Colette Smit

Full participation in harm reduction programmes is associated with decreased risk for human immunodeficiency virus and hepatitis C virus: evidence from the Amsterdam Cohort Studies among drug users

Objectives To investigate the impact of harm-reduction programmes on HIV and hepatitis C virus (HCV) incidence among ever-injecting drug users (DU) from the Amsterdam Cohort Studies (ACS). Methods The association between use of harm reduction and seroconversion for human immunodeficiency virus (HIV) and/or hepatitis C virus (HCV) was evaluated using Poisson regression. A total of 714 DU were at risk for HIV and/or HCV during follow-up. Harm reduction was measured by combining its two most important components—methadone dose and needle exchange programme (NEP) use—and looking at five categories of participation, ranging from no participation (no methadone in the past 6 months, injecting drug use in the past 6 months and no use of NEP) to full participation (≥ 60 mg methadone/day and no current injecting or ≥ 60 mg methadone/day and current injecting but all needles exchanged). Results Methadone dose or NEP use alone were not associated significantly with HIV or HCV seroconversion. However, with combination of these variables and after correction for possibly confounding variables, we found that full participation in a harm reduction programme (HRP) was associated with a lower risk of HIV and HCV infection in ever-injecting drug users (DU), compared to no participation [incidence rate ratio 0.43 (95% CI 0.21–0.87) and 0.36 (95% CI 0.13–1.03), respectively]. Conclusions In conclusion, we found that full participation in HRP was associated with a lower incidence of HCV and HIV infection in ever-injecting DU, indicating that combined prevention measures—but not the use of NEP or methadone alone—might contribute to the reduction of the spread of these infections.

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.

Future challenges for clinical care of an ageing population infected with HIV: a modelling study

Summary Background The population infected with HIV is getting older and these people will increasingly develop age-related non-communicable diseases (NCDs). We aimed to quantify the scale of the change and the implications for HIV care in the Netherlands in the future. Methods We constructed an individual-based model of the ageing HIV-infected population, which followed patients on HIV treatment as they age, develop NCDs—including cardiovascular disease (hypertension, hypercholesterolaemia, myocardial infarctions, and strokes), diabetes, chronic kidney disease, osteoporosis, and non-AIDS malignancies—and start co-medication for these diseases. The model was parameterised by use of data for 10 278 patients from the national Dutch ATHENA cohort between 1996 and 2010. We made projections up to 2030. Findings Our model suggests that the median age of HIV-infected patients on combination antiretroviral therapy (ART) will increase from 43·9 years in 2010 to 56·6 in 2030, with the proportion of HIV-infected patients aged 50 years or older increasing from 28% in 2010 to 73% in 2030. In 2030, we predict that 84% of HIV-infected patients will have at least one NCD, up from 29% in 2010, with 28% of HIV-infected patients in 2030 having three or more NCDs. 54% of HIV-infected patients will be prescribed co-medications in 2030, compared with 13% in 2010, with 20% taking three or more co-medications. Most of this change will be driven by increasing prevalence of cardiovascular disease and associated drugs. Because of contraindications and drug–drug interactions, in 2030, 40% of patients could have complications with the currently recommended first-line HIV regimens. Interpretation The profile of patients in the Netherlands infected with HIV is changing, with increasing numbers of older patients with multiple morbidities. These changes mean that, in the near future, HIV care will increasingly need to draw on a wide range of medical disciplines, in addition to evidence-based screening and monitoring protocols to ensure continued high-quality care. These findings are based on a large dataset of HIV-infected patients in the Netherlands, but we believe that the overall patterns will be repeated elsewhere in Europe and North America. The implications of such a trend for care of HIV-infected patients in high-burden countries in Africa could present a particular challenge. Funding Medical Research Council, Bill & Melinda Gates Foundation, Rush Foundation, and Netherlands Ministry of Health, Welfare and Sport.

Major decline of hepatitis C virus incidence rate over two decades in a cohort of drug users

Injecting drug users (DU) are at high risk for hepatitis C virus (HCV) and HIV infections. To examine the prevalence and incidence of these infections over a 20-year period (1985–005), the authors evaluated 1276 DU from the Amsterdam Cohort Studies who had been tested prospectively for HIV infection and retrospectively for HCV infection. To compare HCV and HIV incidences, a smooth trend was assumed for both curves over calendar time. Risk factors for HCV seroconversion were determined using Poisson regression. Among ever-injecting DU, the prevalence of HCV antibodies was 84.5% at study entry, and 30.9% were co-infected with HIV. Their yearly HCV incidence dropped from 27.5/100 person years (PY) in the 1980s to 2/100 PY in recent years. In multivariate analyses, ever-injecting DU who currently injected and borrowed needles were at increased risk of HCV seroconversion (incidence rate ratio 29.9, 95% CI 12.6, 70.9) compared to ever-injecting DU who did not currently inject. The risk of HCV seroconversion decreased over calendar time. The HCV incidence in ever-injecting DU was on average 4.4 times the HIV incidence, a pattern seen over the entire study period. The simultaneous decline of both HCV and HIV incidence probably results from reduced risk behavior at the population level.

