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Biomedical subjects

M Youle

Publications and source records attributed to M Youle.

At least 19 recordsLinked to original sources
PubMed2002

Naively changing HAART.

BACKGROUND: Few UK studies have systematically investigated which antiretroviral therapy (ART) combinations HIV-infected people are commenced on, when they start and reasons for stopping or changing their regimens. OBJECTIVE: To describe when HIV-infected ART-naive patients started first-, second- or third-line triple ART, classes of drugs prescribed and whether stopping ART was associated with virological, immunological or clinical indicators of treatment failure. DESIGN: A multicentre prospective open cohort study, employing the National Prospective Monitoring System on the use, cost and outcome of HIV service provision in UK hospitals-HIV Health-economics Collaboration (NPMS-HHC). SETTING: Five hundred and eighty-five ART-naive patients seen in one London and two non-London HIV clinics between 1 January 1998 and 31 December 1999. RESULTS: Of 4,044 HIV-infected individuals seen, 585 (15%) were ART naive. Median time interval (interquartile range, IQR) between HIV diagnosis and starting triple ART was 800 (63-2,094) days. Median CD4 count when first diagnosed with HIV infection was 278 (IQR 127-481) cells/ micro L which dropped to 190 (IQR 86-297) cells/ micro L when starting triple ART. Of these 585 patients, 162 started second-line and 46 third-line ART during the study period. Of those patients who stopped ART, 51% did not have evidence of virological, immunological or clinical indicators of therapy failure. CONCLUSIONS: Reasons for the delay between diagnosis of HIV infection and starting ART are varied. The large proportion of individuals who stopped ART for reasons other than virological, immunological or clinical indicators of therapy failure, are most likely due to drug-associated toxicity. Both of these findings need to be elucidated in greater detail through prospective studies.

Adult↗
PubMed2001

Use of a stochastic model to develop understanding of the impact of different patterns of antiretroviral drug use on resistance development.

OBJECTIVE: To use a stochastic model to gain insights into the consequence for resistance development of different drug use patterns. METHODS: We consider use of three drugs (A, B and C) where for each drug one and only one viral mutation is associated with ability to replicate (effective reproductive ratio, R > 1) in the presence of that drug as monotherapy. For drug A mutation is a, etc. We define eight populations of short-lived infected cells that live 1 day: Vo with no mutations a, b, c; Va with mutation a only, Vab with mutations a and b, etc. A random number generator was used to determine whether mutations occur in any one round of replication and to sample from a Poisson distribution to determine for each cell the number of cells of the same population created in the next generation, using the R operative at that time. Values of R depended on drug exposure, cost of resistance and availability of target cells. RESULTS: Treatment strategies and the resulting percentage (over 100 runs) developing full "resistance" in 1500 days (Vabc not equal 0) were: (i) ABC 1500 days 0%; (ii) A 300 days, AB 300 days, ABC 900 days 100%; (iii) AB 300 days, ABC 1200 days 33%; (iv) ABC 2/3 1500 days 15%; (v) ABC 1/2 1500 days 100%; (vi) ABC 50 days, no drugs 50 days, for 1500 days 1%, where ABC 2/3 means on-drug for 2 days in every 3, ABC 1/2 represents on-drug for 1 day in every 2, and represents suboptimal adherence. CONCLUSIONS: This model helps to develop understanding of key principles concerning development of resistance under different patterns of treatment use.

Anti-HIV Agents↗
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

Sexual dysfunction associated with protease inhibitor containing highly active antiretroviral treatment.

