Rose K. Baker

Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study.

Background: AIDS-related death and disease rates have declined in the highly active antiretroviral therapy (HAART) era and remain low; however, current causes of death in HAART-treated patients remain ill defined. Objective: To describe mortality trends and causes of death among HIV-infected patients in the HAART era. Design: Prospective, multicenter, observational cohort study of participants in the HIV Outpatient Study who were treated from January 1996 through December 2004. Measurements: Rates of death, opportunistic disease, and other non-AIDS-defining illnesses (NADIs) determined to be primary or secondary causes of death. Results: Among 6945 HIV-infected patients followed for a median of 39.2 months, death rates fell from 7.0 deaths/100 person-years of observation in 1996 to 1.3 deaths/100 person-years in 2004 (P = 0.008 for trend). Deaths that included AIDS-related causes decreased from 3.79/100 person-years in 1996 to 0.32/100 person-years in 2004 (P = 0.008). Proportional increases in deaths involving liver disease, bacteremia/sepsis, gastrointestinal disease, non-AIDS malignancies, and renal disease also occurred (P = <0.001, 0.017, 0.006, <0.001, and 0.037, respectively.) Hepatic disease was the only reported cause of death for which absolute rates increased over time, albeit not significantly, from 0.09/100 person-years in 1996 to 0.16/100 person-years in 2004 (P = 0.10). The percentage of deaths due exclusively to NADI rose from 13.1% in 1996 to 42.5% in 2004 (P < 0.001 for trend), the most frequent of which were cardiovascular, hepatic, and pulmonary disease, and non-AIDS malignancies in 2004. Mean CD4 cell counts closest to death (n = 486 deaths) increased from 59 cells/&mgr;L in 1996 to 287 cells/&mgr;L in 2004 (P < 0.001 for trend). Patients dying of NADI causes were more HAART experienced and initiated HAART at higher CD4 cell counts than those who died with AIDS (34.5% vs 16.8%, respectively, received HAART for 4 of more years, P < 0.0001; 22.4% vs 7.8%, respectively, initiated HAART with CD4 cell counts of more than 350 cells/&mgr;L, P < 0.001). Conclusions: Although overall death rates remained low through 2004, the proportion of deaths attributable to non-AIDS diseases increased and prominently included hepatic, cardiovascular, and pulmonary diseases, as well as non-AIDS malignancies. Longer time spent receiving HAART and higher CD4 cell counts at HAART initiation were associated with death from non-AIDS causes. CD4 cell count at time of death increased over time.

AIDS-defining opportunistic illnesses in US patients, 1994-2007: a cohort study.

Objectives:To assess the incidence and spectrum of AIDS-defining opportunistic illnesses in the highly active antiretroviral therapy (cART) era. Design:A prospective cohort study of 8070 participants in the HIV Outpatient Study at 12 U.S. HIV clinics. Methods:We calculated incidence rates per 1000 person-years of observation for the first opportunistic infection, first opportunistic malignancy, and first occurrence of each individual opportunistic illness during 1994–2007. Using stratified Poisson regression models, and adjusting for sex, race, and HIV risk category, we modeled annual percentage changes in opportunistic illness incidence rates by calendar period. Results:Eight thousand and seventy patients (baseline median age 38 years; median CD4 cell count 298 cells/μl) experienced 2027 incident opportunistic illnesses during a median of 2.9 years of observation. During 1994–1997, 1998–2002, and 2003–2007, respectively, rates of opportunistic infections (per 1000 person-years) were 89.0, 25.2 and 13.3 and rates of opportunistic malignancies were 23.4, 5.8 and 3.0 (P for trend <0.001 for both). Opportunistic illness rate decreases were similar for the subset of patients receiving cART. During 2003–2007, there were no significant changes in annual rates of opportunistic infections or opportunistic malignancies; the leading opportunistic illnesses (rate per 1000 person-years) were esophageal candidiasis (5.2), Pneumocystis pneumonia (3.9), cervical cancer (3.5), Mycobacterium avium complex infection (2.5), and cytomegalovirus disease (1.8); 36% of opportunistic illness events occurred at CD4 cell counts at least 200 cells/μl. Conclusions:Opportunistic illness rates declined precipitously after introduction of cART and stabilized at low levels during 2003–2007. In this contemporary cART era, a third of opportunistic illnesses were diagnosed at CD4 cell counts at least 200 cells/μl.

