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1.
Trop Med Int Health ; 16(4): 518-26, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21281407

ABSTRACT

OBJECTIVE: To evaluate the role of prophylactic trimethoprim-sulfamethoxazole (co-trimoxazole) antibacterial prophylaxis in reducing morbidity and mortality in HIV-infected post-natal women in southern Africa. METHODS: Double-blind placebo-controlled trial. HIV-infected women with WHO stage 2 or 3 HIV disease who had recently delivered in the Department of Obstetrics and Gynaecology at the University Teaching Hospital, Lusaka, Zambia were randomised to receive daily co-trimoxazole (cotox) or matched placebo daily for the duration of the trial. Participants were followed up for a minimum of 1 year. Primary outcome measures were mortality from any cause or hospital admission and serious adverse events. RESULTS: Of 600 women randomised, follow-up information was available from 355 (180 cotox, 175 placebo) participants. Thirty-six (17 cotox, 19 placebo) women died during the trial, and another 11 (5 cotox, 6 placebo) were admitted to hospital. There was no significant difference in the combined event rates between the two treatment arms: HR = 0.82, 95% CI (0.46, 1.45), P = 0.49; morbidity was reduced over a range of symptoms. Secondary analyses of the outcome in babies indicated some evidence of reduced mortality in those whose mothers were allocated cotox. CONCLUSIONS: Follow-up rates were poor; there was no evidence that co-trimoxazole prophylaxis reduced mortality or hospital admission rates, although fewer symptoms were reported in the cotox arm. Cotox was safe and well tolerated.


Subject(s)
AIDS-Related Opportunistic Infections/prevention & control , Anti-Bacterial Agents/therapeutic use , Antibiotic Prophylaxis/methods , Bacterial Infections/prevention & control , Trimethoprim, Sulfamethoxazole Drug Combination/therapeutic use , AIDS-Related Opportunistic Infections/mortality , Adult , Anti-Bacterial Agents/adverse effects , Antibiotic Prophylaxis/adverse effects , Bacterial Infections/mortality , Epidemiologic Methods , Female , Hospitalization/statistics & numerical data , Humans , Medication Adherence , Postnatal Care/methods , Treatment Outcome , Trimethoprim, Sulfamethoxazole Drug Combination/adverse effects , Young Adult
2.
Antivir Ther ; 13(6): 761-70, 2008.
Article in English | MEDLINE | ID: mdl-18839777

ABSTRACT

BACKGROUND: Cockcroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) formulae are recommended for glomerular filtration rate (GFR) estimation, but neither has been validated or directly compared longitudinally in HIV-infected patients or in Africa. METHODS: We investigated differences between formulae in baseline GFR, GFR changes and incidence of impaired GFR after initiation of antiretroviral therapy (ART) in 3,316 HIV-infected adults in Africa, considering sex, age, body mass index and baseline laboratory parameters as predictors. RESULTS: Participants were 65% women, median age 36.8 years, median weight 56.7 kg. Baseline GFR was lower using CG (median 89 ml/min/1.73 m2, 7.4% <60 ml/min/1.73 m2) versus MDRD (103 ml/min/1.73 m2, 3.1% <60 ml/min/1.73 m2). At 36 weeks, median CG-GFR increased (92 ml/min/1.73 m2), whereas MDRD-GFR decreased (96 ml/min/1.73 m2). Weight (explicitly a factor in CG only) concurrently increased to 62.0 kg. GFR changes from weeks 36-96 (after weight stabilization) were similar across formulae. By 96 weeks, 56 patients developed severe GFR impairment (<30 ml/min/1.73 m2) using one or both formulae (both n=45, CG n=7, MDRD n=4) compared with only 24 by serum creatinine alone. Multivariate models identified different sets of predictors for each formula. CONCLUSIONS: Although severe GFR impairments are similarly classified by different formulae, moderate impairments were more frequently identified using CG-GFR versus MDRD-GFR (with Black ethnicity correction factor 1.21), and creatinine alone had low sensitivity. Given overestimation in underweight patients and sensitivity to weight changes, this MDRD formula might not necessarily be superior for monitoring ART in African HIV-infected adults.


