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Biomedical subjects

P A Volberding

Publications and source records attributed to P A Volberding.

At least 19 recordsLinked to original sources
PubMed1996

Antiretroviral therapy for HIV infection in 1996. Recommendations of an international panel. International AIDS Society-USA.

OBJECTIVE: To provide clinical recommendations for antiretroviral therapy for human immunodeficiency virus (HIV) disease with currently (mid 1996) available drugs. When to start therapy, what to start with, when to change, and what to change to were addressed. PARTICIPANTS: A 13-member panel representing international expertise in antiretroviral research and HIV patient care was selected by the international AIDS Society-USA. EVIDENCE: Available clinical and basic science data, including phase 3 controlled trials, clinical endpoint data, virologic and immunologic endpoint data, interim analyses, studies of HIV pathophysiology, and expert opinions of panel members were considered. Recommendations were limited to drugs available in mid 1996. PROCESS: For each question posed, 1 or more member(s) reviewed and presented available data. Recommendations were determined by group consensus (January 1996); revisions as warranted by new data were incorporated by group consensus (February-May 1996). CONCLUSIONS: Recent data on HIV pathogenesis, methods to determine plasma HIV RNA, clinical trial data, and availability of new drugs point to the need for new approaches to treatment. Therapy is recommended based on CD4+ cell count, plasma HIV RNA level, or clinical status. Preferred initial drug regimens include nucleoside combinations; at present protease inhibitors are probably best reserved for patients at higher progression risk. For treatment failure or drug intolerance, subsequent regimen considerations include reasons for changing therapy, available drug options, disease stage, underlying conditions, and concomitant medication(s). Therapy for primary (acute) infection, high-risk exposures to HIV, and maternal-to-fetal transmission are also addressed. Therapeutic approaches need to be updated as new data continue to emerge.

Antiviral Agents↗
PubMed1996

HIV viral load markers in clinical practice.

Plasma HIV RNA determinations are an important prognostic marker of disease progression and, when used appropriately, provide a valuable tool for the management of individual patients. But what constitutes appropriate use?

Antiviral Agents↗
PubMed1995

A comparison of immediate with deferred zidovudine therapy for asymptomatic HIV-infected adults with CD4 cell counts of 500 or more per cubic millimeter. AIDS Clinical Trials Group.

BACKGROUND: The clinical benefits of zidovudine remain unproved in patients with asymptomatic human immunodeficiency virus (HIV) infection when CD4 cell counts exceed 500 per cubic millimeter. We compared zidovudine therapy given immediately with deferred therapy in such subjects. METHODS: Beginning in 1987, subjects with asymptomatic HIV infection and 500 or more CD4 cells per cubic millimeter were randomly assigned to receive placebo or zidovudine (either 500 or 1500 mg per day, starting immediately). In 1989, the study was modified so that open-label treatment with 500 mg of zidovudine per day (deferred therapy) was offered when CD4 cell counts fell below 500 per cubic millimeter. The study end points included overall survival, survival free of the acquired immunodeficiency syndrome (AIDS), toxic effects, and changes in CD4 cell counts. RESULTS: There were 1637 subjects who could be evaluated: 547 in the deferred-therapy group, 549 in the group receiving 500 mg of zidovudine immediately, and 541 in the 1500-mg group. The subjects were followed for up to 6.5 years (group medians, 4.8, 4.8, and 4.9, respectively). There was no significant difference in AIDS-free survival in the deferred-therapy group as compared with the low-dose or high-dose groups (81 cases of progression to AIDS or death vs. 81 and 74, respectively; P = 0.95 and P = 0.13) or in overall survival (51 deaths vs. 47 and 46; P = 0.25 and P = 0.16). The decline in CD4 cells was slower in both immediate-therapy groups than in the deferred-therapy group (P < 0.001 for both). Adverse effects were uncommon, and before the study modification their incidence was similar among the treatment groups, but severe anemia and granulocytopenia were more frequent in the 1500-mg group than in the deferred-therapy group (P < 0.001). CONCLUSIONS: In asymptomatic, HIV-infected adults with 500 or more CD4 cells per cubic millimeter, treatment with zidovudine slows the decline in the CD4 cell count but does not significantly prolong either AIDS-free or overall survival. These results do not encourage the routine use of zidovudine monotherapy in this population.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Influence of molecular characteristics on clinical outcome in human immunodeficiency virus-associated non-Hodgkin's lymphoma: identification of a subgroup with favorable clinical outcome.

