How U.S. Doctors Die: A Cohort Study of Healthcare Use at the End of Life.

OBJECTIVES: To compare healthcare use in the last months of life between physicians and nonphysicians in the United States. DESIGN: A retrospective observational cohort study. SETTING: United States. PARTICIPANTS: Fee-for-service Medicare beneficiaries: decedent physicians (n = 9,947) and a random sample of Medicare decedents (n = 192,006). MEASUREMENTS: Medicare Part A claims data from 2008 to 2010 were used to measure days in the hospital and proportion using hospice in the last 6 months of life as primary outcome measures adjusted for sociodemographic characteristics and regional variations in health care. RESULTS: Inpatient hospital use in the last 6 months of life was no different between physicians and nonphysicians, although more physicians used hospice and for longer (using the hospital: odds ratio (OR) = 0.98, 95% confidence interval (CI) = 0.93-1.04; hospital days: mean difference 0.26, P = .14); dying in the hospital: OR = 0.99, 95% CI = 0.95-1.04; intensive care unit (ICU) or critical care unit (CCU) days: mean difference 0.35 more days for physicians, P < .001); using hospice: OR = 1.23, 95% CI = 1.18-1.29; number of days in hospice: mean difference 2.06, P < .001). CONCLUSION: This retrospective, observational study is subject to unmeasured confounders and variation in coding practices, but it provides preliminary evidence of actual use. U.S. physicians were more likely to use hospice and ICU- or CCU-level care. Hospitalization rates were similar.

Clinical risk factors for death after release from prison in Washington State: a nested case-control study.

BACKGROUND AND AIMS: While mortality rates after prison release are high, little is known about clinical risk factors for death. We sought to identify risk and protective factors for all-cause and accidental poisoning (overdose) death. DESIGN: Nested case-control study of people released from prison. SETTING: Washington State Department of Corrections, Washington, USA. PARTICIPANTS: Cases (699 all-cause deaths, of which 88 were among women, and 196 additional overdose deaths, of which 76 were among women) between 1999 and 2009 matched 1 : 1 to controls on sex, age and year of release using risk set sampling. MEASUREMENTS: Prison medical charts were abstracted for clinical information. Independent associations between clinical characteristics and all-cause and overdose mortality were assessed using conditional logistic regression. FINDINGS: Key independent risk factors for all-cause mortality included homelessness [odds ratio (OR) = 1.53, 95% confidence interval (CI) = 1.06, 2.23], injection drug use (OR = 1.54, 95% CI = 1.16, 2.06), tobacco use (OR = 1.51, 95% CI = 1.07, 2.13), cirrhosis (OR = 4.42, 95% CI = 1.63, 11.98) and psychiatric medications before release (OR = 2.38, 95% CI = 1.71, 3.30). Independent risk factors for overdose mortality included substance use disorder (OR = 2.33, 95% CI = 1.32, 4.11), injection drug use (OR = 2.43, 95% CI = 1.53, 3.86), panic disorder (OR = 3.87, 95% CI = 1.62, 9.21), psychiatric prescriptions before release (OR = 2.44, 95% CI = 1.55, 3.85) and problems with opiates/sedatives (OR = 2.81, 95% CI = 1.40, 5.63). Substance use disorder treatment during the index incarceration was protective for all-cause (OR = 0.67, 95% CI = 0.49, 0.91) and overdose (OR = 0.57, 95% CI = 0.36, 0.90) mortality. CONCLUSIONS: Injection drug use and substance use disorders are risk factors for death after release from prison. In-prison substance use disorder treatment services may reduce the risk.

Opioid Prescribing at Hospital Discharge Contributes to Chronic Opioid Use.

