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Andrew N Phillips

Publications and source records attributed to Andrew N Phillips.

At least 37 records · Page 2Linked to original sources
PubMed2005

The relationship between CD4 cell count nadirs and the toxicity profiles of antiretroviral regimens.

BACKGROUND: It has been suggested that a lower pre-highly active antiretroviral therapy (HAART) CD4 count nadir may lead to a greater risk of experiencing HAART-related toxicity. We investigated the relationship between the pre-HAART CD4 count nadir, HAART and the occurrence of laboratory-defined toxicities. METHODS: Previously antiretroviral-naive individuals starting HAART at the Royal Free Hospital, London, UK, were included. Drug discontinuation, increases in total cholesterol (by > 1 mmol/l), alanine aspartate transferase/ alanine aminotransferase (AST/ALT) (by >2.5 times the upper limit of normal), bilirubin (by > 2.5 times the upper limit of normal), triglycerides (by > 1 mmol/l) and decreases in haemoglobin (by > 2 g/dl) were assessed. RESULTS: 377/847 (45%) individuals starting HAART stopped at least one antiretroviral within the first 48 weeks. Lower CD4 nadirs were not associated with a greater rate of discontinuing antiretrovirals (adjusted hazard ratio (HR)=1.04 per 100 cells/mm3 higher; 95% confidence intervals (CI) 0.99 - 1.10; P = 0.15). 70/297 (24%), 39/192 (20%) and 73/358 (20%) with a CD4 cell nadir of 0-100, 100-200 and 200+ cells/mm3, respectively, stopped for toxicity reasons; 11/297 (4%), 5/192 (3%) and 3/358 (11%) stopped for reasons of insufficient efficacy; 63/297 (21%), 33/192 (17%) and 80/358 (22%) stopped for other reasons (P = 0.1). Reasons for stopping were similar between CD4 nadir groups. Lower CD4 nadirs were not associated with an increased risk of hypercholesterolaemia, anaemia, hypertriglyceridaemia or increases in AST/ALT but were associated with increased incidence of hyperbilirubinaemia (HR=0.67 per 100 cells/mm3 higher; 95% CI 0.49-0.92; P = 0.01). DISCUSSION: Lower CD4 nadirs were not found to be associated either with discontinuing an antiretroviral or with a higher risk of toxicity, except for an increased risk of experiencing an increase in bilirubin levels.

Antiretroviral Therapy, Highly Active↗
PubMed2005

Are specific antiretrovirals associated with an increased risk of discontinuation due to toxicities or patient/physician choice in patients with hepatitis C virus coinfection?

BACKGROUND: Liver damage associated with hepatitis C (HCV) may influence the likelihood of experiencing discontinuation due to toxicities or patient/physician choice (TOXPC) in patients taking combination antiretroviral therapy (cART). Little information to address this concern is available from clinical trials as patients with HCV are often excluded. AIMS: To compare incidence rates of discontinuation due to TOXPC associated with specific antiretrovial drugs in patients with or without HCV. PATIENTS/METHODS: A total of 4929 patients from EuroSIDA under follow-up from January 1999 on a specific nucleoside pair (zidovudine/lamivudine, didanosine/stavudine, stavudine/lamivudine, or other) with a third drug (abacavir, nelfinavir, indinavir, nevirapine, efavirenz, lopinavir/ritonavir or other boosted-protease inhibitor (PI)-containing regimen) and with known HCV serostatus were studied for the incidence of discontinuation of any nucleoside pair or third drug due to TOXPC. Incidence rate ratios were derived from Poisson regression models. RESULTS: In total 1358 patients had HCV (27.5%). During 12 799 person-years of follow-up there were 2141 discontinuations due to TOXPC for nucleoside pairs and 2501 for third drugs. The incidence of discontinuation due to TOXPC was consistently higher in patients with HCV after stratification by nucleoside pair or third drug. After adjustment for CD4+ count, gender, exposure group, time on HAART, region and treatment regimen, there were few differences in the rate of discontinuation due to TOXPC in those with HCV compared with those without for any nucleoside pairs or third drugs. Similar results were seen when concentrating on discontinuation due to toxicities alone. CONCLUSIONS: Although patients with HCV generally had higher rates of discontinuation due to TOXPC compared with patients without HCV, there was little evidence to suggest that this was associated with any specific nucleoside pair or third drug used as part of cART. Our results do not suggest that any specific component of cART is more poorly tolerated in patients with HCV or that the presence of HCV should influence the choice between antiretrovirals used as part of a cART regimen.