The relationship between clinical and molecular characteristics of 45 treated individuals with histologically-documented human immunodeficiency virus (HIV)-associated B-cell non-Hodgkin's lymphoma was examined to determine whether differences in molecular features of lymphoma were associated with differences in clinical outcome. Tissue specimens from these tumors were evaluated for evidence of Ig heavy-chain gene rearrangements using both Southern blot analysis and reverse transcriptase polymerase chain reaction (RT-PCR). Lymphomas were also evaluated for the presence of Epstein-Barr virus (EBV) DNA sequences and c-myc gene rearrangements. Twenty-five lymphomas were characterized as polyclonal and 20 as monoclonal. PCR amplification of expressed Ig variable (V)-region genes confirmed polyclonality in three extensively studied polyclonal lymphomas. The median CD4 count was significantly higher in the group with polyclonal disease (277/microL) than in the group with monoclonal disease (123/microL), P = .04. The complete response rate to therapy was significantly higher in patients with polyclonal disease (78%) and CD4 greater than 200/microL (81%) than in those with monoclonal disease (31%) and CD4 less than 200/microL (33%). CD4 count, clonality, and presence of EBV DNA sequences were the most important predictors of survival. Both Kaplan-Meier and Cox proportional hazards analyses showed a markedly prolonged survival in those patients with both CD4 > or = 200/microL and polyclonal disease. Histologically the polyclonal lymphomas were high grade in appearance and contained prominent macrophages. All seven surviving patients were in this group. Median survival for those individuals whose tumors contained EBV sequences was only 3.2 months (range, 0.4 to 19.5), whereas those with EBV- tumors survived for a median of 9.0 months (range, 0.7 to 65.2), P = .0007. These data indicate that molecular features of HIV-associated lymphomas may be important predictors of clinical outcome. These characteristics define a distinct subset of patients with polyclonal EBV- tumors and CD4 counts greater than 200/microL that appear to have a less aggressive clinical course.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

The duration of zidovudine benefit in persons with asymptomatic HIV infection. Prolonged evaluation of protocol 019 of the AIDS Clinical Trials Group.

OBJECTIVE: To determine the durability of zidovudine-induced delay in clinical progression of asymptomatic human immunodeficiency virus (HIV) disease and to assess the relationship between this effect and the entry CD4+ cell count. DESIGN AND INTERVENTIONS: Extended follow-up data from subjects participating in protocol 019 of the AIDS [acquired immunodeficiency syndrome] Clinical Trials Group were examined. Subjects were offered a total daily dose of 500 mg of open-label zidovudine after the unblinding of the original randomized trial in 1989. Original treatment groups included placebo, 500 mg of zidovudine, or 1500 mg of zidovudine daily in divided doses. Three distinct analyses were conducted to assess the duration of zidovudine's effect on progression to AIDS or death: (1) analysis of all follow-up information from all subjects, (2) analysis of all subjects but with follow-up of original placebo-assigned subjects censored at the time open-label zidovudine was initiated, and (3) analysis of the effect of initiating zidovudine in subjects initially assigned to receive placebo. SETTING: University-based and university-affiliated AIDS research clinics participating in AIDS Clinical Trials Group protocol 019. PATIENTS: A total of 1565 asymptomatic HIV-infected subjects with entry CD4+ cell counts less than 0.50 x 10(9)/L (500/microL). MAIN OUTCOME MEASURE: Time to progression to AIDS or death. RESULTS: During follow-up of up to 4.5 years (mean, 2.6 years), 232 subjects progressed to AIDS or died. In each of the three analyses described herein, zidovudine was associated with a significant (P = .008, .004, .007) decrease in the risk of such progression. However, each of these analyses also indicated a decreasing placebo:zidovudine relative risk with duration of use (P = .002, .08, .04), suggesting a nonpermanent effect. The duration of benefit appeared to be related to entry CD4+ cell count, with greater benefit in those with higher counts at entry. No significant differences in survival were found between those originally randomized to zidovudine or placebo. CONCLUSIONS: Zidovudine at 500 mg/d caused a significant delay in progression to AIDS or death, but its earlier use in asymptomatic disease was not associated with an additional prolongation of survival compared with delayed initiation. The delay in progression diminished over time especially in subjects with entry CD4+ cell counts less than 0.30 x 10(9)/L (300/microL). Treatment strategies that alter drug regimens before the loss of zidovudine benefit should be explored.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Treatment dilemmas in HIV infection.