Increased Rates of Bone Fracture among HIV-Infected Persons in the HIV Outpatient Study (HOPS) Compared with the US General Population, 2000–2006

BACKGROUND Among persons with HIV infection, low bone mineral density is common and has raised concerns about increased risk of fracture. METHODS We analyzed data from the HIV Outpatient Study (HOPS), an open prospective cohort study of HIV-infected adults who were followed up at 10 US HIV clinics. We assessed rates of first fractures at any anatomic site during the period 2000-2008. We indirectly standardized the rates of fracture in the HOPS to the general population by age and sex, using data from outpatients in the National Hospital Ambulatory Medical Care Survey (NHAMCS-OPD). We examined factors associated with fractures using Cox proportional hazards modeling. RESULTS Among 5826 active HOPS patients whose data were analyzed (median baseline age, 40 years; male sex, 79%; white race, 52%; exposure to antiretroviral therapy, 73%), 233 patients had incident fractures (crude annual rates, 59.6-93.5 fractures per 10,000 persons). Age-standardized fracture rates increased from 2000 to 2002 (P = .01) and stabilized thereafter. Among persons aged 25-54 years, both fracture rates and relative proportion of fragility fractures were higher among HOPS patients than among patients in the NHAMCS-OPD. In addition to older age and substance abuse, nadir CD4+ cell count <200 cells/mm(3) (adjusted hazard ratio [aHR], 1.60; 95% confidence interval [CI], 1.11-2.31), hepatitis C infection (aHR, 1.61; 95% CI, 1.13-2.29) and diabetes (aHR, 1.62; 95% CI, 1.00-2.64) were associated with incident fractures. CONCLUSIONS Age-adjusted fracture rates among HOPS patients were higher than rates in the general US population during the period 2000-2006. Clinicians should regularly assess HIV-infected persons for fracture risk, especially those with low nadir CD4+ cell counts or other established risk factors for fracture.

Influence of coinfection with hepatitis C virus on morbidity and mortality due to human immunodeficiency virus infection in the era of highly active antiretroviral therapy.

To ascertain the impact of hepatitis C virus (HCV) infection on human immunodeficiency virus (HIV) disease progression and associated death in the era of highly active antiretroviral therapy (HAART), we examined mortality rates, the presence of other diseases, and antiretroviral use in an observational cohort of 823 HIV-infected patients with and without HCV coinfection during the period of January 1996 through June 2001. Analyses were used to compare patient characteristics, comorbid conditions, and survival durations in HIV-infected and HIV-HCV-coinfected patients. HIV-HCV-coinfected persons did not have a statistically greater rate of acquired immunodeficiency syndrome or of renal or cardiovascular disease, but they did have more cases of cirrhosis and transaminase elevations. There were proportionately more deaths in the HIV-HCV-coinfected group. Age, baseline CD4+ cell count, and duration of HAART were significantly associated with survival, but HCV infection was not. HAART use was a strong predictor of increased duration of survival, suggesting that treatment is more important to survival than is HCV coinfection status.

Hepatitis A and B Vaccination Practices for Ambulatory Patients Infected with HIV

Few studies exist of adherence to guidelines for vaccination of persons infected with human immunodeficiency virus (HIV), especially in the era of highly active antiretroviral therapy (HAART). In a retrospective, cross-sectional analysis in the HIV Outpatient Study sites, 198 (32.4%) of 612 patients eligible for hepatitis B vaccine received at least 1 dose. In multivariate analysis, hepatitis B vaccination was associated with HIV risk category, education level, and number of visits to the HIV clinic per year. Among 716 patients eligible for hepatitis A vaccine, 167 (23.3%) received > or =1 dose. Response to hepatitis B vaccination was associated with higher nadir CD4+ cell counts (P=.008) and HIV RNA levels less than the level of detection (P=.04), although some response was documented at all CD4+ levels. Although there were low rates of complete hepatitis vaccination in this cohort of ambulatory patients, prompt efforts to vaccinate patients entering care, receipt of antiretroviral therapy, and practice reminder systems may enhance vaccination practices.

Rates of hospitalizations and associated diagnoses in a large multisite cohort of HIV patients in the United States, 1994-2005.

ObjectivesTo assess temporal trends in the rates of hospitalizations and associated diagnoses among HIV-infected patients before and during the era of highly active antiretroviral therapy. DesignA prospective cohort study of 7155 patients enrolled in the HIV Outpatient Study at 10 US HIV clinics. MethodsWe evaluated rates of hospitalizations for major categories of medical conditions during 1994–2005 and modeled trends in these rates using multivariable Poisson regression models for repeated observations. We assessed patient characteristics associated with hospitalization using multiple logistic regression. ResultsThe rates of hospitalizations (per 100 person-years) fell from 24.6 in 1994 to 11.8 in 2005 (P < 0.0001). The rates of hospitalizations for AIDS opportunistic infections decreased from 7.6 in 1994–1996 to 1.0 in 2003–2005 (P < 0.0001). AIDS opportunistic infections were present at 31% of hospitalizations in 1994–1996 versus 9.5% in 2003–2005, and chronic end-organ disease conditions were present at 7.2% of such hospitalizations in 1994–1996 versus 14.3% in 2003–2005. Mean CD4+ cell count at hospitalization increased from 115 cells/μl in 1994 to 310 cells/μl in 2005. Factors independently associated with hospitalization in the highly active antiretroviral therapy era (1997–2005) included older age, history of substance abuse, lower CD4+ cell count, history of AIDS, and public health insurance. ConclusionThe rates of hospitalizations for HIV-infected patients declined substantially during 1994–2005, due mainly to reductions in the AIDS opportunistic infections. Compared with the period 1994–1997, patients in the highly active antiretroviral therapy era were hospitalized with higher CD4+ cell counts and more frequently for chronic end-organ conditions.

