Justyna D. Kowalska

Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration

BACKGROUND With the advent of effective antiretroviral treatment, the life expectancy for people with HIV is now approaching that seen in the general population. Consequently, the relative importance of other traditionally non-AIDS-related morbidities has increased. We investigated trends over time in all-cause mortality and for specific causes of death in people with HIV from 1999 to 2011. METHODS Individuals from the Data collection on Adverse events of anti-HIV Drugs (D:A:D) study were followed up from March, 1999, until death, loss to follow-up, or Feb 1, 2011, whichever occurred first. The D:A:D study is a collaboration of 11 cohort studies following HIV-1-positive individuals receiving care at 212 clinics in Europe, USA, and Australia. All fatal events were centrally validated at the D:A:D coordinating centre using coding causes of death in HIV (CoDe) methodology. We calculated relative rates using Poisson regression. FINDINGS 3909 of the 49,731 D:A:D study participants died during the 308,719 person-years of follow-up (crude incidence mortality rate, 12.7 per 1000 person-years [95% CI 12.3-13.1]). Leading underlying causes were: AIDS-related (1123 [29%] deaths), non-AIDS-defining cancers (590 [15%] deaths), liver disease (515 [13%] deaths), and cardiovascular disease (436 [11%] deaths). Rates of all-cause death per 1000 person-years decreased from 17.5 in 1999-2000 to 9.1 in 2009-11; we saw similar decreases in death rates per 1000 person-years over the same period for AIDS-related deaths (5.9 to 2.0), deaths from liver disease (2.7 to 0.9), and cardiovascular disease deaths (1.8 to 0.9). However, non-AIDS cancers increased slightly from 1.6 per 1000 person-years in 1999-2000 to 2.1 in 2009-11 (p=0.58). After adjustment for factors that changed over time, including CD4 cell count, we detected no decreases in AIDS-related death rates (relative rate for 2009-11 vs 1999-2000: 0.92 [0.70-1.22]). However, all-cause (0.72 [0.61-0.83]), liver disease (0.48 [0.32-0.74]), and cardiovascular disease (0.33 [0.20-0.53) death rates still decreased over time. The percentage of all deaths that were AIDS-related (87/256 [34%] in 1999-2000 and 141/627 [22%] in 2009-11) and liver-related (40/256 [16%] in 1999-2000 and 64/627 [10%] in 2009-11) decreased over time, whereas non-AIDS cancers increased (24/256 [9%] in 1999-2000 to 142/627 [23%] in 2009-11). INTERPRETATION Recent reductions in rates of AIDS-related deaths are linked with continued improvement in CD4 cell count. We hypothesise that the substantially reduced rates of liver disease and cardiovascular disease deaths over time could be explained by improved use of non-HIV-specific preventive interventions. Non-AIDS cancer is now the leading non-AIDS cause and without any evidence of improvement. FUNDING Oversight Committee for the Evaluation of Metabolic Complications of HAART, with representatives from academia, patient community, US Food and Drug Administration, European Medicines Agency and consortium of AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, ViiV Healthcare, Merck, Pfizer, F Hoffmann-La Roche, and Janssen Pharmaceuticals.

Serious Fatal and Nonfatal Non-AIDS-Defining Illnesses in Europe

Background:Little is known about the incidence and risk factors for serious non-AIDS-defining events. Methods:The incidence of non-AIDS events (malignancies, end-stage renal disease, liver failure, pancreatitis, cardiovascular disease), and AIDS after January 1, 2001, was calculated; Poisson regression was used to investigate factors associated with non-AIDS and AIDS. Results:Among 12,844 patients, 1058 were diagnosed with a non-AIDS event [incidence 1.77 per 100 person-years of follow-up; 95% confidence interval (CI): 1.66 to 1.87]; 462 patients (43.7%) died. The incidence of AIDS (1025 diagnoses; 339 deaths, 33.1%) was 1.72 per 100 person-years of follow-up (1.61 to 1.83). After adjustment, older age [incidence rate ratio (IRR): 1.71 per 10 years older, 95% CI: 1.60 to 1.83], diabetes (IRR: 1.49, 95% CI: 1.22 to 1.82) and hypertension (IRR: 1.63, 95% CI: 1.43 to 1.87) were associated with non-AIDS events. Compared with patients without an event, there was a 4-fold increased risk of death after an AIDS event (relative hazard: 4.14; 95% CI 3.47 to 4.94) and almost a 7-fold increased risk of death after a non-AIDS event (relative hazard: 6.72; 95% CI: 5.61 to 8.05). Conclusions:Non-AIDS events were common in the combination antiretroviral therapy era and associated with considerably mortality. Evidence on the impact of modifying immunodeficiency and lifestyle-related factors on the risk of non-AIDS events in HIV-infected persons is an important but unmet research need.