Anti-HIV Agents↗
PubMed2005

Thymidine analogue mutation profiles: factors associated with acquiring specific profiles and their impact on the virological response to therapy.

BACKGROUND: Studies have suggested that HIV-1 may develop thymidine analogue mutations (TAMs) by one of two distinct pathways - the TAM1 pathway (including mutations 41L, 210W and 215Y) or the TAM2 pathway (including mutations 67N, 70R and 219E/Q) - under the pressure of a not fully suppressive thymidine-analogue-containing regimen. METHODS: Frozen plasma samples stored in the EuroSIDA repository were selected and sent to two central laboratories for genotypic analysis. We considered 733 patients with at least one genotypic test showing > or =1 TAMs (the first of these tests in chronological order was used). TAM1 and TAM2 genotypic profiles were defined in accordance with previous literature. Statistical modelling involved logistic regression and linear regression analysis for censored data. RESULTS: The observed frequencies of patterns classifiable as TAM1 or TAM2 profiles were markedly higher than the probabilities of falling into these classifications by chance alone. The chance of detecting a TAM2 profile increased by 25% per additional year of exposure to zidovudine. We found that mutations 67N and 184V were not associated with a particular TAM profile. In the presence of TAM2 profiles, the adjusted mean difference in the 6-month viral reduction was 0.96 log10 copies/ml (95% confidence interval: 0.20; 1.73) higher in patients who started stavudine-containing regimens instead of zidovudine-containing regimens. CONCLUSIONS: This study provides evidence that the suggested TAM clustering is a real phenomenon and that it may be driven by which thymidine analogue the patients has used. In patients with TAM2-resistant viruses, stavudine appears to retain greater viral activity than zidovudine.

Anti-HIV Agents↗
PubMed2004

Causes of death in HIV infection: the key determinant to define the clinical response to anti-HIV therapy.

Studies have shown an increased risk of new AIDS/death among injecting drug users (IDU) starting highly active antiretroviral therapy (HAART). Of 3872 patients starting HAART in the EuroSIDA study, 819 were IDU (21.2%). During 14 769 person-years of follow-up, 499 patients progressed to new AIDS/death. Compared with homosexual individuals, IDU had an increased incidence of new AIDS/death, but only for non-HIV deaths. There is an urgent need to define and standardize causes of death in observational studies.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Late presenters in the era of highly active antiretroviral therapy: uptake of and responses to antiretroviral therapy.

OBJECTIVES: To investigate the characteristics and clinical, immunological and virological outcomes for individuals presenting for care with low CD4 cell counts. METHODS: Individuals aged > 16 years presenting for care for the first time were identified between 1 January 1996 and 31 December 2002. Late presenters were those with CD4 cell count < 50 x 10(6) cells/l. Follow-up was until last contact, death or 31 December 2002. RESULTS: Late presenters formed 15.3% (110) of the group; they were more likely to be female (35% versus 24%), heterosexual (53% versus 38%), and of Black-African ethnicity (39% versus 27%) than other individuals. Over a median follow-up of 2.5 years, 13% of late presenters died. Ninety-nine patients started antiretroviral treatment; Of the 11 patients who did not start antiretroviral treatment, eight died within 3 months of presentation. Among those starting treatment, 87 (87.9%) achieved a viral load < 400 copies/ml and median CD4 cell counts increased from 43 x 10(6) cells/l at 0-2 months after presentation to 204 x 10(6) cells/l at 1 year. Over the first year, 71 patients attended at least one outpatient visit (median, 4.5; range, 0-39), 21 attended at least one day case visit (median, 0; range, 0-15) and 49 were admitted as an inpatient (median, 0; range, 0-4). CONCLUSIONS: Those presenting for care with very low CD4 cell counts may make large demands on clinical resources, particularly over the first few months. While some patients do have a poor outcome on highly active antiretroviral therapy, many will benefit from this therapy and will experience good immunological and virological responses.

