Antiretroviral therapies in women after single-dose nevirapine exposure.

BACKGROUND: Peripartum administration of single-dose nevirapine reduces mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) but selects for nevirapine-resistant virus. METHODS: In seven African countries, women infected with HIV-1 whose CD4+ T-cell counts were below 200 per cubic millimeter and who either had or had not taken single-dose nevirapine at least 6 months before enrollment were randomly assigned to receive antiretroviral therapy with tenofovir­emtricitabine plus nevirapine or tenofovir-emtricitabine plus lopinavir boosted by a low dose of ritonavir. The primary end point was the time to confirmed virologic failure or death. RESULTS: A total of 241 women who had been exposed to single-dose nevirapine began the study treatments (121 received nevirapine and 120 received ritonavir-boosted lopinavir). Significantly more women in the nevirapine group reached the primary end point than in the ritonavir-boosted lopinavir group (26% vs. 8%) (adjusted P=0.001). Virologic failure occurred in 37 (28 in the nevirapine group and 9 in the ritonavir-boosted lopinavir group), and 5 died without prior virologic failure (4 in the nevirapine group and 1 in the ritonavir-boosted lopinavir group). The group differences appeared to decrease as the interval between single-dose nevirapine exposure and the start of antiretroviral therapy increased. Retrospective bulk sequencing of baseline plasma samples showed nevirapine resistance in 33 of 239 women tested (14%). Among 500 women without prior exposure to single-dose nevirapine, 34 of 249 in the nevirapine group (14%) and 36 of 251 in the ritonavir-boosted lopinavir group (14%) had virologic failure or died. CONCLUSIONS: In women with prior exposure to peripartum single-dose nevirapine (but not in those without prior exposure), ritonavir-boosted lopinavir plus tenofovir­emtricitabine was superior to nevirapine plus tenofovir­emtricitabine for initial antiretroviral therapy. (Funded by the National Institute of Allergy and Infectious Diseases and the National Research Center; ClinicalTrials.gov number, NCT00089505.).

Bioavailability of generic ritonavir and lopinavir/ritonavir tablet products in a dog model.

In this study, we explored the bioavailability in dogs and chemical potency of generic ritonavir and lopinavir/ritonavir tablet products manufactured by various pharmaceutical companies. Chemical potency of the products was examined by HPLC quantitation of ritonavir and lopinavir. Using a dog model, we determined point estimates for C(max) and AUC of ritonavir and lopinavir/ritonavir for eight generic products compared to Abbott's Norvir capsule and Kaletra tablet. Chemical potencies ranged from 79.0% to 104.6%. Point estimates for AUC in the generic tablet products ranged from 0.01 to 1.11, indicating that the relative bioavailability of these formulations was in the range of 1-111% compared to the branded products. This study showed significant variability in bioavailability in a dog model amongst generic tablet products containing the protease inhibitors ritonavir or lopinavir/ritonavir. The chemical potency of the generic products was not indicative of the plasma levels of ritonavir or lopinavir that were achieved. These results reinforce the need for human bioequivalence testing of generic products containing ritonavir or lopinavir/ritonavir to assure that efficacy in patients is not compromised prior to these products being made available to patients. Procurement policies of funding agencies should require such quality assurance processes.

Geographic and temporal trends of transmitted HIV-1 drug resistance among antiretroviral-naïve subjects screening for two clinical trials in North America and Western Europe.

PURPOSE: To determine the prevalence of transmitted drug resistance (TDR) in antiretroviral (ARV)-naïve HIV-1-infected subjects who were screened for two clinical trials by geographic region and time. METHODS: Studies M03-613 and M05-730 screened ARV-naïve subjects in 2004 and 2005-2006, respectively. Screening drug resistance genotype assays were performed using population sequencing, and prevalence of drug resistance mutations (DRMs) was assessed at 39 amino acid positions in HIV-1 protease and reverse transcriptase (RT) and compared between geographic regions and calendar years. RESULTS: In 913 subjects, the prevalence of DRMs was higher in North America than in Western Europe, including any DRM (13.6% vs. 6.8%, p < .001), non-nucleoside reverse transcriptase inhibitor (NNRTI) DRMs (7.3% vs. 3.2%, p = .006), protease inhibitor (PI) DRMs (3.6% vs. 0.8%, p = .004), and nucleoside reverse transcriptase inhibitor (NRTI) DRMs (6.1% vs. 3.8%, p = ns). The prevalence of TDR to NNRTIs was higher compared to PIs within each region (p = .031 for North America, and p = .011 for Western Europe). Logistic regression analysis suggested a higher prevalence of DRMs in 2005-2006 compared to 2004 for NNRTIs (p = .03) and, to a lesser extent, for PIs (p = .07). CONCLUSION: TDR to NNRTIs was more frequent than to PIs in both geographic regions, increased over time, and was highest in North America.

A case-control study of gynecomastia in HIV-1-infected patients receiving HAART.

Gynecomastia has been reported to occur in HIV-infected patients receiving HAART. A retrospective case-control study was conducted to determine risk factors associated with this condition. Two control patients were randomly chosen for each of 23 case patients identified. An efavirenz-containing regimen was strongly associated with the development of gynecomastia (odds ratio, 20; P < .001). Case patients were not more likely to have lipodystrophy, low testosterone levels, chronic infection with hepatitis B or C virus, or liver dysfunction compared with control patients. None of these factors altered the efavirenz-associated risk when analyzed by multiple logistic regression. Efavirenz appears to be strongly associated with gynecomastia in HIV-infected patients receiving HAART.

Linezolid-resistant, vancomycin-resistant Enterococcus faecium infection in patients without prior exposure to linezolid.

We describe 2 patients without prior exposure to linezolid who were infected with closely related strains of linezolid- and vancomycin-resistant Enterococcus faecium (LRVREF) that may have been hospital acquired. Polymerase chain reaction amplification of the domain V region of the 23S ribosomal RNA gene demonstrated the presence of the G2576U mutation previously reported to be associated with linezolid resistance. Nosocomial transmission of LRVREF is an ominous sign and underscores the importance of meticulous infection-control measures.