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Biomedical subjects

Robert T Schooley

Publications and source records attributed to Robert T Schooley.

17 recordsLinked to original sources
PubMed2006

Synergy of small molecular inhibitors of hepatitis C virus replication directed at multiple viral targets.

Chronic hepatitis C virus (HCV) infection is a significant worldwide health problem with limited therapeutic options. A number of novel, small molecular inhibitors of HCV replication are now entering early clinical trials in humans. Resistance to small molecular inhibitors is likely to be a significant hurdle to their use in patients. A systematic assessment of combinations of interferon and/or novel anti-hepatitis C virus agents from several different mechanistic classes was performed in vitro. Combinations of inhibitors with different mechanisms of action consistently demonstrated more synergy than did compounds with similar mechanisms of action. These results suggest that combinations of inhibitors with different mechanisms of action should be prioritized for assessment in clinical trials for chronic hepatitis C virus infection.

Antiviral Agents↗
PubMed2006

Small molecules that bind the inner core of gp41 and inhibit HIV envelope-mediated fusion.

HIV-1 enters cells by membrane fusion, mediated by the trimeric viral envelope glycoprotein gp160, which is processed by a single proteolytic cleavage into stably associated gp120 and gp41. The gp120/gp41 trimer can be triggered to undergo an irreversible conformational change. Using a protein-based assay designed to mimic the gp41 conformational change, we screened for small molecules that prevent the formation of postfusion gp41. Several compounds were identified. One set of structurally related molecules inhibited formation of a postfusion-like assembly with an IC50 of approximately 5 microM. The compounds also inhibited envelope-mediated membrane fusion in both cell-cell fusion and viral infectivity assays. Thus, our screen identifies effective fusion inhibitors. Tested against a panel of envelope proteins from primary HIV-1 isolates, the compounds inhibited fusion across a broad range of clades, including both M and T tropic strains. They bind in a highly conserved, hydrophobic pocket on the inner core of the gp41 trimer, a region previously identified as a potential inhibitor site.

Amino Acid Sequence↗
PubMed2006

Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA panel.

CONTEXT: Guidelines for antiretroviral therapy are important for clinicians worldwide given the complexity of the field and the varied clinical situations in which these agents are used. The International AIDS Society-USA panel has updated its recommendations as warranted by new developments in the field. OBJECTIVE: To provide physicians and other human immunodeficiency virus (HIV) clinicians with current recommendations for the use of antiretroviral therapy in HIV-infected adults in circumstances for which there is relatively unrestricted access to drugs and monitoring tools. The recommendations are centered on 4 key issues: when to start antiretroviral therapy; what to start; when to change; and what to change. Antiretroviral therapy in special circumstances is also described. DATA SOURCES AND STUDY SELECTION: A 16-member noncompensated panel was appointed, based on expertise in HIV research and patient care internationally. Data published or presented at selected scientific conferences from mid 2004 through May 2006 were identified and reviewed by all members of the panel. DATA EXTRACTION AND SYNTHESIS: Data that might change previous guidelines were identified and reviewed. New guidelines were drafted by a writing committee and reviewed by the entire panel. CONCLUSIONS: Antiretroviral therapy in adults continues to evolve rapidly, making delivery of state-of-the-art care challenging. Initiation of therapy continues to be recommended in all symptomatic persons and in asymptomatic persons after the CD4 cell count falls below 350/microL and before it declines to 200/microL. A nonnucleoside reverse transcriptase inhibitor or a protease inhibitor boosted with low-dose ritonavir each combined with 2 nucleoside (or nucleotide) reverse transcriptase inhibitors is recommended with choice being based on the individual patient profile. Therapy should be changed when toxicity or intolerance mandate it or when treatment failure is documented. The virologic target for patients with treatment failure is now a plasma HIV-1 RNA level below 50 copies/mL. Adherence to antiretroviral therapy in the short-term and the long-term is crucial for treatment success and must be continually reinforced.

Adult↗
PubMed2006

Cross-sectional study to evaluate factors associated with adherence to antiretroviral therapy by Brazilian HIV-infected patients.

