M. Keuter

The effect of combined antiretroviral therapy on the overall mortality of HIV-infected individuals

Objective:To estimate the effect of combined antiretroviral therapy (cART) on mortality among HIV-infected individuals after appropriate adjustment for time-varying confounding by indication. Design:A collaboration of 12 prospective cohort studies from Europe and the United States (the HIV-CAUSAL Collaboration) that includes 62 760 HIV-infected, therapy-naive individuals followed for an average of 3.3 years. Inverse probability weighting of marginal structural models was used to adjust for measured confounding by indication. Results:Two thousand and thirty-nine individuals died during the follow-up. The mortality hazard ratio was 0.48 (95% confidence interval 0.41–0.57) for cART initiation versus no initiation. In analyses stratified by CD4 cell count at baseline, the corresponding hazard ratios were 0.29 (0.22–0.37) for less than 100 cells/μl, 0.33 (0.25–0.44) for 100 to less than 200 cells/μl, 0.38 (0.28–0.52) for 200 to less than 350 cells/μl, 0.55 (0.41–0.74) for 350 to less than 500 cells/μl, and 0.77 (0.58–1.01) for 500 cells/μl or more. The estimated hazard ratio varied with years since initiation of cART from 0.57 (0.49–0.67) for less than 1 year since initiation to 0.21 (0.14–0.31) for 5 years or more (P value for trend <0.001). Conclusion:We estimated that cART halved the average mortality rate in HIV-infected individuals. The mortality reduction was greater in those with worse prognosis at the start of follow-up.

Poor food hygiene and housing as risk factors for typhoid fever in Semarang, Indonesia

To identify risk factors for typhoid fever in Semarang city and its surroundings, 75 culture‐proven typhoid fever patients discharged 2 weeks earlier from hospital and 75 controls were studied. Control subjects were neighbours of cases with no history of typhoid fever, not family members, randomly selected and matched for gender and age. Both cases and controls were interviewed at home by the same trained interviewer using a standardized questionnaire. A structured observation of their living environment inside and outside the house was performed during the visit and home drinking water samples were tested bacteriologically. Univariate analysis showed the following risk factors for typhoid fever: never or rarely washing hands before eating (OR=3.28; 95% CI=1.41–7.65); eating outdoors at least once a week (OR=3.00; 95% CI=1.09–8.25); eating outdoors at a street food stall or mobile food vendor (OR=3.86; 95% CI=1.30–11.48); consuming ice cubes in beverage in the 2‐week period before getting ill (OR=3.00, 95% CI=1.09–8.25) and buying ice cubes from a street vendor (OR=5.82; 95% CI=1.69–20.12). Water quality and living environment of cases were worse than that of controls, e.g. cases less often used clean water for taking a bath (OR=6.50; 95% CI= 1.47–28.80), for brushing teeth (OR=4.33; 95% CI=1.25–15.20) and for drinking (OR=3.67; 95% CI=1.02–13.14). Cases tended to live in houses without water supply from the municipal network (OR=11.00; 95% CI=1.42–85.2), with open sewers (OR=2.80; 95% CI=1.0–7.77) and without tiles in the kitchen (OR=2.67; 95% CI=1.04–6.81). Multivariate analysis showed that living in a house without water supply from the municipal network (OR=29.18; 95% CI=2.12–400.8) and with open sewers (OR=7.19; 95% CI=1.33–38.82) was associated with typhoid fever. Never or rarely washing hands before eating (OR=3.97; 95% CI=1.22–12.93) and being unemployed or having a part‐time job (OR=31.3; 95% CI=3.08–317.4) also were risk factors. In this population typhoid fever was associated with poor housing and inadequate food and personal hygiene.

Long-term complications in patients with poor immunological recovery despite virological successful HAART in Dutch ATHENA cohort.

