Maria Dorrucci

Non-AIDS-defining deaths and immunodeficiency in the era of combination antiretroviral therapy.

Objective:To assess whether immunodeficiency is associated with the most frequent non-AIDS-defining causes of death in the era of combination antiretroviral therapy (cART). Design:Observational multicentre cohorts. Methods:Twenty-three cohorts of adults with estimated dates of human immunodeficiency virus (HIV) seroconversion were considered. Patients were seroconverters followed within the cART era. Measurements were latest CD4, nadir CD4 and time spent with CD4 cell count less than 350 cells/μl. Outcomes were specific causes of death using a standardized classification. Results:Among 9858 patients (71 230 person-years follow-up), 597 died, 333 (55.7%) from non-AIDS-defining causes. Non-AIDS-defining infection, liver disease, non-AIDS-defining malignancy and cardiovascular disease accounted for 53% of non-AIDS deaths. For each 100 cells/μl increment in the latest CD4 cell count, we found a 64% (95% confidence interval 58–69%) reduction in risk of death from AIDS-defining causes and significant reductions in death from non-AIDS infections (32, 18–44%), end-stage liver disease (33, 18–46%) and non-AIDS malignancies (34, 21–45%). Non-AIDS-defining causes of death were also associated with nadir CD4 while being cART-naive or duration of exposure to immunosuppression. No relationship between risk of death from cardiovascular disease and CD4 cell count was found though there was a raised risk associated with elevated HIV RNA. Conclusion:In the cART era, the most frequent non-AIDS-defining causes of death are associated with immunodeficiency, only cardiovascular disease was associated with high viral replication. Avoiding profound and mild immunodeficiency, through earlier initiation of cART, may impact on morbidity and mortality of HIV-infected patients.

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.

Changes in the incidence and predictors of human immunodeficiency virus-associated dementia in the era of highly active antiretroviral therapy.

Though effective anti–human immunodeficiency virus (HIV) therapies are now available, they have variable penetration into the brain. We therefore aimed to assess changes over calendar time in the risk for HIV‐associated dementia (HIV‐D), and factors associated with HIV‐D risk.

The hepatitis C epidemic among HIV-positive MSM: incidence estimates from 1990 to 2007

Background:Outbreaks of acute hepatitis C virus (HCV) infection among HIV-infected MSM have been described since 2000. However, phylogenetic analysis suggests that the spread of HCV started around 1996. We estimated the incidence of HCV in HIV-infected MSM with well estimated dates of HIV seroconversion from 1990 to 2007. Methods:Data from 12 cohorts within the Concerted Action on SeroConversion to AIDS and Death in Europe (CASCADE) Collaboration were used. HCV incidence was estimated using standard incidence methods and methods for interval-censored data. We accounted for the fact that routine HCV data collection in each cohort started in different calendar years. Results:Of 4724 MSM, 3014 had an HCV test result and were included. Of these, 124 (4%) had only positive HCV test results, 2798 (93%) had only negative results and 92 (3%) had both. In 1990, HCV incidence ranged from 0.9 to 2.2 per 1000 person-years, depending on the analysis strategy used. HCV incidence increased up to 1995 when it was estimated to range between 5.5 and 8.1 per 1000 person-years. From 2002 onwards, it increased substantially to values between 16.8 and 30.0 per 1000 person-years in 2005 and between 23.4 and 51.1 per 1000 person-years in 2007. Conclusion:Our data support phylodynamic findings that HCV incidence had already increased among HIV-infected MSM from the mid-1990s. However, the main expansion of the HCV epidemic started after 2002. Incidence estimates obtained from cohort studies may help identify changes in the spread of important infections earlier and should guide routine testing policies to minimize further disease burden.

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.

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.

HIV disease progression in 854 women and men infected through injecting drug use and heterosexual sex and followed for up to nine years from seroconversion. Italian Seroconversion Study.

Abstract Objective: To compare the progression of HIV-1 infection in men and women followed up for up to nine years after an accurately estimated date of seroconversion. Design: Prospective observational study. Setting: 16 HIV outpatient clinics across Italy. Subjects: 321 women and 533 men infected with HIV through injecting drug use or heterosexual sex and with accurately estimated dates of seroconversion. Main outcome measures: Progression to severe CD4 lymphocytopenia (CD4 lymphocyte count <200 × 106/l), development of AIDS defining diseases, and death from AIDS. Results: Thirty two women and 67 men developed AIDS at Kaplan-Meier progression rates of 25% (95% confidence interval 13.8% to 35.5%) and 23% (15.6% to 30.4%), respectively, 7 years after seroconversion. In a Cox proportional hazards model the relative hazard was 0.93 (that is, a slightly lower hazard in women) before and 1.10 (0.70 to 1.72) after adjusting for age, HIV exposure group, and year of seroconversion. When CD4 lymphocytopenia and death from AIDS were used as end points the results were similar, with adjusted relative hazards of 0.95 (0.63 to 1.42) and 0.72 (0.48 to 1.79) respectively. In both women and men the risk of developing AIDS before the CD4 lymphocyte count had declined below 200 × 106/l was small (3% in women, 6% in men). The estimated median count at which AIDS developed in women (34 × 106/l; 10 × 106 to 44 × 106 was similar to that for men (44 × 106/l; 22 × 106 to 60 × 106. Conclusion: There seems to be little evidence for appreciable differences in the natural course of HIV infection between men and women followed up from the time of seroconversion.

