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Biomedical subjects

G Moyle

Publications and source records attributed to G Moyle.

At least 19 recordsLinked to original sources
PubMed2006

Changes in sleep quality and brain wave patterns following initiation of an efavirenz-containing triple antiretroviral regimen.

BACKGROUND: Initiation of efavirenz is commonly associated with sleep disturbances. Assessment of sleep using the electroencephalogram and electromyogram enables sleep staging to be performed and changes following the introduction of therapy to be evaluated. METHODOLOGY: Using standardized sleep-staging methodology, we investigated sleep staging and sleep quality by patient self-report in an open-label cohort pilot study. Assessments were performed prior to the initiation of efavirenz, 2 weeks after the initiation of efavirenz and 3 months after the initiation of efavirenz. The study included HIV-positive individuals without central neurological disease who were naive to antiretroviral treatment. All patients initiated treatment with two nucleoside reverse transcriptase inhibitors in combination with efavirenz. RESULTS: Ten patients completed all three study visits. Patients reported an increase in recollection of dreams and morning sluggishness after the initiation of efavirenz which persisted for 3 months. Sleep-staging data indicated a modest reduction in stage 2 sleep with a corresponding increase in deep sleep stage 4 and a modest increase in rapid eye movement (REM) sleep. Overall sleep maintenance efficiency did not significantly change from baseline. Changes in sleep staging were most marked 2 weeks after the initiation of efavirenz but remained different from baseline patterns at 3 months. CONCLUSION: The data indicate that efavirenz has a modest but persistent impact on the time spent in several key sleep stages. Patients reported persistence of dream recollection but remained satisfied with sleep quality and overall quality of life.

Alkynes↗
PubMed2003

Restoration of human immunodeficiency virus-1-specific responses in patients changing from protease to non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy.

The effect of altering antiretroviral therapy (ART) on responses to viral, recall and human immunodeficiency virus (HIV)-1-specific recombinant antigens and interleukin-2 (IL-2) in HIV-1-infected patients was assessed. A longitudinal cohort study in eight HIV-1 infected individuals following a clinically indicated therapy change (seven for drug intolerance and one for virological failure) from protease inhibitor (PI) to non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral regimens was performed. CD4 T-cell counts, viral loads, lymphoproliferative responses, cytokine production and latent proviral deoxyribonucleic acid (DNA) were measured at baseline and at weeks 12 and 24 after therapy substitution. Following therapy-switch there was a 33% proportional increase in mitogen response (95% confidence interval (CI), 3-33%) and a 31% increase (95% CI, 15-48%) in viral and recall-antigen responses. Six patients developed proliferative responses to low concentration IL-2 stimulation. All patients demonstrated an increase in median HIV-1-specific responses, as three had detectable virus at baseline (two being viral rebound); this may reflect an autovaccination effect. Proviral DNA changes largely reflected plasma HIV-1 ribonucleic acid (RNA). In conclusion, NNRTI substitution for a PI may favour immune reconstitution with an improvement in HIV-1-specific responses, which may reflect differential effects on antigen processing and presentation, an autovaccination effect or alternatively a potential suppressive effect of the PI.

Anti-HIV Agents↗
PubMed2003

Matched case-control study to evaluate risk factors for hyperlactataemia in HIV patients on antiretroviral therapy.

BACKGROUND: Lactic acidosis is a life-threatening event during antiretroviral therapy (ART). Hyperlactataemia may be a prelude to acidosis. Our database study suggested that female gender, intercurrent illness and didanosine (ddI)-based regimens may increase risk of lactic acidosis. The aim of this matched case-control study was to identify risk factors for hyperlactataemia requiring screening. METHODS: Cases were defined as patients with two consecutive lactate samples > or =3.5 mmol/L taken more than 1 week apart. Cases were matched to two controls on gender, use of ddI and total duration of therapy using a 6-month window on either side. Controls never had raised lactate >2.5 mmol/L. A conditional logistic regression analysis using the PHREG procedure in SAS (SAS Institute Inc, Cary, NC) was performed with a discreet logistic model stratified by matching variables. RESULTS: Twenty-one cases were matched to 42 controls. In the univariate model, current use of stavudine (d4T), total cholesterol >5.3 mmol/L and glucose levels > or =5.2 mmol/L gave increased likelihood of persistent hyperlactataemia. The multivariate model showed current use of d4T to be a significant independent predictor of persistent hyperlactataemia. CONCLUSIONS: The results of this case-control study indicate that, when controlling for ddI use, d4T use is an additional risk factor for hyperlactataemia.

Acidosis, Lactic↗
PubMed2003

Loss of the CD56hiCD16- NK cell subset and NK cell interferon-gamma production during antiretroviral therapy for HIV-1: partial recovery by human growth hormone.

