Original Article
Evaluation of the Quality of Life Associated with Zidovudine Treatment in Asymptomatic Human Immunodeficiency Virus Infection
N Engl J Med 1994; 330:738-743March 17, 1994
- Abstract
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 month without disease progression, as compared with the placebo group, but had severe adverse events an average of 0.6 month 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.
Media in This Article
Figure 1
Estimated Time to the Progression of Disease, According to Treatment Group.Figure 2
Partitioned Kaplan-Meier Survival Plots for the Placebo Group (Panel A), the 500-mg Group (Panel B), and the 1500-mg Group (Panel C).Article Activity
- Article
Infection with the human immunodeficiency virus (HIV) is chronic and results in progressive deterioration of the immune system and, eventually, death. Previous studies have shown that zidovudine delays the progression of disease in both mildly symptomatic and asymptomatic patients over relatively short periods of observation1-4. As a result, zidovudine (at a dose of 500 mg per day) has become the standard initial treatment in the United States for HIV-infected patients with CD4+ cell counts below 500 per cubic millimeter. However, these studies were not designed to demonstrate the effects of treatment on overall survival, and recent studies have found no survival benefit from early administration of zidovudine, raising questions about the optimal time to initiate zidovudine treatment4,5. Complicating the situation are recent data indicating that the clinical benefits of an initial course of zidovudine can be extended by a subsequent switch to didanosine6.
Considerations of the quality of life may become paramount in determining treatment choices. Zidovudine at the currently recommended dose is associated with side effects such as mild nausea and headache, as well as anemia and neutropenia, which in turn may be associated with fatigue and fever and can be life-threatening in some cases2,7. An examination of the trade-off between the clinical benefits of zidovudine (delayed disease progression and decreased disease-related symptoms) and its side effects reveals that outcome measures associated with the quality of life can be used to determine asymptomatic patients' preference regarding early treatment.
In a small pilot study of patients with advanced HIV disease, zidovudine recipients had a higher quality of life than placebo recipients8. We have previously demonstrated that subjective judgments about the relative effects on the quality of life of adverse events and disease progression influence patients' treatment preferences, and that some patients may reasonably prefer no treatment to zidovudine because they wish to avoid the adverse events associated with treatment9. However, this analysis was conducted among patients receiving 1200 mg of zidovudine per day, which is more than twice the currently recommended dose. In addition, the patients had mildly symptomatic HIV infection. Symptomatic patients may be more willing to tolerate adverse events than are asymptomatic patients.
Patients who at the outset are asymptomatic may continue to feel healthy, or they may have treatment- or disease-related symptoms that reduce their sense of well-being. The effect of such symptoms on the quality of life is not usually included as an end point in traditional trials. In a community-based survey of HIV-infected patients, the primary determinant of well-being was found to be the symptoms patients reported, rather than their sociodemographic characteristics or history of Pneumocystis carinii pneumonia or Kaposi's sarcoma10. The current study was conducted to determine whether quality-of-life considerations might justify a modification of the standard recommendation to initiate zidovudine treatment (at a dose of 500 mg per day) in asymptomatic HIV-infected patients with fewer than 500 CD4+ cells per cubic millimeter.
We performed a retrospective analysis of data from Protocol 019, a randomized trial conducted by the AIDS Clinical Trials Group in which zidovudine (1500 or 500 mg per day) was compared with placebo. For this analysis, we classified the trial-associated adverse events as laboratory findings or symptoms. By considering only symptoms as adverse events (including subjective manifestations of objective laboratory findings), we obtained information about how the treatments affected the patients' quality of life. We then weighed these adverse events against the benefits of a delay in the progression of disease.
Methods
The design and results of Protocol 019 have been reported elsewhere2. A double-blind, randomized, placebo-controlled clinical trial, the study was designed to evaluate the efficacy and safety of two doses of zidovudine (1500 mg daily and 500 mg daily) in asymptomatic HIV-infected patients and did not focus on the quality of life. Patients were randomly assigned to treatment groups in two strata according to the CD4+ cell count (<200 and 200 to 499 cells per cubic millimeter). The current analysis considers the same 1338 patients and end points analyzed in the original report of the study findings and includes data on adverse events from May 10, 1989, through August 10, 1989, which were not in the original report.