Objective:We investigated the risk of AIDS and serious non-AIDS-defining diseases (non-ADDs) according to the degree of immunological recovery after 2 years of virological successful antiretroviral therapy (HAART). Design:Retrospective observational cohort study including HIV-infected patients treated with HAART resulting in viral suppression (<500 copies/ml). Methods:Patients were grouped according to their CD4 cell count after 2 years of HAART: CD4 cell count less than 200 cells/&mgr;l (group A), 200–350 cells/&mgr;l (group B), 351–500 cells/&mgr;l (group C) or more than 500 cells/&mgr;l (group D). Analysis was done to assess predictors for poor immunological recovery and the occurrence of a composite endpoint [death, AIDS, malignancies, liver cirrhosis and cardiovascular events (CVEs)], non-ADDs, CVEs and non-AIDS-defining malignancies (non-ADMs). Results:Three thousand and sixty-eight patients were included. Older age, lower CD4 cell nadir and lower plasma HIV-RNA at the start of HAART were independent predictors for a poor immunological recovery. The composite endpoint, non-ADDs and CVE were observed most frequently in group A (overall log rank, P < 0.0001, P = 0.002 and P = 0.01). In adjusted analyses, age was a strong independent predictor for all endpoints. Compared with group A, patients in group D had a lower risk for the composite endpoint [hazard ratio 0.54 (95% confidence interval [CI] 0.33–0.87]; patients in group B had a lower risk for CVEs [hazard ratio 0.34 (95% CI 0.14–0.86)]. Conclusion:Poor immunological recovery despite virological successful HAART is associated with a higher risk for overall morbidity and mortality and CVEs in particular. This study underlines the importance of starting HAART at higher CD4 cell counts, particularly in older patients.

Survey of antibiotic use of individuals visiting public healthcare facilities in Indonesia

OBJECTIVES To estimate the antibiotic use of individuals visiting public healthcare facilities in Indonesia and to identify determinants of use against a background of high resistance rates. METHODS Patients on admission to hospital (group A), visiting a primary health center (group B), and healthy relatives (group C) were included in the study. A questionnaire on demographic, socioeconomic, and healthcare-related items including health complaints and consumption of antibiotics was used. Logistic regression was performed to determine the co-variables of antibiotic use. RESULTS Of 2996 individuals interviewed, 486 (16%) had taken an antibiotic. Compared to group C (7% consumption), groups B and A exhibited a three-fold and four-fold higher use of antibiotics, respectively. Respiratory (80%) and gastrointestinal (13%) symptoms were most frequent. Aminopenicillins and tetracyclines accounted for 80% of the prescribed antibiotics. Similar antibiotics were self-medicated (17% of users). Age less than 18 years and health insurance were independent determinants of antibiotic use. Urban provenance, being adult, male, and having no health insurance were independent determinants of self-medication. CONCLUSIONS In addition to health complaints, other factors determined antibiotic consumption. In view of the likely viral origin of respiratory complaints and the resistance of intestinal pathogens, most antibiotic use was probably unnecessary or ineffective. Future interventions should be directed towards healthcare providers.

Outcome in three groups of patients with typhoid fever in Indonesia between 1948 and 1990.

The outcome in three groups of patients with bacteriologically confirmed typhoid fever caused by Salmonella typhi, treated during three episodes between 1948 and 1990 in Java, Indonesia, was compared by retrospective analysis of hospital records. The study population consisted of three groups of patients. Group I (n= 50) was treated in Batavia (the present Jakarta) from 1948 to 1950, Group II (n= 61) in Yogyakarta from 1952 to 1956, Group III (n= 105) in Semarang from 1989 to 1990. Main outcome measures were days until defervescence, early relapses during hospitalization, duration of hospital stay, complications and mortality. Group I received supportive treatment only, Group II low doses of chloramphenicol (total 12.5 g) and Group III full doses of chloramphenicol (total 27 g); occasionally other antibiotics were used. In Group I, II and III the mean number of days until defervescence was 16, 8 and 6 and the mean number of days in hospital 43, 47 and 15, respectively. Mortality was 26%, 10% and 5% and complications occurred in 38%, 18% and 13%, respectively. Between Group I and Group II the differences in mortality and complications were statistically significant (P < 0.05). Compared to Group I the proportion of early relapses was higher in Group II, but was zero in Group III. There were significantly fewer gastrointestinal complications in Group II than in Group I (P < 0.01) and even fewer in Group III. When no antibiotic against S. typhi was available, typhoid fever had a protracted course, and only 74% of patients survived. Even with low dosages of chloramphenicol, defervescence was earlier and mortality and complications decreased dramatically, but early relapses were frequent. Full doses of chloramphenicol for a sufficient period of time only slightly reduced mortality and complications further, but eliminated early relapses completely.