BACKGROUND: Chronic opioid therapy for chronic pain treatment has increased. Hospital physicians, including hospitalists and medical/surgical resident physicians, care for many hospitalized patients, yet little is known about opioid prescribing at hospital discharge and future chronic opioid use. OBJECTIVE: We aimed to characterize opioid prescribing at hospital discharge among 'opioid naïve' patients. Opioid naïve patients had not filled an opioid prescription at an affiliated pharmacy 1 year preceding their hospital discharge. We also set out to quantify the risk of chronic opioid use and opioid refills 1 year post discharge among opioid naïve patients with and without opioid receipt at discharge. DESIGN: This was a retrospective cohort study. PARTICIPANTS: From 1 January 2011 to 31 December 2011, 6,689 opioid naïve patients were discharged from a safety-net hospital. MAIN MEASURE: Chronic opioid use 1 year post discharge. KEY RESULTS: Twenty-five percent of opioid naïve patients (n = 1,688) had opioid receipt within 72 hours of discharge. Patients with opioid receipt were more likely to have diagnoses including neoplasm (6.3% versus 3.5%, p < 0.001), acute pain (2.7% versus 1.0 %, p < 0.001), chronic pain at admission (12.1% versus 3.3%, p < 0.001) or surgery during their hospitalization (65.1% versus 18.4%, p < 0.001) compared to patients without opioid receipt. Patients with opioid receipt were less likely to have alcohol use disorders (15.7% versus 20.7%, p < 0.001) and mental health disorders (23.9% versus 31.4%, p < 0.001) compared to patients without opioid receipt. Chronic opioid use 1 year post discharge was more common among patients with opioid receipt (4.1% versus 1.3%, p < 0.0001) compared to patients without opioid receipt. Opioid receipt was associated with increased odds of chronic opioid use (AOR = 4.90, 95% CI 3.22-7.45) and greater subsequent opioid refills (AOR = 2.67, 95% CI 2.29-3.13) 1 year post discharge compared to no opioid receipt. CONCLUSION: Opioid receipt at hospital discharge among opioid naïve patients increased future chronic opioid use. Physicians should inform patients of this risk prior to prescribing opioids at discharge.

Development of a Primary Care-Based Clinic to Support Adults With a History of Childhood Cancer: The Tactic Clinic.

PURPOSE: Describe the development and evolution of a primary-care-based, multidisciplinary clinic to support the ongoing care of adult survivors of childhood cancer. METHODS: A consultative clinic for adult survivors of childhood cancer has been developed that is located in an adult, academic internal medicine setting and is based on a long-term follow-up clinic model available at Children's Hospital Colorado. RESULTS: The clinic opened in July 2008. One hundred thirty-five patients have been seen as of April 2014. Referrals and clinic capacity have gradually increased over time, and a template has been developed in the electronic medical record to help facilitate completion of individualized care plan letters. CONCLUSIONS: A primary care-based, multidisciplinary consultative clinic for adults with a history of childhood cancer survivor is feasible and actively engages adult primary care resources to provide risk-based care for long-term pediatric cancer survivors. This model of care planning can help support adult survivors of pediatric cancer and their primary care providers in non-academic, community settings as well.

Research without results: inadequate public reporting of clinical trial results.

OBJECTIVE: In order to increase transparency in the medical literature, the Food and Drug Administration (FDA) Modernization Act of 1997 and the FDA Amendment Act of 2007 required registration of all "applicable trials" with required "basic results" reporting. We evaluated the rate of compliance with the FDA mandatory results reporting in www.clinicaltrials.gov. METHODS: All completed registered interventional studies that may be subject to FDA regulation, one year prior to required results reporting (October 2006 to September 2007, n = 1097) and during the two years after required reporting (October 2007 to September 2008 (07-08), n = 2231 and October 2008 to September 2009 (08-09), n = 2923). RESULTS: Downloading all 99,315 records from clinicaltrials.gov, we excluded all non-applicable studies. Results reporting increased from 6.8% (n = 75) prior to mandatory reporting to 19.1% (n = 427, p<.01) in 07-08 and 10.8% (n = 316, p<.01) in 08-09. The odds ratio for results reporting using the 06-07 time period as the reference was 3.31 (95% CI 2.54-4.32) for 07-08 and 1.74 (1.33-2.28) for 08-09. Of the 818 trials with results in clinicaltrials.gov, the rate of published articles found decreased from 60% (n = 45) in the year prior to required reporting to 33% (n = 140, p<.001) for 07-08 and 20% (n = 63, p<.001) for 08-09 time period. CONCLUSION: The majority of studies registered in clinicaltrials.gov are not required to report data. Of studies that may be required to report data, compliance with data reporting has improved. The clinicaltrials.gov website is not yet a comprehensive resource for study results.

