Mortality According to CD4 Count at Start of Combination Antiretroviral Therapy Among HIV-infected Patients Followed for up to 15 Years After Start of Treatment: Collaborative Cohort Study.

BACKGROUND: CD4 count at start of combination antiretroviral therapy (ART) is strongly associated with short-term survival, but its association with longer-term survival is less well characterized. METHODS: We estimated mortality rates (MRs) by time since start of ART (<0.5, 0.5-0.9, 1-2.9, 3-4.9, 5-9.9, and ≥10 years) among patients from 18 European and North American cohorts who started ART during 1996-2001. Piecewise exponential models stratified by cohort were used to estimate crude and adjusted (for sex, age, transmission risk, period of starting ART [1996-1997, 1998-1999, 2000-2001], and AIDS and human immunodeficiency virus type 1 RNA at baseline) mortality rate ratios (MRRs) by CD4 count at start of ART (0-49, 50-99, 100-199, 200-349, 350-499, ≥500 cells/µL) overall and separately according to time since start of ART. RESULTS: A total of 6344 of 37 496 patients died during 359 219 years of follow-up. The MR per 1000 person-years was 32.8 (95% confidence interval [CI], 30.2-35.5) during the first 6 months, declining to 16.0 (95% CI, 15.4-16.8) during 5-9.9 years and 14.2 (95% CI, 13.3-15.1) after 10 years' duration of ART. During the first year of ART, there was a strong inverse association of CD4 count at start of ART with mortality. This diminished over the next 4 years. The adjusted MRR per CD4 group was 0.97 (95% CI, .94-1.00; P = .054) and 1.02 (95% CI, .98-1.07; P = .32) among patients followed for 5-9.9 and ≥10 years, respectively. CONCLUSIONS: After surviving 5 years of ART, the mortality of patients who started ART with low baseline CD4 count converged with mortality of patients with intermediate and high baseline CD4 counts.

[The Cohort of the Spanish HIV Research Network (CoRIS) and its associated biobank; organizational issues, main findings and losses to follow-up]. / La cohorte de la red española de investigación en sida y su biobanco: organización, principales resultados y pérdidas al seguimiento.

INTRODUCTION: This article describes the development of the Cohort of the Spanish Research Network (CoRIS), its methodological and organizational aspects, the demographic and clinical characteristics of the subjects enrolled and quantifies the losses to follow-up and associated factors. METHODS: Multicentre cohort of HIV-positive naïve subjects recruited in 28 sites of Spain from 2004-onwards. Missing and inconsistent data were submitted to internal quality controls and the datasets were externally audited. Multiple logistic regression models were used. RESULTS: As of October 2009, 5,514 subjects had been recruited, representing 11,708 person-years with a median follow-up time of 1.81 years. Most are men (78.8%), infected by sexual transmission (46.1% men who have sex with men and 35.2% heterosexual persons) and Spanish (69.7%). During follow-up 64.5% have started Antiretroviral Therapy (ART) and 201 deaths have occurred. New HIV diagnoses accounted for 80.7% of the sample. Some 52% of subjects had at least one baseline sample in the BioBank while naïve to ART. Losses to follow-up (18.9%) were more frequent in younger people, in injecting drug users, in persons of non-Spanish origin, in persons with primary or lower educational level, and in those with a CD4 count over 350 cells/mm(3) at time of recruitment. CONCLUSIONS: The implementation of CoRIS has been successful; the cohort has wide representation at national level, is actively recruiting new members and blood samples, and has excellent data quality. Losses to follow-up are of similar magnitude to other cohort studies, as are the factors associated with them.

Impact of late presentation of HIV infection on short-, mid- and long-term mortality and causes of death in a multicenter national cohort: 2004-2013.

