 |
|
Improved Survival Among HIV-Infected Individuals Following Initiation of Antiretroviral Therapy
Robert S. Hogg, MA, PhD;
Katherine V. Heath, MSc;
Benita Yip, BSc(Pharm);
Kevin J. P. Craib, MMath;
Michael V. O'Shaughnessy, PhD;
Martin T. Schechter, OBC, MD, PhD, FRCPC;
Julio S. G. Montaner, MD, FRCPC
JAMA. 1998;279:450-454.
ABSTRACT
| |
Context.— Clinical trials have established the efficacy of antiretroviral therapy with double- and triple-drug regimens for individuals infected with the human immunodeficiency virus (HIV), but the effectiveness of these regimens in the population of patients not enrolled in clinical trials is unknown.
Objective.— To characterize survival following the initiation of antiretroviral therapy among HIV-infected individuals in the province of British Columbia.
Design.— Prospective, population-based cohort study of patients with antiretroviral therapy available free of charge (median follow-up, 21 months).
Setting.— Province of British Columbia, Canada.
Patients.— All HIV-positive men and women 18 years of age or older in the province who were first prescribed any antiretroviral therapy between October 1992 and June 1996 and whose CD4+ cell counts were less than 0.350x109/L.
Main Outcome Measures.— Rates of progression from initiation of antiretroviral therapy to death or a primary acquired immunodeficiency syndrome (AIDS) diagnosis for subjects who initially received zidovudine-, didanosine-, or zalcitabine-based therapy (ERA-I) and for those who initially received therapy regimens including lamivudine or stavudine (ERA-II).
Results.— A total of 1178 patients (951 ERA-I, 227 ERA-II) were eligible. A total of 390 patients died (367 ERA-I, 23 ERA-II), yielding a crude mortality rate of 33.1%. ERA-I group subjects were almost twice as likely to die as ERA-II group subjects, with a mortality risk ratio of 1.86 (95% confidence interval [CI], 1.21-2.86; P=.005). After adjusting for Pneumocystis carinii and Mycobacterium avium prophylaxis use, AIDS diagnosis, CD4+ cell count, sex, and age, ERA-I participants were 1.93 times (95% CI, 1.25-2.97; P=.003) more likely to die than ERA-II participants. Among patients without AIDS when treatment was started, ERA-I participants were 2.50 times (95% CI, 1.59-3.93; P<.001) more likely to progress to AIDS or death than ERA-II participants.
Conclusion.— The HIV-infected individuals who received initial therapy with regimens including stavudine or lamivudine had significantly lower mortality and longer AIDS-free survival than those who received initial therapy with regimens limited to zidovudine, didanosine, and zalcitabine.
INTRODUCTION
ANTIRETROVIRAL therapy has been shown to prolong survival in persons with acquired immunodeficiency syndrome (AIDS) and those with intermediate-stage human immunodeficiency virus (HIV) infection.1-6 Between 1990 and 1995, didanosine and zalcitabine were increasingly used in combination with zidovudine. The available options for combination antiretroviral therapy expanded further when positive results were reported in clinical trials involving lamivudine and stavudine7-9 and, more recently, in trials involving protease inhibitors and nonnucleoside reverse transcriptase inhibitors.10-18 Recently, viral load–driven therapy has been adopted, as a growing body of evidence has established plasma viral load as a meaningful predictor of disease progression.19-21 Overall, these developments have resulted in significant changes to the therapeutic management of this disease22-23 and have led to a dramatic increase in the use of double- and, more recently, triple-combination antiretroviral therapy regimens among HIV-infected persons.
Through clinical trials, much evidence has been generated in support of newer treatment strategies. However, such evidence has not yet been obtained from population-based studies. Therefore, we characterized the treatment regimens and survival rates of HIV-infected individuals over time in the province of British Columbia, building on previous research that showed a substantial decline in AIDS-related mortality in British Columbia in recent years.24
METHODS
Drug Treatment Program
Since the introduction of zidovudine monotherapy in British Columbia in 1986, antiretroviral drugs have been centrally distributed at no cost to eligible HIV-infected individuals. In October 1992, the Drug Treatment Program became the responsibility of the British Columbia Centre for Excellence in HIV/AIDS (the Centre). From 1986 to 1997, a total of 4775 HIV-positive British Columbians received antiretroviral therapy in British Columbia. Of these, 3935 had ever been enrolled in the Drug Treatment Program, and 2192 were currently receiving antiretroviral therapy at the time of this report. The Centre's Drug Treatment Program remains the only free source of antiretroviral medications in the province.
The Centre distributes antiretroviral drugs based on specific guidelines generated by the Centre's Therapeutic Guidelines Committee. These guidelines as well as treatment updates are distributed to all physicians participating in the Drug Treatment Program. In 1992, the therapeutic guidelines recommended double-combination therapy for individuals with CD4+ cell counts lower than 0.350x109/L. In December 1995, this recommendation was expanded to make double-combination therapy available to everyone with CD4+ cell counts lower than 0.500x109/L.
A total of 5 antiretroviral agents were available in the province of British Columbia during the study period. The nucleoside analogue zidovudine has been available since 1986. The other 4 nucleoside analogues were made available over a period of 3 years: didanosine and zalcitabine in October 1992, lamivudine in February 1994, and stavudine in April 1993. The dates for lamivudine and stavudine reflect the availability of these therapies through compassionate release25 ; lamivudine did not become widely available as first-line therapy until December 1995 and stavudine until July 1996. Protease inhibitors and nonnucleoside reverse transcriptase inhibitors did not become available through the program until the summer of 1996.