Adverse events, whether or not they were related to treatment, were classified as laboratory findings or symptoms according to a system previously developed9. Laboratory findings were events that could be verified only by a laboratory analysis. Hepatic abnormalities (for example, elevated liver-function values), hematologic abnormalities (for example, neutropenia), and metabolic abnormalities (for example, hypoglycemia) were grouped as laboratory findings.
Symptoms were adverse events with a definite subjective component experienced by the patients, which therefore had a direct effect on the quality of life. (Severe subjective manifestations of objective laboratory findings, such as fatigue associated with anemia, were documented as symptoms.) Symptoms were classified primarily on the basis of organ systems, as follows: gastrointestinal, psychiatric, rheumatologic, dermatologic, constitutional, neurologic, cardiac, genitourinary, otorhinolaryngologic, gynecologic, respiratory, and ophthalmologic symptoms; malaise and fatigue; headache; fever; and other or uncodable events.
To calculate the frequency of adverse events, we counted only the first occurrence of an event in a defined category for a given patient. Thus, the count within each category represents the number of patients (not the number of events). For example, a patient's report of cough and shortness of breath was counted as one respiratory event. Patients who reported adverse events in more than one category were counted in each. Only severe (grade 3) or life-threatening (grade 4) events were included. Odds ratios and associated 95 percent confidence intervals were calculated by standard methods11. Differences between frequencies of events were calculated without correction for multiple comparisons.
The data came from an events file that contained all reported adverse events recorded in the study data base. Events were graded according to the standard system for grading toxicity outlined in the protocol. For example, in the gastrointestinal category, vomiting requiring intravenous therapy was given a grade of 3, and intractable vomiting a grade of 4. Depending on the type or degree of adverse event, the drug (whether zidovudine or placebo) was reduced in dose, temporarily withheld, or permanently stopped.
The quality-of-life-adjusted treatment comparison was based on a modification of a method originally developed to evaluate adjuvant therapies for breast cancer12,13. This method compares treatments by calculating the period during which patients have no severe symptoms and no progression of disease. To assess individual preferences for zidovudine as compared with placebo, a threshold-utility analysis9,12-14 was used, which incorporated the weights that reflected the relative reduction in the quality of life associated with adverse events on the one hand and disease progression on the other.
Three periods during the course of follow-up in individual patients were identified: the time without symptoms of disease or toxicity (TWiST), calculated as the number of months preceding the development of a symptom with a grade of 3 or higher or the progression of HIV disease, whichever occurred first; the period after the first occurrence of an adverse event with a grade of 3 or higher (AE); and the period after the progression of HIV disease (Prog). A quality-of-life-adjusted survival model was constructed with the use of utility coefficients uAE and uProg to reflect the value of the state of health (time after an adverse event and time after disease progression, respectively) on a utility scale with reference points of 0 and 1: TWiST was assigned a weight of 1, and death a weight of 09,12-14. The quality-of-life-adjusted survival relative to TWiST (Q-TWiST) was calculated as follows:
Q-TWiST = TWiST + (uAE × AE) + (uProg × Prog).
Estimates of the average number of months of Q-TWiST for the three treatment groups were determined by the following procedure. For each group separately, Kaplan-Meier curves for event-free survival and progression-free survival were used to partition the overall survival time during the 18 months of follow-up. Event-free survival was the time from enrollment in the study to the development of a grade 3 or higher symptom or the progression of HIV disease, whichever occurred first. Progression-free survival was the time from enrollment to the progression of disease. Kaplan-Meier estimates of the average periods after an adverse event, after the progression of disease, and without either an adverse event or disease progression were calculated separately for each treatment group. These estimates were represented by the areas between the curves.
For any assumed values of uAE and uProg (ranging from 0 to 1), the Q-TWiST for each treatment group was calculated with the equation given above. A threshold-utility analysis was performed to determine the range of uAE and uProg values for which the Q-TWiST was longer with zidovudine treatment and the range of values for which it was longer with placebo. Ninety-five percent confidence intervals and two-sided P values were calculated with a z-test based on observed differences between treatments, with standard errors calculated by the bootstrap method.
