Association of HIV-1 replication capacity with treatment outcomes in patients with virologic treatment failure

BACKGROUND: The extent to which HIV-1 replication capacity (RC) influences the response to therapy remains to be established. METHODS: Phenotypic susceptibility and RC of baseline isolates (n = 139) from patients enrolled in the ARGENTA trial were measured and correlated to treatment outcomes over 36 months. RESULTS: RC in baseline isolates correlated with the number of phenotypically active drugs (R = 0.34, P < 0.001). Crude viral RC did not predict treatment outcomes. When viral RC was adjusted by baseline CD4 cell counts, HIV-1 RNA levels, and phenotypic susceptibility to the rescue regimen, it showed significant association with the immunologic outcome (per log10 RC higher, mean difference in 36 months' time-averaged change from baseline CD4 count = -68 cells/microL; P = 0.020). In the subgroup of patients with 3 or more phenotypically active drugs in the salvage regimen (n = 35, median RC = 65%), subjects carrying isolates with RC < or =65% as compared to those with RC >65% had better time-averaged HIV-1 RNA responses (mean: -1.04 vs. -0.32 log10 copies/mL; P = 0.012) and CD4 cell responses (mean: 132 vs. -7 cells/microL; P = 0.006). Among patients with HIV-1 RNA levels persistently >500 copies/mL (n = 61), RC, on a log10 basis, was inversely associated with time-averaged 36-month CD4 cell responses (beta = -0.26; P = 0.046). CONCLUSION: After normalizing for viral susceptibility to the employed regimen or in patient subsets with suboptimal virologic response, higher viral RC may predict worse subsequent treatment outcomes.     

A genotypic HIV-1 proviral DNA coreceptor tropism assay: characterization in viremic subjects

Background

Amyloid fibrils such as Semen-Derived Enhancer of Viral Infection (SEVI) or amyloid-β-peptide (Aβ) enhance HIV-1 attachment and entry. Inhibitors destroying or converting those fibrils into non-amyloidogenic aggregates effectively reduce viral infectivity. Thus, they seem to be suitable as therapeutic drugs expanding the current HIV-intervening repertoire of antiretroviral compounds.

Findings

In this study, we demonstrate that the small D-amino acid peptide D3, which was investigated for therapeutic studies on Alzheimer’s disease (AD), significantly reduces both SEVI and Aβ fibril boosted infectivity of HIV-1.

Conclusions

Since amyloids could play an important role in the progression of AIDS dementia complex (ADC), the treatment of HIV-1 infected individuals with D3, that inhibits Aβ fibril formation and converts preformed Aβ fibrils into non-amyloidogenic and non-fibrillar aggregates, may reduce the vulnerability of the central nervous system of HIV patients for HIV associated neurological disorders.     

Quantitative measurement of HER2 expression in breast cancers: comparison with ‘real-world’ routine HER2 testing in a multicenter Collaborative Biomarker Study and correlation with overall survival

Introduction

Accurate assessment of HER2 status is critical in determining appropriate therapy for breast cancer patients but the best HER2 testing methodology has yet to be defined. In this study, we compared quantitative HER2 expression by the HERmark™ Breast Cancer Assay (HERmark) with routine HER2 testing by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), and correlated HER2 results with overall survival (OS) of breast cancer patients in a multicenter Collaborative Biomarker Study (CBS).

Methods

Two hundred and thirty-two formalin-fixed, paraffin-embedded breast cancer tissues and local laboratory HER2 testing results were provided by 11 CBS sites. HERmark assay and central laboratory HER2 IHC retesting were retrospectively performed in a blinded fashion. HER2 results by all testing methods were obtained in 192 cases.

Results

HERmark yielded a continuum of total HER2 expression (H2T) ranging from 0.3 to 403 RF/mm² (approximately 3 logs). The distribution of H2T levels correlated significantly (P <0.0001) with all routine HER2 testing results. The concordance of positive and negative values (equivocal cases excluded) between HERmark and routine HER2 testing was 84% for local IHC, 96% for central IHC, 85% for local FISH, and 84% for local HER2 status. OS analysis revealed a significant correlation of shorter OS with HER2 positivity by local IHC (HR = 2.6, P = 0.016), central IHC (HR = 3.2, P = 0.015), and HERmark (HR = 5.1, P <0.0001) in this cohort of patients most of whom received no HER2-targeted therapy. The OS curve of discordant low (HER2 positive but H2T low, 10% of all cases) was aligned with concordant negative (HER2 negative and H2T low, HR = 1.9, P = 0.444), but showed a significantly longer OS than concordant positive (HER2 positive and H2T high, HR = 0.31, P = 0.024). Conversely, the OS curve of discordant high (HER2 negative but H2T high, 9% of all cases) was aligned with concordant positive (HR = 0.41, P = 0.105), but showed a significantly shorter OS than concordant negative (HR = 41, P <0.0001).

Conclusions

Quantitative HER2 measurement by HERmark is highly sensitive, accurately quantifies HER2 protein expression and correlates well with routine HER2 testing. When HERmark and local HER2 results were discordant, HERmark more accurately predicted overall survival.