Data Collection
Physicians enrolling an HIV-positive individual into the Centre's Drug Treatment Program must complete a drug request enrollment form. The enrollment request form acts as a legal prescription and compiles information on the HIV-positive applicant's address and enrolling physician, HIV-specific drug history, CD4+ cell counts, and current drug requests. Each request is reviewed by a qualified practitioner to ensure that it meets the Centre's established therapeutic guidelines.23 Approved prescriptions are renewed every 2 months. At the time of the initial refill, each participant is asked to complete an enrollment survey and a program consent form, while the physician is asked to complete a clinical staging form. Patients complete the survey and physicians complete the clinical staging forms annually. The clinical staging form records participant-specific information on HIV- and AIDS-related conditions according to the World Health Organization clinical staging system.26
This analysis was restricted to all HIV-positive men and women who were antiretroviral naive and were first prescribed any antiretroviral therapy between October 1, 1992, and June 30, 1996. To limit the effect of changing therapeutic guidelines, we restricted our analysis to persons who had CD4+ cell counts less than 0.350x109/L, thereby ensuring that they were eligible for combination therapy throughout the study period. Study subjects were divided into those who initially received therapy with zidovudine, didanosine, and zalcitabine, denoted as ERA-I, and those who initially received therapy regimens including lamivudine or stavudine, denoted as ERA-II.
Outcome Measures
The primary and secondary end points in this analysis were death and a primary AIDS diagnosis, respectively. Deaths and AIDS diagnoses during the follow-up period were identified on a continuous basis from physician reports and through record linkages carried out with the British Columbia provincial AIDS registry and Division of Vital Statistics. All-cause mortality was used since more than 90% of deaths among participants were directly attributable to HIV-related causes. Baseline clinical information, including primary AIDS diagnosis and use of Pneumocystis carinii pneumonia and Mycobacterium avium prophylaxis, was obtained directly from the Drug Treatment Program records. Information on clinical illnesses defined according to the 1993 Centers for Disease Control and Prevention AIDS definition27 was collected from physician reports and record linkages carried out in collaboration with the provincial and national AIDS registries.
Statistical Analysis
For the purposes of analysis, statistical methods followed the intent-to-treat principle, with subjects retained in their initial treatment groups (ERA-I or -II) irrespective of whether ERA-I participants subsequently switched to regimens available in ERA-II. The outcomes examined were time from the start of antiretroviral therapy to death or a primary AIDS diagnosis. Cumulative mortality and AIDS-free survival rates were estimated using Kaplan-Meier methods. Survival functions were compared using a log-rank test. Event-free subjects were right-censored as of June 30, 1997. Persons unavailable for follow-up were censored at the date of last known contact with the Drug Treatment Program.
Statistical comparisons were conducted using distribution-free methods.28 Categorical variables and ordinal and skewed continuous variables were compared using the Mantel-Haenszel and Wilcoxon rank sum tests, respectively. The Fisher exact test was used for 2x2 contingency tables in which any of the expected cell frequencies was less than 5.
Cox proportional hazard models were used to estimate the hazard of death and to estimate AIDS-free survival for the ERA-I group relative to the ERA-II group, with associated 95% confidence intervals (CIs).29 In this analysis, we adjusted for a number of salient prognostic variables at baseline, including use of P carinii pneumonia and M avium prophylaxis, CD4+ cell count, AIDS diagnosis, age, and sex. A diagnosis of AIDS, sex, and use of P carinii pneumonia and M avium prophylaxis at entry were treated as fixed binary variables (yes vs no). Age (in years) and CD4+ cell count (per 0.100x109/L) at baseline were modeled as continuous variables. All reported P values are 2-sided.
RESULTS
A total of 1687 individuals in British Columbia were first prescribed antiretroviral therapy between October 1, 1992, and June 30, 1996. We excluded 446 subjects from this analysis because they did not meet the inclusion criteria, ie, had baseline CD4+ cell counts of 0.350x109/L or greater (408 participants) or because they were less than 18 years old (38 participants). A further 63 subjects were excluded because CD4+ cell counts were not available within 1 year prior to the start of antiretroviral treatment. The total study sample was based on the remaining 1178 subjects (951 ERA-I, 227 ERA-II).
Compared with study participants, individuals excluded because CD4+ cell counts were not available within 1 year prior to the start of antiretroviral treatment were more likely to be women (25% vs 9%; P=.001). However, these groups did not differ with respect to age (P=.63), P carinii pneumonia (P=.63) or M avium (P=.19) prophylaxis use, or a diagnosis of AIDS (P=.38) at baseline.
The overall median follow-up was 21 months (interquartile range, 14-34 months), with medians of 26 months (interquartile range, 17-38 months) and 15 months (interquartile range, 13-16 months), respectively, for subjects in groups ERA-I and -II (P<.001). A total of 27 (26 ERA-I and 1 ERA-II) study subjects (2%) were unavailable for follow-up in this analysis. In addition, 473 subjects (49.7%) in the ERA-I group switched to ERA-II regimens prior to the end of the study period.