To determine whether our results were affected by the initial CD4+ count, we conducted separate Q-TWiST analyses in each stratum and also performed a proportional-hazards regression for Q-TWiST15.
Results
As reported previously, the mean duration of follow-up was 61, 55, and 51 weeks for the placebo, 500-mg, and 1500-mg groups, respectively2. Disease progression occurred in 38 of the 428 patients in the placebo group, in 17 of the 453 in the 500-mg group (P = 0.01; relative risk, 0.49; 95 percent confidence interval, 0.28 to 0.86), and in 19 of the 457 in the 1500-mg group (P = 0.10; relative risk, 0.65; 95 percent confidence interval, 0.37 to 1.12) (Figure 1Figure 1
Estimated Time to the Progression of Disease, According to Treatment Group.). These data correspond to 7.6, 3.6, and 4.3 end points (progression of disease) per 100 person-years of observation for the placebo, 500-mg, and 1500-mg groups, respectively. There were no deaths until after the first end point, although eight subjects died after the development of the acquired immunodeficiency syndrome (AIDS): four in the placebo group, one in the 500-mg group, and three in the 1500-mg group. The death in the 500-mg group was by suicide, and the others were from physical complications of AIDS.Table 1Table 1
Severe Adverse Events (Grade 3 or Higher) in Patients Receiving Zidovudine (1500 or 500 mg) or Placebo, during 18 Months of Follow-up. shows the numbers of patients with severe or life-threatening adverse events of various types, according to the treatment group, during 18 months of follow-up. Of the 1338 patients, 413 (30.9 percent) had at least one such event. The incidence of severe adverse events 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). Patients receiving 1500 mg of zidovudine were 2.1 times more likely to have a severe adverse event than those receiving placebo (P<0.001; 95 percent confidence interval, 1.6 to 2.8), whereas patients receiving 500 mg of zidovudine were 1.4 times more likely to experience an adverse event (P = 0.037; 95 percent confidence interval, 1.01 to 1.9). This dose-response relation was evident when the adverse events were broken down according to type (laboratory finding or symptom), with odds ratios of 2.2 for adverse laboratory findings in the 1500-mg group as compared with the placebo group (P<0.001; 95 percent confidence interval, 1.5 to 3.3) and 1.8 for the 500-mg group as compared with the placebo group (P = 0.003; 95 percent confidence interval, 1.2 to 2.7). Hematologic toxicity in the 1500-mg group and metabolic toxicity in the 500-mg group accounted for most of the differences in laboratory findings. Similarly, patients in the 1500-mg group were 1.6 times more likely to have symptoms than those in the placebo group (P = 0.015; 95 percent confidence interval, 1.08 to 2.36), whereas patients receiving 500 mg were no more likely to have symptoms than those receiving placebo (P = 0.54; odds ratio, 1.1; 95 percent confidence interval, 0.77 to 1.58). Gastrointestinal symptoms, particularly in the 1500-mg group, accounted for most of the differences in symptoms.A Q-TWiST analysis was performed to compare treatments in terms of the quality-of-life benefits related to a delay in disease progression and the costs due to adverse events. Only symptoms were included as adverse events in this analysis. Figure 2Figure 2
Partitioned Kaplan-Meier Survival Plots for the Placebo Group (Panel A), the 500-mg Group (Panel B), and the 1500-mg Group (Panel C). shows the partitioning of the overall survival time for the placebo group, the 500-mg group, and the 1500-mg group.During the first 18 months in the study, the average period from the first occurrence of an adverse event to the progression of disease was 1.6 months in the placebo group, 2.1 months in the 500-mg group, and 2.7 months in the 1500-mg group (Table 2Table 2
Survival Means for the Components of Q-TWiST, According to Treatment Group.). The average period after disease progression was 0.7, 0.3, and 0.4 months, respectively. Placebo recipients had an average of 15.7 months without symptoms of disease or toxicity, as compared with 15.6 months for the 500-mg group and 14.8 months for the 1500-mg group. When we incorporated severe or life-threatening laboratory findings into the Q-TWiST calculations, we found that placebo recipients actually had an advantage over both zidovudine groups in terms of the time without symptoms of disease or toxicity (14.6, 13.7, and 12.1 months for the placebo, 500-mg, and 1500-mg groups, respectively).Since 500 mg is the currently recommended daily dose of zidovudine, the remaining discussion focuses on the comparison between the group of patients receiving this dose of the drug and the placebo recipients. Figure 3Figure 3
Threshold-Utility Analysis Comparing a 500-mg Dose of Zidovudine with Placebo. shows the results of the threshold-utility analysis. The value of the time after an adverse event and before the progression of disease is represented by the utility coefficient uAE, and the value of the time after disease progression is indicated by uProg, both being relative to the time without symptoms of disease or toxicity. The figure shows the range of possible values for each utility coefficient and indicates which pairs of utility values favor zidovudine and which favor placebo. Subjective judgments provide the weights for the components of Q-TWiST, influencing treatment comparisons.A traditional efficacy analysis uses a delay in the progression of disease as the main end point and assigns a value of 1 to uAE, which is equivalent to time without symptoms or toxicity, and a value of 0 to uProg, which is equivalent to death. At these values, 500 mg of zidovudine is significantly better than placebo at delaying disease progression.
