Jordi Casabona

Causes of death in HIV-1-infected patients treated with antiretroviral therapy, 1996-2006: collaborative analysis of 13 HIV cohort studies

BACKGROUND We examined specific causes of mortality in human immunodeficiency virus type 1 (HIV-1)-infected patients who initiated antiretroviral therapy (ART) in Europe and North America from 1996 through 2006, and we quantified associations of prognostic factors with cause-specific mortality. METHODS We retrospectively classified all deaths among 39,272 patients enrolled in 13 HIV-1 cohorts (154,667 person years of follow-up) into the categories specified in the Cause of Death (CoDe) project protocol. RESULTS In 1597 (85%) of 1876 deaths, a definitive cause of death could be assigned. Among these, 792 deaths (49.5%) were AIDS related, followed by non-AIDS malignancies (189; 11.8%), non-AIDS infections (131; 8.2%), violence- and/or drug-related causes (124; 7.7%), liver disease (113; 7.0%), and cardiovascular disease (103; 6.5%). Rates of AIDS-related death (hazard ratio [HR] per 100 cell decrease, 1.43; 95% confidence interval [CI], 1.34-1.53) and death from renal failure (HR, 1.73; 95% CI, 1.18-2.55) were strongly inversely related to CD4 count at initiation of ART, whereas rates of death attributable to AIDS (HR for viral load >5 vs 5 log copies/mL, 1.31; 95% CI, 1.12-1.53), infection (HR, 1.85; 95% CI, 1.25-2.73), cardiovascular (HR, 1.54; 95% CI, 1.05-2.27), and respiratory causes (HR, 3.62; 95% CI, 1.30-10.09) were higher in patients with baseline viral load >5 log copies/mL than in other patients. Rates of each cause of death were higher in patients with presumed transmission via injection drug use than in other patients, with marked increases in rates of liver-related (HR for injection drug use vs non-injection drug use, 6.06; 95% CI, 4.03-9.09) and respiratory tract-related (HR, 4.94; 95% CI, 1.96-12.45) mortality. The proportion of deaths classified as AIDS related decreased with increasing duration of ART. CONCLUSIONS Important contributors to non-AIDS mortality in treated HIV-1-infected individuals must be addressed if decreases in mortality rates are to continue.

Reemergence of the HIV epidemic among men who have sex with men in North America, Western Europe, and Australia, 1996-2005.

PURPOSE To describe and contextualize changes in rates of human immunodeficiency virus (HIV) notifications in men who have sex with men (MSM) in eight countries (Australia, Canada, France, Germany, Netherlands, Spain, United Kingdom, and United States) from 1996-2005. METHODS We analyzed trends in HIV notification rates from 1996-2000 and 2000-2005 by generalized linear regression and estimated annual percentage change (EAPC) in rates of HIV notifications. To interpret trends, we visually examined graphs of primary and secondary syphilis reports among MSM and the prevalence of recent HIV testing. RESULTS The rate of HIV notifications among MSM declined 5.2% per year (95% confidence interval [CI]: -5.8%, -4.7%) from 1996-2000, and increased 3.3% per year (95% CI: +2.9%,+3.7%) from 2000-2005. During the period of increasing HIV diagnoses, increases in primary and secondary syphilis diagnoses occurred among MSM, but recent HIV testing among MSM did not seem to increase. CONCLUSIONS After declining in the second half of the 1990s, HIV notification rates for MSM increased beginning in 2000. Increased HIV notifications in MSM are not wholly explained by changes in HIV testing. Urgent efforts are required to develop effective HIV prevention interventions for MSM, and implement them broadly in these countries.

When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries: an observational study.