Of the 951 ERA-I subjects, 488 (51%) initially received monotherapy and 463 (49%) received double therapy. Among the ERA-I subjects, 422 (44%) were treated with zidovudine monotherapy, 266 (28%) with zidovudine and didanosine, 197 (21%) with zidovudine and zalcitabine, and 66 (7%) with other monotherapy regimens. As shown in Figure 1, the majority of ERA-I subjects started therapy before 1996: 124 (13%) in 1992, 325 (34%) in 1993, 204 (21%) in 1994, 231 (24%) in 1995, and 67 (7%) in 1996.
|
|
|
|
Figure 1.—Enrollment of ERA-I (initially received zidovudine-, didanosine-, or zalcitabine-based therapy) and ERA-II (initially received therapy including lamivudine or stavudine) participants between October 1, 1992, and June 30, 1996, by the year antiretroviral therapy was first initiated.
|
|
|
Of the 227 subjects in the ERA-II group, 205 (90%) were treated with zidovudine and lamivudine, 10 (4%) with lamivudine, 2 (1%) with stavudine, and 10 (4%) with other regimens, including lamivudine with didanosine or zalcitabine. In the ERA-II group, 225 (99%) initially received antiretroviral therapy with a regimen including lamivudine, 206 (91%) zidovudine, 2 (1%) stavudine, 5 (2%) didanosine, and 5 (2%) zalcitabine. A total of 27 ERA-II subjects (12%) commenced therapy in 1995, and 200 (88%) in 1996.
Table 1 compares the baseline demographic and clinical characteristics of the ERA-I and ERA-II groups. No differences were observed at baseline between treatment groups with respect to P carinii pneumonia (P=.92) or M avium (P=.50) prophylaxis, AIDS diagnosis (P=.24), or CD4+ cell count (P=.48). However, ERA-I subjects were less likely to be women (9% vs 13%; P=.05) and were younger (median, 36 vs 38 years; P=.02) than ERA-II subjects at baseline.
|
|
|
|
Table 1.—Comparison of 1178 HIV-Positive Patients Receiving ERA-I or ERA-II Treatment*
|
|
|
A total of 301 study subjects had AIDS at baseline (250 ERA-I, 51 ERA-II). The numbers and percentages of the AIDS-defining illnesses in both groups were P carinii pneumonia, 150 (50%); other opportunistic infections, 74 (25%); Kaposi sarcoma, 37 (12%); wasting syndrome, 19 (6%); neurologic disease, 14 (5%); and other malignant neoplasms, 7 (2%). There was no statistical difference between the 2 groups in the proportion having Kaposi sarcoma (P=.42) or other opportunistic infections (P=.87). However, more subjects in the ERA-I group than the ERA-II group had P carinii pneumonia (53% vs 35%, P=.02).
As of June 30, 1997, a total of 390 deaths (367 ERA-I, 23 ERA-II) had been identified, yielding a crude mortality rate of 33.1%. Figure 2 displays the Kaplan-Meier survival curves for the ERA-I and ERA-II groups. Product-limit estimates (±SEs) of the cumulative mortality rate at 15 months were 17.1% (±1.2%) and 10.0% (±2.0%) for ERA-I and ERA-II subjects, respectively (P=.004). ERA-I subjects were almost twice as likely to die as ERA-II subjects, with a mortality risk ratio of 1.86 (95% CI, 1.21-2.86; P=.005).
|
|
|
|
Figure 2.—Survival among 1178 human immunodeficiency virus–positive British Columbians who were first prescribed any antiretroviral therapy between October 1, 1992, and June 30, 1996, stratified by ERA-I (initially received zidovudine-, didanosine-, or zalcitabine-based therapy) and ERA-II (initially received double-combination therapy including lamivudine or stavudine) therapy.
|
|
|
The final multivariate model for the baseline factors associated with mortality is presented in Table 2. Use of ERA-II regimens (P=.003), a higher CD4+ cell count (P<.001), absence of AIDS (P<.001), younger age (P<.001), and the use of M avium prophylaxis (P=.009) at baseline were independently associated with longer survival after adjusting for sex and for use of P carinii pneumonia prophylaxis. The adjusted mortality risk ratio from this multivariate model indicates that study subjects in the ERA-I group were 1.93 times (95% CI, 1.25-2.97) more likely to die following the initiation of antiretroviral therapy than subjects in the ERA-II group.
|
|
|
|
Table 2.—Multivariate Analysis of Baseline Factors Associated With Mortality Among 1178 HIV-Positive Patients Receiving ERA-I or ERA-II Treatment*
|
|
|
We also restricted our analysis of survival to the 690 subjects who were initially prescribed dual-nucleoside regimens. After adjusting for other salient prognostic variables (use of P carinii pneumonia and M avium prophylaxis, AIDS diagnosis, CD4+ cell count, sex, and age), ERA-I participants were 1.73 times (95% CI, 1.09-2.74; P=.02) more likely to die than ERA-II participants.
Finally, we repeated all relevant analyses with the time from the start of antiretroviral therapy to diagnosis of AIDS or death as the outcomes of interest. These analyses were restricted to the 877 subjects (701 ERA-I, 176 ERA-II) who were free of AIDS at baseline. As of June 30, 1997, a total of 300 events had been identified, 219 primary AIDS diagnoses (208 ERA-I, 11 ERA-II) and 81 deaths (71 ERA-I, 10 ERA-II). The numbers and percentages of AIDS-defining illnesses in both groups were P carinii pneumonia, 63 (29%); candida infections, 23 (11%); M avium complex infection, 21 (10%); cytomegalovirus infection, 13 (6%); other opportunistic infections, 25 (11%); Kaposi sarcoma, 35 (16%); wasting syndrome, 23 (11%); neurologic disease, 8 (4%); and other malignant neoplasms, 8 (4%).Figure 3 displays the Kaplan-Meier curves for cumulative mortality or progression to AIDS for the ERA-I and ERA-II groups. Product-limit estimates (±SEs) of the rate of progression to AIDS or death at 15 months were 23.8% (±1.6%) and 10.7% (±2.4%) for ERA-I and ERA-II subjects, respectively (P<.001). After adjusting for other prognostic variables (use of P carinii pneumonia and M avium prophylaxis, CD4+ cell count, sex, and age), ERA-I participants were 2.50 times (95% CI, 1.59-3.93; P<.001) more likely than ERA-II participants to die or progress to AIDS. These results were not altered by removing those AIDS-free participants (risk ratio, 2.45; 95% CI, 1.51-3.96; P<.001) who were receiving monotherapy at baseline or by adjusting for an estimated AIDS reporting delay of 9 months (risk ratio, 2.23; 95% CI, 1.33-3.74; P=.002). When our analyses were based on the time from the start of antiretroviral therapy to diagnosis of AIDS, after adjusting for other prognostic variables, (use of P carinii pneumonia and M avium prophylaxis, CD4+ cell count, sex, and age), ERA-I participants were 3.61 times (95% CI, 1.95-6.67; P<.001) more likely than ERA-II participants to progress to AIDS.
