Frederik Neess Engsig

Incidence, Clinical Presentation, and Outcome of Progressive Multifocal Leukoencephalopathy in HIV-Infected Patients during the Highly Active Antiretroviral Therapy Era: A Nationwide Cohort Study

BACKGROUND Human immunodeficiency virus (HIV) infection predisposes to progressive multifocal leukoencephalopathy (PML). Here, we describe the incidence, presentation, and prognosis of PML in HIV-1-infected patients during the period before highly active antiretroviral therapy (HAART) (1995-1996) and during the early HAART (1997-1999) and late HAART (2000-2006) periods. METHODS Patients from a nationwide population-based cohort of adult HIV-1-infected individuals were included. We calculated incidence rates of PML and median survival times after diagnosis. We also described neurological symptoms at presentation and follow-up. RESULTS Among 4,649 patients, we identified 47 patients with PML. The incidence rates were 3.3, 1.8, and 1.3 cases per 1000 person-years at risk in 1995-1996, 1997-1999, and 2000-2006, respectively. The risk of PML was significantly associated with low CD4(+) cell count, and 47% of cases were diagnosed by means of brain biopsy or polymerase chain reaction analysis for JC virus. The predominant neurological symptoms at presentation were coordination disturbance, cognitive defects, and limb paresis. Thirty-five patients died; the median survival time was 0.4 years (95% confidence interval [CI], 0.0-0.7) in 1995-1996 and 1.8 years (95% CI, 0.6-3.0) in both 1997-1999 and 2000-2006. CD4(+) cell count >50 cells/microL at diagnosis of PML was significantly associated with reduced mortality. CONCLUSIONS The incidence of PML in HIV-infected patients decreased after the introduction of HAART. Survival after PML remains poor. In the management of PML, the main focus should be on prophylactic measures to avoid immunodeficiency.

Relationship Between Current Level of Immunodeficiency and Non-acquired Immunodeficiency Syndrome-Defining Malignancies

In the combined antiretroviral therapy (cART) era, non–acquired immunodeficiency syndrome (AIDS)‐defining malignancies account for more morbidity and mortality in human immunodeficiency virus‐infected patients than AIDS‐defining malignancies. However, conflicting data have been reported on the relationship between immunodeficiency and the development of some non–AIDS‐defining malignancies.

Risk of cerebrovascular events in persons with and without HIV: a Danish nationwide population-based cohort study.

Objective:To assess the risk of cerebrovascular events (CVEs) in HIV-infected individuals and evaluate the impact of proven risk factors, injection drug abuse (IDU), immunodeficiency, HAART and family-related risk factors. Design:Nationwide, population-based cohort study. Methods:The study population included all Danish HIV-infected individuals, a population-based comparison cohort and parents of both cohorts – all with no prior cerebral comorbidity. We computed incidence rate ratios (IRRs) of overall CVEs and CVEs with and without proven risk factors, stratifying the analyses on IDU. Impact of immunodeficiency, HAART, protease inhibitors, indinavir, didanosin, tenofovir and abacavir on risk of CVEs was analyzed using time-dependent Cox regression analyses. Results:HIV-infected individuals had an increased risk of CVEs compared with the comparison cohorts [(non-IDU HIV adjusted IRR 1.60; 95% confidence interval [CI] 1.32–1.94), (IDU HIV adjusted IRR 3.94; 95% CI 2.16–7.16)]. The risk was increased with and without proven risk factors. A CD4 cell count of 200 cells/&mgr;l or less before the start of HAART and exposure to abacavir increased the risk of CVE [(adjusted IRR 2.26; 95% CI 1.05–4.86) and (adjusted IRR 1.66; 95% CI 1.03–2.68)]. Protease inhibitors, indinavir, didanosin, tenofovir and HAART in general had no impact. Risk of CVEs was only increased in the parents of IDU HIV-infected individuals. Conclusion:HIV-infected individuals have an increased risk of CVEs with and without proven risk factors. The risk is associated with IDU, low CD4 cell count and exposure to abacavir, but not with HAART. An association with family-related risk factors seems vague except for parents of IDU individuals.

Incidence and Impact on Mortality of Severe Neurocognitive Disorders in Persons With and Without HIV Infection: A Danish Nationwide Cohort Study

OBJECTIVE The risk of neurocognitive disorders in human immunodeficiency virus (HIV)-infected patients in the era of highly active antiretroviral therapy (HAART) is controversial. We aimed to compare the incidence and impact on mortality of severe neurocognitive disorders (SNCDs) in HIV-infected patients with that of the background population. METHODS The method used was a nationwide, population-based cohort study using Danish registries. We calculated incidence rates, incidence rate ratios, mortality rate ratios, and Kaplan-Meier tables to estimate the incidence of and survival after SNCD in HIV-infected patients, compared with a general population control cohort matched by age and sex. RESULTS We observed 32 cases of SNCDs among 4452 HIV-infected patients and 120 cases of SNCDs among 62 328 population control subjects. The overall risk of SNCD among HIV-infected patients was 1.0 case per 1000 person-years (PYR), compared with 0.23 cases per 1000 PYR for population control subjects but became 0.35 cases/1000 PYR after 2004, compared with 0.27 cases/1000 PYR in population control subjects. The absence of HAART and a low CD4 lymphocyte count increased the risk of SNCD. The mortality among HIV-infected patients with SNCD was higher than that among population controls with SNCD (median survival, 4.3 years vs 9.7 years [P = .02]). CONCLUSION HIV-infected patients have an increased risk of SNCD, but the risk is low and has, in recent years, become comparable to that seen in the background population. In contrast, the mortality remains high among HIV-infected patients diagnosed with SNCD.