Subject(s)
AIDS-Associated Nephropathy/physiopathology , Algorithms , Creatinine/blood , Glomerular Filtration Rate , AIDS-Associated Nephropathy/blood , AIDS-Associated Nephropathy/diagnosis , AIDS-Associated Nephropathy/drug therapy , Adult , Age Factors , Anti-HIV Agents/adverse effects , Anti-HIV Agents/therapeutic use , Antiretroviral Therapy, Highly Active/adverse effects , Cohort Studies , Diet , Dietary Carbohydrates/administration & dosage , Female , Glomerular Filtration Rate/drug effects , Humans , Male , Patient Selection , Predictive Value of Tests , Randomized Controlled Trials as Topic/standards , Sex Factors , Uganda , Zimbabwe
3.
BMJ ; 337: a257, 2008 Jul 10.
Article in English | MEDLINE | ID: mdl-18617486

ABSTRACT

OBJECTIVE: To assess the impact of prophylactic oral co-trimoxazole in reducing mortality in HIV positive Zambian adults being treated for pulmonary tuberculosis. DESIGN: Double blind placebo controlled randomised clinical trial. PARTICIPANTS: Two groups of antiretroviral treatment naive adults with HIV infection: patients newly diagnosed as having tuberculosis and receiving tuberculosis treatment either for the first time or for retreatment after relapse; previously treated patients not receiving treatment. INTERVENTION: Oral co-trimoxazole or matching placebo daily. Primary outcome measures Time to death and occurrence of serious adverse events related to study drug. RESULTS: 1003 patients were randomised: 835 (416 co-trimoxazole, 419 placebo) were receiving treatment for tuberculosis, 762 (376 co-trimoxazole, 386 placebo) of them newly diagnosed previously untreated patients and 73 (40 co-trimoxazole, 33 placebo) receiving a retreatment regimen; 168 (84 co-trimoxazole, 84 placebo) were not on treatment but had received treatment in the past. Of 835 participants receiving tuberculosis treatment, follow-up information was available for 757, with a total of 1012.6 person years of follow-up. A total of 310 (147 co-trimoxazole, 163 placebo) participants died, corresponding to death rates of 27.3 and 34.4 per 100 person years. In the Cox regression analysis, the hazard ratio for death (co-trimoxazole:placebo) was 0.79 (95% confidence interval 0.63 to 0.99). The effect of co-trimoxazole waned with time, possibly owing to falling adherence levels; in a per protocol analysis based on patients who spent at least 90% of their time at risk supplied with study drug, the hazard ratio was 0.65 (0.45 to 0.93). CONCLUSIONS: Prophylaxis with co-trimoxazole reduces mortality in HIV infected adults with pulmonary tuberculosis. Co-trimoxazole was generally safe and well tolerated. TRIAL REGISTRATION: Current Controlled Trials ISRCTN15281875.


Subject(s)
Anti-Infective Agents/administration & dosage , HIV Infections/mortality , Trimethoprim, Sulfamethoxazole Drug Combination/administration & dosage , Tuberculosis, Pulmonary/prevention & control , Administration, Oral , Adolescent , Adult , Aged , Double-Blind Method , Epidemiologic Methods , Female , HIV Infections/complications , Humans , Male , Middle Aged , Treatment Outcome , Tuberculosis, Pulmonary/complications , Tuberculosis, Pulmonary/mortality
4.
BMJ ; 335(7613): 239, 2007 Aug 04.
Article in English | MEDLINE | ID: mdl-17626056