In our analysis, we instead assumed that the value of the time after an adverse event is not equivalent to the value of time without symptoms of disease or toxicity but rather is associated with a reduced quality of life. The actual value of that time depends on the individual patient and the specific adverse event. The utility value represents the amount of time without symptoms of disease or toxicity that would be equivalent to a year in the specified state of health (after an adverse event or disease progression). For example, with the values from Table 2, the comparison between 500 mg of zidovudine and placebo is computed as follows: -0.08 + (uAE)(0.6) - (uProg)(0.5). For a patient who would give up 1 month of life from a year after an adverse event (uAE = 0.92) or 4 months from a year after disease progression (uProg = 0.68) to gain time without symptoms of disease or toxicity, 500 mg of zidovudine provides a gain of 0.132 quality-of-life-adjusted months (4 days) over placebo during a period of 18 months, which is a significant difference. For any value of uAE equal to or greater than the value of uProg, 500 mg of zidovudine provides more months of quality-of-life-adjusted time without symptoms of disease or toxicity than does placebo.
As for the effect of base-line CD4+ cell counts on our results, among the patients with a low CD4+ count, therapy was associated with a delay in disease progression of 1.3 months, but this difference between the therapy and placebo groups was not significant, perhaps because of the small sample (n = 162). However, there were no utility values in the threshold-utility plot that showed a significant advantage for zidovudine. In the group of patients with a high CD4+ count (n = 1173), the results were essentially identical to those for the sample as a whole. (Base-line CD4+ counts were not available for three patients.) A proportional-hazards regression model was used to predict threshold-utility values corresponding to CD4+ cell counts of 200, 300, and 400 per cubic millimeter. This analysis resulted in practically identical plots at each level, showing that the base-line CD4+ cell count had a minimal effect on the quality-of-life-adjusted time without symptoms or toxicity.
Discussion
In the United States, early initiation of treatment with zidovudine at a dose of 500 mg per day is currently recommended for asymptomatic HIV-infected patients with CD4+ cell counts below 500 per cubic millimeter. This recommendation is based on evidence that zidovudine delays the progression of disease and that the toxicity associated with the drug is minimal and easily tolerated2,7. However, the magnitude of the difference in disease progression originally reported for asymptomatic patients receiving placebo or 500 mg of zidovudine was relatively small, albeit significant (38 of 428 placebo recipients had disease progression, as compared with 17 of 453 zidovudine recipients, for time-adjusted rates of 7.6 and 3.6 end points per 100 person-years of observation, respectively)2. That study assessed neither the quality of life nor the costs associated with zidovudine therapy. Recent reports suggesting that the initiation of zidovudine treatment when patients are asymptomatic provides no survival benefit have called into question the value of early intervention4,16.
We believe that integrating outcomes related to the quality of life with traditional clinical end points may clarify this controversy. According to our study, asymptomatic patients receiving 500 mg of zidovudine who considered the progression of disease less desirable than a severe adverse event had a better quality of life than patients receiving placebo. However, even for the patient who valued the time after a severe adverse event four times more than the time after the progression of disease, the quality-of-life-adjusted time gained with 500 mg of zidovudine was less than 1 week during a period of 18 months.
