Fiona Lampe

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.

Predictive accuracy of the Framingham coronary risk score in British men: prospective cohort study

Abstract Objective To establish the predictive accuracy of the Framingham risk score for coronary heart disease in a representative British population. Design Prospective cohort study. Setting 24 towns in the United Kingdom. Participants 6643 British men aged 40-59 years and free from cardiovascular disease at entry into the British regional heart study. Main outcome measures Comparison of observed 10 year coronary heart disease mortality and event rates with predicted rates for each individual, using the relevant Framingham risk equation. Results Of 6643 men, 2.8% (95% confidence interval 2.4% to 3.2%) died from coronary heart disease compared with 4.1% predicted (relative overestimation 47%, P < 0.0001). A fatal or non-fatal coronary heart disease event occurred in 10.2% (9.5% to 10.9%) of the men compared with 16.0% predicted (relative overestimation 57%, P < 0.0001). These relative degrees of overestimation were similar at all levels of coronary heart disease risk, so that overestimation of absolute risk was greatest for those at highest risk. A simple adjustment provided an improved level of accuracy. In a “high risk score” approach, most cases occur in the low risk group. In this case, 84% of the deaths from coronary heart disease and non-fatal events occurred in the 93% of men classified at low risk (< 30% in 10 years) by the Framingham score. Conclusion Guidelines for the primary prevention of coronary heart disease advocate offering preventive measures to individuals at high risk. Currently recommended risk scoring methods derived from the Framingham study significantly overestimate the absolute coronary risk assigned to individuals in the United Kingdom.

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.

Outcome of HIV-associated tuberculosis in the era of highly active antiretroviral therapy

BACKGROUND The benefit of highly active antiretroviral therapy (HAART) in the treatment of patients coinfected with tuberculosis (TB) and human immunodeficiency virus (HIV) is unclear because of concerns about treatment-related complications. METHODS We compared outcomes in patients starting TB treatment during the pre-HAART era (before 1996; n=36) with those in patients starting treatment during the HAART era (during or after 1996; n=60). RESULTS During a median of 3.6 years of follow-up, 49 patients died or had an AIDS event. Compared with patients in the pre-HAART group, those in the HAART group had a lower risk of death (cumulative at 4 years, 43% vs. 22%; P=.012) and of death or having an AIDS event (69% vs. 43%; P=.023). Event risk within the first 2 months of TB treatment was exceptionally high in patients with CD4(+) cell counts <100 cells/mm(3) and declined thereafter. HAART use during follow-up was associated with a marked reduction in event risk (adjusted hazard ratio, 0.38 [95% confidence interval, 0.16-0.91]). CONCLUSIONS HAART substantially reduces new AIDS events and death in coinfected patients. Those with a CD4(+) cell count <100 cells/mm(3) have a high event risk during the intensive phase of anti-TB treatment. These data should be taken into account when deciding to delay HAART in coinfected patients with CD4(+) cell counts <100 cells/mm(3).

Late presenters in the era of highly active antiretroviral therapy: uptake of and responses to antiretroviral therapy

Objectives: To investigate the characteristics and clinical, immunological and virological outcomes for individuals presenting for care with low CD4 cell counts. Methods: Individuals aged > 16 years presenting for care for the first time were identified between 1 January 1996 and 31 December 2002. Late presenters were those with CD4 cell count < 50×106 cells/l. Follow-up was until last contact, death or 31 December 2002. Results: Late presenters formed 15.3% (110) of the group; they were more likely to be female (35% versus 24%), heterosexual (53% versus 38%), and of Black-African ethnicity (39% versus 27%) than other individuals. Over a median follow-up of 2.5 years, 13% of late presenters died. Ninety-nine patients started antiretroviral treatment; Of the 11 patients who did not start antiretroviral treatment, eight died within 3 months of presentation. Among those starting treatment, 87 (87.9%) achieved a viral load < 400 copies/ml and median CD4 cell counts increased from 43 × 106 cells/l at 0–2 months after presentation to 204 × 106 cells/l at 1 year. Over the first year, 71 patients attended at least one outpatient visit (median, 4.5; range, 0–39), 21 attended at least one day case visit (median, 0; range, 0–15) and 49 were admitted as an inpatient (median, 0; range, 0–4). Conclusions: Those presenting for care with very low CD4 cell counts may make large demands on clinical resources, particularly over the first few months. While some patients do have a poor outcome on highly active antiretroviral therapy, many will benefit from this therapy and will experience good immunological and virological responses.