BACKGROUND Most clinical guidelines recommend that AIDS-free, HIV-infected persons with CD4 cell counts below 0.350 × 10(9) cells/L initiate combined antiretroviral therapy (cART), but the optimal CD4 cell count at which cART should be initiated remains a matter of debate. OBJECTIVE To identify the optimal CD4 cell count at which cART should be initiated. DESIGN Prospective observational data from the HIV-CAUSAL Collaboration and dynamic marginal structural models were used to compare cART initiation strategies for CD4 thresholds between 0.200 and 0.500 × 10(9) cells/L. SETTING HIV clinics in Europe and the Veterans Health Administration system in the United States. PATIENTS 20, 971 HIV-infected, therapy-naive persons with baseline CD4 cell counts at or above 0.500 × 10(9) cells/L and no previous AIDS-defining illnesses, of whom 8392 had a CD4 cell count that decreased into the range of 0.200 to 0.499 × 10(9) cells/L and were included in the analysis. MEASUREMENTS Hazard ratios and survival proportions for all-cause mortality and a combined end point of AIDS-defining illness or death. RESULTS Compared with initiating cART at the CD4 cell count threshold of 0.500 × 10(9) cells/L, the mortality hazard ratio was 1.01 (95% CI, 0.84 to 1.22) for the 0.350 threshold and 1.20 (CI, 0.97 to 1.48) for the 0.200 threshold. The corresponding hazard ratios were 1.38 (CI, 1.23 to 1.56) and 1.90 (CI, 1.67 to 2.15), respectively, for the combined end point of AIDS-defining illness or death. LIMITATIONS CD4 cell count at cART initiation was not randomized. Residual confounding may exist. CONCLUSION Initiation of cART at a threshold CD4 count of 0.500 × 10(9) cells/L increases AIDS-free survival. However, mortality did not vary substantially with the use of CD4 thresholds between 0.300 and 0.500 × 10(9) cells/L.

Mortality of HIV-infected patients starting potent antiretroviral therapy: comparison with the general population in nine industrialized countries

BACKGROUND Mortality in HIV-infected patients has declined substantially with combination antiretroviral therapy (ART), but it is unclear whether it has reached that of the general population. We compared mortality in patients starting ART in nine countries of Europe and North America with the corresponding general population, taking into account their response to ART. METHODS Eligible patients were enrolled in prospective cohort studies participating in the ART Cohort Collaboration. We calculated the ratio of observed to expected deaths from all causes [standardized mortality ratio (SMR)], measuring time from 6 months after starting ART, according to risk group, clinical stage at the start of ART and CD4 cell count and viral load at 6 months. Expected numbers of deaths were obtained from age-, sex- and country-specific mortality rates. RESULTS Among 29 935 eligible patients, 1134 deaths were recorded in 131 510 person-years of follow-up. The median age was 37 years, 8162 (27%) patients were females, 4400 (15%) were injecting drug users (IDUs) and 6738 (23%) had AIDS when starting ART. At 6 months, 23 539 patients (79%) had viral load measurements <or=500 copies/ml. The lowest SMR, 1.05 [95% confidence interval (CI) 0.82-1.35] was found for men who have sex with men (MSM) who started ART free of AIDS, reached a CD4 cell count of >or=350 cells/microL and suppressed viral replication to <or=500 copies/ml by the sixth month. In contrast, the SMR was 73.7 (95% CI 46.4-116.9) in IDUs who failed to suppress viral replication and had CD4 cell counts <50 cells/microL at 6 months. The percentage of patients with SMRs <2 was 46% for MSM, 42% for heterosexually infected patients and 0% for patients with a history of injection drug use. Corresponding percentages for SMRs >10 were 4, 14 and 47%. CONCLUSIONS In industrialized countries, the mortality experience of HIV-infected patients who start ART and survive the first 6 months continues to be higher than in the general population, but for many patients excess mortality is moderate and comparable with patients having other chronic conditions. Much of the excess mortality might be prevented by earlier diagnosis of HIV followed by timely initiation of ART.

Response to combination antiretroviral therapy: variation by age.

Objective:To provide information on responses to combination antiretroviral therapy in children, adolescents and older HIV-infected persons. Design and setting:Multicohort collaboration of 33 European cohorts. Subjects:Forty-nine thousand nine hundred and twenty-one antiretroviral-naive individuals starting combination antiretroviral therapy from 1998 to 2006. Outcome measures:Time from combination antiretroviral therapy initiation to HIV RNA less than 50 copies/ml (virological response), CD4 increase of more than 100 cells/μl (immunological response) and new AIDS/death were analysed using survival methods. Ten age strata were chosen: less than 2, 2–5, 6–12, 13–17, 18–29, 30–39 (reference group), 40–49, 50–54, 55–59 and 60 years or older; those aged 6 years or more were included in multivariable analyses. Results:The four youngest age groups had 223, 184, 219 and 201 individuals and the three oldest age groups had 2693, 1656 and 1613 individuals. Precombination antiretroviral therapy CD4 cell counts were highest in young children and declined with age. By 12 months, 53.7% (95% confidence interval: 53.2–54.1%) and 59.2% (58.7–59.6%) had experienced a virological and immunological response. The probability of virological response was lower in those aged 6–12 (adjusted hazard ratio: 0.87) and 13–17 (0.78) years, but was higher in those aged 50–54 (1.24), 55–59 (1.24) and at least 60 (1.18) years. The probability of immunological response was higher in children and younger adults and reduced in those 60 years or older. Those aged 55–59 and 60 years or older had poorer clinical outcomes after adjusting for the latest CD4 cell count. Conclusion:Better virological responses but poorer immunological responses in older individuals, together with low precombination antiretroviral therapy CD4 cell counts, may place this group at increased clinical risk. The poorer virological responses in children may increase the likelihood of emergence of resistance.