The current analysis evaluates treatment effects during 18 months of follow-up and cannot rule out the possibility that greater benefits for zidovudine in terms of the quality of life will emerge with a longer follow-up. However, zidovudine alone is likely to be used only for a period of 12 to 18 months, given evidence that its effects are transient,17 that survival may not be improved with early treatment,4 and that a switch to didanosine yields better results than long-term zidovudine alone6. Therefore, a consideration of the quality of life during the first 18 months of therapy is important in determining when to initiate prolonged treatment with a sequence of drugs in asymptomatic patients.
In our study, the entire time after the first occurrence of a severe adverse event was considered to be part of the adverse experience. Although not all this time was actually associated with a poor quality of life, we believed that the occurrence of one of these events had the potential for a considerable effect on the patient. Unfortunately, since reliable information was not available about the duration of adverse events, we could not precisely determine the degree of reduction in the quality of life over time. Furthermore, in clinical practice, dose modifications and discontinuation of therapy may minimize the continuing negative effect of adverse events. We assumed, however, that the quality of life was generally lower (although fluctuating) after the initial adverse event and that the average degree of reduction in the quality of life could be represented by the utility coefficient. Counting all the remaining time after the occurrence of the initial adverse event as part of the adverse experience may have somewhat biased the analysis against zidovudine therapy.
Our main analysis focused on severe or life-threatening adverse events because of their substantially negative effect on the quality of life. Since the toxic effects of zidovudine tend to occur before the disease progresses, patients must be willing to tolerate adverse events in the near future for the sake of delaying the progression of disease, which is a benefit in the more distant future. It is possible, however, that the limited quality-of-life benefit of early initiation of zidovudine therapy would be outweighed by the occurrence of grade 3 or grade 4 laboratory findings, associated mild or moderate symptoms, anxiety over test results, or more intense medical management. Furthermore, grade 1 or 2 symptoms, which were not included in the model but were experienced by nearly all the patients, may be sufficiently disturbing to outweigh the gain associated with a delay in the progression of disease, particularly for asymptomatic patients. In the absence of a demonstrated survival benefit, a reasonable option for HIV-infected asymptomatic patients may be to delay the initiation of antiretroviral therapy until there is clinical or laboratory evidence of disease progression18,19.
These findings suggest that clinicians should attempt to incorporate patients' preferences into treatment recommendations, instead of making such decisions solely on the basis of the CD4+ cell count and published guidelines. Future research may establish utility values for uAE and uProg that are based on patients' preferences, so that information on the quality of life can be integrated into traditional efficacy trials. In addition, a direct assessment of the quality of life should be included in future clinical trials of treatment for HIV infection.
Supported in part by a contract from the Division of AIDS, National Institute of Allergy and Infectious Diseases (NO-A1-95030) and by grants from the American Cancer Society (PBR-53) and the Agency for Health Care Policy and Research (R01 HS07767-01).
We are indebted to the AIDS Clinical Trials Group Protocol 019 investigators and study team who conducted the clinical trial that contributed data to the Q-TWiST analysis, to Drs. Stephen W. Lagakos and Martin S. Hirsch for their helpful comments, and to Janet Grimes, M.S., for assistance with the data base.
Source Information
From the Statistical and Data Analysis Center, AIDS Clinical Trials Group, Harvard School of Public Health (W.R.L., R.D.G., D.J.C., M.A.T.), Dana-Farber Cancer Institute (R.D.G., B.F.C., A.G.), Harvard Medical School (R.D.G., D.J.C.), and Beth Israel Hospital (D.J.C.) -- all in Boston; and the University of California, San Francisco, and San Francisco General Hospital (P.A.V.).
Address reprint requests to Dr. Lenderking at the Department of Biostatistics, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115.