Previous studies have shown that human natural killer (NK) cells are lost from the periphery and are functionally suppressed during HIV-1 infection, and that the administration of highly active antiretroviral therapy (HAART) results in a recovery of NK cell numbers in HIV-1-infected individuals. However, despite this recovery, interleukin (IL)-2 + IL-12-driven interferon (IFN)-gamma production by NK cells has been shown to remain suppressed after HAART. Here we show that the innate immune factor IL-15 in combination with IL-12 is also unable to recover NK cell IFN-gamma production in HAART-treated individuals. Furthermore, we also demonstrate an imbalance in the distribution of CD56loCD16hi and CD56hiCD16- NK subsets after successful HAART, CD56hiCD16- cells being reduced substantially in HIV-1 patients on HAART. Treatment of patients with combined human growth hormone and antiretroviral therapy resulted in further enhancement in the absolute numbers and the proportion of NK cells in some individuals in the absence of parallel effects on CD4+ T cells. Furthermore, in these individuals HAART with growth hormone resulted in an enhancement of cytokine-driven NK cell activation and IFN-gamma production compared to the HAART-only baseline.

Anti-HIV Agents↗
PubMed2003

Once-daily therapy: less is more.

Over the last 20 years, a trend towards regimens with less frequent dosing has been observed across medicine. Recent surveys of people with HIV indicate that there is a strong preference for once-daily dosing and compact therapy. Four antiretrovirals (tenofovir, didanosine, lamivudine and efavirenz) are now available as once-a-day therapies. The range of once-daily options is expanding rapidly, with the potential for two lines of once-daily therapy to be available in the next 12-18 months.

Anti-HIV Agents↗
PubMed2003

The Assessing Patients' Preferred Treatments (APPT-1) study.

Limited information is currently available on patient preferences regarding administration frequency, tablet load and the trade-off between side effects and convenience in choosing antiretroviral regimens. A standardized questionnaire of persons with HIV infection across 5 large European countries was used to assess patient preference. 504 people with HIV participated. Participants showed a preference for once-daily therapy administration. However, several factors affected this preference.

Adult↗
PubMed2001

Comparison of virologic, immunologic, and clinical response to five different initial protease inhibitor-containing and nevirapine-containing regimens.

CONTEXT: The effectiveness of different protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors outside the setting of clinical trials has not been well described. OBJECTIVES: To compare five different PI-and nevirapine (NVP)-containing regimens on virologic, immunologic, and clinical outcomes and treatment discontinuation. DESIGN AND SETTING: Observational cohort study based on an HIV clinic in London. PATIENTS: A total of 690 patients who received either saquinavir hard gel (SQV HG) (n = 183), indinavir (IDV) (n = 189), nelfinavir (NFV) (n = 109), ritonavir (RTV) (n = 42), ritonavir with saquinavir hard gel (RTV/SQV HG) (n = 45), or NVP (n = 122) as part of an initial PI-or NVP-containing treatment regimen between November 1994 and December 1998. A total of 351 (51%) patients had prior exposure to nucleoside reverse transcriptase inhibitors (NRTIs). MAIN OUTCOME MEASURES: The main outcome measures were virologic undetectability, subsequent virologic rebound, CD4 cell count rise, development of AIDS, and treatment discontinuation. All analyses were stratified for year of initiation of the PI-or NVP-containing regimen. RESULTS: Overall, 63% of patients attained an undetectable viral load (VL) within 6 months of starting their PI or NVP regimen. The adjusted relative hazard (95% confidence interval [CI]) for an undetectable VL relative to SQV HG was (in rank order): 2.77 (CI: 1.84-4.17) for NFV, 2.54 (CI: 1.81-3.57) for IDV, 2.43 (CI: 1.52-3.87) for RTV, 2.08 (CI: 1.28-3.37) for RTV/SQV HG, and 1.96 (CI: 1.35-2.85) for NVP. Forty-nine percent of patients experienced VL rebound within 12 months of initial attainment of undetectability, but relative to SQV HG, this did not differ significantly across the different PI and NVP regimens. The CD4 cell count response and rate of AIDS events were also similar across the different regimens. No independent predictors of VL undetectability were identified, but prior NRTI exposure was associated with VL rebound, and a lower baseline VL and CD4 cell count were associated with a reduced CD4 count response. The frequency (95% CI) of treatment discontinuation differed across the regimens; at 6 months, it was lowest for NFV (18% [CI: 13%-24%]), IDV (25% [CI: 22%-29%]), and NVP (28% [CI: 22%-34%]) and highest for RTV (41% [CI: 31%-52%]) and SQV HG (52% [CI: 48%-57%]). CONCLUSIONS: Although PI- and NVP-containing regimens were similar in their CD4 cell count response and rates of subsequent VL rebound, differences were observed in time to VL undetectability and discontinuation rates relative to SQV HG. SQV HG was consistently inferior to the other PIs and NVP. The use of NFV and IDV was associated with the highest rates of undetectability, and together with NVP, the lowest rates of discontinuation.

