JAIDS Journal of Acquired Immune Deficiency Syndromes:
Grade 4 Events Are as Important as AIDS Events in the Era of HAART
Reisler, Ronald B. MD, MPH; Han, Cong PhD; Burman, William J. MD; Tedaldi, Ellen M. MD; Neaton, James D. PhD
From the Institute of Human Virology, University of Maryland, Baltimore, MD (Dr Reisler); University of Washington, Seattle, WA (Dr Han); Denver Public Health Department, University of Colorado, Denver, CO (Dr Burman); Temple University Hospital, Philadelphia, PA (Dr Tedaldi); and University of Minnesota, School of Public Health, Minneapolis, MN (Dr Neaton).
Received for publication April 11, 2003; accepted September 2, 2003.
Presented in part at the 9th Conference on Retroviruses and Opportunistic Infections, Seattle, WA, February 24–28, 2002 (abstracts 36 and 657-M).
Funded in part by cooperative agreements between the National Institute of Allergy and Infectious Diseases and the Terry Beirn Community Programs for Clinical Research on AIDS, Bethesda, MD.
Appropriate informed consent was obtained for all participants and clinical research was conducted in accordance with the guidelines for human experimentation of the US Department of Health and Human Services.
Reprints: Ronald B. Reisler, Institute of Human Virology, University of Maryland Medical Center, 725 West Lombard Street, Room N556, Baltimore, MD 21201 (e-mail: email@example.com).
Objective: To estimate incidence and predictors of serious or life-threatening events that are not AIDS defining, AIDS events, and death among patients treated with highly active antiretroviral therapy (HAART) in the setting of 5 large multicenter randomized treatment trials conducted in the United States.
Methods: Data were analyzed from 2947 patients enrolled from December 1996 through December 2001. All patients were to receive antiretrovirals throughout follow-up. Data collection was uniform for all main outcome measures: serious or life-threatening (grade 4) events, AIDS, and death.
Results: During follow-up, 675 patients experienced a grade 4 event (11.4 per 100 person-years); 332 developed an AIDS event (5.6 per 100 person-years); and 272 died (4.6 per 100 person-years). The most common grade 4 events were liver related (148 patients, 2.6 per 100 person-years). Cardiovascular events were associated with the greatest risk of death (hazard ratio = 8.64; 95% CI: 5.1 to 14.5). The first grade 4 event and the first AIDS event were associated with similar risks of death, 5.68 and 6.95, respectively.
Conclusions: Grade 4 events are as important as AIDS events in the era of HAART. To adequately evaluate the impact of HAART on morbidity, comorbidities and other key factors must be carefully assessed.
The introduction of highly active antiretroviral therapy (HAART) and an improved understanding of HIV-1 viral dynamics led to a dramatic decline in US AIDS-related morbidity and mortality beginning in 1996. 1–4 This dramatic decline, together with the hope that HIV could be eradicated, 5 led clinicians and HIV treatment guideline committees to adopt an aggressive strategy in treating HIV, 6 focusing primarily on the benefits of HAART: “hit early, hit hard.”7 However, as current antiretroviral therapy is unable to eradicate HIV, 8 and is associated with increased toxicities, HIV treatment guideline committees have recently adopted a less aggressive set of guidelines for treating HIV. 9,10
All 4 classes of antiretrovirals (ARVs) and all 19 Food and Drug Administration–approved ARVs have been directly or indirectly associated with life-threatening events and death. 9,11–13 However, the cause of many serious or life-threatening events is multifactorial and clear attribution to the use of HAART, specific ARV drugs, HIV infection, or other factors is frequently not possible. Potential risk factors for the development of life-threatening clinical events among HIV-infected individuals on HAART include HIV virus–host interactions, 14–17 stage of HIV disease, 18–20 ARV drugs, 9,11–13 genetic predisposition, 21–25 age, 26 comorbid conditions, 27–35 coinfections (e.g., hepatitis B or hepatitis C), 36–44 concomitant medications, 43,45–49 nutritional status, 50–55 recreational drugs and alcohol, 56–58 other social behaviors and practices, 53,59–62 and physician experience. 63,64
The short-term toxicities and benefits of HAART have been well described in the setting of clinical trials; however, data quantifying morbidity in the era of HAART are limited. We therefore estimated the incidence and determinants of serious or life-threatening events that are not AIDS defining, AIDS events, and death among patients treated with HAART in the setting of 5 large multicenter randomized treatment trials conducted in the United States.
The Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) is a National Institutes of Health–funded clinical trials group that conducts research through a national network of community-based clinical sites. The trials were conducted in 18 community-based units located in 16 cities throughout the United States: Chicago, IL; San Francisco, CA; Detroit, MI; New York, NY; Portland, OR; Houston, TX; Atlanta, GA; New Haven, CT; Newark, NJ; Camden, NJ; Philadelphia, PA; Washington, DC; Albuquerque, NM; New Orleans, LA; Denver, CO; and Richmond, VA. Each unit provides HIV primary care but differs in its configuration, varying from geographically limited, hospital clinic–based units to geographically widespread units with a variety of hospital-based, private practice, community health care, and health maintenance organization providers.
Patients participating in 1 of 5 CPCRA clinical trials formed the cohort for this investigation. 65–69 These trials were chosen because they used a common system for collection of adverse events and AIDS events, and in all studies patients were to receive antiretroviral therapy (ART) throughout follow-up. Two studies were comparisons of initial HAART regimens (NvR: CPCRA 042 and FIRST: CPCRA 058) 65,66; one study evaluated the effect of stopping prophylaxis for MAC (Mycobacterium Avium Complex) (CR-MAC-CPCRA 048) 67; one study evaluated the effect of interleukin-2 (IL-2) on viral load and CD4 cell count (IL-2: CPCRA 059) 68; and another study (MDR: CPCRA 064) is evaluating the effect of a 4-month interruption of ART on clinical progression. 69 For the latter 2 studies, only patients enrolled in the control groups (i.e., the group without IL-2 in CPCRA 059 and the group assigned to receive continuous ART in CPCRA 064) were used in these analyses.
At the time of enrollment, a medical history was obtained, and demographic data and risk behaviors were recorded. CD4+ T-lymphocyte (CD4+) cell count measurements were performed by the laboratory normally used by the patient's health care provider. In 3 of the studies, serology for hepatitis B (hepatitis B surface antigen) and hepatitis C (hepatitis C antibody) infection was analzyed. During follow-up, for each of the 5 trials, deaths, AIDS events, 70 and non–AIDS-defining events considered severe or life threatening (i.e., meeting grade 4 severity status) were reported using standardized forms and procedures.
With regard to AIDS events, all possible AIDS events were reviewed by an endpoints review committee to determine whether the criteria for the event were met. Those events that met criteria as probable or definite clinical AIDS events were included in these analyses. For these analyses, AIDS events were defined as clinical events that have been associated with advanced HIV-related immunodeficiency that meet the 1993 revised Centers for Disease Control AIDS surveillance definition with 2 exceptions: a CD4+ cell count of <200 was not counted as an AIDS event, and recurrent bacterial pneumonia was not counted as an AIDS event. The rationale for this definition has been described previously. 70
For these analyses, grade 4 events are defined as non–AIDS-related events considered severe or life threatening (i.e., meeting grade 4 severity status). Grade 4 events included laboratory abnormalities, clinical signs and symptoms, diseases, and clinical syndromes. In the case of grade 4 laboratory abnormalities, specific criteria for grade 4 severity is specified in a toxicity manual devised by the Division of AIDS, National Institutes of Allergy and Infectious Diseases, National Institutes of Health. For many clinical conditions, specific criteria for defining grade 4 severity are stated in the manual. In some cases clinical judgment was used to determine the severity grade. In such cases, the following guideline was given to characterize a grade 4 event: “extreme limitation in activity—significant assistance required; significant medical intervention/therapy required, hospitalization or hospice care possible.” For the sake of this analysis, we have presented the most common grade 4 events and have grouped them accordingly: cardiovascular events were grouped to include cardiac or vascular events (i.e., cardiac arrest, myocardial infarction, cerebrovascular accident, deep vein thrombosis, pulmonary embolism, unstable angina, congestive heart failure, and splenic infarct); kidney-related events were grouped to include kidney failure, grade 4 elevation in serum creatinine (>6× upper level of normal [ULN]), and HIV-related nephropathy; hemorrhage events were grouped to include gastrointestinal bleeding, bleeding (at an unspecified location), nose bleeding, and hematuria (gross); liver-related events were grouped to include grade 4 transaminase elevations (>10× ULN), grade 4 elevations of bilirubin (>5× ULN), clinical hepatitis, fulminant hepatitis, liver failure, toxic hepatitis, cirrhosis, fatty liver, hepatic encephalopathy, and liver disorder/disease; pancreatitis events were grouped by grade 4 elevation of amylase (>5× ULN), grade 4 elevation of lipase (>5× ULN), and clinical pancreatitis; thrombocytopenia events included grade 4 diminution of platelets (<20,000/mm3) and idiopathic thrombocytopenic purpura; psychiatric events included suicide attempt, suicidal ideation, hallucinations, depression, anxiety/panic attack, delirium, psychosis, paranoia, bipolar disorder, and manic hyperactivity/agitation; grade 4 anemia is defined as diminution of hemoglobin < 6.5 g/dL; and grade 4 neutropenia is defined as absolute neutrophil count < 500 /mm3.
