Original Article
Zidovudine Alone or in Combination with Didanosine or Zalcitabine in HIV-Infected Patients with the Acquired Immunodeficiency Syndrome or Fewer Than 200 CD4 Cells per Cubic Millimeter
N Engl J Med 1996; 335:1099-1106October 10, 1996
- Abstract
Background
We compared two combinations of nucleosides with zidovudine alone in patients with advanced human immunodeficiency virus (HIV) infection.
Methods
A total of 1102 patients with the acquired immunodeficiency syndrome or fewer than 200 CD4 cells per cubic millimeter were randomly assigned to receive zidovudine alone or zidovudine combined with either didanosine or zalcitabine. Disease progression, survival, toxic effects, and the CD4 cell response were assessed.
Results
After a median follow-up of 35 months, disease progression or death occurred in 62 percent of the 363 patients assigned to zidovudine plus didanosine, 63 percent of the 367 assigned to zidovudine plus zalcitabine, and 66 percent of the 372 assigned to zidovudine alone (P = 0.24). As compared with zidovudine therapy, treatment with zidovudine plus didanosine was associated with a relative risk of disease progression or death of 0.86 (95 percent confidence interval, 0.71 to 1.03), and treatment with zidovudine plus zalcitabine was associated with a relative risk of 0.92 (95 percent confidence interval, 0.76 to 1.10). Survival was similar in the three groups. In a subgroup analysis, combination therapy delayed disease progression or death in patients who had previously received zidovudine for 12 months or less. Therapy with zidovudine plus didanosine resulted in more gastrointestinal adverse effects, and treatment with zidovudine plus zalcitabine, more neuropathy. The mean increases in CD4 cell counts at two months were higher with combination therapy than with zidovudine alone.
Conclusions
In patients with advanced HIV infection, combination therapy with zidovudine and either didanosine or zalcitabine is not superior to zidovudine therapy alone. However, these combinations may be more effective than zidovudine monotherapy in patients with little or no previous zidovudine treatment.
Media in This Article
Figure 1
Cumulative Disease-free Survival and Survival According to Treatment Group.Table 1
Base-Line Characteristics of the Patients, According to Treatment Group.Article Activity
- Article
Better treatments are needed for patients with human immunodeficiency virus (HIV) infection and a condition characteristic of the acquired immunodeficiency syndrome (AIDS) or severe immune suppression. Prior investigations have found that didanosine or zalcitabine combined with zidovudine acts additively or synergistically against HIV in vitro and increases CD4 lymphocyte counts in vivo, more than does zidovudine alone; that cross-resistance between these agents and zidovudine is uncommon; and that they had different dose-limiting toxic effects from zidovudine.1-13 As compared with zidovudine alone, combinations of zidovudine with didanosine or zalcitabine might be expected to delay disease progression and prolong survival with acceptable side effects.
We evaluated the rates of disease progression and survival, changes in CD4 lymphocyte counts, and the incidence of adverse events in a randomized comparison of zidovudine alone or in combination with didanosine or zalcitabine.
Methods
Study Population
The patients were enrolled in 15 units of the Terry Beirn Community Programs for Clinical Research on AIDS, a consortium of 21 units in 17 U.S. cities conducting clinical trials in primary care settings. HIV-infected patients 13 years of age or older were eligible if they had had an AIDS-defining condition or had a CD4 cell count below 200 cells per cubic millimeter or 15 percent of the total lymphocyte count. During the study the patients were required to receive prophylaxis for Pneumocystis carinii pneumonia and to take no antiretroviral therapy except the study drugs. The protocol was approved by each unit's institutional review board, and all patients gave written informed consent.
At entry, patients were required to have a hemoglobin level of at least 8.0 g per deciliter (4.9 mmol per liter), a platelet count of at least 75,000 cells per cubic millimeter, an absolute neutrophil count of at least 1000 cells per cubic millimeter, alanine aminotransferase and alkaline phosphatase concentrations that were no more than five times the upper limit of normal, a total bilirubin concentration that did not exceed 2.5 mg per deciliter (42.75 μmol per liter), a total serum amylase concentration that was no more than twice the upper limit of normal, a serum creatinine concentration of no more than 2 mg per deciliter (176.8 mmol per liter), and a serum triglyceride concentration that was no more than 750 mg per deciliter (8.47 μmol per liter). Patients were excluded if they had a history or symptoms of pancreatitis or peripheral neuropathy, intolerance to any study drug, or AIDS dementia complex of stage 2 or higher14; if they were receiving short-term therapy for any AIDS-defining condition; or if they were pregnant or breast-feeding.
Study Design
The trial's primary objective was to compare the efficacy of zidovudine alone, zidovudine with didanosine, and zidovudine with zalcitabine in delaying disease progression or death in patients with AIDS or CD4 cell counts below 200 cells per cubic millimeter.
To minimize the number of pills that participants would have to take, the patients were initially randomly assigned in an open fashion to receive, in a 1:1 ratio, zidovudine plus didanosine or zidovudine plus zalcitabine, and then assigned in a double-blind fashion, in a 2:1 ratio, to didanosine or its placebo or zalcitabine or its placebo. Randomization was carried out with a permuted block design stratified according to unit. The sample size and length of follow-up were selected to give the study 80 percent power to detect a 33 percent reduction in the rate of disease progression or death with either type of combination therapy, as compared with zidovudine alone.
Disease progression was defined as the first occurrence of an AIDS-defining condition, defined according to published criteria.15 Events reported as indicating disease progression were reviewed by a committee unaware of the patients' treatment assignments and were deemed end points if judged confirmed or probable. We used the five-point scale of adverse events devised by the Division of AIDS of the National Institute of Allergy and Infectious Diseases (NIAID), in which a grade of IV indicates a potentially life-threatening event and a grade of V death, to grade adverse events occurring while the patient was taking study drugs and during the eight weeks after their permanent discontinuation. Adverse events were reported if they led to discontinuation of treatment or were grade IV or V.
Treatment Regimens, Evaluation of Patients, and Follow-up
Zidovudine was prescribed at a dosage of 200 mg three times a day, didanosine at a dosage of 200 mg twice a day, and zalcitabine at a dosage of 0.75 mg three times a day. Placebos for didanosine and zalcitabine were prescribed at the same frequencies. Follow-up evaluations were conducted at weeks 2 and 4, month 2, and then every two months thereafter. At each visit, symptoms were assessed and a blood sample was drawn.
