M. Prins

Effective therapy has altered the spectrum of cause-specific mortality following HIV seroconversion.

Introduction:Although HAART has led to a reduction in overall mortality among HIV-infected individuals, its impact on death from specific causes is unknown. Methods:Twenty-two cohorts of HIV-infected individuals with known dates of seroconversion are pooled in the CASCADE collaboration. Causes of death (COD) were categorized into three AIDS-related and seven non-AIDS-related causes. The unknown causes were assigned a separate category. The cumulative incidence for each COD was calculated in the presence of the other competing COD, for the pre-HAART and HAART eras. A multivariate regression analyses for the cumulative rate of progression to the different COD was performed. Results:A total of 1938 of 7680 HIV-seroconverters died. Pre-HAART, AIDS opportunistic infections (OI) was the most common COD, followed by unknown and HIV/AIDS-unspecified. In the HAART era, the cumulative incidence for all AIDS-related COD decreased, OI remaining the most important. Large reductions in death due to other infections and organ failure were seen. Cumulative death risk decreased in the HAART era for most causes. The effect of HAART was not the same for all risk groups. The cumulative risk of death from AIDS-related malignancies, OI and non-AIDS-related malignancies decreased significantly among homosexual men (MSM), whereas the risk of dying from (un)-intentional death increased significantly among injecting drug users (IDU). A non-significant increase in hepatitis/liver-related death was seen in MSM, IDU and haemophiliacs. Conclusion:Overall and cause specific mortality decreased following the introduction of HAART. OI remain the most common COD in the HAART era, suggesting that AIDS-related events will continue to be important in the future. Future trends in COD should be monitored using standardized guidelines.

Pre-AIDS mortality from natural causes associated with HIV disease progression: Evidence from the European seroconverter study among injecting drug users

Objectives:To study differences in pre-AIDS mortality between European cohorts of injecting drug users (IDU) and to evaluate whether pre-AIDS mortality increased with time since HIV seroconversion and decreasing CD4 count. Methods:The study population consisted of 664 IDU with documented intervals of HIV seroconversion from eight cohort studies. Differences in pre-AIDS mortality were studied between European sites; an evaluation of whether pre-AIDS mortality increased with time since HIV seroconversion and decreasing CD4 count was carried out using Poisson regression. Results:One hundred and seven IDU died, of whom 57 did not have AIDS. Pre-AIDS causes of death were overdose/suicide (49%), natural causes such as bacterial infections/cirrhosis (40%), and unintentional injuries/unknown (11%). Considering pre-AIDS death and AIDS as competing risks, 14.7% were expected to have died without AIDS and 17.3% to have developed AIDS at 7 years from seroconversion. No statistically significant differences in pre-AIDS mortality were found between European regions, men and women, age categories and calendar time periods. Overall pre-AIDS mortality did not increase with time since seroconversion, but did increase with decreasing CD4 count. Evaluating cause-specific mortality, only pre-AIDS mortality from natural causes appeared to be associated with time since seroconversion as well as immunosuppression. For natural causes, the death rate per 100 person-years was 0.13 the first 2 years after seroconversion, 0.73 in years 2–4 [risk relative (RR) to years 0–2, 5.6], 1.83 in years 4–6 (RR, 14.0) and 1.54 for ≥ 6 years (RR, 11.7). This rate was 0 for a CD4 cell count ≥ 500 × 106/l, 1.06 for 200–500 × 106/l and 4.06 for < 200 × 106/l (RR versus ≥ 200 × 106/l, 7.0). In multivariate analysis, both CD4 count and time since seroconversion appeared to be independently associated with death from natural causes; CD4 count appeared to be the strongest predictor (adjusted RR, 5.9). Conclusions:A high pre-AIDS mortality rate was observed among IDU. No significant differences were observed across European sites. Pre-AIDS mortality from natural causes but not from overdose and suicide was associated with HIV disease progression.

Comparison pf progression and non-progression in injecting drug users and homosexual men with documentated dates of HIV-1 seroconversion

Objective:To compare the progression and non-progression of HIV infection among 418 injecting drug users (IDU) and 422 homosexual men with documented dates of HIV seroconversion from 12 cohorts. Methods:Seroconversion dates were calculated for each subject using a cohort-specific estimate of the cumulative HIV seroincidence over calendar time. In survival analysis, we studied the progression from seroconversion to AIDS and death by risk group. We compared non-progression between both risk groups by evaluating annual CD4 decline over the 7 years following seroconversion among AIDS-free subjects. Results:The relative hazard (RH) of AIDS for homosexual men compared with IDU was 1.54 before, and 1.21 after, adjusting for age at seroconversion and year of seroconversion. The risk of death from any cause for homosexual men compared with IDU increased over time since seroconversion. Fifty IDU died prior to AIDS, compared with seven homosexual men (unadjusted RH for homosexual men 0.10). Ignoring this pre-AIDS mortality, the crude RH of death for homosexual men compared with IDU was 2.05. After adjusting for age at seroconversion and year of seroconversion in multivariate analysis, the RH became 1.42. No differences in progression between subgroups aged 24 years or older could be demonstrated, but subjects < 24 years were found to be at a decreased risk. Proportions of nonprogressors based on CD4 slope ≥ 0 at 7 years following seroconversion were higher for IDU than for homosexual men. No differences were found in the proportion (≈ 5%) classified as non-progressors by criteria of both slope ≥ 0 and absolute CD4 counts > 500 cells × 106/l, even if pre-AIDS deaths and losses to follow-up were included. Conclusions:We found little evidence for an effect of risk group on progression and non-progression. Pre-AIDS mortality was much higher among IDU than homosexual men. Pre-AIDS mortality and a nonlinear age effect should be considered in planning interventions as well as studies comparing risk groups and modelling the epidemic.

