Marie Helleberg

Mortality Attributable to Smoking Among HIV-1–Infected Individuals: A Nationwide, Population-Based Cohort Study

BACKGROUND We assessed mortality attributable to smoking among patients with human immunodeficiency virus (HIV). METHODS We estimated mortality rates (MRs), mortality rate ratios (MRRs), life expectancies, life-years lost, and population-attributable risk of death associated with smoking and with HIV among current and nonsmoking individuals from a population-based, nationwide HIV cohort and a cohort of matched HIV-negative individuals. RESULTS A total of 2921 HIV patients and 10 642 controls were followed for 14 281 and 45 122 person-years, respectively. All-cause and non-AIDS-related mortality was substantially increased among smoking compared to nonsmoking HIV patients (MRR, 4.4 [95% confidence interval {CI}, 3.0-6.7] and 5.3 [95% CI, 3.2-8.8], respectively). Excess MR per 1000 person-years among current vs nonsmokers was 17.6 (95% CI, 13.3-21.9) for HIV patients and 4.8 (95% CI, 3.2-6.4) for controls. A 35-year-old HIV patient had a median life expectancy of 62.6 years (95% CI, 59.9-64.6) for smokers and 78.4 years (95% CI, 70.8-84.0) for nonsmokers; the numbers of life-years lost in association with smoking and HIV were 12.3 (95% CI, 8.1-16.4) and 5.1 (95% CI, 1.6-8.5). The population-attributable risk of death associated with smoking was 61.5% among HIV patients and 34.2% among controls. CONCLUSIONS In a setting where HIV care is well organized and antiretroviral therapy is free of charge, HIV-infected smokers lose more life-years to smoking than to HIV. The excess mortality of smokers is tripled and the population-attributable risk of death associated with smoking is doubled among HIV patients compared to the background population.

Smoking and life expectancy among HIV-infected individuals on antiretroviral therapy in Europe and North America

Background:Cardiovascular disease and non-AIDS malignancies have become major causes of death among HIV-infected individuals. The relative impact of lifestyle and HIV-related factors are debated. Methods:We estimated associations of smoking with mortality more than 1 year after antiretroviral therapy (ART) initiation among HIV-infected individuals enrolled in European and North American cohorts. IDUs were excluded. Causes of death were assigned using standardized procedures. We used abridged life tables to estimate life expectancies. Life-years lost to HIV were estimated by comparison with the French background population. Results:Among 17 995 HIV-infected individuals followed for 79 760 person-years, the proportion of smokers was 60%. The mortality rate ratio (MRR) comparing smokers with nonsmokers was 1.94 [95% confidence interval (95% CI) 1.56–2.41]. The MRRs comparing current and previous smokers with never smokers were 1.70 (95% CI 1.23–2.34) and 0.92 (95% CI 0.64–1.34), respectively. Smokers had substantially higher mortality from cardiovascular disease, non-AIDS malignancies than nonsmokers [MRR 6.28 (95% CI 2.19–18.0) and 2.67 (95% CI 1.60–4.46), respectively]. Among 35-year-old HIV-infected men, the loss of life-years associated with smoking and HIV was 7.9 (95% CI 7.1–8.7) and 5.9 (95% CI 4.9–6.9), respectively. The life expectancy of virally suppressed, never-smokers was 43.5 years (95% CI 41.7–45.3), compared with 44.4 years among 35-year-old men in the background population. Excess MRRs/1000 person-years associated with smoking increased from 0.6 (95% CI –1.3 to 2.6) at age 35 to 43.6 (95% CI 37.9–49.3) at age at least 65 years. Conclusion:Well treated HIV-infected individuals may lose more life years through smoking than through HIV. Excess mortality associated with smoking increases markedly with age. Therefore, increases in smoking-related mortality can be expected as the treated HIV-infected population ages. Interventions for smoking cessation should be prioritized.

Risk of cancer among HIV-infected individuals compared to the background population: impact of smoking and HIV.