Audit of antibiotic prescribing in two governmental teaching hospitals in Indonesia

This article estimates the magnitude and quality of antibiotic prescribing in Indonesian hospitals and aims to identify demographic, socio-economic, disease-related and healthcare-related determinants of use. An audit on antibiotic use of patients hospitalized for 5 days or more was conducted in two teaching hospitals (A and B) in Java. Data were collected by review of records on the day of discharge. The method was validated through concurrent data collection in Hospital A. Multivariate logistic regression analysis was performed to determine variables to explain antibiotic prescribing. Prescriptions were assessed by three reviewers using standardized criteria. A high proportion (84%) of 999 patients (499 in Hospital A and 500 in Hospital B) received an antibiotic. Prescriptions could be categorized as therapeutic (53%) or prophylactic (15%), but for 32% the indication was unclear. Aminopenicillins accounted for 54%, and cephalosporins (mostly third generation) for 17%. The average level of antibiotic use amounted to 39 DDD/100 patient-days. Validation revealed that 30% of the volume could be underestimated due to incompleteness of the records. Predictors of antibiotic use were diagnosis of infection, stay in surgical or paediatric departments, low-cost nursing care, and urban residence. Only 21% of prescriptions were considered to be definitely appropriate; 15% were inappropriate regarding choice, dosage or duration, and 42% of prescriptions, many for surgical prophylaxis and fever without diagnosis of infection, were deemed to be unnecessary. Agreement among assessors was low (kappa coefficients 0.13-0.14). Despite methodological limitations, recommendations could be made to address the need for improving diagnosis, treatment and drug delivery processes in this setting.

Declining incidence of imported malaria in the Netherlands, 2000-2007

BackgroundTo describe the epidemiology and trends of imported malaria in the Netherlands from 2000 through 2007.MethodsBased on national surveillance data regarding all reported infections of imported malaria, diagnosed 2000 through 2007, incidence and trends of imported malaria in the Netherlands were estimated. Travellers statistics were used to estimate incidence, and data on malaria chemoprophylaxis prescriptions were used to estimate the number of unprotected travellers.ResultsImportation of malaria to the Netherlands is declining even as more travellers visit malaria-endemic countries. On average, 82% were acquired in sub-Saharan Africa, and 75% were caused by Plasmodium falciparum. The overall incidence in imported falciparum malaria fell from 21.5 to 6.6/10,000 of unprotected travellers. The percentage of unprotected travellers rose from 47% to 52% of all travellers. The incidence of imported falciparum infections is greatest from Middle and West Africa, and decreased from 121.3 to 36.5/10,000 travellers. The import of malaria from this region by immigrants visiting friends and relatives (VFR) decreased from 138 infections in 2000, to 69 infections in 2007.ConclusionThe annual number of imported malaria shows a continuing declining trend, even with an increasing number of travellers visiting malaria endemic countries. VFR import less malaria than previously, and contribute largely to the declining incidence seen. The decline is not readily explained by increased use of chemoprophylaxis and may reflect a reduced risk of infection due to decreasing local malaria transmission as observed in some malaria endemic areas. Nevertheless, the increasing number of unprotected travellers remains worrisome.

The effect of efavirenz versus nevirapine-containing regimens on immunologic, virologic and clinical outcomes in a prospective observational study.