|
|
|
|
Figure 3.—Survival free of the acquired immunodeficiency syndrome (AIDS) among 877 AIDS-free British Columbians who were first prescribed any antiretroviral therapy between October 1, 1992, and June 30, 1996, stratified by ERA-I (initially received zidovudine-, didanosine-, or zalcitabine-based therapy) and ERA-II (initially received double-combination therapy including lamivudine or stavudine) therapy.
|
|
|
COMMENT
This analysis demonstrated a statistically significant improvement in survival and AIDS-free survival among HIV-infected men and women who received initial antiretroviral therapy using ERA-II regimens vs ERA-I regimens. Individuals in the ERA-I group were nearly twice as likely to die as those in the ERA-II group. This result remained statistically significant even after adjusting for P carinii pneumonia and M avium prophylaxis use, CD4+ cell count, AIDS diagnosis, sex, and age at baseline. Furthermore, ERA-I participants who were free of AIDS at baseline were nearly 3 times more likely to progress to AIDS or die than those in the ERA-II group.
Definitive evidence regarding the relative efficacy of various treatment strategies can only be gathered in the context of randomized clinical trials. However, it is also important to monitor the reproducibility of the benefits obtained in controlled settings when therapies are applied to populations. Our findings are likely to reflect, to a substantial extent, the effect of the introduction of lamivudine, as recently established in clinical trials.30 The recently reported CAESAR trial showed that adding lamivudine to regimens including zidovudine reduced the 1-year progression to AIDS or death by 55%. This effect was maintained when subgroup analyses by various CD4+ cell count ranges and prior exposure to antiretroviral agents were performed within the CAESAR trial. In our study, the vast majority of subjects in the ERA-II group received initial therapy with a regimen containing lamivudine, and nearly all these subjects received both zidovudine and lamivudine.
In a population-based study, differences in outcomes between treatment groups might result from nonrandom assignment to therapies or from differential use of cointerventions between groups. In this context, it is reassuring to note that no statistical differences were observed between the 2 treatment arms at entry in P carinii pneumonia and M avium prophylaxis use, prior diagnosis of AIDS, and CD4+ cell count.
Another possible concern is that subjects with more advanced disease or symptoms may have chosen to initiate treatment sooner or to use more aggressive therapy options.31-32 Those who survive a short time from enrollment have less opportunity to select subsequent treatment and are less likely to use any one treatment. In other words, rather than treatment influencing progression to AIDS-free survival or death, survival may lead to treatment use, thus overestimating the calculated treatment effect. We have attempted to control these possible biases in several ways. As noted above, comparisons of indicators of disease severity at baseline demonstrated no significant differences between groups. Furthermore, our analysis avoids any potential bias caused by individuals with more advanced disease discontinuing treatment due to more severe illness. In this type of analysis, those who switch treatment arms are retained in their original treatment group. Thus, the fact that they have remained event-free long enough to initiate new treatment becomes moot. Finally, as noted above, we used multivariate regression techniques to adjust or control simultaneously for the effects of multiple baseline clinical and demographic factors on mortality and AIDS-free survival. This approach, commonly used in observational studies, 33 eliminates potential survival bias because the model compares only persons in the different treatment groups who survive to the same time point.
Strengths of our study include the provision of antiretroviral treatment at no cost, the intent-to-treat analysis, complete follow-up for 98% of the cohort, and the extent of active reporting of deaths (n=175 [93%]; median follow-up from date of death to date of reporting, 7 days [interquartile range, 4-12 days]).
In summary, our analysis demonstrated a significant improvement in mortality and AIDS-free survival for men and women who received initial therapy with regimens including stavudine or lamivudine compared with those who received initial therapy with regimens restricted to zidovudine, didanosine, or zalcitabine. Our results remained statistically significant even after adjusting for P carinii pneumonia and M avium prophylaxis use, CD4+ cell count, AIDS diagnosis, sex, and age at baseline. We therefore attribute this improvement to the introduction of new antiretroviral therapy strategies. While the observational cohort study is subject to a number of inherent constraints, adjustment for salient prognostic covariates, such as age, sex, CD4+ cell count, and use of prophylaxis for P carinii pneumonia and M avium, as well as restriction to antiretroviral-naive participants with CD4+ cell counts lower than 0.350x109/L should do much to attenuate these limitations. Furthermore, the treatment effect estimated here is likely to be conservative and, for the most part, reflects the efficacy of combinations including lamivudine and stavudine. Our results confirm the importance of including data from large-scale observational studies in the evaluation of the many available therapeutic strategies for persons with HIV disease. The long-term impact of these and newer treatment strategies remains to be explored.