Characteristics associated with higher cost per day or longer length of stay in hospitalized patients who died during the hospitalization or were discharged to hospice.

BACKGROUND: Palliative care has been recommended as an approach to improve the quality of care for patients with advanced illness, while achieving hospital cost savings. However, studies are lacking that identify hospitalized patients who are more likely to have higher cost per day or length of stay (LOS) who may benefit from palliative care consultation. OBJECTIVE: Identify characteristics associated with higher cost per day or longer LOS in hospitalized patients at the end of life--those likely to benefit from palliative care consultation. DESIGN: Observational study. SETTING: Academic medical center. PATIENTS: Adult inpatients who died during the hospitalization or were discharged to hospice. INTERVENTION: None. MEASUREMENTS: We hypothesized that several patient characteristics would be associated with higher cost per day and/or longer LOS. Using administrative data, we developed univariate and multivariate models to evaluate association between these patient characteristics and cost per day and LOS. RESULTS: Patients cared for on the cardiothoracic surgery service had significantly higher cost per day ($12,937; P < 0.0001) and LOS (7.0 days; P = 0.001). Neurosurgery patients also had higher cost per day ($2255; P = 0.03), and surgical oncology patients had a longer length of stay (5.3 days; P = 0.003). Patients 65 years and older had a significantly lower cost per day (-$811; P = 0.02) and LOS (-1.8 days; P = 0.003) for each decade increase in age. CONCLUSIONS: Our data suggest that younger patients and those cared for by surgical specialty services may receive the most benefit from palliative care consultation, a finding that needs to be corroborated in other centers.

A comparison of two spirituality instruments and their relationship with depression and quality of life in chronic heart failure.

Spirituality is a multifaceted construct related to health outcomes that remains ill defined and difficult to measure. Spirituality in patients with advanced chronic illnesses, such as chronic heart failure, has received limited attention. We compared two widely used spirituality instruments, the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being (FACIT-Sp) and the Ironson-Woods Spirituality/Religiousness Index (IW), to better understand what they measure in 60 outpatients with chronic heart failure. We examined how these instruments related to each other and to measures of depression and quality of life using correlations and principal component analyses. The FACIT-Sp measured aspects of spirituality related to feelings of peace and coping, whereas the IW measured beliefs, coping, and relational aspects of spirituality. Only the FACIT-Sp Meaning/Peace subscale consistently correlated with depression (r=-0.50, P<0.0001) and quality of life (r=0.41, P=0.001). Three items from the depression measure loaded onto the same factor as the FACIT-Sp Meaning/Peace subscale (r=0.43, -0.43, and 0.71), whereas the remaining 12 items formed a separate factor (Cronbach's alpha=0.82) when combined with the spirituality instruments in a principal component analysis. The results demonstrate several clinically useful constructs of spirituality in patients with heart failure and suggest that psychological and spiritual well-being, despite some overlap, remain distinct phenomena.

Providing massage therapy for people with advanced cancer: what to expect.

There is very little information in the literature to prepare massage therapists for what they might expect when they provide treatment to people with advanced cancer in hospice or palliative care. We report an analysis of a subset of data collected from a large multi-site clinical trial of the efficacy of massage therapy for people with advanced cancer. This is the first analysis of empirical data of patient presentation, massage treatment environment, and the characteristics of massage provided for this population.