Risk of all-cause mortality associated with nonfatal AIDS and serious non-AIDS events among adults infected with HIV.

Objectives:Among patients with HIV, the risk of death associated with different AIDS events has been quantified, but the risk of death associated with non-AIDS events has not been examined. We compared the risk of all-cause mortality following AIDS versus serious non-AIDS (SNA) events in the Strategies for Management of Antiretroviral Therapy (SMART) study and the Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT). Design:Data from 9583 HIV-infected participants, 5472 with a CD4+ cell count more than 350 cells/μl enrolled in SMART and 4111 with a CD4+ cell count 300 cells/μl or more enrolled in ESPRIT, were analyzed. Methods:Cumulative mortality 6 months after AIDS and SNA events (cardiovascular, renal, hepatic disease, and malignancies) was estimated using the Kaplan–Meier method. Cox models were used to estimate hazard ratios associated with AIDS and SNA events on the risk of death overall and by treatment group within study. Results:AIDS and SNA events occurred in 286 and 435 participants with 47 (16%) and 115 (26%) subsequent deaths, respectively. Six-month cumulative mortality was 4.7% [95% confidence interval (CI) 2.8–8.0] after experiencing an AIDS event and 13.4% (95% CI 10.5–17.0) after experiencing an SNA event. The adjusted hazard ratio for all-cause mortality for those who experienced AIDS versus those who did not was 4.9 (95% CI 3.6–6.8). The corresponding hazard ratio for SNA was 11.4 (95% CI 9.0–14.5) (P < 0.001 for difference in hazard ratios). Findings were similar for both treatment groups in SMART and both treatment groups in ESPRIT. Conclusion:Among HIV-infected persons with higher CD4+ cell counts, SNA events occur more frequently and are associated with a greater risk of death than AIDS events. Future research should be aimed at comparing strategies to reduce morbidity and mortality associated with SNA events for HIV-infected persons.

The Coding Causes of Death in HIV (CoDe) project: initial results and evaluation of methodology

Background: The Coding Causes of Death in HIV (CoDe) Project aims to deliver a standardized method for coding the underlying cause of death in HIV-positive persons, suitable for clinical trials and epidemiologic studies. Methods: The project incorporates detailed data collection, a classification system, and a centralized adjudication process performed by 2 independent reviewers. The methodology was tested in the Data Collection on Adverse events of Anti-HIV Drugs Study, and independent reviews of causes of death were compared. Logistic regression models identified factors associated with initial agreement by reviewers on underlying cause of death. Results: A total of 491 reported fatal cases were adjudicated; in only 5% of cases the cause of death remained undetermined after adjudication. Reviewers initially agreed on the underlying cause for 339 (69%) deaths. As compared with deaths due to AIDS-related causes, the odds of agreement were more than 80% lower when deaths were ultimately deemed to be due to non-AIDS-related causes (odds ratio = 0.17 [95% confidence interval = 0.08–0.37]) or undetermined causes (0.11 [0.04–0.36]). The odds of initial agreement were also lower for deaths occurring in subjects with hypertension (0.43 [0.22–0.85]) and depression (0.43 [0.23–0.80]). Conclusions: The extent and format of data collected in the CoDe Project appear to be sufficient for an informed review, and the proposed coding scheme is adequate for obtaining an underlying cause of death.