AUTHOR INFORMATION
Dr Schechter served on a Data Safety and Monitoring Board for Boehringer Ingelheim Pharmaceuticals Inc, Burlington, Ontario. Dr Montaner received grants from, served as an ad hoc adviser to, or spoke at various events sponsored by Abbott Laboratories, Abbott Park, Ill; Boehringer Ingelheim Pharmaceuticals Inc; Bristol-Myers Squibb, Saint-Laurent, Quebec; Glaxo Wellcome, Mississauga, Ontario; Merck Frosst Laboratories, Pointe-Claire-Dorval, Quebec; Merck & Co Inc, Whitehouse Station, NJ; and DuPont Merck Pharmaceutical Co, Wilmington, Del.
Reprints: Julio S. G. Montaner, MD, FRCPC, Chair, AIDS Research Programme, St Paul's Hospital/University of British Columbia, 667-1081 Burrard St, Vancouver, British Columbia, Canada V6Z 1Y6
From the British Columbia Centre for Excellence in HIV/AIDS, St Paul's Hospital (Drs Hogg, O'Shaughnessy, Schechter, and Montaner; Mss Heath and Yip; and Mr Craib), Departments of Health Care and Epidemiology (Drs Hogg, Schechter, and Montaner), Pathology (Dr O'Shaughnessy), and Medicine (Dr Montaner), Faculty of Medicine, University of British Columbia, and Canadian HIV Trials Network (Drs O'Shaughnessy, Schechter, and Montaner), Vancouver, British Columbia.
REFERENCES
| |
1. Fischl MA, Richman DD, Grieco MH, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: a double-blind, placebo-controlled trial. N Engl J Med. 1987;317:185-191.
ABSTRACT
2. Graham NM, Zeger SL, Park LP, et al. The effects on survival of early treatment of human immunodeficiency virus infection. N Engl J Med. 1992;326:1037-1042.
ABSTRACT
3. Volberding PA, Lagakos SW, Koch MA, et al. Zidovudine in asymptomatic human immunodeficiency virus infection: a controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. N Engl J Med. 1990;322:941-949.
ABSTRACT
4. Kahn JO, Lagakos SW, Richman DD, et al. A controlled trial comparing continued zidovudine with didanosine in human immunodeficiency virus infection. N Engl J Med. 1992;327:581-587.
ABSTRACT
5. Hammer S, 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.
FREE FULL TEXT
6. Delta Coordinating Committee. Delta: a randomized double-blind controlled trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-infected individuals. Lancet. 1996;348:283-291.
FULL TEXT
|
ISI
| PUBMED
7. Murray HW, Squires KE, Weiss W, et al. Stavudine in patients with AIDS and AIDS-related complex: ACTG 089. J Infect Dis. 1995;171 Suppl 2:S123-S130.
8. Katlama C, Molina JM, Rozenbaum W, et al. Stavudine (d4T) in HIV infected patients with CD4>350/mm3: results of a double-blind, placebo-controlled study. In: Program and abstracts of the Third Conference on Retroviruses and Opportunistic Infections; January 28–February 1, 1996; Washington, DC. Abstract 196.
9. Eron JJ, Benoit SL, Jemsek J, et al. Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter. N Engl J Med. 1995;333:1662-1669.
FREE FULL TEXT
10. Ridhy T, Leis J. Development of drug resistance to HIV-1 protease inhibitors. J Biol Chem. 1995;270:29621-29623.
FREE FULL TEXT
11. Collier CA, Coombs RW, Schoenfeld DA, et al. Treatment of human immunodeficiency virus disease. N Engl J Med. 1996;334:1011-1017.
FREE FULL TEXT
12. Gulick RM, Mellors JW, Havlir D, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med. 1997;337:734-739.
FREE FULL TEXT
13. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of 2 nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. N Engl J Med. 1997;337:725-733.
FREE FULL TEXT
14. Mathez D, De Truchis P, Gorin I, et al. Ritonavir, AZT, DDC, as a triple combination in AIDS patients. In: Program and abstracts of the Third Conference on Retroviruses and Opportunistic Infections; January 28–February 1, 1996; Washington, DC. Abstract 285.
15. Cameron DW, Heath-Chiozzi M, Kravick S, et al. Prolongation of life and prevention of AIDS complications in advanced HIV immunodeficiency with ritonavir: an update. In: Program and abstracts of the XI International Conference on AIDS; July 7-12, 1996; Vancouver, British Columbia. Abstract Mo.B.411.
16. Vella S. Clinical experience with saquinavir. AIDS. 1995;9 Suppl 2:S21-S25.
17. Myers M, Montaner JSG for the INCAS Study Group. A randomized double-blind, comparative trial of the effects of zidovudine, didanosine, and nevirapine combinations in antiviral naive, AIDS-free, HIV-infected patients with CD4+ cell counts 200-600 µL. In: Program and abstracts of the XI International Conference on AIDS; July 7-12, 1996; Vancouver, British Columbia. Abstract Mo.B.294.
18. Egger M, Hirschel B, Francioli P, et al. Impact of new antiretroviral combination therapies in HIV-infected patients in Switzerland: prospective multicentre study. BMJ. 1997;315:1194-1199.
FREE FULL TEXT
19. O'Brien WA, Hartigan PM, Martin D, Esinhart J. Changes in plasma HIV-1 RNA and CD4+ lymphocyte count relative to treatment and progression to AIDS. N Engl J Med. 1996;334:426-431.