The study drugs were permanently discontinued in the event of unresolved or recurrent peripheral neuropathy, hyperamylasemia (concentrations more than two times the upper limit of normal on retesting or more than five times the upper limit of normal), aphthous ulcers, clinical pancreatitis, a severe cutaneous or allergic reaction attributed to the study drug, a severe or life-threatening toxic reaction, the patient's refusal to continue therapy, or the treating clinician's recommendation. Treatment was also discontinued if the patient was unable or unwilling to take one of the study drugs.
Statistical Analysis
The investigators were unaware of the interim results. At least quarterly, external monitors visited each unit to check case-report forms against source documents for accuracy. Interim findings were monitored by the NIAID Data and Safety Monitoring Board.
All analyses were performed according to the intention to treat and were stratified according to unit. The three groups were compared for disease progression, survival, and adverse events with Kaplan–Meier estimates, log-rank tests (with 2 degrees of freedom), and proportional-hazards models.16 The proportional-hazards models were used for adjusted tests of significance; estimates of relative risk, with the group assigned to zidovudine used as the reference group; and 95 percent confidence intervals. Adjusted analyses, including subgroup analyses, included these base-line measures: history of an AIDS-defining condition, CD4 cell count, Karnofsky score, hemoglobin level, and duration of prior zidovudine use, if any. The treatment groups were also compared by combining the relative risks for individual AIDS-defining conditions.17 All P values were two-tailed; all median times accounted for censoring. Analysis of covariance was used to compare the change in CD4 cell counts from base line to two months. Changes in the CD4 cell count occurring after two months were compared with a random-effects model.18
Results
Study Population and Follow-up
Between April 1992 and June 1994, 1113 patients were enrolled; 366 received zidovudine plus didanosine, 372 received zidovudine plus zalcitabine, and 375 received zidovudine alone (188 and 187 received didanosine and zalcitabine placebo, respectively). A total of 1102 patients (99.0 percent) who met all eligibility criteria are the basis for this report. The number of patients screened and the reasons for exclusion were not recorded during the trial.
The base-line characteristics of the patients were similar among the treatment groups (Table 1Table 1
Base-Line Characteristics of the Patients, According to Treatment Group.). Twenty-three percent had never used zidovudine; among those who had, the median duration of prior use was 12 months. Only 4.4 percent of patients had taken didanosine previously, and 2.5 percent had taken zalcitabine.The median length of follow-up was 35 months (range, 1 to 44). Attendance at follow-up visits averaged 88 percent. At the close of the study, 2.5, 2.5, and 2.7 percent of patients given zidovudine plus didanosine, zidovudine plus zalcitabine, and zidovudine alone, respectively, had unknown vital status and no reported disease progression.
Use of Study Drugs
The median length of blinded treatment was 10, 12, and 12 months in the zidovudine-plus-didanosine, zidovudine-plus-zalcitabine, and zidovudine groups, respectively. Of the time between randomization and the occurrence of a primary end point, 57, 62, and 63 percent, respectively, was spent taking the study drug. The most common reasons for discontinuing study drugs were a patient's request to discontinue didanosine, zalcitabine, or placebo (53, 40, and 43 percent), the physician's decision (40, 40, and 42 percent), and a patient's request to discontinue zidovudine (36, 32, and 30 percent). These reasons were not mutually exclusive.
After discontinuing the study drugs, many patients did not receive antiretroviral therapy. At 12 months, 45, 37, and 43 percent of the surviving patients in the zidovudine-plus-didanosine, zidovudine-plus-zalcitabine, and zidovudine groups were not receiving antiretroviral therapy; at 24 months, the percentages were 44, 49, and 47 percent. Among patients receiving antiretroviral medications after discontinuing study drugs, far more in all treatment groups received monotherapy than combination therapy. For much of the study period, only zidovudine, didanosine, and zalcitabine were available to patients and physicians.
Disease Progression or Death
Disease progression or death occurred in 226, 230, and 244 patients in the zidovudine-plus-didanosine, zidovudine-plus-zalcitabine, and zidovudine groups, respectively; the rates per 100 person-years were 34.3, 36.2, and 39.6 (P = 0.24). At 12 months 74.8 percent, 74.7 percent, and 71.9 percent, respectively, were alive and disease-free; at 24 months the percentages were 50.2, 48.8, and 44.7 percent; and at 36 months they were 35.7, 31.3, and 27.6 percent (Figure 1Figure 1
Cumulative Disease-free Survival and Survival According to Treatment Group.). As compared with zidovudine therapy (Table 2Table 2
The Incidence and Relative Risk of Various Opportunistic Diseases and Death, According to Treatment Group.), treatment with zidovudine plus didanosine was associated with a relative risk of disease progression or death of 0.86 (95 percent confidence interval, 0.71 to 1.03; P = 0.09) and zidovudine plus zalcitabine with a relative risk of 0.92 (95 percent confidence interval, 0.76 to 1.10; P = 0.35). As compared with treatment with zidovudine plus didanosine, treatment with zidovudine plus zalcitabine was associated with a relative risk of disease progression or death of 0.93 (95 percent confidence interval, 0.77 to 1.12; P = 0.45). Adjusting for base-line covariates had little effect.No significant differences among the three groups were found in comparisons of the length of time to a first occurrence or recurrence of the specific conditions examined. The results for zidovudine plus zalcitabine did not differ significantly from those for zidovudine monotherapy for any condition. Zidovudine plus didanosine was associated with a lower risk of P. carinii pneumonia (relative risk, 0.65; 95 percent confidence interval, 0.44 to 0.96; P = 0.03) and a lower risk of Mycobacterium avium complex (relative risk, 0.66; 95 percent confidence interval, 0.44 to 0.98; P = 0.04) than zidovudine monotherapy. When the analyses for individual conditions were combined, we found that the results for zidovudine plus didanosine differed significantly from those for zidovudine alone (P = 0.05), whereas the results for zidovudine plus zalcitabine did not differ significantly from those for zidovudine alone (P = 0.51) (Table 2).