Adult↗
PubMed2001

The steady-state pharmacokinetics of efavirenz and nevirapine when used in combination in human immunodeficiency virus type 1-infected persons.

The steady-state pharmacokinetics of efavirenz and nevirapine, when used in combination to treat human immunodeficiency virus type 1 (HIV-1)-infected subjects, were investigated. HIV-1-infected persons who had used efavirenz (600 mg once daily) for > or =2 weeks were eligible for study inclusion. The plasma pharmacokinetics of efavirenz were determined over 24 h. Subsequently, nevirapine (400 mg once daily) was added to the regimen. After 4 weeks, the pharmacokinetics of efavirenz and nevirapine were assessed over 24 h. The differences between the pharmacokinetic parameters of efavirenz with and without nevirapine were analyzed, and the pharmacokinetics of nevirapine were compared with those in historical control patients. The exposure to efavirenz when combined with nevirapine was significantly decreased by 22% (area under the plasma concentration vs. time curve), 36% (minimum plasma concentration), and 17% (maximum plasma concentration). Nevirapine pharmacokinetics appear to be unaffected by coadministration of efavirenz, compared with data from historical control patients.

Adult↗
PubMed2001

Resistance and cross-resistance to abacavir.

BACKGROUND: Abacavir (ABC) is a potent nucleoside reverse transcriptase inhibitor (NRTI) used in multi-drug antiretroviral regimens and in combination with other NRTIs, protease and/or non-nucleoside reverse transcriptase inhibitors (NNRTIs) in both treatment naive and treatment experienced patients. PATTERNS OF RESISTANCE: Resistance to ABC has been demonstrated in vitro and in vivo. Patterns of emerging mutations may vary when ABC is combined with other NRTIs relative to the mutations observed in monotherapy. Additionally, thymidine NRTIs may select for mutations that, while not selected for by ABC, may confer diminished susceptibility and diminished clinical response to ABC. CLINICAL USE OF ABC: Resistance and clinical data indicate that ABC may be a suitable component of initial regimens and second or subsequent lines of therapy. It may be used as a substitution agent for persons wishing to discontinue protease inhibitor therapy who have not previously experienced viral rebound on NRTI therapy.

Anti-HIV Agents↗
PubMed2001

Antiretroviral therapy for HIV-2 infected patients.

OBJECTIVES: To evaluate clinical and RNA load response to antiretroviral therapy amongst patients infected with HIV-2 and to study the development of drug resistance. METHODS: Seven HIV-2 seropositive patients were monitored with clinical examination, CD4 cell count and HIV-2 viral RNA load. Viruses from four subjects were genotyped and in vitro recovery of virus by co-cultivation with PBMCs and HVS T-cells was attempted. Viruses isolated from two subjects were assayed for phenotypic antiviral resistance. The main outcome measures were the relationship between disease stage, viral load, CD4 cell count, viral subtype and the clinical course of HIV-2 infection and the effect of combination antiretroviral therapy on disease progression, CD4 cell count, HIV-2 RNA viral load and drug resistance. RESULTS: The median time of follow-up was 3 years (range 0-8 years). Three patients had AIDS, and one had symptomatic disease. Of the four patients genotyped, three were infected with HIV-2 subtype B and one with subtype A. Viraemia was detectable only at CD4 counts of less than 300 x 10(6)/ml. Two patients with high viral loads failed to respond to antiretroviral therapy although their treatment may not have been optimal. One developed in vitro phenotypic antiviral resistance. The genotype of this patient's viral reverse transcriptase is being analysed. CONCLUSIONS: In contrast to HIV-1, HIV-2 RNA levels were often undetectable despite advanced disease and low CD4 cell counts. However, HIV-2 was clearly capable of causing CD4 cell depletion resulting in symptomatic disease. The principles of highly active antiretroviral therapy seem to apply to HIV-2 and suboptimal therapy may lead to drug resistance. The timing of therapy initiation, monitoring of response and the measurement of resistance remain unresolved issues and conclusions cannot be extrapolated from HIV-1.

Acquired Immunodeficiency Syndrome↗
PubMed2001

The emerging roles of non-nucleoside reverse transcriptase inhibitors in antiretroviral therapy.

