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Biomedical subjects

G J Moyle

Publications and source records attributed to G J Moyle.

At least 19 recordsLinked to original sources
PubMed2003

A 48-week, randomized, open-label comparison of three abacavir-based substitution approaches in the management of dyslipidemia and peripheral lipoatrophy.

BACKGROUND: The mechanisms by which dyslipidemia and lipoatrophy develop during antiretroviral therapy are not clear. No treatment of lipoatrophy is currently established. METHODS: This was an open-label randomized study of HIV-positive individuals on a first-line therapy containing stavudine (d4T) with either a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI) and with hypercholesterolemia (defined as total cholesterol >5.2 mmol/L or >180 mg/dL) and/or lipoatrophy and with a viral load of <50 copies/mL. Patients switched d4T to abacavir (ABC) (group 1), a PI or NNRTI to ABC (group 2), or d4T and PI or NNRTI to ABC plus AZT (group 3). Patients were followed-up with fasting blood levels, dual-energy X-ray absorptiometry (DXA), and computed tomography (CT) scans for 48 weeks. RESULTS: Thirty patients were included, with 27 completing 48 weeks of therapy. One ABC hypersensitivity reaction was the only serious adverse event. All patients' viral loads remained at <50 copies/mL. CD4 cell counts rose in groups 2 and 3 but fell modestly in group 1. Total and low-density lipoprotein cholesterol improved significantly in groups 2 and 3. Triglycerides fell significantly in group 2. In contrast, total, arm, and leg fat mass (by DXA) rose significantly in group 1 but fell modestly in groups 2 and 3. Visceral adiposity (by CT scan) was unaffected in all groups. CONCLUSIONS: Abacavir represents a virologically effective replacement for d4T, PI, or NNRTI in persons on successful first-line therapy. Replacement of a PI or NNRTI with ABC leads to modest improvement in both cholesterol and triglycerides. Replacement of d4T with ABC leads to modest improvements in fat mass.

Adult↗
PubMed2002

Interaction between saquinavir soft-gel and rifabutin in patients infected with HIV.

AIMS: To evaluate the potential pharmacokinetic interaction between the HIV protease inhibitor saquinavir and rifabutin. METHODS: Fourteen HIV-infected patients provided full steady-state pharmacokinetic profiles following administration of rifabutin alone (300 mg once daily) or saquinavir soft-gel formulation (1200 mg three times daily) plus rifabutin (300 mg once daily) in this open label, partially randomized study. RESULTS: Coadministration of saquinavir and rifabutin resulted in a reduction in saquinavir AUC(0,8 h) and C(max)(0,8 h) of 47% (95% CI 30, 60%) and 39% (95% CI 11, 59%), respectively. Rifabutin AUC(0,24 h) and C(max)(0,24 h) was increased by an average of 44% (95% CI 17, 78%) and 45% (95% CI 14, 85%), respectively. Saquinavir in combination with rifabutin was well tolerated. Gastrointestinal intolerance and asymptomatic increases in liver enzymes were the only adverse events of note. CONCLUSIONS: Administration of rifabutin with saquinavir may decrease the efficacy of this HIV protease inhibitor.

Adult↗
PubMed2001

Dietary advice with or without pravastatin for the management of hypercholesterolaemia associated with protease inhibitor therapy.

BACKGROUND: Therapy with a HIV protease inhibitor is associated with elevations in cholesterol and triglycerides. HMG-CoA reductase inhibitors ('statins') are the established therapy for persons with primary hypercholesterolaemia. Because of drug interactions, pravastatin may represent the preferred choice in those taking HIV protease inhibitors. DESIGN: A randomized, open-label comparative 24 week trial of dietary advice alone or with pravastatin in 31 male patients established on protease inhibitor-based regimens for greater than 12 weeks with viral load < 500 copies/ml and cholesterol > 6.5 mmol/l. RESULTS: There were no significant clinical or laboratory events and no patient discontinuation secondary to adverse effects. Viral rebound did not occur. Relative to baseline, total cholesterol at week 24 fell significantly in the pravastatin (1.2 mmol/l; 17.3%) (P < 0.05) but not in the dietary advice (0.3 mmol/l; 4%) group. The difference between the two groups approached significance at week 24 (P = 0.051). This fall was accounted for entirely by a reduction in low density lipoprotein [calculated change 1.24 mmol/l (19%) and 0.07 mmol (5.5%) in pravastatin and dietary advice groups, respectively] as high density lipoprotein rose non-significantly by 0.6 mmol/l in both groups. Weight, basal metabolic rate, fasting glucose and triglycerides did not change significantly in either group. CONCLUSIONS: Dietary advice plus pravastatin significantly reduced total cholesterol in HIV-positive individuals taking protease inhibitors, without significant adverse effects. The inclusion of pravastatin substantially increases the magnitude of the change, which is comparable with changes achieved in endogenous hyperlipidaemia.

