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Biomedical subjects

N Clumeck

Publications and source records attributed to N Clumeck.

At least 19 recordsLinked to original sources
PubMed2006

CD4+ count-guided interruption of antiretroviral treatment.

BACKGROUND: Despite declines in morbidity and mortality with the use of combination antiretroviral therapy, its effectiveness is limited by adverse events, problems with adherence, and resistance of the human immunodeficiency virus (HIV). METHODS: We randomly assigned persons infected with HIV who had a CD4+ cell count of more than 350 per cubic millimeter to the continuous use of antiretroviral therapy (the viral suppression group) or the episodic use of antiretroviral therapy (the drug conservation group). Episodic use involved the deferral of therapy until the CD4+ count decreased to less than 250 per cubic millimeter and then the use of therapy until the CD4+ count increased to more than 350 per cubic millimeter. The primary end point was the development of an opportunistic disease or death from any cause. An important secondary end point was major cardiovascular, renal, or hepatic disease. RESULTS: A total of 5472 participants (2720 assigned to drug conservation and 2752 to viral suppression) were followed for an average of 16 months before the protocol was modified for the drug conservation group. At baseline, the median and nadir CD4+ counts were 597 per cubic millimeter and 250 per cubic millimeter, respectively, and 71.7% of participants had plasma HIV RNA levels of 400 copies or less per milliliter. Opportunistic disease or death from any cause occurred in 120 participants (3.3 events per 100 person-years) in the drug conservation group and 47 participants (1.3 per 100 person-years) in the viral suppression group (hazard ratio for the drug conservation group vs. the viral suppression group, 2.6; 95% confidence interval [CI], 1.9 to 3.7; P<0.001). Hazard ratios for death from any cause and for major cardiovascular, renal, and hepatic disease were 1.8 (95% CI, 1.2 to 2.9; P=0.007) and 1.7 (95% CI, 1.1 to 2.5; P=0.009), respectively. Adjustment for the latest CD4+ count and HIV RNA level (as time-updated covariates) reduced the hazard ratio for the primary end point from 2.6 to 1.5 (95% CI, 1.0 to 2.1). CONCLUSIONS: Episodic antiretroviral therapy guided by the CD4+ count, as used in our study, significantly increased the risk of opportunistic disease or death from any cause, as compared with continuous antiretroviral therapy, largely as a consequence of lowering the CD4+ cell count and increasing the viral load. Episodic antiretroviral therapy does not reduce the risk of adverse events that have been associated with antiretroviral therapy. (ClinicalTrials.gov number, NCT00027352 [ClinicalTrials.gov].).

AIDS-Related Opportunistic Infections↗
PubMed2005

Indinavir/ritonavir-based therapy in HIV-1-infected antiretroviral therapy-naive patients: comparison of 800/100 mg and 400/100 mg twice daily.

Objectives To compare the efficacy and tolerability of indinavir (IDV)/ritonavir (RTV) at 800/100 and 400/100 mg twice daily (bid) in antiretroviral therapy (ART)-naive patients. Methods An open comparison of two groups of ART-naive patients treated with IDV/RTV 800/100 or 400/100 mg bid plus two nucleoside analogues was carried out. Viral load, CD4 cell count and tolerability were measured at baseline and at weeks 4, 12, 24 and 48. IDV plasma concentrations were measured retrospectively. Results A total of 107 patients were included in the study. Of these, 57 were treated with 800/100 and 50 with 400/100 mg IDV/RTV bid. At week 48, a viral load of <50 HIV-1 RNA copies/mL was achieved by 77 and 64% of the patients, respectively, and the median CD4 cell count increases were +171 and +164 cells/muL (intent-to-treat; P not significant), respectively. Side effects leading to protease inhibitor discontinuation occurred in 61% of subjects in the 800/100 mg group vs. 20% in the 400/100 mg group (P<0.0001). Switching from 800/100 to 400/100 mg dosage improved adverse events in 16 of 20 patients. IDV concentrations were above 0.15 mg/L in 89% of the 28 patients tested in the 400/100 mg group. Conclusions Indinavir/ritonavir 400/100 mg bid provided the same efficacy as 800/100 mg bid at 48 weeks in an ART-naive population, but safety and tolerance were significantly better for 400/100 mg, while convenience was also improved and cost was reduced.

