Publications

Many antiretroviral drugs continue to exert an anti-human immunodeficiency virus (HIV) benefit in the presence of drug resistance mutations. The degree to which enfuvirtide exerts continued antiviral activity in the presence of incomplete viral suppression has not been defined. To address this question, 25 subjects interrupted enfuvirtide while remaining on a stable background regimen. Enfuvirtide interruption was associated with an immediate but limited increase in plasma HIV-1 RNA levels. Enfuvirtide resistance waned rapidly in the absence of drug pressure and was no longer detectable by week 16 in most individuals. These data indicate that enfuvirtide has measurable antiviral activity in the setting of incomplete viral suppression. Although enfuvirtide resistance mutations are associated with significant fitness defects in vivo, the clinical significance of these mutations remains undefined.

INTRODUCTION

Follow-up among women who have had an abnormal Papanicolaou (Pap) smear is often poor in public hospitals that serve women at increased risk for cervical cancer. This randomized controlled trial evaluated and compared the total cost and cost per follow-up of a tailored outreach intervention plus usual care with the total cost and cost per follow-up of usual care alone.

METHODS

Women with an abnormal Pap smear (n = 348) receiving care at Alameda County Medical Center (Alameda County, California) were randomized to intervention or usual care. The intervention used trained community health advisors to complement the clinic's protocol for usual care. We assessed the costs of the intervention and the cost per follow-up within 6 months of the abnormal Pap smear test result.

RESULTS

The intervention increased the rate of 6-month follow-up by 29 percentage points, and the incremental cost per follow-up was 959 dollars (2005 dollars). The cost per follow-up varied by the severity of the abnormality. The cost per follow-up for the most severe abnormality (high-grade squamous intraepithelial lesion) was 681 dollars, while the cost per follow-up for less severe abnormalities was higher.

CONCLUSION

In a health care system in which many women fail to get follow-up care for an abnormal Pap smear, outreach workers were more effective than usual care (mail or telephone reminders) at increasing follow-up rates. The results suggest that outreach workers should manage their effort based on the degree of abnormality; most effort should be placed on women with the most severe abnormality (high-grade squamous intraepithelial lesion).

The surface of the airway epithelium represents a battleground in which the host intercepts signals from pathogens and activates epithelial defenses to combat infection. Wound repair is an essential function of the airway epithelium in response to injury in chronic airway diseases, and inhaled pathogens such as Pseudomonas bacteria are implicated in the pathobiology of several of these diseases. Because epidermal growth factor receptor (EGFR) activation stimulates wound repair and because LPS activates EGFR, we hypothesized that LPS accelerates wound repair via a surface signaling cascade that causes EGFR phosphorylation. In scrape wounds of NCI-H292 human airway epithelial cells, high concentrations of LPS were toxic and decreased wound repair. However, lower concentrations of LPS accelerated wound repair. This effect was inhibited by treatment with a selective inhibitor of EGFR phosphorylation (AG 1478) and by an EGFR neutralizing Ab. Metalloprotease inhibitors and TNF-alpha-converting enzyme (TACE) small interfering RNA inhibited wound repair, implicating TACE. Additional studies implicated TGF-alpha as the active EGFR ligand cleaved by TACE during wound repair. Reactive oxygen species scavengers, NADPH oxidase inhibitors, and importantly small interfering RNA of dual oxidase 1 inhibited LPS-induced wound repair. Inhibitors of protein kinase C isoforms alphabeta and a TLR-4 neutralizing Ab also inhibited LPS-induced wound repair. Normal human bronchial epithelial cells responded similarly. Thus, LPS accelerates wound repair in airway epithelial cells via a novel TLR-4-->protein kinase C alphabeta-->dual oxidase 1-->reactive oxygen species-->TACE-->TGF-alpha-->EGFR phosphorylation pathway.

BACKGROUND

The use of genotyping to distinguish recrudescent from new infections is currently recommended for all clinical antimalarial efficacy trials by the World Health Organization. However, genotyping-adjusted drug efficacy estimates may vary between trials due to the use of different genotyping methods and to the different settings in which these methods are applied.

METHODS

A systematic review of all clinical antimalarial efficacy trials published from 1995-2005 was performed to characterize the use of genotyping, including the methods used and the effect of these methods on estimates of drug efficacy.

RESULTS

In a multivariate analysis, the method of interpretation of genotyping results, the studied therapy, the location of the trial, and the duration of study follow-up all had statistically significant effects on the percent of genotyped outcomes classified as new infections.

CONCLUSION

Criteria for defining appropriate, standardized genotyping methods for use in different settings are needed to enable more accurate estimates of antimalarial drug efficacy and better comparison between trials. The advantages and disadvantages of different genotyping methods and their potential impact in various settings are discussed.