ABSTRACT

OBJECTIVE: To assess the long term risks and benefits of hormone replacement therapy (combined hormone therapy versus placebo, and oestrogen alone versus combined hormone therapy). DESIGN: Multicentre, randomised, placebo controlled, double blind trial. SETTING: General practices in UK (384), Australia (91), and New Zealand (24). PARTICIPANTS: Postmenopausal women aged 50-69 years at randomisation. At early closure of the trial, 56,583 had been screened, 8980 entered run-in, and 5692 (26% of target of 22,300) started treatment. INTERVENTIONS: Oestrogen only therapy (conjugated equine oestrogens 0.625 mg orally daily) or combined hormone therapy (conjugated equine oestrogens plus medroxyprogesterone acetate 2.5/5.0 mg orally daily). Ten years of treatment planned. PRIMARY OUTCOMES: major cardiovascular disease, osteoporotic fractures, and breast cancer. SECONDARY OUTCOMES: other cancers, death from all causes, venous thromboembolism, cerebrovascular disease, dementia, and quality of life. RESULTS: The trial was prematurely closed during recruitment, after a median follow-up of 11.9 months (interquartile range 7.1-19.6, total 6498 women years) in those enrolled, after the publication of early results from the women's health initiative study. The mean age of randomised women was 62.8 (SD 4.8) years. When combined hormone therapy (n=2196) was compared with placebo (n=2189), there was a significant increase in the number of major cardiovascular events (7 v 0, P=0.016) and venous thromboembolisms (22 v 3, hazard ratio 7.36 (95% CI 2.20 to 24.60)). There were no statistically significant differences in numbers of breast or other cancers (22 v 25, hazard ratio 0.88 (0.49 to 1.56)), cerebrovascular events (14 v 19, 0.73 (0.37 to 1.46)), fractures (40 v 58, 0.69 (0.46 to 1.03)), and overall deaths (8 v 5, 1.60 (0.52 to 4.89)). Comparison of combined hormone therapy (n=815) versus oestrogen therapy (n=826) outcomes revealed no significant differences. CONCLUSIONS: Hormone replacement therapy increases cardiovascular and thromboembolic risk when started many years after the menopause. The results are consistent with the findings of the women's health initiative study and secondary prevention studies. Research is needed to assess the long term risks and benefits of starting hormone replacement therapy near the menopause, when the effect may be different. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 63718836.


Subject(s)
Estrogen Replacement Therapy/adverse effects , Aged , Breast Neoplasms/chemically induced , Cardiovascular Diseases/chemically induced , Double-Blind Method , Female , Fractures, Bone/chemically induced , Humans , Middle Aged , Osteoporosis/chemically induced , Postmenopause , Quality of Life , Risk Factors , Treatment Outcome
5.
Antivir Ther ; 12(1): 47-54, 2007.
Article in English | MEDLINE | ID: mdl-17503747

ABSTRACT

OBJECTIVE: To evaluate whether the addition of a fourth drug for up to 32 weeks to a standard three-drug antiretroviral combination decreases the risk of virological failure without increasing toxicity in treatment-naive patients. DESIGN: Induction/maintenance (IM) therapy [two nucleoside reverse transcriptase inhibitors (NRTIs) + one non-NRTI (NNRTI) + one protease inhibitor for 24-32 weeks until plasma HIV RNA viral load (VL) < or =50 copies/ml then two NRTIs + NNRTI] was compared with standard therapy (ST) (two NRTIs + NNRTI). The primary endpoint was virological failure: VL >50 copies/ml at 32 (and 24) weeks or subsequent rebound to >400 copies/ml. RESULTS: 122 (62 IM, 60 ST) participants were randomized and followed for a median of 81 weeks (IQR 64-145). 52% were asymptomatic; median CD4+ T-cell count was 160 x 10(6)/l (IQR 92-260) and median VL 98,830 copies/ml (IQR 37,500-241,290). In an intent-to-treat analysis, the proportion of participants with virological failure at or after 32 weeks was higher in the ST arm [26 (43%) versus 11 (18%), P = 0.002]. The mean decrease in VL at 48 weeks was 0.84 95% confidence interval (CI) (0.15, 1.53) log10 copies/ml greater in the IM arm (P = 0.02). There were no significant differences between the two arms in the change in CD4+ T-cell count from baseline to 48 weeks, the number of participants with adverse events or the frequency of progression to AIDS/death. Drug resistance at failure was detected less frequently in the IM arm. CONCLUSIONS: Starting antiretroviral therapy with an IM strategy improved virological outcomes compared with a three-drug regimen, without significantly increasing toxicity.


