Anne C. Moorman

Declining Morbidity and Mortality among Patients with Advanced Human Immunodeficiency Virus Infection

BACKGROUND AND METHODS National surveillance data show recent, marked reductions in morbidity and mortality associated with the acquired immunodeficiency syndrome (AIDS). To evaluate these declines, we analyzed data on 1255 patients, each of whom had at least one CD4+ count below 100 cells per cubic millimeter, who were seen at nine clinics specializing in the treatment of human immunodeficiency virus (HIV) infection in eight U.S. cities from January 1994 through June 1997. RESULTS Mortality among the patients declined from 29.4 per 100 person-years in the first quarter of 1995 to 8.8 per 100 in the second quarter of 1997. There were reductions in mortality regardless of sex, race, age, and risk factors for transmission of HIV. The incidence of any of three major opportunistic infections (Pneumocystis carinii pneumonia, Mycobacterium avium complex disease, and cytomegalovirus retinitis) declined from 21.9 per 100 person-years in 1994 to 3.7 per 100 person-years by mid-1997. In a failure-rate model, increases in the intensity of antiretroviral therapy (classified as none, monotherapy, combination therapy without a protease inhibitor, and combination therapy with a protease inhibitor) were associated with stepwise reductions in morbidity and mortality. Combination antiretroviral therapy was associated with the most benefit; the inclusion of protease inhibitors in such regimens conferred additional benefit. Patients with private insurance were more often prescribed protease inhibitors and had lower mortality rates than those insured by Medicare or Medicaid. CONCLUSIONS The recent declines in morbidity and mortality due to AIDS are attributable to the use of more intensive antiretroviral therapies.

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.

Incidence of Types of Cancer among HIV-Infected Persons Compared with the General Population in the United States, 1992–2003

BACKGROUND Persons who are HIV-infected may be at higher risk for certain types of cancer than the general population. OBJECTIVE To compare cancer incidence among HIV-infected persons with incidence in the general population from 1992 to 2003. DESIGN Prospective observational cohort studies. SETTING United States. PATIENTS 54,780 HIV-infected persons in the Adult and Adolescent Spectrum of HIV Disease Project (47,832 patients) and the HIV Outpatient Study (6948 patients), who contributed 157,819 person-years of follow-up from 1992 to 2003, and 334,802,121 records from the Surveillance, Epidemiology, and End Results program of 13 geographically defined, population-based, central cancer registries. MEASUREMENTS Standardized rate ratios (SRRs) to compare cancer incidence in the HIV-infected population with standardized cancer incidence in the general population. RESULTS The incidence of the following types of non-AIDS-defining cancer was significantly higher in the HIV-infected population than in the general population: anal (SRR, 42.9 [95% CI, 34.1 to 53.3]), vaginal (21.0 [CI, 11.2 to 35.9]), Hodgkin lymphoma (14.7 [CI, 11.6 to 18.2]), liver (7.7 [CI, 5.7 to 10.1]), lung (3.3 [CI, 2.8 to 3.9]), melanoma (2.6 [CI, 1.9 to 3.6]), oropharyngeal (2.6 [CI, 1.9 to 3.4]), leukemia (2.5 [CI, 1.6 to 3.8]), colorectal (2.3 [CI, 1.8 to 2.9]), and renal (1.8 [CI, 1.1 to 2.7]). The incidence of prostate cancer was significantly lower among HIV-infected persons than the general population (SRR, 0.6 [CI, 0.4 to 0.8]). Only the relative incidence of anal cancer increased over time. LIMITATIONS Lower ascertainment of cancer in the HIV cohorts may result in a potential bias to underestimate rate disparities. Tobacco use as a risk factor and the effect of changes in cancer screening practices could not be evaluated. CONCLUSION The incidence of many types of non-AIDS-defining cancer was higher among HIV-infected persons than among the general population from 1992 to 2003.

Protease inhibitors and cardiovascular outcomes in patients with HIV-1

Protease inhibitors for treatment of HIV-1 have been linked with increased risk of hyperlipidaemia and hyperglycaemia. In a cohort of 5672 outpatients with HIV-1 seen at nine US HIV clinics between January, 1993, and January, 2002, the frequency of myocardial infarctions increased after the introduction of protease inhibitors in 1996 (test for trend, p=0.0125). We noted that 19 of 3247 patients taking, but only two of 2425 who did not take, protease inhibitors had a myocardial infarction (odds ratio 7.1, 95% CI 1.6-44.3; Cox proportional hazards model-adjusted for smoking, sex, age, diabetes, hyperlipidaemia, and hypertension-hazard ratio 6.5, 0.9-47.8). Our findings suggest that, although infrequent, use of protease inhibitors is associated with increased risk of myocardial infarction in patients with HIV-1.