Increased HIV Incidence in Men Who Have Sex with Men Despite High Levels of ART-Induced Viral Suppression: Analysis of an Extensively Documented Epidemic

Background There is interest in expanding ART to prevent HIV transmission, but in the group with the highest levels of ART use, men-who-have-sex-with-men (MSM), numbers of new infections diagnosed each year have not decreased as ARTcoverage has increased for reasons which remain unclear. Methods We analysed data on the HIV-epidemic in MSM in the UK from a range of sources using an individual-based simulation model. Model runs using parameter sets found to result in good model fit were used to infer changes in HIV-incidence and risk behaviour. Results HIV-incidence has increased (estimated mean incidence 0.30/100 person-years 1990–1997, 0.45/100 py 1998–2010), associated with a modest (26%) rise in condomless sex. We also explored counter-factual scenarios: had ART not been introduced, but the rise in condomless sex had still occurred, then incidence 2006–2010 was 68% higher; a policy of ART initiation in all diagnosed with HIV from 2001 resulted in 32% lower incidence; had levels of HIV testing been higher (68% tested/year instead of 25%) incidence was 25% lower; a combination of higher testing and ART at diagnosis resulted in 62% lower incidence; cessation of all condom use in 2000 resulted in a 424% increase in incidence. In 2010, we estimate that undiagnosed men, the majority in primary infection, accounted for 82% of new infections. Conclusion A rise in HIV-incidence has occurred in MSM in the UK despite an only modest increase in levels of condomless sex and high coverage of ART. ART has almost certainly exerted a limiting effect on incidence. Much higher rates of HIV testing combined with initiation of ART at diagnosis would be likely to lead to substantial reductions in HIV incidence. Increased condom use should be promoted to avoid the erosion of the benefits of ART and to prevent other serious sexually transmitted infections.

Mortality of HIV-infected patients starting potent antiretroviral therapy: comparison with the general population in nine industrialized countries

BACKGROUND Mortality in HIV-infected patients has declined substantially with combination antiretroviral therapy (ART), but it is unclear whether it has reached that of the general population. We compared mortality in patients starting ART in nine countries of Europe and North America with the corresponding general population, taking into account their response to ART. METHODS Eligible patients were enrolled in prospective cohort studies participating in the ART Cohort Collaboration. We calculated the ratio of observed to expected deaths from all causes [standardized mortality ratio (SMR)], measuring time from 6 months after starting ART, according to risk group, clinical stage at the start of ART and CD4 cell count and viral load at 6 months. Expected numbers of deaths were obtained from age-, sex- and country-specific mortality rates. RESULTS Among 29 935 eligible patients, 1134 deaths were recorded in 131 510 person-years of follow-up. The median age was 37 years, 8162 (27%) patients were females, 4400 (15%) were injecting drug users (IDUs) and 6738 (23%) had AIDS when starting ART. At 6 months, 23 539 patients (79%) had viral load measurements <or=500 copies/ml. The lowest SMR, 1.05 [95% confidence interval (CI) 0.82-1.35] was found for men who have sex with men (MSM) who started ART free of AIDS, reached a CD4 cell count of >or=350 cells/microL and suppressed viral replication to <or=500 copies/ml by the sixth month. In contrast, the SMR was 73.7 (95% CI 46.4-116.9) in IDUs who failed to suppress viral replication and had CD4 cell counts <50 cells/microL at 6 months. The percentage of patients with SMRs <2 was 46% for MSM, 42% for heterosexually infected patients and 0% for patients with a history of injection drug use. Corresponding percentages for SMRs >10 were 4, 14 and 47%. CONCLUSIONS In industrialized countries, the mortality experience of HIV-infected patients who start ART and survive the first 6 months continues to be higher than in the general population, but for many patients excess mortality is moderate and comparable with patients having other chronic conditions. Much of the excess mortality might be prevented by earlier diagnosis of HIV followed by timely initiation of ART.

Effect of inhaled corticosteroids on episodes of wheezing associated with viral infection in school age children: randomised double blind placebo controlled trial