BACKGROUND: A high proportion of individuals receiving highly active antiretroviral treatment (HAART) complain of sexual dysfunction (SD), encompassing a lack of desire or erectile dysfunction. OBJECTIVE: To determine whether SD was associated with particular components of the HAART regimens and to identify risk factors for the development of SD in patients on HAART. METHODS: A survey among patients with HIV infection using an anonymous questionnaire was conducted in 10 European countries between December 1998 and December 1999. A total of 904 individuals currently receiving antiretroviral agents were included in the analyses. RESULTS: A decrease in sexual interest was significantly more frequently reported by subjects (men and women) using HAART containing protease inhibitors (PI) (308/766, 40%), compared with PI-naive patients (22/138, 16%; OR 3.55; 95% CI 2.15--5.89). In addition, a significantly larger number of PI-experienced men reported a decrease in sexual potency (216/628, 34%) compared with PI-naive men (12/99, 12%; OR 2.56; 95% CI 1.33--5.03). In multivariate analyses the following factors were associated with a decrease in sexual interest: a current PI-containing regimen, a history of a PI regimen, symptomatic HIV infection, age and homosexual contact as HIV transmission mode. Factors associated with a decrease in sexual potency were: current use of a PI-containing regimen, symptomatic HIV disease, age and the use of tranquillisers. CONCLUSION: SD appears to be a common side-effect of HAART regimens containing a PI. The potential association between SD and other side-effects of HAART, such as lipodystrophy syndrome and neuropathy, should be investigated further.

Adult↗
PubMed2001

Reasons for modification and discontinuation of antiretrovirals: results from a single treatment centre.

OBJECTIVE: To describe the reasons for, and factors associated with, modification and discontinuation of highly active antiretroviral therapy (HAART) regimens at a single clinic. SUBJECTS: A total of 556 patients who started HAART at the Royal Free Hospital were included in analyses. Modification was defined as stopping or switching any antiretrovirals in the regimen, whereas discontinuation was defined as the simultaneous stopping of all antiretrovirals included in the initial regimen. Reasons were classified as immunological/virological failure (IVF) and toxicities and patient choice/poor compliance (TPC). RESULTS: The median CD4 count at starting HAART was 171 x 10(6) cells/l and viral load 5.07 log copies/ml. During a median follow-up of 14.2 months, 247 patients (44.4%) modified their HAART regimen, 72 due to IVF (29.1%) and 159 due to TPC (64.4%) and a total of 148 patients (26.6%) discontinued HAART. Older patients were less likely to modify HAART [relative hazard (RH), 0.73 per 10 years; P = 0.0008], as were previously treatment-naive patients (RH, 0.65; P = 0.0050), those in a clinical trial (RH, 0.64; P = 0.027) and those who started nelfinavir (RH, 0.57; P = 0.035). Patients who started with four or more drugs (RH, 2.21, P < 0.0001), who included ritonavir in the initial regimen (RH, 1.41; P = 0.035) or who had higher viral loads during follow-up (RH per log increase, 1.51; P < 0.0001) were more likely to modify HAART. CONCLUSIONS: There was a high rate of modification and discontinuation of HAART regimens in the first 12 months, particularly due to toxicities, patient choice or poor compliance.

Antiretroviral Therapy, Highly Active↗
PubMed2001

Assessing the cost-effectiveness of HAART for adults with HIV in England.

OBJECTIVE: To assess the cost-effectiveness of highly active antiretroviral therapy (HAART) compared with two nucleoside reverse transcriptase inhibitors (NRTIs) for HIV infected individuals. DESIGN: Different data sources on the clinical effects and costs of treatments were combined using a Markov model. SETTING: English HIV treatment centres. Perspective UK public finance. INTERVENTIONS: HAART - dual NRTI therapy plus a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor - vs. dual NRTI therapy. PARTICIPANTS: Hypothetical cohorts of 1000 individuals infected with HIV. Outcome measures Projected life expectancy, cost-effectiveness in UK pound per life-year saved and per quality-adjusted life-years (QALYs) saved. RESULTS: Assuming a 2-year additional treatment effect of therapy with HAART produced incremental cost-effectiveness ratios of pound14 602 per life-year saved and pound17 698 per QALY saved. CONCLUSIONS: The results were sensitive to a number of assumptions including the cost of HAART and the discount rate, but they suggest that the use of HAART in England is at least moderately cost-effective compared with treatment with two NRTIs alone.

Adult↗
PubMed2001

A randomized, double-blind, placebo-controlled study of itraconazole capsules for the prevention of deep fungal infections in immunodeficient patients with HIV infection.

