Original Article
The Effects on Survival of Early Treatment of Human Immunodeficiency Virus Infection
N Engl J Med 1992; 326:1037-1042April 16, 1992
- Abstract
- Abstract
Background.
Zidovudine has been shown to prolong survival in patients with the acquired immunodeficiency syndrome (AIDS) and, in persons with human immunodeficiency virus (HIV) infection but not AIDS, to delay the progression to AIDS. However, it is still uncertain whether treatment before the development of AIDS prolongs survival.
Methods.
We analyzed data from a cohort of 2162 high-risk men who were already seropositive for HIV type 1 (HIV-1) and 406 men who seroconverted from October 1986 through April 1991. There were 306 deaths. The probabilities of death were compared among men at similar stages of disease who began zidovudine therapy before the diagnosis of AIDS and among those who did not. Relative risks of death were calculated for each of five initial disease states on the basis of CD4+ cell counts and clinical symptoms and signs appearing over follow-up periods of 6, 12, 18, and 24 months. Adjustments were also made for the use of prophylaxis against Pneumocystis carinii pneumonia (PCP).
Results.
After we controlled for CD4+ cell count and symptoms, the use of zidovudine with or without PCP prophylaxis before the development of AIDS significantly reduced mortality in all follow-up periods. The relative risks of death were 0.43 (95 percent confidence interval, 0.23 to 0.78) at 6 months, 0.54 (95 percent confidence interval, 0.38 to 0.78) at 12 months, 0.59 (95 percent confidence interval, 0.44 to 0.79) at 18 months, and 0.67 (95 percent confidence interval, 0.52 to 0.86) at 24 months. After we adjusted for the effects of PCP prophylaxis, zidovudine alone significantly reduced mortality at 6, 12, and 18 months (relative risks, 0.45, 0.59, and 0.70, respectively), but not at 24 months (relative risk, 0.81). Among zidovudine users, those who also used PCP prophylaxis before the development of AIDS had significantly lower mortality at 18 and 24 months than those who did not (relative risks, 0.62 and 0.60, respectively).
Conclusions.
The results of this study support the hypothesis that in HIV-1 infection, early treatment with zidovudine and PCP prophylaxis improves survival in addition to slowing the progression to AIDS. (N Engl J Med 1992;326:1037–42.)
Article Activity
- Article
THE efficacy of zidovudine in prolonging the survival of patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex was first reported in 1987.1 Subsequent clinical trials examined the efficacy of zidovudine in early human immunodeficiency virus (HIV) infection but used the development of AIDS, rather than death, as the primary outcome measure.2 , 3 Our own observations in the Multicenter AIDS Cohort Study strongly support the findings that zidovudine slows the progression to AIDS and that prophylaxis against Pneumocystis carinii pneumonia (PCP) also reduces the incidence of PCP among persons taking zidovudine.4
In an observational study of patients with AIDS in Maryland, zidovudine users had a median survival of 690 days, as compared with 280 days for patients who had never used zidovudine.5 In Australia, patients with AIDS who received zidovudine had a median survival of 124 weeks, as compared with 44 weeks for historical controls who never received the drug.6 Although the available experimental1 and observational5 , 6 evidence shows clearly that zidovudine prolongs survival in patients with AIDS, it is not clear whether giving the drug earlier in the course of infection (i.e., before the development of AIDS) prolongs survival in addition to prolonging the time until AIDS develops.2 3 4 Data from the Veterans Affairs Cooperative Zidovudine Study have raised doubts about the efficacy of early zidovudine use in prolonging survival.7 In the Veterans Affairs trial, 338 patients with CD4+ lymphocyte counts of 0.2 to 0.5 cells ×109 per liter (200 to 500 per cubic millimeter) were randomly assigned to early zidovudine therapy (at the beginning of the study) or later treatment (when the CD4+ lymphocyte count fell below 0.2 cells ×l09 per liter). After two years of follow-up, the early-treatment group had significantly fewer AIDS-defining events than the late-treatment group (25 vs. 44, P = 0.02), but no significant differences in numbers of deaths (23 vs. 19).7 The small numbers of outcomes, the use of high-dose treatment regimens (1500 mg per day), and alterations to the protocol during the study suggest that these mortality data may not reflect the true treatment effect in persons taking zidovudine at currently recommended doses (500 mg per day). Nonetheless, further data are urgently needed to elucidate the effect of early therapy on survival in HIV-infected patients. Several clinical trials, including the Concorde trial of zidovudine in Europe8 and the continuation of AIDS Clinical Trials Group protocols 019 and 016 in patients with more than 0.5 CD4+ cells × 109 per liter, may not provide data from controlled trials to address this issue for several years.