Anticholesteremic Agents↗
PubMed2001

Principles and practice of HIV-protease inhibitor pharmacoenhancement.

Continually maintaining maximally suppressive drug concentrations represents a key defence against the emergence of resistance. If drug levels fall and replication occurs, the opportunity for mutant virus to be selected occurs. It has been increasingly recognized that variability in the pharmacokinetics of antiretrovirals, particularly protease inhibitors (PIs), means that drug exposure is not always optimal, giving the virus a chance to replicate. A significant number of patients receiving PIs two or three times daily will have trough (Ctrough or Cmin) plasma concentrations, which are close to, or below, the plasma protein binding-corrected inhibitory concentration (IC50 or IC95) during the dosing interval. It is primarily in this context that therapeutic drug monitoring of PIs has been proposed as an aid to patient management, to ensure that patients maintain adequate drug concentrations throughout the dosing interval. Ideally, an antiretroviral drug will have a pharmacokinetic (PK) profile that maintains drug levels well above the viral inhibitory concentration throughout the entire dosing interval. Beneficial drug-drug interactions have been shown to improve PI pharmacokinetics. Ritonavir (RTV) inhibits the key enzymes that limit the bioavailability or speed the metabolism of other PIs. It is therefore increasingly used for boosting and maintaining PI plasma concentrations. At low (100 mg twice a day) doses it acts as a pharmacoenhancer of indinavir (IDV), amprenavir, saquinavir, lopinavir and to a more limited degree nelfinavir. Using a pharmacoenhancer with a PI results in increased exposure to the PI, higher Cmin levels, and in most cases prolonged elimination half-lives. The long-term clinical benefits of PK enhancing are unknown as are the long-term toxicities, although the incidence of nephrolithiasis with IDV appears increased when IDV is combined with low-dose RTV in HIV-infected patients. Head-to-head clinical comparisons of boosted PI regimens will help answer some of the questions that remain with regard to PK enhancement.

Anti-HIV Agents↗
PubMed2000

Absence of association between individual thymidine analogues or nonnucleoside analogues and lipid abnormalities in HIV-1-infected persons on initial therapy.

Changes in levels of triglycerides and cholesterol during antiretroviral therapy raise concerns regarding an increased future risk of atherogenic disease and may precede the appearance of fat redistribution. Hypotheses regarding the impact of nucleoside analogues on adipocytes provide a possible explanation for metabolic and clinical fat disturbances. It is unclear whether the choice of nucleoside analogue combination or coadministration of nonnucleoside agents influences change in lipids. We performed a cross-sectional analysis of 135 persons receiving their first nucleoside analogue plus nonnucleoside-based combination antiretroviral regimen for at least 1 month and for whom cholesterol and triglyceride values were available on therapy. Univariate and multivariate regression models were used to explore the relation between cholesterol and triglycerides, as continuous variables with other variables. Both significant and nonsignificant variables from univariate analyses were evaluated in multivariate models to limit possible confounders. No association with drug choice was observed, either when comparing thymidine analogues (stavudine or zidovudine), all nucleoside analogue combinations or choice of either efavirenz or nevirapine as nonnucleoside. Age and triglyceride levels were found in a multivariate analysis to be associated with higher cholesterol. Only higher cholesterol was associated with higher triglyceride levels. In conclusion, no differences were observed between choice of drug or combination on cholesterol or triglyceride values during therapy. Older individuals may be more likely to have elevated cholesterol values.

Adult↗
PubMed1999

A risk-benefit assessment of HIV protease inhibitors.

