Efficacy of raltegravir switching strategies in HIV-infected patients with suppressed viraemia according to the genotypic sensitivity score.

BACKGROUND AND PURPOSE: The lack of antiretroviral (ARV) backbone activity associated with raltegravir has been proposed as the main explanation for virological relapse observed in patients with undetectable viraemia who are switched from a ritonavir-boosted protease inhibitor (PI) to raltegravir. However ARV activity remains difficult to assess in this context. The aim of our study was to precisely assess the ARV backbone activity in patients with undetectable viraemia who underwent raltegravir switching strategies and to evaluate the efficacy of such switching strategies based on the genotypic sensitivity score (GSS). METHODS: Patients with a plasma human immunodeficiency virus type 1 (HIV-1) RNA level of <50 copies/mL on a stable two ARV-class regimen were enrolled if they switched one of their ARV drugs to raltegravir 400 mg twice daily. The GSS was calculated using a genotyping test performed on the HIV-1 RNA of the last plasma measurement with a HIV-1 RNA level of >50 copies/mL before the switch and on the results of all previous genotyping tests. The primary endpoint was the proportion of patients with a plasma HIV-1 RNA level of <50 copies/mL at week 24. RESULTS: Fifty-six patients were enrolled in this study. The proportion of patients with a plasma HIV-1 RNA level of <50 copies/mL at week 24 was 92.9 % (range 83.0-97.2 %) in the intent-to-treat analysis and 98.1 % (90.0-99.7 %) in per-protocol analysis. When the backbone was fully active, the proportion was 100.0 % (86.7-100.0 %) at week 24 and week 48 in the per-protocol analysis. We observed a decrease in plasma total cholesterol and triglycerides of -12.7 % (p = 0.005) and -26.5 % (p = 0.001), respectively. CONCLUSIONS: Raltegravir switching strategies are effective when the associated backbone is fully active according to the GSS. In the context of undetectable viraemia, where ARV activity remains difficult to assess, the determination of the GSS requires the entire ARV history of the patient and all previous HIV-RNA genotyping test results.

Switch from etravirine twice daily to once daily in non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV-infected patients with suppressed viremia: the Monetra study.

BACKGROUND: Etravirine (ETR) is recommended as twice-daily dosing in pretreated patients. There are no data regarding the use of ETR once daily in HIV-experienced patients with prior resistance to first-generation non-nucleoside reverse transcripase inhibitors (NNRTIs). OBJECTIVES: To evaluate the capacity of once-daily ETR to maintain suppressed viremia over 48 weeks after switching from ETR twice daily in NNRTI-experienced patients. METHODS: In this pilot open-label study, patients with plasma viral load (pVL) <50 copies/mL on a stable ETR 200 mg bid regimen were enrolled to switch to ETR 400 mg qd and followed up over 48 weeks. The primary endpoint was the proportion of patients with pVL <50 copies/mL at week 24. Secondary endpoints included the rate of pVL< 50 copies/mL at week 48, ETR pharmacokinetic parameters, and tolerability and resistance profile. RESULTS: Twenty-four patients were included. They had extensive antiretroviral treatment for a median of 14 years (range, 1-19). All except for 2 had prior resistance to NNRTIs. Seven patients discontinued ETR once daily prior to week 48 for virological failure (3), protocol deviation (3), and side effects (1). At week 24, 95% of patients maintained pVL< 50 copies/mL (95% CI, 78.4-99.7) and 85% at week 48 (95%CI, 65.6-95.8). Two of the 3 patients with virological failure had ETR resistance mutations prior to initiation. The median ETR C(trough) level remained stable after switching from twice daily 515 ng/mL (340-758) to once daily 422 ng/mL (264-655). CONCLUSION: These results suggest that ETR is effective as a once-daily regimen in patients with prior NNRTI experience when HIV is sensitive to ETR. The stability of C(trough) concentrations on a once-daily regimen confirms the once-daily profile of the drug in experienced patients.

The nipple valve as a sphincter substitute for the ileocecal valve: prevention of bacterial overgrowth in the small bowel.

We evaluated the bacteriologic effect of a nipple valve substitute for the ileocecal valve in a canine model. Resection of the ileocecal valve and the distal 40% of the jejunoileum with end-to-end anastomosis was carried out in 10 dogs. In five of the dogs chosen randomly, a nipple valve was constructed at the anastomosis; in the remainder , a two-layer jejunocolostomy was formed. Microbiologic samples were taken at operation in the ascending colon and at three sites in the small intestine before resection and at reoperation 4 weeks later. These revealed a dramatic increase in anaerobic bacteria in the distal jejunum following jejunocolostomy without valve insertion but no increase following jejunocolostomy with nipple valve. There was a seven-log difference between the two groups in the mean anaerobic bacterial counts (P less than 0.05) measured 60 cm proximal to the anastomosis at the second operation. Results of aerobic cultures were similar but less dramatic. We conclude that construction of a nipple valve jejunocolostomy prevents anaerobic bacterial colonization of the proximal small bowel and may therefore be useful in the treatment or prevention of short bowel syndrome.

Medium-term follow-up of the Ionescu-Shiley heterograft valve.

Utilizing a questionnaire specifically designed to uncover potential thromboembolic episodes, we personally interviewed 97 patients who underwent valve replacement with the Ionescu-Shiley valve between January, 1977, and June, 1980. In both the aortic and mitral positions, the attrition rate after the first year was low; cumulative survival at 3 to 4 years was 78% (aortic) and 61% (mitral). None of the deaths were attributed to primary valve failure. Patients with aortic prostheses, none of whom were anticoagulated, had a cumulative thromboembolism-free rate of 94% at 3 to 4 years. Patients with mitral prostheses had a thromboembolism-free rate of 71% at 3 to 4 years with 80% of the episodes occurring in patients in atrial fibrillation. Most emboli produced only transient symptoms, and only 1 patient has residual impairment. The Ionescu-Shiley valve performs well in the early years after valve replacement. Anticoagulation should be strongly considered for patients with mitral prostheses who are in atrial fibrillation.

Microbiologic efficacy of a surgically constructed nipple valve.

The efficacy of a surgically constructed nipple valve in preventing reflux of colonic bacteria into the small bowel was evaluated. The nipple valve significantly decreased the number of S. marcescens, a marker bacterium, in the small bowel when compared with plain ileocolic anastomosis. In this study, the nipple valve prevented the reflux of bacteria similar to an intact ileocecal valve which suggests that the nipple valve is an effective bacteriologic barrier and may be used as a substitute for the ileocecal valve in patients with short bowel syndrome.

Effect of steroids on the cardiac output and renal changes of bacteremia.

The effects of methyl prednisolone pretreatment in dogs prior to a bacterial infusion were measured in relation to cardiac output, blood pressure, intrarenal blood flow, and glomerular filtration rate. In dogs not pretreated with steroid, cardiac output fell 61.1 per cent 30 min postbacterial infusion and remained depressed for the balance of the experiment. Pretreated animals showed a similar 61 per cent depression in cardiac output immediately following bacterial infusion, but then experienced recovery of cardiac output and blood pressure to levels not significantly different from controls at the conclusion of the experiment. Changes in outer cortical bloodflow and glomerular filtration rate were not affected by steroid pretreatment. Based on the above data, the author concludes that the salutary effect of steroid pretreatment on cardiovascular dynamics occurs independently of changes in renal function.