To study this question, we carried out an analysis of mortality in the Multicenter AIDS Cohort Study.9 The relative risks of death after 6, 12, 18, and 24 months of follow-up were compared in participants who started zidovudine therapy (with or without PCP prophylaxis) before the development of AIDS and in those who did not start to take zidovudine before AIDS developed. These analyses have the advantage of including a large number of outcome events and a large, well-characterized study population representing the spectrum of HIV infection and disease. Since treatment is not randomly assigned in observational prospective studies, selection bias can confound inferences about treatment effects. Care has been taken to minimize potential effects of selection and participation bias.4
Methods
Study Population
The Multicenter AIDS Cohort Study is a prospective study of the natural history of HIV infection among homosexual and bisexual men in the United States. From April 1984 through March 1985, 4954 homosexual and bisexual men were enrolled in four metropolitan areas — Chicago, Pittsburgh, Los Angeles, and the area including Baltimore and Washington, D.C. Men who had been given a diagnosis of AIDS before the time of enrollment in 1984 and those under 18 years of age were excluded from the study. From April 1987 through December 1990, an additional 587 men were recruited to increase representation from ethnic and racial minority groups; these men were included in the analysis. The participants returned for semiannual follow-up visits, at each of which they completed a study questionnaire, underwent a physical examination, and had blood drawn for hematologic, serologic, and virologic studies. Details of the study design and methods have been described elsewhere.9 , 10 Of the 4954 men enrolled into the study in 1984 and 1985, 1809 (36.5 percent) were seropositive for HIV type 1 (HIV-1) at entry, and 393 (7.9 percent) who were seronegative at entry became HIV-1—seropositive by April 1991 (i.e., they seroconverted within the first seven years of follow-up). Among the 587 later recruits, 353 (60.1 percent) were seropositive at entry, and 13 (2.2 percent) seroconverted by April 1991. HIV-1 seropositivity was determined by enzyme-linked immunosorbent assay and confirmed with Western blot testing. This analysis included all men seropositive for HIV-1 at entry and those who seroconverted before the time of the visit used as a base line in this study and who had not contracted AIDS or died by the time of their sixth study visit (visit 6).
The analysis was restricted to the period beginning with study visit 6 (October 1986 through March 1987). This period was chosen because previously zidovudine was unavailable, and no participants in the study reported its use until visit 6. In addition, the selection of this starting time for the study minimized the effect of any secular trends in survival time in the patients not taking zidovudine. Deaths and diagnoses of AIDS from October 1, 1986, through April 1, 1991, were included in the study.
Stage of Disease and Risk of Death
To examine the effect on survival of treatment (with zidovudine and PCP prophylaxis) before the onset of AIDS, mortality rates were calculated for patients who entered the study period in one of five starting disease states and were followed for periods of 6, 12, 18, and 24 months. For each participant a separate starting disease state was defined for each study visit, beginning with visit 6 (October 1986 through March 1987). The five disease states, as defined by CD4+ lymphocyte counts and clinical symptoms and signs, were as follows: state 1, ≥0.35 CD4+ cells × 109 per liter (≥350 per cubic millimeter); state 2, 0.2 to 0.349 CD4+ cells × 109 per liter (200 to 349 per cubic millimeter) and asymptomatic; state 3, 0.2 to 0.349 CD4+ lymphocytes ×l09 per liter and symptomatic; state 4, <0.2 CD4+ cells × 109 per liter (<200 per cubic millimeter) and asymptomatic; and state 5, <0.2 CD4+ cells ×l09 per liter and symptomatic. Symptomatic status was defined by the presence during the previous six months of one or more of the following clinical symptoms or signs: fever (temperature, >37.9°C) for ≥2 weeks, oral candidiasis, diarrhea for ≥2 weeks, weight loss of ≥4.5 kg (10 lb), oral hairy leukoplakia, or herpes zoster. Since treatment before the diagnosis of AIDS during the follow-up period was the independent variable of primary interest, AIDS could not be present at base line. Death was the primary outcome. The rates of death at 6, 12, 18, and 24 months were then calculated separately for men who started treatment before their diagnosis of AIDS and for those who did not.
The use of zidovudine was defined as any such use reported as having occurred before the time of a first AIDS-defining illness. The comparison group either did not take zidovudine at any time or delayed the start of treatment until after a first AIDS-defining illness. Data were also collected on the concurrent use of drugs to prevent first episodes of PCP. PCP prophylaxis was defined as the reported use of trimethoprim–sulfamethoxazole, aerosolized pentamidine, trimethoprim—dapsone, or dapsone alone at any time before a first AIDS-defining illness.
Outcomes and Follow-up
We report analyses in which mortality from all causes was used as the outcome variable. There were 306 deaths during the study period (October 1, 1986, through April 1, 1991). Analyses were also conducted with only HIV-related deaths used as the outcome variable, but these yielded essentially the same results. Causes of death were obtained from death certificates, autopsy reports, and reviews of medical records. Causes of death were available for 96 percent of all deaths reported through April 1, 1991.
In the cohort recruited in 1984 and 1985, follow-up data as of April 1, 1991, were available for 91 percent of the men who seroconverted and 90 percent of those who had been seropositive. During the period of the study (October 1, 1986, through April 1, 1991), loss to follow-up did not differ substantially between the group that used zidovudine before the onset of AIDS (3 percent) and the group that did not (5 percent).
Log-Linear Models
A log-linear regression model11 was used to estimate the effect of treatment on survival. The model assumes that the risk of death during any follow-up period is a function of the disease state at the beginning of the period, the use of zidovudine before the development of AIDS, and the use of PCP prophylaxis before the development of AIDS. Interactions of zidovudine with the starting disease state were included in the model to examine whether the effectiveness of zidovudine varied according to the stage of disease when the treatment was begun. Because insufficient numbers of men used PCP prophylaxis during early disease states to permit analysis of the effect of the stage of disease, only a main effect was included in all models. The timing of the base-line study visit was included to test for secular trends in rates of disease progression. To determine whether the use of PCP prophylaxis before the onset of AIDS independently reduced mortality in addition to the effects of zidovudine, the risk of mortality was compared between men who used such prophylaxis along with zidovudine before the development of AIDS and men who used only zidovudine. In this subgroup analysis, the risk of death was assumed to depend on the starting disease state and on the use of PCP prophylaxis before the development of AIDS. Because of small numbers, only three disease-state categories were used: 5≥0.35, 0.2 to 0.349, and <0.2 CD4+ cells × 109 per liter.