Importantly, according to protocol, any event considered to be grade 4 in severity was to be reported irrespective of the relationship to the treatments under investigation and irrespective of any other medications taken concomitantly. Grade 4 events were to be reported even if study treatments had been temporarily discontinued. All grade 4 events were reported, not just the first to occur. At minimum, patients were to be seen every 4 months during follow-up. Grade 4 events were centrally reviewed by a nurse who coded the event according to a coding system based on the 9th revision of the International Classification of Diseases. 71
We performed a subset analysis with regard to liver events, attempting to see whether chronic viral hepatitis co-infection impacted on grade 4 liver events, grade 4 events overall, AIDS events, and death. In the serology analysis, we limited our analysis to the 3 studies that collected hepatitis serology at baseline: CPCRA 058, CPCRA 059, and CPCRA 064. In these 3 studies, serology for hepatitis B (hepatitis B surface antigen) and hepatitis C (hepatitis C antibody) infection was performed at baseline. This analysis reflects 1628 patients from these 3 studies with baseline serologies that were treated with ART. The serology data were collected uniformly in these 3 studies, although the assay methodology varied by site and over time. We do not attempt to compare this subset to the overall group. To facilitate the analysis of the impact of chronic viral hepatitis coinfection on the incidence of grade 4 events, mortality, and AIDS, in the serology cohort, we considered hepatitis B and hepatitis C together.
Incidence rates per 100 person-years are cited, as well as cumulative event probabilities based on Kaplan-Meier estimates. Proportional hazards regression was used to study predictors of grade 4 events and to estimate the risk of death associated with different types of grade 4 events. Hazard ratios (HRs) obtained from the regression model were adjusted for the following covariates assessed at the time of enrollment: age, gender, race, injection drug use, body mass index, CD4 cell count, prior AIDS, and use of prior ART. Regression analyses were also stratified by protocol (5 strata). Two-sided P values and 95% CIs are cited. To determine the risk of death associated with grade 4 and AIDS-defining events, the development of the event was considered a time-dependent co-variate in the regression analysis. These analyses were adjusted for the same set of baseline covariates as mentioned previously. The closing date used for time-to-event analyses was July 2000 for 2 of the studies (CPCRA 048 and CPCRA 059), 67,68 December 31, 2001 for 1 study (CPCRA 042), 65 and February 28, 2002 for the 2 ongoing studies (CPCRA 058 and CPCRA 064). 66,69 All analyses ignored treatment interruptions during follow-up. In that respect the analyses carried out here are analogous to an intent-to-treat analysis for a clinical trial.
Between December 1996 and December 2001, 2947 patients with a diagnosis of HIV infection were enrolled into 1 of 5 CPCRA clinical trials defining the cohort for this analysis. Patient's clinical status ranged from relatively early HIV disease to advanced HIV disease (Table 1). Fifty-three percent of patients were ARV naive, and 47% were treatment experienced at the time of enrollment. Average age was 39.3 years; 83% were male and 17% were female; 41.5% were white, 44.8% were African American, and 13.7% were Latino. Approximately 16% of patients reported a history of injection drug use, and 55% reported homosexual activity as an HIV risk factor. CD4+ cell count averaged 211 cells/mm3 (interquartile range: 38–322 cells/mm3), and 40.0% had a prior clinical AIDS diagnosis.
All patients in this cohort were prescribed ART following enrollment. At 12 months of follow-up, 1951/2120 (92%) were prescribed ART with 1475/2120 (70%) on protease inhibitor–based regimens, 421/2120 (20%) on nonnucleoside reverse transcription inhibitor–based regimens (no protease inhibitor), and 55/2120 (3%) solely on nucleoside reverse transcription inhibitors. Thus, at 12 months, 169/2120 (8%) had either temporarily or permanently discontinued ART.
Median follow-up was 20.7 months (interquartile range: 13.3–32.3 months), a total of 5940 person-years. During follow-up, 675 patients experienced a grade 4 event (11.4 per 100 person-years); 332 developed an AIDS event (5.6 per 100 person-years); and 272 died (4.6 per 100 person-years). Cumulative event curves are shown in Figure 1. The cumulative percentage of patients with a grade 4 event after 12, 24, and 36 months are, respectively, 15.6%, 23.7%, and 30.8%. Corresponding percentages for AIDS are, respectively, 7.3%, 10.8%, and 16.5% and corresponding percentages for death are, respectively, 3.9%, 7.9%, and 13.1%.
The most common grade 4 events were: liver related (148 patients; rate = 2.6 per 100 person-years); neutropenia (89; 1.5/100 person-year); anemia (64; 1.1/100 person-year); cardiovascular (51; 0.89/100 person-year); pancreatitis (50; 0.85/100 person-year); psychiatric (44; 0.75/100 person-year); kidney-related (34; 0.58/100 person-year); thrombocytopenia (32; 0.54/100 person-year); and hemorrhage (25; 0.42/100 person-year) (Fig. 2).
