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Biomedical subjects

Graeme Moyle

Publications and source records attributed to Graeme Moyle.

At least 19 recordsLinked to original sources
PubMed2006

Influence of atazanavir 200 mg on the intracellular and plasma pharmacokinetics of saquinavir and ritonavir 1600/100 mg administered once daily in HIV-infected patients.

OBJECTIVES: To examine cellular and plasma concentrations of atazanavir when given in combination with saquinavir/ritonavir in HIV+ patients. METHODS: Twelve HIV+ patients were receiving saquinavir/atazanavir/ritonavir 1600/200/100 mg once daily and venous blood samples were taken to determine cellular and plasma concentrations of each protease inhibitor at 2, 6, 12 and 24 h. Peripheral blood mononuclear cells were separated by density gradient centrifugation. The ratio of the cellular AUC0-24/plasma AUC0-24 was calculated to determine cellular drug accumulation. Lymphocyte P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated protein (MRP1) expression was determined by flow cytometry. Nine of the patients had previously received a regimen of saquinavir/ritonavir 1600/100 mg; therefore the effect of atazanavir on the cellular and plasma pharmacokinetics of saquinavir and ritonavir was examined. RESULTS: In vivo cellular and plasma determinations of saquinavir, atazanavir and ritonavir gave accumulation ratios of 4.9, 1.2 and 1.7, respectively. There was no relationship between saquinavir, atazanavir or ritonavir accumulation and P-gp, MRP1 or BCRP expression. When comparing pharmacokinetic values in the nine patients receiving saquinavir/ritonavir with and without atazanavir, the median cellular saquinavir AUC0-24 was significantly increased (34.9-117.2 mg.h/L) on addition of atazanavir (P=0.004). The C24 of saquinavir in plasma and cells was significantly higher with atazanavir (plasma C24 0.05 versus 0.14 mg/L with atazanavir; cellular C24 0.61 versus 2.03 mg/L with atazanavir, P=0.02). CONCLUSIONS: The mechanism of differential intracellular protease inhibitor accumulation is unclear. Co-administration of atazanavir caused an increase in both the plasma and cellular exposure (AUC0-24) and C24 of saquinavir but not ritonavir.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Pharmacokinetics of saquinavir hard-gel/ritonavir and atazanavir when combined once daily in HIV Type 1-infected individuals administered different atazanavir doses.

The pharmacokinetics and short-term safety of atazanavir 150 and 200 mg, when coadministered with saquinavir/ritonavir 1600/100 mg once daily, were evaluated. On day 1, atazanavir 150 mg once daily, was added to saquinavir/ritonavir regimens and sampling was performed to evaluate saquinavir, ritonavir, and atazanavir pharmacokinetics (day 11). Atazanavir was increased to 200 mg and pharmacokinetic assessment repeated (day 30). Geometric mean ratios (GMR) and 95% confidence intervals (CI) were used to compare saquinavir, ritonavir, and atazanavir pharmacokinetic parameters in the present study and for 14 of the subjects treated with saquinavir/ritonavir 1600/100 mg once daily without and with atazanavir 300 mg who participated in a previous trial. Geometric mean (GM) saquinavir AUC0-24, Ctrough, and Cmax were 30,589 and 32,312 ng . h/ml, 166 and 182 ng/ml, and 4267 and 4261 ng/ml when coadministered with atazanavir 150 and 200 mg (n = 18). On days 11 and 30, saquinavir and atazanavir Ctrough remained >100 ng/ml in 13/18, 14/18, 18/18, and 17/18 patients. Among the above mentioned 14 subjects, significant increases in saquinavir Ctrough (87%, 92%, 99%), Cmax (40%, 55%, 44%), and AUC0-24 (51%, 60%, 63%) were observed with atazanavir 300, 150, and 200 mg. Ritonavir AUC0-24 and Cmax were significantly increased with the addition of atazanavir 300 mg only. Atazanavir enhances saquinavir and ritonavir by a mechanism that requires elucidation. While saquinavir enhancement was apparently independent of atazanavir dose, atazanavir 300 mg produced an increase in ritonavir Cmax, which is not observed with lower atazanavir doses. Atazanavir-related hyperbilirubinemia was dose dependent. However, higher saquinavir and atazanavir exposure may be required to suppress HIV-resistant strain replication.

