Christian Pradier

Cardiovascular disease risk factors in HIV patients - association with antiretroviral therapy. Results from the DAD study

Objective: To determine the prevalence of risk factors for cardiovascular disease (CVD) among HIV-infected persons, and to investigate any association between such risk factors, stage of HIV disease, and use of antiretroviral therapies. Design: Baseline data from 17 852 subjects enrolled in DAD, a prospective multinational cohort study initiated in 1999. Methods: Cross-sectional analyses of CVD risk factors at baseline. The data collected includes data on demographic variables, cigarette smoking, diabetes mellitus, hypertension, dyslipidaemia, body mass index, stage of HIV infection, antiretroviral therapy. Results: Almost 25% of the study population were at an age where there is an appreciable risk of CVD, with those receiving a protease inhibitor (PI) and/or non-nucleoside reverse transcriptase inhibitor (NNRTI) tending to be older. 1.4% had a previous history of CVD and 51.5% were cigarette smokers. Increased prevalence of elevated total cholesterol (⩾ 6.2 mmol/l) was observed among subjects receiving an NNRTI but no PI [odds ratio (OR), 1.79; 95% confidence interval (CI), 1.45–2.22], PI but no NNRTI (OR, 2.35; 95% CI, 1.92–2.87), or NNRTI + PI (OR, 5.48; 95% CI, 4.34–6.91) compared to the prevalence among antiretroviral therapy (ART)-naive subjects. Subjects who have discontinued ART as well as subjects receiving nucleoside reverse transcriptase inhibitors had similar cholesterol levels to treatment-naive subjects. Higher CD4 cell count, lower plasma HIV RNA levels, clinical signs of lipodystrophy, longer exposure times to NNRTI and PI, and older age were all also associated with elevated total cholesterol level. Conclusion: HIV-infected persons exhibit multiple known risk factors for CVD. Of specific concern is the fact that use of the NNRTI and PI drug classes (alone and especially in combination), particularly among older subjects with normalized CD4 cell counts and suppressed HIV replication, was associated with a lipid profile known to increase the risk of coronary heart disease.

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.

Anaemia is an independent predictive marker for clinical prognosis in HIV-infected patients from across Europe

OBJECTIVES To describe changes in haemoglobin over time and to determine the joint prognostic value of the current haemoglobin, CD4 lymphocyte count and viral load among patients from across Europe. PATIENTS The analysis included 6725 patients from EuroSIDA, an observational, prospective cohort of patients with HIV from across Europe. METHODS Normal haemoglobin was defined as haemoglobin greater than 14 g/dl for men and 12 g/dl for women; mild anaemia was 8-14 g/dl for men and 8-12 g/dl for women; severe anaemia was defined as less than 8 g/dl for both males and females. Linear regression techniques were used to estimate the annual change in haemoglobin; standard survival techniques were used to describe disease progression and risk of death. RESULTS At recruitment to the study, 40.4% had normal levels of haemoglobin, 58.2% had mild anaemia and 1.4% had severe anaemia. At 12 months after recruitment, the proportion of patients estimated to have died was 3.1% [95% confidence interval (CI) 2.3-3.9] for patients without anaemia, 15.9% for patients with mild anaemia (95% CI 14.5-17.2) and 40.8% for patients with severe anaemia (95% CI 27.9-53.6; P < 0.0001). In a multivariate, time-updated Cox proportional hazards model, adjusted for demographic factors, AIDS status and each antiretroviral treatment as time-dependent covariates, a 1 g/dl decrease in the latest haemoglobin level increased the hazard of death by 57% [relative hazard (RH) 1.57; 95% CI 1.41-1.75; P < 0.0001], a 50% drop in the most recent CD4 lymphocyte count increased the hazard by 51% (RH 1.51; 95% CI 1.35-1.70; P < 0.0001) and a log increase in the latest viral load increased the hazard by 37% (RH 1.37; 95% CI 1.15-1.63; P = 0.0005). CONCLUSIONS Severe anaemia occurred infrequently among these patients but was associated with a much faster rate of disease progression. Among patients with similar CD4 lymphocyte counts and viral load, the latest value of haemoglobin was a strong independent prognostic marker for death.