- References
References
1
Fischl MA ,Richman DD ,Hansen N , et al. The safety and efficacy of zidovudine (AZT) in the treatment of subjects with mildly symptomatic human immunodeficiency virus type 1 (HIV) infection: a double-blind, placebo-controlled trial. Ann Intern Med 1990;112:727-737
Web of Science | Medline2
Volberding PA ,Lagakos SW ,Koch MA , et al. Zidovudine in asymptomatic human immunodeficiency virus infection: a controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. N Engl J Med 1990;322:941-949
Full Text | Web of Science | Medline3
Merigan TC ,Amato DA ,Balsley J , et al. Placebo-controlled trial to evaluate zidovudine in treatment of human immunodeficiency virus infection in asymptomatic patients with hemophilia: NHF-ACTG 036 Study Group. Blood 1991;78:900-906
Web of Science | Medline4
Hamilton JD ,Hartigan PM ,Simberkoff MS , et al. A controlled trial of early versus late treatment with zidovudine in symptomatic human immunodeficiency virus infection. N Engl J Med 1992;326:437-443
Full Text | Web of Science | Medline5
Aboulker JP ,Swart AM . Preliminary analysis of the Concorde trial: Concorde Coordinating Committee. Lancet 1993;341:889-890
CrossRef | Web of Science | Medline6
Kahn J . New developments in the clinical use of didanosine. J Acquir Immune Defic Syndr 1993;6:Suppl 1:S47-S50
Web of Science | Medline7
Richman DD ,Fischl MA ,Grieco MH , et al. The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. N Engl J Med 1987;317:192-197
Full Text | Web of Science | Medline8
Wu AW ,Mathews WC ,Brysk LT , et al. Quality of life in a placebo-controlled trial of zidovudine in patients with AIDS and AIDS-related complex. J Acquir Immune Defic Syndr 1990;3:683-690
Web of Science | Medline9
Gelber RD ,Lenderking WR ,Cotton DJ , et al. Quality-of-life evaluation in a clinical trial of zidovudine therapy in patients with mildly symptomatic HIV infection. Ann Intern Med 1992;116:961-966
Web of Science | Medline10
Wachtel T ,Piette J ,Mor V ,Stein M ,Fleishman J ,Carpenter C . Quality of life in persons with human immunodeficiency virus infection: measurement by the Medical Outcomes Study instrument. Ann Intern Med 1992;116:129-137
Web of Science | Medline11
Rosner BA. Fundamentals of biostatistics. 3rd ed. Boston: PWS-Kent, 1990.
12
Goldhirsch A ,Gelber RD ,Simes RJ ,Glasziou P ,Coates AS . Costs and benefits of adjuvant therapy in breast cancer: a quality-adjusted survival analysis. J Clin Oncol 1989;7:36-44
Web of Science | Medline13
Gelber RD ,Goldhirsch A ,Cavalli F . Quality-of-life-adjusted evaluation of adjuvant therapies for operable breast cancer. Ann Intern Med 1991;114:621-628
Web of Science | Medline14
Glasziou PP ,Simes RJ ,Gelber RD . Quality adjusted survival analysis. Stat Med 1990;9:1259-1276
CrossRef | Web of Science | Medline15
Cole BF ,Gelber RD ,Goldhirsch A . Cox regression models for quality adjusted survival analysis. Stat Med 1993;12:975-987
CrossRef | Web of Science | Medline16
Cohen J . Early AZT takes a pounding in French-British `Concorde' trial. Science 1993;260:157-157
CrossRef | Web of Science | Medline17
Larder BA ,Darby G ,Richman DD . HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science 1989;243:1731-1734
CrossRef | Web of Science | Medline18
Altman LK. Experts change guides for using drugs for HIV. New York Times. June 27, 1993:1, 23.