Adult↗
PubMed2006

Abacavir/lamividune combination in the treatment of HIV-1 infection: a review.

Consensus guidelines for the management of HIV infection recommend the use of two nucleoside analogues in combination with either a non-nucleoside reverse transcriptase inhibitor or a ritonavir-boosted protease inhibitor in therapy-naive patients. As adherence is crucial for treatment success, regimens with fewer pills, simpler dosing schedules and fewer adverse events have become the first choice for antiretroviral therapy. Fixed-dose combinations further improve the convenience of therapy. There are three dual-nucleoside fixed-dose combinations licensed for treating HIV-infected individuals, which include a combination of abacavir and lamivudine. This article reviews the pharmacology, efficacy, resistance profiles, safety and tolerability of abacavir focussing on its use in combination with lamivudine and discusses the role of this nucleoside backbone in antiretroviral therapy.

Dideoxynucleosides↗
PubMed2006

An open-label, randomized comparative pilot study of a single-class quadruple therapy regimen versus a 2-class triple therapy regimen for individuals initiating antiretroviral therapy.

OBJECTIVE: To examine the antiviral potency and tolerability profile of a single-class four drug (quadruple) nucleoside reverse transcriptase inhibitor (NRTI) regimen compared with a 2-class standard-of-care regimen. METHODOLOGY: A three-centre, randomized, open-label comparative pilot study of zidovudine/lamivudine/efavirenz (triple) versus abacavir/lamivudine/zidovudine/tenofovir (quadruple) therapy in HIV-1-infected, treatment-naive individuals. Both regimens were taken without regard to food and consisted of a twice-daily regimen and 3 pills/day. The study power was based on time-weighted average changes in HIV-1 RNA load. RESULTS: A total of 114 individuals (56 triple, 57 quadruple) received at least one dose of medication. Patients were well matched at baseline for viral load (mean 5.26 log10 versus 5.13 log10, respectively) and CD4 cell count (median 193 versus 153 cells/mm3, respectively). The two regimens performed similarly with regards to all endpoints. At week 48, by intention-to-treat, missing=failure analysis, 68% of triple- and 67% of quadruple-drug treated patients had an HIV-1 RNA <50copies/ml (P>0.05). On-treatment analysis showed 40/40 (100%) of triple- and 39/40 (97.5%) of quadruple-drug treated patients (P=0.996) had responded to <50copies/ml. No unexpected adverse events were reported. Changes in total cholesterol and triglycerides were modest but significantly favoured the quadruple therapy regimen at multiple time points. CONCLUSION: This pilot study suggests a quadruple NRTI-based regimen provides similar antiviral potency, tolerability and administrative characteristics to a 2-class triple therapy regimen. These findings should be confirmed in a more fully powered study. Potent quadruple NRTI-based regimens may have advantages for some individuals with regards to salvageability, tolerability and drug interactions.

Adenine↗
PubMed2005

Early virologic failure in HIV-1 infected subjects on didanosine/tenofovir/efavirenz: 12-week results from a randomized trial.

OBJECTIVE: To compare the safety and efficacy of two once-daily antiretroviral regimens containing lamivudine (3TC) or tenofovir disoproxil fumarate (TDF), each administered with didanosine (ddI) and efavirenz (EFV) as initial therapy to HIV-1-infected subjects. METHODS: Single centre, randomized (1: 1), open-label study in antiretroviral-naive, HIV-infected adults. Subjects commenced either 3TC/ddI/EFV (3TC group) or TDF/ddI/EFV (TDF group). Safety, Medication Event Monitoring System (MEMScap) and plasma EFV concentration monitoring was performed over the study period. Comparisons between groups were assessed using chi test and linear regression analysis was used to assess the relationship between EFV concentrations and virological response. RESULTS: Seventy-seven subjects were enrolled prior to recruitment being suspended, 36 to the 3TC group and 41 to the TDF group. Intention-to-treat analysis in which last observation carried forward (LOCF) found the mean viral log10 load [95% confidence interval (CI)] at weeks 4 and 12 to be 2.67 (2.47-2.87) and 1.83 (1.74-1.92) for the 3TC group and 2.75 (2.45-3.05) and 2.28 (1.96-2.6) for the TDF group (P = 0.013). Emergence of resistance occurred in five of 41 (12.2%) subjects in the TDF group up to week 12 compared with none of 36 in the 3TC group, (P < 0.05); these five subjects shared similar baseline characteristics (CD4+ cell counts < 200 x 10 cells/l and HIV-1 RNA > 100,000 copies/ml). Despite MEMScap monitoring showing > 99% adherence in all subjects, among the five failures, three had low EFV concentrations. CONCLUSION: TDF/ddI/EFV as initial therapy appears to have diminished efficacy in subjects with CD4 < 200 x 10 cells/l and viral load > 100,000 copies/ml. Treatment failure with resistance was not attributable to baseline resistance, efavirenz exposure or poor adherence.