Immunodeficiency at the start of combination antiretroviral therapy in low-, middle- and high-income countries

Objective:To describe the CD4 cell count at the start of combination antiretroviral therapy (cART) in low-income (LIC), lower middle-income (LMIC), upper middle-income (UMIC), and high-income (HIC) countries. Methods:Patients aged 16 years or older starting cART in a clinic participating in a multicohort collaboration spanning 6 continents (International epidemiological Databases to Evaluate AIDS and ART Cohort Collaboration) were eligible. Multilevel linear regression models were adjusted for age, gender, and calendar year; missing CD4 counts were imputed. Results:In total, 379,865 patients from 9 LIC, 4 LMIC, 4 UMIC, and 6 HIC were included. In LIC, the median CD4 cell count at cART initiation increased by 83% from 80 to 145 cells/&mgr;L between 2002 and 2009. Corresponding increases in LMIC, UMIC, and HIC were from 87 to 155 cells/&mgr;L (76% increase), 88 to 135 cells/&mgr;L (53%), and 209 to 274 cells/&mgr;L (31%). In 2009, compared with LIC, median counts were 13 cells/&mgr;L [95% confidence interval (CI): −56 to +30] lower in LMIC, 22 cells/&mgr;L (−62 to +18) lower in UMIC, and 112 cells/&mgr;L (+75 to +149) higher in HIC. They were 23 cells/&mgr;L (95% CI: +18 to +28 cells/&mgr;L) higher in women than men. Median counts were 88 cells/&mgr;L (95% CI: +35 to +141 cells/&mgr;L) higher in countries with an estimated national cART coverage >80%, compared with countries with <40% coverage. Conclusions:Median CD4 cell counts at the start of cART increased 2000–2009 but remained below 200 cells/&mgr;L in LIC and MIC and below 300 cells/&mgr;L in HIC. Earlier start of cART will require substantial efforts and resources globally.

Risk factors for human Herpesvirus 8 infection and AIDS-associated Kaposi's sarcoma among men who have sex with men in a European multicentre study

We aimed to identify risk factors for Kaposis sarcoma (KS) among HIV‐positive patients and behaviors associated with human Herpesvirus 8 (HHV‐8) infection, as well as to assess KS incidence and mortality rates longitudinally. To fulfill the first objective, a European case‐control study was designed in the early 1990s (each KS case was matched to 2 controls with another AIDS indicative disease). After the discovery of HHV‐8, serology testing enabled us to assess risk factors for KS development among HHV‐8 and HIV‐1 coinfected men who have sex with men (MSM), as well as risk factors for HHV‐8 infection. HHV‐8 seroprevalence was determined using a latent immunofluorescence assay. Relevant information was obtained by means of a questionnaire and medical charts review. Assessment of risk factors for KS development and HHV‐8 infection was performed using conditional and unconditional logistic regression models, respectively. A low CD4 count was the only significant risk factor for KS. HHV‐8 infection was most strongly linked to the number of life‐time sex partners, and multiple body fluids such as saliva and semen are quite likely involved in sexual transmission. Longitudinal follow up showed a significant protective role for highly‐active antiretroviral therapy (HAART) both on KS development and mortality of KS patients. Although more conclusive data from cohort studies are needed to better define specific transmission mechanisms for HHV‐8, our results contribute to explain why KS incidence is higher among MSM, and the decreasing KS incidence trend observed in countries with universal access to HAART.