Clinical assessment of Hiv-associated lipodystrophy in an ambulatory population

ObjectiveTo identify clinical factors associated with prevalence of fat atrophy (lipoatrophy) and fat accumulation (lipoaccumulation) in HIV-1 infected patients. DesignEvaluation of HIV-1 infected patients seen for routine care between 1 October and 31 December 1998 in the eight HIV Outpatient Study (HOPS) clinics. SettingEight clinics specializing in the care of HIV-1 infected patients. PatientsA total of 1077 patients were evaluated for signs of fat maldistribution. InterventionsA standardized set of questions and specific clinical signs were assessed. Demographic, clinical and pharmacological data for each patient were also included in the analysis. Main outcome measuresDemographic, immunologic, virologic, clinical, laboratory, and drug treatment factors were assessed in stratified and multivariate analyses for their relationship to the presence and severity of fat accumulation and atrophy. ResultsIndependent factors for moderate/severe lipoatrophy for 171 patients were increasing age, any use of stavudine, use of indinavir for longer than 2 years, body mass index (BMI) loss, and measures of duration and severity of HIV disease. Independent risk factors for moderate/severe fat accumulation for 104 patients were increasing age, BMI gain, measures of amount and duration of immune recovery, and duration of antiretroviral therapy (ART). The number of non-drug risk factors substantially increased the likelihood of lipoatrophy. If non-drug risk factors were absent, lipoatrophy was unusual regardless of the duration of drug use. ConclusionsHIV-associated lipodystrophy is associated with several host, disease, and drug factors. While prevalence of lipoatrophy increased with the use of stavudine and indinavir, and lipoaccumulation was associated with duration of ART, other non-drug factors were strongly associated with both fat atrophy and accumulation.

Survival Benefit of Initiating Antiretroviral Therapy in HIV-Infected Persons in Different CD4+ Cell Strata

