Impact of the HIV-1 env Genetic Context outside HR1–HR2 on Resistance to the Fusion Inhibitor Enfuvirtide and Viral Infectivity in Clinical Isolates

Resistance mutations to the HIV-1 fusion inhibitor enfuvirtide emerge mainly within the drug's target region, HR1, and compensatory mutations have been described within HR2. The surrounding envelope (env) genetic context might also contribute to resistance, although to what extent and through which determinants remains elusive. To quantify the direct role of the env context in resistance to enfuvirtide and in viral infectivity, we compared enfuvirtide susceptibility and infectivity of recombinant viral pairs harboring the HR1–HR2 region or the full Env ectodomain of longitudinal env clones from 5 heavily treated patients failing enfuvirtide therapy. Prior to enfuvirtide treatment onset, no env carried known resistance mutations and full Env viruses were on average less susceptible than HR1–HR2 recombinants. All escape clones carried at least one of G36D, V38A, N42D and/or N43D/S in HR1, and accordingly, resistance increased 11- to 2800-fold relative to baseline. Resistance of full Env recombinant viruses was similar to resistance of their HR1–HR2 counterpart, indicating that HR1 and HR2 are the main contributors to resistance. Strictly X4 viruses were more resistant than strictly R5 viruses, while dual-tropic Envs featured similar resistance levels irrespective of the coreceptor expressed by the cell line used. Full Env recombinants from all patients gained infectivity under prolonged drug pressure; for HR1–HR2 viruses, infectivity remained steady for 3/5 patients, while for 2/5 patients, gains in infectivity paralleled those of the corresponding full Env recombinants, indicating that the env genetic context accounts mainly for infectivity adjustments. Phylogenetic analyses revealed that quasispecies selection is a step-wise process where selection of enfuvirtide resistance is a dominant factor early during therapy, while increased infectivity is the prominent driver under prolonged therapy

Characteristics and outcomes of patients with a haematological malignancy admitted to the intensive care unit for a neurological event

Objectives: Patients with haematological malignancies are at risk of concomitant critical neurological events warranting intensive care unit admission. We aimed to examine the characteristics and outcomes of this patient population, as more knowledge could facilitate decision making on ICU admission and treatment. Design, setting and participants: A retrospective cohort study of 68 patients in adult ICUs of six Dutch university hospitals between 2003 and 2011. Results: The median Acute Physiology and Chronic Health Evaluation (APACHE) II score was 23 (IQR, 16-27), and 77% of patients needed mechanical ventilation within the first 24 hours of admission. Forty percent of patients had received an allogeneic stem cell transplantation, and 22% were neutropenic on admission. The most frequent underlying haematological condition was non-Hodgkin lymphoma (27%). Seizures were the most common neurological event for ICU admission (29%). The median ICU length of stay was 5 days (IQR, 1-13 days). ICU mortality (28%), hospital mortality (37%) and 3-month mortality (50%) were comparable with other studies of ICU patients with haematological malignancies. Factors associated with 3-month survival were baseline platelet count (113x10(9)/L in survivors v 39x10(9)/L in non-survivors, P < 0.01) and APACHE II score (20 in survivors v 25 in non-survivors, P=0.02). Conclusions: Patients with a history of haematological malignancy presenting with a critical neurological event have comparable survival rates with other patients with a haematologic malignancy admitted to the ICU. Our findings suggest that restrictions in ICU care are not justified for this patient population

Characteristics and outcomes of patients with a haematological malignancy admitted to the intensive care unit for a neurological event

Objectives: Patients with haematological malignancies are at risk of concomitant critical neurological events warranting intensive care unit admission. We aimed to examine the characteristics and outcomes of this patient population, as more knowledge could facilitate decision making on ICU admission and treatment. Design, setting and participants: A retrospective cohort study of 68 patients in adult ICUs of six Dutch university hospitals between 2003 and 2011. Results: The median Acute Physiology and Chronic Health Evaluation (APACHE) II score was 23 (IQR, 16-27), and 77% of patients needed mechanical ventilation within the first 24 hours of admission. Forty percent of patients had received an allogeneic stem cell transplantation, and 22% were neutropenic on admission. The most frequent underlying haematological condition was non-Hodgkin lymphoma (27%). Seizures were the most common neurological event for ICU admission (29%). The median ICU length of stay was 5 days (IQR, 1-13 days). ICU mortality (28%), hospital mortality (37%) and 3-month mortality (50%) were comparable with other studies of ICU patients with haematological malignancies. Factors associated with 3-month survival were baseline platelet count (113x10(9)/L in survivors v 39x10(9)/L in non-survivors, P <0.01) and APACHE II score (20 in survivors v 25 in non-survivors, P=0.02). Conclusions: Patients with a history of haematological malignancy presenting with a critical neurological event have comparable survival rates with other patients with a haematologic malignancy admitted to the ICU. Our findings suggest that restrictions in ICU care are not justified for this patient population

Prevalence of HIV and syphilis in pregnant women in Leon, Nicaragua

The objective of this study was to determine the prevalence of HIV and syphilis and to identify risk factors among pregnant women visiting antenatal clinics in León, Nicaragua. During February to April 2004, blood samples from pregnant women were collected after written consent had been obtained. The samples were tested for antibodies against HIV and Treponema pallidum. A questionnaire was also completed. In total, 1,059 women were included. Antibodies against HIV were not detected in any of the women, whereas antibodies against T. pallidum were detected in 16 (1.5%). Risk factors for syphilis included illiteracy, lower education, and two or more pregnancies. HIV does not seem to be highly prevalent among pregnant women in León (prevalence, 0%; 95% CI, 0.0-0.3). The higher proportion of women infected with syphilis than found in earlier studies suggests that sexually transmitted diseases are circulating in the general population and highlights the increasing importance of HIV prevention