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ABSTRACT: The aim of the study was to assess whether a simple, routinely available measure of antiretroviral therapy (ART) adherence predicts viral rebound at the next HIV viral load (VL) measurement in virally suppressed patients.
The analysis was performed on the Royal Free HIV Cohort, London, UK. Each 'drug coverage-viral load episode' (DCVL episode) was defined as a 6-month period immediately prior to a VL < or =50 HIV-1 RNA copies/mL (time-zero), during which the patient had been continuously on HAART, with all measured VLs < or =50 copies/mL. The next VL after time-zero was used to assess whether VL rebound (defined as >200 copies/mL) had occurred. Drug coverage, our measure of adherence, was calculated as the proportion of days in the 6-month period covered by a valid prescription for at least three antiretroviral drugs.
A total of 376 (2.4%) VL rebounds occurred in 15 660 DCVL episodes among 1632 patients. Drug coverage was 100% for 32% of episodes, 95-99% for 16% of episodes and < or =60% for 10% of episodes. The risk ratio of rebound associated with a 10% increase in drug coverage, adjusted for potential confounding variables, was 0.93 (95% confidence interval 0.88-0.98).
Antiretroviral drug coverage assessed at the time of VL measurement in patients with undetectable VL is potentially clinically useful for predicting VL rebound at the next VL measurement.
HIV Medicine 12/2009; 11(3):216-24. · 3.01 Impact Factor
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ABSTRACT: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are associated with a favorable increase in high-density lipoprotein cholesterol (HDL-c) level. Isolated studies have found a direct correlation between efavirenz (EFV) exposure and HDL-c level changes. Here we explore the impact that drug disposition variants associated with EFV exposure have on changes in HDL-c level. Seventy-six patients on first-line EFV-based regimens were genotyped for CYP2B6 516G>T and ABCB1 3435C>T. There was a 37% increase (+0.32 mmol/l, P < 0.001) in mean HDL-c level over 48 weeks, and this was univariately associated with gender (male +0.26 mmol/l, female +0.55 mmol/l; P = 0.03), ABCB1 3435C>T (CC +0.26 mmol/l, CT +0.16 mmol/l, TT +0.54 mmol/l; P(ANOVA) = 0.003) and CYP2B6 516 G>T (GG +0.27 mmol/l, GT +0.29 mmol/l, TT +0.72 mmol/l; P(ANOVA) = 0.08). There was a significant association between the cumulative number of predictive genotypes (CYP2B6 516TT or ABCB1 3435TT) and mean HDL-c level change: (group 0 +0.20 mmol/l, group 1 +0.47 mmol/l, group 2 +1.00 mmol/l; P(ANOVA) < 0.0001). These findings need to be validated in independent cohorts.
Clinical Pharmacology & Therapeutics 06/2009; 86(2):204-11. · 6.04 Impact Factor
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ABSTRACT: To assess the prevalence of an undetectable viral load (VL) (<50 HIV-1 RNA copies/mL) in a clinical population and to identify those viraemic and at risk of failing antiretroviral therapy (ART).
An audit of a complete clinical population on 1 January 2005 via a clinical database and clinical note review.
On 1 January 2005, 1910 patients were under care; 1229/1332 (92%) of those exposed to ART for >16 weeks had a VL of <50 copies/mL. We examined 49/56 case notes of viraemic patients to identify explanations for viraemia. Common reasons included previous initial mono- or dual therapy, adherence problems, more advanced HIV disease, concomitant medications, physical and mental health issues and being less well linked into the service. A review of these patients' current status on 1 April 2007 showed that six of the 49 had since died. However, of those still alive, 20 (47%) had a VL <500 copies/mL.
The proportion of patients on ART with detectable viraemia is low in current clinical practice. New drugs may help those who are failing because of resistance. However, there is a small minority of patients who, for various reasons, appear unable to maintain sufficient adherence to ART.
HIV Medicine 05/2008; 9(4):208-13. · 3.01 Impact Factor
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ABSTRACT: The diagnosis of tuberculosis (TB) may be rejected in the absence of symptoms such as fever, sweats or weight loss.