Lymphogranuloma venereum proctitis in men who have sex with men is associated with anal enema use and high-risk behavior

Objectives: In the industrialized world, lymphogranuloma venereum proctitis (LGVP) has been reported only in men who have sex with men. Factors responsible for the outbreak remain to be elucidated. GOAL: The goal of the present work was to elucidate risk factors associated with LGVP. Study Design: The study design comprised a cross-sectional study including 32 men with LGVP and 93 men without LGVP (22 with gonorrheal proctitis, 30 with a non-LGV chlamydial proctitis, and 41 with proctitis of unknown etiology). Factors associated with LGVP were analyzed by (multinomial) logistic regression. Results: Comparing men with LGVP with men without LGVP, factors significantly associated with higher risk of LGVP in multivariate analyses were as follows: anal enema use [odds ratio (OR): 7.8, 95% confidence interval (CI): 2.6–23.2], having sex on sex parties (OR: 5.7, 95% CI: 1.5–21.8), and having sex with human immunodeficiency virus-positive partners (OR: 3.2, 95% CI: 1.1–9.3). Evaluating the 4 proctitis groups separately in a multinomial logistic regression model, similar associations between anal enema use and LGVP were found. Men with non-LGV chlamydial proctitis showed less risk behavior than men with LGVP. No substantial difference in risk behavior was found, except for attending sex parties, between men with LGVP, and gonorrheal proctitis or proctitis of unknown etiology. Conclusions: Apart from men with LGVP, men with gonorrheal proctitis or proctitis of unknown etiology exhibit high risk behavior. Enema use seems to play a key role in transmission of LGVP, and needs further investigation.

Immunodeficiency as a risk factor for non-AIDS-defining malignancies in HIV-1-infected patients receiving combination antiretroviral therapy.

BACKGROUND The aim of this study was to investigate the association between immunodeficiency, viremia, and non-AIDS-defining malignancies (NADM). METHODS Patients starting combination antiretroviral therapy (cART) as of 1 January 1996 were selected from the AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort. In Cox models, risk factors for NADM were investigated. These included age, sex, transmission route, smoking, alcohol abuse, prior AIDS diagnosis, duration of exposure to cART, and estimated duration of human immunodeficiency virus infection. CD4+ cell count and viral load (VL) were considered as time-updated variables and as measures of cumulative exposure to CD4+ cell counts of < 200, < 350, or < 500 cells/mm³ and detectable VL >50, >400, and >1000 copies/mL, respectively. RESULTS In a cohort of 11,459 patients, 236 NADMs were diagnosed; 102 were caused by infection, and 134 were attributable to other causes. Median CD4+ cell count at NADM diagnosis was 340 cells/mm³ (range, 210-540 cells/mm³). Median time to first NADM after starting cART was 5.0 years (range, 2.2-8.2 years). In multivariate models, cumulative exposure to CD4+ cell counts < 200 cells/mm³ remained significant (hazard ratio [HR], 1.12; range, 1.03-1.22) for each additional year of exposure. In stratified analyses, cumulative exposure to CD4+ cell counts < 200 cells/mm³ was associated with malignancies possibly caused by infection (HR, 1.16; range, 1.03-1.31]) but was not associated with other types of cancers. No significant effect of viremia was seen in either type of cancer. CONCLUSIONS Cumulative exposure to CD4+ cell counts < 200 cells/mm³ during cART was associated with an increased risk of infection-related non-AIDS-defining malignancies.

Risk of hepatitis-related mortality increased among hepatitis C virus/HIV-coinfected drug users compared with drug users infected only with hepatitis C virus: A 20-year prospective study

Background:Progression of liver-related disease is accelerated in individuals coinfected with HIV and hepatitis C virus (HCV). Because the life expectancy of HIV-infected drug users (DUs) improved after the widespread use of highly active antiretroviral therapy (HAART), HCV-related death is likely to become more important. To disentangle the effects of HCV and HIV, we compared the overall and cause-specific mortality between HCV/HIV-infected DUs and HCV-infected DUs and DUs without HCV or HIV, followed up between 1985 and 2006. Methods:A total of 1295 participants in the Amsterdam Cohort Study were included. Cause-specific hazard ratios (CHRs) were estimated for the eras before (<1997) and since HAART (≥1997) within and among serologic groups. Results:The risk of dying decreased for most causes of death ≥1997; this decrease was not the same for the different serologic groups. Among HCV/HIV-coinfected DUs, the risk of hepatitis/liver-related death did not substantially change over time (CHR = 0.87, 95% confidence interval [CI]: 0.21 to 3.58), whereas the risk of AIDS-related mortality decreased. Compared with DUs solely infected with HCV, HCV/HIV-coinfected DUs were at increased risk of dying from hepatitis/liver-related disease (CHR = 7.15, 95% CI: 1.98 to 25.8), other natural causes (CHR = 3.09, 95% CI: 1.41 to 6.79), and nonnatural causes (CHR = 2.30, 95% CI: 1.07 to 4.95) in the HAART era. Conclusions:HCV/HIV-coinfected DUs remain at increased risk of dying from hepatitis/liver-related death in the HAART era compared with HCV-monoinfected DUs. This risk did not change in HCV/HIV-coinfected DUs after HAART was introduced, suggesting that in the HAART era, HIV continues to accelerate HCV disease progression. Efforts should be made to establish effective treatment for HCV infection in HCV/HIV-coinfected individuals.