Adolescent↗
PubMed2004

Factors influencing increases in CD4 cell counts of HIV-positive persons receiving long-term highly active antiretroviral therapy.

BACKGROUND: Highly active antiretroviral therapy (HAART) results in an improvement in immunologic function. We sought to investigate the factors associated with increases in CD4 cell count among human immunodeficiency virus (HIV)-positive antiretroviral-naive patients starting HAART. METHODS: Five hundred ninety-six subjects were followed for a median of 2.5 years (interquartile range, 1.0-4.0 years). Factors associated with changes in CD4 cell counts in the first 3 months of HAART and from 3 months onwards were analyzed. RESULTS: After 6, 12, and 24 months of HAART, the median increases in CD4 cell counts were 114, 181, and 248 cells/mm3, respectively; 84%, 84%, and 80% of subjects had a virus load of <400 copies/mL during the same periods. White ethnicity, higher pre-HAART virus load, and lower pre-HAART CD4 and CD8 cell counts were associated with greater increases in CD4 cell counts during the first 3 months of HAART. From 3 months onward, a greater cumulative proportion of time spent with virus load <400 copies/mL was associated with a more favorable change in CD4 cell count (an average increase of 5.2 cells/mm3/year [95% confidence interval [CI], 3.8-6.7 cells/mm3/year] for each extra 10% cumulative time spent with a virus load <400 copies/mL) (P<.0001). For every 100 cells/mm3 higher in baseline CD4 cell count, the increase was 6 cells/mm3/year less (95% CI, 2-11 cells/mm3/year) (P=.02). Sex, risk group, age, and HAART regimen were not associated with increases in CD4 cell counts. CONCLUSIONS: These findings emphasize the importance of maintaining virological suppression and suggest other factors that influence long-term CD4 cell response.

Age Factors↗
PubMed2004

Rate of viral rebound according to specific drugs in the regimen in 2120 patients with HIV suppression.

BACKGROUND: It is currently unclear whether the tendency for viral rebound in patients with viral load < 50 copies/ml differs according to the specific drug regimen being used. METHODS: To follow 2120 patients in EuroSIDA who had attained < 50 copies/ml on highly active antiretroviral therapy (HAART), without previously virologically failing HAART. RESULTS: The rate of viral rebound (two consecutive values > 400 copies/ml) was 4.9/100 person-years [95% confidence interval (CI), 4.0-5.8] for patients who were naive pre-HAART and 8.0/100 person-years (95% CI, 7.0-9.0) for those who were experienced with nucleoside analogue reverse transcriptase inhibitors (NRTI) pre-HAART. The rate of rebound was significantly higher in those taking nelfinavir than in those taking efavirenz, both in patients who were naive pre-HAART and those who were NRTI experienced [adjusted rate ratios, 2.83 (95% CI, 1.51-5.31) and 2.86 (95% CI, 1.65-5.00), respectively]. Among patients who were naive pre-HAART, those on abacavir had no evidence of a raised risk of viral rebound (adjusted rate ratio 1.17; 95% CI, 0.51-2.69), but in those with pre-HAART NRTI experience the rate was markedly raised (adjusted rate ratio, 4.48; 95% CI, 2.51-8.00). A similar picture was seen when comparing those on nevirapine with those on efavirenz, although the elevated rate ratio in pre-HAART experienced patients was of lower magnitude (adjusted rate ratio, 1.93). There was no strong evidence that rebound rates differed significantly for any NRTI pairs compared with zidovudine/lamivudine. CONCLUSION: Viral rebound rates in patients who have attained < 50 copies/ml appear to differ according to the specific drugs being used.

