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Biomedical subjects

Joseph Cofrancesco

Publications and source records attributed to Joseph Cofrancesco.

At least 19 recordsLinked to original sources
PubMed2006

Marked intraindividual variability in antiretroviral concentrations may limit the utility of therapeutic drug monitoring.

BACKGROUND: Effective therapeutic drug monitoring for antiretrovirals requires a better understanding of intraindividual variability in pharmacokinetics. METHODS: We determined concentrations of human immunodeficiency virus (HIV) protease and nonnucleoside reverse-transcriptase inhibitors for 10 patients with undetectable plasma HIV RNA levels who had been receiving stable regimens for > or = 11 months. Plasma samples were collected at the same time of day 3 times per week for up to 4 months. Patients were instructed to take their antiretrovirals at the same time every day. Plasma protease and nonnucleoside reverse-transcriptase inhibitor concentrations were determined using high-performance liquid chromatographic methods. Pharmacokinetic variability was expressed as intraindividual percentage coefficient of variation (ICV), which was calculated as the patient's standard deviation divided by the mean drug concentration for that patient. RESULTS: ICV was determined for 6 drugs for 10 patients, for a total of 17 different patient-drug combinations, using 600 total samples. ICV was unexpectedly high for most patients who were receiving protease inhibitors (ICVs for individual patients taking lopinavir/ritonavir were 24%, 33%, 51%, and 92%; for patients taking nelfinavir/M8 metabolite, they were 30%/44% and 39%/54%; for patients taking ritonavir, they were 34% and 43%; for patients taking saquinavir, they were 52% and 55%). ICVs for patients receiving nonnucleoside reverse-transcriptase inhibitors were lower (for patients receiving efavirenz, they were 7%, 13%, 29%, and 51%; for a patient receiving nevirapine, it was 25%). The median ICV for all patients receiving protease inhibitors (n = 12) was 43.5%, and for all patients receiving nonnucleoside reverse-transcriptase inhibitors (n = 5), the median ICV was 25%. CONCLUSIONS: Intraindividual variability in concentrations of antiretrovirals was surprisingly high in virologically suppressed patients. Possible contributors include food effects, concomitant use of prescription and herbal medications, assay variability, or medication timing, which was assessed by self-report. High intraindividual pharmacokinetic variability may limit the utility of single measurements in therapeutic drug monitoring for some antiretroviral agents.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Metabolic abnormalities in HIV-infected patients: an update.

In recent years, substantial progress has been made in our understanding of the pathogenesis, risk factors, and treatment of glucose and lipid abnormalities in HIV-infected patients. Newer antiretrovirals, such as abacavir and tenofovir in the nucleoside reverse transcriptase class and atazanavir in the protease inhibitor class, have been shown to improve metabolic profiles compared to other medications. In addition, new information regarding the efficacy of glucose and lipid-lowering medications in HIV-infected patients has become available. It has also been demonstrated that aggressive risk factor modification can reduce the burden of cardiovascular disease in this population. This article reviews these recent advances in order to help providers respond to these important clinical challenges.

Journal Article↗
PubMed2006

The effects of illicit drug use and HIV infection on sex hormone levels in women.

Drug use and HIV infection may affect sex hormone levels in women. One hundred and ninety-six women with and without a history of illicit drug use (50 HIV-negative and 148 HIV-infected), with regular menses, who never used antiretrovirals, were evaluated. Luteinizing hormone levels were significantly higher in women with a CD4 cell count <200/microl (p < 0.002). Current methadone use was associated with lower levels of total testosterone (p = 0.03) and higher levels of prolactin (p = 0.002); mean estradiol levels were 43% lower in women who used intravenous drugs (p < 0.001). Alcohol and crack cocaine use was not associated with sex hormone levels. Age, race, body mass index and degree of HIV immunosuppression were also associated with differences in sex hormone levels.

Adult↗
PubMed2006

Prevalence of complementary and alternative medicine use among HIV patients for perceived lipodystrophy.