Context When to start antiretroviral therapy (ART) for HIV infection is controversial. Starting too early exposes patients to side effects and uncertain benefits. Starting too late deprives patients of benefits. Contribution In this cohort study, HIV-infected patients with baseline CD4+ cell counts between 0.201 and 0.350 109 cells/L who began ART immediately had lower mortality rates than those who started therapy after their CD4+ cell count decreased to less than 0.201 109 cells/L. Optimal timing of therapy is unclear when the CD4+ cell count is greater than 0.350 109 cells/L. Cautions A randomized, controlled trial is the best way to identify the optimal timing of ART. The Editors Optimal timing of antiretroviral therapy (ART) initiation for persons with HIV infection is of great clinical and public health importance. Therapy reduces HIV-related mortality and morbidity for patients with substantial CD4+ cell depletion (<0.100 109 cells/L) who initiate treatment (1). Although data demonstrate the viral suppressive and immunologic (CD4+ cell count) benefits of therapy in persons with higher CD4+ cell counts (2-8), long-term improvements in disease-associated morbidity and mortality with earlier therapy are less clear (9, 10). In such patients, the potential benefits of ART and highly active ART (HAART) will probably be weighed against possible untoward sequelae of earlier treatment, including the development of metabolic abnormalities; emergence of drug-resistant virus, with resultant exhaustion of effective remaining therapies; cost; and access (9, 11-13). Current treatment guidelines allowing for the delay of ART until a lower CD4+ thresholdusually 0.350 109 cells/L or, for some patients, 0.200 109 cells/Lreflect a lack of consensus on the benefits of earlier initiation of therapy (13, 14). Sparse data exist on which to base specific recommendations for the initiation of ART relative to CD4+ cell count. Longitudinal data comparing ART recipients to appropriate comparison groups not receiving ART (especially patients with CD4+ cell counts > 0.200 109 cells/L) are limited (10, 15). Analyses that include extended follow-up data on such patients are critical because these patients are unlikely to develop or die of an HIV-related condition over the short term, in contrast to those who start therapy with lower CD4+ cell counts. Another challenge is related to the relatively brief time that HAART has been available (since early 1996), making comparative longitudinal studies of sufficient duration difficult. We compare mortality rates among ambulatory HIV-infected patients who initiated ART and those who delayed ART in various CD4+ strata. Patients were enrolled in the HIV Outpatient Study (HOPS), a dynamic cohort of ambulatory HIV-infected patients demographically representative of treated HIV-infected patients in the United States. Methods HOPS HOPS is an ongoing prospective observational cohort study into which patients have been continuously recruited and followed since 1993 (1, 16). Study sites are 10 clinics (8 private, 2 public) in 8 U.S. cities that provide care for more than 2400 HIV-infected patients per year. Participating physicians have extensive experience treating HIV-infected patients. Information is abstracted from outpatient charts at each visit and entered electronically by trained staff; it is then compiled centrally and reviewed and edited before being analyzed. Information abstracted includes demographic characteristics and risk factors for HIV infection; symptoms; diagnosed diseases (both definitive and presumptive); medications prescribed, including dose and duration; and laboratory values, including CD4+ cell counts and measurements of plasma HIV-1 RNA (viral load). Selection of Patients for Analysis We identified HOPS participants who had at least two CD4+ measurements and reliable data on ART initiation and use for at least 30 consecutive days from January 1994 through March 2001. We defined HAART as the use of at least three drugs simultaneously, including one protease inhibitor or non-nucleoside reverse-transcriptase inhibitor, or any regimen with at least two full-dose protease inhibitors. Three patient subgroups were analyzed: those observed to have a pre-ART CD4+ cell count of 0.501 to 0.750 109 cells/L, those with a pre-ART CD4+ cell count of 0.351 to 0.500 109 cells/L, and those with a pre-ART CD4+ cell count of 0.201 to 0.350 109 cells/L. Patients could be in more than one subgroup if they had a pre-ART CD4+ cell count in more than one of the defined ranges. Thus, analyses within a subgroup are distinct from analyses in other subgroups. We then stratified patients in each subgroup into one of three treatment groups: those who began ART while still in the same CD4+ subgroup range (subsequently called patients who initiated ART), those who began ART after their CD4+ cell count decreased to less than the CD4+ subgroup range (subsequently called patients who delayed ART), and those who never received ART (untreated patients). The closest (in time) CD4+ cell count available within 6 months before or 2 weeks after ART initiation was used to define the CD4+ cell count at the start of therapy. By definition, because patients who delayed ART had to have at least 1 additional CD4+ measurement during follow-up, patients who initiated ART and those who were untreated were also required to have at least 1 additional CD4+ measurement during follow-up to reduce potential bias in the analysis as a result of differential time under observation. For all treatment groups, time under observation began with the date of the earliest CD4+ cell count within the CD4+ stratum in which the patient was analyzed. Patients included in the analyses of the CD4+ subgroups of 0.201 to 0.350 109 cells/L and 0.351 to 0.500 109 cells/L were those whose earliest CD4+ cell count within the subgroup-defined range was observed after 1 January 1994. The analysis of the CD4+ subgroup of 0.501 to 0.750 109 cells/L was limited to those whose earliest CD4+ cell count within this range was observed between January 1994 and December 1995. This allowed longer elapsed time to observe clinical events. For analysis, the observation period for each patient ended at 6 months after the last contact with a HOPS clinic or at death. We analyzed all deaths, including those not directly due to AIDS or indirectly from conditions exacerbated by HIV infection (such as hepatic, renal, or cardiac disease). Causes of death were ascertained through review of clinic and hospital charts, death certificates, and national AIDS surveillance data. Deaths from suicide (one patient in the CD4+ subgroup of 0.201 to 0.350 109 cells/L who delayed ART and one patient in the CD4+ subgroup of 0.501 to 0.750 109 cells/L who initiated treatment) were treated as censored. Statistical Analysis We used SAS software, version 8.0 (SAS Institute, Inc., Cary, North Carolina), for all analyses. Patient characteristics were compared by chi-square test or the Fisher exact test for categorical variables and the Wilcoxon rank-sum test or t-test for continuous variables. We analyzed mortality rates per 1000 person-years and calculated the relative risk for death, 95% CIs, and approximate two-sided P values for each subgroup (17). Cox proportional-hazards regression was used to estimate hazard ratios, adjusted for age, sex, race, insurance status, viral load (log scale) at time of first ART (a dummy variable was used to include patients missing viral load data), receipt of HAART, and CD4+ cell count at the time of first observation within each stratum. Role of the Funding Source The funding source participated in the design, conduct, analysis, and reporting of the study and in the decision to submit the manuscript for publication. Results We evaluated data from 1464 HIV-infected HOPS participants. Of these patients, 596 who initiated ART had at least one additional CD4+ measurement after ART initiation, and 175 who delayed ART had at least one additional recorded CD4+ cell count in a higher stratum before ART initiation. We compared the demographic and baseline characteristics of patients described in this report to those of the larger overall group of HOPS participants and found no meaningful differences (data not shown). We analyzed data from 399 patients (340 who initiated and 59 who delayed ART) with pre-ART CD4+ cell counts between 0.201 and 0.350 109 cells/L, 327 patients (240 who initiated and 87 who delayed ART) with pre-ART CD4+ cell counts between 0.351 and 0.500 109 cells/L, and 122 patients (55 who initiated and 67 who delayed ART) with pre-ART CD4+ cell counts between 0.501 and 0.750 109 cells/L. Median years of follow-up for patients who initiated and those who delayed ART, by CD4+ subgroup, were as follows: 3.8 and 3.9 years for the subgroup of 0.201 to 0.350 109 cells/L, 4.1 and 4.2 years for the subgroup of 0.351 to 0.500 109 cells/L, and 5.4 and 5.3 years for the subgroup of 0.501 to 0.750 109 cells/L, respectively. Table 1 shows the demographic, immunologic, virologic, and care characteristics of patients who initiated ART and those who delayed ART, by CD4+ subgroup. Across subgroups, at least 69% of patients were men, 64% were younger than 40 years of age, 62% were white, and 35% had private health care insurance. Patients who initiated ART and those who delayed ART did not differ significantly except for the following: Patients in the CD4+ subgroup of 0.351 to 0.500 109 cells/L with private insurance tended to initiate rather than delay ART, and men in the CD4+ subgroup of 0.501 to 0.750 109 cells/L tended to delay therapy. Table 1. Characteristics of the HIV Outpatient Study Patients Who Initiated or Delayed Antiretroviral Therapy, by Preantiretroviral CD4+ Cell Count Stratum In general, most patients in a CD4+ subgroup who delayed ART initiated therapy in the next lowest CD4+ subgroup, that is, those who did not start in one subgroup started approximat