Death
Death occurred in 176, 182, and 191 patients in the zidovudine-plus-didanosine, zidovudine-plus-zalcitabine, and zidovudine groups, respectively (Table 2); the respective rates of death per 100 person-years were 21.9, 22.7, and 24.1 (P = 0.44). The survival rate at 12 months was 89.2 percent in the group assigned to zidovudine plus didanosine, 90.9 percent in the group assigned to zidovudine plus zalcitabine, and 90.5 percent in the group assigned to zidovudine alone; at 24 months the rates were 67.5 percent, 67.7 percent, and 65.4 percent; and at 36 months they were 49.4 percent, 46.2 percent, and 41.6 percent (Figure 1). As compared with zidovudine therapy (Table 2), treatment with zidovudine plus didanosine was associated with a relative risk of death of 0.88 (95 percent confidence interval, 0.71 to 1.08; P = 0.22) and treatment with zidovudine plus zalcitabine was associated with a relative risk of 0.96 (95 percent confidence interval, 0.78 to 1.17; P = 0.67). As compared with treatment with zidovudine plus didanosine, therapy with zidovudine plus zalcitabine was associated with a relative risk of death of 0.92 (95 percent confidence interval, 0.74 to 1.13; P = 0.42). Kaplan–Meier estimates of survival in each treatment group are shown in Figure 1.
Adverse Events
The rates of adverse events leading to discontinuation of treatment were 32.9, 32.6, and 26.5 per 100 person-years in the zidovudine-plus-didanosine, zidovudine-plus-zalcitabine, and zidovudine groups, respectively. As compared with zidovudine therapy, treatment with zidovudine plus didanosine was associated with a relative risk of discontinuation of treatment of 1.29 (95 percent confidence interval, 1.01 to 1.64; P = 0.04) and treatment with zidovudine plus zalcitabine with a relative risk of 1.21 (95 percent confidence interval, 0.95 to 1.54; P = 0.12) (Table 3Table 3
The Incidence and Relative Risk of Adverse Events, According to Treatment Group.).The numbers of patients with a first occurrence of each type of adverse event are shown in Table 3. Nausea or vomiting, diarrhea, abdominal pain or gastrointestinal distress, and pancreatitis were more common during treatment with zidovudine plus didanosine, whereas neuropathy was more common during treatment with zidovudine plus zalcitabine. Patients taking zidovudine plus zalcitabine had lower rates of diarrhea than those taking zidovudine alone. However, half the patients assigned to zidovudine alone received a didanosine placebo, and these patients had higher rates of some adverse events than the patients who received the zalcitabine placebo; the difference between groups was significant for diarrhea (P = 0.008). The increased rate of diarrhea with didanosine placebo is related to the buffer used (magnesium hydroxide).
CD4 Cell Counts
The mean change in the CD4 cell counts from base line to two months was +19.2, +12.9, and -4.0 cells per cubic millimeter in the zidovudine-plus-didanosine, zidovudine-plus-zalcitabine, and zidovudine groups, respectively (P<0.001 for the comparisons of each combination therapy with the monotherapy group). The rate of decline in the CD4 cell count after two months was similar for the three groups.
Subgroup Findings
When patients were grouped according to covariates assessed at base line (history of an AIDS-defining condition, Karnofsky score, hemoglobin level, race [nonwhite vs. white], and sex), no significant interactions were found between the subgroups and the treatment effects.
The results were also analyzed according to the extent of zidovudine use before randomization: no prior use, use for 12 months or less, and more than 12 months of use (Table 4Table 4
Incidence and Relative Risk of Disease Progression and Death According to Treatment and Prior Zidovudine Use.). The patients in these subgroups took the study drugs for similar lengths of time (data not shown). The treatment effects in these subgroups differed with respect to disease progression or death (P = 0.04) but not with respect to death alone (P = 0.39). (Homogeneity was assessed with a test with 4 degrees of freedom, adjusted for other base-line variables; the unadjusted P values were 0.19 and 0.52, respectively.) For both combination therapies, as compared with zidovudine therapy, the adjusted relative risk of disease progression or death increased with increasing prior use of zidovudine. Patients with no prior use and those with 12 months of use or less showed a benefit from combination therapy, whereas patients with more than 12 months of previous use did not. The change in the CD4 cell count at two months showed a similar relation to prior zidovudine use (data not shown): patients with no prior use had significant increases in CD4 cell counts in all three treatment groups.Discussion
In this study of patients with advanced HIV infection, combined treatment with zidovudine and either didanosine or zalcitabine did not delay disease progression or prolong survival, as compared with treatment with zidovudine alone, and patients who received combination therapy had more adverse events. It is unclear why the combination of two antiretroviral medications provided no benefit. Their toxic effects may be more pronounced in patients with advanced disease. About three quarters of the patients had already taken zidovudine before they entered the study; the lack of benefit might be explained by the findings in recent studies that susceptibility to didanosine and zalcitabine decreases when zidovudine resistance occurs19 and that zidovudine resistance in patients with extensive prior zidovudine use predicts disease progression and death whether they continue to take zidovudine or switch to another medication.20
Our study was designed to detect a 33 percent reduction in the rate of disease progression or death with combination therapy as compared with zidovudine therapy alone. Smaller differences may have been present but undetected; considering the toxicity of the study medications in patients with AIDS or severe immunosuppression, we felt that such differences would not be clinically relevant.
The conclusions of our study may not extend to other nucleoside monotherapies or combination therapies. In particular, it included only zidovudine monotherapy, unlike AIDS Clinical Trials Group Study 175, which included both zidovudine and didanosine monotherapy.21 The benefit of zidovudine as monotherapy diminishes after two years22,23; many of the patients we studied had extensive prior zidovudine use.
Although we did not find an overall benefit of combination therapy, it did appear to be more beneficial than zidovudine alone in the subgroup of patients with no or limited prior zidovudine use.
The optimal time to begin therapy with these medications remains unresolved. Recent studies show that lymph-node destruction and cell death are caused by viral replication after primary HIV infection; early antiretroviral therapy could reduce viral replication and may delay disease progression.24 Further data from trials with clinical end points are necessary to answer this question.
In summary, we found that combination therapy with zidovudine plus didanosine or zidovudine plus zalcitabine was not superior to zidovudine monotherapy in patients with AIDS or severe immunosuppression and that it produced considerably more side effects. However, subgroup analyses indicate that these combinations may be more effective in patients with little or no prior zidovudine use than in patients with extensive prior use.
Presented in part at the Terry Beirn Community Programs for Clinical Research on AIDS Group Meeting, Washington, D.C., January 18, 1996; the Third Conference on Retroviruses and Opportunistic Infections, Washington, D.C., January 28–February 1, 1996; and the 11th International Conference on AIDS, Vancouver, B.C., July 7–12, 1996.
Supported by contracts (NO1-AI-04045, NO1-AI-45227, NO1-AI45231, NO1-AI-45233, NO1-AI-45222, NO1-AI-4040, NO1-AI-45224, NO1-AI-05047, NO1-AI-45230, NO1-AI-05046, NO1-AI-45229, NO1-AI-45220, NO1-AI-45235, NO1-AI-45228, NO1-AI-45234, NO1-AI-55258, NO1-AI-55255, and NO1-AI-55261) with the National Institute of Allergy and Infectious Diseases and by Bristol-Myers Squibb, Glaxo–Wellcome, and Hoffmann–LaRoche.