Adolescent↗
PubMed2004

A randomized study investigating the efficacy and safety of amprenavir in combination with low-dose ritonavir in protease inhibitor-experienced HIV-infected adults.

OBJECTIVES: To compare the safety and efficacy of amprenavir [APV/j Agenerase trade mark; GlaxoSmithKline, [Ware, UK; 600 mg twice a day (bid)] boosted with low-dose ritonavir (RTV, 100 mg bid) with those of other protease inhibitors (PIs) in PI-experienced HIV-infected patients. STUDY DESIGN: Parallel-group, randomized, open-label, multicentre study. METHODS: One hundred and sixty-three patients with HIV predicted to be sensitive to APV, another PI and a nucleoside reverse transcriptase inhibitor (NRTI) were randomly assigned to receive either APV boosted with low-dose RTV (APV/r) or a standard of care (SOC) PI with or without low-dose RTV. The non-inferiority of APV/r to the SOC PIs was assessed by time-weighted average change from baseline (AAUCMB) in plasma viral load (vRNA) at week 16. RESULTS: The antiviral response for APV/r bid was non-inferior to that for the SOC PI group: the vRNA AAUCMB mean treatment difference was 0.043 log(10) HIV-1 RNA copies/mL [95% confidence interval (CI)-0.250, 0.335]. APV/r bid was generally well tolerated. CONCLUSIONS: Results confirm the antiviral activity, short-term safety and tolerability of APV/r bid in PI-experienced patients.

Adolescent↗
PubMed2004

Updated European recommendations for the clinical use of HIV drug resistance testing.

In most European countries, HIV drug resistance testing has become a routine clinical tool. However, its practical implementation in a clinical context is demanding. The European HIV Drug Resistance Panel was established to make recommendations to clinicians and virologists on this topic and to propose quality control measures. The panel recommends resistance testing for the following indications: i) drug-naive patients with acute or recent infection; ii) therapy failure, including suboptimal treatment response, when treatment change is considered; iii) pregnant HIV-1-infected women and paediatric patients with detectable viral load when treatment initiation or change is considered; and iv) genotype source patient when post-exposure prophylaxis is considered. In addition, for drug-naive patients with chronic infection in whom treatment is to be started, the panel suggests that resistance testing should be strongly considered and recommends testing the earliest sample for drug resistance if suspicion of resistance is high or prevalence of resistance in this population exceeds 10%. The panel does not favour genotyping over phenotype, however it is anticipated that genotyping will be used more often because of its greater accessibility, lower cost and faster turnaround time. For the interpretation of resistance data, clinically validated systems should be used to the greatest extent possible. It is mandatory that laboratories performing HIV resistance tests take regular part in quality assurance programs. Similarly, it is necessary that HIV clinicians and virologists take part in continuous education and meet regularly to discuss problematic clinical cases. Indeed, resistance test results should be used in the context of all other clinically relevant information for predicting therapy response. The panel also encourages the timely collection of epidemiological information to estimate the impact of transmission of resistant HIV and the prevalence of HIV-1 non-B subtypes in the different European countries.

Anti-HIV Agents↗
PubMed2003

TRIZAL study: switching from successful HAART to Trizivir (abacavir-lamivudine-zidovudine combination tablet): 48 weeks efficacy, safety and adherence results.