Symptom burden, depression, and spiritual well-being: a comparison of heart failure and advanced cancer patients.

BACKGROUND: A lower proportion of patients with chronic heart failure receive palliative care compared to patients with advanced cancer. OBJECTIVE: We examined the relative need for palliative care in the two conditions by comparing symptom burden, psychological well-being, and spiritual well-being in heart failure and cancer patients. DESIGN: This was a cross-sectional study. PARTICIPANTS: Sixty outpatients with symptomatic heart failure and 30 outpatients with advanced lung or pancreatic cancer. MEASUREMENTS: Symptom burden (Memorial Symptom Assessment Scale-Short Form), depression symptoms (Geriatric Depression Scale-Short Form), and spiritual well-being (Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being scale). MAIN RESULTS: Overall, the heart failure patients and the cancer patients had similar numbers of physical symptoms (9.1 vs. 8.6, p = 0.79), depression scores (3.9 vs. 3.2, p = 0.53), and spiritual well-being (35.9 vs. 39.0, p = 0.31) after adjustment for age, gender, marital status, education, and income. Symptom burden, depression symptoms, and spiritual well-being were also similar among heart failure patients with ejection fraction < or =30, ejection fraction >30, and cancer patients. Heart failure patients with worse heart failure-related health status had a greater number of physical symptoms (13.2 vs. 8.6, p = 0.03), higher depression scores (6.7 vs. 3.2, p = 0.001), and lower spiritual well-being (29.0 vs. 38.9, p < 0.01) than patients with advanced cancer. CONCLUSIONS: Patients with symptomatic heart failure and advanced cancer have similar needs for palliative care as assessed by symptom burden, depression, and spiritual well-being. This implies that heart failure patients, particularly those with more severe heart failure, need the option of palliative care just as cancer patients do.

Massage therapy versus simple touch to improve pain and mood in patients with advanced cancer: a randomized trial.

BACKGROUND: Small studies of variable quality suggest that massage therapy may relieve pain and other symptoms. OBJECTIVE: To evaluate the efficacy of massage for decreasing pain and symptom distress and improving quality of life among persons with advanced cancer. DESIGN: Multisite, randomized clinical trial. SETTING: Population-based Palliative Care Research Network. PATIENTS: 380 adults with advanced cancer who were experiencing moderate-to-severe pain; 90% were enrolled in hospice. INTERVENTION: Six 30-minute massage or simple-touch sessions over 2 weeks. MEASUREMENTS: Primary outcomes were immediate (Memorial Pain Assessment Card, 0- to 10-point scale) and sustained (Brief Pain Inventory [BPI], 0- to 10-point scale) change in pain. Secondary outcomes were immediate change in mood (Memorial Pain Assessment Card) and 60-second heart and respiratory rates and sustained change in quality of life (McGill Quality of Life Questionnaire, 0- to 10-point scale), symptom distress (Memorial Symptom Assessment Scale, 0- to 4-point scale), and analgesic medication use (parenteral morphine equivalents [mg/d]). Immediate outcomes were obtained just before and after each treatment session. Sustained outcomes were obtained at baseline and weekly for 3 weeks. RESULTS: 298 persons were included in the immediate outcome analysis and 348 in the sustained outcome analysis. A total of 82 persons did not receive any allocated study treatments (37 massage patients, 45 control participants). Both groups demonstrated immediate improvement in pain (massage, -1.87 points [95% CI, -2.07 to -1.67 points]; control, -0.97 point [CI, -1.18 to -0.76 points]) and mood (massage, 1.58 points [CI, 1.40 to 1.76 points]; control, 0.97 point [CI, 0.78 to 1.16 points]). Massage was superior for both immediate pain and mood (mean difference, 0.90 and 0.61 points, respectively; P < 0.001). No between-group mean differences occurred over time in sustained pain (BPI mean pain, 0.07 point [CI, -0.23 to 0.37 points]; BPI worst pain, -0.14 point [CI, -0.59 to 0.31 points]), quality of life (McGill Quality of Life Questionnaire overall, 0.08 point [CI, -0.37 to 0.53 points]), symptom distress (Memorial Symptom Assessment Scale global distress index, -0.002 point [CI, -0.12 to 0.12 points]), or analgesic medication use (parenteral morphine equivalents, -0.10 mg/d [CI, -0.25 to 0.05 mg/d]). LIMITATIONS: The immediate outcome measures were obtained by unblinded study therapists, possibly leading to reporting bias and the overestimation of a beneficial effect. The generalizability to all patients with advanced cancer is uncertain. The differential beneficial effect of massage therapy over simple touch is not conclusive without a usual care control group. CONCLUSION: Massage may have immediately beneficial effects on pain and mood among patients with advanced cancer. Given the lack of sustained effects and the observed improvements in both study groups, the potential benefits of attention and simple touch should also be considered in this patient population.