To determine how frequently these features and blood test evidence of inflammation were absent in individuals with TB.
Prospective cohort study of 175 unselected subjects diagnosed with TB at a UK TB service between 2003 and 2006.
Eight (5%) subjects identified by screening and 24 (14%) without culture confirmation were excluded. Of the remaining 143, fever, sweats or weight loss were absent in respectively 37%, 39% and 38%. All three symptoms were absent in 25%. In 88 subjects with pulmonary disease, all three symptoms were absent in 20% (10% of smear-positive cases). Overall, C-reactive protein was normal in 15%, erythrocyte sedimentation rate in 21% and lactate dehydrogenase in 55%. In a multivariable model, factors associated with absent symptoms included drug-resistant TB (adjusted odds ratio [aOR] 3.58, P = 0.004) and female sex (aOR 3.15, P = 0.004).
In our population, TB, including pulmonary disease, frequently presented without fever, sweats or weight loss and with normal blood inflammatory markers. This information is of as much relevance to policy makers seeking to improve active case detection as to clinicians and the general public.
The international journal of tuberculosis and lung disease: the official journal of the International Union against Tuberculosis and Lung Disease 02/2008; 12(1):44-9. · 2.73 Impact Factor
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ABSTRACT: Immunological ex vivo assays to diagnose tuberculosis (TB) have great potential but have largely been blood-based and poorly evaluated in active TB. Lung sampling enables combined microbiological and immunological testing and uses higher frequency antigen-specific responses than in blood.
A prospective evaluation was undertaken of a flow cytometric assay measuring the percentage of interferon-gamma synthetic CD4+ lymphocytes following stimulation with purified protein derivative of Mycobacterium tuberculosis (PPD) in bronchoalveolar lavage fluid from 250 sputum smear-negative individuals with possible TB. A positive assay was defined as >1.5%.
Of those who underwent lavage and were diagnosed with active TB, 95% (106/111) had a positive immunoassay (95% CI 89% to 98%). In 139 individuals deemed not to have active TB, 105 (76%) were immunoassay negative (95% CI 68% to 82%). Of the remaining 24% (34 cases) with a positive immunoassay, a substantial proportion had evidence of untreated TB; in two of these active TB was subsequently diagnosed. Assay performance was unaffected by HIV status, disease site or BCG vaccination. In culture-positive pulmonary cases, response to PPD was more sensitive than nucleic acid amplification testing (94% vs 73%). The use of early secretory antigen target-6 (ESAT-6) responses in 71 subjects was no better than PPD, and 19% of those with culture-confirmed TB and a positive PPD immunoassay had no detectable response to ESAT-6.
These findings suggest that lung-orientated immunological investigation is a potentially powerful tool in diagnosing individuals with sputum smear-negative active TB, regardless of HIV serostatus.
Thorax 01/2008; 63(1):67-71. · 6.84 Impact Factor
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ABSTRACT: The aims of the study were (i) to investigate the prevalence of overt and subclinical thyroid disease in HIV-positive patients in a London teaching hospital; (ii) to determine risk factors associated with the development of thyroid dysfunction, including highly active antiretroviral therapy (HAART) and individual antivirals, and (iii) to determine the occurrence of thyroid dysfunction longitudinally over 3 years.
The study consisted of retrospective analyses of thyroid function tests (TFT) in HIV-positive patients. The period prevalence of and factors associated with clinical and subclinical thyroid dysfunction were investigated. Patients with normal TFT but previous thyroid disease were identified from pharmacy records and included in the overt category.
A total of 1565 patients (73% of the clinic population) had at least one TFT taken since 2001. Overall, 3584 samples were analysed. Of the patients included in the study, 1233 (79%) were male, 1043 (66%) were white and 365 (23%) were black African, and in 969 (62%) the main risk for HIV was homosexual sex. Median age at baseline was 37 years. Nine hundred patients (58%) were on HAART at the start of the study. Thirty-nine (2.5%) were found to have overt hypothyroidism, and eight (<1%) had overt hyperthyroidism. Sixty-one (4%) had subclinical hypothyroidism, five (<1%) had subclinical hyperthyroidism and 263 (17%) had a nonthyroidal illness. A normal TFT was obtained for 1118 patients (75.5%). Multivariate analysis suggested that no independent variables were significantly associated with overt hypothyroidism, including HAART and stavudine use specifically. Repeated measurements over 3 years were available for 825 patients and only eight new cases (1%) of overt thyroid disease occurred.