Recent trials of early treatment with the nucleoside analogues have produced conflicting data, raising fundamental questions about this therapy. Nevertheless, these drugs do lengthen clinical latency and delay the onset of AIDS, and for that reason alone should not be abandoned. The new treatment guidelines of the National Institute of Allergy and Infectious Diseases are discussed.

CD4-Positive T-Lymphocytes↗
PubMed1994

Evaluation of the quality of life associated with zidovudine treatment in asymptomatic human immunodeficiency virus infection. The AIDS Clinical Trials Group.

BACKGROUND: Zidovudine therapy is recommended for asymptomatic patients infected with the human immunodeficiency virus (HIV) who have fewer than 500 CD4+ cells per cubic millimeter. An analysis of the quality of life associated with therapy that integrated both the effects of adverse events and the benefits of delayed disease progression might influence this recommendation. METHODS: We applied a survival analysis adjusted for the quality of life to data from a randomized trial conducted by the AIDS Clinical Trials Group. The trial compared treatment with 500 mg of zidovudine per day, 1500 mg of zidovudine per day, and placebo (Protocol 019) in 1338 asymptomatic HIV-infected patients. RESULTS: The average time with neither a progression of disease nor an adverse event (symptom or laboratory finding) was 15.7, 15.6, and 14.8 months for patients receiving placebo, 500 mg of zidovudine, and 1500 mg of zidovudine, respectively. The incidence of severe symptoms was 13.8 percent in the placebo group, 15.2 percent in the 500-mg group, and 19.9 percent in the 1500-mg group (P = 0.038). After 18 months, the 500-mg group gained an average of 0.5 months without disease progression, as compared with the placebo group, but had severe adverse events an average of 0.6 months sooner. The 500-mg group had more quality-of-life--adjusted time than the placebo group only if the time lived after the progression of disease was considered by a patient to have less value than the time after the occurrence of a severe symptom. CONCLUSIONS: For asymptomatic patients treated with 500 mg of zidovudine, a reduction in the quality of life due to severe side effects of therapy approximately equals the increase in the quality of life associated with a delay in the progression of HIV disease.

CD4-Positive T-Lymphocytes↗
PubMed1994

Within-subject variation in CD4 lymphocyte count in asymptomatic human immunodeficiency virus infection: implications for patient monitoring.

Changes in CD4 lymphocyte counts are widely used in monitoring human immunodeficiency virus (HIV)-infected patients for disease progression. However, random fluctuations may obscure clinically significant changes. CD4 cell counts from 1020 untreated subjects with asymptomatic HIV infection monitored by standardized methods for up to 2 years were assessed. The within-subject coefficient of variation averaged 25% but was higher in subjects with lower counts; in 6% of subjects the count was half or double the one obtained 8 weeks before. Proportionate rates of decline, which had negligible correlation with the baseline count, averaged 14.3%/year but varied considerably between subjects: An estimated 29% had increasing trends. Declines were greater in HIV p24-positive subjects and those with higher lymphocyte percentages or lower platelet counts or hemoglobin levels. With such high variation, changes between single counts should be interpreted cautiously. Using multiple counts and other markers may provide more precise assessment of immune status.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Combination therapy with zidovudine and didanosine compared with zidovudine alone in HIV-1 infection.

