Amy C. Justice

Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies.

BACKGROUND Insufficient data are available from single cohort studies to allow estimation of the prognosis of HIV-1 infected, treatment-naive patients who start highly active antiretroviral therapy (HAART). The ART Cohort Collaboration, which includes 13 cohort studies from Europe and North America, was established to fill this knowledge gap. METHODS We analysed data on 12,574 adult patients starting HAART with a combination of at least three drugs. Data were analysed by intention-to-continue-treatment, ignoring treatment changes and interruptions. We considered progression to a combined endpoint of a new AIDS-defining disease or death, and to death alone. The prognostic model that generalised best was a Weibull model, stratified by baseline CD4 cell count and transmission group. FINDINGS During 24,310 person-years of follow up, 1094 patients developed AIDS or died and 344 patients died. Baseline CD4 cell count was strongly associated with the probability of progression to AIDS or death: compared with patients starting HAART with less than 50 CD4 cells/microL, adjusted hazard ratios were 0.74 (95% CI 0.62-0.89) for 50-99 cells/microL, 0.52 (0.44-0.63) for 100-199 cells/microL, 0.24 (0.20-0.30) for 200-349 cells/microL, and 0.18 (0.14-0.22) for 350 or more CD4 cells/microL. Baseline HIV-1 viral load was associated with a higher probability of progression only if 100,000 copies/microL or above. Other independent predictors of poorer outcome were advanced age, infection through injection-drug use, and a previous diagnosis of AIDS. The probability of progression to AIDS or death at 3 years ranged from 3.4% (2.8-4.1) in patients in the lowest-risk stratum for each prognostic variable, to 50% (43-58) in patients in the highest-risk strata. INTERPRETATION The CD4 cell count at initiation was the dominant prognostic factor in patients starting HAART. Our findings have important implications for clinical management and should be taken into account in future treatment guidelines.

Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies

BACKGROUND Combination antiretroviral therapy has led to significant increases in survival and quality of life, but at a population-level the effect on life expectancy is not well understood. Our objective was to compare changes in mortality and life expectancy among HIV-positive individuals on combination antiretroviral therapy. METHODS The Antiretroviral Therapy Cohort Collaboration is a multinational collaboration of HIV cohort studies in Europe and North America. Patients were included in this analysis if they were aged 16 years or over and antiretroviral-naive when initiating combination therapy. We constructed abridged life tables to estimate life expectancies for individuals on combination antiretroviral therapy in 1996-99, 2000-02, and 2003-05, and stratified by sex, baseline CD4 cell count, and history of injecting drug use. The average number of years remaining to be lived by those treated with combination antiretroviral therapy at 20 and 35 years of age was estimated. Potential years of life lost from 20 to 64 years of age and crude mortality rates were also calculated. FINDINGS 18 587, 13 914, and 10 854 eligible patients initiated combination antiretroviral therapy in 1996-99, 2000-02, and 2003-05, respectively. 2056 (4.7%) deaths were observed during the study period, with crude mortality rates decreasing from 16.3 deaths per 1000 person-years in 1996-99 to 10.0 deaths per 1000 person-years in 2003-05. Potential years of life lost per 1000 person-years also decreased over the same time, from 366 to 189 years. Life expectancy at age 20 years increased from 36.1 (SE 0.6) years to 49.4 (0.5) years. Women had higher life expectancies than did men. Patients with presumed transmission via injecting drug use had lower life expectancies than did those from other transmission groups (32.6 [1.1] years vs 44.7 [0.3] years in 2003-05). Life expectancy was lower in patients with lower baseline CD4 cell counts than in those with higher baseline counts (32.4 [1.1] years for CD4 cell counts below 100 cells per muL vs 50.4 [0.4] years for counts of 200 cells per muL or more). INTERPRETATION Life expectancy in HIV-infected patients treated with combination antiretroviral therapy increased between 1996 and 2005, although there is considerable variability between subgroups of patients. The average number of years remaining to be lived at age 20 years was about two-thirds of that in the general population in these countries.

Effect of Early versus Deferred Antiretroviral Therapy for HIV on Survival

BACKGROUND The optimal time for the initiation of antiretroviral therapy for asymptomatic patients with human immunodeficiency virus (HIV) infection is uncertain. METHODS We conducted two parallel analyses involving a total of 17,517 asymptomatic patients with HIV infection in the United States and Canada who received medical care during the period from 1996 through 2005. None of the patients had undergone previous antiretroviral therapy. In each group, we stratified the patients according to the CD4+ count (351 to 500 cells per cubic millimeter or >500 cells per cubic millimeter) at the initiation of antiretroviral therapy. In each group, we compared the relative risk of death for patients who initiated therapy when the CD4+ count was above each of the two thresholds of interest (early-therapy group) with that of patients who deferred therapy until the CD4+ count fell below these thresholds (deferred-therapy group). RESULTS In the first analysis, which involved 8362 patients, 2084 (25%) initiated therapy at a CD4+ count of 351 to 500 cells per cubic millimeter, and 6278 (75%) deferred therapy. After adjustment for calendar year, cohort of patients, and demographic and clinical characteristics, among patients in the deferred-therapy group there was an increase in the risk of death of 69%, as compared with that in the early-therapy group (relative risk in the deferred-therapy group, 1.69; 95% confidence interval [CI], 1.26 to 2.26; P<0.001). In the second analysis involving 9155 patients, 2220 (24%) initiated therapy at a CD4+ count of more than 500 cells per cubic millimeter and 6935 (76%) deferred therapy. Among patients in the deferred-therapy group, there was an increase in the risk of death of 94% (relative risk, 1.94; 95% CI, 1.37 to 2.79; P<0.001). CONCLUSIONS The early initiation of antiretroviral therapy before the CD4+ count fell below two prespecified thresholds significantly improved survival, as compared with deferred therapy.