Background:The relative impact of immune deficiency and lifestyle-related factors on risk of cancer in the HIV-infected population is controversial. We aimed to estimate the population-attributable fractions (PAFs) associated with smoking, being HIV-infected and with immune deficiency. Methods:In a Danish, nationwide, population-based cohort study (1995–2011), incidences of cancer were compared between an HIV-infected cohort and a population-based matched cohort in analyses stratified on cancer category, smoking status and for HIV patients: low CD4+ cell count. Results:We included 3503 HIV patients [baseline CD4+ 450 cells/&mgr;l (inter-quartile range 310–630)] and 12 979 population controls. Smoking-related and virological cancers accounted for 23 and 43% of cancers in the HIV-infected population. The risk of these cancers were higher among HIV patients compared to controls [incidence rate ratio (IRR) 2.8, 95% confidence interval (CI) 1.6–4.9; and IRR 11.5, 95% CI 6.5–20.5], whereas the risk of other cancers did not differ (IRR 1.0, 95% CI 0.7–1.3). Non-smoking HIV patients did not have increased risk of non-virological cancers compared to non-smoking controls (IRR 1.2, 95% CI 0.7–2.1). The PAFs of cancer associated with smoking and with being HIV-infected were 27 and 49%, respectively. For cancers not strongly related to smoking or viral infections, the PAFs associated with being HIV-infected and with immune deficiency were 0%. Conclusion:The risk of cancer is increased in HIV patients compared to the background population. In absence of smoking, the increase in risk is confined to cancers related to viral infections, whereas the risk of other cancers is not elevated and does not seem to be associated with immune deficiency.

Myocardial Infarction Among Danish HIV-Infected Individuals: Population-Attributable Fractions Associated With Smoking

BACKGROUND Human immunodeficiency virus-infected individuals have increased risk of myocardial infarction (MI); however, the contribution from smoking and potentiating effects of HIV are controversial. METHODS From the Danish HIV Cohort Study and the Copenhagen General Population Study, we identified 3251 HIV-infected individuals and 13 004 population controls matched on age and gender. Data on MI were obtained from the National Hospital Registry and the National Registry of Causes of Death. We calculated adjusted incidence rate ratios (aIRR) for risk of MI and population-attributable fractions (PAF) of MI associated with smoking. RESULTS In never smokers, HIV was not associated with an increased risk of MI (aIRR, 1.01; 95% confidence interval [CI], .41-2.54). In previous and current smokers, HIV was associated with a substantially increased risk of MI (aIRR, 1.78; 95% CI, .75-4.24 and aIRR, 2.83; 95% CI, 1.71-4.70). The PAF associated with ever smoking (previous or current) was 72% (95% CI, 55%-82%) for HIV-infected individuals and 24% (95% CI, 3%-40%) for population controls. If all current smokers stopped smoking, 42% (95% CI, 21%-57%) and 21% (95% CI, 12%-28%) of all MIs could potentially be avoided in these 2 populations. CONCLUSIONS Smoking is associated with a higher risk of MI in the HIV-infected population than in the general population. Approximately 3 of 4 MIs among HIV-infected individuals are associated with ever smoking compared with only 1 of 4 MIs among population controls. Smoking cessation could potentially prevent more than 40% of MIs among HIV-infected individuals, and smoking cessation should be a primary focus in modern HIV care.

Bone marrow suppression and severe anaemia associated with persistent Plasmodium falciparum infection in African children with microscopically undetectable parasitaemia

BackgroundSevere anaemia can develop in the aftermath of Plasmodium falciparum malaria because of protracted bone marrow suppression, possibly due to residual subpatent parasites.Materials and methodsBlood was collected from patients with recent malaria and negative malaria microscopy. Detection of the Plasmodium antigens, lactate dehydrogenase (Optimal®), aldolase and histidine rich protein 2 (Now malaria®) were used to differentiate between patients with (1) no malaria, (2) recent cleared malaria, (3) persistent P. falciparum infection. Red cell distribution width (RDW), plasma levels of soluble transferrin receptor (sTfR) and erythropoietin (EPO) were measured as markers of erythropoiesis. Interleukin (IL) 10 and tumour necrosis factor (TNF)α were used as inflammation markers.ResultsEPO was correlated with haemoglobin, irrespective of malaria (R = -0.36, P < 0.001). Persistent P. falciparum infection, but not recent malaria without residual parasites, was associated with bone marrow suppression i.e., low RDW (P < 0.001 vs. P = 0.56) and sTfR (P = 0.02 vs. P = 0.36). TNF-α and IL-10 levels were not associated with bone marrow suppression.ConclusionIn the treatment of malaria, complete eradication of parasites may prevent subsequent development of anaemia. Severely anaemic children may benefit from antimalarial treatment if antigen tests are positive, even when no parasites can be demonstrated by microscopy.