BACKGROUND: Complementary and alternative medicine (CAM) use is common among some patients who test positive for human immunodeficiency virus (HIV). Changes in body-fat distribution can occur in some patients on prolonged highly active antiretroviral therapy. Currently, there are fewer effective treatments for the condition. Patients with lipodystrophy may be turning to CAM. OBJECTIVE: The objective was to investigate the prevalence and perceived benefit of CAM use for perceived body-shape changes among a cohort of HIV-positive patients. DESIGN/SETTING/SUBJECTS: We surveyed a cross-sectional convenience sample of 74 patients from urban and suburban HIV outpatient clinics in Baltimore, MD, who indicated concerns about body-shape changes. The survey instrument was developed based on validated questionnaires previously used in clinical trials and published work. RESULTS: CAM use including both supplements and visits to CAM providers was 74% in our study population. In multivariate analysis, users of CAM were more likely to be men (p = 0.016) and to have noticed bodyshape changes after taking HIV medications (p = 0.012). However, very few subjects reported using CAM specifically for lipodystrophy changes. CAM use was more commonly reported for "general health." CAM was primarily more conventional, such as multivitamins or minerals, but several subjects reported using meditation and/or prayer (38%), ginseng (Panax spp.) (3%), St John's wort (Hypericum perforatum) (1%), and acupuncture (1%). More conventional CAM, such as exercise, diet, and vitamins as well as meditation/prayer were perceived to be effective for lipodystrophy as well as for improving the overall sense of well-being. CONCLUSIONS: The rate of CAM use among the HIV-positive population is high and is primarily used to improve general health.

Adult↗
PubMed2006

Residual human immunodeficiency virus type 1 viremia in some patients on antiretroviral therapy is dominated by a small number of invariant clones rarely found in circulating CD4+ T cells.

Antiretroviral therapy can reduce human immunodeficiency virus type 1 (HIV-1) viremia to below the detection limit of ultrasensitive clinical assays (50 copies of HIV-1 RNA/ml). However, latent HIV-1 persists in resting CD4+ T cells, and low residual levels of free virus are found in the plasma. Limited characterization of this residual viremia has been done because of the low number of virions per sample. Using intensive sampling, we analyzed residual viremia and compared these viruses to latent proviruses in resting CD4+ T cells in peripheral blood. For each patient, we found some viruses in the plasma that were identical to viruses in resting CD4+ T cells by pol gene sequencing. However, in a majority of patients, the most common viruses in the plasma were rarely found in resting CD4+ T cells even when the resting cell compartment was analyzed with assays that detect replication-competent viruses. Despite the large diversity of pol sequences in resting CD4+ T cells, the residual viremia was dominated by a homogeneous population of viruses with identical pol sequences. In the most extensively studied case, a predominant plasma sequence was also found in analysis of the env gene, and linkage by long-distance reverse transcriptase PCR established that these predominant plasma sequences represented a single predominant plasma virus clone. The predominant plasma clones were released for months to years without evident sequence change. Thus, in some patients on antiretroviral therapy, the major mechanism for residual viremia involves prolonged production of a small number of viral clones without evident evolution, possibly by cells other than circulating CD4+ T cells. The sequences have been deposited in GenBank. The accession numbers are DQ 391282 to DQ 391351 (for env) and DQ 391352 to DQ 392955 (for RT).

Antiretroviral Therapy, Highly Active↗
PubMed2005

Intermittent HIV-1 viremia (Blips) and drug resistance in patients receiving HAART.

CONTEXT: Many patients infected with human immunodeficiency virus type 1 (HIV-1) and receiving highly active antiretroviral therapy experience intermittent episodes of detectable viremia ("blips"), which may raise concerns about drug resistance, lead to costly repeat measurements of viral RNA, and sometimes trigger alterations in therapy. OBJECTIVE: To test the hypothesis that blips represent random biological and statistical variation around mean steady-state HIV-1 RNA levels slightly below 50 copies/mL rather than biologically significant elevations in viremia. DESIGN, SETTING, AND PATIENTS: Between June 19, 2003, and February 9, 2004, patients receiving therapy underwent intensive sampling (every 2-3 days) over 3 to 4 months to define the frequency, magnitude, and duration of blips and their association with drug levels and other clinical variables. Blips were defined as HIV-1 RNA measurements greater than or equal to 50 copies/mL preceded and followed by measurements less than 50 copies/mL without a change in treatment. To determine whether blips result from or lead to drug resistance, an ultrasensitive genotyping assay was used to detect drug resistance mutations before, during, and after blips. Patients were 10 HIV-1-infected asymptomatic adults recruited by clinicians and followed up in the Moore Clinic at the Johns Hopkins Hospital. Patients had suppression of viremia to below 50 copies/mL while receiving a stable antiretroviral regimen for 6 months or longer. MAIN OUTCOME MEASURES: At each time point, plasma HIV-1 RNA levels were measured in 2 independent laboratories and drug resistance mutations were analyzed by clonal sequencing. RESULTS: With the intensive sampling, blips were detected in 9 of 10 patients. Statistical analysis was consistent with random assay variation around a mean viral load below 50 copies/mL. Blips were not concordant on independent testing and had a short duration (median, <3 days) and low magnitude (median, 79 copies/mL). Blip frequency was not associated with demographic, clinical, or treatment variables. Blips did not occur in relation to illness, vaccination, or directly measured antiretroviral drug concentrations. Blips were marginally associated (P = .08) with reported episodes of nonadherence. Most importantly, in approximately 1000 independent clones sequenced for both protease and reverse transcriptase, no new resistance mutations were seen before, during, or shortly after blips. CONCLUSION: Most blips in this population appear to represent random biological and statistical variation around mean HIV-1 levels below 50 copies/mL rather than clinically significant elevations in viremia.