OBJECTIVES: To determine whether systemic or deep fungal infections can be prevented, a double-blind, placebo-controlled, phase III trial of itraconazole prophylaxis was undertaken in HIV-infected patients. METHODS: HIV-1 infected patients with CD4 counts < 300 cells/microL were treated with itraconazole (200 mg per day) or matching placebo and followed for 2 years. Development of deep fungal infections, episodes of mucocutaneous candidiasis, change in CD4 count, survival and safety data were collected at each study visit. RESULTS: Three hundred and seventy-four patients received study medication, 187 were given itraconazole and 187 matching placebo. Time to development of deep fungal infection did not differ between groups, in an intention to treat analysis. Low CD4 cell count and prior use of Pneumocystis carinii pneumonia (PCP) prophylaxis were significantly associated with a more rapid development of deep fungal infection (P = 0.044 and 0.017, respectively). Itraconazole treatment significantly reduced the incidence of oral candidosis (25% vs. 48% P < 0.001) and time to development of oral candidosis (508 vs. 413 days, P < 0.001) but not the number of deep fungal infections (11 vs. 13). Survival did not differ significantly between groups (nine vs. 14 deaths). CD4 counts decreased significantly over time in both study arms. Adverse events did not differ between groups; 20% vs. 23% stopped study medication due to an adverse experience. CONCLUSIONS: Although itraconazole prophylaxis significantly reduced the number and time to development of oral candidosis, too few episodes of deep fungal infection were noted to determine whether itraconazole prophylaxis was effective for this condition. Chronic itraconazole treatment is well tolerated in HIV-infected patients with marked immunodeficiency.

AIDS-Related Opportunistic Infections↗
PubMed2001

A phase I/II study of the safety and activity of a microsphere formulation of KNI-272 in patients with HIV-1 infection.

Eighteen patients with symptomatic HIV disease were enrolled into a phase I/II study of a microsphere formulation of the HIV protease inhibitor KNI-272, with doses escalated up to a maximum dose of 60 mg/kg/day. One patient developed reversible elevation in hepatic transaminase. The plasma half-life of the drug was very short, varying between 0.25 and 1.1 h. No consistent effect on plasma HIV RNA levels or CD4(+) lymphocyte counts was seen.

Adult↗
PubMed2001

Salvage treatment in HIV disease.

The need for salvage treatment is related to the imperfection of current antiretroviral therapy. Sequential therapy with suboptimally suppressive regimens results in a need for this intervention. The aim of salvage treatment is as yet uncertain; virological suppression; immunoenhancement or stability or avoidance of clinical disease. Therapeutic options are constantly improving and the knowledge base concerning individual agents and different combinations comprising highly active antiretroviral treatment (HAART) regimens increases daily. The utility of new agents in salvage appears vital with numbers of new or recycled agents to which no demonstrable resistance exists is a major predictive factor of a positive outcome in this setting. Patient commitment, physician knowledge and an informed supportive environment are also conducive to success in salvage treatment.

Anti-HIV Agents↗
PubMed2001

Thalidomide is distributed into human semen after oral dosing.

As part of a double-blind placebo-controlled study of the effect of thalidomide on body weight and the viral load of human immunodeficiency virus-seropositive patients, plasma and semen samples were analyzed for the presence of thalidomide. Patients were orally dosed with 100 mg of thalidomide/day for 8 weeks. Blood samples were obtained at baseline and weeks 4, 8, and 12, and semen was obtained at baseline and weeks 4 and 8. Samples were extracted with solid-phase cartridges and analyzed by liquid chromatography/tandem mass spectrometry using atmospheric pressure chemical ionization in the negative ion mode. Two of four patients taking thalidomide were able to provide semen samples. Both had detectable levels of thalidomide in their plasma (10-350 ng/ml) and semen (10-250 ng/g) at weeks 4 and 8. There was an apparent correlation between plasma and semen levels. Semen levels could be significantly greater for therapeutic doses of more than 100 mg/day. Since the threshold dose for birth defects and thalidomide exposure is not known, male patients are advised to use barrier contraception.

Administration, Oral↗
PubMed2000

Changes in CD4 lymphocyte counts after interruption of therapy in patients with viral failure on protease inhibitor-containing regimens. Royal Free Centre for HIV Medicine.