OBJECTIVES: To analyze the impact of late presentation (LP) on overall mortality and causes of death and describe LP trends and risk factors (2004-2013). METHODS: Cox models and logistic regression were used to analyze data from a nation-wide cohort in Spain. LP is defined as being diagnosed when CD4 < 350 cells/ml or AIDS. RESULTS: Of 7165 new HIV diagnoses, 46.9% (CI95%:45.7-48.0) were LP, 240 patients died. First-year mortality was the highest (aHRLP.vs.nLP = 10.3[CI95%:5.5-19.3]); between 1 and 4 years post-diagnosis, aHRLP.vs.nLP = 1.9(1.2-3.0); and >4 years, aHRLP.vs.nLP = 1.5(0.7-3.1). First-year's main cause of death was HIV/AIDS (73%); and malignancies among those surviving >4 years (32%). HIV/AIDS-related deaths were more likely in LP (59.2% vs. 25.0%; p < 0.001). LP declined from 55.9% (2004-05) to 39.4% (2012-13), and reduced in 46.1% in men who have sex with men (MSM) and 37.6% in heterosexual men, but increased in 22.6% in heterosexual women. Factors associated with LP: sex (ORMEN.vs.WOMEN = 1.4[1.2-1.7]); age (OR31-40.vs.<30 = 1.6[1.4-1.8], OR41-50.vs.<30 = 2.2[1.8-2.6], OR>50.vs.<30 = 3.6[2.9-4.4]); behavior (ORInjectedDrugUse.vs.MSM = 2.8[2.0-3.8]; ORHeterosexual.vs.MSM = 2.2[1.7-3.0]); education (ORPrimaryEducation.vs.University = 1.5[1.1-2.0], ORLowerSecondary.vs.University = 1.3[1.1-1.5]); and geographical origin (ORSub-Saharan.vs.Spain = 1.6[1.3-2.0], ORLatin-American.vs.Spain = 1.4[1.2-1.8]). CONCLUSIONS: LP is associated with higher mortality, especially short-term- and HIV/AIDS-related mortality. Mid-term-, but not long-term mortality, remained also higher in LP than nLP. LP decreased in MSM and heterosexual men, not in heterosexual women. The groups most affected by LP are low educated, non-Spanish and heterosexual women.

Clinical outcomes of patients infected with HIV through use of injected drugs compared to patients infected through sexual transmission: late presentation, delayed anti-retroviral treatment and higher mortality.

AIMS: To compare patients who acquired HIV infection through use of injected drugs (HIV-IDU) with patients who acquired HIV by sexual transmission (HIV-ST) in terms of late presentation (LP), delay in anti-retroviral treatment (ART) initiation, virological and immunological response to ART, mortality and progression to AIDS. DESIGN: Prospective multi-centre cohort study of HIV-infected subjects naive to ART at entry (Cohort of the Spanish HIV Research Network: CoRIS). SETTING: Thirty-one centres from the Spanish public health-care system. PARTICIPANTS: A total of 9355 patients were included (1064 HIV-IDU and 8291 HIV-ST) during 2004-13. MEASUREMENTS: We compared LP (defined as presentation for care with a CD4 cell count < 350/µl and/or AIDS-defining illness), delayed ART initiation (defined as initiating treatment more than 6 months after the date when treatment was indicated by the guidelines, or not initiating treatment at all when it was indicated), virological and immunological response to ART (defined as viral load < 50 HIV-1 RNA copies/ml and a CD4 count increase of at least 100 cells/µl, respectively, after 1 year of treatment), mortality and progression to AIDS in HIV-IDU and HIV-ST. FINDINGS: Compared with HIV-ST, HIV-IDU had higher risk of LP [odds ratio (OR) = 1.76; 95% confidence interval (CI) = 1.41-2.18], delayed ART initiation (OR 1.87; 95% CI = 1.46-2.40) and higher mortality [hazard ratio (HR) = 1.43; 95% CI = 1.03-2.01] and risk of progression to AIDS [subhazard ratio (SHR) = 1.68; 95% CI = 1.29-2.18]. Virological suppression due to ART was lower in HIV-IDU than in patients with HIV-ST only among patients without hepatitis C virus (HCV) infection [adjusted OR (aOR) = 0.59; 95% CI = 0.36-0.95]; among patients with HCV infection, virological suppression due to ART did not show significant differences between HIV-IDU and HIV-ST. There were no significant differences in immunological response after adjusting by HCV (aOR = 0.74; 95% CI = 0.52-1.06). CONCLUSIONS: In Spain, patients who acquire HIV infection through use of injected drugs appear to have a higher risk of late presentation, delayed initiation of anti-retroviral treatment and progression to AIDS and death than patients who acquire HIV by sexual transmission.