The changing spectrum of pulmonary disease in patients with HIV infection on antiretroviral therapy.

The pulmonary manifestations of HIV disease in 2005 can be divided into two sets of presentations. For patients who do not have access to care, and who are not taking antiretroviral or chemoprophylactic drugs, opportunistic infections and neoplasms continue to occur. Pulmonary disease caused by Streptococcus pneumoniae, Pneumocystis carinii (now known as Pneumocystis jiroveci pneumonia; PCP), Mycobacterium tuberculosis, lymphoma, and Kaposi’s sarcoma present much as they did in the 1980s. Management has improved in terms of new diagnostic, therapeutic, and preventive strategies, as reviewed in guidelines issued jointly by the National Institutes of Health, Centers for Disease Control and Prevention, and Infectious Disease Society of America (available online at http://www.aidsinfo.nih.gov).

Disparities in prevalence of key chronic diseases by gender and race/ethnicity among antiretroviral-treated HIV-infected adults in the US.

BACKGROUND Certain sociodemographic subgroups of HIV-infected patients may experience more chronic disease than others due to behavioural risk factors, advanced HIV disease or complications from extended use of combination antiretroviral therapy (cART), but recent comparative data are limited. METHODS We studied HIV-infected adult patients in care during 2006-2010 who had been prescribed ≥ 6 months of cART. We analysed the prevalence of selected key chronic conditions and polymorbidity (having 2 or more out of 10 key conditions) by gender and race/ethnicity. RESULTS Of the 3,166 HIV-infected patients (median age 47 years, CD4⁺ T-cell count 496 cells/mm³, duration of cART use 6.8 years), 21% were female, 57% were non-Hispanic White and over half were current or former tobacco smokers. The five most frequent conditions among women (median age 45 years) were dyslipidaemia (67.3%), hypertension (57.4%), obesity (31.7%), viral hepatitis B or C coinfection (29.0%) and low high-density lipoprotein cholesterol (HDLc; 27.3%). The five most frequent conditions in men (median age 47 years) were dyslipidaemia (81.2%), hypertension (54.4%), low HDLc (41.1%), elevated triglycerides (32.3%) and elevated non-HDLc (26.8%). In multivariable analyses, Hispanic patients had higher prevalence of obesity and diabetes than White patients; Black patients had higher prevalence of obesity and hypertension but lower rates of lipid abnormalities. Of all patients, 73.7% of women and 66.8% of men had polymorbidity, with no evidence of disparities by race/ethnicity. CONCLUSIONS Among contemporary cART-treated HIV-infected adults, chronic conditions and polymorbidity were common, underscoring the importance of chronic disease prevention and management among ageing HIV-infected patients.

Renal Function in Tenofovir-Exposed and Tenofovir-Unexposed Patients Receiving Highly Active Antiretroviral Therapy in the HIV Outpatient Study

Background: Cases of renal dysfunction have been reported in HIV-infected patients taking tenofovir (TDF), but few large studies have examined population-level changes in renal function associated with TDF use in patients in routine care. Methods: The authors analyzed data from participants in the HIV Outpatient Study (HOPS) who had normal baseline renal function and received >1 month of TDF-containing (n = 593) or TDF-sparing (n = 521) HAART after November 1, 2001. Results: Median baseline CrCl estimated by Cockcroft-Gault equation was 106 mL/min for TDF-exposed and 110 mL/min for TDF-unexposed patients (P = 0.06). In multivariable analyses, 1-year changes in CrCl (mL/min) from baseline were —5.7 among TDF-exposed and 2.6 among TDF-unexposed (P < 0.001). Incident renal disease was diagnosed in 7 TDF-exposed and 3 TDF-unexposed patients. Conclusions: In this large cohort of HIV-infected outpatients, use of TDF-containing HAART was associated with modest decreases in CrCl during the first year, but not with frequent, clinically significant renal toxicity.

Evaluation of hypophosphataemia in tenofovir disoproxil fumarate (TDF)-exposed and TDF-unexposed HIV-infected out-patients receiving highly active antiretroviral therapy

Cases of hypophosphataemia (often coincident with renal dysfunction) have been reported in HIV‐infected patients taking tenofovir disoproxil fumarate (TDF), but randomized placebo‐controlled trials of HIV‐infected persons with normal baseline renal function have found a comparable incidence of hypophosphataemia in the TDF and placebo groups. We assessed the incidence of grade 2 and higher hypophosphataemia in the HIV Outpatient Study (HOPS).