Prevalence and distribution of Hhv-8 in different subpopulations, with and without Hiv infection, in Spain

ObjectiveTo estimate the seroprevalence of HHV-8 in several Spanish subpopulations with different risk levels of acquiring HIV-1 infection and from different geographical regions. DesignCross-sectional seroprevalence study. MethodsA total of 1699 serum samples from blood donors (613), children under the age of 12 years (100), injecting drug users (IDU) (382), heterosexuals attending a sexually transmitted disease (STD) clinic (273) and homosexual men attending a STD clinic or a HIV-based hospital unit (331) were analysed for anti-HHV-8 antibodies. The presence of antibodies against HHV-8 was tested with an indirect immunofluorescence assay (IFA). A subsample of HHV-8-positive samples was also tested for antibody titre against HHV-8. ResultsThe overall seroprevalence of antibodies against HHV-8 for the blood donor population was 6.5% (7.0% in Andalusia, 8.0% in Catalonia and 4.5% in the Basque Country). None of the children tested positive for HHV-8. The HHV-8 prevalence was 86.7% in HIV-positive homosexual men and 28.0% in HIV-negative homosexual men (P < 0.001). Of heterosexual men attending STD clinics, 17.2% tested positive for HHV-8; 11.5% of IDU tested positive for HHV-8. HHV-8 antibody titres by groups parallel the distribution of HHV-8 prevalence. No association between HHV-8 antibody titres and CD4 cell count or HIV viral load was identified. ConclusionsThe HHV-8 prevalence among blood donors in Spain is higher than in Northern Europe and the USA, but is similar to that in Northern Italy. The distribution of HHV-8 is compatible with a sexually transmitted agent. The distribution of HHV-8 correlates with that of Kaposis sarcoma but factors other than HHV-8 seem to explain the Kaposi sarcoma distribution.

Prevalence of human immunodeficiency virus, Chlamydia trachomatis, and Neisseria gonorrhoeae and risk factors for sexually transmitted infections among immigrant female sex workers in Catalonia, Spain.

Objectives: To determine the prevalence of human immunodeficiency virus (HIV), Chlamydia trachomatis (CT), and Neisseria gonorrhoeae (NG) among immigrant female sex workers (FSW) according to their geographic area of origin and identify possible risk factors independently associated with current infection with CT and/or NG. Study Design: Cross-sectional study of 357 FSW in Catalonia in 2005. Information on sociodemographic and sex work characteristics, use of alcohol and drugs, sexual practices, and the use of social and health care services was collected. Oral fluid and urine samples were collected to determine the prevalence of HIV and CT/NG, respectively. Factors independently associated with CT/NG were assessed using multivariate logistic regression models. Results: A total of 36.4% of women were from Eastern Europe, 34.5% from Latin America, and 29.1% from Africa. Overall CT and NG prevalence were 5.9% [95% confidence interval (CI): 3.7–8.9] and 0.6% (95% CI: 0.1–2.0), respectively. No differences were observed by geographic origin. Three African women were HIV positive (overall HIV prevalence was 0.8%, 95% CI: 0.2–2.4). In multivariate analysis, younger age and unprotected sex with clients were associated with the presence of CT/NG. Conclusions: The prevalence of sexually transmitted infections among FSW in Catalonia was lower than in other European countries. Even though the prevalence of HIV was only 0.8%, it could increase in the future given the high vulnerability of these women and their wide geographic mobility. It is necessary to continue with the work carried out by nongovernmental organizations (harm reduction programs, outreach programs, and safe sex workshops) as well as to facilitate the access to health centers, especially for the youngest women.

Cohort Profile: Antiretroviral Therapy Cohort Collaboration (ART-CC)

The advent of effective combination antiretroviral therapy (ART) in 1996 resulted in fewer patients experiencing clinical events, so that some prognostic analyses of individual cohort studies of human immunodeficiency virus-infected individuals had low statistical power. Because of this, the Antiretroviral Therapy Cohort Collaboration (ART-CC) of HIV cohort studies in Europe and North America was established in 2000, with the aim of studying the prognosis for clinical events in acquired immune deficiency syndrome (AIDS) and the mortality of adult patients treated for HIV-1 infection. In 2002, the ART-CC collected data on more than 12,000 patients in 13 cohorts who had begun combination ART between 1995 and 2001. Subsequent updates took place in 2004, 2006, 2008, and 2010. The ART-CC data base now includes data on more than 70,000 patients participating in 19 cohorts who began treatment before the end of 2009. Data are collected on patient demographics (e.g. sex, age, assumed transmission group, race/ethnicity, geographical origin), HIV biomarkers (e.g. CD4 cell count, plasma viral load of HIV-1), ART regimen, dates and types of AIDS events, and dates and causes of death. In recent years, additional data on co-infections such as hepatitis C; risk factors such as smoking, alcohol and drug use; non-HIV biomarkers such as haemoglobin and liver enzymes; and adherence to ART have been collected whenever available. The data remain the property of the contributing cohorts, whose representatives manage the ART-CC via the steering committee of the Collaboration. External collaboration is welcomed. Details of contacts are given on the ART-CC website (www.art-cohort-collaboration.org).