Antiretroviral therapy success is highly dependent on the ability of the patient to fully adhere to the prescribed treatment regimen. We present the results of a cross-sectional study that evaluates the predictive value of a self-administered questionnaire of adherence to antiretroviral (ARV) therapy. Study participants were interviewed using a 36-item Patient Medication Adherence Questionnaire (PMAQ) designed to assess knowledge about ARV therapy, motivation to adhere to treatment, and behavioral skills. Plasma HIV-1 RNA levels were correlated with the results obtained from the PMAQ. Of the 182 study participants, 82 (45%) were receiving their initial ARV regimen. Of the remaining patients, 39 (21%) and 61 (34%) were on a second or additional ARV regimen, respectively. An undetectable viral load was documented in 47/62 (76%) patients on their first regimen who reported missing medication on less than 4 days in the last 3 months. The PMAQ had a higher predictive value of plasma viral suppression for patients in the initial regimen than for patients in salvage therapy. The overall predictive value of the PMAQ to identify adherence was 74%, and 59% for nonadherence, with an overall efficacy of 64%. Of the 74 patients (45%) who did not understand the concept of antiretroviral therapy, 80% were failing or had previously failed the ARV treatment. Of 35 patients with doubts about their HIV status or skeptical of the benefits of ARV therapy, 29 (84%) were nonadherent. Despite the positive predictive value of PMAQ in identifying adherence, self-reported adherence is not a sufficiently precise predictor of treatment success to substitute for viral load monitoring. On the other hand, the use of such an instrument to identify factors associated with nonadherence provides an excellent opportunity to apply early intervention designed to specifically address factors that might be contributing to the lack of adherence prior to regimen failure.

Adolescent↗
PubMed2004

Treatment for adult HIV infection: 2004 recommendations of the International AIDS Society-USA Panel.

CONTEXT: Substantial changes in the field of human immunodeficiency virus (HIV) treatment have occurred in the last 2 years, prompting revision of the guidelines for antiretroviral management of adults with established HIV infection. OBJECTIVE: To update recommendations for physicians who provide HIV care regarding when to start antiretroviral therapy, what drugs to start with, when to change drug regimens, and what drug regimens to switch to after therapy fails. DATA SOURCES: Evidence was identified and reviewed by a 16-member noncompensated panel of physicians with expertise in HIV-related basic science and clinical research, antiretroviral therapy, and HIV patient care. The panel was designed to have broad US and international representation for areas with adequate access to antiretroviral management. STUDY SELECTION: Evidence considered included published basic science, clinical research, and epidemiological data (identified by experts in the field or extracted through MEDLINE searches using terms relevant to antiretroviral therapy) and abstracts from HIV-oriented scientific conferences between July 2002 and May 2004. DATA EXTRACTION: Data were reviewed to identify any information that might change previous guidelines. Based on panel discussion, guidelines were drafted by a writing committee and discussed by the panel until consensus was reached. DATA SYNTHESIS: Four antiretroviral drugs recently have been made available and have broadened the options for initial and subsequent regimens. New data allow more definitive recommendations for specific drugs or regimens to include or avoid, particularly with regard to initial therapy. Recommendations are rated according to 7 evidence categories, ranging from I (data from prospective randomized clinical trials) to VII (expert opinion of the panel). CONCLUSION: Further insights into the roles of drug toxic effects, drug resistance, and pharmacological interactions have resulted in additional guidance for strategic approaches to antiretroviral management.

Adult↗
PubMed2004

Increased replication of HIV-1 minor variants during hematopoietic stem-cell mobilization with filgrastim.

The hypothesis that filgrastim (r-met-huG-CSF) activates replication of minor variants of human inmmunodeficiency virus type 1 (HIV-1) was tested by analysis of plasma quasi-species composition in 7 subjects in whom plasma HIV-1 RNA had increased during filgrastim treatment. Inferred phylogenetic trees of env sequences from 3 subjects during filgrastim treatment contained unique intrasubject subclusters that shared a most recent common ancestor with the baseline HIV-1 quasi species. Genotypes in the unique subclusters were not detected before filgrastim treatment, yet they composed 40%-70% of the plasma quasi species during treatment. The minority variants that appeared in 1 subject were more distantly related to plasma quasi species present 5 years before filgrastim treatment than were the majority of the pretreatment plasma quasi species. These findings provide evidence that increased HIV-1 replication during filgrastim treatment was associated with activation of HIV-1 variants that, before filgrastim treatment, were minor components of the plasma quasi species.

Amino Acid Sequence↗
PubMed2004

Stimulation of Kaposi's sarcoma-associated herpesvirus viremia during hematopoietic stem cell mobilization with filgrastim.

The effects of hematopoietic stem cell (HSC) mobilization on Kaposi's sarcoma-associated herpesvirus (KSHV) were evaluated in three KSHV and human immunodeficiency virus type 1 co-infected subjects. KSHV DNA was not detected in purified CD34+ cell preparations from the period of filgrastim treatment. However, two of 3 subjects had transiently increased cell-free plasma KSHV DNA during filgrastim treatment. Peak plasma KSHV DNA (2,600 and 4,300 copies/mL) occurred on day 4 and declined to below the limit of detection by day 7. These findings suggest that, although CD34+ cell preparations do not have evidence of KSHV infection, HSC mobilization may stimulate KSHV replication in other cellular compartments that contribute to KSHV viremia.

DNA, Viral↗
PubMed2003

An adherence trilogy is essential for long-term HAART success.