Incidence of Clinical Events by Baseline CD4+ Cell Count
The numbers of patients and rates per 100 person-years of risk for AIDS, grade 4 events, and death are summarized in Table 2. The rates of each type of event increased with lower CD4+ cell count levels. The slope of this relationship was much steeper for AIDS and death than for grade 4 events. As a consequence, among patients with higher CD4+ cell counts, the great majority of events occurring were grade 4 events.
Baseline Predictors of Grade 4 Events Using a Multivariate Model
Based on multivariate analysis of predictors of any grade 4 event and specific grade 4 events, younger patients (for every decade in years, HR = 0.83, P = 0.0001) and patients who were ARV naive (HR = 0.59, P = 0.001) had a lower risk of grade 4 events; patients with a history of injection drug use (HR = 1.41, P = 0.0006), lower baseline CD4+ cell count (for every 100 cells, HR = 1.06, P = 0.04), and a prior diagnosis of AIDS (HR = 1.22, P = 0.03) had an increased risk of grade 4 events. Female gender was significantly associated only with grade 4 neutropenia (HR = 1.76, P = 0.03), while African American race was associated with neutropenia (HR = 3.78, P = 0.0001), anemia (HR = 2.46, P = 0.008), and kidney-related events (HR = 22.41, P = 0.0025). Latino race was associated with neutropenia (HR = 2.75, P = 0.01). Higher body mass index at entry was associated with significantly less neutropenia (for 1 kg/m2 HR = 0.93, P = 0.01) and less anemia (HR = 0.90, P = 0.003).
Risk of Death Associated With Grade 4 Events and AIDS
Of the 272 deaths, 117 experienced an AIDS event during follow-up prior to death and 153 experienced a grade 4 event prior to death. One hundred fifty-nine patients (69 of whom died later) experienced both a grade 4 and an AIDS event. Table 3 gives the risk of death associated with each of these categories of grade 4 events, the first grade 4 event that occurred, and the first AIDS event that occurred. Cardiovascular events were associated with the greatest risk of death (HR = 7.08; 95% CI: 4.2–12.1). The first grade 4 event and the first AIDS event were associated with similar risks of death: 5.68 and 6.95, respectively.
Hepatitis Serology Subset
Baseline results of serologic testing for hepatitis B and C were available for 1628 patients. Seroprevalence in this subset was as follows: 6.4% for hepatitis B infection (positive hepatitis B surface antigen); 17.9% for hepatitis C infection (positive hepatitis C antibody); 0.7% for both hepatitis B and hepatitis C; and 24.3% for hepatitis B and/or C. Among the 1628 patients with baseline hepatitis serology information, the rate of grade 4 adverse events was 11.2 per 100 person-years for those not coinfected, 14.9 for those coinfected with hepatitis B, 16.7 for those coinfected with hepatitis C, and 16.4 for those coinfected with hepatitis B and/or hepatitis C.
Coinfection with hepatitis B was strongly associated with an increased risk for developing a grade 4 liver event, with a HR = 5.97 (95% CI: 3.05–11.71; P = 0.0001). Similarly, coinfection with hepatitis C was strongly associated with an increased risk for developing a grade 4 liver-related event with a HR = 2.74 (95% CI: 1.29–5.84; P = 0.009). Hence, coinfection with hepatitis B or hepatitis C yielded a HR = 4.15 (95% CI: 2.26–7.60; P = 0.0001). After adjustment for other covariates, coinfection with hepatitis B or hepatitis C was not significantly associated with developing any grade 4 event, HR = 1.27 (95% CI: 0.92–1.74; P = 0.15), mortality, HR = 1.19 (95% CI: 0.61–2.32; P = 0.60), or AIDS (HR = 1.20; 95% CI: 0.70–2.05; P = 0.51) (Table 4).
This is one of the first analyses to quantify the rate of serious or life-threatening events, AIDS events, and death in a large cohort of patients treated with HAART. Our principal finding is that the rate of grade 4 events is greater than the rate of AIDS events, and that the risk of death associated with these grade 4 events was very high for many events. Thus, the incidence of AIDS events fails to capture most of the morbidity experienced by patients with HIV infection prescribed HAART. Furthermore, among patients with higher CD4+ cell count, those for whom the benefits of therapy are most uncertain, nearly all of the morbidity was due to grade 4 events. For patients with lower CD4+ cell counts, the rates of both grade 4 and AIDS events were higher. Nonetheless, it is reassuring that these rates are much lower than rates seen in a similar cohort that received dual nucleosides. 72 Thus, although more effective ART is associated with decreased morbidity from both grade 4 and AIDS events, significant morbidity remains.