Inconsistencies in opioid equianalgesic ratios: clinical and research implications.

Cancer pain is common, occurring in up to 60% of patients and opioid conversion may be required for effective pain management. Conversion from one opioid to another can be problematic due to differences in equianalgesic ratios found in established resources. This study explores the implications of using various published equianalgesic ratios when converting to a common opioid unit. This secondary analysis includes 105 advanced cancer patients who reported use of transdermal fentanyl, long-acting oxycodone, or oral methadone. Common clinically used equianalgesic ratios were identified and utilized to calculate a parenteral morphine equivalent for each of the selected agents. When the equianalgesic ratios were applied to each drug, there were substantial differences in the calculated morphine equivalent for transdermal fentanyl (2-fold difference) and methadone (100-fold difference). The calculated difference for oxycodone was lower, with a 1.5-fold difference. This study demonstrates large variability in opioid conversions based on the use of common equianalgesic ratios for transdermal fentanyl, long-acting oxycodone, and methadone. These findings have important clinical and research implications. First, this study substantiates the use of these ratios as only guidelines for treatment. Second, it supports the need for well-designed, rigorous studies to evaluate opioid conversions. Third, this study demonstrates the need for a standard reporting system of opioid equianalgesic ratios employed in clinical trials.

Symptoms, depression, and quality of life in patients with heart failure.

BACKGROUND: Little is known about symptoms and their burden in outpatients with chronic heart failure. Diverse symptoms may be associated with poor heart failure-related quality of life, and depression may be related to increased symptoms. METHODS AND RESULTS: The number of symptoms and symptom distress (physical symptoms on the Memorial Symptom Assessment Scale-Short Form), depression (Geriatric Depression Scale-Short Form), and heart failure-related quality of life (Kansas City Cardiomyopathy Questionnaire) were measured cross-sectionally in 60 patients with heart failure from two outpatient cardiology clinics. Patients experienced a mean of nine symptoms in the previous week. More than half reported shortness of breath, lack of energy, pain, feeling drowsy, or dry mouth. In unadjusted analyses, more severe depression was associated with a greater number of symptoms (r = 0.51, P < .0001) and greater overall symptom distress (r = 0.58, P < .0001). For each additional depression symptom, the number of symptoms reported increased by 0.6 after adjustment for age, race, and N-terminal pro-brain natriuretic peptide (P = .01). The number of symptoms accounted for 32% of the variance in quality of life (P < .0001). CONCLUSIONS: Patients with heart failure report a large number of distressing symptoms. Depression in patients with heart failure is associated with a greater number of symptoms, which in turn is associated with a decrease in heart failure-related quality of life. Treatment of depression and the diverse symptoms reported by patients with heart failure might significantly improve quality of life.

Spiritual well-being and depression in patients with heart failure.

