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Biomedical subjects

G Moyle

Publications and source records attributed to G Moyle.

At least 37 records · Page 2Linked to original sources
PubMed2000

Clinical manifestations and management of antiretroviral nucleoside analog-related mitochondrial toxicity.

OBJECTIVES: This article reviews the clinical manifestations of mitochondrial toxicity associated with the use of nucleoside analog reverse transcriptase inhibitors (NRTIs) and outlines strategies to manage these sequelae. BACKGROUND: NRTIs are the key components of the antiretroviral combinations used in the management of patients infected with HIV. The available NRTIs differ in their convenience of administration, frequency of dosing, resistance profiles, and side-effect profiles. NRTIs act as competitive inhibitors of the RNA/DNA polymerase reverse transcriptase of HIV and cause chain termination in the growing viral DNA chain. Many of the important and treatment-limiting side effects of NRTIs may be related to the effect of these agents on human DNA polymerases, in particular, mitochondrial DNA polymerase gamma. Depletion of mitochondrial DNA during chronic NRTI therapy may lead to cellular respiratory dysfunction and generalized and tissue- and drug-specific toxicities, including myopathy, peripheral neuropathy, and lactic acidosis. Recently, it has been proposed that the fat redistribution syndrome, or lipodystrophy, reported during chronic antiretroviral therapy is a manifestation of the differential impact of at least some NRTIs on peripheral and visceral adipocytes. Management of potential mitochondrial toxicity during NRTI therapy remains a challenge. A range of nutritional supplements, both as treatments and prophylaxes, have been proposed, and some have been investigated in vitro; no in vivo studies have yet been conducted. METHODS: The information in this review was compiled using MEDLINE and AIDSLINE searches of the literature, including conference abstracts. CONCLUSIONS: At present, interruption of NRTI therapy or substitution of the probable causative agent with alternative NRTIs that appear to be better tolerated represents the mainstay of management for mitochondrial toxicity and its clinical manifestations.

Anti-HIV Agents↗
PubMed2000

Persistence of episomal HIV-1 infection intermediates in patients on highly active anti-retroviral therapy.

Treatment of HIV-1-infected individuals with a combination of anti-retroviral agents results in sustained suppression of HIV-1 replication, as evidenced by a reduction in plasma viral RNA to levels below the limit of detection of available assays. However, even in patients whose plasma viral RNA levels have been suppressed to below detectable levels for up to 30 months, replication-competent virus can routinely be recovered from patient peripheral blood mononuclear cells and from semen. A reservoir of latently infected cells established early in infection may be involved in the maintenance of viral persistence despite highly active anti-retroviral therapy. However, whether virus replication persists in such patients is unknown. HIV-1 cDNA episomes are labile products of virus infection and indicative of recent infection events. Using episome-specific PCR, we demonstrate here ongoing virus replication in a large percentage of infected individuals on highly active anti-retroviral therapy, despite sustained undetectable levels of plasma viral RNA. The presence of a reservoir of 'covert' virus replication in patients on highly active anti-retroviral therapy has important implications for the clinical management of HIV-1-infected individuals and for the development of virus eradication strategies.

Anti-HIV Agents↗
PubMed2000

Toxicity of antiretroviral nucleoside and nucleotide analogues: is mitochondrial toxicity the only mechanism?

Nucleoside analogues represent the cornerstones of antiretroviral regimens. A range of drug- or tissue-specific toxicities, such as peripheral neuropathy, myopathy, pancreatitis and lactic acidosis with hepatic steatosis, has been documented with these agents. The fat atrophy seen on long term antiretroviral therapy may also be related to nucleoside analogues. The mechanisms by which nucleoside analogues cause toxicity are not clearly established. In vitro, the triphosphates of these agents are weak to modest substrates for human DNA polymerases, showing the greatest affinity for mitochondrial DNA polymerase gamma. Short term exposure in vitro to some nucleoside analogues has been demonstrated to cause increased lactate production or falls in mitochondrial DNA suggestive of mitochondrial toxicity. However, stavudine and to a lesser extent zidovudine are poor substrates for mitochondrial thymidine kinase type 2, the predominant form in cells that are not actively mitotic such as neurons, myocytes and adipocytes. These are the cell types where the proposed mitochondrial toxicities neuropathy, myopathy and lipoatrophy are observed. Thus, active concentrations of phosphorylated products of stavudine and zidovudine may not be present in mitochondria. The familial mitochondrial diseases do not have identical presentations to nucleoside analogue toxicities. These disorders most commonly involve the CNS, typically with seizures or dementia, and occasionally the kidneys. Although nucleoside analogues are known to penetrate the CNS and are commonly renally excreted unchanged, mitochondrial toxicities at these sites have not been documented. Furthermore, toxicity caused by nucleoside or nucleotide analogues does not always appear to arise through the mitochondrial route. Cidofovir appears to cause renal tubular dysfunction via a toxic intracellular metabolite, and zidovudine-related anaemia appears to be related to decreased globin RNA synthesis. In vitro or animal models suggest that zidovudine myopathy, stavudine-related (but not zalcitabine- or didanosine-related) neuropathy and didanosine-related pancreatitis may all be not related, or not exclusively related, to mitochondrial dysfunction. The integration of nucleoside analogues into nuclear DNA, best documented with zidovudine but likely to occur with other agents, represents an alternative but potentially delayed pathway to cytotoxicity and cell apoptosis. This is the mechanism of cell death during therapy with antineoplastic nucleoside analogues, and may have contributed to the multisystem toxicities observed with the anti-hepatitis B drug fialuridine. New research evaluating the effects of long term exposure of cell lines is required to address the possibility that nuclear genotoxicity plays a role in long term nucleoside analogue toxicity.