FREE FULL TEXT
20. Mellors JW, Kingsley LA, Rinaldo CR, et al. Quantification of HIV-RNA in plasma predicts outcome after seroconversion. Ann Intern Med. 1995;122:573-579.
FREE FULL TEXT
21. Mellors JW, Rinaldo CR, Gupta P, et al. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science. 1996;272:1167-1170.
ABSTRACT
22. Carpenter CCJ, Fischl MA, Hammer SM, et al. Antiretroviral therapy for HIV infection in 1996: recommendation of an international panel. JAMA. 1996;276:146-154.
FREE FULL TEXT
23. Therapeutic Guidelines for the Treatment of HIV/AIDS and Related Conditions. Vancouver, British Columbia: Centre for Excellence in HIV/AIDS; 1995.
24. Hogg RS, O'Shaughnessy MV, Gataric N, et al. Decline in deaths from AIDS due to new antiretrovirals. Lancet. 1997;349:1294.
ISI
| PUBMED
25. Montaner JSG, Hogg RS, Yip B, Gataric N, Schechter MT, O'Shaughnessy MV. Increased zidovudine prescribing associated with lamivudine availability. JAMA. 1996;275:598.
FREE FULL TEXT
26. World Health Organization. Acquired immune deficiency syndrome (AIDS): interim proposal for a WHO staging system for HIV infection and disease. Wkly Epidemol Rec. 1990;65:221-228.
27. Centers for Disease Control. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Morb Mortal Wkly Rep. 1992;41(RR-17):1-19.
28. Neave HR, Worthington PL. Distribution-Free Tests. London, England: Routledge; 1998.
29. Cox DR. Regression models and life tables (with discussion). J R Stat Soc B. 1972;34:187-202.
30. CAESAR Coordinating Committee. Randomised trial of addition of lamivudine or lamivudine plus loviride to zidovidine-containing regimens for patients with HIV-1 infection: the CAESAR trial. Lancet. 1997;349:1413-1421.
FULL TEXT
|
ISI
| PUBMED
31. Glesby MJ, Hoover DR. Survivor treatment selection bias in observational studies: examples from the AIDS literature. Ann Intern Med. 1996;124:999-1005.
FREE FULL TEXT
32. Brookmeyer R, Gail MH, Polk BF. The prevalent cohort study and the acquired immunodeficiency syndrome. Am J Epidemiol. 1987;126:14-24.
FREE FULL TEXT
33. Graham NH, Hoover DR, Park LP, et al. Survival in HIV-infected patients who have received zidovudine: comparison of combination therapy with sequential monotherapy and continued zidovudine monotherapy. Ann Intern Med. 1996;124:1031-1038.
FREE FULL TEXT
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
RELATED LETTER
Antiretroviral Therapy and Improving AIDS Survival
, , , , , , , , , and
JAMA. ;279():1874-1875.
FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Antiretroviral Tissue Kinetics: In Vivo Imaging Using Positron Emission Tomography
Di Mascio et al.
Antimicrob. Agents Chemother. 2009;53:4086-4095.
ABSTRACT
| FULL TEXT
Adherence to Medical Regimens: Understanding the Effects of Cognitive Appraisal, Quality of Life, and Perceived Family Resiliency
Frain et al.
Rehabil Couns Bull 2009;52:237-250.
ABSTRACT
Comparison of emergency department HIV testing data with visit or patient as the unit of analysis
Lyons et al.
J Med Screen 2009;16:29-32.
ABSTRACT
| FULL TEXT
Changing Global Epidemiology of Pulmonary Manifestations of HIV/AIDS
Hull et al.
Chest 2008;134:1287-1298.
ABSTRACT
| FULL TEXT
Pharmacokinetic and Safety Evaluation of BILR 355, a Second-Generation Nonnucleoside Reverse Transcriptase Inhibitor, in Healthy Volunteers
Huang et al.
Antimicrob. Agents Chemother. 2008;52:4300-4307.
ABSTRACT
| FULL TEXT
The Economic Impact of AIDS Treatment: Labor Supply in Western Kenya
Thirumurthy et al.
J. Human Resources 2008;43:511-552.
ABSTRACT
Association Between Living With Children and Adherence to Highly Active Antiretroviral Therapy in the Women's Interagency HIV Study
Merenstein et al.
Pediatrics 2008;121:e787-e793.
ABSTRACT
| FULL TEXT
Prolongation and quality of life for HIV-infected adults treated with highly active antiretroviral therapy (HAART): a balancing act
Burgoyne and Tan
J Antimicrob Chemother 2008;61:469-473.
ABSTRACT
| FULL TEXT
Safety and Pharmacokinetics of Bevirimat (PA-457), a Novel Inhibitor of Human Immunodeficiency Virus Maturation, in Healthy Volunteers
Martin et al.
Antimicrob. Agents Chemother. 2007;51:3063-3066.
ABSTRACT
| FULL TEXT
Hospital-Based Directly Observed Therapy for HIV-Infected Children and Adolescents to Assess Adherence to Antiretroviral Medications
Glikman et al.
Pediatrics 2007;119:e1142-e1148.
ABSTRACT
| FULL TEXT
Surgical Outcomes in Human Immunodeficiency Virus-Infected Patients in the Era of Highly Active Antiretroviral Therapy
Horberg et al.
Arch Surg 2006;141:1238-1245.
ABSTRACT
| FULL TEXT
Model for intracellular Lamivudine metabolism in peripheral blood mononuclear cells ex vivo and in human immunodeficiency virus type 1-infected adolescents.
Zhou et al.
