Highly active antiretroviral therapy (HAART) results in potent and durable suppression of HIV-1 viremia. However, HIV-1 replication resumes if therapy is interrupted. Although it is generally believed that active replication has been halted in individuals on HAART, immune activation and inflammation continue at abnormal levels, suggesting continued, low-level viral replication. To assess whether active replication might be driving immune activation in HAART, we examined the impact of treatment intensification with the integrase inhibitor raltegravir on viral complementary DNA and immune activation parameters. In the presence of raltegravir, linear HIV-1 cDNA is prevented from integrating into chromatin and is subsequently converted to episomal cDNAs. Raltegravir intensification of a three-drug suppressive HAART regimen resulted in a specific and transient increase in episomal DNAs in a large percentage of HAART-suppressed subjects. Furthermore, in subjects with these episomal DNAs, immune activation was higher at baseline and was subsequently normalized after raltegravir intensification. These results suggest that, despite suppressive HAART, active replication persists in some infected individuals and drives immune activation. The ability of raltegravir intensification to perturb the reservoir that supports active replication has implications for therapeutic strategies aimed at achieving viral eradication.

Seventy-eight (24%) episodes of nosocomial pneumonia (NP) were detected in 322 consecutive mechanically ventilated patients admitted to a 1,000-bed teaching hospital from April 1987 through May 1988 to assess the incidence, risk, and prognosis factors of NP acquired during mechanical ventilation (MV). The risk and prognosis factors for developing NP during MV were studied using both univariate and multivariate statistical techniques. Multivariate analysis selected the following variables significantly associated with a higher risk for developing ventilator-associated pneumonia: more than one intubation during MV (p = 0.000012), a prior episode of aspiration of gastric content (p = 0.00018), a MV period longer than 3 days (p = 0.015), the presence of chronic obstructive pulmonary disease (COPD) (p = 0.048), and the use of positive end-expiratory pressure (PEEP) during MV (p = 0.092). The presence of an ultimately or rapidly fatal underlying disease (p = 0.0018), worsening of acute respiratory failure caused by pneumonia (p = 0.0096), the presence of septic shock (p = 0.016), an inappropriate antibiotic treatment (p = 0.02), and the type of intensive care unit (ICU) hospitalization (noncardiac surgery and nonsurgical ICU compared with post-cardiac surgery ICU) (p = 0.08) were those factors selected by a stepwise logistic regression analysis as independently worsening the prognosis. The overall fatality rate was 23% (73 of 322). The mortality of patients with NP was higher (33%; 26 of 78; p less than 0.01) when compared with fatality rates of patients without NP (19%; 47 of 244).(ABSTRACT TRUNCATED AT 250 WORDS)

In order to confirm that re-intubation can be a risk factor of nosocomial pneumonia in mechanically ventilated patients, a case-control study was performed. Forty consecutive patients needing re-intubation were selected as cases. Each case was paired with a matched control for the previous duration of mechanical ventilation (+/- 2 d). Nineteen (47%) of the cases developed pneumonia after re-intubation compared with 4 (10%) of the controls (odds ratio [OR] = 8.5; 95% confidence interval [CI] 1.7 to 105.9; p = 0.0007). After adjusting for age, sex, and presence of prior bronchoscopy, the conditional logistic regression analysis demonstrated that re-intubation was the only significant factor related to the development of pneumonia (OR: 5.94; 95% CI 1.27 to 22.71; p = 0.023). Sixteen (73%) of the 22 patients lying semirecumbent during the interval between extubation and re-intubation developed nosocomial pneumonia versus three (16%) of the 18 in supine position (p = 0.001). These results indicate that semirecumbency during the period between extubation and re-intubation may play a role in nosocomial pneumonia development in patients who need re-intubation. Total intensive care unit stay (19.4 +/- 10 versus 13.9 +/- 11.9 days, p = 0.0008) and crude mortality (35 versus 20%, p = 0.14) were also higher in re-intubated patients when compared with controls. We conclude that re-intubation is a risk factor for ventilator-associated pneumonia and might be avoided in a substantial number of cases.

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Intensification of HAART with raltegravir during 48 weeks was safe and associated with a significant decrease in CD8(+) T-cell activation, and a transient increase of episomal HIV-1 DNA. However, raltegravir did not significantly contribute to changes in CD4(+) T-cell counts, ultrasensitive VL, and total and integrated HIV-1 DNA. These findings suggest that raltegravir impacts residual HIV-1 replication and support new strategies to impair HIV-1 persistence. ClinicalTrials.gov identifier: NCT00554398.