Dr. Abrams was an ad hoc consultant to Bristol-Myers Squibb during the conduct of this study.
We are indebted to the Terry Beirn Community Programs for Clinical Research on AIDS (007) NuCombo protocol team: L. Besch, M.D., B. Brizz, B.S.N., M.H.S.Ed., M. Dehlinger, D.N.Sc., L. Deyton, M.S.P.H., M.D., R. Donovan, Ph.D., V. Dratter, R.N., M.S., W. El-Sadr, M.D., M.P.H., A. Martinez, R.Ph., C. McLaren, Ph.D., M.R.C.Path., M. Salgo, M.D., Ph.D., F. Rousseau, M.D., M. Myers, R.N., M. Thurnherr, D. Mayers, M.D., T. Church, Ph.D., P. Gourley, R.N., C. Nauss-Karol, Ph.D., R. Swilley, R.N., C.R.N.A., K. Pattishall, B.S., R. Doolittle, R.N., D. McClure, M.S., Ph.D., M. Elkins, J. Warwick, Pharm.D., W. Rida, Ph.D., P. Stampone, M.S., and S. Wakefield.
Source Information
From St. John Hospital, Detroit (L.D.S.); the Delaware Community Program for Clinical Research on AIDS, Wilmington (D.L.W.); the Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis (G.C., J.S.H.); the Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. (C.P.); Albany Medical College, Albany, N.Y. (D.S.S.); Henry Ford Hospital, Detroit (N.M.); the Denver Community Program for Clinical Research on AIDS, Denver (R.R.); the Research and Education Group, Portland, Oreg. (M.O.L.); Wayne State University–Detroit Medical Center, Detroit (L.C.); the AIDS Research Consortium of Atlanta, Atlanta (M.T.); and the Community Consortium of San Francisco, San Francisco (D.A.).
Address reprint requests to Dr. Lawrence Deyton at the National Institutes of Health, 6003 Executive Blvd., Bethesda, MD 20892.
Other study participants are listed in the Appendix.
Appendix
The following centers and investigators also participated in the study: Henry Ford Hospital, Detroit — J. Kumi, B. Al-Ujayli, and D. Mastro-Polak; Denver Community Program for Clinical Research on AIDS — D. Cohn, M. Grodesky, and J. Saldanha; the Research and Education Group — J. Sampson, J. Godbey, and K. Loveless; Wayne State University–Detroit Medical Center — G. Deisinger, K. Mooney, and R. Fakhry; AIDS Research Consortium of Atlanta — S. Thompson, R. Hudson, and M. Tanner; Community Consortium of San Francisco — W.J. Fessel and A. Harris (Kaiser Medical Center), R.C. Scott (Alta Bates Medical Associates, Oakland); Addiction Research and Treatment Corporation, Brooklyn, N.Y. — L.S. Brown, Jr., S. John, and J. Rawls; AIDS Research Alliance, Chicago — R. Luskin-Hawk, R. Slotten, and J. Bonnell-Lucia; Clinical Directors Network of Region II, New York — R.A. Torres; Louisiana Community AIDS Research Programs — J. Osterberger, J. Walker, and S. Pablovich; North Jersey Community Research Initiative, Newark, N.J. — G. Perez; Richmond AIDS Consortium — T.M. Kerkering, E. Fisher, and R. Artz; Washington Regional AIDS Program, Washington, D.C. — F. Gordin; the NIAID Data and Safety Monitoring Board — C. Carpenter, Brown University, Providence, R.I.; B. Brody, Baylor College of Medicine, Houston; D. DeMets, University of Wisconsin Medical School, Madison; T. Fleming, University of Washington, Seattle; K. Mayer, Memorial Hospital, Pawtucket, R.I.; D. Murphy, University of Florida Health Sciences, Gainesville; J. O'Fallon, Mayo Clinic, Rochester, Minn.; J. Rahal, The New York Hospital Medical Center of Queens and Cornell University; M. Sande, San Francisco General Hospital; S. Straus, NIAID, Bethesda, Md.; L. Walters, Georgetown University, Washington, D.C.; R. Whitley, University of Alabama, Birmingham; P. Whitley-Williams, University of Medicine and Dentistry of New Jersey; the Division of AIDS, NIAID — S. Schnittman, W. Duncan, J. Killen, and D.O. Dixon; and the Terry Beirn Community Programs for Clinical Research on AIDS Statistical Center, University of Minnesota — J.D. Neaton.
- References
References
1
Mitsuya H ,Broder S . Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotrophic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) by 2',3'-dideoxynucleosides. Proc Natl Acad Sci U S A 1986;83:1911-1915
CrossRef | Web of Science | Medline2
Yarchoan R ,Perno CF ,Thomas RV , et al. Phase I studies of 2',3'-dideoxycytidine in severe human immunodeficiency virus infection as a single agent and alternating with zidovudine (AZT). Lancet 1988;1:76-81
CrossRef | Web of Science | Medline3
Yarchoan R, Thomas RV, Pluda JM, et al. Escalating dose phase I study of intravenous and oral 2',3'-dideoxyinosine (didanosine) in patients with AIDS or ARC. In: Proceedings of the Fifth International Conference on AIDS, Montreal, June 4–9, 1989. Ottawa, Ont.: International Development Research Centre, 1989:212. abstract.
4
Yarchoan R ,Mitsuya H ,Thomas RV , et al. In vivo activity against HIV and favorable toxicity profile of 2',3'-dideoxyinosine. Science 1989;245:412-415
CrossRef | Web of Science | Medline5
Yarchoan R ,Mitsuya H ,Pluda JM , et al. The National Cancer Institute phase I study of 2',3'-dideoxyinosine administration in adults with AIDS or AIDS-related complex: analysis of activity and toxicity profiles. Rev Infect Dis 1990;12:Suppl 5:S522-S533
CrossRef | Medline6
Gottlieb M, Galpin J, Thompkins J, et al. 2',3'-Dideoxycytidine (zalcitabine) in the treatment of patients with AIDS and ARC. In: Proceedings of the Fifth International Conference on AIDS, Montreal, June 4–9, 1989. Ottawa, Ont.: International Development Research Centre, 1989:212. abstract.