Antimicrob. Agents Chemother. 2006;50:2686-2694.
ABSTRACT
| FULL TEXT
AIDS-related lymphoproliferative disease
Navarro and Kaplan
Blood 2006;107:13-20.
ABSTRACT
| FULL TEXT
Outcome of Critically Ill Human Immunodeficiency Virus-Infected Patients in the Era of Highly Active Antiretroviral Therapy
Khouli et al.
J Intensive Care Med 2005;20:279-285.
ABSTRACT
Adherence to Antiretroviral Therapy: The Emerging Role of HIV Pharmacotherapy Specialists
Hardy
Journal of Pharmacy Practice 2005;18:247-257.
ABSTRACT
Nonadherence to Antiretroviral Therapy Among a Community With Endemic Rates of Injection Drug Use
Shannon et al.
J Int Assoc Physicians AIDS Care (Chic Ill) 2005;4:66-72.
ABSTRACT
Evaluation of HIV RNA and markers of immune activation as predictors of HIV-associated dementia
Sevigny et al.
Neurology 2004;63:2084-2090.
ABSTRACT
| FULL TEXT
Nonadherence With Pediatric Human Immunodeficiency Virus Therapy as Medical Neglect
Roberts et al.
Pediatrics 2004;114:e346-e353.
ABSTRACT
| FULL TEXT
Preclinical Pharmacology and Pharmacokinetics of GW433908, a Water-Soluble Prodrug of the Human Immunodeficiency Virus Protease Inhibitor Amprenavir
Furfine et al.
Antimicrob. Agents Chemother. 2004;48:791-798.
ABSTRACT
| FULL TEXT
Analysis of protease inhibitor combinations in vitro: activity of lopinavir, amprenavir and tipranavir against HIV type 1 wild-type and drug-resistant isolates
Bulgheroni et al.
J Antimicrob Chemother 2004;53:464-468.
ABSTRACT
| FULL TEXT
Influence of Reverse Transcriptase Variants, Drugs, and Vpr on Human Immunodeficiency Virus Type 1 Mutant Frequencies
Mansky et al.
J. Virol. 2003;77:2071-2080.
ABSTRACT
| FULL TEXT
A Two-way Messaging System to Enhance Antiretroviral Adherence
Dunbar et al.
J. Am. Med. Inform. Assoc. 2003;10:11-15.
ABSTRACT
| FULL TEXT
Medication adherence among HIV+ adults: Effects of cognitive dysfunction and regimen complexity
Hinkin et al.
Neurology 2002;59:1944-1950.
ABSTRACT
| FULL TEXT
Interruption of antiretroviral therapy to augment immune control of chronic HIV-1 infection: Risk without reward
Abbas and Mellors
Proc. Natl. Acad. Sci. USA 2002;99:13377-13378.
FULL TEXT
Changes in the Incidence and Predictors of Wasting Syndrome Related to Human Immunodeficiency Virus Infection, 1987-1999
Smit et al.
Am J Epidemiol 2002;156:211-218.
ABSTRACT
| FULL TEXT
Dual vs Single Protease Inhibitor Therapy Following Antiretroviral Treatment Failure: A Randomized Trial
Hammer et al.
JAMA 2002;288:169-180.
ABSTRACT
| FULL TEXT
Hepatitis C and Progression of HIV Disease
Sulkowski et al.
JAMA 2002;288:199-206.
ABSTRACT
| FULL TEXT
Antiretroviral Treatment for Adult HIV Infection in 2002: Updated Recommendations of the International AIDS Society-USA Panel
Yeni et al.
JAMA 2002;288:222-235.
ABSTRACT
| FULL TEXT
Evaluation of the Effectiveness of Highly Active Antiretroviral Therapy in Persons with Human Immunodeficiency Virus using Biomarker-based Equivalence of Disease Progression
Jacobson et al.
Am J Epidemiol 2002;155:760-770.
ABSTRACT
| FULL TEXT
Unrecognized HIV Infection Among Patients Attending Sexually Transmitted Disease Clinics
Weinstock et al.
AJPH 2002;92:280-283.
ABSTRACT
| FULL TEXT
Rates of Disease Progression by Baseline CD4 Cell Count and Viral Load After Initiating Triple-Drug Therapy
Hogg et al.
JAMA 2001;286:2568-2577.
ABSTRACT
| FULL TEXT
Changes in AIDS-related lymphoma since the era of highly active antiretroviral therapy
Besson et al.
Blood 2001;98:2339-2344.
ABSTRACT
| FULL TEXT
Methods to Assess Population Effectiveness of Therapies in Human Immunodeficiency Virus Incident and Prevalent Cohorts
Tarwater et al.
Am J Epidemiol 2001;154:675-681.
ABSTRACT
| FULL TEXT
Use of Protease Inhibitors and Non-Nucleoside Reverse Transcriptase Inhibitors Among Medicaid Beneficiaries With AIDS
Sambamoorthi et al.
AJPH 2001;91:1474-1481.
ABSTRACT
| FULL TEXT
Nelfinavir, Efavirenz, or Both after the Failure of Nucleoside Treatment of HIV Infection
Albrecht et al.
NEJM 2001;345:398-407.
ABSTRACT
| FULL TEXT
Antiretroviral Therapy for Previously Treated Patients
Montaner and Mellors
NEJM 2001;345:452-455.
FULL TEXT
Highly Active Antiretroviral Therapy Decreases Mortality and Morbidity in Patients with Advanced HIV Disease
Murphy et al.
ANN INTERN MED 2001;135:17-26.