The use of triple regimens, often called highly active antiretroviral therapy (HAART), generally involving 2 nucleoside analogues and an HIV protease inhibitor, have been endorsed as the standard of care for persons with HIV initiating therapy by a number of sets of international guidelines. The widespread availability of protease inhibitor-containing regimens has been associated with a dramatic drop in the incidence of new AIDS events and mortality throughout the developed world. Use of HAART regimens, particularly in treatment-naïve individuals, is also associated with dramatic reductions in HIV RNA load, rises in CD4+ cell numbers and improvements in some aspects of immune function. However, protease inhibitor therapy is associated with a range of adverse effects, which varies between agents, and regimens frequently involve inconvenient administration schedules and disruption to patient's lives. Thus, the undoubted benefits of antiretroviral therapy come at some cost in terms of both physical and psychological morbidity to the recipient. In assessing an individual for therapy, consideration of the risk of disease events and the benefit of therapy in reducing or preventing these events must be weighed against the potential of therapy to cause morbidity. Using these criteria, we suggest that an individual with a 3 year risk of disease progression of less than 10% (based on CD4+ cell count and HIV RNA load) is more likely to a experience a morbidity if treated with HAART than if left untreated and monitored. For individuals with higher risks of HIV progression the risk versus benefit of initiating therapy may, in many cases, still be in favour of no therapy and continued observation. This will vary depending on the individuals risks (such as family and past medical history) and on the choice of agents in the regimen, some regimens having greater risks than others.

HIV Infections↗
PubMed1998

Safety, pharmacokinetics, and antiretroviral activity of the potent, specific human immunodeficiency virus protease inhibitor nelfinavir: results of a phase I/II trial and extended follow-up in patients infected with human immunodeficiency virus.

The safety, antiretroviral activity, and pharmacokinetic profile of nelfinavir, a potent and specific inhibitor of human immunodeficiency virus (HIV) protease, were assessed in a small open-label phase I/II dose-ranging study in protease inhibitor-naive HIV-positive men. A total of 22 patients with baseline plasma HIV RNA > or = 20,000 copies/mL and CD4+ counts between 200 and 500 cells/mm3 were enrolled in the study. Of the 22 patients, 20 were evaluated for activity; 10 patients assigned to 771 mg/day base equivalent (300 mg three times daily) and 10 patients assigned to 1,026 mg/day base equivalent (600 mg twice daily) given monotherapy. A capsule formulation of nelfinavir was used. The initial study period was 28 days; patients showing a virologic response of 1 log10 reduction were eligible for enrollment in an extension phase and addition of nucleoside analogues. A maximally tolerated dose of nelfinavir was not established. A dose-response relationship was observed for four (40%) patients in the 771-mg group and six (60%) patients in the 1,026-mg group experiencing a reduction from baseline in plasma HIV RNA of at lest 1 log during the 28-day study. Of these patients, five sustained the reduction in plasma HIV RNA beyond day 28 (2 patients receiving 771 mg/day and 3 patients receiving 1,026 mg/day). Median increases from baseline in CD4+ counts at day 28 were 216 cell/mm3 and 86 cell/mm3 in the 771-mg and 1,026-mg groups, respectively. After oral administration, median nelfinavir plasma concentrations on day 28 reached a maximum at 1 hour (2,966 ng/mL) in the 771-mg group and at 3 hours (3,157 ng/mL) in the 1,026-mg group. Data for 22 patients were included in the safety analysis; 12 patients (55%) reported at least one grade 2 or worse (moderate, severe, or very severe) adverse event. The most common grade 2 or worse adverse event was diarrhea, reported by two patients (20%) receiving 771 mg/day and seven patients (70%) receiving 1,026 mg/day; followed by nausea, flatulence, asthenia, and headache (each reported in 1 patient [10%] in the 771-mg group) and dizziness (reported in 1 patient [10%] receiving 1,026 mg/day). In the small subgroup (n = 6) who continued taking nelfinavir for longer periods (between 8 and 15 months), virologic responses were sustained in the majority of patients with good tolerability. Nelfinavir is an active HIV-protease inhibitor with favorable pharmacokinetics, good tolerability, and sustained antiviral effects. Results of this early phase I/II dose-ranging study provided data for the safety and antiretroviral activity of nelfinavir and led to the selection of higher doses for phase II/III trials to further optimize virologic and immunologic responses.