BACKGROUND: In patients with chronic heart failure, depression is common and associated with poor quality of life, more frequent hospitalizations, and higher mortality. Spiritual well-being is an important, modifiable coping resource in patients with terminal cancer and is associated with less depression, but little is known about the role of spiritual well-being in patients with heart failure. OBJECTIVE: To identify the relationship between spiritual well-being and depression in patients with heart failure. DESIGN: Cross-sectional study. PARTICIPANTS: Sixty patients aged 60 years or older with New York Heart Association class II-IV heart failure. MEASUREMENTS: Spiritual well-being was measured using the total scale and 2 subscales (meaning/peace, faith) of the Functional Assessment of Chronic Illness Therapy-Spiritual Well-being scale, depression using the Geriatric Depression Scale-Short Form (GDS-SF). RESULTS: The median age of participants was 75 years. Nineteen participants (32%) had clinically significant depression (GDS-SF > 4). Greater spiritual well-being was strongly inversely correlated with depression (Spearman's correlation -0.55, 95% confidence interval -0.70 to -0.35). In particular, greater meaning/peace was strongly associated with less depression (r = -.60, P < .0001), while faith was only modestly associated (r = -.38, P < .01). In a regression analysis accounting for gender, income, and other risk factors for depression (social support, physical symptoms, and health status), greater spiritual well-being continued to be significantly associated with less depression (P = .05). Between the 2 spiritual well-being subscales, only meaning/peace contributed significantly to this effect (P = .02) and accounted for 7% of the variance in depression. CONCLUSIONS: Among outpatients with heart failure, greater spiritual well-being, particularly meaning/peace, was strongly associated with less depression. Enhancement of patients' sense of spiritual well-being might reduce or prevent depression and thus improve quality of life and other outcomes in this population.

Individual variation in CD4 cell count trajectory among human immunodeficiency virus-infected men and women on long-term highly active antiretroviral therapy: an application using a Bayesian random change-point model.

The authors evaluated population- and individual-level CD4-positive T-lymphocyte (CD4 cell) count trajectories over a 7-year period (July 1995-March 2004) following initiation of highly active antiretroviral therapy (HAART) in the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study. The study population included 404 human immunodeficiency virus (HIV)-infected men and 609 HIV-infected women who 1) had a CD4 cell count measurement available from their last pre-HAART study visit, 2) provided at least four post-HAART CD4 cell count measurements, and 3) reported HAART usage for at least 80% of the post-HAART visits. The CD4 cell count trajectory was analyzed by means of a Bayesian random change-point model. The results indicated that CD4 cell count trajectories for long-term frequent HAART users can be well modeled with change points at both the population and individual levels. At the population level, regardless of CD4 cell count before HAART initiation, the gains in CD4 cell count ended approximately 2 years after HAART initiation in both men and women. At the individual level, 35% of men in the Multicenter AIDS Cohort Study versus 25% of women in the Women's Interagency HIV Study had a statistically significant change in CD4 cell count trajectory within 7 years after HAART initiation.

Update on the Virologic and Immunologic Response to Highly Active Antiretroviral Therapy.

Highly active antiretroviral therapy (HAART) delays clinical progression by suppressing viral replication, measured by a substantial reduction in HIV RNA, allowing the immune system to reconstitute, measured in most studies by an increase in CD4 cells. These virologic and immunologic consequences do not occur uniformly among HAART users. Markers of HIV disease stage at the time of HAART initiation are critical determinants of the progression while receiving HAART. In this report, we review studies describing the heterogeneous virologic and immunologic progression after the initiation of HAART, discuss methodologic concerns in the study of the response of biomarkers, and update findings obtained in the Multicenter AIDS Cohort Study, which show that CD4 cell count, history of antiretroviral therapy, and age at the time of initiation are independent determinants of response.

Persistent GB virus C infection and survival in HIV-infected men.

