interpretation of CD4% measures.Methods of managing human immunodeficiency virus (HIV) disease are evolving rapidly. The most mature and well-established markers of disease progression are CD4 T-helper cell count and RNA copy number (2, 3, 5, 7). While these parameters are straightforwardly used for cross-sectional classification of patients with respect to clinical state, much uncertainty exists regarding evaluation and interpretation of changes in these markers over time (4). Recovery of CD4 T cells is an important criterion for immune reconstitution in patients who are given antiretroviral therapy. This report focuses on the short-term variability of repeated measures of CD4% in HIVinfected children enrolled in the Pediatric AIDS Clinical Trials Group (PACTG) treatment trials. Data from six clinical trials conducted in the past decade are combined for approximate estimation of measurement error variability. The impact of using replicated CD4% measures (i.e., averaging two measures obtained simultaneously or separated by a very short time intervals) to reduce effects of measurement error is illustrated. MATERIALS AND METHODSParticipants. Data were collected from six clinical trials conducted in the PACTG: protocols 152, 190, 300, 338, 377, and 382. Of these, protocols 152, 190, and 300 were the earlier treatment trials, consisting of one-or two-nucleoside analog reverse transcriptase inhibitor therapies, with protocols 152 and 190 completing by 1996 and 300 completing in 2001. Protocols 338, 377, and 382 were instituted later (ending by 2002) and evaluated triple-antiretroviral therapies, including protease inhibitors and/or nonnucleoside analogues.Measurement protocols. The six trials enumerated above used the same protocol for T-cell subset measurement. Imm...

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Predictors of Virologic and Clinical Outcomes in HIV-1–Infected Patients Receiving Concurrent Treatment with Indinavir, Zidovudine, and Lamivudine: AIDS Clinical Trials Group Protocol 320

Abstract: The HIV-1 RNA level and CD4 cell count achieved at 8 weeks of treatment are important predictors of subsequent virologic and clinical outcomes.

Cited by 60 publications

References 20 publications

Detection of Replication-Competent Human Immunodeficiency Virus Type 1 (HIV-1) in Cultures from Patients with Levels of HIV-1 RNA in Plasma Suppressed to Less Than 500 or 50 Copies Per Milliliter

Detection of Replication-Competent Human Immunodeficiency Virus Type 1 (HIV-1) in Cultures from Patients with Levels of HIV-1 RNA in Plasma Suppressed to Less Than 500 or 50 Copies Per Milliliter

Nonadherence With Pediatric Human Immunodeficiency Virus Therapy as Medical Neglect

Reliability of CD4 Quantitation in Human Immunodeficiency Virus-Positive Children: Implications for Definition of Immunologic Response to Highly Active Antiretroviral Therapy

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