The prevalence of overt thyroid disease was low in this cohort, suggesting that screening is not warranted.
HIV Medicine 01/2007; 8(1):22-7. · 3.01 Impact Factor
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ABSTRACT: The aims of the study were to describe gender differences in haemoglobin and albumin and to investigate the prognostic value of these measurements in relation to highly active antiretroviral therapy (HAART).
Anaemia was defined as haemoglobin <13.5 g/dL for men and <11.5 g/dL for women. Albumin <35 g/L was defined as hypoalbuminaemia. Proportional hazards models were used to describe relationships between these markers and HIV progression and death.
A total of 291 patients had pre-HAART and 1-year measurements. Mean haemoglobin and albumin levels pre-HAART were lower in women than in men (haemoglobin: 11.2 vs 13.2 g/dL, respectively, P<0.0001; albumin: 37.4 vs 40.2 g/L, respectively, P<0.0001), and a higher proportion of women were anaemic and hypoalbuminaemic compared with men. Despite a rise in both markers in the first year on HAART, mean haemoglobin levels remained lower by 2.08 g/dL (P<0.0001) and albumin by 2.88 g/L (P<0.0001) in women. In the 495 patients included in this analysis, haemoglobin and albumin levels were both significantly related to short-term risk of AIDS and death independently of CD4 count [hazards ratio (HR)=0.73/g/dL higher haemoglobin, 95% confidence interval (CI) 0.55-0.82, P<0.0001 and HR=0.87/g/L higher albumin, 95% CI 0.83-0.91, P<0.0001]. The prognostic value did not differ by gender.
Women were more likely to be anaemic and/or hypoalbuminaemic pre-HAART, but post-HAART increases were similar to those in men. Both haemoglobin and albumin were strong independent prognostic factors for risk of AIDS and death, regardless of gender.
HIV Medicine 01/2007; 8(1):38-45. · 3.01 Impact Factor
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ABSTRACT: To describe outcomes in patients starting first-line antiretroviral regimens including lopinavir/ritonavir (LPV/r) in a routine clinic setting.
Previously naïve patients starting LPV/r-containing antiretroviral therapy were included in the study. Virological failure was defined as the first of two viral loads >500 HIV-1 RNA copies/mL more than 6 months after starting LPV/r. Cumulative percentages experiencing virological failure were calculated using Kaplan-Meier methods.
A total of 195 individuals had a median follow-up time of 1.7 years. At 48 weeks, 87.9, 77.4 and 71.6% of patients with pretreatment CD4 counts of <50, 50-200 and >200 cells/microL, respectively, remained on LPV/r. By 48, 72 and 96 weeks, 2.2, 3.0 and 5.0% of patients, respectively, had experienced virological failure, ignoring treatment changes but censoring follow-up at discontinuation of all antiretrovirals; these percentages became 24.0, 33.7 and 42.3% when LPV/r discontinuation was considered as virological failure. Censoring those who stopped LPV/r with a viral load <50 copies/mL and considering as virological failures those who stopped LPV/r with a viral load >50 copies/mL gave 12.1, 14.6 and 17.0% virological failure at 48, 72 and 96 weeks, respectively. Median CD4 count increases at 24, 48 and 72 weeks were 167, 230 and 253 cells/microL, respectively.
Few patients experienced virological failure whilst on a LPV/r-based regimen, although it was not uncommon for patients in our clinic with higher baseline CD4 counts to discontinue LPV/r.