Late presenters, repeated testing, and missed opportunities in a Danish nationwide HIV cohort

Abstract Background: We aimed to estimate the incidence and predictors of late presentation among human immunodeficiency virus (HIV)-infected individuals in Denmark. Methods: Incidence rates (IR) of presentation with advanced HIV (CD4 < 200 cells/μl and/or acquired immune deficiency syndrome (AIDS)) and late presentation (CD4 < 350 cells/μl and/or AIDS) were calculated per 100,000 population aged 16–60 y. Mortality rate ratios (MRR) were estimated using Poisson regression analysis. Results: Three thousand and twenty-seven individuals were diagnosed with HIV in 1995–2009; 34.7% presented with advanced HIV and 51.2% were late presenters. The IR of HIV was stable (6.2/100,000 population), but IR of presentation with advanced HIV declined during the study period from 2.2 (95% confidence interval (CI) 1.8–2.8) to 1.1 (95% CI 0.8–1.5). Age >50 y, heterosexuals of non-Danish origin, ‘other’ route of transmission, and diagnosis before 2002 were associated with an increased risk of presenting with advanced HIV, whereas a negative HIV test prior to diagnosis was associated with a significantly reduced risk. A total of 414 individuals (40.0%) had attended a hospital 1–3 y before presenting with advanced HIV. After 2002 the proportion of men who have sex with men with a negative HIV test prior to diagnosis increased (incidence rate ratio (IRR) 1.3, 95% CI 1.1–1.6), coinciding with a reduction in IR of presentation with advanced HIV. Mortality rates were increased the first 2 y following presentation with advanced HIV (MRR 5.9, 95% CI 3.6–9.4 and MRR 2.5, 95% CI 1.4–4.1, respectively). Conclusion: In a setting with a low HIV prevalence, the rate of presentation with advanced HIV can potentially be reduced by repeated HIV testing of individuals with a continuous high risk of transmission and by adhering to guidelines for targeted HIV testing.

Course and Clinical Significance of CD8+ T-Cell Counts in a Large Cohort of HIV-Infected Individuals

OBJECTIVES To examine trajectories of CD8(+) T-cell counts before and after combination antiretroviral therapy (cART) in human immunodeficiency virus (HIV)-infected individuals and associations with mortality. METHODS CD8(+) T-cell counts were measured in 3882 HIV-infected individuals who received care in Copenhagen during 1995-2012. Reference values were obtained from 1230 persons from the background population. Mortality rate ratios were estimated by Poisson regression. RESULTS CD8(+) T-cell counts were elevated during untreated HIV infection and remained elevated through 10 years of cART. A slight drop of 130 cells/µL (interquartile range, -160 to 410 cells/μL) in the median CD8(+) T-cell count was observed after cART initiation. CD8(+) T-cell counts stabilized at approximately 900 cells/µL (95th percentile of the background population, 835 cells/µL). Markedly elevated CD8(+) T-cell counts at cART initiation were associated with a poor increase in the CD4(+) T-cell count (relative risk, 2.22; 95% confidence interval [CI], 1.42-3.48). Individuals with a CD8(+) T-cell count of <500 cells/µL 1 year after cART initiation had an increased mortality rate (mortality rate ratio, 1.73; 95% CI, 1.29-2.32) and a higher proportion of deaths attributable to AIDS-related conditions, compared with individuals with CD8(+) T-cell counts of ≥500 cells/µL. After receiving cART for 10 years, a CD8(+) T-cell count of >1500 cells/µL was associated with increased non-AIDS-related mortality (mortality rate ratio, 1.82; 95% CI, 1.09-3.22), compared with a CD4(+) T-cell count of 500-1500 cells/µL. CONCLUSIONS CD8(+) T-cell counts are elevated during HIV infection and do not normalize despite long-term cART. Low CD8(+) T-cell counts are associated with increased AIDS-related mortality. Marked elevations in CD8(+) T-cell counts after long-term cART are associated with increased non-AIDS-related mortality.

HIV care in the Swedish-Danish HIV cohort 1995-2010, closing the gaps.