OBJECTIVE: To assess the antiviral efficacy, safety, and adherence in subjects who switched to Trizivir following long-term HIV-1 RNA suppression. STUDY DESIGN: A randomized, open-label, multicentre, 48-week comparative study in subjects who have received two nucleoside reverse transcriptase inhibitors plus a protease inhibitor or an nonnucleoside reverse transcriptase inhibitor or three nucleoside reverse transcriptase inhibitors for at least 6 months, with a history of undetectable plasma HIV-1 RNA since initiation of therapy and plasma viral load of < 50 HIV-1 RNA copies/mL at screening. METHODS: Subjects were randomized 1:1 to continue their current treatment or to switch to a simplified treatment with Trizivir administered twice daily. Assessments included plasma HIV-1 RNA, lymphocyte counts, clinical laboratory evaluations, adverse events, and adherence to treatment (obtained via subject self-report). Treatment failure was defined as a plasma viral load of >/= 400 HIV-1 RNA copies/mL on two consecutive occasions or premature discontinuation of randomized treatment. RESULTS: At week 48, the proportion of treatment failures in Trizivir arm (23/106, 22%) was noninferior to that observed in continued arm (23/103, 22%) with a treatment difference stratified by prior ART of 1.2%[-10.1; 12.5]. Incidence of adverse events was similar in both treatment groups. The incidence of possible hypersensitivity reaction in the Trizivir trade mark arm was 10%. Significant reductions in cholesterol and triglyceride plasma levels were observed in the Trizivir arm (P < 0.001 and P = 0.006, respectively). CONCLUSION: Switching to Trizivir offers a potent and simplified regimen with equivalent efficacy and significant improvement in lipid abnormalities compared to continued triple therapy.

Adult↗
PubMed2001

Simplification with abacavir-based triple nucleoside therapy versus continued protease inhibitor-based highly active antiretroviral therapy in HIV-1-infected patients with undetectable plasma HIV-1 RNA.

OBJECTIVE: To assess the antiviral efficacy, safety and adherence in patients switched to an abacavir-containing nucleoside reverse transcriptase inhibitor (NRTI) regimen after long-term HIV-1 RNA suppression with a dual NRTI/protease inhibitor (PI) combination. METHODS: In an open-label, multicentre study, patients receiving 2NRTI plus PI for at least 6 months, with a history of undetectable plasma HIV-1 RNA since the initiation of therapy and plasma HIV-1 RNA < 50 copies/ml at screening, were randomly assigned to replace the PI with abacavir (n = 105) or continue the same treatment (n = 106). Clinical assessments included plasma HIV-1 RNA, chemistry, haematology, lymphocyte counts, and adverse event reports. Adherence to treatment was assessed by patient self-report. RESULTS: A significantly longer time to treatment failure was demonstrated in the abacavir arm compared with the PI arm (P = 0.03) while treatment failure was experienced by significantly more patients in the PI arm: 24 (23%) versus 12 (12%) (P = 0.03). Therapy-limiting toxicity led to treatment failure in eight versus 14 cases in the abacavir and PI arms, respectively, whereas virological rebound was the cause in four versus two cases. Significant reductions in cholesterol and non-fasting triglyceride plasma levels at 48 weeks were observed in the abacavir arm (P < 0.001 andP = 0.035, respectively). The number of patients reporting no difficulty in taking their therapy showed a marked increase from baseline in the abacavir arm. CONCLUSION: The replacement of PI by abacavir in a triple combination regimen following prolonged suppression of plasma HIV-1 RNA provides continued virological suppression, significant improvements in lipid abnormalities and enhanced ease of dosing.

Adult↗
PubMed2001

[Polymyositis associated with HIV immunodeficiency: clinical case and literature review].

A 33 year old female, suffering from HIV infection, presents with diffuse myalgia, generalized muscle weakness and painless dysphagia. An extensive work-up allows to diagnose an HIV-related polymyositis; while well-known, this entity is however rarely observed. Technetium-99m MDP skeletal scintigraphy shows multiple extra-osseous accumulations of the tracer: these observations, as well as the differential diagnoses of muscular involvement during HIV infection, are discussed.

Adult↗
PubMed2001

A dose-ranging study to evaluate the antiretroviral activity and safety of amprenavir alone and in combination with abacavir in HIV-infected adults with limited antiretroviral experience.

