Discrepancies between Protease Inhibitor Concentrations and Viral Load in Reservoirs and Sanctuary Sites in Human Immunodeficiency Virus-Infected Patients

The variable penetration of antiretroviral drugs into sanctuary sites may contribute to the differential evolution of human immunodeficiency virus (HIV) and the emergence of drug resistance. We evaluated the penetration of indinavir, nelfinavir, and lopinavir-ritonavir (lopinavir/r) in the central nervous system, genital tract, and lymphoid tissue and assessed the correlation with residual viral replication. Plasma, cerebrospinal fluid (CSF), semen, and lymph node biopsy samples were collected from 41 HIV-infected patients on stable highly active antiretroviral therapy regimens to determine drug concentrations and HIV RNA levels. When HIV RNA was detectable, sequencing of the reverse transcriptase and protease genes was performed. Ratios of the concentration in semen/concentration in plasma were 1.9 for indinavir, 0.08 for nelfinavir, and 0.07 for lopinavir. Only indinavir was detectable in CSF, with a concentration in CSF/concentration in plasma ratio of 0.17. Differential penetration into lymphoid tissue was observed, with concentration in lymph node tissue/concentration in plasma ratios of 2.07, 0.58, and 0.21 for indinavir, nelfinavir, and lopinavir, respectively. HIV RNA levels were <50 copies/ml in all CSF samples of patients in whom HIV RNA was not detectable in plasma. HIV RNA was detectable in the semen of three patients (two patients receiving nelfinavir and one patient receiving lopinavir/r), and its detection was associated with multiple resistance mutations, while the viral load in plasma was undetectable. HIV RNA was detectable in all lymph node tissue samples. Differential drug penetration was observed among the three protease inhibitors in the sanctuary sites, but there was no correlation between drug levels and HIV RNA levels, suggesting that multiple factors are involved in the persistence of viral reservoirs. Further studies are required to clarify the role and clinical relevance of drug penetration in sanctuaries in terms of long-term efficacy and drug resistance

Hamsi scoring in the prediction of unfavorable outcomes from tuberculous meningitis:results of Haydarpasa-II study

WOS: 000353295400011PubMed ID: 25634680Predicting unfavorable outcome is of paramount importance in clinical decision making. Accordingly, we designed this multinational study, which provided the largest case series of tuberculous meningitis (TBM). 43 centers from 14 countries (Albania, Croatia, Denmark, Egypt, France, Hungary, Iraq, Italy, Macedonia, Romania, Serbia, Slovenia, Syria, Turkey) submitted data of microbiologically confirmed TBM patients hospitalized between 2000 and 2012. Unfavorable outcome was defined as survival with significant sequela or death. In developing our index, binary logistic regression models were constructed via 200 replicates of database by bootstrap resampling methodology. The final model was built according to the selection frequencies of variables. The severity scale included variables with arbitrary scores proportional to predictive powers of terms in the final model. The final model was internally validated by bootstrap resampling. A total of 507 patients' data were submitted among which 165 had unfavorable outcome. Eighty-six patients died while 119 had different neurological sequelae in 79 (16 %) patients. The full model included 13 variables. Age, nausea, vomiting, altered consciousness, hydrocephalus, vasculitis, immunosuppression, diabetes mellitus and neurological deficit remained in the final model. Scores 1-3 were assigned to the variables in the severity scale, which included scores of 1-6. The distribution of mortality for the scores 1-6 was 3.4, 8.2, 20.6, 31, 30 and 40.1 %, respectively. Altered consciousness, diabetes mellitus, immunosuppression, neurological deficits, hydrocephalus, and vasculitis predicted the unfavorable outcome in the scoring and the cumulative score provided a linear estimation of prognosis

Features of cryptococcosis among 652 HIV-seronegative individuals in France: a cross-sectional observational study (2005-2020)

International audienceObjectives: We aimed to describe features and outcomes of cryptococcosis among HIV-seronegative individuals in a large surveillance network for cryptococcosis in France.Methods: We included incident cases of cryptococcosis in HIV-seronegative individuals from 2005 to 2020. We compared patient characteristics, disease presentations, cryptococcal antigen (CrAg) results, and induction antifungal treatments according to underlying disease. We examined factors associated with 90-day mortality. Among patients with disseminated infections, we investigated whether receipt of flucytosine and polyene combination was associated with lower mortality.Results: Among 652 individuals, 209 (32.1%) had malignancy, 130 (19.9%) were solid-organ transplant (SOT) recipients, 204 (31.3%) had other immunocompromising conditions, and 109 (16.7%) had no reported underlying factor. The commonest presentations were disseminated infections (63.3%, 413/652) and isolated pulmonary infections (25.3%, 165/652). SOT patients were most likely to have disseminated infections and a positive serum CrAg result. Patients with malignancy were older and less likely to receive a flucytosine-containing regimen for disseminated infections than others (58.7%, 78/133 vs. 73.2%, 194/265, p=0.029). The crude 90-day case-fatality ratio was 27.2% (95%CI: 23.5%-31.1%). Age ≥60 years (aOR: 2.75 [1.78-4.26], p<0.001), meningitis/fungaemia (aOR: 4.79 [1.80-12.7], p=0.002), and malignancy (aOR: 2.4 [1.14-5.07], p=0.02) were associated with higher 90-day mortality. Receipt of flucytosine and polyene combination was associated with lower 90-day mortality (aOR: 0.40 [0.23-0.71], p=0.002) in multivariable analysis and inverse probability of treatment weighted analysis (aOR: 0.45 [0.25-0.80], p=0.006).Conclusions: HIV-seronegative individuals with cryptococcosis comprise a wide range of underlying conditions with different presentations and outcomes, requiring a tailored approach to diagnosis and management