Joanne Reekie

Vitamin D and clinical disease progression in HIV infection: results from the EuroSIDA study

Background:We examined the association between vitamin D [25(OH)D] level and disease progression in HIV infection. Methods:Within the EuroSIDA study, 2000 persons were randomly selected for 25(OH)D measurement in stored plasma samples closest to study entry. 25(OH)D results were stratified into tertiles. Factors associated with 25(OH)D levels and associations of 25(OH) levels with subsequent risk of all-cause mortality, AIDS and non-AIDS events were analyzed. Results:Of 1985 persons with 25(OH)D levels available, 23.7% had 25(OH)D below 10, 65.3% between 10 and 30, and 11% above 30 ng/ml. At the time of 25(OH)D measurement, older persons, persons of black ethnic origin, living outside Southern Europe/Argentina, sampled during winter, and infected with HIV through nonhomosexual exposure were at higher odds of having low 25(OH)D levels, whereas persons receiving protease inhibitors were at lower odds. Compared to those in the lowest 25(OH)D tertile (<12 ng/ml), those in the middle (12–20) and higher (>20) tertiles had a significantly lower risk of clinical progression during subsequent follow-up. Adjusted incidence rate ratios for all-cause mortality were 0.68 (95% CI 0.47–0.99, P = 0.045) and 0.56 (95% CI 0.37–0.83, P = 0.0039), and for AIDS events were 0.58 (95% CI 0.39–0.87, P = 0.0086) and 0.61 (95% CI 0.40–0.93, P = 0.020), for the middle and higher tertiles, respectively. There was a similar, nonsignificant reduced incidence of non-AIDS events in the middle and higher tertiles. Conclusion:25(OH)D deficiency was frequent in HIV-infected persons (83% on combined antiretroviral therapy), and was independently associated with a higher risk of mortality and AIDS events. Causality relationships should be examined, because of potential public health consequences.

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.

Feasibility and Effectiveness of Indicator Condition-Guided Testing for HIV: Results from HIDES I (HIV Indicator Diseases across Europe Study)

Improved methods for targeting HIV testing among patients most likely to be infected are required; HIDES I aimed to define the methodology of a European wide study of HIV prevalence in individuals presenting with one of eight indicator conditions/diseases (ID); sexually transmitted infection, lymphoma, cervical or anal cancer/dysplasia, herpes zoster, hepatitis B/C, mononucleosis-like illness, unexplained leukocytopenia/thrombocytopenia and seborrheic dermatitis/exanthema, and to identify those with an HIV prevalence of >0.1%, a level determined to be cost effective. A staff questionnaire was performed. From October 2009– February 2011, individuals, not known to be HIV positive, presenting with one of the ID were offered an HIV test; additional information was collected on previous HIV testing behaviour and recent medical history. A total of 3588 individuals from 16 centres were included. Sixty-six tested positive for HIV, giving an HIV prevalence of 1.8% [95% CI: 1.42–2.34]; all eight ID exceeded 0.1% prevalence. Of those testing HIV positive, 83% were male, 58% identified as MSM and 9% were injecting drug users. Twenty percent reported previously having potentially HIV-related symptoms and 52% had previously tested HIV negative (median time since last test: 1.58 years); which together with the median CD4 count at diagnosis (400 cell/uL) adds weight to this strategy being effective in diagnosing HIV at an earlier stage. A positive test was more likely for non-white individuals, MSM, injecting drug users and those testing in non-Northern regions. HIDES I describes an effective strategy to detect undiagnosed HIV infection. All eight ID fulfilled the >0.1% criterion for cost effectiveness. All individuals presenting to any health care setting with one of these ID should be strongly recommended an HIV test. A strategy is being developed in collaboration with ECDC and WHO Europe to guide the implementation of this novel public health initiative across Europe.

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.

Does less frequent routine monitoring of patients on a stable, fully suppressed cART regimen lead to an increased risk of treatment failure?