OBJECTIVE: To evaluate the antiretroviral activity and safety of multiple escalating doses of amprenavir administered alone, and in combination with abacavir in HIV-1-infected adults. DESIGN: Sixty-two HIV-1-infected subjects were enrolled in a multicentre, open-label, non-randomized, dose-escalating trial. METHODS: Subjects were assigned to one of six dose groups and received amprenavir 300 mg twice daily, 300 mg three times daily, 900, 1050, or 1,200 mg twice daily for 4 weeks. One dose group received amprenavir 900 mg twice daily in combination with abacavir 300 mg twice daily for 4 weeks. Antiretroviral activity was assessed by measuring changes from baseline in plasma HIV-1 RNA levels and CD4 cell counts. Safety was evaluated by monitoring clinical adverse events and changes in laboratory values. Genotypic and phenotypic analyses were performed using ABI sequencing and the recombinant virus assay, respectively. RESULTS: At week 4, amprenavir monotherapy (900, 1,050, or 1,200 mg twice daily) resulted in marked decreases in plasma HIV-1 RNA levels (1.3-1.6 log10 copies/ml), and substantial increases in CD4 cell counts in the two dose groups who received 1,050 mg twice daily (118 x 10(6) cells/mm3) or 1,200 mg twice daily (114 x 10(6) cells/mm3). Amprenavir/abacavir resulted in median plasma HIV-1 RNA reductions of 1.8 log10 copies/ml, and median CD4 cell count increases of 138 x 10(6) cells/mm3. Amprenavir was reasonably well tolerated with few treatment-limiting adverse events. No known active site mutations associated with amprenavir resistance were selected in any of the dose groups, and no significant phenotypic resistance to amprenavir developed during 4 weeks of therapy. CONCLUSIONS: The antiviral effect of amprenavir monotherapy increased with escalating doses, and all amprenavir doses were reasonably well tolerated over 4 weeks of therapy. Amprenavir/abacavir combination therapy elicited a potent antiviral effect. The three highest doses of amprenavir (900, 1,050 and 1,200 mg twice daily) were selected to design subsequent Phase II and III studies that confirmed the safety profile and efficacy of amprenavir in combination regimens and led to the approval of amprenavir in the USA in 1999.

Administration, Oral↗
PubMed2001

Ritonavir/saquinavir plus one nucleoside reverse transcriptase inhibitor (NRTI) versus indinavir plus two NRTIs in protease inhibitor-naive HIV-1-infected adults (IRIS study).

OBJECTIVES: To compare the efficacy, tolerability and safety of a ritonavir 400 mg/saquinavir hard gel fomulation 400 mg twice daily versus an indinavir 800 mg once every 8 h containing first-line protease inhibitor (PI) treatment regimen. METHODS: Open, randomized, multicentre clinical trial. PI-naive patients received either ritonavir/saquinavir and one nucleoside reverse transcriptase inhibitor (NRTI) or indinavir and two NRTIs. Intention-to-treat (ITT) and on-treatment (OT) analyses were performed. RESULTS: The baseline characteristics of the study participants were similar in both arms, 67 patients (37%) were naive to antiretroviral treatment. The proportion of patients who achieved a plasma viral load below the level of detection of 400 copies/ml at week 48 was 43% (39/90) in the ritonavir/saquinavir arm and 63% (57/90) in the indinavir arm (P=0.005, I

Acquired Immunodeficiency Syndrome↗
PubMed2000

Virological and immunological effects of combination antiretroviral therapy with zidovudine, lamivudine, and indinavir during primary human immunodeficiency virus type 1 infection.

Forty-seven patients presenting with primary human immunodeficiency virus (HIV) infection were treated with zidovudine 200 mg 3 times a day, lamivudine 150 mg 2 times a day, and indinavir 800 mg 3 times a day for 1 year. From a mean pretreatment viral RNA level of 4.93 log(10) copies/mL, the proportions of patients having <500 copies/mL at 24 and 52 weeks were 92.0% and 89.2%, respectively. For the 35 patients with data available at 24 and 52 weeks, the corresponding proportions for the <50 copies/mL analysis were 86.6% and 79.3%, respectively. The change in virus load was -2.19 and -2.41 log(10) copies/mL at weeks 8 and 52, respectively. CD4 cell counts increased, from a mean of 546 cells/mm(3), by 142 cells/mm(3) at week 24 and by 210 cells/mm(3) at week 52. Three patients discontinued the study because of drug-related toxicity. Six (12.8%) patients had adverse experiences associated with nephrolithiasis. Combination therapy with zidovudine, lamivudine, and indinavir during primary HIV infection results in a profound and sustained reduction in virus load with concurrent recovery of the CD4 cell population.