Adenine↗
PubMed2005

Boosted saquinavir hard gel formulation exposure in HIV-infected subjects: ritonavir 100 mg once daily versus twice daily.

OBJECTIVES: The amount of ritonavir needed to enhance saquinavir hard gel (hg) plasma concentrations is unclear. Reduced ritonavir dosing may help to reduce ritonavir-related side effects and costs. This study examined the pharmacokinetics of twice-daily saquinavir-hg (1000 mg) in the presence of ritonavir 100 mg, dosed twice-daily and once-daily on one single occasion. METHODS: Eighteen HIV-infected adults taking saquinavir/ritonavir 1000/100 mg twice-daily underwent pharmacokinetic (PK) assessment of saquinavir/ritonavir on day 1 following a morning saquinavir/ritonavir dose. On day 2, PK assessment was repeated when subjects took saquinavir without ritonavir. Drug intake (with a standard meal containing 20 g of fat) was timed on days -1, 1 and 2. Geometric mean ratios (GMR) and 95% confidence intervals (CI) were calculated to assess changes in saquinavir PK parameters. RESULTS: Geometric mean saquinavir AUC(0-12), C(trough), C(max) and elimination half-life on days 1 and 2 were 14 389 and 9590 ng.h/mL, 331 and 234 ng/mL, 2503 and 1893 ng/mL and 2.80 and 2.82 h, respectively. The GMR (95% CI) for these parameters were 0.67 (0.53-0.84), 0.71 (0.48-1.04), 0.76 (0.58-0.98) and 1.01 (0.86-1.18), respectively. CONCLUSIONS: Withholding a ritonavir dose significantly reduces overall saquinavir exposure and C(max), but had no impact on the elimination half-life. These data establish the need to administer saquinavir and ritonavir simultaneously.

Area Under Curve↗
PubMed2005

Pharmacokinetics of saquinavir hard gel/ritonavir (1000/100 mg twice daily) when administered with tenofovir diproxil fumarate in HIV-1-infected subjects.

AIMS: To investigate whether the administration of tenofovir diproxil fumarate 300 mg once daily alters the plasma pharmacokinetics of the saquinavir hard gel/ritonavir combination in HIV-1 infected individuals. METHODS: On day 1, 12 h pharmacokinetic profiles for saquinavir/ritonavir (1000/100 mg given twice daily) were obtained for 18 subjects. All subjects were receiving ongoing treatment with a saquinavir/ritonavir-containing regimen. Tenofovir diproxil fumarate 300 mg given once daily was then added to the regimen and blood sampling was repeated at days 3 and 14. Saquinavir and ritonavir concentrations were measured by HPLC-MS/MS, and tenofovir concentrations by HPLC with UV detection. RESULTS: Following the addition of tenofovir diproxil fumarate to the regimen, saquinavir and ritonavir plasma concentrations were not significantly different compared with day 1. Thus the geometric mean ratios (95% confidence intervals) for the area under the concentration-time curve were 1.16 (0.97, 1.59) and 0.99 (0.87, 1.30) for saquinavir and 1.05 (0.92, 1.28) and 1.08 (0.97, 1.30) for ritonavir, on days 3 and 14, respectively. CONCLUSIONS: Tenofovir diproxil fumarate did not alter the pharmacokinetics of saquinavir hard gel/ritonavir.

Adenine↗
PubMed2005

Mechanisms of HIV and nucleoside reverse transcriptase inhibitor injury to mitochondria.