The use of the Framingham equation to predict myocardial infarctions in HIV-infected patients: comparison with observed events in the D : A : D Study

The D:A:D (Data Collection on Adverse Events of Anti‐HIV Drugs) Study, a prospective observational study on a cohort of 23 468 patients with HIV infection, indicated that the incidence of myocardial infarction (MI) increased by 26% per year of exposure to combination antiretroviral treatment (CART). However, it remains unclear whether the observed increase in the rate of MI in this population can be attributed to changes in conventional cardiovascular risk factors.

DISCONTINUATION OF SECONDARY PROPHYLAXIS AGAINST PNEUMOCYSTIS CARINII PNEUMONIA IN PATIENTS WITH HIV INFECTION WHO HAVE A RESPONSE TO ANTIRETROVIRAL THERAPY

BACKGROUND Patients with human immunodeficiency virus (HIV) infection and a history of Pneumocystis carinii pneumonia are at high risk for relapse if they are not given secondary prophylaxis. Whether secondary prophylaxis against P. carinii pneumonia can be safely discontinued in patients who have a response to highly active antiretroviral therapy is not known. METHODS We analyzed episodes of recurrent P. carinii pneumonia in 325 HIV-infected patients (275 men and 50 women) in eight prospective European cohorts. Between October 1996 and January 2000, these patients discontinued secondary prophylaxis during treatment with at least three anti-HIV drugs after they had at least one peripheral-blood CD4 cell count of more than 200 cells per cubic millimeter. RESULTS Secondary prophylaxis was discontinued at a median CD4 cell count of 350 per cubic millimeter; the median nadir CD4 cell count had been 50 per cubic millimeter. The median duration of the increase in the CD4 cell count to more than 200 per cubic millimeter after discontinuation of secondary prophylaxis was 11 months. The median follow-up period after discontinuation of secondary prophylaxis was 13 months, yielding a total of 374 person-years of follow-up; for 355 of these person-years, CD4 cell counts remained at or above 200 per cubic millimeter. No cases of recurrent P. carinii pneumonia were diagnosed during this period; the incidence was thus 0 per 100 patient-years (99 percent confidence interval, 0 to 1.2 per 100 patient-years, on the basis of the entire follow-up period, and 0 to 1.3 per 100 patient-years, on the basis of the follow-up period during which CD4 cell counts remained at or above 200 per cubic millimeter). CONCLUSIONS It is safe to discontinue secondary prophylaxis against P. carinii pneumonia in patients with HIV infection who have an immunologic response to highly active antiretroviral therapy.

Rates of cardiovascular disease following smoking cessation in patients with HIV infection: results from the D:A:D study(*)

The aim of the study was to estimate the rates of cardiovascular disease (CVD) events after stopping smoking in patients with HIV infection.

Risk of invasive cervical cancer among women with, or at risk for, HIV infection.

Although invasive cervical cancer (ICC) has been included among the AIDS‐defining conditions since 1993, it remains controversial whether HIV infection increases the risk of developing such neoplasm. In this study, ICC risk was longitudinally investigated among 1,340 HIV‐positive intravenous drug user (IDU), 811 HIV‐negative IDU, and 801 HIV‐positive heterosexual women. These women, aged 15–49 years, were followed up at the Italian HIV Seroconverter Study, at the San Patrignano Community (Rimini, North Italy), and in South‐eastern France (the DMI‐2 study). The number of observed cases of ICC was compared with the expected one, based on ICC incidence rates among women of the same age in the general population of Italy or France, and standardized incidence ratios (SIR) were computed; 9,070 person‐years of observation were accumulated among HIV‐positive women and 2,310 among HIV‐negative ones. Ten cases of ICC were diagnosed among HIV‐positive women (SIR = 12.8): ICC risk was apparently higher among HIV‐positive IDU (SIR = 16.7) than among heterosexual women (SIR = 6.7). No cases of ICC were diagnosed among HIV‐negative IDU women admitted to the San Patrignano Community (0.15 cases were expected). Our findings confirm previous suggestions showing an increased risk of ICC among HIV‐infected women and have important implications at the individual and public health levels. Int. J. Cancer 82:334–337, 1999.