7
Bozzette S, Skowron G, Arrezo J, et al. ACTG 050: alternating (ALT) and intermittent (INT) zalcitabine and AZT in the treatment of persons with advanced HIV infection and hematologic intolerance to AZT. In: Abstracts of the Sixth International Conference on AIDS, San Francisco, June 20–24, 1990. Vol. 3. San Francisco: University of California, 1990:192. abstract.
8
Cooley T, Kunches LM, Saunders CA, et al. Therapy of AIDS and ARC with 2',3'-dideoxyinosine (didanosine) given once daily: results of long-term followup. In: Abstracts of the Sixth International Conference on AIDS, San Francisco, June 20–24, 1990. Vol. 3. San Francisco: University of California, 1990:205. abstract.
9
Johnson VA, Merrill DP, Chou TC, Hirsch MS. HIV-1 inhibitory interactions between 2',3'-dideoxyinosine (didanosine) and either zidovudine (AZT), recombinant soluble CD4 (rsCD4) or recombinant interferon-alpha-A (rIFN-a-A). In: Abstracts of the Sixth International Conference on AIDS, San Francisco, June 20–24, 1990. Vol. 2. San Francisco: University of California, 1990:106. abstract.
10
Merigan TC . Treatment of AIDS with combinations of antiretroviral agents. Am J Med 1991;90:Suppl:8S-17S
CrossRef | Web of Science | Medline11
Meng TC ,Fischl MA ,Boota AM , et al. Combination therapy with zidovudine and dideoxycytidine in patients with advanced human immunodeficiency virus infection: a phase I/II study. Ann Intern Med 1992;116:13-20
Web of Science | Medline12
Ragni M, Dafni R, Amato DA, et al. Combination zidovudine and dideoxyinosine in asymptomatic HIV(+) patients. In: Abstracts of the Eighth International Conference on AIDS/Third STD World Congress, Amsterdam, July 19–24, 1992. Vol. 1. Amsterdam: CONGREX, 1992:Mo15. abstract.
13
Collier AC ,Coombs RW ,Fischl MA , et al. Combination therapy with zidovudine and didanosine compared with zidovudine alone in HIV-1 infection. Ann Intern Med 1993;119:786-793
Web of Science | Medline14
Price RW ,Brew BJ . The AIDS dementia complex. J Infect Dis 1988;158:1079-1083
CrossRef | Web of Science | Medline15
Revision of the CDC surveillance case definition for acquired immunodeficiency syndromeMMWR Morb Mortal Wkly Rep 1987;36:Suppl 1:3S-15S
Medline16
Lawless JF. Statistical models and methods for lifetime data. New York: John Wiley, 1982.
17
Wei LJ ,Lin DY ,Weissfeld L . Regression analysis of multivariate incomplete failure time data by modeling marginal distributions. J Am Stat Assoc 1989;84:1065-1073
CrossRef | Web of Science18
Laird NM ,Ware JH . Random-effects models for longitudinal data. Biometrics 1982;38:963-974
CrossRef | Web of Science | Medline19
Mayers DL ,Japour AJ ,Arduino J-M , et al. Dideoxynucleoside resistance emerges with prolonged zidovudine monotherapy. Antimicrob Agents Chemother 1994;38:307-314
Web of Science | Medline20
D'Aquila RT ,Johnson VA ,Welles SL , et al. Zidovudine resistance and HIV-1 disease progression during antiretroviral therapy. Ann Intern Med 1995;122:401-408
Web of Science | Medline21
Hammer SM ,Katzenstein DA ,Hughes MD , et al. A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. N Engl J Med 1996;335:1081-1090
Full Text | Web of Science | Medline22
Concorde Coordinating Committee
CrossRef | Web of Science | Medline23
Volberding PA ,Lagakos SW ,Grimes JM , et al. The duration of zidovudine benefit in persons with asymptomatic HIV infection: prolonged evaluation of protocol 019 of the AIDS Clinical Trials Group. JAMA 1994;272:437-442
CrossRef | Web of Science | Medline24
Ho DD . Time to hit HIV, early and hard. N Engl J Med 1995;333:450-451
Full Text | Web of Science | Medline
- Citing Articles (78)
Citing Articles
1
Lisa K. Naeger, Kimberly A. Struble, Jeffrey S. Murray, Debra B. Birnkrant. (2010) Running a tightrope: Regulatory challenges in the development of antiretrovirals. Antiviral Research 85:1, 232-240
CrossRef2
Edward M Gardner, William J Burman, John F Steiner, Peter L Anderson, David R Bangsberg. (2009) Antiretroviral medication adherence and the development of class-specific antiretroviral resistance. AIDS 23:9, 1035-1046
CrossRef3
Kristin H Busse, Scott R Penzak. (2008) Pharmacological enhancement of protease inhibitors with ritonavir: an update. Expert Review of Clinical Pharmacology 1:4, 533-545
CrossRef4
Edward M Gardner, Shweta Sharma, Grace Peng, Katherine Huppler Hullsiek, William J Burman, Rodger D MacArthur, Margaret Chesney, Edward E Telzak, Gerald Friedland, Sharon B Mannheimer. (2008) Differential adherence to combination antiretroviral therapy is associated with virological failure with resistance. AIDS 22:1, 75-82
CrossRef5
A. Mocroft, C. A. Sabin, M. Youle, S. Madge, M. Tyrer, H. Devereux, J. Deayton, A. Dykhoff, M. C. I. Lipman, A. N. Phillips, M. A. Johnson. (2006) Changes in AIDS-Defining Illnesses in a London Clinic, 1987???1998. Journal of Acquired Immune Deficiency Syndromes 21:5, 401
