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Biomedical subjects

G J Moyle

Publications and source records attributed to G J Moyle.

At least 37 records · Page 2Linked to original sources
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

Saquinavir-soft gel: establishing saquinavir in HAART regimens.

The initial formulation of the HIV protease inhibitor (PI) saquinavir (SQV) in hard gel capsules (Invirase) demonstrated significant clinical benefit in double and triple combination regimens in comparative studies. However, pharmacological limitations of this preparation resulted in fewer patients achieving optimal treatment responses than observed with other PIs. Changes in formulation and dosing to a new soft gelatin capsule formulation of SQV (SQV-SGC, Fortovase result in an average 8-fold increase in SQV exposure with SQV-SGC. Data from clinical trials indicate that this enhanced plasma exposure translates into more potent antiviral activity, with small comparative studies suggesting activity to be similar to other available PIs in triple therapy highly-active antiretroviral therapy (HAART) regimens. Additionally, SQV-SGC appears to be an excellent candidate for PI combination use. SQV-SGC appears well-tolerated with a low incidence of mainly gastrointestinal side-effects. The lower affinity to P450 isozymes of SQV means that the incidence of drug interactions is low, indeed probably lower than with other approved members of this class. Current obstacles to SQV-SGC's widespread use include only limited, short-term bid dosing data (outside of combination with ritonavir) and the pill burden of 18 capsules per day.

Journal Article↗
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↗
PubMed1997

Current knowledge of HIV-1 reverse transcriptase mutations selected during nucleoside analogue therapy: the potential to use resistance data to guide clinical decisions.

Massive viral turnover and the high error rate of reverse transcriptase create the potential for drug-resistant viral variants to appear rapidly under the selective pressure of antiretroviral therapy. Loss of antiviral effect in treatment compliant persons is most commonly coincident with the appearance of viral mutants with reduced drug sensitivity. Thus, detection of viral resistance may represent an early marker of therapy failure. Similarly, substantial reduction in viral replication in the plasma compartment, to below quantification of a viral load assay, is associated with a sustained therapeutic response and delayed development of viral resistance. Information on patterns of resistance to and cross-resistance between antiretroviral agents are increasingly well characterized and represents an important consideration when deciding how to combine and/or sequence antiretrovirals to achieve optimal antiviral effects. When switching therapy, the change of several agents in the treatment regimen is currently recommended. The use of novel means of evaluating resistance, such as a genotypic probe, may guide clinicians in choosing an agent to which the patient's dominant viral quasispecies remains sensitive, potentially increasing the chances of achieving a therapeutic response. However, no studies using resistance to guide clinical decision making have yet been reported and available sequencing studies have focused largely on switching or adding therapies to patients who have received zidovudine monotherapy. Thus, no resistance driven treatment algorithm is currently available.

Anti-HIV Agents↗
PubMed1997

Stavudine:pharmacology,clinical use and future role.

Stavudine is a nucleoside analogue reverse transcriptase inhibitor of HIV-1 and HIV-2 and demonstrates in vitro activity with an acceptable therapeutic index in a range of T-lymphocyte and haematopoietic precursor cell lines. It is additive or synergistic in vitro with a range of other antiretrovirals, including the proteinase inhibitor saquinavir, in two- and three-way combinations and is active against zidovudine (ZDV)-resistant virus. It exhibits excellent oral bioavailability, with cerebrospinal fluid (CSF)/plasma penetration. In clinical use, stavudine monotherapy exhibits similar antiretroviral activity to ZDV, and is of proven clinical benefit in ZDV-pre-treated patients. In combination with ddI and/or nelfinavir it results in more substantial and durable responses in immunological and virological markers than reported with either drug alone. Further data on stavudine in combination with other antiretrovirals are now awaited. Comparative trials in ZDV-experienced patients suggest a similar frequency of adverse events to that observed with ZDV. Peripheral neuropathy is the most common dose-limiting toxicity, with haematological and hepatic function disturbance being infrequent. Resistance to stavudine develops slowly in vitro and in vivo but may lead to co-resistance to ZDV or ddI. Stavudine will be used clinically as a combination agent both in initial therapy and in patients with prior ZDV experience.

Journal Article↗
PubMed1997

Viral resistance patterns selected by antiretroviral drugs and their potential to guide treatment choice.

