Performance of HIV-1 drug resistance testing at low-level viremia and its ability to predict future virologic outcomes and viral evolution in treatment-naive individuals.

BACKGROUND: Low-level viremia (LLV; human immunodeficiency virus [HIV-1] RNA 50-999 copies/mL) occurs frequently in patients receiving antiretroviral therapy (ART), but there are few or no data available demonstrating that HIV-1 drug resistance testing at a plasma viral load (pVL) <1000 copies/mL provides potentially clinically useful information. Here, we assess the ability to perform resistance testing by genotyping at LLV and whether it is predictive of future virologic outcomes in patients beginning ART. METHODS: Resistance testing by genotyping at LLV was attempted on 4915 plasma samples from 2492 patients. A subset of previously ART-naive patients was analyzed who achieved undetectable pVL and subsequently rebounded with LLV (n = 212). A genotypic sensitivity score (GSS) was calculated based on therapy and resistance testing results by genotyping, and stratified according to number of active drugs. RESULTS: Eighty-eight percent of LLV resistance assays produced useable sequences, with higher success at higher pVL. Overall, 16 of 212 (8%) patients had pretherapy resistance. Thirty-eight of 196 (19%) patients without pretherapy resistance evolved resistance to 1 or more drug classes, primarily the nucleoside reverse transcriptase (14%) and/or nonnucleoside reverse transcriptase (9%) inhibitors. Patients with resistance at LLV (GSS <3) had a 2.1-fold higher risk of virologic failure (95% confidence interval, 1.2- to 3.7-fold) than those without resistance (P = .007). Progressively lower GSS scores at LLV were associated with a higher increase in pVL over time (P < .001). Acquisition of additional resistance mutations to a new class of antiretroviral drugs during LLV was not found in a subset of patients. CONCLUSIONS: Routine HIV-1 genotyping of LLV samples can be performed with a reasonably high success rate, and the results appear predictive of future virologic outcomes.

A single untimed plasma drug concentration measurement during low-level HIV viremia predicts virologic failure.

Suboptimal untimed plasma drug levels (UDL) have been associated with lower rates of virologic suppression and the emergence of drug resistance. Our aim was to evaluate whether UDL among patients with low-level viremia (LLV) while receiving highly active antiretroviral therapy (HAART) can predict subsequent virologic failure (plasma viral load ≥1000 copies/mL) and emergence of resistance. The first documented LLV episode of 328 consenting patients was analysed in terms of drug levels, viral load and resistance, which were monitored while patients were on a consistent HAART regimen. UDL of protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), were categorized as 'therapeutic' or 'subtherapeutic' based on predefined target trough concentrations. Drug resistance genotype was assessed using the Stanford algorithm. Time to virologic failure was evaluated by Kaplan-Meier analysis and Cox proportional hazards regression. We found 78 of 328 patients (24%) with subtherapeutic drug levels at time of first detectable LLV, while 19% harboured drug-resistant virus. Both subtherapeutic UDL and drug resistance independently increased the risk of subsequent virologic failure (p <0.001 and p 0.04, respectively). In a multivariable model, variables associated with LLV and virologic failure included subtherapeutic UDL, elevated plasma viral load, and drug resistance. Patients with subtherapeutic UDL accumulated further drug resistance faster during follow-up (p 0.03). Together, resistance and UDL variables can explain a higher proportion of virologic failure than either measure alone. Our results support further prospective evaluation of UDL in the management of low-level viremia.

Monoclonal antibodies in ovarian and prostate cancer.

Radioimmunoscintigraphy (RIS)--using radiolabeled monoclonal antibodies (MoAbs) to image disease--is a growing subspecialty of nuclear medicine. RIS of the reproductive tracts of men and women has shown encouraging results in imaging both primary lesions and metastases of these cancers. Ovarian cancer is the most fatal gynecologic cancer in the United States, and prostate cancer is the most prevalent form of cancer in men. Several MoAbs against reproductive tumor antigens were used with limited success in clinical trials before 1989. Most recently, MoAbs CYT-103 (satumomab pendetide) and OV-TL 3 have shown promise as safe, sensitive imaging tools for ovarian cancer. Although to date more agents have been used to image ovarian carcinoma than prostate cancer, research has been restimulated in prostate carcinoma imaging because of development of a promising MoAb conjugate, CYT-356. Radionuclide indium-111 appears to be the most promising radiolabeled to date for ovarian and prostate carcinoma RIS performed in the United States. In future clinical trials, consideration of safety issues and a standardization of methods among institutions using RIS are needed before the use of MoAb technology in cancer imaging will become routine. Comparative studies with more traditional methods like computed tomography are needed, as well as more trials comparing radioimmunoscintigraphic findings with pathological evidence.

