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Biomedical subjects

Peter J Piliero

Publications and source records attributed to Peter J Piliero.

At least 19 recordsLinked to original sources
PubMed2006

Interaction between fosamprenavir, with and without ritonavir, and nevirapine in human immunodeficiency virus-infected subjects.

Fosamprenavir (FPV) with and without ritonavir (RTV) was added to the antiretroviral regimens of human immunodeficiency virus-infected subjects receiving nevirapine (NVP) to evaluate this drug interaction. Significant reductions in plasma amprenavir exposure (25 to 35%) were observed following coadministration of 1,400 mg of FPV twice a day (BID) and 200 mg of NVP BID. A regimen of 700 mg of FPV BID plus 100 mg of RTV BID may be coadministered with NVP without dose adjustment.

Adult↗
PubMed2005

Durable efficacy of enfuvirtide over 48 weeks in heavily treatment-experienced HIV-1-infected patients in the T-20 versus optimized background regimen only 1 and 2 clinical trials.

BACKGROUND: The T-20 Versus Optimized Background Regimen Only (TORO) 1 and TORO 2 clinical trials are open-label, controlled, parallel-group, phase 3 studies comparing enfuvirtide plus an optimized background (OB) of antiretrovirals (n = 661) with OB alone (n = 334) in treatment-experienced HIV-1-infected patients. METHODS: The primary objective at week 48 was to investigate durability of efficacy, as measured by the percentage of patients maintaining their week 24 response or improving. Efficacy analyses used the intent-to-treat population. RESULTS: A total of 73.7% of patients randomized to the enfuvirtide group remained on treatment through week 48 versus 21.3% originally randomized to the control group. At week 48, a higher proportion of week 24 responders maintained their response or were new responders in the enfuvirtide group than in the control group in each responder category: HIV-1 RNA level > or =1.0 log(10) change from baseline, <400 copies/mL and <50 copies/mL (37.4%, 30.4%, and 18.3% in the enfuvirtide group vs. 17.1%, 12.0%, and 7.8% in the control group, respectively; P < 0.0001 for all comparisons). CD4 cell count increases from baseline were twice as great in the enfuvirtide group as in the control group. CONCLUSION: These data demonstrate durable efficacy of enfuvirtide plus OB over 48 weeks.

Adolescent↗
PubMed2005

Strategies for initiating combination antiretroviral therapy.

Numerous potent antiretroviral regimens have proven successful as initial therapy in treatment-naive HIV-infected patients. As the development of new agents makes possible new treatment regimens, providers are faced with increasingly complex questions of when to initiate treatment and which regimen to select for individual patients. Clinical trial data provide a foundation for choosing an initial regimen and play a key role in the formation of treatment guidelines issued by the United States Public Health Service and other organizations. This paper reviews the results of recent clinical trials focusing on initial therapy and addresses important considerations when beginning antiretroviral therapy (ART) in treatment-naive individuals.

Antiretroviral Therapy, Highly Active↗
PubMed2004

Pharmacokinetic properties of nucleoside/nucleotide reverse transcriptase inhibitors.

Options for antiretroviral therapy in patients infected with HIV continue to expand as new drugs are integrated into treatment regimens. Nonetheless, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs) remain the backbone of highly active antiretroviral therapy (HAART). With the approval of emtricitabine in 2003, there are now 8 Food and Drug Administration (FDA)-approved NRTIs/NtRTIs. Several of these agents are effective as once-daily therapy, including didanosine, lamivudine, extended-release stavudine (FDA approved, but not currently available), tenofovir DF, and emtricitabine. Recent results from pharmacokinetic and clinical trials indicate that another NRTI, abacavir, may also be effective as a once-daily therapy, and FDA approval of once-daily dosing is anticipated. NRTIs are inactive as administered, requiring anabolic phosphorylation within target cells to achieve their antiretroviral effects. All NRTIs are converted to nucleoside triphosphates, which serve as the active metabolites (the NtRTI, tenofovir DF, only requires conversion to the diphosphate form). Frequency of drug administration is closely related to the pharmacokinetic properties of a drug. The key parameter is the half-life; however, the plasma elimination half-life of the NRTIs/NtRTIs as administered is of little use in developing a dosing schedule. Rather, the intracellular half-life of the nucleoside triphosphate is the relevant parameter. This article reviews the pharmacokinetic properties, particularly those of the various phosphorylation steps, of the NRTIs/NtRTIs.