Massive viral turnover and reverse transcriptase's high error rate create the potential for drug-resistant viral variants to appear rapidly under the selective pressure of antiretroviral therapy. Loss of antiviral effect in treatment-adherent persons is most commonly coincident with the appearance of viral mutants with reduced drug sensitivity. Thus, detection of viral resistance may represent an early marker of therapy failure. Similarly, control of viral replication in the plasma compartment, as defined by plasma viral load below the levels of assay quantification, is associated with a sustained therapeutic response and delayed development of viral resistance. Information on patterns of resistance to and cross-resistance between antiretroviral agents is increasingly well characterised and represents an important consideration when deciding how to combine and/or sequence antiretrovirals to achieve optimal antiviral effects. Given the limited number of antiretrovirals presently available or in advanced development, it is important not to limit future therapeutic options by using therapies early in the treatment sequence which may select for cross-resistant viral variants and hence potentially reduce the magnitude of therapeutic response when treatment is changed to another member of that drug class. However, no studies using resistance to guide clinical decision making have been reported to date and available sequencing studies have focused largely on switching or adding therapies to patients experienced with zidovudine monotherapy. Thus, no resistance driven treatment algorithm is currently available.

Journal Article↗
PubMed1997

The role of didanosine in the management of HIV-1 infection.

Large-scale clinical end point studies comparing antiretroviral therapy with zidovudine alone, didanosine alone, and zidovudine combined with didanosine indicate that both didanosine alone and zidovudine/didanosine provide a better clinical outcome than zidovudine alone in patients with human immunodeficiency virus (HIV) infection. The superiority of combination didanosine/zidovudine therapy over zidovudine monotherapy was most significant in treatment-naive patients, but benefit was also seen in patients who had previously received zidovudine and also in all stages of disease. Activity marker data from other studies suggest that double or triple combination therapies that include didanosine and nucleoside analogues other than zidovudine, non-nucleoside reverse transcriptase inhibitors or protease inhibitors result in powerful suppression of viral replication that will provide additional clinical benefits. Apart from mostly mild gastrointestinal disturbances, didanosine alone and in various combination therapies has been generally well tolerated. Thus, didanosine represents a potent, versatile nucleoside analogue with potential benefits in both current and future antiretroviral regimens for HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1997

The role of stavudine in the management of adults with HIV infection.

Combinations of two nucleoside analogue reverse transcriptase inhibitors plus a third agent represent the current standard for antiretroviral therapy. Stavudine is a nucleoside analogue that demonstrates in vitro activity against human immunodeficiency virus type 1 (HIV-1) and HIV-2 within an acceptable therapeutic index in a range of T lymphocyte and haematopoietic precursor cell lines. It is additive or synergistic in vitro with a number of other antiretrovirals including protease inhibitors in two and three way combinations and is active against zidovudine-resistant virus. It exhibits excellent oral bioavailability, with CSF penetration. In clinical use, stavudine exhibits antiretroviral activity as a monotherapy similar to zidovudine, and is of proven clinical benefit in zidovudine-pretreated patients. In combination with didanosine and/or nelfinavir it results in more substantial and durable responses in immunological and virological markers than reported with either drug alone. Comparative trials in zidovudine-experienced patients suggest a similar frequency of adverse events to that observed with zidovudine. Peripheral neuropathy is the most common dose-limiting toxicity with haematological and hepatic function disturbance being infrequent. Reasons for stavudine failure are not established, with no consistent genotypic pattern being associated with changes in stavudine sensitivity in vitro or in vivo. The role of stavudine is as a component of triple therapy regimens both in initial therapy and in patients with prior zidovudine experience.

Adult↗
PubMed1997

Zidovudine monotherapy versus zidovudine plus zalcitabine combination therapy in HIV-positive persons with CD4 cell counts 300-500 cells/mm3: a double-blind controlled trial. The M50003 Study Group Coordinating and Writing Committee.

OBJECTIVE: To assess the safety and clinical and immunological activity of zalcitabine/zidovudine combination therapy compared with zidovudine monotherapy in persons with no or limited antiretroviral experience and CD4 counts of 300-500 cells/mm3. DESIGN AND SETTING: A double-blind controlled multi-centre study conducted in specialist human immunodeficiency virus (HIV) care centres in Spain, Portugal and Australia. Participants were randomized at study entry to zidovudine (200 mg three times daily) plus zalcitabine (0.75 mg three times daily) or matched placebo. The primary end point was the proportion of patients with CD4 above baseline value at 24 months. The secondary end points were time to AIDS/death, quality of life (by MOS-30) and safety. RESULTS: The study was terminated prematurely following the results of the Delta and ACTG 175 studies. Two-hundred and fifty-six patients entered the protocol of whom all but 15 were treatment naive. One hundred and twenty-seven patients commenced zidovudine and 129 commenced a combination of zidovudine/zalcitabine. The median duration of follow-up was 634 days with a median time on blinded therapy of 500 days. Using the last available CD4 count data, 32.4% randomized to zidovudine and 65.1% randomized to zidovudine/zalcitabine remained above baseline at study close (P < 0.001). No significant differences were observed in the time taken for CD4 count to return to baseline. Over 104 weeks, median CD4 counts rose in the combination group from 399 to 509 cells/mm3 whereas those randomized to zidovudine fell from 410 to 374 cells/mm3. Only 12 AIDS events and two deaths (both accidental) occurred during the study with no differences between groups. No differences in quality of life were observed. Adverse events were the cause of treatment discontinuation in 8.6% of patients with no differences between treatment arms. A further 8.2% of patients were lost to follow-up. At least one adverse event (all severities, all relationships) was experienced by 80.3% of patients randomized to zidovudine and 79.8% of patients on combination. Peripheral neuropathy (all grades) was reported in 10.1% of patients randomized to the combination and 3. 1% in the zidovudine arm (P = 0.026). Oral ulcers were reported in 7.8% and 4.7% of combination and zidovudine monotherapy arms, respectively. Neutropenia was more common in the zidovudine group (22%) than the combination group (14%). CONCLUSIONS: Combination of zidovudine/zalcitabine as initial therapy maintains CD4 count above commencement levels in a significantly greater proportion of patients than zidovudine monotherapy. In persons with CD4 counts > or = 300 cells/mm3 inclusion of zalcitabine with zidovudine does not increase the incidence of adverse events or adversely affect quality of life.