Absence of the septum pellucidum and related disorders.

We present an illustration of the spectrum of intracranial abnormalities associated with absence of the septum pellucidum to better define and illustrate this disorder. CT and 1.5 Tesla MRI examinations of fifteen patients with absence of the septum pellucidum were meticulously analyzed and correlated with clinical and laboratory studies. The findings were compiled and categorized based upon the presence and type of associated radiologic abnormalities. Absence of the septum pellucidum may occur as an isolated abnormality (n = 3). In most patients (n = 12), associated complex developmental abnormalities are present which include heterotopias, hypoplastic falx, ventricular clefts, encephalocele, small pituitary gland, small optic nerves and chiasm, and corpus callosal dysgenesis. Inferior pointing and a squared-off appearance of the frontal horns are frequently noted. These, or other, more severe ventricular configuration deformities are present in all patients. We have portrayed the complete range of findings associated with absence of the septum pellucidum using an illustrative approach to clarify the different patterns of radiologic abnormalities which may be seen with this complex entity.

Lumbar epidural lipomatosis: the "Y" sign of thecal sac compression.

PURPOSE: We have identified a specific sign of lumbar thecal sac compression seen in patients with symptomatic lumbar epidural lipomatosis. Recognition of this sign will aid with proper diagnosis of this unusual disorder. METHODS: Computerized Tomography (CT) and Magnetic Resonance Imaging (MRI) examinations of the lumbar spine performed in the evaluation of low back pain over a 24 mo period demonstrated nine patients with excessive fat in the epidural space. Myelography was performed on five of these patients. Detailed analysis of the shape and degree of thecal sac compression was made. RESULTS: Eight of the nine patients with epidural lipomatosis demonstrated a characteristic type of thecal sac compression not seen with other spinal disorders. On cross sectional imaging, the thecal sac has a striking stellate appearance with three rays emanating from a central core. This produces a trifid shape resembling the letter "Y". In two patients scanned following subsequent surgical removal of the epidural fat, the thecal sac had resumed its normal configuration. CONCLUSION: A seemingly specific and easily recognized type of compression of the thecal sac may occur with lumbar epidural lipomatosis. This creates a trifid appearance of the thecal sac; we have termed this the "Y" sign.

MRI evaluation of "solitary" brain metastases with triple-dose gadoteridol: comparison with contrast-enhanced CT and conventional-dose gadopentetate dimeglumine MRI studies in the same patients.

The purpose of this investigation was to compare the sensitivity and safety of high dose gadoteridol (Pro Hance) with routine dose gadopentetate dimeglumine (Magnevist) in the detection of intracranial metastases on magnetic resonance imaging (MRI) when a solitary intracranial lesion was detected on contrast-enhanced cranial computed tomography (CT). Four patients, each with a solitary intracranial metastasis demonstrated on contrast-enhanced CT were studied prospectively with both 0.3 mmol/kg gadoteridol and 0.1 mmol/kg gadopentetate dimeglumine. Images were acquired before and immediately following contrast administration. Both of the MR studies were performed between two and six days of each other and within 1 wk of the cranial CT. Scan parameters and injection rates were identical on both occasions. Patient monitoring for the gadoteridol study included physical examination, vital signs and laboratory tests at several pre-determined times. Eighteen total metastases were demonstrated on MRI compared to the four on CT. Seven were visualized on the unenhanced MR images, nine on the scans using gadopentetate dimeglumine, and all eighteen on the scans using gadoteridol. Additional lesions were seen on the gadoteridol images in all four patients. No adverse events attributable to contrast media occurred. No significant changes in vital signs or laboratory values occurred.