Antibiotic treatment is associated with reduced risk of a subsequent exacerbation in obstructive lung disease: an historical population based cohort study

Objectives: The risk of a subsequent exacerbation after treatment of an exacerbation with oral corticosteroids without (OS) or with (OSA) antibiotics was evaluated in a historical population based cohort study comprising patients using maintenance medication for obstructive lung disease. Methods: The Pharmo database includes drug dispensing records of more than 2 million subjects in The Netherlands. Eligible were patients ⩾50 years who in 2003 were dispensed ⩾2 prescriptions of daily used inhaled β2 agonists, anticholinergics and/or corticosteroids, and experienced at least one exacerbation before 1 January 2006. Exacerbation was defined as a prescription of OS or OSA. The times to the second and third exacerbations were compared using Kaplan–Meier survival analysis. Independent determinants of new exacerbations were identified using multivariable Cox recurrent event survival analysis. Results: Of 49 599 patients using maintenance medication, 18 928 had at least one exacerbation; in 52%, antibiotics had been added. The OS and OSA groups were comparable for potential confounding factors. Median time to the second exacerbation was 321 days in the OS group and 418 days in the OSA group (p<0.001); and between the second and third exacerbation 127 vs 240 days (p<0.001). The protective effect of OSA was most pronounced during the first 3 months following treatment (hazard ratio (HR) 0.62; 99% CI 0.60 to 0.65). In the OSA group, mortality during follow-up was lower (HR 0.82; 99% CI 0.66 to 0.98). Conclusion: Treatment with antibiotics in addition to oral corticosteroids was associated with a longer time to the next exacerbation, and a decreased risk of developing a new exacerbation.

Prevalence and risk factors of HSV-1 and HSV-2 antibodies in European HIV infected women.

Objectives: To investigate the prevalence and risk factors of HSV-1 and HSV-2 antibodies in HIV infected women and the association between recurrent genital ulcerations and HIV disease progression in HSV-2 positive women. Methods: The presence of HSV antibodies was tested in 276 of the 487 women participating in a European cohort study of HIV infected women. Prevalence rate ratios described the association between HSV infection and its risk factors, using log binomial regression. Generalised estimating equations (GEE) analysis was performed to determine the impact of markers of HIV disease progression on recurrent genital ulcerations. Results: The prevalence of HSV-1 and HSV-2 antibodies was 76% (95% confidence interval (95% CI): 71–81) and 42% (95% CI: 36–50); 30% (95% CI: 24–35) of the women had antibodies against both HSV-1 and HSV-2. The prevalence of HSV-1 was 86% (95% CI: 80–92) in southern Europe compared with 69% (95% CI: 57–79) and 67% (95% CI: 55–77) in central and northern Europe (p=0.002). This geographical variation remained after adjustment for other risk factors. An increasing number of years of sexual activity (p=0.0002) and a history of prostitution (p=0.0001) were independently associated with HSV-2 prevalence. In HSV-2 positive women, symptomatic cases of HSV infection were minimal, but increased with decreasing CD4 count. Conclusion: In HIV infected women, the prevalence of HSV antibodies is high and symptomatic cases of HSV infection are minimal, but increase with decreasing CD4 count. HSV-2 but not HSV-1 was related to sexual behaviour (that is, a history of prostitution and the number of sexually active years) in this group of HIV infected women.

Has the rate of progression to AIDS changed in recent years

Objectives:To investigate whether the rate of progression to AIDS has changed over time by testing an effect of the year of seroconversion on AIDS onset (Centers for Disease Control and Prevention 1987 revised classification), next to an effect of the calendar period of follow-up. Design:French multicentre prospective study of 385 homosexual and heterosexual subjects and 231 subjects from a multicentre study of European injecting drug users (IDU), all with a documented date of HIV-1 seroconversion. Method:The effect of the year of seroconversion was compared by the log-rank test. Crude and adjusted relative hazard (ARH) were quantified using the Cox model. Calendar period of follow-up was studied separately for sexual exposure group and IDU and treated as a time-dependent variable in a Cox model. Results:In the 616 study subjects the year of seroconversion was not significantly related to AIDS occurrence (n = 108); the ARH was 0.88 [95% confidence interval (CI), 0.56–1.38] for those who seroconverted in 1988–1989, and 1.17 (95% CI, 0.61–2.25) for those who seroconverted after 1989, compared with those who seroconverted before 1988. In the sexual exposure group, a clear trend towards less rapid progression to AIDS was observed in subjects followed in 1991–1992 (ARH, 0.49; 95% CI, 0.24–0.99) and after 1992 (ARH, 0.54; 95% CI; 0.24–1.21), compared with those followed before 1991. This favorable trend was not observed in IDU despite a significant decrease over time of Pneumocystis carinii pneumonia as AIDS-defining illness. Conversely to sexual exposure groups, the frequency of antiretroviral treatment (mainly zidovudine) prescription was still low during the most recent calendar periods in IDU when the CD4 count threshold of 200 × 106/l was reached. Conclusions:No evidence was found of a change in the rate of progression to AIDS in subjects who seroconverted in recent years. Furthermore, conversely to sexual exposure groups, the lack of favorable trends in IDU users followed in recent years suggest that health-care systems are not always adapted to their lifestyles.