Adult↗
PubMed2004

Use of viral load measured after 4 weeks of highly active antiretroviral therapy to predict virologic outcome at 24 weeks for HIV-1-positive individuals.

Early prediction of suboptimal viral response to highly active antiretroviral therapy (HAART) is vital to prevent early development of drug resistance. We used logistic regression to predict the odds of achieving virologic suppression (<50 copies/mL) after 24 weeks of HAART in 656 antiretroviral-naive patients starting HAART at the J.W. Goethe University, Chelsea and Westminster, and Royal Free Hospitals according to their week 4 viral load. Therapy changes involving the switch of a single antiretroviral were assumed to have occurred for toxicity reasons and ignored. Because complete regimen changes or additions of new antiretrovirals could be due to virologic failure, patients were counted as virological failures at week 24. Three hundred sixty (84%) of 430 patients with viral loads of <1000 copies/mL, 106 (61%) of 175 with viral loads between 1001 and 10,000 copies/mL, 11 (37%) of 30 with viral loads between 10,001 and 100,000 copies/mL, and 5 (24%) of 21 with viral loads of >100,000 copies/mL at week 4 subsequently attained virologic suppression at 24 weeks. The odds of attaining virologic suppression at 24 weeks was 65% lower for every 1-log higher viral load at week 4 (odds ratio, 0.35; 95% confidence interval, 0.27-0.45). The proportion of patients with an undetectable viral load at 24 weeks among those who have not attained a viral load of <1000 copies/mL by 4 weeks is quite low. We suggest that this group of patients should be particularly closely monitored.

Adult↗
PubMed2004

The changing pattern of Kaposi sarcoma in patients with HIV, 1994-2003: the EuroSIDA Study.

BACKGROUND: The introduction of highly active antiretroviral therapy (HAART) has radically changed the clinical course of human immunodeficiency virus (HIV) infection. The goals of the current study were to assess the change in the incidence of Kaposi sarcoma (KS) among European patients with HIV since the introduction of HAART and to identify the factors associated with the development of KS among patients receiving HAART. METHODS: The incidence of KS and the factors associated with the development of this malignancy in patients receiving HAART were evaluated using Poisson regression. Patients examined in the current study were among the 9803 individuals with HIV who were enrolled in the EuroSIDA study, a pan-European multicenter investigation. RESULTS: There was an estimated annual reduction of 39% (95% confidence interval [CI], 35-43%; P < 0.0001) in the incidence of KS between 1994 and 2003. The proportion of acquired immunodeficiency syndrome (AIDS) diagnoses made due to KS during prospective follow-up ranged from 4.1% to 7.5%, and there was no significant change over time in this figure (P = 0.97). Four thousand fourteen patients began receiving HAART during prospective follow-up; 41 of these 4014 were subsequently diagnosed with KS (1.0%). After adjustment in multivariate analyses, patients with higher current CD4 counts were found to have a decreased incidence of KS (incidence rate ratio [IRR], 0.60; 95% CI, 0.53-0.68; P < 0.0001), as were those for whom more time had elapsed since the initiation of HAART (IRR, 0.77; 95% CI, 0.60-0.98; P = 0.037). In contrast, homosexual men were found to have a significantly increased incidence of KS (IRR, 2.12; 95% CI, 1.00-4.54; P = 0.050) CONCLUSIONS: The current incidence of KS among patients with HIV is less than 10% of the incidence reported in 1994; the proportion of AIDS diagnoses made on the basis of KS diagnoses remains near 6%. Most individuals who developed KS while receiving HAART began treatment with low CD4 cell counts and developed KS within 6 months of the initiation of HAART. There continues to be an increased incidence of KS among homosexual men and a greatly reduced incidence of KS among patients with higher CD4 counts.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Baseline resistance and virological outcome in patients with virological failure who start a regimen containing abacavir: EuroSIDA study.