Adherence is the milestone of a successful therapy. Over the last decade several authors have addressed the importance of adherence for optimal results of antiretroviral (ARV) therapy. Many health care systems are investing substantial resources to make available contemporary antiretroviral therapy. Despite the large investment in medications, insufficient investments have been made into an integrated adherence component to maximize the impact of these medications. Adherence, unlike drug therapy, cannot be defined as a single method with a defined prescription or formula. Instead, it is the result of a complex interaction between the patient, a prescribed medication and the health system. Many reports are available analyzing each of these components. We have found that critical elements of adherence include the patient's knowledge about the disease and how medications will help achieve a longer and healthier life, together with the motivation to adapt to a new style of life. A trilogy composed of information, motivation and behavioral skills is essential to achieve the maximum desired level of adherence. We have computerized this trilogy in a software program for self-administration in which each of the three components is provided to the patient as many times as necessary to transmit an understanding of the problem and to help make a rational decision to adhere to the ARV treatment program. In this review we analyze several efforts and techniques to improve adherence to any recommended medication that may interfere with the patient's lifestyle and outline how the adherence trilogy can be best used to optimize the ability of ARV therapy to durably suppress plasma HIV RNA to undetectable levels.

Anti-HIV Agents↗
PubMed2002

Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS Society-USA Panel.

OBJECTIVE: New information warrants updated recommendations for the 4 central issues in antiretroviral therapy: when to start, what drugs to start with, when to change, and what to change to. These updated recommendations are intended to guide practicing physicians actively involved in human immunodeficiency virus (HIV)- and acquired immunodeficiency syndrome (AIDS)-related care. PARTICIPANTS: In 1995, physicians with specific expertise in HIV-related basic science and clinical research, antiretroviral therapy, and HIV patient care were invited by the International AIDS Society-USA to serve on a volunteer panel. In 1999, others were invited to broaden international representation. The 17-member panel met regularly in closed meetings between its last report in 2000 and April 2002 to review current data. The effort was sponsored and funded by the International AIDS Society-USA, a not-for-profit physician education organization. EVIDENCE AND CONSENSUS PROCESS: The full panel was convened in late 2000 and assigned 7 section committees. A section writer and 3 to 5 section committee members (each panel member served on numerous sections) identified relevant evidence and prepared draft recommendations. Basic science, clinical research, and epidemiologic data from the published literature and abstracts from recent (within 2 years) scientific conferences were considered by strength of evidence. Extrapolations from basic science data and expert opinion of the panel members were included as evidence. Draft sections were combined and circulated to the entire panel and discussed in a series of full-panel conference calls until consensus was reached. Final recommendations represent full consensus agreement of the panel. CONCLUSIONS: Because of increased awareness of the activity and toxicity of current drugs, the threshold for initiation of therapy has shifted to a later time in the course of HIV disease. However, the optimal time to initiate therapy remains imprecisely defined. Availability of new drugs has broadened options for therapy initiation and management of treatment failure, which remains a difficult challenge.

Adjuvants, Immunologic↗
PubMed2002

Genotypic and phenotypic analyses of HIV-1 in antiretroviral-experienced patients treated with tenofovir DF.

OBJECTIVE: To evaluate the virologic responses and mutational profiles in antiretroviral-experienced patients adding tenofovir DF once-daily to their existing regimens. DESIGN: Resistance analyses were performed for patients in a phase II placebo-controlled clinical trial of tenofovir DF. METHODS: HIV-1 reverse transcriptase and protease genes from plasma samples were analyzed genotypically and phenotypically at baseline, week 24, and week 48. RESULTS: Of 184 patients, 173 (94%) had baseline HIV-1 expressing one or more nucleoside reverse transcriptase inhibitor-associated resistance mutation. Protease inhibitor and non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations were observed in 57% and 32% of patients, respectively. Compared to placebo, significant reductions in HIV-1 RNA were observed for tenofovir DF-treated patients who had thymidine analog- (TAM), lamivudine- (M184V), NNRTI- or protease inhibitor-associated mutations. Patients with phenotypic susceptibility to tenofovir within 4-fold of wild-type responded durably to tenofovir DF 300 mg therapy with a decline in plasma HIV-1 RNA of > or = 0.5 log10 copies/ml; few patients had a more than 4-fold reduced susceptibility to tenofovir at baseline. Four patients (2%) developed the K65R mutation (selected by tenofovir in vitro) and showed 3- to 4-fold reductions in tenofovir susceptibility but no evidence of rebound viremia. Thirty-four percent of patients developed additional TAMs, coincident with concurrent zidovudine or stavudine therapy, but also showed durable HIV-1 reductions. There was no evidence of novel resistance to tenofovir. CONCLUSIONS: Adding tenofovir DF 300 mg to an existing regimen in patients with ongoing viral replication and a wide range of genotypic resistance patterns resulted in significant and durable HIV-1 RNA reductions. In addition, there was a low incidence of genotypic or phenotypic resistance to tenofovir DF arising during 48 weeks of therapy.