Determinants of response to first HAART regimen in antiretroviral‐naïve patients with an estimated time since HIV seroconversion

To study the determinants of immunological and virological response to highly active antiretroviral therapy (HAART) in naïve patients, adjusting for time since HIV‐1 seroconversion.

Estimating the force of infection for HCV in injecting drug users using interval-censored data

Injecting drug users (IDUs) account for most new HCV infections. The objectives of this study were: to estimate the force of infection for hepatitis C virus in IDUs within the interval-censoring framework and to determine the impact of risk factors such as frequency of injection, drug injected, sharing of syringes and time of first injection on the time to HCV infection. We used data from the Amsterdam Cohort Study collected in The Netherlands and focused on those individuals who were HCV negative upon entry into the study. Based on the results, the force of infection was found to vary with time of first injection. The risk of infection was higher in the first 3 years of an IDUs career, implying estimates based on single cross-sectional studies could be biased. Frequency of injection and type of drug injected were found to be highly significant predictors, whereas sharing syringes was not.

BMI, male sex and IL28B genotype associated with persistently high hepatitis C virus RNA levels among chronically infected drug users up to 23 years following seroconversion.

The natural course of serum HCV RNA levels during chronic infection remains unclear. We investigated HCV RNA levels and factors associated with HCV RNA levels for the entire course from HCV seroconversion. We measured HCV RNA levels of 54 HCV seroconverters from the Amsterdam Cohort Studies among drug users at yearly intervals up to 23 years using bDNA (VERSANT 3.0, lower limit of detection 615 IU/mL). Samples below the cut‐off of the assay were tested by TMA (Siemens VERSANT, detection limit 5 IU/mL). We used a latent class linear mixed model to examine the HCV RNA patterns and factors associated with HCV RNA levels. The median follow‐up time was 10.8 years (IQR 6.5–14.9). We found two distinct HCV RNA patterns characterized by 45/54 cases and 9/54 cases. In multivariable analyses, HCV RNA levels were 0.41 log10 IU/mL (95% confidence interval (CI) 0.06–0.75) higher for males as compared to females. Individuals with the IL28B CC genotype had 0.40 log10 IU/mL (95% 0.08–0.73) higher HCV RNA levels than individuals with IL28B CT/TT genotypes. Body mass index (BMI) was associated with higher HCV RNA levels, 0.055 log10 IU/mL per BMI point (95% CI 0.027–0.083). In this unique study, which examines the HCV RNA patterns over an extended period and following seroconversion, male sex, IL28B CC genotype and BMI were independently associated with higher average HCV RNA levels. These results contribute to defining the natural history of HCV infection and could play an important part in clinical decision‐making.

50 IS ADDING HCV SCREENING TO THE ANTENATAL NATIONAL SCREENING PROGRAM IN AMSTERDAM, THE NETHERLANDS COST-EFFECTIVE?

Introduction: Hepatitis C virus infection (HCV) can lead to severe liver disease. Recently new improved treatment options have been introduced. Pregnant women are already routinely screened for several infectious diseases, however not yet for HCV infection. Here we examine whether adding HCV screening to routine screening is cost-effective. Methods: To estimate the cost-effectiveness of implementing HCV screening of all pregnant women and HCV screening of first generation non-Western pregnant women compared to no screening, a Markov model was developed. This model was parameterized with prevalence data from pregnant women retrospectively tested for HCV in Amsterdam, the Netherlands, and literature sources. In addition, we estimated the effect of possible treatment improvement in the future. Results: Screening all pregnant women resulted in the incremental cost per women screened of €41, 0.0008 life years gained, and thus an incremental cost-effectiveness ratio (ICER) of €52,473 which is above the cost-effectiveness threshold of €50,000. For screening first generation non-Western migrants, the ICER was €47,113. Best case analysis for both scenarios showed ICERs of respectively €19,505 and €17,533. We estimated that if costs per treatment will decline to €3750, screening all pregnant women will be costeffective. Conclusions: In the current situation, adding HCV screening to the already existing screening program for pregnant women is not costeffective for women in general. However, adding HCV screening for first generation non-Western women shows a moderate costeffective outcome. Yet, best-case analyses shows potentials for an ICER below €20,000 per life-year gained. Treatment options will improve further in the next coming years enhancing costeffectiveness even more.