Animals↗
PubMed2000

Switching from a PI-based to a PI-sparing regimen for management of metabolic or clinical fat redistribution.

Concerns regarding metabolic perturbations occurring during protease inhibitor (PI)-based regimens have led to investigation of switching from a PI-based to a non-nucleoside reverse transcriptase inhibitor- or abacavir-based regimen. There appear to be considerable benefits to switching from a PI-based regimen to one of these PI-sparing regimens. In particular, patients appear generally pleased with the improved administration characteristics of the new regimens, and improvements in quality of life have been reported. However, resolution of the metabolic abnormalities that may arise during PI therapy is incomplete. Peripheral or subcutaneous fat mass improvements are not evident in the studies reported to date. Weight gain, probably in part due to removal of PI-related dietary restrictions, has been observed and may lead to improvements in appearance. Maintenance of virologic control varies among studies but is generally in the range of 85% to 100% of the patients receiving the PI-sparing regimen. The extent of prior drug exposure (or drug resistance) in patients entering the studies may be a key risk factor for loss of virologic control.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Quality of life outcomes of combination zalcitabine-zidovudine, saquinavir-zidovudine, and saquinavir-zalcitabine-zidovudine therapy for HIV-infected adults with CD4 cell counts between 50 and 350 per cubic millimeter. PISCES (SV14604) Study Group.

BACKGROUND: This double-blind study evaluated treatment with zalcitabine-zidovudine, saquinavir-zidovudine, or saquinavir-zalcitabine-zidovudine on the health-related quality of life of HIV-infected adults with CD4 cell counts between 50 and 350 cells/mm3. METHODS: Nine hundred and ninety-three HIV-infected male or female quality of life substudy patients aged 18 years or older, with CD4 cell counts between 50 and 350 cells/mm3 naïve to antiretroviral therapy or with less than 16 weeks of zidovudine therapy, were randomly assigned to one of three daily regimens: zalcitabine 0.75 mg and zidovudine 200 mg every 8 h (ddC/ZDV); saquinavir 600 mg and zidovudine 200 mg every 8 h (SQV/ZDV); or saquinavir 600 mg, zalcitabine 0.75 mg and zidovudine 200 mg every 8 h (SQV/ddC/ZDV). The health-related quality of life was measured using the Medical Outcome Study HIV (MOS-HIV) Health Survey subscale and physical and mental health summary scores, and a global visual analogue scale (VAS) score. The primary health-related quality of life endpoints were the MOS-HIV physical and mental health summary scores. RESULTS: After 24 weeks of treatment, no statistically significant differences were observed between the three treatment groups on physical health and mental health summary scores (global test P = 0.118). After 48 weeks of treatment, statistically significant differences among the groups were observed for physical health and mental health summary scores (global test P = 0.020); no change in physical health summary scores from the baseline were seen in the triple combination therapy, whereas the ddC/ZDV combination therapy group showed decreases from baseline in physical health summary scores (P = 0.008). Six of the 10 individual MOS-HIV subscale scores and the VAS scores showed results consistent with the physical health summary endpoints after 48 weeks of therapy. No statistically significant differences in baseline to 48 week changes in MOS-HIV subscale or summary scores were seen between the ddC/ZDV and SQV/ZDV groups (P > 0.05). CONCLUSIONS: Patients on triple combination therapy maintained their quality of life over 48 weeks compared with significant decreases in the quality of life for ddC/ZDV combination therapy.

Adult↗
PubMed1999

Poor reduction of HIV-1 RNA titres in nucleoside reverse transcriptase inhibitor experienced patients treated with indinavir combination therapy.