Objective:To compare regimens consisting of either efavirenz or nevirapine and two or more nucleoside reverse transcriptase inhibitors (NRTIs) among HIV-infected, antiretroviral-naive, and AIDS-free individuals with respect to clinical, immunologic, and virologic outcomes. Design:Prospective studies of HIV-infected individuals in Europe and the US included in the HIV-CAUSAL Collaboration. Methods:Antiretroviral therapy-naive and AIDS-free individuals were followed from the time they started an NRTI, efavirenz or nevirapine, classified as following one or both types of regimens at baseline, and censored when they started an ineligible drug or at 6 months if their regimen was not yet complete. We estimated the ‘intention-to-treat’ effect for nevirapine versus efavirenz regimens on clinical, immunologic, and virologic outcomes. Our models included baseline covariates and adjusted for potential bias introduced by censoring via inverse probability weighting. Results:A total of 15 336 individuals initiated an efavirenz regimen (274 deaths, 774 AIDS-defining illnesses) and 8129 individuals initiated a nevirapine regimen (203 deaths, 441 AIDS-defining illnesses). The intention-to-treat hazard ratios [95% confidence interval (CI)] for nevirapine versus efavirenz regimens were 1.59 (1.27, 1.98) for death and 1.28 (1.09, 1.50) for AIDS-defining illness. Individuals on nevirapine regimens experienced a smaller 12-month increase in CD4 cell count by 11.49 cells/&mgr;l and were 52% more likely to have virologic failure at 12 months as those on efavirenz regimens. Conclusions:Our intention-to-treat estimates are consistent with a lower mortality, a lower incidence of AIDS-defining illness, a larger 12-month increase in CD4 cell count, and a smaller risk of virologic failure at 12 months for efavirenz compared with nevirapine.

Circulating lipoproteins are a crucial component of host defense against invasive Salmonella typhimurium infection.

Background Circulating lipoproteins improve the outcome of severe Gram-negative infections through neutralizing lipopolysaccharides (LPS), thus inhibiting the release of proinflammatory cytokines. Methods/Principal Findings Low density lipoprotein receptor deficient (LDLR−/−) mice, with a 7-fold increase in LDL, are resistant against infection with Salmonella typhimurium (survival 100% vs 5%, p<0.001), and 100 to 1000-fold lower bacterial burden in the organs, compared with LDLR+/+ mice. Protection was not due to differences in cytokine production, phagocytosis, and killing of Salmonella organisms. The differences were caused by the excess of lipoproteins, as hyperlipoproteinemic ApoE−/− mice were also highly resistant to Salmonella infection. Lipoproteins protect against infection by interfering with the binding of Salmonella to host cells, and preventing organ invasion. This leads to an altered biodistribution of the microorganisms during the first hours of infection: after intravenous injection of Salmonella into LDLR+/+ mice, the bacteria invaded the liver and spleen within 30 minutes of infection. In contrast, in LDLR−/− mice, Salmonella remained constrained to the circulation from where they were efficiently cleared, with decreased organ invasion. Conclusions plasma lipoproteins are a potent host defense mechanism against invasive Salmonella infection, by blocking adhesion of Salmonella to the host cells and subsequent tissue invasion.

Persisting arthralgia due to Mayaro virus infection in a traveler from Brazil: Is there a risk for attendants to the 2014 FIFA World Cup?

The 2014 FIFA World Cup and the 2016 Olympic Games will attract large groups of visitors to Brazil. These visitors will be at risk for different arboviral infections, some of which not well known outside endemic areas. We report a case of a 52-year-old Dutch woman who presented with persistent arthralgia due to a Mayaro virus (MAYV) infection which she contracted in the Amazon basin in Brazil. MAYV is a mosquito-borne alphavirus which primarily circulates in humid tropical forests of South America. Infections are rarely reported in travelers and are characterized by an acute febrile illness which is often followed by a prolonged and sometimes incapacitating polyarthralgia. Both travelers and physicians should be aware of the risk of these arboviral infections and the importance of mosquito bite prevention should be stressed.