OBJECTIVE: To describe the short-term changes in CD4 lymphocyte counts after the interruption of antiretroviral HIV therapy in order to increase the understanding of CD4 lymphocyte dynamics, and so that appropriate monitoring strategies can be designed. METHODS: We studied 35 HIV-infected patients with late-stage disease who had therapy interruptions leading to high viral load levels, median greater than 750 000 RNA log10 copies/ml, and in whom two CD4 cell counts (median 28 days apart) were available before beginning a salvage regimen. RESULTS: Overall, there was a substantial decline in CD4 cell counts from a median of 125 to 83 cells/mm3 in the average 28 day period, with median proportionate and absolute losses of 26% and 24 cells/mm3 per month, respectively (P < 0.008). This tended to be greater in individuals studied sooner after interrupting therapy (P = 0.03) and in those with CD4 cell counts above the pre-therapy baseline (P = 0.06). There was a strong negative correlation between the proportionate increase in viral load and the absolute change in CD4 cell count (-0.66, P = 0.0002). CONCLUSION: Patients with relatively advanced HIV infection interrupting antiretroviral therapy after failing a protease inhibitor-containing regimen require frequent monitoring because CD4 cell counts appear to fall quite rapidly, at least in the first few weeks after interruption.

Adult↗
PubMed2000

Immunological, virological and clinical response to highly active antiretroviral therapy treatment regimens in a complete clinic population. Royal Free Centre for HIV Medicine.

BACKGROUND: Highly active antiretroviral therapy (HAART) is now widely used in clinical practice and gives rise to a range of immunological, virological and clinical responses. OBJECTIVES: To describe the immunological, virological and clinical response to HAART and to examine the frequency of modification of the HAART regimen among patients from a single treatment centre. METHODS: Kaplan-Meier estimation and incidence rates were used to describe responses to HAART (a protease inhibitor or non-nucleoside drug in addition to at least two nucleoside analogues) among 421 patients from the Royal Free Hospital in London. RESULTS: The median CD4 cell count at starting HAART was 186 x 10(6) cells/l [interquartile range (IQR) 76-310] and viral load was 5.13 log10 copies/ml (IQR 4.66-5.56). At 6 months after starting HAART, 51.1% of patients were estimated to have experienced a 100 x 10(6) cells/l increase in CD4 cell count; the median time for viral load to fall below 400 copies/ml was 3.7 months (95% confidence interval 3.2-4.4). At 6 months after the first viral load was < 400 copies/ml, 16.4% of patients were estimated to have failed on the basis of a single viral load > 400 copies/ml and 12.4% were estimated to have failed if the more stringent definition of two viral loads above the limit of detection was used. Compared with the pre-HAART era, the incidence of death among patients on HAART was one sixth of that level; new AIDS-defining illnesses was one seventh; and hospital admissions was one fifth. In total, 141 patients (33.5%) stopped at least one of the antiretroviral agents included as part of their HAART regimen; the occurrence of side effects was the most common reason (n = 63; 44.7%). CONCLUSION: A good response occurred to an initial HAART regimen. There was a high rate of virological relapse, which varied considerably according to the definition of failure used. Even so, the rates of clinical progression and hospital admissions observed to date were low. Further follow-up of these patients is required to determine their long-term immunological, virological and clinical outcome.

Anti-HIV Agents↗
PubMed2000

Substantial correlation between HIV type 1 drug-associated resistance mutations in plasma and peripheral blood mononuclear cells in treatment-experienced patients.

The correlation of detectable HIV-1 drug resistance mutations in plasma and PBMCs in patients extensively treated with all antiretroviral drug classes has not been fully elucidated. The detection of mutations in PBMCs may reveal resistant HIV-1 associated with past therapies. In addition, these measures in PBMCs may have a practical value when plasma virus is at low levels that are difficult to detect with current assays. The reverse transcriptase (RT) and protease (P) genes were analyzed for drug resistance, using an in-house method carried out on 36 paired samples of plasma and PBMCs from 12 treatment-experienced patients in order to investigate resistance in the two compartments. When viruses in plasma and PBMCs were analyzed by patient, the mean of the Cohen kappa values was 0.728 (substantial agreement). When viruses were analyzed by codon the mean of the Cohen kappa values was 0.715 (substantial agreement). Baseline samples were concordant at 280 of 288 (97%) codons analyzed. This study shows that a minority of mutations associated with previous therapy can be detected in PBMCs and not in plasma. Overall, mutations in plasma and PBMCs showed a substantial correlation in extensively treated patients, suggesting that either compartment is suitable for the detection of mutations as a virological guide for clinical care.