OBJECTIVES: The long term effectiveness of combination therapy at reducing viral loads in seminal fluid and blood plasma obtained from HIV-1 infected men who had undergone previous antiretroviral therapy was assessed. METHODS: Samples of semen and blood were obtained from a cohort of 12 nucleoside reverse transcriptase inhibitor experienced men before and during 25-68 weeks of combination therapy, which included the protease inhibitor indinavir. HIV-1 RNA titres present in the cell free blood and seminal plasma samples were determined using the nucleic acid sequence based amplification (NASBA)/Nuclisens assay system. RESULTS: Viral RNA was detected in 9/12 and 7/12 baseline blood plasma and seminal plasma samples, with median viral titres of 10(4.81) and 10(4.56) per ml, respectively. By the end of the study period the detection rates of HIV RNA in the blood and seminal plasma samples were 5/12 and 2/12, respectively, with the median viral titres below the assay cut off level for both sample types. Of the nine patients who had detectable viral RNA in the baseline sample, only three cleared virus from both compartments by the end of the study. CONCLUSIONS: These data show that stable reduction of blood and seminal fluid viral titres is not achievable in a significant proportion of nucleoside reverse transcriptase inhibitor experienced men.

Drug Therapy, Combination↗
PubMed1999

Triple nucleoside analogue antiretroviral therapy: expanding the treatment approaches for management of HIV infection.

The expanding range of drug options for the management of persons with HIV infection and concerns about the long-term safety of some treatment approaches has precipitated the HIV treatment community to examine a wider range of treatment approaches. One new therapeutic approach is to consider using three nucleoside analogue reverse transcriptase inhibitors, particularly as initial therapy. Recent data comparing triple nucleoside analogue therapy with established 'standard of care' triple therapy regimens have demonstrated similar antiviral effects and tolerability for such regimens. Efficacy and tolerability of triple nucleoside therapy has been demonstrated up to 96 weeks of therapy. This approach has advantages over conventional two nucleoside plus either a protease inhibitor or non-nucleoside reverse transcriptase inhibitor in terms of drug interactions and maintenance of multiple class options. It creates regimens which are, for the most part, compact, twice daily and non-food dependent. Specifically, this approach has already become widely established for individuals for whom drug interactions exclude the use of protease or non-nucleoside antiretrovirals. Triple nucleoside analogue therapy is likely to represent an attractive option for both physicians and patients; its use in clinical practice is likely to further expand.

Journal Article↗
PubMed1999

Efavirenz: practicalities, considerations and new issues.

Concerns about the long-term safety issues with protease inhibitors (PIs) and recent reports of non-PI-containing regimens demonstrating potent and durable suppression of viral replication have brought into question the role of PI therapy. However, a number of issues surrounding PI-sparing regimens, such as the durability of the antiretroviral effect, the virologic benefits in sanctuary sites, and the extent of changes in immune function, need to be clarified. The role of efavirenz in both PI-sparing first-line and salvage regimens is currently being investigated. Evidence to date has indicated that efavirenz has a highly potent and durable antiviral activity in such regimens. Efavirenz is well tolerated with adverse events generally being mild in intensity and infrequently prompting discontinuation.

Alkynes↗
PubMed1998

1998 revision to the British HIV Association guidelines for antiretroviral treatment of HIV seropositive individuals. BHIVA Guidelines Writing Committee.

When the British HIV-1 Association (BHIVA) guidelines on the treatment of HIV-seropositive individuals with antiretrovirals were published in The Lancet in April 1997, it was clear that they would require updating on a frequent basis. The guidelines have been useful in ensuring that viral-load testing and combination therapy is widely available in the UK. However, standards of treatment are rapidly changing as new evidence becomes available. Since formulation of the guidelines, data from two large clinical endpoint studies have been presented that show superior clinical benefit for the use of triple therapy compared with dual therapy in treatment of both naive individuals and patients who have been given zidovudine. Here we update the BHIVA guidelines with a consensus drawn from a wide range of UK medical opinion. The guidelines include input from groups representing individuals living with HIV-1. A more detailed reflection of these views may be found in publications such as the National AIDS Manual and the AIDS Treatment Project's Doctor fax.

Anti-HIV Agents↗
PubMed1998

The role of combinations of HIV protease inhibitors in the management of persons with HIV infection.

The current standard of care in antiretroviral therapy includes two nucleoside analogue reverse transcriptase inhibitors (NRTIs) plus a potent third agent, usually an HIV protease inhibitor (PI). However, around 20 - 30% of patients initiating therapy in clinical studies, and probably more in clinical practice, fail to achieve an optimal therapeutic response, a sustained undectectable viral load, using these regimens. Additionally, many triple therapy regimens currently require three times per day dosing, making treatment adherence difficult to sustain. Combinations of two PIs with or without NRTIs provide impressive reductions in viral load, with emerging data suggesting a higher proportion of patients on four drug regimens achieving below detection responses than those on three drug regimens. Additionally, pharmacokinetic interactions between PIs provide the potential for both dose reductions and twice daily dosing with PI combinations. However, limited resistance data are available from dual PI failures, and concerns regarding disturbances in fat metabolism, lipodystrophy and glucose intolerance remain obstacles to the widespread use of these regimens as initial therapy.