Assessing the Generalizability of Prognostic Information

This paper describes an approach for evaluating prognostic systems based on the accuracy and generalizability of the systems predictions.

HIV Infection and the Risk of Acute Myocardial Infarction

IMPORTANCE Whether people infected with human immunodeficiency virus (HIV) are at an increased risk of acute myocardial infarction (AMI) compared with uninfected people is not clear. Without demographically and behaviorally similar uninfected comparators and without uniformly measured clinical data on risk factors and fatal and nonfatal AMI events, any potential association between HIV status and AMI may be confounded. OBJECTIVE To investigate whether HIV is associated with an increased risk of AMI after adjustment for all standard Framingham risk factors among a large cohort of HIV-positive and demographically and behaviorally similar (ie, similar prevalence of smoking, alcohol, and cocaine use) uninfected veterans in care. DESIGN AND SETTING Participants in the Veterans Aging Cohort Study Virtual Cohort from April 1, 2003, through December 31, 2009. PARTICIPANTS After eliminating those with baseline cardiovascular disease, we analyzed data on HIV status, age, sex, race/ethnicity, hypertension, diabetes mellitus, dyslipidemia, smoking, hepatitis C infection, body mass index, renal disease, anemia, substance use, CD4 cell count, HIV-1 RNA, antiretroviral therapy, and incidence of AMI. MAIN OUTCOME MEASURE Acute myocardial infarction. RESULTS We analyzed data on 82 459 participants. During a median follow-up of 5.9 years, there were 871 AMI events. Across 3 decades of age, the mean (95% CI) AMI events per 1000 person-years was consistently and significantly higher for HIV-positive compared with uninfected veterans: for those aged 40 to 49 years, 2.0 (1.6-2.4) vs 1.5 (1.3-1.7); for those aged 50 to 59 years, 3.9 (3.3-4.5) vs 2.2 (1.9-2.5); and for those aged 60 to 69 years, 5.0 (3.8-6.7) vs 3.3 (2.6-4.2) (P < .05 for all). After adjusting for Framingham risk factors, comorbidities, and substance use, HIV-positive veterans had an increased risk of incident AMI compared with uninfected veterans (hazard ratio, 1.48; 95% CI, 1.27-1.72). An excess risk remained among those achieving an HIV-1 RNA level less than 500 copies/mL compared with uninfected veterans in time-updated analyses (hazard ratio, 1.39; 95% CI, 1.17-1.66). CONCLUSIONS AND RELEVANCE Infection with HIV is associated with a 50% increased risk of AMI beyond that explained by recognized risk factors.

Workshop on HIV Infection and Aging: What Is Known and Future Research Directions

Highly active antiretroviral treatment has resulted in dramatically increased life expectancy among patients with HIV infection who are now aging while receiving treatment and are at risk of developing chronic diseases associated with advanced age. Similarities between aging and the courses of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome suggest that HIV infection compresses the aging process, perhaps accelerating comorbidities and frailty. In a workshop organized by the Association of Specialty Professors, the Infectious Diseases Society of America, the HIV Medical Association, the National Institute on Aging, and the National Institute on Allergy and Infectious Diseases, researchers in infectious diseases, geriatrics, immunology, and gerontology met to review what is known about HIV infection and aging, to identify research gaps, and to suggest high priority topics for future research. Answers to the questions posed are likely to help prioritize and balance strategies to slow the progression of HIV infection, to address comorbidities and drug toxicity, and to enhance understanding about both HIV infection and aging.

Causes of death in HIV-1-infected patients treated with antiretroviral therapy, 1996-2006: collaborative analysis of 13 HIV cohort studies