We believe these findings have 2 immediate implications. First, the usual procedure used in clinical trials of collecting adverse event data only while patients are taking study therapy and not collecting adverse event data after patients discontinue study treatment may need to be reevaluated. It is entirely possible that treatments may cause toxicities (e.g., liver damage or acceleration of atherosclerosis) that may not be apparent while the patient is taking the therapy and may only be manifest many months or years later. A rigorous intention-to-treat analysis for adverse event data as was employed here could provide important data with respect to establishing the toxicity profile of different regimens. Also, longer-term follow-up is necessary as many adverse events are not likely to emerge in the limited follow-up carried out for treatment trials for licensure. 73 As has been recently pointed out by others, complete and rigorous safety data collection and reporting in trials 74,75 would be exceedingly helpful. Perhaps trials could incorporate review committees of medical experts to classify serious events uniformly.
A second implication of these findings is that there is a need to carefully assess comorbid conditions, socioeconomic status, recreational drug and alcohol use, and concomitant medications at baseline and throughout follow-up. If therapy could be optimized to reduce the incidence of these serious or life-threatening events by even a modest amount, the impact on morbidity and mortality would be great. For example, patients at increased risk for cardiovascular events might benefit from being placed on a protease inhibitor–sparing HAART regimen. 76–78 Similarly, patients with a history of severe depression may be better off with an efavirenz-sparing HAART regimen. 79,80
The findings for patients coinfected with hepatitis B and/or C emphasize the importance of evaluating comorbidities. Patients coinfected with hepatitis B and/or C have higher incidence rates of grade 4 liver events. In multivariate analyses for these patients who were all prescribed HAART, hepatitis B and/or C coinfection was the only significant predictor of grade 4 liver events, the most common grade 4 event seen in this cohort. It is possible that the risks and benefits of HAART therapy on morbidity and mortality are different among patients with these coinfections.
Likewise, our finding that African American race was associated with an increased risk of renal events illustrates the difficulty in attribution of adverse events to HAART outside of the context of a randomized trial. It is well established that blacks have a higher risk of renal failure than whites in the US population. 81 Whether HAART exacerbates this risk is uncertain. If it does, and we know that some specific drugs have been associated with acute renal changes (e.g., adefovir), 82 then this would be an important consideration for risk stratification for starting or maintaining ART.
Our study had several limitations. Grade 4 event classifications were crudely grouped for the purpose of this analysis and were composed of laboratory and/or clinical events. Grade 4 events were not reviewed and classified with the same rigor as AIDS events (e.g., a central review committee of medical experts was not used to classify grade 4 events). Some potentially important predictors were not adjusted for in the multivariate analysis (e.g., history of grade 4 event prior to enrollment, socioeconomic status, recreational drug and alcohol use, co-morbid conditions besides hepatitis B or C infection, and concomitant use of other medications). Finally, this observational analysis cannot clearly establish an association of specific grade 4 events with ART, in general, or with specific treatments. Some patients continued the same regimen throughout follow-up, whereas others stopped or started new regimens during follow-up.
In summary, morbidity and mortality for patients with HIV infection have been substantially reduced with HAART. However, morbidity remains high in the era of HAART. Better evidence is needed to determine how much of this morbidity is directly due to HAART. To adequately assess the impact of HAART on morbidity, we need to obtain more comprehensive data with regard to comorbid conditions, socioeconomic status, recreational drug and alcohol use, and concomitant medications at baseline and throughout follow-up.
1. Fleming PL, Ward JW, Karon JM, et al. Declines in AIDS incidence and deaths in the USA: a signal change in the epidemic. AIDS. 1998; 12(suppl A):S55–S61.
2. Detels R, Munoz A, McFarlane G, et al. Effectiveness of potent antiretroviral therapy on time to AIDS and death in men with known HIV infection duration. JAMA. 1998; 280:1497–1503.
3. Mellors JW, Rinaldo Jr, CR Gupta P, et al. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science. 1996; 272:1167–1170.
4. Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced Human Immunodeficiency Infection. N Engl J Med. 1998; 338:853–860.
5. Ho DD. Toward HIV eradication or remission: the tasks ahead. Science. 1998; 280:1866–1867.
6. Carpenter CC, Fischl MA, Hammer SM, et al. Antiretroviral therapy for HIV infection in 1997. Updated recommendations of the International AIDS Society-USA panel. JAMA. 1997; 277:1962– 1969.
7. Ho DD. Time to hit HIV, early and hard. N Engl J Med. 1995; 333:450–451.
8. Chun TW, Fauci AS. Latent reservoirs of HIV: obstacles to the eradication of the virus. Proc Natl Acad Sci U S A. 1999; 96:10958–10961.
9. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents.
Rockville, MD: US Department of Health and Human Services; 2003. Available at: http://aidsinfo.nih.gov/guidelines/
Accessed July 31, 2003.