OBJECTIVE: To assess safety, pharmacokinetics, and in-vivo virologic activity of five different combination regimens of zidovudine and didanosine compared with zidovudine alone in patients with human immunodeficiency virus type 1 (HIV-1) infection. DESIGN: Open-label, partially randomized, dose-ranging study. SETTING: University-affiliated, medical center clinics. PATIENTS: A total of 69 patients with HIV-1 infection, CD4+ cell counts fewer than 400 cells/mm3, and fewer than 121 days of previous zidovudine treatment. INTERVENTIONS: Fifty-five patients received combination therapy with zidovudine and didanosine, and 14 received zidovudine therapy alone (600 mg/d). Daily dosages in milligrams of zidovudine and didanosine, respectively, in the five combination groups were 150 and 90 mg, 300 and 334 mg, 600 and 334 mg, 300 and 500 mg, and 600 and 500 mg. MEASUREMENTS: CD4+ cell counts, HIV-1 RNA titers in plasma, and toxic effects. RESULTS: The combination regimens were associated with higher and more sustained increases in CD4+ cells than zidovudine alone, even after adjustment for initial CD4+ counts and previous zidovudine therapy (P < 0.001). The median increase in CD4+ cell counts was 166 cells/mm3 with combination therapy and 77 cells/mm3 with zidovudine alone (P = 0.001) and did not differ statistically among the five combination regimens. Human immunodeficiency virus type 1 RNA titers in plasma decreased in 15 (83%) of 18 combination-therapy recipients compared with 2 of 7 zidovudine-alone recipients (P = 0.017). No pharmacokinetic interactions were seen between zidovudine and didanosine. Toxicity rates were low among all treatment groups. A greater decrease in hemoglobin levels was seen with the regimen using zidovudine alone (-8 g/L) compared with combination regimens using the same zidovudine dose (-1.5 g/L, P = 0.03). CONCLUSIONS: Combination therapy with zidovudine and didanosine produced larger and more sustained increases in CD4+ cell counts, more frequent decreases in plasma HIV-1 RNA titers, and more stable hematologic status than zidovudine therapy alone. The effects of this combination on the progression of HIV disease merit further study, to provide information about clinical outcome, because this was a relatively small study based on surrogate markers of HIV-1 infection.

Adult↗
PubMed1993

CD4+ lymphocytes are an incomplete surrogate marker for clinical progression in persons with asymptomatic HIV infection taking zidovudine.

OBJECTIVE: To determine the extent to which lymphocytes, particularly those with the CD4 surface antigen, are a surrogate marker for the development of the acquired immunodeficiency syndrome (AIDS) in persons with asymptomatic human immunodeficiency virus (HIV) infection. DESIGN: Analysis of data from the AIDS Clinical Trials Group Protocol 019, a placebo-controlled, double-blind, randomized trial. SETTING: University-based referral centers. PATIENTS: Asymptomatic HIV-infected patients with 500 or fewer CD4+ cells/mm3 at baseline who were given placebo (350 patients) or one of two daily doses of zidovudine (725 patients). MEASUREMENTS: Baseline and interim measurements of CD4+ and other leukocytes were assessed. Patients were followed for progression to AIDS. RESULTS: Patients' lymphocyte levels were correlated with progression to AIDS (P < 0.001; relative risk for each depletion of 50 CD4+ cells/mm3, 1.75; 95% CI, 1.53 to 2.01); however, only a small portion (0% to 37%) of the effect of zidovudine on this progression was statistically explained by its effect on CD4+ lymphocyte levels. A substantial portion of zidovudine's effect on delaying progression to AIDS that was independent of the levels of these markers occurred within the first 16 weeks of therapy. In patients who had not progressed to AIDS by week 16, most of the subsequent zidovudine effect in reducing the risk for progression could be explained by its effect on net CD4+ percent (percentage of CD4+ lymphocytes among all leukocytes) for the first 16 weeks of therapy. CONCLUSION: Levels of CD4+ lymphocytes are an incomplete surrogate marker for progression to AIDS, and the association is especially weak during the first 16 weeks of zidovudine therapy.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Weekly doxorubicin in the treatment of patients with AIDS-related Kaposi's sarcoma. AIDS Clinical Trials Group.