CrossRef6
2006. Zidovudine. , 3713-3717.
CrossRef7
2006. Zalcitabine. , 3710.
CrossRef8
Stephen P Raffanti, Jennifer S Fusco, Beth H Sherrill, Nellie I Hansen, Amy C Justice, Richard D???Aquila, Wendy J Mangialardi, Gregory P Fusco. (2004) Effect of Persistent Moderate Viremia on Disease Progression During HIV Therapy. JAIDS Journal of Acquired Immune Deficiency Syndromes 37:1, 1147-1154
CrossRef9
F. Antunes, M. Walker, Graeme J. Moyle. (2004) Efficacy and Tolerability of Zalcitabine Twice Daily (HIVBID Study). JAIDS Journal of Acquired Immune Deficiency Syndromes 35:2, 205-206
CrossRef10
Ronald B. Reisler, Cong Han, William J. Burman, Ellen M. Tedaldi, James D. Neaton. (2003) Grade 4 Events Are as Important as AIDS Events in the Era of HAART. JAIDS Journal of Acquired Immune Deficiency Syndromes 34:4, 379-386
CrossRef11
Thomas R. Fleming, Susan Ellenberg, David L. DeMets. (2002) Monitoring clinical trials: issues and controversies regarding confidentiality. Statistics in Medicine 21:19, 2843-2851
CrossRef12
Lisa E. Cox. (2002) Social Support, Medication Compliance and HIV/AIDS. Social Work in Health Care 35:1-2, 425-460
CrossRef13
Eva Lonn. (2001) The use of surrogate endpoints in clinical trials: focus on clinical trials in cardiovascular diseases. Pharmacoepidemiology and Drug Safety 10:6, 497-508
CrossRef14
Susan S. Ellenberg. (2001) Independent data monitoring committees: rationale, operations and controversies. Statistics in Medicine 20:17-18, 2573-2583
CrossRef15
J. G. Kahn, B. Haile, J. Kates, S. Chang. (2001) Health and Federal Budgetary Effects of Increasing Access to Antiretroviral Medications for HIV by Expanding Medicaid. American Journal of Public Health 91:9, 1464-1473
CrossRef16
C Scully, P Diz Dios. (2001) Orofacial effects of antiretroviral therapies. Oral Diseases 7:4, 205-210
CrossRef17
(2001) An Open-Label Randomized Trial to Evaluate Different Therapeutic Strategies of Combination Therapy in HIV-1 Infection Design, Rationale, and Methods of the Initio Trial. Controlled Clinical Trials 22:2, 160-175
CrossRef18
Stephen L. Becker, Stephen R. Raffanti, Nellie I. Hansen, Jennifer S. Fusco, Gregory P. Fusco, Gary H. Slatko, Ebere F. Igboko, Neil M. H. Graham. (2001) Zidovudine and Stavudine Sequencing in HIV Treatment Planning: Findings From the CHORUS HIV Cohort. JAIDS Journal of Acquired Immune Deficiency Syndromes 26:1, 72-81
CrossRef19
Eduard J. Beck, Alec H. Miners, Keith Tolley. (2001) The Cost of HIV Treatment and Care. PharmacoEconomics 19:1, 13-39
CrossRef20
Stephen L. Becker, Stephen R. Raffanti, Nellie I. Hansen, Jennifer S. Fusco, Gregory P. Fusco, Gary H. Slatko, Ebere F. Igboko, Neil M. H. Graham. (2001) Zidovudine and Stavudine Sequencing in HIV Treatment Planning: Findings From the CHORUS HIV Cohort. Journal of Acquired Immune Deficiency Syndromes 26:1, 72-81
CrossRef21
Daniel S. Stein, Katy H. P. Moore. (2001) Phosphorylation of Nucleoside Analog Antiretrovirals: A Review for Clinicians. Pharmacotherapy 21:1, 11-34
CrossRef22
(2000) Changes in the uptake of antiretroviral therapy and survival in people with known duration of HIV infection in Europe: results from CASCADE. HIV Medicine 1:4, 224-231
CrossRef23
Stefano Rusconi, Simona La Seta Catamancio, Francis Sheridan, David Parker. (2000) A genotypic analysis of patients receiving Zidovudine with either Lamivudine, Didanosine or Zalcitabine dual therapy using the LiPA point mutation assay to detect genotypic variation at codons 41, 69, 70, 74, 184 and 215. Journal of Clinical Virology 19:3, 135-142
CrossRef24
Yueming Li, Ann M. McDonald, Gregory J. Dore, John M. Kaldor. (2000) Improving survival following AIDS in Australia, 1991???1996. AIDS 14:15, 2349-2354
CrossRef25
M. A. Albrecht, M. D. Hughes, S. H. Liou, D. A. Katzenstein, R. Murphy, H. H. Balfour, M. F. Para, H. Valdez, S. M. Hammer. (2000) Effect of Lamivudine in HIV-Infected Persons with Prior Exposure to Zidovudine/Didanosine or Zidovudine/Zalcitabine. AIDS Research and Human Retroviruses 16:14, 1337-1344
CrossRef26
(2000) Effect of ignoring the time of HIV seroconversion in estimating changes in survival over calendar time in observational studies: results from CASCADE*. AIDS 14:13, 1899-1906
CrossRef27
(2000) Human Immunodeficiency Virus Type 1 RNA Level and CD4 Count as Prognostic Markers and Surrogate End Points: A Meta-Analysis. AIDS Research and Human Retroviruses 16:12, 1123-1133
CrossRef28
Janet Darbyshire, Mary Foulkes, Richard Peto, William Duncan, Abdel Babiker, Rory Collins, Mike Hughes, Tim EA Peto, Sarah A Walker, Janet Darbyshire. 2000. Zidovudine (AZT) versus AZT plus didanosine (ddI) versus AZT plus zalcitabine (ddC) in HIV infected adults. .