The availability of potent non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens for antiretroviral therapy and concerns regarding protease inhibitor (PI)-related metabolic disturbances have led to significant shifts in treatment practices in HIV infection. NNRTI-based regimens may have several advantages over PI-based therapy for initial or prolonged therapy, including more convenient administration regimens, lower tablet volume, fewer drug interactions, and central nervous system penetration. No data from prospective clinical trials currently exist comparing the 3 approved agents (efavirenz, nevirapine or delavirdine). Both efavirenz and nevirapine have been compared to triple therapy with the PI indinavir over 48 weeks as initial therapy, with similar responses being observed with nevirapine regimens and superiority observed with efavirenz. A smaller 24-week study has suggested nevirapine may be superior to the PI nelfinavir. Limited comparative data in patients with high viral loads treated with nevirapine- or delavirdine-based regimens currently exist. However, cohort data and selected patient data from clinical trials suggest comparable activity to PI-based regimens in these patients. The superiority of efavirenz over indinavir-based regimens has been observed in comparative data in a subset of patients with high viral loads. In treatment-experienced patients, available uncontrolled data suggest these agents contribute to regimen efficacy in NNRTI-naïve, treatment-experienced patients. Efavirenz has demonstrated superiority over nelfinavir in nucleoside-experienced patients, although combining these 2 agents may represent the best approach in these circumstances. The tolerability of NNRTIs appears generally good with few individuals discontinuing in clinical studies as a result of adverse drug events. The majority of adverse events with NNRTIs occur within the first month, and are predictable and manageable without therapy interruption.

Alkynes↗
PubMed2001

Use of HIV protease inhibitors as pharmacoenhancers.

Short- and long-term therapy with many protease inhibitors (PIs) at standard dosing may be limited by inconvenient dosing regimens, high tablet volumes, and variable drug exposure. Booster agents, such as low (or "baby") doses of ritonavir, and codosing with the nonnucleoside analogue delavirdine are increasingly used to maintain high PI trough exposures. Combinations of HIV PIs, either alone or coadministered with nucleoside analogues, have demonstrated substantial virologic and immunologic responses sustained over long periods of follow-up. This approach is rapidly becoming the standard of care with PI use. The advantages of the boosted PI approach include raising trough drug concentrations, diminishing interpatient variability, prolonging drug half-life to allow twice-daily and possibly once-daily dosing, and diminishing food requirements and tablet volume. In addition, increases in drug exposure may potentially enable inhibition of the virus in the presence of reduced sensitivity to PIs. Using a boosted PI, in the absence of comparative data on resistance profiles of boosted regimens, should be considered differently from dual-PI combinations, where there is exposure to 2 active PIs. Some physicians are now using a booster agent plus 2 PIs in the salvage therapy setting in an attempt to achieve effective, yet less toxic, concentrations of 2 PIs to overcome different resistant populations in a patient's viral quasispecies.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

The SPICE study: 48-week activity of combinations of saquinavir soft gelatin and nelfinavir with and without nucleoside analogues. Study of Protease Inhibitor Combinations in Europe.

OBJECTIVES: To compare the efficacy and safety of saquinavir soft gelatin capsules (SQV-SGC) and nelfinavir (NFV), with or without two concomitant nucleoside reverse transcriptase inhibitors (NRTIs), in an exploratory objective to identify populations most likely to benefit from quadruple therapy. DESIGN: Phase II/III, open-label, randomized, parallel-arm, multicenter trial. PARTICIPANTS: Enrollment included 157 protease inhibitor-naive adults (> or = 13 years) with HIV-1 RNA > or = 10,000 copies/ml; 132 participants completed 48 weeks of therapy. INTERVENTIONS: SQV-SGC 1200 mg, NFV 750 mg, SQV-SGC 800 mg plus NFV 750 mg, all with two NRTIs, and SQV-SGC 800 mg plus NFV 750 mg alone, all three times daily for 48 weeks. MAIN OUTCOME MEASURES: Proportion of participants with HIV-1 RNA <50 copies/ ml (16 and 48 weeks); time to virologic relapse (48 weeks). RESULTS: Proportions of patients with HIV RNA <50 copies/ml were not statistically significantly different between arms at 16 or 48 weeks, although trends favored the quadruple-therapy arm. In patients experiencing virologic relapse, time to relapse was statistically significantly longer in the quadruple-therapy arm than in the other three arms (p = .007). Quadruple therapy provided benefit in NRTI-experienced patients and those with viral loads above the median value at baseline. Adverse events were mainly mild gastrointestinal disorders in all treatment arms. CONCLUSIONS: Quadruple therapy, including SQV-SGC and NFV, gave a more durable response than triple therapy with either single protease inhibitor. Quadruple therapy might particularly benefit NRTI-experienced patients and those with high baseline viral loads.

Adult↗