Journal Article↗
PubMed1998

A re-evaluation of zalcitabine.

Early in the HIV epidemic, zalcitabine (ddC) emerged as a nucleoside analogue reverse transcriptase inhibitor (NRTI) alternative to zidovudine (ZDV). However, a comparative study suggested ZDV monotherapy provided superior clinical benefit in treatment-naive patients with advanced immunodeficiency. Thus, ddC became most widely used in those patients no longer benefitting from or intolerant of ZDV. In ZDV-failed or -intolerant patients, ddC demonstrated similar benefit (or absence of benefit) to ddI monotherapy. In the first clinical end-point study of combination therapy, addition of ddC to on-going ZDV in patients substantially pre-treated with ZDV resulted in no overall benefit but some clinical advantage in a subset of patients with CD4 cell counts of 150 - 300/mm. Furthermore, initial studies of ddC, mostly performed in persons with advanced immunodeficiency and symptomatic HIV infection, indicated that 10 - 20% of ddC recipients developed a treatment-limiting peripheral neuropathy. Based on these early trials, a widespread perception that ddC was an antiviral with both limited activity and a potentially problematic safety profile evolved. More recent data suggest that the role of ddC requires re-evaluation. Indeed, the European Medicines Evaluation Agency (EMEA) has recently expanded the licencing claim of ddC stating that it "is indicated in HIV-infected adults in combination with other antiretroviral agents". The purpose of this short review is to discuss data that have shed new light on what in antiretroviral terms is an 'old' drug.

Journal Article↗
PubMed1997

To sequence or not to sequence?

There is now incontrovertible evidence that a combination of two nucleoside analogues is superior to AZT monotherapy for the treatment of HIV infection. There is also evidence that a range of antiretroviral combinations can produce profound drops in plasma HIV viral load, often below the detectable limits of the assay. A lower rate of viral replication is associated with delays in the selection of viral mutants resistant to drugs; the principal reason for therapeutic failure. These highly effective combinations are likely to delay clinical events and considerably improve the prognosis in HIV-infected individuals. Using mathematical modelling techniques to assess the half-life of plasma virus infectious cells and proviral DNA, one group has gone so far as to suggest it may be possible to stop therapy after several years, as the virus will have been eliminated. More sanguine investigators, however, believe that this is unlikely, as some infected cellular compartments may have long half-lives and the virus may persist, or even continue to replicate slowly, in sanctuary sites, such as the CNS and genital tract, poorly penetrated by drugs. Thus, some virologists and clinicians believe that it is crucially important to give initial therapy with the strongest possible combination of drugs to achieve an 'undetectable' plasma viral load and that, providing compliance is good, this will lead to a prolonged therapeutic effect. In these circumstances no sequencing issues arise. Others, however, continue to believe that, in due course, the virus is likely to evade drug pressure. In these circumstances, consideration of a sequence of drugs, to avoid initial and subsequent therapy from squandering future therapy options through, principally, cross-resistance, becomes an important issue. None of the issues discussed in this review has been tested by controlled clinical trials but they generate hypotheses requiring urgent evaluation.

Editorial↗
PubMed1997

Antiretroviral therapies in HIV-1 infection.

Recent progress in our understanding of the viral dynamics and immunobiology of HIV infection, coupled with the introduction of a new generation of antiretroviral agents, has led to significant advances in the medical management of HIV infection. Eleven antiretroviral drugs are currently licensed in the United States, and eight are licensed in Europe. These include the nucleoside reverse transcriptase inhibitors (AZT, ddI, ddC, 3TC and d4T); the non-nucleoside reverse transcriptase inhibitors (nevirapine and delavirdine) and the protease inhibitors (saquinavir, indinavir and ritonavir). This report summarises recent developments in the use of antiretroviral therapies and the main treatment strategies under evaluation in current trials. These strategies include the evaluation of novel antiretroviral agents; combinations to achieve maximal viral suppression; optimal sequencing of antiretroviral agents; and subtraction therapy. However, many important issues in the use of antiretroviral therapies remain unresolved, including the optimal role of new agents, such as protease inhibitors (PIs), and the use of triple combination therapy in initial and subsequent treatment regimens; when therapy should be changed; which alternative agents should then be used; and the most appropriate methods for monitoring the efficacy of therapy.

Journal Article↗