Available evidence suggests that a number of important clinical events in individuals with HIV infection are related to mt dysfunction. Several factors may contribute to the development of these events and the tissue(s) in which the event occurs. Some individuals are likely to have important genetic predispositions for mt disease, which may be unmasked by the presence of HIV infection or the introduction of NRTI antiretrovirals. HIV infection per se is associated with reduction in mtDNA content and changes in mt morphology and function, which in some cases leads to clinical events such as myopathy or peripheral neuropathy. NRTI antiretrovirals may impact mtDNA content and function through a number of different mechanisms and have been demonstrated to be causative of a number of clinical toxicities. In in vitro and in clinical studies, newer nucleoside and nucleotides agents such as lamivudine, emtricitabine, abacavir and tenofovir appear to be much weaker inhibitors of mtDNA polymerase-gamma or other mt functions, and appear to be associated with a lower risk of events thought to be related to mt toxicity. Simple, non-invasive tests for mt function are not available at present in the clinical routine, and assays of mtDNA content in blood cells may miss key aspects of mt function, require careful sample handling and may not reflect events occurring in other tissues. There remains a need for the development of rapid, cheap and clinically applicable assays that would enable the prediction of increased likelihood of mt events.

Anti-HIV Agents↗
PubMed2004

A randomized study comparing a three- and four-drug HAART regimen in first-line therapy (QUAD study).

BACKGROUND: Evidence from randomized controlled trials supports the use of triple therapy. Research is required on the effectiveness of quadruple therapy in comparison to this and the relative effectiveness of specific highly active antiretroviral therapy (HAART) combinations. METHODS: Antiretroviral-naive individuals (n = 53) with an HIV-1 viral load >100 000 copies/mL were randomized to receive three-drug HAART with zidovudine/lamivudine (Combivir) and efavirenz or quadruple therapy with zidovudine/lamivudine/abacavir (Trizivir) and efavirenz (quad regimen). Patients continued on HAART for 48 weeks with regular clinical and immunological assessment. Standard and ultrasensitive (<5 copies/mL) viral load testing was carried out. RESULTS: A DAVG (difference in averages) analysis of the fall in viral load and increase in CD4 count showed no significant differences between regimens. Triple therapy resulted in a -4.17 log change (95% CI, -4.48 to -3.85) and quadruple therapy in a -4.36 log change (95% CI, -4.68 to -4.03) in viral load. For CD4 counts, the triple therapy arm increased by 164 cells/mm(3) (95% CI 112-217) and the quadruple arm by 185 (95% CI, 133-237). In an intent-to-treat analysis, 77% of patients in the triple therapy group reached an undetectable viral load (<50 copies/mL) compared with 84.2% of the quadruple therapy group. For ultrasensitive viral load testing, 23% and 18% of each group, respectively, reached undetectable viral loads. The hazard ratio for attaining a viral load of <5 copies/mL was 0.59 (95% CI, 0.26-1.33) for quadruple versus triple therapy. Three individuals in the triple therapy arm and nine in the quadruple therapy arm discontinued treatment. CONCLUSIONS: No differences in any analyses were observed between a standard of care regimen (zidovudine/lamivudine and efavirenz) and the quad regimen (zidovudine/lamivudine/abacavir and efavirenz).

Alkynes↗
PubMed2004

Renal dysfunction with tenofovir disoproxil fumarate-containing highly active antiretroviral therapy regimens is not observed more frequently: a cohort and case-control study.