10. Yeni PG, Hammer SM, Carpenter CCJ, et al. Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS Society: USA panel. JAMA. 2002; 288:222–235.
11. Lalezari JP, Henry K, O'Hearn M, et al. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med. 2003; 348:2186–2195.
12. Sanne I, Piliero P, Squires K, et al. Results of a phase 2 clinical trial at 48 weeks (AI424-007): a dose-ranging, safety, and efficacy comparative trial of atazanavir at three doses in combination with didanosine and stavudine in antiretroviral-naive subjects. J Acquir Immune Defic Syndr. 2003; 32:18–29.
13. Emtriva (emtricitabine) [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2003.
14. Moses A, Nelson J, Bagby Jr. GC The influence of human immunodeficiency virus-1 on hematopoiesis. Blood. 1998; 91:1479–1495.
15. Peruzzi M, Azzari C, Rossi ME, et al. Inhibition of natural killer cell cytotoxicity and interferon gamma production by the envelope protein of HIV and prevention by vasoactive intestinal peptide. AIDS Res Hum Retroviruses 2000; 16:1067–1073.
16. Boutet A, Altmeyer R, Hery C, et al. Direct role of plasma membrane-expressed gp120/41 in toxicity to human astrocytes induced by HIV-1-infected macrophages. AIDS. 2000; 14:2687–2697.
17. Ferri KF, Jacotot E, Blanco J, et al. Mitochondrial control of cell death induced by HIV-1-encoded proteins. Ann N Y Acad Sci. 2000; 926:149–164.
18. Coopman SA, Johnson RA, Platt R, et al. Cutaneous disease and drug reactions in HIV infection. N Engl J Med. 1993; 328:1670–1674.
19. Gates AE, Kaplan LD. AIDS malignancies in the era of highly active antiretroviral therapy. Oncology (Huntingt) 2002; 16:441–451, 456, 459.20.
20. Childs EA, Lyles RH, Selnes OA, et al. Plasma viral load and CD4 lymphocytes predict HIV-associated dementia and sensory neuropathy. Neurology. 1999; 52:607–613.
21. Hetherington S, Hughes AR, Mosteller M, et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet. 2002; 359:1121–1122.
22. Mallal S, Nolan D, Witt C, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet. 2002; 359:727–732.
23. Freedman BI, Soucie JM, Stone SM, et al. Familial clustering of end-stage renal disease in blacks with HIV-associated nephropathy. Am J Kidney Dis. 1999; 34:254–258.
24. Telenti A, Aubert V, Spertini F. Individualizing HIV Treatment—pharmacogenetics and immunogenetics. Lancet. 2002; 359:722–723.
25. Phillips KA, Veenstra DL, Oren E, et al. Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review. JAMA. 2001; 286:2270–2279.
26. Babiker AG, Peto T, Porter K, et al. Age as a determinant of survival in HIV infection. J Clin Epidemiol. 2001; 54:S1, S16–S21.
27. Semba RD, Shah N, Strathdee SA, et al. High prevalence of iron deficiency and anemia among female injection drug users with and without HIV infection. J Acquir Immune Defic Syndr. 2002; 29:142–144.
28. Moore RD, Forney D. Anemia in HIV-infected patients receiving highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2002; 29:54–57.
29. Semba RD, Shah N, Klein RS, et al. Prevalence and cumulative incidence of and risk factors for anemia in a multicenter cohort study of human immunodeficiency virus-infected and -uninfected women. Clin Infect Dis. 2002; 34:260–266.
30. Levine AM, Berhane K, Masri-Lavine L, et al. Prevalence and correlates of anemia in a large cohort of HIV-infected women: Women's Interagency HIV Study. J Acquir Immune Defic Syndr. 2001; 26:28–35.
31. Gordeuk VR, Delanghe JR, Langlois MR, et al. Iron status and the outcome of HIV infection: an overview. J Clin Virol. 2001; 20:111–115.
32. Abbott KC, Hypolite I, Welch PG, et al. Human immunodeficiency virus/acquired immunodeficiency syndrome-associated nephropathy at end-stage renal disease in the United States: patient characteristics and survival in the pre highly active antiretroviral therapy era. J Nephrol. 2001; 14:377–383.
33. Gold J, Pocock N, Li Y. Bone mineral density abnormalities in patients with HIV infection. J Acquir Immune Defic Syndr. 2002; 30:131–132.
34. Falusi OM, Aberg JA. HIV and cardiovascular risk factors. AIDS Read. 2001; 11:263–268.
35. Kilbourne AM, Justice AC, Rabeneck L, et al. General medical and psychiatric comorbidity among HIV-infected veterans in the post-HAART era. J Clin Epidemiol. 2001; 54(Suppl 1):S22–S28.