In this analysis, the follow-up periods for each participant could overlap when the observation period exceeded six months. Such repeated observations were likely to be correlated. This correlation was taken into account when standard errors and confidence intervals were estimated from the statistical model.11
Validation of Zidovudine Reporting
As we have reported earlier,4 , 12 the questionnaire about zidovudine use was validated in relation to the values for mean corpuscular volume that were ascertained at the respective study visits. The degree of validity of the questionnaire was high, with results for sensitivity and specificity very close to those reported in AIDS Clinical Trials Group protocol 019.3
Results
Overall Mortality Rates
The probabilities of death according to starting disease state and follow-up period were calculated by dividing the total number of deaths in each stratum by the total number of observations in that stratum. These data are presented in Table 1Table 1
Overall Rates of Death, According to Duration of Follow-up and Starting Disease State.. Mortality increased predictably with more advanced disease and increasing duration of follow-up. Mortality rates remained low for men who entered the follow-up period with ≥0.35 CD4+ cells ×l09 per liter (Table 1 and Fig. 1Figure 1
Rates of Death According to Zidovudine Use (with or without PCP Prophylaxis) before the Development of AIDS, the Number of Months of Follow-up, and the Participants' Starting Disease State at the Beginning of the Follow-up Period.). Thus, the mortality rate in this group was not high enough to allow the precise estimation of differential mortality between the two treatment groups of primary interest (zidovudine therapy before the development of AIDS and no such therapy before that time), and confidence intervals remained wide in this stratum (Table 2Table 2
Rates of Death among Participants Using and Not Using Zidovudine before the Development of AIDS, According to Duration of Follow-up and Starting Disease State.*). However, there were substantially more deaths among men beginning with CD4+ cell counts below 0.35 × 109 per liter, allowing a more powerful assessment of early treatment within these strata (Table 1).Effect of Early Zidovudine Use on Mortality
Mortality rates in the two study groups are presented in Figure 1 according to starting disease state, and relative risks of death associated with early treatment are shown in Table 2. After six months of follow-up, early treatment was associated with a reduced risk of dying for men in disease states 3, 4, and 5 at the start of the study. The protective trend was statistically significant for men starting with fewer than 0.2 CD4+ cells × 109 per liter and no symptoms (state 4), but wide confidence intervals were found for men starting in states 3 and 5. The effect of treatment did not vary significantly according to starting state, so a pooled relative risk was calculated as a summary statistic of the overall association of treatment with death. At six months of follow-up, after adjustment for the starting state, the use of zidovudine (with or without PCP prophylaxis) before the development of AIDS was significantly associated with a reduced risk of mortality (relative risk, 0.43; 95 percent confidence interval, 0.23 to 0.78). After adjustment for the effects of PCP prophylaxis, zidovudine use alone remained independently associated with reduced mortality (relative risk, 0.45; 95 percent confidence interval, 0.21 to 0.98) after six months of follow-up.
After 12, 18, and 24 months of follow-up, there were trends toward lower mortality with early treatment in all groups. These trends reached statistical significance for men in starting state 4 after 12 months, for those in states 3 and 4 after 18 months, and for those in states 2 and 4 after 24 months. The overall effects of treatment before the development of AIDS were significant at all three follow-up periods: the pooled relative risks of death were 0.54 after 12 months (95 percent confidence interval, 0.38 to 0.78), 0.59 after 18 months (95 percent confidence interval, 0.44 to 0.79), and 0.67 after 24 months (95 percent confidence interval, 0.52 to 0.86) (Fig. 2). Zidovudine use alone remained independently associated with a reduction in mortality, after adjustment for the effects of PCP prophylaxis, at 12 months (relative risk, 0.59; 95 percent confidence interval, 0.38 to 0.91) and 18 months (relative risk, 0.70; 95 percent confidence interval, 0.50 to 0.99), but not at 24 months (relative risk, 0.81; 95 percent confidence interval, 0.61 to 1.08).
Patterns of zidovudine use varied according to the length of follow-up. The mean proportion of time in which the zidovudine users actually took the drug during the follow-up periods was 75 percent, 60 percent, 53 percent, and 46 percent of the periods lasting 6, 12, 18, and 24 months, respectively.