Anti-HIV Agents↗
PubMed2004

Pharmacokinetics and safety of GW433908 and ritonavir, with and without efavirenz, in healthy volunteers.

OBJECTIVE: To evaluate the safety and pharmacokinetic interaction between GW433908, ritonavir (RTV), and efavirenz (EFV). METHODS: In period 1, subjects received either a once daily (QD) regimen of GW433908 1395 mg + RTV 200 mg (Study 1) or a twice daily (bid) regimen of GW433908 700 mg + RTV 100 mg (Study 2) for 14 days. In period 2, subjects received EFV 600 mg QD with either the same GW433908 + RTV regimen as in period 1 (arm 1) or with a GW433908 + RTV regimen that included an additional 100 mg of RTV (arm 2) for 14 days. Amprenavir (APV) pharmacokinetic sampling and safety assessments were performed on the last day of each period. RESULTS: Plasma APV exposure was not significantly altered when EFV was coadministered with GW433908 700 mg twice daily (BID) + RTV 100 mg BID. Plasma APV exposure was decreased when EFV was coadministered with GW433908 1395 mg QD + RTV 200 mg QD. However, administration of EFV with GW433908 1395 mg QD + RTV 300 mg QD (i.e., adding an extra 100 mg of RTV) was able to negate this interaction. Adverse events were consistent with prior data for each of the separate agents. CONCLUSION: When EFV is coadministered with the GW433908 700 mg + RTV 100 mg BID regimen, no dosage adjustment is recommended. However, when EFV is coadministered with the GW433908 1400 mg + RTV 200 mg QD regimen, an increase to RTV 300 mg QD is needed to maintain plasma APV exposure.

Adult↗
PubMed2004

Atazanavir: A novel once-daily protease inhibitor.

Atazanavir (formerly BMS-232632), an azapeptide protease inhibitor (PI), is a new human immunodeficiency virus (HIV) treatment that has recently received marketing approval from the FDA. It has a pharmacokinetic profile that supports once-daily dosing and has demonstrated a unique resistance profile and superior virologic potency compared with other antiretrovirals in vitro. In subjects with HIV, atazanavir (400 mg once daily) produced rapid and sustained improvements in viral load and CD4 counts in both antiretroviral-naive as well as previously treated patients when used in combination with dual nucleoside reverse transcriptase inhibitor (NRTI) treatment. In these studies atazanavir demonstrated comparable anti-HIV efficacy to nelfinavir (twice or three times daily), efavirenz and the combination of ritonavir and saquinavir. However, unlike these comparator agents, atazanavir did not adversely affect the plasma lipid profile, an advantage that sets it apart from other currently available PIs. Atazanavir was inferior to lopinavir/ritonavir in patients who previously failed an initial protease inhibitor containing regimen. Preliminary results in multiple PI-experienced patients indicate comparable efficacy to lopinavir/ritonavir in subjects receiving a boosted regimen of atazanavir plus ritonavir. In summary, atazanavir offers several therapeutic advantages, including a convenient once-daily dosing schedule, neutral lipid effects and a distinct resistance profile. These characteristics may ultimately help improve adherence, reduce the potential risk of long-term cardiovascular events associated with dyslipidemia, and increase the range of therapeutic options available for patients failing other antiretroviral regimens.

Area Under Curve↗
PubMed2003

Mechanisms of lipid elevations associated with the treatment of patients with HIV infection.