Adult↗
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↗
PubMed2000

Update on highly active antiretroviral therapy: progress and strategies.

HIV patients who have detectable viral loads (1,000-5,000 copies/mL) and/or evidence of immunologic dysfunction (CD4+ T-lymphocyte count < 500/mm3) should be treated with a potent combination antiretroviral regimen. Currently, this is to consist of two nucleoside reverse transcriptase inhibitors (NRTIs) with at least one protease inhibitor (PI), or a non-nucleoside reverse transcriptase inhibitor (NNRTI), or another combination with adequate potency. The specific regimen should be designed to achieve an undetectable viral load by an ultrasensitive method (< 50 copies/mL). It should be chosen with a view towards maximizing adherence and minimizing significant drug-drug interactions and side effects. Long-term adherence with the initial highly-active regimen will minimize development of resistant viral mutants and preclude the use of higher complexity regimens. If a regimen is failing in the setting of adequate patient adherence, a new regimen should be chosen using at least two new medications to which viral strains are likely to be sensitive (by genotyping determination). If this is not possible, one may consider treatment interruption or, depending on the clinical status of the patient, continue the current suboptimal regimen until new drugs become available. The predictive value of resistance testing is currently being examined in patients who have failed their first therapy. Further developments include vaccine, cytokine-, and gene therapy-based treatment strategies.

Anti-HIV Agents↗
PubMed2000

HIV-associated multinucleated giant cells in lymphoid tissue of the Waldeyer's ring: a detailed study.

Hyperplastic lymphoid tissues of the Waldeyer's ring in human immunodeficiency virus (HIV)-infected patients may occasionally contain multinucleated giant cells (MGCs). These cells, which are unrelated to any opportunistic infection, previously have been demonstrated to harbor significant amounts of HIV. Studies undertaken to characterize these MGCs have generated conflicting results: some reports suggested a macrophage origin, whereas others supported a dendritic cell lineage. This study was performed to determine the occurrence of MGCs in a series of adenoid/tonsil specimens from HIV-seropositive patients showing no histological evidence of opportunistic infection in order to further characterize the phenotype of these cells and to investigate the role of a viral infection in their pathogenesis. Adenoid/tonsil tissue specimens from 21 HIV-seropositive patients with no documented opportunistic infection were scrutinized for the presence of MGCs and evaluated immunohistochemically on paraffin sections by antibodies directed against various macrophage and DC antigens. These antigens included CD68, the macrophage marker 3A5, major histocompatibility complex Class II, S-100 protein, CD1a, and CD83. Additional immunostainings directed at CD21 and CD35 as well as at the HIV-associated p24 antigen were also performed. Finally, the presence of Epstein-Barr virus and human herpesvirus 8 viral sequences was investigated by in situ hybridization and by polymerase chain reaction analysis, respectively. MGCs were found in 14 patients (66.7%), regardless of gender, age, method of viral transmission, CD4 cell count, viral load, or ethnic group. These cells were mostly localized at the lymphoepithelium layer of the tonsillar crypts and, to a lesser extent, in the interfollicular areas of the underlying lymphoid tissue, which consistently exhibited features of follicular hyperplasia. Phenotypically, MGCs were found to be CD68+, 3A5+, major histocompatibility complex Class II+, S-100 protein+/-, CD1a-, CD21-, CD35-, and CD83-. Although the HIV-associated p24 protein was consistently present in the cytoplasm of these cells, no sign of Epstein-Barr virus or human herpesvirus 8 infection could be demonstrated. Consequently, our study didn't show any conclusive evidence to support that MGCs in hyperplastic lymphoid tissues of the Waldeyer's ring from HIV-seropositive patients originated from dendritic cells. The definite nature of these cells has yet to be elucidated, but it is plausible that they simply represent activated macrophages that are infected with HIV present in the oropharyngeal secretions during the circulation of their precursor through the lymphoepithelium area of adenoids and tonsils.

Adenoids↗