Subject(s)
HIV Infections/drug therapy , HIV Protease Inhibitors/therapeutic use , HIV-1/genetics , RNA, Viral/blood , Reverse Transcriptase Inhibitors/therapeutic use , Adult , Antiretroviral Therapy, Highly Active , CD4 Lymphocyte Count , Didanosine/therapeutic use , Disease Progression , Drug Resistance, Multiple, Viral/genetics , Female , Follow-Up Studies , HIV Infections/immunology , HIV Infections/mortality , HIV Infections/virology , HIV Protease Inhibitors/adverse effects , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Mutation , Nelfinavir/therapeutic use , Nevirapine/therapeutic use , Patient Compliance , Remission Induction , Reverse Transcriptase Inhibitors/adverse effects , Stavudine/therapeutic use , Time Factors , Treatment Failure , United Kingdom , Viral Load
6.
Antivir Ther ; 11(6): 741-9, 2006.
Article in English | MEDLINE | ID: mdl-17310818

ABSTRACT

OBJECTIVE: To describe the prevalence, incidence and predictors of severe anaemia in previously untreated symptomatic HIV-infected adults with CD4+ T-cells <200 cells/mm(3) initiating zidovudine-containing regimens in Africa. DESIGN: DART is a randomized trial comparing two strategies for HIV/AIDS management in Uganda and Zimbabwe. METHODS: We analysed the occurrence of anaemia at weeks 4 and 12, and then every 12 weeks. We also evaluated sex, age, WHO stage, body mass index (BMI), baseline laboratory measurements and first regimen as predictors of developing grade 4 anaemia (<6.5 mg/dl) by week 48 using logistic regression. RESULTS: To May 2005, 3,314 participants (65% women, 23% at WHO stage 4, median age=37 years, baseline CD4+ T-cell=86 cells/mm(3) and median baseline haemoglobin=11.4 g/dl) had a median 72 weeks follow-up. Prevalence of grade 4 anaemia was 0.70, 2.0%, 0.5% and <0.5% at weeks 4, 12, 24 and > or =36, respectively. Overall, 219 (6.6%) participants developed grade 4 anaemia by week 48; women and those with lower haemoglobin, CD4+ T-cell count and BMI at baseline were at significantly higher risk (P<0.05), but not those with lower neutrophils or receiving cotrimoxazole at baseline. CONCLUSIONS: We observed a higher incidence of grade 4 anaemia than in studies from industrialized countries, which is likely to be due in part to population characteristics and in part to a higher rate of concurrent HIV-related clinical events. Clinical vigilance and haemoglobin measurements 4, 8 and 12 weeks after starting zidovudine could help to manage serious anaemia.


Subject(s)
Anemia/epidemiology , Anti-HIV Agents/adverse effects , HIV Infections/complications , Reverse Transcriptase Inhibitors/adverse effects , Zidovudine/adverse effects , Adult , Anemia/etiology , Anemia/mortality , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/therapeutic use , Drug Therapy, Combination , Female , HIV Infections/drug therapy , HIV Infections/epidemiology , HIV Infections/virology , Hemoglobins/analysis , Humans , Incidence , Male , Predictive Value of Tests , Prevalence , Reverse Transcriptase Inhibitors/administration & dosage , Reverse Transcriptase Inhibitors/therapeutic use , Severity of Illness Index , Uganda/epidemiology , Zidovudine/administration & dosage , Zidovudine/therapeutic use , Zimbabwe/epidemiology
7.
N Engl J Med ; 352(9): 865-74, 2005 Mar 03.
Article in English | MEDLINE | ID: mdl-15745977