Adenine↗
PubMed2002

Tenofovir DF in antiretroviral-experienced patients: results from a 48-week, randomized, double-blind study.

OBJECTIVE: To evaluate the safety and efficacy of once daily doses of tenofovir DF (TDF) administered in combination with other antiretroviral therapy (ART) in treatment-experienced HIV-1-infected patients with incomplete virological suppression. DESIGN: One-hundred and eighty-nine subjects with plasma HIV-1 RNA levels between 400 and 100,000 copies/ml and stable ART (> or = 8 weeks) were randomized (2 : 2 : 2 : 1 ratio) to add TDF 75 mg, 150 mg, or 300 mg or placebo to existing ART in a double-blinded manner. After 24 weeks, patients initially randomized to placebo received blinded TDF 300 mg. METHODS: Efficacy was analyzed by the mean changes HIV-1 RNA levels (log10 copies/ml plasma; DAVG(xx)) from week 0 to weeks 4, 24, and 48. Safety was analyzed by incidence of grade 3 or 4 clinical and laboratory adverse events. RESULTS: At baseline, patients had mean 4.6 years prior ART use with 94% having HIV-1 with nucleoside-associated resistance mutations. There were statistically significant decreases in DAVG(4) and DAVG(24) for all doses of TDF compared with placebo, with the greatest effect seen with TDF 300 mg (DAVG(4), -0.62, P < 0.001; DAVG(24), -0.58; P < 0.001; DAVG(48), -0.62). The incidence of adverse events was similar among the TDF groups and placebo through week 24. Throughout the 48-week study, no significant changes in renal function were observed. CONCLUSIONS: In treatment-experienced patients with baseline nucleoside resistance mutations, TDF provided dose-related, durable reductions in HIV-1 RNA. Through 24 weeks, the safety profile of TDF was similar to that of placebo.

Adenine↗
PubMedDate not supplied

HIV and hepatitis C virus coinfection: bad bedfellows.

Hepatitis C virus (HCV) infection is common in HIV-infected individuals and is responsible for increasing morbidity in these patients. HIV infection increases HCV replication and accelerates progression of HCV disease. HCV infection increases the risk of antiretroviral treatment. HCV genotype 1 is the predominant genotype in HCV/HIV-coinfected individuals living in the United States. State-of-the-art treatment with peginterferon alfa plus ribavirin results in lower sustained HCV virologic response rates in patients with genotype 1 infection than in those infected with other genotypes. Data from studies of HCV infection treatment in coinfected patients are discussed, as are prospects for future therapy. This article summarizes a presentation on HIV/HCV coinfection by Robert T. Schooley, MD, at the International AIDS Society-USA course in San Francisco in June 2005.

Antiviral Agents↗
PubMedDate not supplied

Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society--USA panel.

CONTEXT: Guidelines for antiretroviral therapy are important for clinicians worldwide given the complexity of the field and the varied clinical situations in which these agents are used. The International AIDS Society-USA panel has updated its recommendations as warranted by new developments in the field. OBJECTIVE: To provide physicians and other human immunodeficiency virus (HIV) clinicians with current recommendations for the use of antiretroviral therapy in HIV-infected adults in circumstances for which there is relatively unrestricted access to drugs and monitoring tools. The recommendations are centered on 4 key issues: when to start antiretroviral therapy; what to start; when to change; and what to change. Antiretroviral therapy in special circumstances is also described. DATA SOURCES AND STUDY SELECTION: A 16-member noncompensated panel was appointed, based on expertise in HIV research and patient care internationally. Data published or presented at selected scientific conferences from mid 2004 through May 2006 were identified and reviewed by all members of the panel. DATA EXTRACTION AND SYNTHESIS: Data that might change previous guidelines were identified and reviewed. New guidelines were drafted by a writing committee and reviewed by the entire panel. CONCLUSIONS: Antiretroviral therapy in adults continues to evolve rapidly, making delivery of state-of-the-art care challenging. Initiation of therapy continues to be recommended in all symptomatic persons and in asymptomatic persons after the CD4 cell count falls below 350/microL and before it declines to 200/microL. A nonnucleoside reverse transcriptase inhibitor or a protease inhibitor boosted with low-dose ritonavir each combined with 2 nucleoside (or nucleotide) reverse transcriptase inhibitors is recommended with choice being based on the individual patient profile. Therapy should be changed when toxicity or intolerance mandate it or when treatment failure is documented. The virologic target for patients with treatment failure is now a plasma HIV-1 RNA level below 50 copies/mL. Adherence to antiretroviral therapy in the short-term and the long-term is crucial for treatment success and must be continually reinforced.

Journal Article↗