Background Successful treatment reduces morbidity, mortality and transmission of HIV. We evaluated trends in the treatment status of HIV infected individuals enrolled in care in Sweden and Denmark during the years 1995-2010. Our aim was to assess the proportion of HIV-infected individuals who received services along the continuum of care in Denmark in 2010, and to discuss the findings in relation to the organization of the health care system. Methods We analyzed CD4 counts and viral loads (VL) among all HIV patients enrolled in the cohort. For each month of the study period we estimated the proportions of patients who 1) had initiated highly active antiretroviral treatment (HAART) and had VL<500 copies/mL, 2) were not eligible for HAART, 3) had initiated HAART but had VL≥500 copies/mL, 4) were eligible for, but had not initiated HAART and 5) had initiated HAART but no VL monitoring for >13 months or 6) no HAART or monitoring of CD4 for >13 months. Patients fulfilling criteria 1 or 2 were considered successfully managed. Results The proportion of successfully managed patients continued to increase throughout the study period and reached 83% in 2010, 92% of Swedish/Danish men who have sex with men and heterosexual patients, but only 74% of immigrants and 78% of injection drug users were successfully managed due to higher rates of inadequate monitoring in the latter two groups. In 2010, 70% of all individuals diagnosed with HIV in Denmark were virally suppressed. Conclusion In a public health care system with free access to specialized care, successful management of the majority of HIV patients is achievable. Interventions tailored to retain immigrants and injection drug users in care are needed to further reduce the proportion of sub-optimally treated HIV patients.

Retention in a public healthcare system with free access to treatment: a Danish nationwide HIV cohort study.

Objective:We aimed to assess retention of HIV-infected individuals in the Danish healthcare system over a 15-year period. Methods:Loss to follow-up (LTFU) was defined as 365 days without contact to the HIV care system. Data were obtained from the nationwide Danish HIV Cohort study, The Danish National Hospital Registry and The Danish Civil Registration System. Incidence rates, risk factors for LTFU and return to care and mortality rate ratios (MRRs) were estimated using Poisson regression analyses. Results:We included 4745 HIV patients who were followed for 36 692 person-years. Patients were retained in care 95.0% of person-years under observation, increasing to 98.1% after initiation of highly active antiretroviral treatment (HAART). The overall incidence rate/100 person-years for first episode of LTFU was 2.6 [95% confidence interval (CI) 2.5–2.8] and was significantly lower after initiation of HAART [1.2 (95% CI 1.0–1.3)]. Five years after LTFU the probability of return to care was 0.87 (95% CI 0.84–0.90). The risk of death was significantly increased after LTFU [MRR 1.9 (95% CI 1.6–2.6)] and 6 months or less after return to care [MRR 10.9 (95% CI 5.9–19.9)]. Conclusion:Retention in care of Danish HIV patients is high, especially after initiation of HAART. Absence from HIV care is associated with increased mortality. We conclude that high rates of retention can be achieved in a healthcare system with free access to treatment and is associated with a favorable outcome.

CD4 Decline Is Associated With Increased Risk of Cardiovascular Disease, Cancer, and Death in Virally Suppressed Patients With HIV

BACKGROUND The clinical implications of a considerable CD4 decline despite antiretroviral treatment and viral suppression are unknown. We aimed to test the hypothesis that a major CD4 decline could be a marker of cardiovascular disease or undiagnosed cancer. METHODS Patients with human immunodeficiency virus (HIV) were followed in the Danish nationwide, population-based cohort study in the period 1995-2010 with quarterly CD4 measurements. Associations between a CD4 decline of ≥30% and cardiovascular disease, cancer, and death were analyzed using Poisson regression with date of CD4 decline as a time-updated variable. RESULTS We followed 2584 virally suppressed HIV patients for 13 369 person-years (PY; median observation time, 4.7 years). Fifty-six patients developed CD4 decline (incidence rate, 4.2/1000 PY [95% confidence interval {CI}, 3.2-5.4]). CD4 counts dropped from a median of 492 cells/µL to 240 cells/µL. CD8, CD3, and total lymphocyte counts dropped concomitantly. No HIV-related factors, apart from treatment with didanosine, were associated with CD4 decline. The risk of cardiovascular disease, cancer, and death increased markedly ≤6 months after CD4 decline (incidence rate ratio, 11.7 [95% CI, 3.6-37.4] and 13.7 [95% CI, 4.3-43.6], respectively, and mortality rate ratio 4.3 [95% CI, 1.1-17.6]). CONCLUSION A major decline in CD4 count is associated with a marked increased risk of cardiovascular disease, cancer, and death among virally suppressed HIV patients.