Hepatitis C in the United States

Recent analyses suggest that of the estimated 3.2 million people infected with hepatitis C virus, only about half have been tested and know their status, about a third have been referred for HCV care, and only 5 to 6% have been successfully treated.

Incidence of and risk factors for lipoatrophy (abnormal fat loss) in ambulatory HIV-1-infected patients.

To identify clinical factors associated with the incidence of HIV-1–associated lipoatrophy, HIV-1–infected patients in the HIV Outpatient Study (HOPS) were prospectively evaluated for clinical signs of lipoatrophy at two visits about 21 months apart. Development of lipoatrophy was analyzed in stratified and multivariate analyses for its relationship to immunologic, virologic, clinical, and drug treatment information for each patient. Of 337 patients with no lipoatrophy at Survey 1, 44 (13.1%) developed moderate or severe lipoatrophy between the two surveys. In multivariate analyses, significant risk factors for incident lipoatrophy were white race (OR = 5.2; 95% CI: 1.9–17.1;p = .003), CD4 T-lymphocyte count at Survey 2 less than 100 cells/mm3 (OR = 4.2; 95% CI: 1.3–13.1;p = .013), and body mass index (BMI) less than 24 kg/m2 (OR = 2.4; 95% CI: 1.1–5.4;p = .024). Analyses that controlled for the severity of HIV illness demonstrated no significant association with use of or time on any antiretroviral agent or class of agents and the development of lipoatrophy. Some host factors and factors associated with previous or current severity of HIV infection, especially CD4 T-lymphocyte cell count, appeared to have the strongest association with incidence of lipoatrophy.

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.

Modification of the Incidence of Drug-Associated Symmetrical Peripheral Neuropathy by Host and Disease Factors in the HIV Outpatient Study Cohort

BACKGROUND We sought to identify factors associated with the clinical diagnosis of symmetrical peripheral neuropathy (SPN) during the era of highly active antiretroviral therapy (HAART) in a retrospective, longitudinal cohort analysis. METHODS Patients infected with human immunodeficiency virus type 1 were evaluated for clinical signs of SPN and its association with immunologic, virologic, clinical, and drug treatment factors by means of univariate and multivariate logistic regression analyses. RESULTS Of 2515 patients, 329 (13.1%) received a diagnosis of SPN. In the logistic regression analysis, statistically significant non-drug-based risk factors for SPN were age >40 years (adjusted odds ratio [aOR], 1.17), diabetes mellitus (aOR, 1.79), white race (aOR, 1.33), nadir CD4(+) T lymphocyte count <50 cells/mm(3) (aOR, 1.64), CD4(+) T lymphocyte count 50-199 cells/mm(3) (aOR, 1.40), and viral load >10,000 copies/mL at first measurement (aOR, 1.44). Although initial use of didanosine, stavudine (40 mg b.i.d.), nevirapine, or 4 protease inhibitors was associated with SPN (ORs for all 4 treatments, >1.41), the strength of association decreased with continued use of all medications studied. CONCLUSION Since HAART was introduced, the incidence of SPN has decreased. Host factors and signs of increased disease severity were associated with an increased risk of developing SPN during the initial period of exposure to drug therapy. Immunity improved and the risk of SPN decreased with continued use of HAART. Delaying the initiation of therapy may select those individuals who will be more likely to develop SPN, and earlier initiation of HAART may decrease the risk of developing this common problem, as well as increase the therapeutic effects and decrease the toxic effects of the drugs.