Abstract Objectives: To determine the effect of regular prophylactic inhaled corticosteroids on wheezing episodes associated with viral infection in school age children. Design: Randomised, double blind, placebo controlled trial. Setting: Community based study in Southampton. Subjects: 104 children aged 7 to 9 years who had had wheezing in association with symptoms of upper and lower respiratory tract infection in the preceding 12 months. Interventions: After a run in period of 2–6 weeks children were randomly allocated twice daily inhaled beclomethasone dipropionate 200 μg or placebo through a Diskhaler for 6 months with a wash out period of 2 months. Children were assessed monthly. Main outcome measures: Forced expiratory volume in 1 second (FEV1); bronchial responsiveness to methacholine (PD20); percentage of days with symptoms of upper and lower respiratory tract infection with frequency, severity, and duration of episodes of upper and lower respiratory symptoms and of reduced peak expiratory flow rate. Results: During the treatment period there was a significant increase in mean FEV1 (1.63 v 1.53 l; adjusted difference 0.09 l (95% confidence interval 0.04 to 0.14); P=0.001) and methacholine PD20 (12.8 v 7.2 μmol/l; adjusted ratio of means 1.7 (1.2 to 2.4); P=0.007) in children receiving beclomethasone dipropionate compared with placebo. There were, however, no significant differences in the percentage of days with symptoms or in the frequency, severity, or duration of episodes of upper or lower respiratory symptoms or of reduced peak expiratory flow rate during the treatment period between the two groups. Conclusions: Although lung function is improved with regular beclomethasone dipropionate 400 μg/day, this treatment offers no clinically significant benefit in school age children with wheezing episodes associated with viral infection. Key messages Increasing evidence suggests that episodic wheezing in children in association with viral infections is a separate entity from atopic asthma Although inhaled corticosteroids are beneficial in asthma, their role in treating wheezing associated with viral infections is unclear In this study regular inhaled corticosteroids resulted in improved lung function and decreased bronchial responsiveness but did not have any effect on episodes of wheezing Inhaled corticosteroids are of little benefit in children with episodic wheezing associated with viral infection

Validity of a self-reported history of doctor-diagnosed angina.

The objective of this study was to assess the validity of a self-reported history of doctor-diagnosed angina in population-based studies in men. Subjects were 5789 men from the British Regional Heart Study who reported being without an angina diagnosis at entry (1978-1980) and were alive at the end of 1992, aged 52 to 75 years. In 1992, subjects were asked in a self-administered questionnaire if they recalled ever having had a doctor diagnosis of angina. Self-report of diagnosed angina was compared with general practice (GP) record of angina obtained from reviews of medical records from study entry to the end of 1992. Men were followed for a further 3 years from 1992 for major ischemic heart disease events. The prevalence of diagnosed angina in 1992 was 10.1% according to self-reported history and 8.9% according to GP record review. There was substantial agreement between the two sources of information: 80% of men with a GP record of angina reported their diagnosis, and 70% of men who reported an angina diagnosis had confirmation of this from the record review. When all ischemic heart disease (angina or myocardial infarction) was considered, agreement was higher. Genuine angina was likely in many of the 177 men who had self-reported angina not confirmed by the GP record review: 78 had an ischemic heart disease history (myocardial infarction or coronary revascularization) identified by the review, and 31 had a GP record of angina after 1992. Angina symptoms, nitrate use, cardiological investigation, and surgical intervention for angina compared between agreement groups showed a very consistent pattern. All these indicators of angina were most common in men with both self-report and GP record of angina, least common in men with neither self-report nor GP record of angina, but had a substantially higher prevalence in men with self-reported angina only than in those with GP-recorded angina only. After 3 years follow-up from 1992, 9.5% of men with both self-report and GP record of angina, and 11.3% of men with self-reported angina only had experienced a new major ischemic heart disease event; compared to 5.7% of men with a GP record of angina only and 2.7% of those without angina by either criteria. This pattern of risk remained similar after adjustment for age and previous myocardial infarction. These results suggest that self-reported history of a doctor diagnosis of angina is a valid measure of diagnosed angina in population-based studies in men.

Management of Invasive Pulmonary Aspergillosis in Hematology Patients: A Review of 87 Consecutive Cases at a Single Institution

Eighty-seven patients with hematologic malignancies and invasive pulmonary aspergillosis (IPA) were identified between 1982 and 1995. Of these, 39 underwent lung resection on the basis of radiological detection of at least 1 lesion with imaging suggestive of aspergillosis (LISA). IPA was confirmed histologically in 35. The presence of LISA had 90% positive predictive value for IPA. The actuarial survival at 2 years was 36% for 37 patients treated surgically, 20% for 12 patients with unresected LISA but no cultures of Aspergillus species, and 5% for 21 patients diagnosed only by isolation of Aspergillus from respiratory secretions. Analysis by proportional hazard models showed a significant independent negative association between the radiological appearance of LISA and death from all causes. Relapsed hematologic disease was independently significantly associated with death. Age, sex, surgery, previous bone marrow transplantation, or Aspergillus isolation were not independent predictors of death. IPA presenting as LISA carries a relatively good prognosis, possibly explaining the better survival of patients undergoing surgery for such lesions.