CrossRef29
Thomas N. Kakuda. (2000) Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clinical Therapeutics 22:6, 685-708
CrossRef30
Felipe García, Joan Romeu, Inmaculada Grau, María Antonia Sambeat, David Dalmau, Hernado Knobel, Juan Luis Gomez-Sirvent, Julio Arrizabalaga, Anna Cruceta, Bonaventura Clotet, Daniel Podzamczer, Tomás Pumarola, Teresa Gallart, William A. O‚Brien, José M Miró, José M Gatell. (1999) A randomized study comparing triple versus double antiretroviral therapy or no treatment in HIV-1-infected patients in very early stage disease: the Spanish Earth-1 study. AIDS 13:17, 2377-2388
CrossRef31
(1999) Parents' attitudes to their HIV-infected children being enrolled into a placebo-controlled trial: the PENTA 1 trial. HIV Medicine 1:1, 25-31
CrossRef32
A. Mocroft, CA. Sabin, M. Youle, L. Swaden, M. Tyrer, D. Wilson, S. Madge, MA. Johnson, AN. Phillips. (1999) Changing treatment patterns among patients with HIV: Royal Free Hospital 1987-97. HIV Medicine 1:1, 32-39
CrossRef33
Andrew N. Phillips, Sophie Grabar, Jean-Michel Tassie, Dominique Costagliola, Jens D. Lundgren, Matthias Egger. (1999) Use of observational databases to evaluate the effectiveness of antiretroviral therapy for HIV infection: comparison of cohort studies with randomized trials. AIDS 13:15, 2075-2082
CrossRef34
A. Mocroft, C. A. Sabin, M. Youle, S. Madge, M. Tyrer, H. Devereux, J. Deayton, A. Dykhoff, M. C. I. Lipman, A. N. Phillips, M. A. Johnson. (1999) Changes in AIDS-Defining Illnesses in a London Clinic, 1987–1998. JAIDS Journal of Acquired Immune Deficiency Syndromes 21:5, 401
CrossRef35
A. Mocroft, C. A. Sabin, M. Youle, S. Madge, M. Tyrer, H. Devereux, J. Deayton, A. Dykhoff, M. C. I. Lipman, A. N. Phillips, M. A. Johnson. (1999) Changes in AIDS-Defining Illnesses in a London Clinic, 1987–1998. Journal of Acquired Immune Deficiency Syndromes 21:5, 401
CrossRef36
Emmanuelle Le Corfec, Sylvie Chevret, Dominique Costagliola. (1999) Visit-driven endpoints in randomized HIV/AIDS clinical trials: impact of missing data on treatment difference measured on summary statistics. Statistics in Medicine 18:14, 1803-1817
CrossRef37
Zelalem Temesgen. (1999) Overview of HIV infection. Annals of Allergy, Asthma & Immunology 83:1, 1-7
CrossRef38
Amanda Mocroft, Simon Barry, Caroline A. Sabin, Alessandro Cozzi Lepri, Sabine Kinloch, Anthony Drinkwater, Marc Lipman, Michael Youle, Margaret A. Johnson, Andrew N. Phillips. (1999) The changing pattern of admissions to a London hospital of patients with HIV: 1988-1997. AIDS 13:10, 1255-1261
CrossRef39
Fran
oise Baudouin, Marie N. Kolopp Sarda, Alain Goguel, Marie C. B
CrossRef40
(1999) Zidovudine, didanosine, and zalcitabine in the treatment of HIV infection: meta-analyses of the randomised e vidence. The Lancet 353:9169, 2014-2025
CrossRef41
P. Bonfanti, A. Capetti, G. Rizzardini. (1999) HIV disease treatment in the era of HAART. Biomedicine & Pharmacotherapy 53:2, 93-105
CrossRef42
J. Izopet, L. Sailler, K. Sandres, C. Pasquier, E. Bonnet, C. Aquilina, J. Puel, P. Massip, B. Marchou. (1999) Intermittent selection pressure with zidovudine plus zalcitabine treatment reduces the emergence in vivo of zidovudine resistance HIV mutations. Journal of Medical Virology 57:2, 163-168
CrossRef43
Brent Johnson, Bradley P. Carlin, James S. Hodges. (1999) CROSS-STUDY HIERARCHICAL MODELING OF STRATIFIED CLINICAL TRIAL DATA. Journal of Biopharmaceutical Statistics 9:4, 617-640
CrossRef44
Khurram Z. Rana, Michael N. Dudley. (1999) Human Immunodeficiency Virus Protease Inhibitors. Pharmacotherapy 19:1, 35-59
CrossRef45
Mauro Schechter, Cláudio J. Struchiner, Lee H. Harrison. (1999) Protease inhibitors as initial therapy for individuals with an intermediate risk of HIV disease progression: is more necessarily better?. AIDS 13:1, 97-102
CrossRef46
Keith Henry, Alejo Erice, Camlin Tierney, Henry H. Balfour, Margaret A. Fischl, Anne Kmack, Song-Heng Liou, Antoinette Kenton, Martin S. Hirsch, John Phair, Ana Martinez, James O. Kahn. (1998) A Randomized, Controlled, Double-Blind Study Comparing the Survival Benefit of Four Different Reverse Transcriptase Inhibitor Therapies (Three-Drug, Two-Drug, and Alternating Drug) for the Treatment of Advanced AIDS. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 19:4, 339-349
CrossRef47
A Mocroft, S Vella, TL Benfield, A Chiesi, V Miller, P Gargalianos, A d'Arminio Monforte, I Yust, JN Bruun, AN Phillips, JD Lundgren. (1998) Changing patterns of mortality across Europe in patients infected with HIV-1. The Lancet 352:9142, 1725-1730
CrossRef48
Lisa A. Green, Frank S. Rhame, Richard W. Price, David C. Perlman, Linnea G. Capps, James H. Sampson, Lawrence R. Deyton, Steven M. Schnittman, Evelyn J. Fisher, Glenn E. Bartsch, Eric A. Krum, James D. Neaton. (1998) Experience with a cross-study endpoint review committee for AIDS clinical trials. AIDS 12:15, 1983-1990
CrossRef49
Ole Kirk, Amanda Mocroft, Terese L. Katzenstein, Adriano Lazzarin, Francisco Antunes, Patrick Francioli, Ray P. Brettle, Jacqueline M. Parkin, Juan Gonzales-Lahoz, Jens D. Lundgren. (1998) Changes in use of antiretroviral therapy in regions of Europe over time. AIDS 12:15, 2031-2039
CrossRef50
François Raffi, Véronique Reliquet, Sylvie Auger, Jean-Marc Besnier, Jean-Marie Chennebault, Eric Billaud, Christian Michelet, Philippe Perre, Alain Lafeuillade, Thierry May, Sylviane Billaudel. (1998) Efficacy and safety of stavudine and didanosine combination therapy in antiretroviral-experienced patients. AIDS 12:15, 1999-2005
CrossRef51
Norbert A. Foudraine, Jacques J. de Jong, Gerrit Jan Weverling, Birgit H.B. van Benthem, Jaap Maas, Ireneus P.M. Keet, Suzanne Jurriaans, Marijke T.L. Roos, Kati Vandermeulen, Frank de Wolf, Joep M.A. Lange. (1998) An open randomized controlled trial of zidovudine plus lamivudine versus stavudine plus lamivudine. AIDS 12:12, 1513-1519
CrossRef52
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
CrossRef53