OBJECTIVE: Dyslipidemia and other metabolic abnormalities, which are associated with the use of highly active antiretroviral therapy (HAART) for the treatment of HIV infection, are of concern to patients and healthcare providers. The objective of this review is to present the current understanding of the dyslipidemia associated with the protease inhibitor (PI)-component of HAART: its possible origin, potential consequences, and management techniques. DATA SOURCES, STUDY SELECTION: Peer-reviewed, published literature was identified via MEDLINE. Other sources included abstracts from recent HIV-related conferences that presented data pertinent to the topic. Studies were selected based on their impact on our understanding of HIV infection and its treatment. DATA EXTRACTION, SYNTHESIS: Relevant portions of the publications considered were compiled and conclusions were drawn based on the clinical experience of the author. CONCLUSION: Dyslipidemia associated with current PIs should be a serious consideration when initiating long-term treatment of HIV infection. Current management techniques that include lipid-lowering agents may be improved and streamlined by incorporating a lipid-friendly PI into HAART.

Antiretroviral Therapy, Highly Active↗
PubMed2003

T cells containing T cell receptor excision circles are inversely related to HIV replication and are selectively and rapidly released into circulation with antiretroviral treatment.

OBJECTIVE: To examine baseline predictors of T-cell receptor rearrangement excision circle (TREC) levels and their changes during treatment with combined antiretroviral therapy. METHODS: Peripheral blood and lymph node lymphocytes were examined for the presence of TREC by real-time polymerase chain reaction and circulating lymphocyte phenotypes were examined by flow cytometry. Correlates for CD4 and CD8 cell TREC levels at baseline were identified among CD4 and CD8 immunophenotypes, viral load and patient demographics; the significance of TREC changes after initiation of antiretroviral therapy was assessed. RESULTS: Circulating TREC levels correlated inversely with age, with HIV RNA levels, with activation markers on circulating T cells and with naive CD4 but not CD8 cell frequencies. With initiation of antiretroviral therapy, TREC and naive T cell frequencies increased in peripheral blood during the first 2 weeks of treatment and these changes correlated negatively with TREC frequencies in lymph node aspirates, particularly among CD8 T cells. CONCLUSIONS: These findings suggest that recent thymic emigrants are sequestered in lymphoid tissue during uncontrolled HIV replication and are selectively released into circulation rapidly after initiation of antiretroviral therapies.

Adult↗
PubMed2003

Guillain-Barré syndrome associated with immune reconstitution.

We report a case of acute Guillain-Barré syndrome (GBS) associated with a prompt and vigorous immune reconstitution and decrease in the virus load noted during treatment with a potent regimen of highly active antiretroviral therapy. We hypothesize that GBS may have been due to an aberrant immune response or an adverse drug reaction in association with preexisting peripheral neurologic disease.

Anti-HIV Agents↗
PubMed2003

Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America.

BACKGROUND: The T-20 vs. Optimized Regimen Only Study 1 (TORO 1) was a randomized, open-label, phase 3 study of enfuvirtide (T-20), a human immunodeficiency virus type 1 (HIV-1) fusion inhibitor. METHODS: Patients from 48 sites in the United States, Canada, Mexico, and Brazil with at least six months of previous treatment with agents in three classes of antiretroviral drugs, resistance to drugs in these classes, or both, and with at least 5000 copies of HIV-1 RNA per milliliter of plasma were randomly assigned in a 2:1 ratio to receive enfuvirtide plus an optimized background regimen of three to five antiretroviral drugs or such a regimen alone (control group). The primary efficacy end point was the change in the plasma HIV-1 RNA level from base line to week 24. RESULTS: A total of 501 patients underwent randomization, and 491 received at least one dose of study drug and had at least one measurement of plasma HIV-1 RNA after treatment began. The two groups were balanced in terms of the median base-line HIV-1 RNA level (5.2 log10 copies per milliliter in both groups), median CD4+ cell count (75.5 cells per cubic millimeter in the enfuvirtide group, and 87.0 cells per cubic millimeter in the control group), demographic characteristics, and previous antiretroviral therapy. At 24 weeks, the least-squares mean change from base line in the viral load (intention-to-treat, last observation carried forward) was a decrease of 1.696 log10 copies per milliliter in the enfuvirtide group, and a decrease of 0.764 log10 copies per milliliter in the control group (P<0.001). The mean increases in CD4+ cell count were 76 cells per cubic millimeter and 32 cells per cubic millimeter, respectively (P<0.001). Reactions at the site of the injections were reported by 98 percent of patients receiving enfuvirtide. There were more cases of pneumonia in the enfuvirtide group than in the control group. CONCLUSIONS: The addition of enfuvirtide to an optimized antiretroviral regimen provided significant antiretroviral and immunologic benefit through 24 weeks in patients who had previously received multiple antiretroviral drugs and had multidrug-resistant HIV-1 infection.

