Publications

OBJECTIVES

Adherence to the American Association for the Study of Liver Disease (AASLD) guidelines for the management of chronic hepatitis B (CHB) has not been systematically assessed. We sought to comprehensively evaluate adherence to five key areas of these guidelines. We also evaluated physician and patient factors underlying nonadherence, and predictors of nonadherence such as physician type, patient demographic factors, and phase of CHB infection.

METHODS

Nine hundred and sixty-two adult patients were retrospectively identified. Each patient chart was reviewed in detail. The primary outcome was adherence to five areas of the AASLD guidelines: (i) timely alanine aminotransferase (ALT)/hepatitis B virus DNA level checks needed to monitor inactive carrier and immune-tolerant phases; (ii) liver biopsy to guide decisions on initiating treatment; (iii) treatment initiation when indicated; (iv) hepatocellular carcinoma (HCC) screening; (v) testing for hepatitis A virus (HAV) immunity, HIV, and hepatitis C virus (HCV) co-infections.

RESULTS

Sixty percent did not undergo clinically indicated liver biopsies, largely owing to physician nonadherence. Eighty-nine percent of these missed biopsies were needed to further assess possible e-antigen-negative CHB. A high treatment initiation rate was found for the treatment eligible, but 121 patients had unclear treatment eligibility as they warranted, but did not undergo, liver biopsy. Forty-five percent did not have timely HCC screening, although gastroenterology physicians had the highest odds of adherence, and 29% did not have timely CHB lab assessment; patients seen by gastroenterologists had twice the odds compared with primary care physicians of undergoing timely lab monitoring. Thirty-five, 24, and 54% were not tested for HAV, HCV, and HIV co-infections.

CONCLUSIONS

Our findings show remarkably poor adherence to AASLD guidelines, particularly in the areas of liver biopsy, timely HCC and ALT monitoring, and testing for co-infection. These findings call for greater efforts to meet physician knowledge gaps, incorporation of decision support tools, and improved communication among providers.

BACKGROUND

In the Prevention of Malaria and HIV disease in Tororo pediatrics trial, HIV-infected Ugandan children randomized to receive lopinavir/ritonavir (LPV/r)-based antiretroviral therapy (ART) experienced a lower incidence of malaria compared with children receiving nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART. Here we present the results of the noninferiority analysis of virologic efficacy and comparison of immunologic outcomes.

METHODS

ART-naive or -experienced (HIV RNA <400 copies/mL) children aged 2 months to 6 years received either LPV/r or NNRTI-based ART. The proportion of children with virologic suppression (HIV RNA <400 copies/mL) at 48 weeks was compared using a prespecified noninferiority margin of -11% in per-protocol analysis. Time to virologic failure by 96 weeks, change in CD4 counts and percentages, and incidence of adverse event rates were also compared.

RESULTS

Of 185 children enrolled, 91 initiated LPV/r and 92 initiated NNRTI-based ART. At baseline, the median age was 3.1 years (range, 0.4-5.9), and 131 (71%) children were ART-naive. The proportion of children with virologic suppression at 48 weeks was 80% (67/84) in the LPV/r arm vs. 76% (59/78) in the NNRTI arm, a difference of 4% (95% confidence interval: -9% to +17%). Time to virologic failure, CD4 changes, and the incidence of Division of AIDS grade III/IV adverse events were similar between arms.

CONCLUSIONS

LPV/r-based ART was not associated with worse virologic efficacy, immunologic efficacy, or adverse event rates compared with NNRTI-based ART. Considering these results and the reduction in malaria incidence associated with LPV/r previously reported for this trial, wider use of LPV/r to treat HIV-infected African children in similar malaria-endemic settings could be considered.

BACKGROUND

Symptom-based tuberculosis screening identifies less than one-third of eligible HIV-infected patients as candidates for isoniazid preventive therapy (IPT). We evaluated whether testing for C-reactive protein (CRP) improves patient selection for IPT.

METHODS

We measured CRP levels (normal <10 mg/L) using a point-of-care (POC) assay on stored serum samples from HIV-infected Ugandan adults initiating antiretroviral therapy. We assessed diagnostic accuracy in reference to baseline tuberculosis status adjudicated by an expert committee and calculated net reclassification improvement to quantify the incremental discriminatory benefit of POC-CRP in determining IPT eligibility compared to the World Health Organization (WHO) symptom screen.

RESULTS

Of 201 patients (median CD4 cell count, 137 cells/μL; interquartile range, 83-206), 5 (2.5%) had tuberculosis. Compared to the WHO symptom screen, POC-CRP had similar sensitivity (100% vs. 80%, P = 0.30) but greater specificity (21% vs. 87%, P < 0.0001) for tuberculosis. If based on the WHO symptom screen, no patients with tuberculosis but only 42 of 196 patients without tuberculosis would have been considered IPT eligible. If POC-CRP were used instead, 1 patient with tuberculosis (reclassification of cases, -20%; P = 0.32) and 129 patients without tuberculosis (reclassification of noncases, +66%; P < 0.001) would have been reclassified as IPT eligible, a net reclassification improvement of 46% (P = 0.03). In addition, POC-CRP testing would have reduced the proportion of patients without active tuberculosis requiring confirmatory tuberculosis testing (87% vs. 21%, P < 0.0001).

CONCLUSIONS

POC-CRP testing increased more than 4-fold the proportion of HIV-infected adults immediately identified as IPT eligible and decreased the proportion of patients requiring referral for further tuberculosis diagnostic testing. POC-CRP testing could substantially improve implementation of tuberculosis screening guidelines.

Tumor heterogeneity confounds cancer diagnosis and the outcome of therapy, necessitating analysis of tumor cell subsets within the tumor mass. Elevated expression of hyaluronan (HA) and HA receptors, receptor for HA-mediated motility (RHAMM)/HA-mediated motility receptor and cluster designation 44 (CD44), in breast tumors correlates with poor outcome. We hypothesized that a probe for detecting HA-HA receptor interactions may reveal breast cancer (BCa) cell heterogeneity relevant to tumor progression. A fluorescent HA (F-HA) probe containing a mixture of polymer sizes typical of tumor microenvironments (10-480 kDa), multiplexed profiling, and flow cytometry were used to monitor HA binding to BCa cell lines of different molecular subtypes. Formulae were developed to quantify binding heterogeneity and to measure invasion in vivo. Two subsets exhibiting differential binding (HA(-/low) vs. HA(high)) were isolated and characterized for morphology, growth, and invasion in culture and as xenografts in vivo. F-HA-binding amounts and degree of heterogeneity varied with BCa subtype, were highest in the malignant basal-like cell lines, and decreased upon reversion to a nonmalignant phenotype. Binding amounts correlated with CD44 and RHAMM displayed but binding heterogeneity appeared to arise from a differential ability of HA receptor-positive subpopulations to interact with F-HA. HA(high) subpopulations exhibited significantly higher local invasion and lung micrometastases but, unexpectedly, lower proliferation than either unsorted parental cells or the HA(-/low) subpopulation. Querying F-HA binding to aggressive tumor cells reveals a previously undetected form of heterogeneity that predicts invasive/metastatic behavior and that may aid both early identification of cancer patients susceptible to metastasis, and detection/therapy of invasive BCa subpopulations.