HIV Medicine 01/2007; 8(1):55-63. · 3.01 Impact Factor
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R A M Breen,
R F Miller,
T Gorsuch, C J Smith,
A Schwenk,
W Holmes,
J Ballinger,
L Swaden,
M A Johnson,
I Cropley,
M C I Lipman
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ABSTRACT: Serious treatment associated adverse events are thought to occur more frequently in individuals with tuberculosis (TB) who are co-infected with HIV. A study was undertaken to assess the frequency of serious (grade III/IV) adverse events and interruption of anti-TB treatment in the era of effective antiretroviral therapy.
The incidence of serious adverse events was retrospectively compared in 312 individuals treated for TB, 156 of whom were co-infected with HIV.
111 HIV infected individuals (71%) received highly active antiretroviral therapy at the same time as anti-TB treatment. Serious adverse events were recorded in 40% HIV infected and 26% HIV uninfected individuals (p = 0.008). Peripheral neuropathy and persistent vomiting were more common in co-infected patients (p<0.001; p = 0.006), although all cause interruption of anti-TB treatment occurred with similar frequency in the two groups (13% in HIV infected patients and 15% in HIV uninfected patients; p = 0.74). In 85% of HIV infected patients and 87% of HIV uninfected individuals this was due to hepatotoxicity, which typically presented within 2 months of starting treatment. The median delay in restarting treatment was 4 weeks, so most individuals required full TB re-treatment.
Despite a greater rate of serious (grade III/IV) adverse events among HIV infected individuals, discontinuation of anti-TB treatment occurred with a similar frequency in HIV infected and HIV uninfected individuals.
Thorax 09/2006; 61(9):791-4. · 6.84 Impact Factor
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ABSTRACT: We compared 156 human immunodeficiency virus (HIV)-infected patients who had tuberculosis with control populations of similar size. Of 111 patients with HIV infection and tuberculosis who received highly active antiretroviral therapy (HAART) and therapy for tuberculosis concurrently, 92 (83%) achieved or maintained virus loads of <50 copies/mL, and 99 (89%) achieved or maintained a >or=2 log10 reduction in virus load after 6 months. Virological response and changes in CD4 cell count were equivalent to those in 111 matched HIV-infected subjects without tuberculosis starting HAART. Tuberculosis recurrence rates were similar to those found in an HIV-uninfected population of 156 subjects (3% and 1%, respectively). Treatment for HIV and tuberculosis does not compromise outcomes for either disease.
The Journal of Infectious Diseases 06/2006; 193(10):1437-40. · 6.41 Impact Factor
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ABSTRACT: Highly active antiretroviral therapy (HAART) has extended survival of HIV-infected children into adulthood, raising concerns about long-term metabolic changes in childhood.
A longitudinal study of metabolite levels in paediatric HIV-infected patients before and after starting HAART (January 2000 to June 2003). The effects of HAART on nonfasting blood levels of total (TC), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol, cholesterol ratio and lactate were analysed using mixed-effects regression.
A total of 146 children attended 1208 appointments (median 6.7/child). Of these, 99 (68%) were African. At baseline, 75 (51%) were on HAART and had higher TC (4.19 vs 3.49 mmol/L, P<0.0001), HDL (1.03 vs 0.82 mmol/L, P<0.0001), and LDL (2.54 vs 2.11 mmol/L, P=0.0003) than those not on HAART. Metabolites increased with time on HAART exposure and then stabilized. At 2 years, TC had increased by 0.93 mmol/L (P<0.0001), with 29 children (20%) having repeated TC levels above the 95th centile. LDL and HDL had increased by 0.69 and 0.31 mmol/L at 2 years, respectively (both P<0.0001). Lactates declined with increasing age (-0.06 mmol/L/year, P=0.0001).
This is the first cohort study to demonstrate significant elevations of HDL as well as LDL in children on HAART. This rise in cardio-protective HDL may represent a positive effect of treatment.
HIV Medicine 01/2006; 7(1):16-24. · 3.01 Impact Factor
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ABSTRACT: It has been suggested that deterioration of tuberculosis (TB) during appropriate treatment, termed a paradoxical reaction (PR), is more common and severe in HIV positive individuals on highly active antiretroviral therapy (HAART).