Adult↗
PubMed2003

Pharmacodynamics and clinical use of anti-HIV drugs.

Antiretroviral drug exposure has been linked to both antiviral efficacy and the development of toxicity and further research in this area is ongoing and necessary. Use of these data may have important implications for TDM of HAART regimens in clinical practice. TDM, in conjunction with an assessment of the patient's viral resistance in the form of an IQ, needs to be examined and validated in large clinical trials.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Simplified regimens for treating HIV infection and AIDS.

PURPOSE: To review the variables that greatly affect adherence to the complex treatment regimens used in HIV disease and to examine available options that could improve patient outcomes. DATA SOURCES: Comprehensive review of current medical and scientific literature, drug-prescribing literature, and randomized clinical trials of drug treatments. CONCLUSIONS: Effective treatment of HIV infection is dependent on consistent adherence to prescribed antiretroviral medications. A large pill burden, multiple daily doses, and adverse events are some of the complexities that negatively impact patient adherence. For example, lipodystrophy and hyperlipidemia are two serious side effects associated with some agents. Once-daily antiretroviral agents offer many advantages over historical treatment options but are associated with possible drawbacks. IMPLICATIONS FOR PRACTICE: Currently, four single agents are available for once-daily administration, and a few others are under investigation. In addition, combination therapy with either dual or boosted protease inhibitor regimens is becoming a popular way of overcoming the poor pharmacokinetic characteristics of individual protease inhibitors.

Acquired Immunodeficiency Syndrome↗
PubMed2003

In vitro-in vivo model for evaluating the antiviral activity of amprenavir in combination with ritonavir administered at 600 and 100 milligrams, respectively, every 12 hours.

The study objective was to evaluate the pharmacodynamics of amprenavir in an in vitro system, develop an exposure target for maximal viral suppression, and determine the likelihood of target attainment based on the pharmacokinetics of amprenavir and ritonavir in human immunodeficiency virus (HIV)-infected patients. Population pharmacokinetic data were obtained from 13 HIV-infected patients receiving amprenavir and ritonavir in doses of 600 and 100 mg, respectively, every 12 h. A 2,500-subject Monte Carlo simulation was performed. Target attainment was also estimated for a target derived from clinical data. Maximal viral suppression (in vitro) was achieved when amprenavir free-drug concentrations remained greater than four times the 50% effective concentration (EC(50)) for 80% of the dosing interval. At an amprenavir EC(50) of 0.03 microM, the likelihood of target attainment is 97.4%. For reduced-susceptibility isolates for which the EC(50)s are 0.05 and 0.08 microM, target attainment is 91.0 and 75.8%, respectively. For the clinical target of a trough concentration/EC(50) ratio of 5, the target attainment rates were similar. Treatment with amprenavir and ritonavir at doses of 600 and 100 mg, respectively, twice a day provides excellent suppression of wild-type isolates and reduced-susceptibility isolates up to an EC(50) of 0.05 micro M. Even at 0.12 microM, target attainment likelihood exceeds 50%, making this an option for patients with extensive exposure to protease inhibitors when this treatment is used with additional active antiretroviral agents.

Adult↗
PubMed2003

Drug interactions associated with HAART: focus on treatments for addiction and recreational drugs.

The advent of HAART has improved survival in patients infected with HIV; however, treatment is complicated by potential drug interactions. The risk of drug interactions is compounded by the use of additional therapies for comorbid conditions, such as substance abuse, and by the use of recreational drugs. HIV health care providers should be aware of the potential interaction of recreational drugs and addiction treatments with HAART because of the potential for significant adverse effects for their HIV-infected patients. This article provides a review of the literature on drug interactions among addiction therapies, recreational drugs, and HAART.

Antiretroviral Therapy, Highly Active↗