Anti-HIV Agents↗
PubMed2000

Reduction in human immunodeficiency virus type 1 mutations associated with drug resistance after initiating new therapeutic regimens in pretreated patients.

The objective of this study was to investigate the effect of initiating a salvage-therapy regimen on resistant viruses in heavily treated patients infected with human immunodeficiency virus type 1 (HIV-1). Nineteen patients receiving multiple antiretroviral drugs were tested for HIV-1 mutations associated with drug resistance by using an in-house method at baseline and at weeks 2, 4, and 8 of the salvage-therapy regimen. For the majority of mutations analyzed, the mean number of detectable mutations at baseline was significantly higher than the mean at weeks 2, 4, and 8 of salvage therapy. Introducing new and more potent therapy reduces the number of detectable drug resistance-associated mutations within 8 weeks, and no evidence was found that the new therapy promoted the emergence of novel mutations.

Anti-HIV Agents↗
PubMed2000

Measuring the effect of clinical guidelines on patient outcomes.

OBJECTIVES: To identify and examine the methodologic issues related to evaluating the effectiveness of treatment adherence to clinical guidelines. The example of antiretroviral therapy guidelines for human immunodeficiency virus (HIV) disease is used to illustrate the points. METHODS: Regression analysis was applied to observational HIV clinic data for patients with CD4+ cell counts less than 500 per microL and greater than 50 per microL at baseline (n = 704), using Cox proportional hazards time-varying covariates models controlling for baseline risk. The results are compared with simpler models (Cox model [without time-varying covariates] and logistic regression). In addition, the effect of including a measure of exposure to antiretroviral guidelines in the model is explored. RESULTS: This study has three implications for modeling clinical guideline effectiveness. To capture events that are time-sensitive, a duration model should be used, and covariates that are time-varying should be modeled as time-varying. Thirdly, incorporating a threshold measure of exposure to reflect the minimum period of time for guideline adherence required for a measurable effect on patient outcome should be considered. CONCLUSIONS: The methods proposed in this paper are important to consider if guidelines are to evolve from being a tool for summarizing and transferring the results of research from the literature to clinicians into a practical tool that influences clinical practice patterns. However, the methodology tested in this study needs to be validated using additional data on similar patients and using data on patients with other diseases.

Anti-HIV Agents↗
PubMed2000

Participation in clinical studies among patients infected with HIV-1 in a single treatment centre over 12 years.

OBJECTIVE: To examine a complete population of clinic attenders in order to compare the demographics of patients who participated in a clinical study with those who had not. These were subdivided into trials of antivirals, trials for drugs used in opportunistic infections or symptomatic HIV and epidemiological studies. The setting was an established London teaching hospital. All patients diagnosed HIV-positive and attending between July 1983 and 1 January 1999 with one measured CD4 count and at least one follow-up visit were included. METHODS: The demographics of those participating in a clinical study were compared to those not enrolling using chi2 tests and Wilcoxon tests. Cox models were used to determine factors related to participation in clinical studies. RESULTS: Data from 2703 patients representing 5342.7 person-years' follow-up were assessed. Median time of follow-up was 23.6 months. Six hundred and eighty-seven (33%) patients had ever participated in a clinical study. After adjustment for demographic factors in multivariate analysis using Cox models, homosexuals were more likely to participate compared with heterosexuals or injecting drug users (IDU) (P = 0.0035 and P = 0.0001, respectively). Women were more likely to enter a study (P = 0.02) and there was no difference between Caucasians and black Africans (P = 0.35). Between the three types of studies few differences were seen. CONCLUSION: High rates of participation in clinical trials and epidemiological studies were seen in this cohort. In keeping with other studies, homosexual men were well represented but IDU were under-represented. However, women and black African patients showed good uptake of all clinical studies. Hence in this population there is some success in targeting representative groups to participate in clinical studies, but more effort needs to be made with IDU.

AIDS-Related Opportunistic Infections↗