Adult↗
PubMed2004

Genotypic resistance in HIV-1-infected patients with persistently detectable low-level viremia while receiving highly active antiretroviral therapy.

BACKGROUND: Technical limitations in the sensitivity of commercial genotyping methods may prevent clinicians from determining whether drug-resistant human immunodeficiency virus type 1 (HIV-1) is present in patients with low-level viremia. We performed ultrasensitive HIV-1 genotyping for patients with persistent plasma virus loads of 50-400 copies/mL to better define the prevalence of drug resistance and the most common resistance mutations during persistently detectable low-level viremia. METHODS: Genotyping of HIV-1 was performed with an ultrasensitive clonal genotyping method. RESULTS: We studied 21 patients who had persistent, detectable, low-level viremia for a median of 11 months. Nine (43%) of 21 patients had HIV-1 isolates with significant resistance mutations. The most common mutations were M184V, K65R, and M41L/T215Y. CONCLUSIONS: The finding that clinically significant resistance mutations were present in some but not all patients with persistent viremia (range, 50-400 copies/mL) highlights the need to improve the sensitivity of current clinical assays for detection of drug resistance.

Adult↗
PubMed2004

Questionnaires to measure sexual quality of life.

CONTEXT: Sex is important to quality of life. There are a number of questionnaires to measure sexual-function, but many lack applicability and usefulness to certain groups. OBJECTIVE: To identify questionnaires measuring sexual function, determine the domains most commonly assessed, and examine evidence for their usefulness in different populations. DATA SOURCES: Computerized literature search using Medline, PubMed and PsychLit, reference lists, and unpublished reports, published in English between 1957 and 2001. MESH terms included sexual function, sexual dysfunction, sexual satisfaction, quality of life, and questionnaire. Articles were excluded if the questionnaire did not measure sexual function from the patient perspective. DATA EXTRACTION: Questionnaires were grouped as general questionnaires that include a sexual function domain, and sexual-function-specific questionnaires. Questionnaires were evaluated for domains, applicability to different populations, and evidence for reliability, validity and responsiveness. DATA SYNTHESIS: Literature search yielded 62 questionnaires, 57 which assessed sexual function from the patient perspective; 12 were general and 45 specific. Six domains were commonly represented, including interest and desire, satisfaction/quality of experience, excitement/arousal, performance, attitude/behavior, and relationship. Only 28% could be used in homosexual patients, and 52% were applicable to both genders; 57% were designed for use in chronic disease populations. Only nine questionnaires had evidence for both adequate reliability and validity. CONCLUSIONS: Current measures of sexual functioning often exclude important domains, lack applicability to gender and sexual preference groups, or lack adequate testing of validity and testing in important populations. Future questionnaires should take into account these concerns.

Humans↗
PubMed2004

Novel single-cell-level phenotypic assay for residual drug susceptibility and reduced replication capacity of drug-resistant human immunodeficiency virus type 1.

Human immunodeficiency virus type 1 (HIV-1)-infected individuals who develop drug-resistant virus during antiretroviral therapy may derive benefit from continued treatment for two reasons. First, drug-resistant viruses can retain partial susceptibility to the drug combination. Second, therapy selects for drug-resistant viruses that may have reduced replication capacities relative to archived, drug-sensitive viruses. We developed a novel single-cell-level phenotypic assay that allows these two effects to be distinguished and compared quantitatively. Patient-derived gag-pol sequences were cloned into an HIV-1 reporter virus that expresses an endoplasmic reticulum-retained Env-green fluorescent protein fusion. Flow cytometric analysis of single-round infections allowed a quantitative analysis of viral replication over a 4-log dynamic range. The assay faithfully reproduced known in vivo drug interactions occurring at the level of target cells. Simultaneous analysis of single-round infections by wild-type and resistant viruses in the presence and absence of the relevant drug combination divided the benefit of continued nonsuppressive treatment into two additive components, residual virus susceptibility to the drug combination and selection for drug-resistant variants with diminished replication capacities. In some patients with drug resistance, the dominant circulating viruses retained significant susceptibility to the combination. However, in other cases, the dominant drug-resistant viruses showed no residual susceptibility to the combination but had a reduced replication capacity relative to the wild-type virus. In this case, simplification of the regimen might still allow adequate suppression of the wild-type virus. In a third pattern, the resistant viruses had no residual susceptibility to the relevant drug regimen but nevertheless had a replication capacity equivalent to that of wild-type virus. In such cases, there is no benefit to continued treatment. Thus, the ability to simultaneously analyze residual susceptibility and reduced replication capacity of drug-resistant viruses may provide a basis for rational therapeutic decisions in the setting of treatment failure.