BACKGROUND We examined specific causes of mortality in human immunodeficiency virus type 1 (HIV-1)-infected patients who initiated antiretroviral therapy (ART) in Europe and North America from 1996 through 2006, and we quantified associations of prognostic factors with cause-specific mortality. METHODS We retrospectively classified all deaths among 39,272 patients enrolled in 13 HIV-1 cohorts (154,667 person years of follow-up) into the categories specified in the Cause of Death (CoDe) project protocol. RESULTS In 1597 (85%) of 1876 deaths, a definitive cause of death could be assigned. Among these, 792 deaths (49.5%) were AIDS related, followed by non-AIDS malignancies (189; 11.8%), non-AIDS infections (131; 8.2%), violence- and/or drug-related causes (124; 7.7%), liver disease (113; 7.0%), and cardiovascular disease (103; 6.5%). Rates of AIDS-related death (hazard ratio [HR] per 100 cell decrease, 1.43; 95% confidence interval [CI], 1.34-1.53) and death from renal failure (HR, 1.73; 95% CI, 1.18-2.55) were strongly inversely related to CD4 count at initiation of ART, whereas rates of death attributable to AIDS (HR for viral load >5 vs 5 log copies/mL, 1.31; 95% CI, 1.12-1.53), infection (HR, 1.85; 95% CI, 1.25-2.73), cardiovascular (HR, 1.54; 95% CI, 1.05-2.27), and respiratory causes (HR, 3.62; 95% CI, 1.30-10.09) were higher in patients with baseline viral load >5 log copies/mL than in other patients. Rates of each cause of death were higher in patients with presumed transmission via injection drug use than in other patients, with marked increases in rates of liver-related (HR for injection drug use vs non-injection drug use, 6.06; 95% CI, 4.03-9.09) and respiratory tract-related (HR, 4.94; 95% CI, 1.96-12.45) mortality. The proportion of deaths classified as AIDS related decreased with increasing duration of ART. CONCLUSIONS Important contributors to non-AIDS mortality in treated HIV-1-infected individuals must be addressed if decreases in mortality rates are to continue.

Risk of Anal Cancer in HIV-Infected and HIV-Uninfected Individuals in North America

BACKGROUND Anal cancer is one of the most common cancers affecting individuals infected with human immunodeficiency virus (HIV), although few have evaluated rates separately for men who have sex with men (MSM), other men, and women. There are also conflicting data regarding calendar trends. METHODS In a study involving 13 cohorts from North America with follow-up between 1996 and 2007, we compared anal cancer incidence rates among 34 189 HIV-infected (55% MSM, 19% other men, 26% women) and 114 260 HIV-uninfected individuals (90% men). RESULTS Among men, the unadjusted anal cancer incidence rates per 100 000 person-years were 131 for HIV-infected MSM, 46 for other HIV-infected men, and 2 for HIV-uninfected men, corresponding to demographically adjusted rate ratios (RRs) of 80.3 (95% confidence interval [CI], 42.7-151.1) for HIV-infected MSM and 26.7 (95% CI, 11.5-61.7) for other HIV-infected men compared with HIV-uninfected men. HIV-infected women had an anal cancer rate of 30/100 000 person-years, and no cases were observed for HIV-uninfected women. In a multivariable Poisson regression model, among HIV-infected individuals, the risk was higher for MSM compared with other men (RR, 3.3; 95% CI, 1.8-6.0), but no difference was observed comparing women with other men (RR, 1.0; 95% CI, 0.5-2.2). In comparison with the period 2000-2003, HIV-infected individuals had an adjusted RR of 0.5 (95% CI, .3-.9) in 1996-1999 and 0.9 (95% CI, .6-1.2) in 2004-2007. CONCLUSIONS Anal cancer rates were substantially higher for HIV-infected MSM, other men, and women compared with HIV-uninfected individuals, suggesting a need for universal prevention efforts. Rates increased after the early antiretroviral therapy era and then plateaued.

Development and validation of a self-completed HIV symptom index.

Traditional, open-ended provider questions regarding patient symptoms are insensitive. Better methods are needed to measure symptoms for clinical management, patient-oriented research, and adverse drug-event reporting. Our objective was to develop and initially validate a brief, self-reported HIV symptom index tailored to patients exposed to multidrug antiretroviral therapies and protease inhibitors, and to compare the new index to existing symptom measures. The research design was a multistage design including quantitative review of existing literature, qualitative and quantitative analyses of pilot data, and quantitative analyses of a prospective sample. Statistical analyses include frequencies, chi-square tests for significance, linear and logistic regression. The subjects were from a multisite convenience sample (n = 73) within the AIDS Clinical Trials Group and a prospective sample from the Cleveland Veterans Affairs Medical Center (n = 115). Measures were patient-reported symptoms and health-related quality of life, physician-assessed disease severity, CD4 cell count, and HIV-1 RNA viral quantification. A 20-item, self-completed HIV symptom index was developed based upon prior reports of symptom frequency and bother and expert opinion. When compared with prior measures the index included more frequent and bothersome symptoms, yet was easier to use (self-report rather than provider interview). The index required less than 5 minutes to complete, achieved excellent completion rates, and was thought comprehensive and comprehensible in a convenience sample. It was further tested in a prospective sample of patients and demonstrated strong associations with physical and mental health summary scores and with disease severity. These associations were independent of CD4 cell count and HIV-1 RNA viral quantification. This 20-item HIV symptom index has demonstrated construct validity, and offers a simple and rational approach to measuring HIV symptoms for clinical management, patient-oriented research, and adverse drug reporting.

The relationship between clinical assessments of nutritional status and adverse outcomes in older hospitalized medical patients

BACKGROUND: Malnutrition is common in hospitalized older people and may predict adverse outcomes. Previous studies of the relationship between nutritional status and hospital outcomes are limited by inadequate accounting for other potential predictors of adverse outcomes, the failure to consider functional outcomes, and the omission of clinical assessments of nutritional status.