19
Sande MA ,Carpenter CCJ ,Cobbs CG ,Holmes KK ,Sanford JP . Antiretroviral therapy for adult HIV-infected patients: recommendations from a state-of-the-art conference. JAMA 1993;270:2583-2589
CrossRef | Web of Science | Medline
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Barbara Greenberg, Ruth Mccorkle, David Vlahov, Peter A. Selwyn. (2000) Palliative care for HIV disease in the era of highly active antiretroviral therapy. Journal of Urban Health 77:2, 150-165
CrossRef17
J Barnert. (2000) Dyspepsia in AIDS is correlated to ultrasonographic changes of antral distension. European Journal of Ultrasound 11:3, 189-197
CrossRef18
Sophie Low-Beer, Keith Chan, Benita Yip, Evan Wood, Julio S. G. Montaner, Michael V. O'Shaughnessy, Robert S. Hogg. (2000) Depressive Symptoms Decline Among Persons on HIV Protease Inhibitors. JAIDS Journal of Acquired Immune Deficiency Syndromes 23:4, 295-301
CrossRef19
Sophie Low-Beer, Keith Chan, Benita Yip, Evan Wood, Julio S. G. Montaner, Michael V. O'Shaughnessy, Robert S. Hogg. (2000) Depressive Symptoms Decline Among Persons on HIV Protease Inhibitors. Journal of Acquired Immune Deficiency Syndromes 23:4, 295-301
CrossRef20
Susan Murray, Bernard Cole. (2000) Variance and Sample Size Calculations in Quality-of-Life-Adjusted Survival Analysis (Q-TWiST). Biometrics 56:1, 173-182
CrossRef21
Rainer Weber, Lisanne Christen, Monika Loy, Silvio Schaller, Stephan Christen, Charles R. B. Joyce, Ueli Ledermann, Bruno Ledergerber, Richard Cone, Ruedi Lüthy, Misha R. Cohen. (1999) Randomized, Placebo-Controlled Trial of Chinese Herb Therapy for HIV-1–Infected Individuals. Journal of Acquired Immune Deficiency Syndromes 22:1, 56
CrossRef22
Ira B. Wilson. (1999) Clinical understanding and clinical implications of response shift. Social Science & Medicine 48:11, 1577-1588
CrossRef23
Dennis A. Revicki, Graeme Moyle, Hans-Jurgen Stellbrink, Chris Barker. (1999) Quality of life outcomes of combination zalcitabine-zidovudine, saquinavir-zidovudine, and saquinavir-zalcitabine-zidovudine therapy for HIV-infected adults with CD4 cell counts between 50 and 350 per cubic millimeter. AIDS 13:7, 851-858
CrossRef24
Ingvar Rosendahl, Gwendoline M. Kiebert, Desmond Curran, Bernhard F. Cole, Jane C. Weeks, Louis J. Denis, Reginald R. Hall. (1999) Quality-adjusted survival (Q-TWiST) analysis of EORTC trial 30853: Comparing goserelin acetate and flutamide with bilateral orchiectomy in patients with metastatic prostate cancer. The Prostate 38:2, 100-109
CrossRef25
Calvin Cohen, Dennis A. Revicki, Azmi Nabulsi, Phillip W. Sarocco, Ping Jiang. (1998) A randomized trial of the effect of ritonavir in maintaining quality of life in advanced HIV disease. AIDS 12:12, 1495-1502
CrossRef26
Alastair G. Smith, Shirley E. Crofts. (1998) Quality of life—An overdue clinical measurement in multiple myeloma. Leukemia Research 22:1, 19-23
CrossRef27
Rita Murri, Adriana Ammassari, Massimo Fantoni, Giancarlo Scoppettuolo, Antonella Cingolani, Andrea De Luca, Fernando Damiano, Andrea Antinori. (1997) Disease-Related Factors Associated With Health-Related Quality of Life in People With Nonadvanced HIV Disease Assessed Using an Italian Version of the MOS-HIV Health Survey. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 16:5, 350-356
CrossRef28
Ann B. Williams. (1997) New horizons: Antiretroviral therapy in 1997. Journal of the Association of Nurses in AIDS care 8:4, 26-38
CrossRef29
J. Rivero, M. Fraga, I. Cancio, J. Cuervo, P. López-Saura. (1997) Long-term treatment with recombinant interferon alpha-2b prolongs survival of asymptomatic HIV-infected individuals. Biotherapy 10:2, 107-113
CrossRef30