Impact of hepatitis B virus co‐infection on response to highly active antiretroviral treatment and outcome in HIV‐infected individuals: a nationwide cohort study

The impact of chronic hepatitis B virus (HBV) infection on viral suppression, immune recovery and mortality in HIV‐1 infected patients on highly active antiretroviral treatment (HAART) is a matter of debate. The impact of HBeAg status is unknown.

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.

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.

Lung cancer in HIV patients and their parents: A Danish cohort study

BackgroundHIV patients are known to be at increased risk of lung cancer but the risk factors behind this are unclear.MethodsWe estimated the cumulative incidence and relative risk of lung cancer in 1) a population of all Danish HIV patients identified from the Danish HIV Cohort Study (n = 5,053) and a cohort of population controls matched on age and gender (n = 50,530) (study period; 1995 - 2009) and 2) their parents (study period; 1969 - 2009). Mortality and relative risk of death after a diagnosis of lung cancer was estimated in both populations.Results29 (0.6%) HIV patients vs. 183 (0.4%) population controls were diagnosed with lung cancer in the observation period. HIV patients had an increased risk of lung cancer (adjusted incidence rate ratio (IRR); 2.38 (95% CI; 1.61 - 3.53)). The IRR was considerably increased in HIV patients who were smokers or former smokers (adjusted IRR; 4.06 (95% CI; 2.66 - 6.21)), male HIV patients with heterosexual route of infection (adjusted IRR; 4.19 (2.20 - 7.96)) and HIV patients with immunosuppression (adjusted IRR; 3.25 (2.01 - 5.24)). Both fathers and mothers of HIV patients had an increased risk of lung cancer (adjusted IRR for fathers; 1.31 (95% CI: 1.09 - 1.58), adjusted IRR for mothers 1.35 (95% CI: 1.07 - 1.70)). Mortality after lung cancer diagnose was increased in HIV patients (adjusted mortality rate ratio 2.33 (95%CI; 1.51 - 3.61), but not in the parents. All HIV patients diagnosed with lung cancer were smokers or former smokers.ConclusionThe risk was especially increased in HIV patients who were smokers or former smokers, heterosexually infected men or immunosuppressed. HIV appears to be a marker of behavioural or family related risk factors that affect the incidence of lung cancer in HIV patients.

Incidence, risk factors and mortality of tuberculosis in Danish HIV patients 1995-2007

BackgroundHuman Immunodeficiency Virus (HIV) infection predisposes to tuberculosis (TB). We described incidence, risk factors and prognosis of TB in HIV-1 infected patients during pre (1995-1996), early (1997-1999), and late Highly Active Antiretroviral Therapy (HAART) (2000-2007) periods.MethodsWe included patients from a population-based, multicenter, nationwide cohort. We calculated incidence rates (IRs) and mortality rates (MRs). Coxs regression analysis was used to estimate risk factors for TB infection with HAART initiation included as time updated variable. Kaplan-Meier was used to estimate mortality after TB.ResultsAmong 2,668 patients identified, 120 patients developed TB during the follow-up period. The overall IR was 8.2 cases of TB/1,000 person-years of follow-up (PYR). IRs decreased during the pre-, early and late-HAART periods (37.1/1000 PYR, 12.9/1000 PYR and 6.5/1000 PYR respectively). African and Asian origin, low CD4 cell count and heterosexual and injection drug user route of HIV transmission were risk factors for TB and start of HAART reduced the risk substantially. The overall MR in TB patients was 34.4 deaths per 1,000 PYR (95% Confidence Interval: 22.0-54.0) and was highest in the first two years after the diagnosis of TB.ConclusionsIncidence of TB still associated with conventional risk factors as country of birth, low CD4 count and route of HIV infection while HAART reduces the risk substantially. The mortality in this patient population is high in the first two years after TB diagnosis.

Renal function and incidence of chronic kidney disease in HIV patients: A Danish cohort study

Abstract Background: Impaired renal function is of major concern in human immunodeficiency virus (HIV)-infected patients. Methods: We used a mixed effects linear regression model to determine estimated glomerular filtration rates (eGFRs) in a population-based cohort of incident Danish HIV patients and stratified on baseline eGFR (eGFRB) < 90 and ≥ 90 ml/min per 1.73 m2. Incidence rate ratios (IRRs) for chronic kidney disease (CKD) – 2 consecutive eGFR values < 60 ml/min per 1.73 m2 measured > 3 months apart – were estimated (time-updated Cox-regression model). Results: The effect of time with HIV on eGFR was small in both strata (− 0.09 (95% confidence interval (CI) − 0.27, 0.09) and − 0.46 (95% CI − 0.64, − 0.27) ml/min per 1.73 m2 per y). Treatment with tenofovir and indinavir was associated with lower eGFR in both strata: tenofovir − 2.00 (95% CI − 3.45, − 0.56) and − 1.94 (95% CI − 3.43, − 0.44) ml/min per 1.73 m2 and indinavir − 2.14 (95% CI − 3.63, − 0.64) and − 3.29 (95% CI − 5.25, − 1.32) ml/min per 1.73 m2. Nevirapine, atazanavir, and the combination of tenofovir and atazanavir were associated with lower eGFR in patients with eGFRB < 90 ml/min per 1.73 m2. Highly active antiretroviral therapy (HAART) and exposure to tenofovir and atazanavir in combination were associated with CKD in patients with eGFRB < 90 ml/min per 1.73 m2 (adjusted IRRs 6.08 (95% CI 2.76–13.41) and 26.75 (95% CI 9.54–75.05)). Conclusion: Tenofovir and indinavir reduce eGFR, while time with HIV only has a modest effect on this parameter. Low eGFRB is associated with an increased risk of CKD, especially when receiving HAART regimens containing the combination tenofovir/atazanavir.