ABSTRACT
| FULL TEXT
Short-Term Measures of Relative Efficacy Predict Longer-Term Reductions in Human Immunodeficiency Virus Type 1 RNA Levels following Nelfinavir Monotherapy
Mittler et al.
Antimicrob. Agents Chemother. 2001;45:1438-1443.
ABSTRACT
| FULL TEXT
Management of HIV-1 Infection in Adults and Adolescents
Eugenio and Zeind
Journal of Pharmacy Practice 2000;13:426-441.
ABSTRACT
Highly Active Antiretroviral Therapy and Incidence of Cancer in Human Immunodeficiency Virus-Infected Adults
International Collaboration on HIV and Cancer
JNCI J Natl Cancer Inst 2000;92:1823-1830.
ABSTRACT
| FULL TEXT
Selection by Indication of Potent Antiretroviral Therapy Use in a Large Cohort of Women Infected with Human Immunodeficiency Virus
Ahdieh et al.
Am J Epidemiol 2000;152:923-933.
ABSTRACT
| FULL TEXT
Differential Access in the Receipt of Antiretroviral Drugs for the Treatment of AIDS and Its Implications for Survival
Anderson and Mitchell
Arch Intern Med 2000;160:3114-3120.
ABSTRACT
| FULL TEXT
Evaluation of HIV-1 Immunogen, an Immunologic Modifier, Administered to Patients Infected With HIV Having 300 to 549 x 106/L CD4 Cell Counts: A Randomized Controlled Trial
Kahn et al.
JAMA 2000;284:2193-2202.
ABSTRACT
| FULL TEXT
AIDS-related focal brain lesions in the era of highly active antiretroviral therapy
Ammassari et al.
Neurology 2000;55:1194-1200.
ABSTRACT
| FULL TEXT
Delayed Medical Care After Diagnosis in a US National Probability Sample of Persons Infected With Human Immunodeficiency Virus
Turner et al.
Arch Intern Med 2000;160:2614-2622.
ABSTRACT
| FULL TEXT
Phase angle from bioelectrical impedance analysis remains an independent predictive marker in HIV-infected patients in the era of highly active antiretroviral treatment
Schwenk et al.
Am. J. Clin. Nutr. 2000;72:496-501.
ABSTRACT
| FULL TEXT
Impact of Protease Inhibitors and Other Antiretroviral Treatments on Acquired Immunodeficiency Syndrome Survival in San Francisco, California, 1987-1996
Schwarcz et al.
Am J Epidemiol 2000;152:178-185.
ABSTRACT
| FULL TEXT
Adherence to Protease Inhibitor Therapy and Outcomes in Patients with HIV Infection
Paterson et al.
ANN INTERN MED 2000;133:21-30.
ABSTRACT
| FULL TEXT
Ethical Considerations in the Treatment of Infertility in Women with Human Immunodeficiency Virus Infection
Minkoff and Santoro
NEJM 2000;342:1748-1750.
FULL TEXT
Psychological Effects of HAART: A 2-Year Study
Rabkin et al.
Psychosom. Med. 2000;62:413-422.
ABSTRACT
| FULL TEXT
Effect of Antiretroviral Therapy on Viral Load, CD4 Cell Count, and Progression to Acquired Immunodeficiency Syndrome in a Community Human Immunodeficiency Virus-Infected Cohort
Erb et al.
Arch Intern Med 2000;160:1134-1140.
ABSTRACT
| FULL TEXT
Antiretroviral Therapy in Adults: Updated Recommendations of the International AIDS Society-USA Panel
Carpenter et al.
JAMA 2000;283:381-390.
ABSTRACT
| FULL TEXT
Bioelectrical impedance analysis in HIV-infected patients treated with triple antiretroviral treatment
Schwenk et al.
Am. J. Clin. Nutr. 1999;70:867-873.
ABSTRACT
| FULL TEXT
Effects of Anticoagulant, Processing Delay, and Assay Method (Branched DNA versus Reverse Transcriptase PCR) on Measurement of Human Immunodeficiency Virus Type 1 RNA Levels in Plasma
Kirstein et al.
J. Clin. Microbiol. 1999;37:2428-2433.
ABSTRACT
| FULL TEXT
Induction/Maintenance Treatment Regimens for HIV
Montaner
JAMA 1999;281:1680-1682.
FULL TEXT
Gaining ground in progressive multifocal leukoencephalopathy
Dolin
Neurology 1999;52:440-440.
FULL TEXT
The Costs, Clinical Benefits, and Cost-Effectiveness of Screening for Cervical Cancer in HIV-Infected Women
Goldie et al.
ANN INTERN MED 1999;130:97-107.
ABSTRACT
| FULL TEXT
Effectiveness of Potent Antiretroviral Therapy on Time to AIDS and Death in Men With Known HIV Infection Duration
Detels et al.
JAMA 1998;280:1497-1503.
ABSTRACT
| FULL TEXT
Barriers to Use of Free Antiretroviral Therapy in Injection Drug Users
Strathdee et al.
JAMA 1998;280:547-549.
ABSTRACT
| FULL TEXT
Antiretroviral Therapy for HIV Infection in 1998: Updated Recommendations of the International AIDS Society-USA Panel
Carpenter et al.
JAMA 1998;280:78-86.
ABSTRACT
| FULL TEXT
Antiretroviral Therapy and Improving AIDS Survival
De Luca et al.
JAMA 1998;279:1874-1875.
FULL TEXT
Effective AIDS Treatment Predated the Protease Inhibitors
JWatch General 1998;1998:2-2.
FULL TEXT
|