A study was undertaken to determine the frequency of PR and its associated features in a population of HIV+TB+ patients and a similar sized group of HIV-TB+ individuals.
PR occurred in 28% of 50 HIV+TB+ patients and 10% of 50 HIV-TB+ patients. Disseminated TB was present in eight of 13 HIV+TB+ patients and four of five HIV-TB+ patients with PR. In 28 HIV+TB+ patients starting HAART, PR was significantly associated with commencing HAART within 6 weeks of starting antituberculosis treatment (p = 0.03) and was more common in those with disseminated TB (p = 0.09). No association was found between development of PR and baseline CD4 count or CD4 response to HAART.
PR is common in HIV infected and uninfected individuals with TB. Early introduction of HAART and the presence of disseminated TB appear to be important in co-infected patients.
Thorax 09/2004; 59(8):704-7. · 6.84 Impact Factor
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ABSTRACT: Although the benefits of antiretroviral therapy (ART) have been dramatic, studies have started to report a variety of drug-related side effects and toxicities. We sought to characterize the risk factors for cardiovascular disease present in an HIV-positive population.
A total of 394 HIV-positive ambulant patients attending the Royal Free Hospital, London, were asked to complete a questionnaire. Questions focused on smoking habits and general health.
In total, 38% of patients were aged >40 years, 37% had a family history of heart disease, 3% had diabetes, 14% suffered from raised blood pressure, 20% had a body mass index (BMI)>26 kg/m3, 7% had an alcohol consumption above the recommended UK limit, and 18% had total cholesterol levels >6.3 mmol/L [corrected]. The rate of smoking observed (45%) was much higher than that observed amongst the general population in the British Health Survey for England (34%). There were significant differences between those receiving and not receiving ART. Those on ART tended to be younger (P<0.0001) and less likely to smoke cigarettes (P=0.06) or have an alcohol consumption above the recommended limit (P=0.08), but were more likely to have diabetes (P=0.05). More patients receiving ART reported, and so perceived themselves to have, raised blood fats (P<0.0001). This was confirmed when considering blood lipid levels, where those on ART had significantly raised total cholesterol levels compared to those not currently receiving ART (P<0.0001).
We have demonstrated an excess of cardiovascular risk factors in this cohort. These issues must be addressed if we wish to maintain the benefit of treating HIV infection.
HIV Medicine 03/2004; 5(2):88-92. · 3.01 Impact Factor
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ABSTRACT: Use of dideoxynucleoside reverse transcriptase inhibitors (dNRTIs) may lead to increased mitochondrial toxicity. We compared nucleoside reverse transcriptase inhibitor (NRTI) use as part of antiretroviral therapy (ART) in two HIV clinics: one in a low-middle income (HIV Centre Belgrade [HCB], Serbia) and one a high income (ICDC, Royal Free Hospital, London, UK) country.
Antiretroviral naïve patients starting ART from 2003 to 2005 were included. Specific NRTIs were compared between centers, focusing on dNRTI use. Kaplan-Meier estimates of the percentage of patients making changes to their NRTI backbone (a) for any reason or (b) for mitochondrial toxicity (peripheral neuropathy, pancreatitis, lactic acidosis) were calculated.
Of 287 HCB patients, 89 (31.0%) received didanosine (ddI)-containing, 39 (13.6%) stavudine (d4T)-containing, and 39 (13.6%) ddI+d4T-containing regimens; for 539 ICDC patients, these were 18 (3.3%), 66 (12.2%), and 0 (0.0%), respectively (p < .0001). After 12 months, 57.5% and 52.6% at HCB and ICDC had switched their NRTI backbone. This was reduced to 34.5% at HCB after excluding changes due to drug supply interruption and to 11.2% and 1.3% at HCB and ICDC after changes were made for mitochondrial-related reasons. At 6 months, 73/80 (91.3%) and 385/488 (78.9%) had viral load below 50 copies/mL at HCB and ICDC, respectively.
Patients treated at HCB faced higher levels of mitochondrial-related toxicity, likely due to greater dNRTI use.
HIV Clinical Trials 10(5):306-13. · 1.64 Impact Factor