Fifty-three patients with AIDS-related Kaposi's sarcoma and no previous treatment with cytotoxic chemotherapy enrolled in a phase II multicenter study to evaluate the safety and efficacy of weekly doxorubicin treatment. Doxorubicin was given intravenously at a dose of 15 mg/m2. Patients were stratified for purposes of analyses by tumor burden and coexistence of HIV-associated signs and symptoms; stratum I included patients with cutaneous disease alone and no symptoms, and stratum II included patients with visceral disease, tumor-associated edema, a previous opportunistic infection, or systemic symptoms. Fifty-one patients were evaluable for toxicity and 50 for tumor response. Five patients had a partial response (10%); 32, a minor response (64%); 12, no change (24%); and one, progression (2%) as the best measurable response. Partial response durations ranged from 4 to 14 weeks. Fifteen patients subsequently showed progression while on treatment. A significantly greater number of patients in stratum I (20.1%) had a partial response compared with those in stratum II (0%, p = 0.009). The major toxicities included nausea (37%), stomatitis (9.8%), mucositis (13.7%), and moderate to severe neutropenia (71%). Neutropenia was dose limiting and resulted in discontinuation of doxorubicin in 18% of the patients. Two patients developed cardiac toxicity. In conclusion, doxorubicin treatment induced relatively few tumor responses and remission durations were short. Treatment was limited by a high rate of toxicity.

AIDS-Related Opportunistic Infections↗
PubMed1992

A controlled trial comparing continued zidovudine with didanosine in human immunodeficiency virus infection. The NIAID AIDS Clinical Trials Group.

BACKGROUND: Although zidovudine is effective in patients with human immunodeficiency virus (HIV) infection, its efficacy may decline with prolonged use. Didanosine is another inhibitor of HIV reverse transcriptase. We evaluated the effectiveness of changing anti-HIV treatment from zidovudine to didanosine. METHODS: This multicenter, double-blind study involved 913 patients who had tolerated zidovudine for at least 16 weeks. The patients had the acquired immunodeficiency syndrome (AIDS), AIDS-related complex with less than or equal to 300 CD4 cells per cubic milliliter, or asymptomatic HIV infection with less than or equal to 200 CD4 cells per cubic milliliter. They were randomly assigned to receive 600 mg per day of zidovudine, 750 mg per day of didanosine, or 500 mg per day of didanosine. RESULTS: There were significantly fewer new AIDS-defining events and deaths among the 298 subjects assigned to 500 mg per day of didanosine than among the subjects who continued to receive zidovudine (relative risk, 1.39; 95 percent confidence interval, 1.06 to 1.82; P = 0.015). With 750 mg of didanosine, there was no clear benefit over zidovudine (relative risk, 1.10; 95 percent confidence interval, 0.86 to 1.42). The efficacy of didanosine was unrelated to the duration of previous zidovudine treatment. In the two didanosine groups, there were improvements in the number of CD4 cells (P less than 0.001 for both groups) and in p24 antigen levels (P = 0.03 in the 500-mg group; P = 0.005 in the 750-mg group), as compared with the zidovudine group. CONCLUSIONS: Changing treatment from zidovudine to 500 mg per day of didanosine appears to slow the progression of HIV disease.

AIDS-Related Complex↗