Incidence of hepatitis C virus (HCV) in a multicenter cohort of HIV-positive patients in Spain 2004-2011: increasing rates of HCV diagnosis but not of HCV seroconversions.

OBJECTIVES: We aim to describe rates and risk factors of Hepatitis C Virus (HCV) diagnoses, follow-up HCV testing and HCV seroconversion from 2004-2011 in a cohort of HIV-positive persons in Spain. METHODS: CoRIS is a multicentre, open and prospective cohort recruiting adult HIV-positive patients naïve to antiretroviral therapy. We analysed patients with at least one negative and one follow-up HCV serology. Incidence Rates (IR) were calculated and multivariate Poisson regression was used to estimate adjusted Rates Ratios (aIRR). RESULTS: Of 2112 subjects, 53 HCV diagnoses were observed, IR = 0.93/100 py (95%CI: 0.7-1.2). IR increased from 0.88 in 2004-05 to 1.36 in 2010-11 (aIRR = 1.55; 95%CI: 0.37-6.55). In men who have sex with men (MSM) from 0.76 to 1.10 (aIRR = 1.45; 95%CI: 0.31-6.82); in heterosexual (HTX) subjects from 1.19 to 1.28 (aIRR = 1.08; 95%CI: 0.11-10.24). HCV seroconversion rates decreased from 1.77 to 0.65 (aIRR = 0.37; 95%CI: 0.12-1.11); in MSM from 1.06 to 0.49 (aIRR = 0.46; 95%CI: 0.09-2.31); in HTX from 2.55 to 0.59 (aIRR = 0.23; 95%CI: 0.06-0.98). HCV infection risk was higher for injecting drug users (IDU) compared to HTX (aIRR = 9.63;95%CI: 2.9-32.2); among MSM, for subjects aged 40-50 compared to 30 or less (IRR = 3.21; 95%CI: 1.7-6.2); and among HTX, for female sex (aIRR = 2.35; 95%CI: 1.03-5.34) and <200 CD4-count (aIRR = 2.39; 95%CI: 0.83-6.89). CONCLUSION: We report increases in HCV diagnoses rates which seem secondary to intensification of HCV follow-up testing but not to rises in HCV infection rates. HCV IR is higher in IDU. In MSM, HCV IR increases with age. Among HTX, HCV IR is higher in women and in subjects with impaired immunological situation.

Imputation of the Date of HIV Seroconversion in a Cohort of Seroprevalent Subjects: Implications for Analysis of Late HIV Diagnosis.

Objectives. Since subjects may have been diagnosed before cohort entry, analysis of late HIV diagnosis (LD) is usually restricted to the newly diagnosed. We estimate the magnitude and risk factors of LD in a cohort of seroprevalent individuals by imputing seroconversion dates. Methods. Multicenter cohort of HIV-positive subjects who were treatment naive at entry, in Spain, 2004-2008. Multiple-imputation techniques were used. Subjects with times to HIV diagnosis longer than 4.19 years were considered LD. Results. Median time to HIV diagnosis was 2.8 years in the whole cohort of 3,667 subjects. Factors significantly associated with LD were: male sex; Sub-Saharan African, Latin-American origin compared to Spaniards; and older age. In 2,928 newly diagnosed subjects, median time to diagnosis was 3.3 years, and LD was more common in injecting drug users. Conclusions. Estimates of the magnitude and risk factors of LD for the whole cohort differ from those obtained for new HIV diagnoses.

Differences in the causes of death of HIV-positive patients in a cohort study by data sources and coding algorithms.