Adult↗
PubMed1996

Use of viral resistance patterns to antiretroviral drugs in optimising selection of drug combinations and sequences.

High rates of viral replication throughout HIV infection, and the frequency of mutation occurring during each replication cycle due to the inaccuracy of reverse transcriptase, drive the potential for drug-resistant viral variants to appear under the selective pressure of antiretroviral therapy. Loss of antiviral effect with a variety of antiretroviral agents has been reported to coincide with the appearance of viral mutants with reduced drug sensitivity. Additionally, the presence of both phenotypic and genotypic zidovudine resistance is associated with an increased risk of clinical disease progression and death, independent of a change of therapy to didanosine. The patterns of resistance to and cross-resistance between antiretroviral agents are increasingly well characterised, and represent an important consideration when deciding how to combine and/or sequence antiretrovirals to achieve optimal antiviral effects. Given the limited number of antiretrovirals currently available or in advanced development, it is important not to potentially limit future therapeutic options by using, early in the treatment sequence, therapies which may select for cross-resistant viral variants and hence potentially reduce the additional therapeutic response when treatment is changed to another member of that drug class.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Safety and activity of zalcitabine and zidovudine combination in HIV-positive people with CD4 cell counts < or = 300 cells/mm3. The Roche M50002 Study Group.

We carried out an open-label, single-arm, multicentre 1-year study of the safety and activity of therapy with a zalcitabine-zidovudine combination in 561 patients with CD4 cell counts < or = 300 cells/mm3 who were either established on zidovudine or had not previously received antiretroviral therapy. Additionally, we assessed the impact of baseline characteristics on clinical outcome during therapy. The study used specialist HIV-care centres in Argentina, Belgium, Brazil, Hungary, Italy, Luxembourg, Mexico, Peru, Spain and Venezuela. Participants were regularly assessed for adverse experiences, changes in laboratory values and clinical progression. A total of 561 patients entered the study, with 353 completing 12 months of follow-up. The 492 zidovudine-experienced patients had a mean duration of previous therapy of 18.5 months. No unexpected adverse events were reported. Peripheral neuropathy was observed in 12.7% of patients and was more common in participants with CD4 cell counts < or = 100 cells/mm3 at baseline. Clinical disease progression was significantly associated with lower baseline CD4 cell counts, a history of previous AIDS-defining events and a baseline haemoglobin < 11 g/dl. The median CD4 cell count at baseline was 141.5 cells/mm3, rising to 174 cells/mm3 after 12 weeks and to 148 cells/mm3 at 12 months. In conclusion, zalcitabine-zidovudine combination therapy was found to be well tolerated in this patient population, although patients with CD4 cell counts < or = 100 cells/mm3 were found to require more intensive monitoring for toxicities and disease events. The changes in the CD4 cell count seen in this study and in others provide evidence of the therapeutic activity of this combination.

Adult↗
PubMed1995

AIDS: clinical and scientific issues past, present and future.

The time from the recognition that AIDS was an infectious disease, to the discovery of HIV as the causative agent and the identification of the first specific antiviral agent that showed some clinical benefit, was impressively short. Over the last few years it would appear that progress against AIDS has slowed down considerably. Neither new treatments nor vaccines have given much grounds for optimism and back to basics has been the main battle cry. However it is easy to overlook the tremendous improvements that have taken place in the management of HIV disease in the absence of a curative treatment. Many of the opportunistic infections that used to kill patients are not only treatable but are able to be treated prophylactically. This has altered the clinical spectrum of disease with many patients surviving several years with virtually no CD4 lymphocytes only to succumb to other HIV related disease such as non Hodgkins lymphoma. This review identifies the major advances that have occurred in our understanding of AIDS and identifies the major problems to be overcome in the next few years at both the clinical and basic levels.

Acquired Immunodeficiency Syndrome↗