Effect of Early PCP Prophylaxis on Mortality
To separate the effects on mortality of zidovudine use before the development of AIDS and of PCP prophylaxis, relative risks were estimated from log-linear models in which we adjusted for the independent effects of each treatment variable. In these models, after adjustment for zidovudine use, PCP prophylaxis was associated with a trend toward lower mortality at 6, 12, and 18 months (relative risk, 0.45, 0.59, and 0.70, respectively), but this trend reached statistical significance only after 24 months of follow-up (relative risk, 0.64; 95 percent confidence interval, 0.43 to 0.95). As we have reported previously,4 , 12 relatively few participants in the Multicenter AIDS Cohort Study used PCP prophylaxis during this period (1986 through 1991), and they almost always used it in conjunction with zidovudine. Therefore, to assess whether PCP prophylaxis offered any protection in addition to that afforded by zidovudine, we conducted subanalyses in which only those men who used zidovudine before the development of AIDS were included. In this group the risk of mortality was compared between men who also used primary PCP prophylaxis (i.e., that preceding a diagnosis of AIDS) and those who did not (Table 3Table 3
Rates of Death among Men Taking Zidovudine, According to Use or Nonuse of PCP Prophylaxis before a Diagnosis of AIDS.). No consistent reduction in mortality associated with the use of primary PCP prophylaxis was seen in participants starting with ≥0.2 CD4+ cells × 109 per liter. For those with CD4+ cell counts below this level, however, protective trends were seen at 6, 12, 18, and 24 months. To determine whether primary PCP prophylaxis reduced overall mortality, pooled relative risks and confidence intervals were calculated from the log-linear models for each follow-up period (Table 3). These estimates were adjusted to reflect the starting disease state. Protective trends were again seen at 6 and 12 months, and they reached statistical significance at 18 and 24 months (Table 3).Discussion
In a previous study, we showed that early zidovudine use and primary PCP prophylaxis were both associated with a slowing in the progression of HIV-1 infection to AIDS in a large observational cohort of homosexual and bisexual men.4 Clinical trials had also shown that zidovudine was efficacious in slowing this progression,2 , 3 but data from such trials that addressed the efficacy of primary PCP prophylaxis given early in the course of infection were not available until 1991.13 In both a clinical trial1 and observational studies,5 , 6 zidovudine has been shown to increase survival in patients with AIDS. However, a recent clinical trial of zidovudine therapy starting before as compared with after either the development of AIDS or CD+ cell counts <0.2× 109 per liter showed no survival advantage for the early-treatment group, despite a slowing of the progression to AIDS.7 There are also now adequate data from observational studies4 and clinical trials14 , 15 to show that PCP prophylaxis (starting either before or after an AIDS diagnosis) reduces the incidence of PCP during HIV-1 infection, but it is still not clear that such prophylaxis reduces mortality.14 , 16 To determine whether early treatment alters the natural history of progression of HIV-1 infection to death, we used observational methods to study the effectiveness of treatment in a community-based cohort. The relative risks of death were compared between subjects who started treatment with zidovudine (with or without PCP prophylaxis) before the development of AIDS and those who did not. To minimize the effects of a bias related to selection or participation, we stratified the analyses according to the starting disease state on the basis of CD4+ cell counts and HIV-related symptoms and signs.4 , 12 Since sicker patients are more likely to receive zidovudine,12 this bias tends to be conservative; that is, to minimize treatment effects.4 In addition, the overall effects of early use of zidovudine and PCP prophylaxis were calculated from log-linear models that were adjusted for starting disease state and that accounted for the multiple observations available for each participant (i.e., one for each study visit since October 1986).
Early treatment was found to be associated with significantly reduced mortality at 6, 12, 18, and 24 months (Fig. 2Figure 2
Pooled Relative Risk of Death in the Participants Treated with Zidovudine before the Development of AIDS, as Compared with Those Not So Treated, with Adjustment for Starting State and the Correlation of Values from Multiple Observations for Individual Participants.). In general, men starting with 0.2 to 0.349 CD4+ cells ×l09 per liter appeared to benefit most from treatment. This finding is consistent with that from our earlier study,4 but the differential effect of treatment between strata did not reach statistical significance in either study. The confidence intervals were wide for participants starting with CD4+ cell counts ≥0.35 × 109 per liter. Since very few outcomes were seen in this group, a longer follow-up period will be needed before we can confidently exclude a significant therapeutic effect in this group. Zidovudine use was independently associated with reduced mortality at 6, 12, and 18 months, but not at 24 months. Further studies are needed to determine whether this finding represents a diminution of the therapeutic effect of zidovudine over time or whether it merely reflects the fact that zidovudine users took the drug for only 46 percent of this longer period.PCP prophylaxis was more clearly protective after 18 and 24 months than after shorter follow-up periods. This may reflect its specificity of action. Since it has no antiviral effect, it can reduce overall mortality only by reducing mortality from PCP. This relation is likely to be more difficult to discern over shorter periods, in which there are fewer outcome events. The prevention of PCP is likely to shift the cause of death from PCP to opportunistic infections that occur later in the course of infection (e.g., Mycobacterium avium complex), thus lengthening overall survival.