BACKGROUND: GB virus C (GBV-C), which is not known to be pathogenic in humans, replicates in lymphocytes, inhibits the replication of human immunodeficiency virus (HIV) in vitro, and has been associated with a decreased risk of death among HIV-positive persons in some, but not all, studies. Previous studies did not control for differences in the duration of HIV or GBV-C infection. METHODS: We evaluated 271 men who were participants in the Multicenter Acquired Immunodeficiency Syndrome Cohort Study for GBV-C viremia (by means of a reverse-transcriptase-polymerase-chain-reaction assay) or E2 antibody (by means of an enzyme-linked immunosorbent assay) 12 to 18 months after seroconversion to positivity for HIV (the early visit); a subgroup of 138 patients was also evaluated 5 to 6 years after HIV seroconversion (the late visit). RESULTS: GBV-C infection was detected in 85 percent of men with HIV seroconversion on the basis of the presence of E2 antibody (46 percent) or GBV-C RNA (39 percent). Only one man acquired GBV-C viremia between the early and the late visit, but 9 percent of men had clearance of GBV-C RNA between these visits. GBV-C status 12 to 18 months after HIV seroconversion was not significantly associated with survival; however, men without GBV-C RNA 5 to 6 years after HIV seroconversion were 2.78 times as likely to die as men with persistent GBV-C viremia (95 percent confidence interval, 1.34 to 5.76; P=0.006). The poorest prognosis was associated with the loss of GBV-C RNA (relative hazard for death as compared with men with persistent GBV-C RNA, 5.87; P=0.003). CONCLUSIONS: GBV-C viremia was significantly associated with prolonged survival among HIV-positive men 5 to 6 years after HIV seroconversion, but not at 12 to 18 months, and the loss of GBV-C RNA by 5 to 6 years after HIV seroconversion was associated with the poorest prognosis. Understanding the mechanisms of interaction between GBV-C and HIV may provide insight into the progression of HIV disease.

Virologic and immunologic response to highly active antiretroviral therapy.

Highly active antiretroviral therapy (HAART) delays clinical progression by suppressing viral replication, measured by a substantial reduction in HIV RNA, allowing the immune system to reconstitute, measured in most studies by an increase in CD4 cells. These virologic and immunologic consequences do not occur uniformly among HAART users. Markers of HIV disease stage at the time of HAART initiation are critical determinants of the progression while receiving HAART. In this report, we review studies describing the heterogeneous virologic and immunologic progression after the initiation of HAART, discuss methodologic concerns in the study of the response of biomarkers, and update findings obtained in the Multicenter AIDS Cohort Study, which show that CD4 cell count, history of antiretroviral therapy, and age at the time of initiation are independent determinants of response.

When to initiate highly active antiretroviral therapy: a cohort approach.

The appropriate immunologic stage of human immunodeficiency virus infection at which to initiate highly active antiretroviral therapy (HAART) among asymptomatic persons is a core question. A cohort approach using longitudinal data from the US Multicenter AIDS Cohort Study was used to mimic a clinical trial to assess the risk of acquired immunodeficiency syndrome (AIDS) by timing of therapy. Three treatment groups were defined according to CD4(+) count (cells/microl) at HAART initiation between July 1995 and January 2000: <200 (deferral to <200, n = 127), 200-349 (deferral to 200-349, n = 130), and 350-499 (immediate treatment, n = 92). Survival analysis was used to compare time to AIDS between groups from the index visit until July 2000. The index visit for the immediate group was the one prior to HAART initiation. For the deferral groups, the index visit was a randomly selected, pre-HAART, AIDS-free visit after July 1990 at which CD4(+) counts were 350-499 cells/microl. This strategy accounted for lead time bias. Compared with immediate treatment, the relative hazards of AIDS were 2.68 (p = 0.003) and 1.05 (p = 0.897) for deferral to <200 cells/microl and 200-349 cells/ micro l, respectively. These results support recent US public health guidelines for deferring HAART initiation until a count of <350 cells/microl. Furthermore, results suggest a potential threshold for HAART initiation in the neighborhood of 275 cells/microl.