ABSTRACT

BACKGROUND: Intrapleural fibrinolytic agents are used in the drainage of infected pleural-fluid collections. This use is based on small trials that did not have the statistical power to evaluate accurately important clinical outcomes, including safety. We conducted a trial to clarify the therapeutic role of intrapleural streptokinase. METHODS: In this double-blind trial, 454 patients with pleural infection (defined by the presence of purulent pleural fluid or pleural fluid with a pH below 7.2 with signs of infection or by proven bacterial invasion of the pleural space) were randomly assigned to receive either intrapleural streptokinase (250,000 IU twice daily for three days) or placebo. Patients received antibiotics and underwent chest-tube drainage, surgery, and other treatment as part of routine care. The number of patients in the two groups who had died or needed surgical drainage at three months was compared (the primary end point); secondary end points were the rates of death and of surgery (analyzed separately), the radiographic outcome, and the length of the hospital stay. RESULTS: The groups were well matched at baseline. Among the 427 patients who received streptokinase or placebo, there was no significant difference between the groups in the proportion of patients who died or needed surgery (with streptokinase: 64 of 206 patients [31 percent]; with placebo: 60 of 221 [27 percent]; relative risk, 1.14 [95 percent confidence interval, 0.85 to 1.54; P=0.43), a result that excluded a clinically significant benefit of streptokinase. There was no benefit to streptokinase in terms of mortality, rate of surgery, radiographic outcomes, or length of the hospital stay. Serious adverse events (chest pain, fever, or allergy) were more common with streptokinase (7 percent, vs. 3 percent with placebo; relative risk, 2.49 [95 percent confidence interval, 0.98 to 6.36]; P=0.08). CONCLUSIONS: The intrapleural administration of streptokinase does not improve mortality, the rate of surgery, or the length of the hospital stay among patients with pleural infection.


Subject(s)
Bacterial Infections/drug therapy , Fibrinolytic Agents/therapeutic use , Pleural Diseases/drug therapy , Streptokinase/therapeutic use , Anti-Bacterial Agents/therapeutic use , Bacterial Infections/diagnostic imaging , Bacterial Infections/mortality , Bacterial Infections/surgery , Combined Modality Therapy , Community-Acquired Infections/drug therapy , Cross Infection/drug therapy , Double-Blind Method , Drainage , Empyema, Pleural/drug therapy , Empyema, Pleural/mortality , Empyema, Pleural/surgery , Female , Fibrinolytic Agents/adverse effects , Humans , Instillation, Drug , Length of Stay , Lung/diagnostic imaging , Male , Middle Aged , Pleural Diseases/diagnostic imaging , Pleural Diseases/mortality , Pleural Diseases/surgery , Pneumonia/complications , Radiography , Streptokinase/adverse effects , United Kingdom
8.
Antivir Ther ; 9(5): 641-8, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15535402

ABSTRACT

OBJECTIVES: To assess the strength of evidence supporting the routine use of HIV drug resistance testing. DESIGN: A critical review of all studies relating to the clinical utility of HIV resistance testing, with a focus on randomized trials. RESULTS: Two cohort studies found no evidence of a difference in virological response in patients who had resistance testing compared with matched controls. We identified nine published randomized trials that were specifically designed to assess the clinical utility of drug resistance testing. In a meta-analysis of these trials, resistance testing increased the proportion of patients who achieved undetectable viral load by an average of 7% (95% confidence interval: 3-11%). However, this may be an over-estimate of the impact of resistance testing in clinical practice because of the idealized design and analytical approaches used in most of the studies. CONCLUSIONS: The available evidence does not clearly demonstrate that HIV drug resistance testing is clinically effective. To optimize their value for health decision-making, future trials of HIV resistance testing should be carefully designed to mimic the circumstances of routine clinical practice.