Observational studies of the effectiveness of treatment are potentially subject to bias. As we have previously discussed,4 such bias tends to be conservative (i.e., likely to underestimate the true effect of treatment), since patients who receive treatment tend to be somewhat sicker than those who do not.12 In HIV infection, the CD4+ cell count and clinical symptoms determine who will receive antiviral therapy, as well as who is likely to have progression of disease.17 Therefore, stratification according to starting disease state and estimation of risk adjusted according to starting state reduce the biases in selection and participation that can be anticipated in cohort studies.4 In a previous study, therapy reduced the risk of progression to AIDS by 49 percent at 12 months,4 a figure that is comparable to the magnitude of benefit measured in clinical trials.2 , 3
Another potential source of bias is the differential follow-up of treated and untreated persons. In the Multicenter AIDS Cohort Study, complete follow-up data were available for 91 percent of the men who seroconverted and 90 percent of those who were already seropositive when they were recruited in 1984 and 1985. This analysis was restricted to the time of their sixth visit and thereafter, when the loss to follow-up was only 3 percent among men using zidovudine before the development of AIDS, as compared with 5 percent in the group that did not use zidovudine before that point. This difference is not significant, but if it had any effect, it would be to underestimate the effectiveness of treatment slightly if the proportion of deaths was either the same in each group or higher in the untreated group (the most likely possibilities). Finally, zidovudine use was validated in relation to values for mean corpuscular volume obtained at the time the medication questionnaire was completed. As has been outlined previously, the reporting of zidovudine use had a high level of validity and compared favorably in this respect with data from clinical trials.3 , 4 , 12
In conclusion, we found that the initiation of treatment with zidovudine (with or without PCP prophylaxis) before the development of AIDS was significantly associated with a reduced risk of mortality after 6, 12, 18, and 24 months of follow-up. The use of zidovudine alone was independently associated with reduced mortality after 6, 12, and 18 months, as was the use of PCP prophylaxis after 18 and 24 months. These data suggest that both antiviral and anti-PCP prophylaxis are necessary to maximize the survival benefit. The additional survival time attributable to these drugs and to newer treatments, such as didanosine and dideoxycytidine, and prophylaxis against opportunistic infections other than PCP, should be the focus of ongoing investigation in observational studies,18 in addition to experimental investigation in therapeutic clinical trials.
Supported by research contracts (NO 1-A 1–72634, 72676, 32535, 72631, and 72632) with the National Institutes of Health.
We are indebted to Dr. Donald Hoover for helpful discussions on methods and to Ms. Harriet Grossman for assistance in the preparation of the manuscript.
Source Information
From the Departments of Epidemiology (N.M.H.G., S.L.Z., L.P.P.) and Biostatistics (S.L.Z.), Johns Hopkins University School of Hygiene and Public Health, and the Department of Medicine, Johns Hopkins University School of Medicine (N.M.H.G.), both in Baltimore; the Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Md. (S.H. V.); the Department of Epidemiology, University of California School of Public Health, Los Angeles (R.D.); the Department of Infectious Diseases and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh (C.R.R.); and the Howard Brown Memorial Clinic and the Department of Medicine, Northwestern University, Chicago (J.P.P.). Address reprint requests to Dr. Graham at the Department of Epidemiology, Johns Hopkins University School of Hygiene and Public Health, 624 N. Broadway, Baltimore, MD 21205.
* The following additional persons participated in the study: at the Johns Hopkins School of Hygiene and Public Health, Baltimore: A. Saah, H. Farzadegan, J. Margolick, and J. McArthur; at the Howard Brown Memorial Clinic—North-western University Medical School, Chicago: J.S. Chmiel, B. Cohen, K. Sheridan, and S. Wolinsky; at the University of Pittsburgh School of Public Health, Pittsburgh: P. Gupta, M. Ho, L.A. Kingsley, and A. Winkelstein; at the University of California Schools of Public Health and Medicine, Los Angeles: B.R. Visscher, J. Dudley, J.L. Fahey, J.V. Giorgi, D. Imagawa, J. Taylor, and P. Nishanian; Data coordinating center — The Johns Hopkins School of Hygiene and Public Health: A. Muñoz, D.R. Hoover, L.P. Jacobson, N. Galai, and S. Su; at the National Institute of Allergy and Infectious Diseases: L.K. Schrager, R.A. Kaslow, and M.J. vanRaden; at the National Cancer Institute: I. Obrams.
- References
References
1
Fischl
Full Text | Web of Science | Medline2
Fischl
Web of Science | Medline3
Volberding
Full Text | Web of Science | Medline4
Graham
CrossRef | Web of Science | Medline5
Moore
Full Text | Web of Science | Medline6
Swanson
CrossRef | Web of Science | Medline7
Hamilton
Full Text | Web of Science | Medline8
Zidovudine in symptomless HIV infection . Lancet 1989;1:415–6.
Web of Science | Medline9
Kaslow
Web of Science | Medline10
Chmiel
Web of Science | Medline11
Zeger
CrossRef | Web of Science | Medline12
Graham
Web of Science | Medline13
Hirschel
Full Text | Web of Science | Medline14
Leoung
Full Text | Web of Science | Medline15
Fischl
CrossRef | Web of Science | Medline16
Chaisson RE, Keruly J, Richman DD, Moore RD. Prophylaxis for Pneumocystis and survival in advanced HIV infection treated with zidovudine. Presented at the Seventh International Conference on AIDS, Florence, Italy, June 16–21, 1991. abstract.
17
Polk
Full Text | Web of Science | Medline18
Vermund
CrossRef | Medline
- Citing Articles (61)
Citing Articles
1
Marianne Strazza, Vanessa Pirrone, Brian Wigdahl, Michael R. Nonnemacher. (2011) Breaking down the barrier: The effects of HIV-1 on the blood–brain barrier. Brain Research 1399, 96-115
CrossRef2
S. M. Breathnach. 2010. Drug Reactions. , 1-177.
CrossRef3
Imad M. Tleyjeh, Hassan M.K. Ghomrawi, James M. Steckelberg, Victor M. Montori, Tanya L. Hoskin, Felicity Enders, W. Charles Huskins, Farouk Mookadam, Walter R. Wilson, Valerie Zimmerman, Larry M. Baddour. (2010) Conclusion about the association between valve surgery and mortality in an infective endocarditis cohort changed after adjusting for survivor bias. Journal of Clinical Epidemiology 63:2, 130-135