(1998) Long-term follow-up of randomized trials of immediate versus deferred zidovudine in symptom-free HIV infection. AIDS 12:11, 1259???1265
CrossRef54
Mark J. Sculpher, Diana Gibb, A E. Ades, Julie Ratcliffe, Trinh Duong. (1998) Modelling the costs of paediatric HIV infection and AIDS. AIDS 12:11, 1371-1380
CrossRef55
Martin Gebhardt, Martin Rickenbach, Matthias Egger. (1998) Impact of antiretroviral combination therapies on AIDS surveillance reports in Switzerland. AIDS 12:10, 1195-1201
CrossRef56
David A. Wheeler, Cynthia L. Gibert, Cynthia A. Launer, Norma Muurahainen, Richard A. Elion, Donald I. Abrams, Glenn E. Bartsch. (1998) Weight Loss as a Predictor of Survival and Disease Progression in HIV Infection. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 18:1, 80-85
CrossRef57
Wendy J. Watson, Timothy P. Stevens, Geoffrey A. Weinberg. (1998) PROFOUND ANEMIA IN A NEWBORN INFANT OF A MOTHER RECEIVING ANTIRETROVIRAL THERAPY. The Pediatric Infectious Disease Journal 17:5, 435-436
CrossRef58
John C. Walsh, Colin D. Jones, Eric A. Barnes, Brian G. Gazzard, Suzanne M. Mitchell. (1998) Increasing survival in AIDS patients with cytomegalovirus retinitis treated with combination antiretroviral therapy including HIV protease inhibitors. AIDS 12:6, 613-618
CrossRef59
Gerd Horneff, Ortwin Adams, Volker Wahn. (1998) Pilot study of zidovudine–lamivudine combination therapy in vertically HIV-infected antiretroviral-naive children. AIDS 12:5, 489-494
CrossRef60
Andrew N. Phillips, Christine Katlama, Simon Barton, Stefano Vella, Anders Blaxhult, Bonaventura Clotet, Frank-Detlef Goebel, B. Hirschel, Court Pedersen, Jens D. Lundgren. (1998) Survival in 2367 Zidovudine-Treated Patients According to Use of Other Nucleoside Analogue Drugs. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 17:3, 239-244
CrossRef61
Graeme Moyle. (1998) A re-evaluation of zalcitabine. Expert Opinion on Investigational Drugs 7:3, 451-462
CrossRef62
M. Barry, F. Mulcahy, D. J. Back. (1998) Antiretroviral therapy for patients with HIV disease. British Journal of Clinical Pharmacology 45:3, 221-228
CrossRef63
D William Cameron, Margo Heath-Chiozzi, Sven Danner, Calvin Cohen, Stephen Kravcik, Clement Maurath, Eugene Sun, David Henry, Richard Rode, Amy Potthoff, John Leonard. (1998) Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. The Lancet 351:9102, 543-549
CrossRef64
Philippe Sudre, Jean Philippe Chave, Christian Ruef, Anne Iten, Heiner C. Bucher, Pietro L. Vernazza, Hansjakob Furrer, Enos Bernasconi, Norberto Ceserani, Manuel Battegay, Jan Von Overbeck, Ignazio Cassis, Adriano Lazzarin, Victor Gabriel, Bernard J. Hirschel, . (1997) Low doses of zidovudine plus didanosine are less effective than higher doses of didanosine monotherapy: a randomized trial in patients pretreated with zidovudine. Clinical Microbiology and Infection 3:6, 629-633
CrossRef65
R TUOMALA. (1997) PREVENTION OF TRANSMISSIONPharmaceutical and Obstetric Approaches. Obstetrics and Gynecology Clinics of North America 24:4, 785-795
CrossRef66
Gostin, Lawrence O., , Ward, John W., , Baker, A. Cornelius. (1997) National HIV Case Reporting for the United States — A Defining Moment in the History of the Epidemic. New England Journal of Medicine 337:16, 1162-1167
Full Text67
Francoise Brun-Vezinet, Charles Boucher, Clive Loveday, Diane Descamps, Veronique Fauveau, Jacques Izopet, Don Jeffries, Steve Kaye, Corinne Krzyanowski, Andrew Nunn, Rob Schuurman, Jean-Marie Seigneurin, Catherine Tamalet, Richard Tedder, Jonathan Weber, Gerrit-Jan Weverling. (1997) HIV-1 viral load, phenotype, and resistance in a subset of drug-naive participants from the Delta trial. The Lancet 350:9083, 983-990
CrossRef68
Jonathan Weber. (1997) Trials and tribulations: ethical dilemmas in HIV therapy. Current Opinion in Immunology 9:5, 625-627
CrossRef69
. (1997) Internationale richtlijnen voor antiretrovirale therapie bij HIV-infectie. Medisch-Farmaceutische Mededelingen 35:9, 180-181
CrossRef70
Stephen Morris-Jones, Graeme Moyle, Philippa J Easterbrook. (1997) Antiretroviral therapies in HIV-1 infection. Expert Opinion on Investigational Drugs 6:8, 1049-1061
CrossRef71
Sean Emery, H Clifford Lane. (1997) Immune reconstitution in HIV infection. Current Opinion in Immunology 9:4, 568-572
CrossRef72
(1997) Randomised trial of addition of lamivudine or lamivudine plus loviride to zidovudine-containing regimens for patients with HIV-1 infection: the CAESAR trial. The Lancet 349:9063, 1413-1421
CrossRef73
Meredith Y. Smith, PhD, Bruce D. Rapkin, Anne Morrison, Sandra Kammerman. (1997) Zidovudine Adherence in Persons with AIDS The Relation of Patient Beliefs About Medication to Self-Termination of Therapy. Journal of General Internal Medicine 12:4, 216-223
CrossRef74
BG Gazzard, GJ Moyle, J Weber, M Johnson, JS Bingham, R Brettle, D Churchill, M Fisher, G Griffin, D Jefferies, E King, R Gormer, C Lee, A Pozniak, JR Smith, G Tudor-Williams, I Williams. (1997) British HIV Association guidelines for antiretroviral treatment of HIV seropositive individuals. The Lancet 349:9058, 1086-1092
CrossRef75
J. Misson, W. Clark, M. J. Kendall. (1997) Therapeutic advances: protease inhibitors for the treatment of HIV-1 infection. Journal of Clinical Pharmacy and Therapeutics 22:2, 109-117
CrossRef76
Malcolm D Zaretsky. (1997) The Delta trial. The Lancet 349:9048, 358-359
CrossRef77
Corey, Lawrence, , Holmes, King K., . (1996) Therapy for Human Immunodeficiency Virus Infection — What Have We Learned?. New England Journal of Medicine 335:15, 1142-1144
Full Text78
Hammer, Scott M., Katzenstein, David A., Hughes, Michael D., Gundacker, Holly, Schooley, Robert T., Haubrich, Richard H., Henry, W. Keith, Lederman, Michael M., Phair, John P., Niu, Manette, Hirsch, Martin S., Merigan, Thomas C., . (1996) A Trial Comparing Nucleoside Monotherapy with Combination Therapy in HIV-Infected Adults with CD4 Cell Counts from 200 to 500 per Cubic Millimeter. New England Journal of Medicine 335:15, 1081-1090
Full Text