Impact of antiretroviral treatment on progression of hepatic fibrosis in HIV/hepatitis C virus co-infected patients.

Background: The impact of immune reconstitution on liver fibrosis in HIV/hepatitis C virus (HCV) patients is unknown. In this case–control study, we investigated the impact of HIV infection on the severity of liver fibrosis and identified related factors. Methods: We studied 116 HIV/HCV patients and 235 HCV only patients all untreated for HCV. Each co-infected patient was matched with two singly-infected patients according to gender, age at contamination and duration of infection. Liver biopsy was analysed using the METAVIR score. Results: Alcohol consumption and route of contamination differed between HCV-infected and HCV/HIV co-infected patients. Among co-infected patients, a F3–F4 Metavir score was significantly more frequent than in mono-infected patients. Co-infected patients with severe fibrosis (F3–F4) had higher transaminase, ferritin levels and lower CD4 T-cell count than patients with none to moderate fibrosis (F0–F2). Although median duration of treatment with nucleoside analogues, non-nucleoside analogues and protease inhibitors were comparable in both groups, the delay between the presumed date of contamination and treatment initiation with highly active antiretroviral therapy (HAART) was significantly longer for patients with severe fibrosis than those with none to moderate fibrosis. Finally, the mean rate of fibrosis progression was significantly slower among patients exposed to HAART. Conclusion: Early antiretroviral therapy in co-infected HIV-HCV patients may slow liver fibrosis progression.

HIV and Leishmania Coinfection: A Review of 91 Cases with Focus on Atypical Locations of Leishmania

A retrospective study was conducted in France in 1998 to determine the clinical features of visceral leishmaniasis (VL) in 91 patients infected cocomitantly with human immunodeficiency virus. Our data suggest that the clinical manifestations of VL may be influenced by the immunological status, with atypical locations of Leishmania amastigotes more frequently found in severely immunocompromised patients. In such patients, the involvement of atypical locations may lead to the discovery of VL.

Cancer risk among men with, or at risk of, HIV infection in southern Europe.

Objective:To evaluate the cancer risk in southern European men with, or at risk of, HIV infection. Design:An analysis of longitudinal data to assess time-dependent rare events. Methods:Data from a cohort of HIV seroconverters, and from two hospital-based HIV seroprevalent cohorts were combined and analysed. The number of cancer cases observed was compared with the expected number, obtained from cancer incidence rates among men in the general population. Age-standardized incidence ratios (SIR) and their 95% confidence intervals (CI) were computed. Results:A total of 19 609 person-years of observation were accumulated among HIV-positive men, and 7957 person-years among HIV-negative men. Among HIV-positive men, statistically significant increased SIR were seen for Hodgkins disease (HD) (SIR = 8.7), liver cancer (SIR = 11.0), and cancer of the salivary glands (SIR = 33.6). An excess of lung cancer was seen among intravenous drug users (IDU), but not among homosexual men. When the risk of all non-AIDS-defining cancers was considered, HIV-positive men had a nearly twofold excess (95% CI: 1.2–2.8). A risk of similar magnitude emerged among HIV-negative IDU (95% CI: 1.0–4.5), largely attributable to lung cancer and HD. Conclusion:These findings confirm that HIV infection increases the risk of HD, whereas they suggest that the risk of hepatocellular carcinoma may also be enhanced by HIV infection. The observation of an elevated risk of lung cancer in both HIV-positive and HIV-negative IDU points to personal behaviours unrelated to HIV infection.