CrossRef4
S. M. Breathnach. 2010. , 1.
CrossRef5
O.F. Amegor, D.A. Bigila, O.A. Oyesola, T.O. Oyesola, S.T. Buseni. (2009) Hematological Changes in HIV Patients Placed on Anti Retroviral Therapy in Markurdi, Benue State of Nigeria. Asian Journal of Epidemiology 2:4, 97-103
CrossRef6
Orapun Metadilogkul, Vichai Jirathitikal, Aldar S. Bourinbaiar. (2005) Prolonged survival of end-stage AIDS patients immunized with therapeutic HIV vaccine V-1 Immunitor. Biomedicine & Pharmacotherapy 59:8, 469-473
CrossRef7
Babette A. Brumback, Miguel A. Hernán, Sebastien J. P. A. Haneuse, James M. Robins. (2004) Sensitivity analyses for unmeasured confounding assuming a marginal structural model for repeated measures. Statistics in Medicine 23:5, 749-767
CrossRef8
Mari M. Kitahata, Stephen E. Rompaey, Peter W. Dillingham, Thomas D. Koepsell, Richard A. Deyo, Wayne Dodge, Edward H. Wagner. (2003) Primary Care Delivery Is Associated With Greater Physician Experience and Improved Survival Among Persons with AIDS. Journal of General Internal Medicine 18:2, 95-103
CrossRef9
Véronique Bortolotti, Anne Buvé. (2002) Prophylaxis of opportunistic infections in HIV-infected adults in sub-Saharan Africa: opportunities and obstacles. AIDS 16:10, 1309-1317
CrossRef10
Milos Opravil, Bruno Ledergerber, Hansjakob Furrer, Bernard Hirschel, Alexander Imhof, Serge Gallant, Thomas Wagels, Enos Bernasconi, Fabian Meienberg, Martin Rickenbach, Rainer Weber. (2002) Clinical efficacy of early initiation of HAART in patients with asymptomatic HIV infection and CD4 cell count > 350 × 106/l. AIDS 16:10, 1371-1381
CrossRef11
Miguel A. Hern
n, Babette A. Brumback, James M. Robins. (2002) Estimating the causal effect of zidovudine on CD4 count with a marginal structural model for repeated measures. Statistics in Medicine 21:12, 1689-1709
CrossRef12
Miguel A Hernán, Babette Brumback, James M Robins. (2001) Marginal Structural Models to Estimate the Joint Causal Effect of Nonrandomized Treatments. Journal of the American Statistical Association 96:454, 440-448
CrossRef13
Terence L. Chorba, Robert C. Holman, Matthew J. Clarke, Bruce L. Evatt. (2001) Effects of HIV infection on age and cause of death for persons with hemophilia A in the United States. American Journal of Hematology 66:4, 229-240
CrossRef14
Andrew L. Rosenberg, Michael G. Seneff, Lyna Atiyeh, Randall Wagner, Leody Bojanowski, Jack E Zimmerman. (2001) The importance of bacterial sepsis in intensive care unit patients with acquired immunodeficiency syndrome: Implications for future care in the age of increasing antiretroviral resistance. Critical Care Medicine 29:3, 548-556
CrossRef15
Miguel Ángel Hernán, Babette Brumback, James M. Robins. (2000) Marginal Structural Models to Estimate the Causal Effect of Zidovudine on the Survival of HIV-Positive Men. Epidemiology 11:5, 561-570
CrossRef16
A. D. McNaghten, Debra L. Hanson, Jeffery L. Jones, Mark S. Dworkin, John W. Ward. (1999) Effects of antiretroviral therapy and opportunistic illness primary chemoprophylaxis on survival after AIDS diagnosis. AIDS 13:13, 1687-1695
CrossRef17
Somsit Tansuphasawadikul, Pauli N. Amornkul, Chana Tanchanpong, Khanchit Limpakarnjanarat, Jaranit Kaewkungwal, Sirirat Likanonsakul, Boonchuey Eampokalap, Thananda Naiwatanakul, Dwip Kitayaporn, Nancy L. Young, Dale J. Hu, Timothy D. Mastro. (1999) Clinical Presentation of Hospitalized Adult Patients With HIV Infection and AIDS in Bangkok, Thailand. JAIDS Journal of Acquired Immune Deficiency Syndromes 21:4, 326
CrossRef18
M. Battegay, M. Wirz, M. H. Steuerwald, M. Egger, M. Egger. (1998) Early participation in an HIV cohort study slows disease progression and improves survival. Journal of Internal Medicine 244:6, 479-487
CrossRef19
Lois J. Eldred, Albert W. Wu, Richard E. Chaisson, Richard D. Moore. (1998) Adherence to Antiretroviral and Pneumocystis Prophylaxis in HIV Disease. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 18:2, 117-125
CrossRef20
F. Saillour, N. Bernard, J.-M. Ragnaud, P. Morlat, Y. Blanchard, E. Monlun, E. Labouyrie, G. Chene, F. Dabis. (1997) Incidence of cytomegalovirus disease in the aquitaine cohort of HIV-infected patients: A retrospective survey, 1987–1993. Journal of Infection 35:2, 155-161
CrossRef21
Maria Dorrucci, Patrizio Pezzotti, Andrew N. Phillips, Maria B. Alliegro, Giovanni Rezza. (1997) Antiretroviral treatment and progression to AIDS in HIV seroconverters from different risk groups. AIDS 11:4, 461-467