36. Dore GJ, Cooper DA. The impact of HIV therapy on co-infection with hepatitis B and hepatitis C viruses. Curr Opin Infect Dis. 2001; 14:749–755.
37. Graham CS, Baden LR, Yu E, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis. 2001; 33:562–569.
38. Duong M, Petit JM, Piroth L, et al. Association between insulin resistance and hepatitis C virus chronic infection in HIV-hepatitis C virus-coinfected patients undergoing antiretroviral therapy. J Acquir Immune Defic Syndr. 2001; 27:245–250.
39. den Brinker M, Wit FW, Wertheim-van Dillen PM, et al. Hepatitis B and C virus co-infection and the risk for hepatotoxicity of highly active antiretroviral therapy in HIV-1 infection. AIDS. 2000; 14:2895–2902.
40. Sulkowski MS, Thomas DL, Chaisson RE, et al. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA. 2000; 283:74–80.
41. Manegold C, Hannoun C, Wywiol A, et al. Reactivation of hepatitis B virus replication accompanied by acute hepatitis in patients receiving highly active antiretroviral therapy. Clin Infect Dis. 2001; 32:144–148.
42. French MAH. Antiretroviral therapy immune restoration disease in HIV-infected patients on HAART. AIDS Read. 1999; 9:548–562.
43. Burman WJ, Jones BE. Treatment of HIV-related tuberculosis in the era of effective antiretroviral therapy. Am J Crit Care Med. 2001; 164:7–12.
44. Steketee RW, Nahlen BL, Parise ME, et al. The burden of malaria in pregnancy in malaria-endemic areas. Am J Trop Med Hyg. 2001; 64:28–35.
45. Fichtenbaum CJ, Gerber JG, Rosenkranz SL, et al. Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047. AIDS. 2002; 16:569–77.
46. Clarke SM, Mulcahy FM, Tjia J, et al. The pharmacokinetics of methadone in HIV-positive patients receiving the non-nucleoside reverse transcriptase inhibitor efavirenz. Br J Clin Pharmacol. 2001; 51:213–217.
47. Rainey PM. HIV drug interactions: the good, the bad, and the other. Ther Drug Monit. 2002; 24:26–31.
48. Morse GD. Drug interactions with antiretrovirals. Curr Infect Dis Rep. 2000; 2:257–266.
49. Ernst E. Second thoughts about safety of St John's wort. Lancet. 1999; 354:1014–1015.
50. Wheeler DA, Gibert CL, Launer CA, et al. Weight loss as a predictor of survival and disease progression in HIV infection. Terry Beirn Community Programs for Clinical Research on AIDS. J Acquir Immune Defic Syndr Hum Retrovirol. 1998; 18:80–85.
51. Villamor E, Msamanga G, Spiegelman D, et al. HIV status and sociodemographic correlates of maternal body size and wasting during pregnancy. Eur J Clin Nutr. 2002; 56:415–424.
52. Shuter J, Chang CJ, Klein RS. Prevalence and predictive value of overweight in an urban HIV care clinic. J Acquir Immune Defic Syndr. 2001; 26:291–297.
53. Forrester JE, Woods MN, Knox TA, et al. Body composition and dietary intake in relation to drug abuse in a cohort of HIV-positive persons. J Acquir Immune Defic Syndr. 2000; 25(Suppl 1):S43–S48.
54. Shor-Posner G, Campa A, Zhang G, et al. When obesity is desirable: a longitudinal study of the Miami HIV-1-infected drug abusers (MIDAS) cohort. J Acquir Immune Defic Syndr. 2000; 23:81–88.
55. Melchior JC, Niyongabo T, Henzel D, et al. Malnutrition and wasting, immunodepression, and chronic inflammation as independent predictors of survival in HIV-infected patients. Nutrition. 1999; 15:865–869.
56. Lucas GM, Gebo KA, Chaisson RE, et al. Longitudinal assessment of the effects of drug and alcohol abuse on HIV-1 treatment outcomes in an urban clinic. AIDS. 2002; 16:767–774.
57. Flexner CW, Cargill VA, Sinclair J, et al. Alcohol use can result in enhanced drug metabolism in HIV pharmacotherapy. AIDS Patient Care STDS. 2001; 15:57–58.
58. Lucas GM, Cheever LW, Chaisson RE, et al. Detrimental effects of continued illicit drug use on the treatment of HIV-1 infection. J Acquir Immune Defic Syndr. 2001; 27:251–259.
59. Shapiro MF, Morton SC, McCaffrey DF, et al. Variations in the care of HIV-infected adults in the United States: results from the HIV Cost and Services Utilization Study. JAMA. 1999; 281:2305–2315.
60. Piketty C, Castiel P, Giral P, et al. Lack of legal income is strongly associated with an increased risk of AIDS and death in HIV-infected injecting drug users. AIDS Care. 1999; 11:429–436.