Subject(s)
Anti-HIV Agents/pharmacology , Drug Resistance, Viral , HIV-1/drug effects , Reverse Transcriptase Inhibitors/pharmacology , Anti-HIV Agents/therapeutic use , Cohort Studies , Drug Resistance, Viral/genetics , HIV Infections/virology , Humans , Microbial Sensitivity Tests/methods , Randomized Controlled Trials as Topic , Reverse Transcriptase Inhibitors/therapeutic use
9.
Epidemiology ; 13(3): 347-55, 2002 May.
Article in English | MEDLINE | ID: mdl-11964938

ABSTRACT

BACKGROUND: Many cohort studies and clinical trials use repeated measurements of laboratory markers to track disease progression and to evaluate new therapies. A major problem in the analysis of such studies is that marker data are censored in some patients owing to withdrawal, loss to follow-up, or death. The objective of this paper is to evaluate the impact of selective dropouts attributable to death or disease progression on the estimates of marker change among different groups. METHODS: Data on CD4 cell count in human immunodeficiency virus 1-infected individuals from a clinical trial and a cohort study are used to illustrate this problem and a possible solution. Simulation studies are also presented. RESULTS: When the rate of dropout is greater in subjects whose marker status is declining rapidly, commonly used methods, like random effects models, that ignore informative dropouts lead to overoptimistic statements about the marker trends in all compared groups, because subjects with steeper marker drops tend to have shorter follow-up times and hence are weighted less in the estimation of the group rate of the average marker decline. CONCLUSIONS: The potential biases attributable to incomplete data require greater recognition in longitudinal studies. Sensitivity analyses to assess the effect of dropouts are important.


Subject(s)
Bias , Patient Dropouts/statistics & numerical data , Randomized Controlled Trials as Topic/statistics & numerical data , Adolescent , Adult , CD4 Lymphocyte Count , Child , Child, Preschool , Cohort Studies , Data Interpretation, Statistical , Didanosine/therapeutic use , HIV Infections/complications , HIV Infections/drug therapy , HIV Infections/immunology , Hemophilia A/blood , Hemophilia A/complications , Hemophilia A/immunology , Humans , Infant , Least-Squares Analysis , Longitudinal Studies , Middle Aged , Models, Theoretical
10.
Control Clin Trials ; 23(2): 198-220, 2002 Apr.
Article in English | MEDLINE | ID: mdl-11943448

ABSTRACT

The Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT) is a large ongoing randomized trial of subcutaneous interleukin-2 (IL-2) plus antiretroviral therapy versus antiretroviral therapy alone in patients with HIV (human immunodeficiency virus) disease and CD4 cell counts of at least 300 cells/mm(3). The primary objective is to determine whether the addition of IL-2 to combination antiretroviral therapy improves morbidity and mortality. The aim is to recruit 4000 participants and follow them for an average of 5 years. Eligible subjects will be recruited at 275 investigational sites in 23 countries around the world. Coupled with broad eligibility criteria this will ensure widely applicable results. A range of secondary objectives will also be addressed in this setting that will include the conduct of observational studies and nested substudies with a public health focus. This article describes the rationale supporting the trial in addition to reviewing the study design, coordination, and governance.


Subject(s)
HIV Infections/drug therapy , Interleukin-2/therapeutic use , Randomized Controlled Trials as Topic/methods , Research Design , Adult , Anti-HIV Agents/therapeutic use , Clinical Trials, Phase III as Topic/methods , Data Collection/methods , Disease Progression , Drug Therapy, Combination , Female , Humans , Injections, Subcutaneous , Male , Multicenter Studies as Topic/methods , Patient Selection , Randomized Controlled Trials as Topic/economics , Randomized Controlled Trials as Topic/statistics & numerical data , Sample Size , Survival Analysis , United States
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