Population pharmacokinetics of dolutegravir: influence of drug-drug interactions in a real-life setting.

OBJECTIVES: Dolutegravir is widely prescribed owing to its potent antiviral activity, high genetic barrier and good tolerability. The aim of this study was to characterize dolutegravir's pharmacokinetic profile and variability in a real-life setting and to identify individual factors and co-medications affecting dolutegravir disposition. METHODS: A population pharmacokinetic model was developed using NONMEM®. Relevant demographic factors, clinical factors and co-medications were tested as potential covariates. Simulations based on the final model served to compare expected dolutegravir concentrations under standard and alternative dosage regimens in the case of drug-drug interactions. RESULTS: A total of 620 dolutegravir plasma concentrations were collected from 521 HIV-infected individuals under steady-state conditions. A one-compartment model with first-order absorption and elimination best characterized dolutegravir pharmacokinetics. Typical dolutegravir apparent clearance (CL/F) was 0.93 L/h with 32% between-subject variability, the apparent volume of distribution was 20.2 L and the absorption rate constant was fixed to 2.24 h-1. Older age, higher body weight and current smoking were associated with higher CL/F. Atazanavir co-administration decreased dolutegravir CL/F by 38%, while darunavir modestly increased CL/F by 14%. Rifampicin co-administration showed the largest impact on CL/F. Simulations suggest that average dolutegravir trough concentrations are 63% lower after 50 mg/12h with rifampicin compared with a standard dosage of 50 mg/24h without rifampicin. Average trough concentrations after 100 mg/24h and 100 mg/12h with rifampicin are 92% and 25% lower than the standard dosage without rifampicin, respectively. CONCLUSIONS: Patients co-treated with dolutegravir and rifampicin might benefit from therapeutic drug monitoring and individualized dosage increase, up to 100 mg/12 h in some cases.

Seroprotection rates of vaccine-preventable diseases among newly arrived Eritrean asylum seekers in Switzerland: a cross-sectional study.

BACKGROUND: According to 2016 World Health Organization and United Nations Children's Fund country estimates, Eritrea has overall high vaccination coverage with immunization rates for three doses of diphtheria/tetanus/pertussis and polio vaccine of 95%, for two doses measles vaccine of 85% and for three doses hepatitis B vaccine of 85%. If confirmed, this could imply that routine basic vaccination of newly arrived Eritreans could be safely omitted. METHODS: We used stored serum samples from two cross-sectional studies that screened newly arrived Eritrean refugees for infectious diseases. Consenting refugees aged 16 years and older who registered in one of three neighbouring cantons in northwestern Switzerland were enrolled between January 2016 and December 2017. Antibody titers against the following vaccine-preventable diseases were measured (applied thresholds for seroprotection in brackets): diphtheria (>0.1 IU/ml), tetanus (>0.1 IU/ml), measles (>150 mIU/ml), rubella (only for women, >11 IU/ml), varicella (>50 mIU/ml), hepatitis B [hepatitis B surface antigen (HBsAg) Index >0.9, Hepatitis B core antibody (anti-HBc) Index >0.9 and antibodies to HBsAg (anti-HBs) >10 IE/L]. Differences between sex and age groups (≤25 and >25 years) were measured by Fisher's exact test. RESULTS: We analysed samples of 133 study participants (20 women, 15%) with a median age of 25 years (range 16-61). Rates of seropositivity were as follows for women/men, respectively: diphtheria 57.9%/74.8% (difference non-significant), tetanus 94.8%/41.1% (P < 0.001), measles 73.7%/76.6% (non-significant), rubella in women 78.9%, varicella 89.5%/95.3% (non-significant), anti-HBc 15.8%/26.2% (non-significant) and anti-HBs 15.8%/17.8% (non-significant). CONCLUSION: Seroprevalence for vaccine-preventable infections did not meet levels required to confer herd immunity in any of the human-to-human transmissible diseases that were studied. In general, the strategy proposed by the Federal Office of Public Health to offer basic immunization to all newly arrived refugees, including newly arriving Eritrean refugees, is justified.

Coverage of atypical pathogens for hospitalised patients with community-acquired pneumonia is not guided by clinical parameters.

BACKGROUND: Although most experts recommend empirical antibiotic treatment, covering also atypical bacteria, for patients admitted to an intensive care unit (ICU), the data are not clear for patients admitted to a general ward. European guidelines recommend starting empirical treatment with a beta-lactam antibiotic with or without a macrolide, but the with/without is not clarified. We investigated whether the use of antibiotic coverage for atypical pathogens was guided by clinical parameters. METHODS: We retrospectively analysed 300 patients hospitalised with community-acquired pneumonia. Four parameters for possible atypical pneumonia (age <55 years, abdominal symptoms, sodium <130 mmol/l, immunosuppression) and three for pneumonia severity (pneumonia severity index [PSI], ICU admission, pO2 <8 kPa (60 mm Hg) or O2 saturation <90%) were defined and correlated with the probability of coverage for atypical pathogens. Correlations were calculated using the chi-square test for 2 x 2 tables. RESULTS: Patients younger than 55 years significantly more likely to receive coverage for atypical pathogens than older patients (odds ratio [OR] 2.68; 95% confidence interval [CI] 1.3-5.5, p = 0.009). In patients with a PSI >III the proportion receiving coverage for atypical bacteria was even smaller than in patients with less severe pneumonia (OR 0.77; 95% CI 0.60-0.99, p = 0.03), but no difference was found for PSI >IV compared with PSI ≤IV (OR = 1.03; 95% CI 0.61-1.74, p = 0.9). The other clinical parameters had no effect on antibiotic coverage: ICU admission (OR =1.39; 95% CI 0.87-2.4, p = 0.15); pO2 >8 kPa or O2-Saturation >90% (OR 1.36; 95% CI 0.85-2.17, p = 0.19); abdominal symptoms (OR 1.06; 95% CI 0.51-2.25, p = 0.88); sodium <130 mmol/l (OR 0.63; 95% CI 0.29-1.36, p = 0.2) or immunosuppression (OR 1.007; 95% CI 0.462-44, p = 1). There was also no correlation between the number of clinical parameters present and the coverage of atypical pathogens (r = 0.48). Mortality was no different between patients in whom atypical pathogens were covered compared with those with beta-lactam therapy alone (OR 1.2; 95% CI 0.66-2.25, p = 0.43). CONCLUSION: Physicians have difficulties deciding when to cover atypical pathogens in hospitalised patients with community-acquired pneumonia. Guidelines should clarify under what circumstances combination therapy is warranted.