Fatal and nonfatal Aids and non-aids events in Hiv-1-positive individuals with high Cd4 cell counts according to viral load strata

Background:This study compared the incidence of fatal and nonfatal AIDS and non-AIDS events in HIV-positive individuals with a CD4 cell count more than 350 cells/&mgr;l among viral load strata: low (<500 copies/ml), intermediate (500–9999.9 copies/ml) and high (≥10000 copies/ml). Methods:Individuals contributed person-years at risk if their most recent CD4 cell count was more than 350 cells/&mgr;l. Follow-up was censored if their CD4 cell count dropped below 350 cells/&mgr;l. Poisson regression analysis investigated the relationship between viraemia and the incidence of AIDS and non-AIDS events. Results:Three hundred and fifty-four AIDS events occurred during 51 732 person-years of follow-up (PYFU), crude incidence rate of AIDS across the three strata was 0.53, 0.90 and 2.12 per 100 PYFU, respectively. After adjustment, a higher rate of AIDS was observed in individuals with moderate [incidence rate ratio (IRR) 1.44, 1.02–2.05, P = 0.03] and high viraemia had a higher rate (IRR 3.91, 2.89–5.89, P < 0.0001) compared with low viraemia. Five hundred and seventy-two non-AIDS events occurred during 43 784 PYFU, the crude incidence rates were 1.28, 1.52, and 1.38 per 100 PYFU, respectively. After adjustment, particularly for age, region of Europe and starting combination antiretroviral therapy, there was a 61% (IRR 1.61, 1.21–2.14, P = 0.001) and 66% (IRR 1.66, 1.17–2.32, P = 0.004) higher rate of non-AIDS in individuals with intermediate and high viraemia compared with low viraemia. Conclusion:In individuals with a CD4 cell count more than 350 cells/&mgr;l, an increased incidence of AIDS and a slightly increased incidence of non-AIDS was found in those with uncontrolled viral replication. The association with AIDS was clear and consistent. However, the association with non-AIDS was only apparent after adjustment and no differences were observed between intermediate and high viraemia.

A standardized algorithm for determining the underlying cause of death in HIV infection as AIDS or non-AIDS related: results from the EuroSIDA study.

Abstract Objectives: Analyzing changes in causes of death over time is essential for understanding the emerging trends in HIV population mortality, yet data on cause of death are often missing. This poses analytic limitations, as does the changing approach in data collection by longitudinal studies, which are a natural consequence of an increased awareness and knowledge in the field. To monitor and analyze changes in mortality over time, we have explored this issue within the EuroSIDA study and propose a standardized protocol unifying data collected and allowing for classification of all deaths as AIDS or non-AIDS related, including events with missing cause of death. Methods: Several classifications of the underlying cause of death as AIDS or non-AIDS related within the EuroSIDA study were compared: central classification (CC-reference group) based on an externally standardised method (the CoDe procedures), local cohort classification (LCC) as reported by the site investigator, and 4 algorithms (ALG) created based on survival times after specific AIDS events. Results: A total of 2,783 deaths occurred, 540 CoDe forms were collected, and 488 were used to evaluate agreements. The agreement between CC and LCC was substantial (κ = 0.7) and the agreement between CC and ALG was moderate (κ < 0.6). Consequently, a stepwise algorithm was derived prioritizing CC over LCC and, in patients with no information available, best-fit ALG. Using this algorithm, 1,332 (47.9%) deaths were classified as AIDS and 1,451 (52.1%) as non-AIDS related. Conclusions: Our proposed stepwise algorithm for classifying deaths provides a valuable tool for future research, however validation in another setting is warranted.