61. Leserman J, Jackson ED, Petitto JM, et al. Progression to AIDS: the effects of stress, depressive symptoms, and social support. Psychosom Med. 1999; 61:397–406.
62. Leserman J, Petitto JM, Golden RN, et al. Impact of stressful life events, depression, social support, coping, and cortisol on progression to AIDS. Am J Psychiatry. 2000; 157:1221–1228.
63. Kitahata MM, Van Rompaey SE, Shields AW. Physician experience in the care of HIV-infected persons is associated with earlier adoption of new antiretroviral therapy. J Acquir Immune Defic Syndr. 2000; 24:106–114.
64. Kitahata MM, Koepsell TD, Deyo RA, et al. Physician's experience with the acquired immunodeficiency syndrome as a factor in patient's survival. N Engl J Med. 1996; 334:701–706.
65. MacArthur RD, Perez G, Walmsley S, et al. CD4+ Cell Count Is a Better Predictor of Disease Progression than HIV RNA Level in Persons with Advanced HIV Infection on Highly Active Antiretroviral Therapy. Abstract 203; CROI 8, February 4–8, 2001, Chicago, IL.
66. MacArthur RD, Chen L, Mayers DL, et al. The rationale and design of the CPCRA (Terry Beirn Community Programs for Clinical Research on AIDS) 058 FIRST (Flexible Initial Retrovirus Suppressive Therapies) trial. Control Clin Trials. 2001; 22:176–190.
67. El-Sadr WM, Burman WJ, Grant LB, et al. Discontinuation of prophylaxis for Mycobacterium avium complex disease in HIV-infected patients who have a response to antiretroviral therapy. Terry Beirn Community Programs for Clinical Research on AIDS. N Engl J Med. 2000; 342:1085–1092.
68. Abrams DI, Bebchuk JD, Denning ET, et al. Randomized, open-label study of the impact of two doses of subcutaneous recombinant interleukin-2 on viral burden in patients with HIV-1 infection and CD4+ cell counts of > or = 300/mm3: CPCRA 059. J Acquir Immune Defic Syndr. 2002; 29:221–231.
69. Lawrence, J, Mayers D, Huppler-Hullsiek K, et al. Structured treatment interruption in patients with multidrug resistant human immunodeficiency virus. N Engl J Med. 2003, 349:837–846.
70. Green LA, Price RW, Perlman DC, et al. Experience with a cross-study endpoint review committee for AIDS clinical trials. AIDS. 1998; 12:1983–1990.
71. International Classification of Diseases. Ninth Revision, Clinical Modification (ICD-9-CM).
Washington, DC: U.S. Dept. of Health and Human Services, Public Health Service, Health Care Financing Administration; 1988.
72. Saravolatz LD, Winslow DL, Collins G, et al. 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; 335:1099–1106.
73. Lasser KE, Allen PD, Woolhandler SJ, et al. Timing of new black box warnings and withdrawals for prescription medications. JAMA. 2002; 287:2215–2220.
74. Ioannidis JP, Lau J. Completeness of safety reporting in randomized trials: an evaluation of 7 medical areas. JAMA. 2001; 285:437–443.
75. Edwards JE, McQuay HJ, Moore RA, et al. Reporting of adverse effects in clinical trials should be improved: lessons from acute postoperative pain. J Pain Symptom Manage. 1999; 18:427–437.
76. Periard D, Telenti A, Sudre P, et al. Atherogenic dyslipidemia in HIV-infected individuals treated with protease inhibitors. The Swiss HIV Cohort Study. Circulation. 1999; 100:700–705.
77. Stein JH, Klein MA, Bellehumeur JL, et al. Use of human immunodeficiency virus-1 protease inhibitors is associated with atherogenic lipoprotein changes and endothelial dysfunction. Circulation. 2001; 104:257–262.
78. Dressman J, Kincer J, Matveev SV, et al. HIV protease inhibitors promote atherosclerotic lesion formation independent of dyslipidemia by increasing CD36-dependent cholesteryl ester accumulation in macrophages. J Clin Invest. 2003; 111:389–397.
79. Puzantian T. Central nervous system adverse effects with efavirenz: case report and review. Pharmacotherapy. 2002; 22:930–933.
80. Welch KJ, Morse A. Association between efavirenz and selected psychiatric and neurological conditions. J Infect Dis. 2002; 185:268–269.
81. United States Renal Data System 1999 Annual Data Report: part II. Incidence and prevalence of ESRD. Am J Kidney Dis. 1999; 34(2 Suppl 1):S40–S50.
82. Fisher EJ, Chaloner K, Cohn DL, et al. The safety and efficacy of adefovir dipivoxil in patients with advanced HIV disease: a randomized, placebo-controlled trial. AIDS. 2001; 15:1695–1700.
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