Decline in HIV incidence and injecting, but not in sexual risk behaviour, seen in drug users in Amsterdam: a 19-year prospective cohort study.

Objective:To study temporal changes in HIV incidence, HIV transmission routes, and both injecting and sexual risk behaviour in the open Amsterdam Cohort Study (ACS) among drug users. Initiated in 1985, the ACS enables us to study changes in trends since HAART became widespread in 1996. Methods:Person-time techniques were used to study the trend in HIV incidence among HIV-negative drug users. HIV transmission routes were determined using detailed standardised questionnaires. Trends in injecting and sexual risk behaviours were evaluated with a logistic regression model adjusted for correlations between visits of the same individual. Results:The 1315 HIV-negative individuals, of whom 93 seroconverted for HIV, yielded 6970 HIV-negative person-years of follow-up. The HIV incidence was seven per 100 person-years in 1986 and varied between 0 and 0.5 per 100 person-years after 1999. The odds ratio was 15.6 (95% confidence interval, 2.6–94.6) for HIV transmission through unprotected heterosexual contact versus injecting after 1996 compared with the period before. Reports of both injecting and borrowing needles significantly declined over the period 1985–2004. Reports of sexual risk behaviour and sexually transmitted infections at follow-up visits decreased before 1996, but not after 1996. Conclusion:The HIV incidence among drug users in the ACS has declined since 1985. Accompanied by a reduction in injecting drug use and needle sharing, this decline occurred despite continued sexual risk behaviour. At present, new HIV seroconversions are related mainly to unprotected heterosexual contacts. Therefore, HIV prevention programmes for drug users should pay specific attention to the importance of safe sex practices.

Health-Related Quality of Life and Survival among HIV-Infected Patients Receiving Highly Active Antiretroviral Therapy: A Study of Patients in the AIDS Therapy Evaluation in the Netherlands (ATHENA) Cohort

BACKGROUND Previous studies have shown that health-related quality of life (HRQL) predicts survival in patients infected with human immunodeficiency virus (HIV). However, these studies predated the highly active antiretroviral therapy (HAART) era, included only a few patients receiving HAART, or had a limited duration of follow-up. This study investigates whether HRQL predicts survival among HIV-infected patients receiving HAART. METHODS HIV-infected patients participating in the focus group of the AIDS Therapy Evaluation in the Netherlands (ATHENA) study and starting or already receiving HAART completed the Medical Outcomes Study HIV Health Survey at study entry (1 May 1998 through 31 December 2000). The physical health summary (PHS) and mental health summary (MHS) scores were calculated. All-cause mortality was established at 31 March 2008. Kaplan-Meier analysis and Cox regression models were performed to predict survival. RESULTS The median follow-up was 8.4 years. Sixty-six patients (11.8%) died during follow-up. We found a significant relation between quartiles of PHS and survival (P < .001, log-rank test). Of patients with a PHS, 26 (20%) died in quartile 1 (indicating worst HRQL), 17 (13%) died in quartile 2, 10 (8%) died in quartile 3, and 5 (4%) died in quartile 4 (indicating best HRQL) (P< .001). The prediction of PHS on survival was independent of other (clinical) parameters (P< .001). No relation was found between MHS and survival (P= .13). CONCLUSION Patient-reported HRQL predicted survival among HIV-infected patients receiving HAART. This information could be highly useful for physicians in determining the prognosis of their patients.

Late Entry to HIV Care Limits the Impact of Anti-Retroviral Therapy in the Netherlands

Objective To explain differences in survival in the first three years of combination anti-retroviral therapy (cART) between HIV treatment centres in the Netherlands. Methodology/Principal Findings We developed a mathematical simulation model, parameterised using data from the ATHENA cohort that describes patients entering care, being monitored and starting cART. Three scenarios were used to represent three treatment centres with widely varying mortality rates on cART that were differentiated by: (i) the distribution of CD4 counts of patients entering care; (ii) the age distribution of patients entering care; (iii) the average rate of monitoring the patients not on cART. At the level of the treatment centre, the fraction of Dutch MSM dying in the first three years of treatment ranged from 0% to 8%. The mathematical model captured the large variation in observed mortality between the three treatment centres. Manipulating the age-distribution of patients or the frequency of monitoring did not affect the model predictions. In contrast, when the same national average distribution of CD4 count at entry was used in all the scenarios, the variation in predicted mortality between all centres was diminished. Conclusions/Significance Patients entering care with low CD4 counts appears to be the main source of variation in the mortality rates between Dutch treatment centres. Recruiting HIV-infected individuals to care earlier could lead to substantial improvements in cART outcomes. For example, if patients were to present with at least 400 CD4 cells/mm3, as they do already in some centres, then our model predicts that the mortality in the first three years of cART could be reduced by approximately 20%.