Regional differences in AIDS and non-AIDS related mortality in HIV-positive individuals across Europe and Argentina: the EuroSIDA study

Background Differences in access to care and treatment have been reported in Eastern Europe, a region with one of the fastest growing HIV epidemics, compared to the rest of Europe. This analysis aimed to establish whether there are regional differences in the mortality rate of HIV-positive individuals across Europe, and Argentina. Methods 13,310 individuals under follow-up were included in the analysis. Poisson regression investigated factors associated with the risk of death. Findings During 82,212 person years of follow-up (PYFU) 1,147 individuals died (mortality rate 14.0 per 1,000 PYFU (95% confidence interval [CI] 13.1–14.8). Significant differences between regions were seen in the rate of all-cause, AIDS and non-AIDS related mortality (global p<0.0001 for all three endpoints). Compared to South Europe, after adjusting for baseline demographics, laboratory measurements and treatment, a higher rate of AIDS related mortality was observed in East Europe (IRR 2.90, 95%CI 1.97–4.28, p<.0001), and a higher rate of non-AIDS related mortality in North Europe (IRR 1.51, 95%CI 1.24–1.82, p<.0001). The differences observed in North Europe decreased over calendar-time, in 2009–2011, the higher rate of non-AIDS related mortality was no longer significantly different to South Europe (IRR 1.07, 95%CI 0.66–1.75, p = 0.77). However, in 2009–2011, there remained a higher rate of AIDS-related mortality (IRR 2.41, 95%CI 1.11–5.25, p = 0.02) in East Europe compared to South Europe in adjusted analysis. Interpretations There are significant differences in the rate of all-cause mortality among HIV-positive individuals across different regions of Europe and Argentina. Individuals in Eastern Europe had an increased risk of mortality from AIDS related causes and individuals in North Europe had the highest rate of non-AIDS related mortality. These findings are important for understanding and reviewing HIV treatment strategies and policies across the European region.

Long-term exposure to combination antiretroviral therapy and risk of death from specific causes: no evidence for any previously unidentified increased risk due to antiretroviral therapy

Background:Despite the known substantial benefits of combination antiretroviral therapy (cART), cumulative adverse effects could still limit the overall long-term treatment benefit. Therefore we investigated changes in the rate of death with increasing exposure to cART. Methods:A total of 12 069 patients were followed from baseline, which was defined as the time of starting cART or enrolment into EuroSIDA whichever occurred later, until death or 6 months after last follow-up visit. Incidence rates of death were calculated per 1000 person-years of follow-up (PYFU) and stratified by time of exposure to cART (≥3 antiretrovirals): less than 2, 2–3.99, 4–5.99, 6–7.99 and more than 8 years. Duration of cART exposure was the cumulative time actually receiving cART. Poisson regression models were fitted for each cause of death separately. Results:A total of 1297 patients died during 70 613 PYFU [incidence rate 18.3 per 1000 PYFU, 95% confidence interval (CI) 17.4–19.4], 413 due to AIDS (5.85, 95% CI 5.28–6.41) and 884 due to non-AIDS-related cause (12.5, 95% CI 11.7–13.3). After adjustment for confounding variables, including baseline CD4 cell count and HIV RNA, there was a significant decrease in the rate of all-cause and AIDS-related death between 2 and 3.99 years and longer exposure time. In the first 2 years on cART the risk of non-AIDS death was significantly lower, but no significant difference in the rate of non-AIDS-related deaths between 2 and 3.99 years and longer exposure to cART was observed. Conclusion:In conclusion, we found no evidence of an increased risk of both all-cause and non-AIDS-related deaths with long-term cumulative cART exposure.

Implementing the number needed to harm in clinical practice: risk of myocardial infarction in HIV-1-infected patients treated with abacavir

The D:A:D study group reported a 1.9‐fold increased relative risk (RR) of myocardial infarction (MI) associated with current or recent use of abacavir. The number needed to harm (NNH) incorporates information about the underlying risk of MI and the increased RR of MI in patients taking abacavir.

Euroguidelines in Central and Eastern Europe (ECEE) conference and the Warsaw Declaration - a comprehensive meeting report.

The objective of this paper is to summarize the outcomes of the Euroguidelines in Central and Eastern Europe (ECEE) conference held in Warsaw in February 2016. The main aim of this conference was to facilitate a discussion on European AIDS Clinical Society (EACS) guidelines implementation across the region and neighbouring countries and to present the current obstacles in benchmarking HIV care in Europe.