BACKGROUND: Tenofovir disoproxil fumarate (tenofovir DF), the first nucleotide analogue reverse transcriptase inhibitor approved for the treatment of HIV infection, has been associated with renal dysfunction in isolated cases. We investigated the overall incidence and risk of renal dysfunction in individuals receiving tenofovir DF and compared this with other antiretrovirals. METHODS: Data from the Chelsea and Westminster cohort were analyzed to reveal HIV-positive individuals with a creatinine value greater than 120 micromol/L at any time, the upper limit of normal used by our reference laboratory. These individuals were classified according to antiretroviral exposure and time exposed. A matched case-control study was performed comparing patients who had received tenofovir DF and subsequently developed a creatinine value greater than 120 micromol/L against controls who had been treated with tenofovir DF and had not experienced a creatinine elevation. RESULTS: Of 4183 HIV-positive patients, 1175 were identified as having a recorded creatinine value >120 micromol/L. Comparison of antiretroviral-naive patients and patients exposed to tenofovir DF- and non-tenofovir DF-containing regimens revealed a lower rate ratio and probability of developing a creatinine value >120 micromol/L in patients exposed to tenofovir DF (rate ratio vs. no antiretrovirals = 0.22, 95% confidence interval [CI]: 0.07-0.69; P < 0.001) with no significant difference between HAART regimens, corrected for duration of exposure. Of the 1058 individuals who were exposed to tenofovir DF, 84 (8%) patients experienced a creatinine value >120 micromol/L subsequent to exposure. An alternative etiology of renal dysfunction was found in 75 (90%) of these individuals. CONCLUSIONS: Tenofovir DF is not associated with renal dysfunction more frequently than other antiretroviral drugs, and the occurrence of renal dysfunction in this context is usually attributable to other causes.

Adenine↗
PubMed2004

Steady-State pharmacokinetics of saquinavir hard-gel/ritonavir/fosamprenavir in HIV-1-infected patients.

BACKGROUND: In vitro synergy and complementary resistance profiles provide a strong rationale for combining fosamprenavir with saquinavir as part of a potent double-boosted protease inhibitor regimen. This study evaluated the steady-state pharmacokinetics of saquinavir 1000 mg twice daily (bid) and fosamprenavir 700 mg bid administered with 2 different doses of ritonavir (100 and 200 mg bid) in HIV-1-infected subjects. METHODS: On day 1, 12-hour pharmacokinetic profiles for saquinavir/ritonavir (1000/100 mg bid) were obtained for 18 subjects. All subjects were receiving ongoing treatment with a saquinavir/ritonavir-containing regimen. Fosamprenavir 700 mg bid was then added to the regimen, and pharmacokinetic sampling was repeated for all 3 agents at day 11. The ritonavir daily dose was then increased to 200 mg bid, and a 3rd pharmacokinetic profile was obtained at day 22. RESULTS: The coadministration of fosamprenavir 700 mg bid with saquinavir/ritonavir 1000/100 mg bid resulted in a statistically nonsignificant decrease in saquinavir concentrations (by 14, 9, and 24%, for saquinavir area under the concentration-time curve [AUC]0-12, C(max), and C(trough), respectively). This was compensated for by an increased ritonavir dose of 200 mg bid, which resulted in a statistically nonsignificant increase in saquinavir exposure compared with baseline. Amprenavir levels did not appear to be significantly influenced by coadministration of saquinavir with fosamprenavir. Fosamprenavir significantly reduced ritonavir exposure, but the increased ritonavir dose compensated for this interaction. CONCLUSIONS: Our findings showed that saquinavir/ritonavir/fosamprenavir was well tolerated over the study period. Saquinavir plasma concentrations were slightly lowered by the addition of fosamprenavir to the regimen. However, the addition of a further 100 mg ritonavir bid restored the small and insignificant decrease.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Clinical management of treatment-experienced, HIV-infected patients with the fusion inhibitor enfuvirtide: consensus recommendations.

The introduction of enfuvirtide (FUZEON) represents an important advance in the treatment of therapy-experienced patients with HIV-1 infection. However, parenteral self-administration, and the advanced disease and antiretroviral experience of patients currently most needing enfuvirtide introduce unique usage considerations. Enfuvirtide has been shown to provide clinically relevant improvements in CD4 cell counts and reductions in HIV viraemia across all subgroups of treatment-experienced patients studied, including those taking few or no other active drugs. However, optimal outcome results from initiation when the CD4 cell count is above 100 x 10(6) cells/l and viraemia below 1 x 10(5) copies/ml, as part of a newly constructed third or fourth antiretroviral regimen in combination with one or two other antiretrovirals to which the virus remains sensitive. Resistance testing should be used where available to guide background drug selection. Where insufficient options for an effective background exist, enfuvirtide should still be considered and treatment undertaken with the aim of achieving an immunological or clinical response, despite the unlikelihood of a sustained virological outcome. Similarly, where there is no viable alternative treatment, enfuvirtide should be continued following virological failure wherever ongoing immunological or clinical benefit is discerned. Injection site reactions (ISRs) are common on enfuvirtide and will affect almost all patients. ISRs are manageable and seldom activity- or treatment-limiting. Bacterial pneumonia and systemic hypersensitivity reactions have also been reported uncommonly. A structured series of patient visits with a healthcare professional provides an atmosphere of ongoing training and support that may prevent 'injection fatigue', maintain adherence and minimise the incidence of ISRs. An initial investment in establishing such procedures can be expected to yield significant returns in patient confidence and benefit on enfuvirtide.