Adult↗
PubMed2004

Management options for facial lipoatrophy.

Lipoatrophy of the face, limbs, buttocks, and other subcutaneous tissue is increasingly recognized in HIV-infected patients. Although the pathogenesis of lipoatrophy and its association with metabolic abnormalities are becoming better understood with intense research efforts, there are very few treatment options, and the appearance of facial lipoatrophy can be devastating to patients. Treatment strategies include antiretroviral substitution, medications, and dermatologic and surgical interventions. Switching the HAART regimen produces only a modest effect. There are conflicting and generally disappointing data on the benefit of medications such as rosiglitazone. Surgical and dermatologic procedures are available for treatment of facial lipoatrophy, and several facial fillers have gained popularity as a means to restore the facial contour. Most are expensive, require multiple visits, and can produce scars. Temporary fillers require ongoing reapplication, and permanent fillers may sag if lipoatrophy progresses. All require a pure compound and expert technique and can be prohibitively expensive because these procedures are not generally covered by insurance. Prevention and early recognition of lipoatrophy and proper selection or early modification of antiretroviral treatment remain the best options.

Anti-HIV Agents↗
PubMed2003

Promotion criteria for clinician-educators.

OBJECTIVE: Department of medicine chairs have a critical role in the promotion of clinician-educators. Our primary objective was to determine how chairs viewed: 1) the importance of specific areas of clinician-educator performance in promotion decisions; and 2) the importance and quality of information on available measures of performance. A secondary objective was to compare the views of department chairs with those of promotion and tenure committee chairs. METHODS: In October 1997, a questionnaire was mailed to all department chairs in the United States and Canada asking them to rate the importance of 11 areas of clinician-educators' performance in evaluating them for promotion. We also asked them to rate 36 measures of performance. We compared their responses to a similar 1996 survey administered to promotion committee chairs. RESULTS: One hundred fourteen of 139 department chairs (82%) responded to the survey. When considering a clinician-educator for promotion, department chairs view teaching skills and clinical skills as the most important areas of performance, as did the promotion committee chairs. Of the measures used to evaluate teaching performance, teaching awards were considered most important and rated as a high-quality measure. When evaluating a clinician-educator's clinical skills, peer and trainee evaluation were considered as the most important measures of performance, but these were rated low in quality. Patient satisfaction and objective outcome measures also were viewed as important measures that needed improvement. Promotion committee chairs placed more emphasis on productivity in publications and external grant support when compared to department chairs. CONCLUSION: It is reassuring that both department chairs and promotion committee chairs value teaching skills and clinical skills as the most important areas of a clinician-educator's performance when evaluating for promotion. However, differences in opinion regarding the importance of several performance measures and the need for improved quality measures may represent barriers to the timely promotion of clinician-educators.

Academic Medical Centers↗
PubMedDate not supplied

Psychological distress and physical pain appear to have no short-term adverse impact on plasma HIV-1 RNA levels in patients on successful HAART.

PURPOSE: Previous studies have linked depression and stressful life events in HIV disease with a more rapid decline in CD4 count and progression to AIDS. However, the short-term effect of psychological and physical distress on HIV-1 RNA levels in patients on successful HAART has not been well studied. METHOD: Ten asymptomatic HIV-infected adults with suppression of viremia to <50 copies/mL on a stable HAART regimen for > or =6 months were studied. Participants donated blood every 2-3 days over a 3-4 month period for duplicate independent viral load measurements and drug level monitoring. At each time point, psychological distress was measured using the Mental Health Inventory-5 (MHI-5) and an 11-point numeric rating scale for emotional stress. Physical pain was assessed using an 11-point numeric rating scale. RESULTS: All patients maintained successful viral suppression throughout the study. Twenty-six of 713 (3.6%) viral load measurements were >50 copies/mL. Psychological distress and physical pain were not associated with episodes of detectable viremia. CONCLUSION: Using frequent monitoring of HIV-1 RNA levels and patient ratings of mood, stress, and pain, we found that psychological distress and physical pain had no short-term adverse impact on HIV-1 RNA levels in highly adherent patients with stable suppression of viremia on HAART.

Adult↗