OBJECTIVES: To compare causes of death (CoDs) from two independent sources: National Basic Death File (NBDF) and deaths reported to the Spanish HIV Research cohort [Cohort de adultos con infección por VIH de la Red de Investigación en SIDA CoRIS)] and compare the two coding algorithms: International Classification of Diseases, 10th revision (ICD-10) and revised version of Coding Causes of Death in HIV (revised CoDe). METHODS: Between 2004 and 2008, CoDs were obtained from the cohort records (free text, multiple causes) and also from NBDF (ICD-10). CoDs from CoRIS were coded according to ICD-10 and revised CoDe by a panel. Deaths were compared by 13 disease groups: HIV/AIDS, liver diseases, malignancies, infections, cardiovascular, blood disorders, pulmonary, central nervous system, drug use, external, suicide, other causes and ill defined. RESULTS: There were 160 deaths. Concordance for the 13 groups was observed in 111 (69%) cases for the two sources and in 115 (72%) cases for the two coding algorithms. According to revised CoDe, the commonest CoDs were HIV/AIDS (53%), non-AIDS malignancies (11%) and liver related (9%), these percentages were similar, 57, 10 and 8%, respectively, for NBDF (coded as ICD-10). When using ICD-10 to code deaths in CoRIS, wherein HIV infection was known in everyone, the proportion of non-AIDS malignancies was 13%, liver-related accounted for 3%, while HIV/AIDS reached 70% due to liver-related, infections and ill-defined causes being coded as HIV/AIDS. CONCLUSION: There is substantial variation in CoDs in HIV-infected persons according to sources and algorithms. ICD-10 in patients known to be HIV-positive overestimates HIV/AIDS-related deaths at the expense of underestimating liver-related diseases, infections and ill defined causes. CoDe seems as the best option for cohort studies.

Educational gradient in HIV diagnosis delay, mortality, antiretroviral treatment initiation and response in a country with universal health care.

BACKGROUND: The aim of this study was to analyse associations between educational level and delayed HIV diagnosis (DD), late initiation of combined antiretroviral therapy (cART), overall and in subjects with timely HIV diagnosis, virological and immunological responses to cART, and mortality from HIV diagnosis and cART initiation. METHODS: This was a multicentre cohort study of HIV-positive treatment-naive subjects in Spain between 2004-2009. Logistic and Cox regression analyses were used. RESULTS: Of 4,549 subjects, 44.5% had low education level (LOW), 34.4% medium education level (MED) and 21.1% high education level (HIG). In men, DD was more common in MED (OR 1.3 [95% CI 1.0, 1.7]) or LOW [OR 1.8 (95% CI 1.4, 2.3)] compared to HIG. In women, the opposite was observed; women with HIG were 40% more likely to have DD than those with LOW (OR 1.4 [95% CI 0.8, 2.5]). In individuals with timely HIV diagnoses, percentages of late cART initiators were similar (LOW 9.5%, MED 11.4% and HIG 7.0%; P=0.114). Immunological (LOW 68%, MED 76% and HIG 84%) and virological (LOW 76%, MED 83% and HIG 86%) responses to cART increased significantly with educational level; these increases remained significant in multivariate analyses. Mortality for LOW subjects was higher than for HIG, from HIV diagnosis (hazard ratio [HR] 2.3 [95% CI 1.1, 4.9]) and from cART initiation (HR 1.8 [95% CI 0.8, 3.9]). CONCLUSIONS: We found important differences by educational level in diagnosis delay, virological and immunological responses to cART and mortality in a country with universal health care. Women with high educational level are at higher risk of having delayed HIV diagnoses. Educational level should be taken into account when designing HIV testing and clinical management strategies.

Heterogeneity in outcomes of treated HIV-positive patients in Europe and North America: relation with patient and cohort characteristics.