Effect of maternal HIV and malaria infection on pregnancy and perinatal outcome in Zimbabwe.

Objective: To investigate the effect of isolated or concomitant infection with malaria and HIV on pregnancy and neonatal outcome. Methods: Data were collected on pregnant women admitted during the rainy seasons in the obstetric division of a district referral hospital in northern Zimbabwe in 2000 and 2001. The effects of malaria and HIV infection were determined by multivariate analysis. Results: The prevalence of HIV seropositivity and symptomatic malaria in 986 pregnant women was 8.3% and 14.7%, respectively. HIVinfected women were more likely to develop malaria attacks during pregnancy than seronegative women (odds ratio [OR] = 3.96, 95% confidence interval (CI): 2.42‐6.46). Malaria and HIV infections were associated with increased risk of stillbirth (OR = 4.74, 95% CI: 1.34‐16.78) and preterm delivery (OR = 4.10, 95% CI: 2.17‐7.75), respectively. They were independently associated with increased risk of low birth weight (malaria: OR = 10.09, 95% CI: 6.50‐15.65; HIV: OR = 3.16, 95% CI: 1.80‐5.54) and very low birth weight (malaria: OR = 5.04, 95% CI: 1.00‐25.43; HIV: OR = 10.74, 95% CI: 2.1254.41), low Apgar score (malaria: OR = 4.45, 95% CI: 1.42‐13.94; HIV: OR = 5.94, 95% CI: 1.66‐21.30), and fetal growth restriction (malaria: OR = 3.98, 95% CI: 2.51‐6.30; HIV: OR = 4.07, 95% CI: 2.40‐6.92). Dual infection with malaria and HIV was associated with increased risk of maternal, perinatal, and early infant death. Conclusions: Women with single HIV or malaria infection have a significantly increased risk of adverse outcomes of pregnancy and childbirth. Dual infection has additional detrimental effects on maternal and infant survival in an area where HIV and malaria coexist.

The Presence of Anti-Tat Antibodies Is Predictive of Long-Term Nonprogression to AIDS or Severe Immunodeficiency: Findings in a Cohort of HIV-1 Seroconverters

The human immunodeficiency virus (HIV) type 1 Tat protein plays a key role in the life cycle of the virus and in pathogenesis and is highly conserved among HIV subtypes. On the basis of this and of safety, immunogenicity, and efficacy findings in monkeys, Tat is being tested as a vaccine in phase 1 trials. Here, we evaluated the incidence and risk of progression to advanced HIV disease by anti-Tat serostatus in a cohort of 252 HIV-1 seroconverters. The risk of progression was lower in the anti-Tat-positive subjects than in the anti-Tat-negative subjects. Progression was faster in the persistently anti-Tat-negative subjects than in the transiently anti-Tat-positive subjects, and no progression was observed in the persistently anti-Tat-positive subjects.

Category of exposure to HIV and age in the progression to AIDS: Longitudinal study of 1199 people with known dates of seroconversion

Abstract Objectives: To determine whether rate of development of AIDS is affected by category of exposure to HIV and whether the more rapid development found in older subjects persists for each exposure category. Design: Longitudinal study of people with known date of seroconversion to HIV. Setting: 16 HIV treatment centres throughout Italy. Subjects: 1199 people infected with HIV through use of injected drugs, homosexual sex, or heterosexual sex. Main outcome measures: AIDS as defined by 1987 definition of Centers for Disease Control (including and excluding neoplasms) and by 1993 European definition. Results: 225 subjects (18.8%) progressed to AIDS (Centers for Disease Control 1987 definition) during median follow up of 5.8 years. Univariate analyses showed more rapid progression to AIDS for older subjects compared with younger subjects and for homosexual men compared with other exposure categories. The age effect was of similar size in each exposure category and in men and women. In a bivariate model with age and exposure categories simultaneously included as covariates, differences by exposure category disappeared for use of injected drugs and heterosexual sex compared with homosexual sex (relative hazards 1.02 (95% confidence interval 0.71 to 1.45) and 1.07 (0.70 to 1.64) respectively), while the age effect remained (relative hazard 1.55 (1.32 to 1.83) for 10 year increase in age). Analyses using the other definitions for AIDS did not appreciably change these results. Conclusions: There was no evidence of differences in rate of development of AIDS by exposure category, while there was a strong tendency for more rapid development in older subjects for all three groups. This supports the view that external cofactors do not play major role in AIDS pathogenesis but that age is of fundamental importance. Key messages Many studies have found an age effect on progression to AIDS, but it is not clear if this is due to specific AIDS defining diseases such as neoplasms and if it differs by exposure groups or by sex Our study of 1199 subjects with known date of seroconversion to HIV showed that older subjects progressed to AIDS more rapidly in all exposure groups considered, for both men and women, and for different definitions of AIDS After adjustment for age at seroconversion, there was no evidence of different rates of progression among subjects belonging to different exposure categories Behavioural cofactors do not seem to play a major role in AIDS pathogenesis but age is of fundamental importance in disease progression