Objective: To investigate whether HIV-infected patients on a stable and fully suppressive combination antiretroviral therapy (cART) regimen could safely be monitored less often than the current recommendations of every 3 months. Design: Two thousand two hundred and forty patients from the EuroSIDA study who maintained a stable and fully suppressed cART regimen for 1 year were included in the analysis. Methods: Risk of treatment failure, defined by viral rebound, fall in CD4 cell count, development of new AIDS-defining illness, serious opportunistic infection or death, in the 12 months following a year of a stable and fully suppressed regimen was assessed. Results: One hundred thirty-one (6%) patients experienced treatment failure in the 12 months following a year of stable therapy, viral rebound occurred in 99 (4.6%) patients. After 3, 6 and 12 months, patients had a 0.3% [95% confidence interval (CI) 0.1–0.5], 2.2% (95% CI 1.6–2.8) and 6.0% (95% CI 5.0–7.0) risk of treatment failure, respectively. Patients who spent more than 80% of their time on cART with fully suppressed viraemia prior to baseline had a 38% reduced risk of treatment failure, hazard ratio 0.62 (95% CI 0.42–0.90, P = 0.01). Conclusion: Patients who have responded well to cART and are on a well tolerated and durably fully suppressive cART regimen have a low chance of experiencing treatment failure in the next 3–6 months. Therefore, in this subgroup of otherwise healthy patients, it maybe reasonable to extend visit intervals to 6 months, with cost and time savings to both the treating clinics and the patients.

Prognostic value of vitamin D level for all-cause mortality, and association with inflammatory markers, in HIV-infected persons

BACKGROUND Low 25-hydroxyvitamin D (25(OH)D) has been associated with inflammation, human immunodeficiency virus (HIV) disease progression, and death. We aimed to identify the prognostic value of 25(OH)D for AIDS, non-AIDS-defining events and death, and its association with immunological/inflammatory markers. METHODS Prospective 1-1 case-control study nested within the EuroSIDA cohort. Matched cases and controls for AIDS (n = 50 matched pairs), non-AIDS-defining (n = 63) events and death (n = 41), with plasma samples during follow-up were selected. Conditional logistic regression models investigated associations between 25(OH)D levels and annual 25(OH)D change and the probability of events. Mixed models investigated relationships between 25(OH)D levels and immunological/inflammatory markers. RESULTS In sum, 250 patients were included. Median time between first and last sample and last sample and event was 44.6(interquartile range [IQR]: 22.7-72.3) and 3.1(IQR: 1.4-6.4) months. Odds of death decreased by 46.0%(95% confidence interval [CI], 2.0-70.0, P = .04) for a 2-fold increase in latest 25(OH)D level. There was no association between 25(OH)D and the occurrence of AIDS or non-AIDS-defining events (P > .05). In patients with current 25(OH)D <10 ng/mL, hsIL-6 concentration increased by 4.7%(95% CI, .2,9.4, P = .04) annually after adjustment for immunological/inflammatory markers, and no change in hsCRP rate was observed (P = .76). CONCLUSIONS Low Vitamin D predicts short term mortality in HIV-positive persons. Effectiveness of vitamin D supplementation on inflammation and patient outcomes should be investigated.

Trends in prevalence of HIV infection, hepatitis B and hepatitis C among Australian prisoners - 2004, 2007, 2010

Objective: To report the prevalence of markers for HIV infection, hepatitis B and hepatitis C among Australian prison entrants.

Does traumatic brain injury lead to criminality? A whole-population retrospective cohort study using linked data

Background Traumatic brain injury (TBI) may be a risk factor for criminal behaviour however multiple factors potentially confound the association. Methods Record linkage and Cox proportional hazards regression analyses were used to examine the association between hospital-recorded TBI (n = 7,694) and subsequent first criminal conviction in a retrospective cohort matched 1:3 with 22,905 unaffected community controls and full-sibling controls (n = 2,397). Aboriginality, substance abuse, social disadvantage, and mental illness were included in analyses as potential confounders Results In multivariable models, relative to general population controls, TBI was associated with any conviction (males: Hazard Ratio (HR) = 1·58 (95% CI 1·46 to 1·72); females: HR = 1·52 (95% CI 1·28 to 1·81)); and similar Hazard Ratios were obtained for the sibling analyses in males (HR = 1.68 (95% CI 1.31-2.18)) and females (HR 1.27 (95% CI 0.71-2.29)). TBI was also associated with violent convictions relative to the general population, (males: HR = 1.65 (95% CI 1.42 to 1.92); females HR = 1.73 (95% CI 1.21 to 2.47)), and in analyses with sibling controls in men (HR = 1.89 (95% CI 1.20-3.00)), but not in women (HR 0.73, 95% CI 0.29-1.81)). Conclusion The results support a modest causal link between TBI and criminality after comprehensive adjustment for confounding. Reducing the rate of TBI, a major public health imperative, might have benefits in terms of crime reduction.

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.