CrossRef22
Stefano Vella, Marco Floridia, Leonard G. Dally, Carlo Tomino, Vincenzo Fragola, Liliana E. Weimer, Francesco Milazzo, Francesco Mazzotta, Mauro Moroni, Giuseppe Pastore, Giorgio Scalise, Alessandro Sinicco, Luigi Ortona, Bruno De Rienzo, Ferdinando Dianzani. (1996) A Randomized Trial (ISS 901) of Switching to Didanosine Versus Continued Zidovudine after the Diagnosis of AIDS. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 12:5, 462-469
CrossRef23
Carol B. Gable, Jonothan C. Tierce, Diane Simison, Douglas Ward, Katy Motte. (1996) Costs of HIV+/AIDS at CD4+ Counts Disease Stages Based on Treatment Protocols. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 12:4, 413-420
CrossRef24
STEVEN R. NESHEIM. (1996) The Diagnosis and Management of Perinatal HIV Infection. Clinical Obstetrics and Gynecology 39:2, 396-410
CrossRef25
Margaret A. Fischl, Dianne M. Finkelstein, Weili He, William G. Powderly, Pierre L. Triozzi, Roy T. Steigbigel. (1996) A Phase II Study of Recombinant Human Interferon-α2a and Zidovudine in Patients with AIDS-Related Kaposi's Sarcoma. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 11:4, 379-384
CrossRef26
Kitahata, Mari M., Koepsell, Thomas D., Deyo, Richard A., Maxwell, Clare L., Dodge, Wayne T., Wagner, Edward H., . (1996) Physicians' Experience with the Acquired Immunodeficiency Syndrome as a Factor in Patients' Survival. New England Journal of Medicine 334:11, 701-707
Full Text27
Denise Kirschner, G. F. Webb. (1996) A model for treatment strategy in the chemotherapy of AIDS. Bulletin of Mathematical Biology 58:2, 367-390
CrossRef28
Michael S. Simberkoff, Pamela M. Hartigan, John D. Hamilton, Philip L. Day, Gigi R. Diamond, Gordon M. Dickinson, George L. Drusano, Merrill J. Egorin, W. Lance George, Fred M. Gordin, Clifton A. Hawkes, Peter C. Jensen, Nancy G. Klimas, Ann M. Labriola, Christopher J. Lahart, William A. O'Brien, Charles N. Oster, Kent J. Weinhold, Nelda P. Wray, Susan B. Zolla Pazner. (1996) Long-Term Follow-Up of Symptomatic HIV-Infected Patients Originally Randomized to Early Versus Later Zidovudine Treatment: Report of a Veterans Affairs Cooperative Study. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 11:2, 142-150
CrossRef29
Chaisson, Richard E., Keruly, Jeanne C., Moore, Richard D., . (1995) Race, Sex, Drug Use, and Progression of Human Immunodeficiency Virus Disease. New England Journal of Medicine 333:12, 751-756
Full Text30
S. Emery, D. A. Cooper. (1995) Antiretro viral therapy of human immunodeficiency virus type-1 (HIV-1) infection. Australian and New Zealand Journal of Medicine 25:4, 344-349
CrossRef31
M. A. BIRCHALL, P. D. HORNER, N. D. STAFFORD. (1994) Changing patterns of HIV infection in otolaryngology. Clinical Otolaryngology 19:6, 473-477
CrossRef32
P.J. Flegg. (1994) The natural history of HIV infection: A study in Edinburgh drug users. Journal of Infection 29:3, 311-321
CrossRef33
S. L. Meyer, M. Lasser, W. D. Reekie. (1994) Economics and the treatment of AIDS: a preliminary assessment. Applied Economics 26:11, 1093-1098
CrossRef34
Donald R. Hoover, Alvaro Muñtoz, Yanhua He, Jeremy M. G. Taylor, Lawrence Kingsley, Joan S. Chmiel, Alfred Saah. (1994) The effectiveness of interventions on incubation of AIDS as measured by secular increases within a population. Statistics in Medicine 13:19-20, 2127-2139
CrossRef35
Neil M.H. Graham, Lisa P. Jacobson, Victor Kuo, Joan S. Chmiel, Hal Morgenstern, Sharon L. Zucconi. (1994) Access to therapy in the multicenter AIDS Cohort Study, 1989–1992. Journal of Clinical Epidemiology 47:9, 1003-1012
CrossRef36
ANN C. COLLIER. (1994) Early Intervention in HIV Infection: Where Are We?. AIDS Research and Human Retroviruses 10:8, 893-899
CrossRef37
D. Havlir And, D. D. Richman. (1994) Zidovudine should be given before HIV-positive individuals develop symptoms. Reviews in Medical Virology 4:2, 75-80
CrossRef38
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
CrossRef39
J. Rivero, M. Limonta, A. Aguilera, M. Fraga, P. López Saura. (1994) Use of recombinant interferon-α in Human Immunodeficiency Virus (HIV)-infected individuals. Biotherapy 8:1, 23-31
CrossRef40
A. Carr, D. A. Cooper. (1994) In HIV-infected individuals who desire combination antiviral therapy, zidovudine plus zalcitabine is preferred to zidovudine plus didanosine. Reviews in Medical Virology 4:1, 5-8
CrossRef41