Jeffrey H. Burack, Misha R. Cohen, Judith A. Hahn, Donald I. Abrams. (1996) Pilot Randomized Controlled Trial of Chinese Herbal Treatment for HIV-Associated Symptoms. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 12:4, 386-393
CrossRef31
Barbara Wise. (1996) Antiretroviral Therapy in Adults. Journal of the American Academy of Nurse Practitioners 8:7, 329-341
CrossRef32
IRA B. WILSON, PAUL D. CLEARY. (1996) Clinical Predictors of Functioning in Persons with Acquired Immunodeficiency Syndrome. Medical Care 34:6, 610-623
CrossRef33
Philippe Vanhems, Emil Toma, Raynald Pineault. (1996) Quality of life assessment and HIV infection: A review. European Journal of Epidemiology 12:3, 221-228
CrossRef34
LYNNE M. MOFENSON. (1996) The Role of Antiretroviral Therapy in the Management of HIV Infection in Women. Clinical Obstetrics and Gynecology 39:2, 361-385
CrossRef35
Sumner J. La Croix, Gerard Russo. (1996) A cost-benefit analysis of voluntary routine HIV-antibody testing for hospital patients. Social Science & Medicine 42:9, 1259-1272
CrossRef36
A. E. Copfer, N. M. Ampel, T. E. Hughes, K. J. Gregor, C. L. Dols, S. J. Coons, K. Colgan, A. W. Wu. (1996) The use of two measures of health-related quality of life in HIV-infected individuals: a cross-sectional comparison. Quality of Life Research 5:2, 281-286
CrossRef37
Testa, Marcia A., Simonson, Donald C., . (1996) Assessment of Quality-of-Life Outcomes. New England Journal of Medicine 334:13, 835-840
Full Text38
Denise Kirschner, G. F. Webb. (1996) A model for treatment strategy in the chemotherapy of AIDS. Bulletin of Mathematical Biology 58:2, 367-390
CrossRef39
Ron Stall, Colleen Hoff, Thomas J. Coates, Jay Paul, Kathryn A. Phillips, Maria Ekstrand, Susan Kegeles, Joe Catania, Dennis Daigle, Rafael Diaz. (1996) Decisions to Get HIV Tested and to Accept Antiretroviral Therapies among Gay/Bisexual Men: Implications for Secondary Prevention Efforts. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 11:2, 151-160
CrossRef40
K. Robin Yabroff, Benjamin P. Linas, Kevin Schulman. (1996) Evaluation of quality of life for diverse patient populations. Breast Cancer Research and Treatment 40:1, 87-104
CrossRef41
JOEL TSEVAT, JENNY G. SOLZAN, KAREN M. KUNTZ, JULIA RAGLAND, JUDITH S. CURRIER, RANDALL L. SELL, MILTON C. WEINSTEIN. (1996) Health Values of Patients Infected with Human Immunodeficiency Virus. Medical Care 34:1, 44-57
CrossRef42
B. Messing. (1995) Long-term outcome and quality of life of adult patients on home parenteral nutrition. Clinical Nutrition 14, 24-27
CrossRef43
Malcolm D. Zaretsky. (1995) AZT toxicity and AIDS prophylaxis: Is AZT beneficial for HIV+ asymptomatic persons with 500 or more T4 cells per cubic millimeter?. Genetica 95:1-3, 91-101
CrossRef44
Peter H. Duesberg. (1995) Foreign-protein-mediated immunodeficiency in hemophiliacs with and without HIV. Genetica 95:1-3, 51-70
CrossRef45
(1994) Zidovudine and the Quality of Life. New England Journal of Medicine 331:5, 332-333
Full Text46
ANN C. COLLIER. (1994) Early Intervention in HIV Infection: Where Are We?. AIDS Research and Human Retroviruses 10:8, 893-899
CrossRef47
Matthias Egger, JamesD Neaton, AndrewN Phillips, George Davey Smith, NeilM.H Graham, JulioS.G Montaner, Janet Raboud, Michael O'Shaughnessy, PeterA Laing, SheilaM Gore, A Graham Bird, Bernard Hirschel, J-P Aboulker, A.G Babiker, J.H Darbyshire, J Dormont, T.E.A Peto, M Seligmann, A.M Swart, I.V.D Weller. (1994) Concorde trial of immediate versus deferred zidovudine. The Lancet 343:8909, 1355-1358
CrossRef48
JamesJ. Lipsky. (1994) Concorde lands. The Lancet 343:8902, 866-867
CrossRef
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