BACKGROUND: HIV cohort collaborations, which pool data from diverse patient cohorts, have provided key insights into outcomes of antiretroviral therapy (ART). However, the extent of, and reasons for, between-cohort heterogeneity in rates of AIDS and mortality are unclear. METHODS: We obtained data on adult HIV-positive patients who started ART from 1998 without a previous AIDS diagnosis from 17 cohorts in North America and Europe. Patients were followed up from 1 month to 2 years after starting ART. We examined between-cohort heterogeneity in crude and adjusted (age, sex, HIV transmission risk, year, CD4 count and HIV-1 RNA at start of ART) rates of AIDS and mortality using random-effects meta-analysis and meta-regression. RESULTS: During 61 520 person-years, 754/38 706 (1.9%) patients died and 1890 (4.9%) progressed to AIDS. Between-cohort variance in mortality rates was reduced from 0.84 to 0.24 (0.73 to 0.28 for AIDS rates) after adjustment for patient characteristics. Adjusted mortality rates were inversely associated with cohorts' estimated completeness of death ascertainment [excellent: 96-100%, good: 90-95%, average: 75-89%; mortality rate ratio 0.66 (95% confidence interval 0.46-0.94) per category]. Mortality rate ratios comparing Europe with North America were 0.42 (0.31-0.57) before and 0.47 (0.30-0.73) after adjusting for completeness of ascertainment. CONCLUSIONS: Heterogeneity between settings in outcomes of HIV treatment has implications for collaborative analyses, policy and clinical care. Estimated mortality rates may require adjustment for completeness of ascertainment. Higher mortality rate in North American, compared with European, cohorts was not fully explained by completeness of ascertainment and may be because of the inclusion of more socially marginalized patients with higher mortality risk.

All-cause mortality in treated HIV-infected adults with CD4 ≥500/mm3 compared with the general population: evidence from a large European observational cohort collaboration.

BACKGROUND: Using data from a large European collaborative study, we aimed to identify the circumstances in which treated HIV-infected individuals will experience similar mortality rates to those of the general population. METHODS: Adults were eligible if they initiated combination anti-retroviral treatment (cART) between 1998 and 2008 and had one prior CD4 measurement within 6 months. Standardized mortality ratios (SMRs) and excess mortality rates compared with the general population were estimated using Poisson regression. Periods of follow-up were classified according to the current CD4 count. RESULTS: Of the 80 642 individuals, 70% were men, 16% were injecting drug users (IDUs), the median age was 37 years, median CD4 count 225/mm(3) at cART initiation and median follow-up was 3.5 years. The overall mortality rate was 1.2/100 person-years (PY) (men: 1.3, women: 0.9), 4.2 times as high as that in the general population (SMR for men: 3.8, for women: 7.4). Among 35 316 individuals with a CD4 count ≥500/mm(3), the mortality rate was 0.37/100 PY (SMR 1.5); mortality rates were similar to those of the general population in non-IDU men [SMR 0.9, 95% confidence interval (95% CI) 0.7-1.3] and, after 3 years, in women (SMR 1.1, 95% CI 0.7-1.7). Mortality rates in IDUs remained elevated, though a trend to decrease with longer durations with high CD4 count was seen. A prior AIDS diagnosis was associated with higher mortality. CONCLUSIONS: Mortality patterns in most non-IDU HIV-infected individuals with high CD4 counts on cART are similar to those in the general population. The persistent role of a prior AIDS diagnosis underlines the importance of early diagnosis of HIV infection.

Delayed diagnosis of HIV infection in a multicenter cohort: prevalence, risk factors, response to HAART and impact on mortality.

To study the prevalence of Delayed HIV Diagnosis (DHD) and its associated risk factors, to evaluate the effect of DHD on virological and immunological responses to HAART and to estimate the impact of DHD on all-causes mortality. Prospective cohort of 2, 564 HIV-positive HAART-naïve subjects attending 19 hospitals in Spain, 2004-2006. Estimations were made by logistic regression and survival analyses by Cox regression models. Prevalence of DHD was 37.3% (35.0-39.6). DHD was related to low educational level (OR:1.31, 95% CI:1.0-1.7). Compared to men who have sex with men (MSM), DHD was more frequent in heterosexuals (OR:1.9 95% CI:1.5-2.5) and injection drug users (IDUs) (OR:2.0 95% CI:1.5-2.8). An interaction between age and sex was found. Although risk of having DHD did not increase after age 30 in women, it increased linearly with age in men. No differences in virological (OR 1.2 95% CI: 0.8-1.8) and CD4 T cell (OR 1.1 95% CI: 0.7-1.8) responses to HAART were seen. The adjusted hazard ratio for death in patients with DHD was 5.2, (95% CI: 1.9-14.5). DHD is very common, especially in older men, heterosexuals and IDUs. Although we did not find differences in virological and immunological responses to HAART, we did observe higher mortality in people with DHD. Increased efforts to early diagnose HIV infection are urgently needed.