Terence L. Chorba, Robert C. Holman, Tara W. Strine, Matthew J. Clarke, Bruce L. Evatt. (1994) Changes in longevity and causes of death among persons with hemophilia A. American Journal of Hematology 45:2, 112-121
CrossRef42
Enrico Garaci, Giovanni Rocchi, Luigi Perroni, Cartesio D'Agostini, Fabrizio Soscia, Sandro Grelli, Antonio Mastino, Cartesio Favalli. (1994) Combination treatment with zidovudine, thymosin α1 and interferon-α in human immunodeficiency virus infectionand interferon-α in human immunodeficiency virus infection. International Journal of Clinical & Laboratory Research 24:1, 23-28
CrossRef43
Neil M.H. Graham, Susan Rubb, Donald R. Hoover, L.Diane McCall, John G. Palenicek, Alfred J. Saah. (1994) Beta2-microglobulin and other early predictors of human immunodeficiency virus type 1-related wasting. Annals of Epidemiology 4:1, 32-39
CrossRef44
Patricia A. Ganz, C. Anne Coscarelli Schag, Barbara Kahn, Laura Petersen. (1994) Assessing the quality of life of HIV infected persons: Clinical and descriptive information from studies with the hopes. Psychology & Health 9:1-2, 93-110
CrossRef45
Roy H. Rhodes. (1993) Histopathologic features in the central nervous system of 400 acquired immunodeficiency syndrome cases: Implications of rates of occurrence. Human Pathology 24:11, 1189-1198
CrossRef46
I. Varthalitis, F. Meunier. (1993) Pneumocystis carinii pneumonia in cancer patients. Cancer Treatment Reviews 19:4, 387-413
CrossRef47
ANNE A. GERSHON. (1993) Antiviral Therapy for HIV Infection in Infants and Children. Annals of the New York Academy of Sciences 693:1 Pediatric AID, 166-177
CrossRef48
Scott H. Isaacman, Lisa A. Miller. (1993) Neonatal HIV Seroprevalence studies. Journal of Legal Medicine 14:3, 413-461
CrossRef49
Cooper, David A.Gatell, Jose M.Kroon, SusanneClumeck, NathanMillard, JudithGoebel, Frank-DBruun, Johan N.Stingl, GeorgMelville, Rex L.Gonzalez-Lahoz, JuanStevens, John W.Fiddian, A. Paulthe European-Australian Collaborative Group. (1993) Zidovudine in Persons with Asymptomatic HIV Infection and CD4+ Cell Counts Greater than 400 per Cubic Millimeter. New England Journal of Medicine 329:5, 297-303
Full Text50
Elyse J. Singer, Carlos Zorilla, Bridget Fahy-Chandon, Susan Chi, Karl Syndulko, Wallace W. Tourtellotte. (1993) Painful symptoms reported by ambulatory HIV-infected men in a longitudinal study. Pain 54:1, 15-19
CrossRef51
M. Spadaro, G. Tilia, M. C. Massara, A. Damiani, L. Parisi, G. Tomelleri, G. D'Offizi, C. Morocutti. (1993) Myopathy in long-term AZT therapy: Clinical, electrophysiological and biopsy study in 67 HIV+subjects. The Italian Journal of Neurological Sciences 14:5, 369-374
CrossRef52
J. C. C. BORLEFFS, H.-J. SCHUURMAN, H. M. VREHEN, M. VAN SCHAIK, E. J. E. G. BAST. (1993) In Vitro and In Vivo Measurement of Cell-Mediated Immunity in Patients with HIV-1 Infection. Scandinavian Journal of Immunology 37:6, 634-636
CrossRef53
Ellen D. Nannis, Lydia R. Temoshok, Mickey Smith, Richard A. Jenkins. (1993) Perceptions of AZT: Implications for Adherence to Medical Regimens. Journal of Applied Biobehavioral Research 1:1, 39-54
CrossRef54
Richard P. Keeling. (1993) HIV Disease: Current Concepts. Journal of Counseling & Development 71:3, 261-274
CrossRef55
(1992) Early Zidovudine and Survival in HIV Infection. New England Journal of Medicine 327:11, 814-816
Full Text56
Kahn, James O., Lagakos, Stephen W., Richman, Douglas D., Cross, Anne, Pettinelli, Carla, Liou, Song-heng, Brown, Michael, Volberding, Paul A., Crumpacker, Clyde S., Beall, Gildon, Sacks, Henry S., Merigan, Thomas C., Beltangady, Mohan, Smaldone, Laurie, Dolin, Raphael, the NIAID AIDS Clinical Trials Group . (1992) A Controlled Trial Comparing Continued Zidovudine with Didanosine in Human Immunodeficiency Virus Infection. New England Journal of Medicine 327:9, 581-587
Full Text57
SheilaM Gore, DavidW Jolliffe, A Graham Bird. (1992) Prisoners' uptake of confidential, named HIV testing. The Lancet 339:8807, 1491-1492
CrossRef58
S.H. Khoo, G. Bailey, E.G.L. Wilkins, D.W. Denning. (1992) Time to finish with "AIDS"?. The Lancet 339:8804, 1298
CrossRef59
(1992) Zidovudine again. The Lancet 339:8801, 1105-1106
CrossRef60
M. J. Koziel, B. D. Walker. (1992) Viruses, chemotherapy and immunity. Parasitology 105:S1, S85
CrossRef61
H. Clifford Lane. (1992) Current status of therapy for human immunodeficiency virus type 1. Current Opinion in Immunology 4:4, 486-489
CrossRef
- Letters