Adolescent↗
PubMed1998

Peripheral neuropathy with nucleoside antiretrovirals: risk factors, incidence and management.

Distal symmetrical peripheral neuropathy is a common adverse experience in persons with HIV infection. This condition, which presents as a pain, numbness. burning and/or dysaethesia initially in the feet, is often multi-factorial in its origin. Nucleoside analogue reverse transcriptase inhibitors represent an important contributor to peripheral neuropathy. Specifically, around 10% of patients receiving stavudine or zalcitabine and 1 to 2% of didanosine recipients may have to discontinue therapy with these agents due to neuropathy. Prompt withdrawal of these therapies enables gradual resolution of signs and symptoms in most patients, although a period of symptom intensification may occur shortly after withdrawal. Risk factors for developing peripheral neuropathy during nucleoside analogue therapy include low CD4+ cell count (<100 cells/mm3), a prior history of an AIDS defining illness or neoplasm, a history of peripheral neuropathy, use of other neurotoxic agents including high alcohol (ethanol) consumption and nutritional deficiencies such as low serum hydroxocobalamin levels. Thus, patients at increased risk of peripheral neuropathy should potentially avoid the use of the neurotoxic nucleoside analogues or be more carefully monitored during therapy. Management of this problem includes patient education. prompt withdrawal of the likely causative agent (giving consideration not to leave the patient on a sub-optimal therapy regimen) and simple analgesia. with augmentation with tricyclic antidepressants or anticonvulsant agents when pain is severe. New agents that may assist in managing this condition include levacecarnine (acetyl-L-carnitine) and nerve growth factors such as recombinant human nerve growth factor.

Clinical Trials, Phase I as Topic↗
PubMed1998

Antiretroviral therapy for HIV infection. A knowledge-based approach to drug selection and use.

In the absence of evidence that eradication of HIV from an infected individual is feasible, the established goal of antiretroviral therapy is to reduce viral load to as low as possible for as long as possible. Achieving this with the currently available antiretroviral agents involves appropriate selection of components of combination regimens to obtain an optimal antiviral response. In addition, consideration of a plan for a salvage or second-line regimen is required if initial therapy fails to achieve an optimal response or should loss of virological control occur despite effective initial therapy. Such a planned approach, based on consideration of the likely modes of therapeutic failure (viral resistance, cellular resistance, toxicity) could be called rational sequencing. Choice of therapy should never involve compromise in terms of activity. However, the choice of drug should also be guided by tolerability profiles and considerations of coverage of the widest range of infected cells, compartmental penetration, pharmacokinetic interactions and, importantly, the ability of an agent or combination to limit future therapeutic options through selection of cross-resistant virus. Available clinical end-point data clearly indicate that combination therapy is superior to monotherapy, with clinical and surrogate marker data supporting the use of triple drug (or double protease inhibitor) combinations over double nucleoside analogue combinations. Thus, 3-drug therapy should represent current standard practice in a nontrials setting. Treatment should be considered as early as practical, and may be best guided by measurement of viral load, with a range of other markers having potential utility in individualising treatment decisions. Therapeutic failure may be defined clinically, immunologically or, ideally, virologically, and should prompt substitution of at least 2, and preferably all, components of the treatment regimen. Drug intolerance may also be best managed by rational substitution.

Anti-HIV Agents↗
PubMed1998

Finding a role for zalcitabine in the HAART era.

Zalcitabine (ddC) is a nucleoside analogue reverse transcriptase inhibitor with demonstrated clinical benefit in combination use. More widespread use of zalcitabine has been limited by a number of factors including peripheral neuropathy and three times daily dosing. However, screening for the risk factors for peripheral neuropathy may enable a reduction in the incidence of neuropathy to below 10%. Additionally, new data on the use of zalcitabine twice daily suggest, based on the long intracellular half-life of the active triphosphate, that this is feasible. Additionally, while limited data exist for zalcitabine in true HAART combinations, data from small trials suggest a similar proportion of responders to standard HAART regimens.

Anti-HIV Agents↗