Clinical Trials, Phase III as Topic↗
PubMed2004

Surveillance of HIV antiretroviral drug resistance in treated individuals in England: 1998-2000.

OBJECTIVES: To establish a surveillance programme for HIV drug resistance within the UK covering the years from 1998 to 2000, following the introduction of triple combination antiretroviral therapy. METHODS: Sentinel sites included large, medium sized and small clinical centres. Data were analysed until December 2000. RESULTS: Of nearly 300 samples tested, results from 91, 92 and 92 patients, respectively in 1998, 1999 and 2000, who were receiving HIV therapy with a viral load >2000 copies/mL, the majority had viruses with some degree of drug resistance. Overall, the presence of any resistance increased between 1998 and 1999, and fell again in 2000 (69% versus 88% versus 55%). However, major differences were observed between drug classes, such that non-nucleoside analogue reverse transcriptase inhibitor (NNRTI) resistance rose dramatically over the period studied. We show that this correlated with increased NNRTI prescribing. Furthermore, an overall increase in prevalence of viruses with resistance to one or more drugs within all three available classes was observed. A higher prevalence of drug resistance was observed in patients from smaller clinical centres. CONCLUSIONS: This is the first such sentinel surveillance dataset from the UK, and is unique in correlating these data with national antiretroviral prescribing patterns. Our findings are relevant to the increased transmission of HIV drug resistance observed over this period.

Anti-HIV Agents↗
PubMed2004

Changes in hematologic parameters and efficacy of thymidine analogue-based, highly active antiretroviral therapy: a meta-analysis of six prospective, randomized, comparative studies.

BACKGROUND: Hematologic changes that occur with HIV infection and antiretroviral therapy may impact the quality of life of patients and have been associated with morbidity and mortality. The management of anemia and neutropenia has improved survival in persons with HIV. OBJECTIVES: This meta-analysis was performed to assess the changes in hemoglobin (Hb) levels and neutrophil counts that occur during thymidine analogue-based triple therapy and to establish whether different regimens of triple therapy are similar in efficacy based on CD4(+) T-cell count and viral load changes. METHODS: This was a meta-analysis of the impact of zidovudine (AZT) compared with stavudine (d4T) in triple therapy regimens in HIV patients with regard to hematologic parameters and efficacy markers. The peer-reviewed literature was searched with use of MEDLINE, PubMed, EMBASE, and the Cochrane database of systematic reviews (key terms: HIV, antiretroviral therapy, CD4, viral load, three, triple, and highly active antiretroviral therapy [HAART]). Searches were initially not limited by publication type, study design, date, or language but subsequently were sorted to include only studies performed in treatment-naive adult patients; randomized; and comparative of a regimen that included d4T with a regimen that included AZT; to involve regimens that included a minimum of 3 drugs each; and to include hematologic outcomes data. Outcomes were CD4(+), viral load, and hematologic parameters. RESULTS: This meta-analysis included 6 studies. Treatment efficacy as measured by changes in CD4(+) T-cell counts and viral load did not differ significantly between regimens. Hb levels decreased with AZT treatment by a mean (SE) 0.4 (0.05) g/dL and 0.2 (0.06) g/dL at weeks 24 and 48, respectively, but increased with d4T treatment by 0.45 (0.03) g/dL and 0.58 (0.04) g/dL, respectively. All grades of anemia and neutropenia events were consistently more common with AZT-based regimens relative to d4T-based therapy. CONCLUSIONS: AZT-based HAART has a greater negative impact on hematologic parameters relative to d4T-based regimens. AZT recipients are more likely than d4T recipients to experience anemia and neutropenia events of any grade, and AZT is associated with a net decrease in Hb level relative to a net increase with d4T. These factors may influence the choice of drug used in the treatment of certain patient populations.

Anemia↗