OBJECTIVES: To investigate the ability of several HIV-1 drug-resistance interpretation systems, as well as the number of pre-specified combinations of abacavir-related mutations, to predict virological response to abacavir-containing regimens in antiretroviral therapy-experienced, abacavir-naive patients starting an abacavir-containing regimen in the EuroSIDA cohort. PATIENTS AND METHODS: A total of 100 HIV-infected patients with viral load (VL) >500 copies/ml who had a plasma sample available at the time of starting abacavir (baseline) were included. Resistance to abacavir was interpreted by using eight different commonly used systems that consisted of rules-based algorithms or tables of mutations. Correlation between baseline abacavir-resistance mutations and month 6 virological response was performed on this population using a multivariable linear regression model accounting for censored data. RESULTS: The baseline VL was 4.36 log10 RNA copies/ml [interquartile range (IQR): 3.65-4.99 log10 RNA copies/ml] and the median CD4 cell count was 210 cells/microl (IQR: 67-305 cells/microl). Our patients were pre-exposed to a median of seven antiretrovirals (2-12) before starting abacavir therapy. The median (range) number of abacavir mutations (according to the International AIDS Society-USA) detected at baseline was 3.5 (0-8). Overall, the Kaplan-Meier estimate of the median month 6 VL decline was 0.86 log10 RNA copies/ml [95% confidence intervals (95% CI): 0.45-1.24]. The VL in those patients (n=31) who intensified treatment by adding only abacavir decreased by a median 0.20 log10 RNA copies/ml (95% CI: -0.18; +0.94). The proportion of patients who harboured viruses fully resistant to abacavir among the eight genotypic resistance interpretation algorithms ranged from 12% [Agence Nationale de Recherches sur le SIDA (ANRS)] to 79% [Stanford HIV RT and PR Sequence Database (HIVdb)]. Some interpretation systems showed statistically significant associations between the predicted resistance status and the virological response while others showed no consistent association. The number of active drugs in the regimen was associated with greater virological suppression (additional month 6 VL reduction per additional sensitive drug=0.51, 95% CI: 0.15-0.88, P=0.006); baseline VL was also weakly associated (additional month 6 VL reduction per log10 higher=0.30, 95% CI: -0.02; +0.62, P=0.06). In contrast, the number of drugs previously received was associated with diminished viral reduction (additional month 6 VL reduction per additional drug=-0.14, 95% CI: -0.28; 0.00, P=0.05). CONCLUSIONS: Our results revealed a high degree of variability among several genotypic resistance interpretation algorithms currently in use for abacavir. Therefore, the interpretation of genotypic resistance for predicting response to regimens containing abacavir remains a major challenge.

Adult↗
PubMed2003

Combination antiretroviral therapy and the risk of myocardial infarction.

BACKGROUND: It remains controversial whether exposure to combination antiretroviral treatment increases the risk of myocardial infarction. METHODS: In this prospective observational study, we enrolled 23,468 patients from 11 previously established cohorts from December 1999 to April 2001 and collected follow-up data until February 2002. Data were collected on infection with the human immunodeficiency virus and on risk factors for and the incidence of myocardial infarction. Relative rates were calculated with Poisson regression models. Combination antiretroviral therapy was defined as any combination regimen of antiretroviral drugs that included a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor. RESULTS: Over a period of 36,199 person-years, 126 patients had a myocardial infarction. The incidence of myocardial infarction increased with longer exposure to combination antiretroviral therapy (adjusted relative rate per year of exposure, 1.26 [95 percent confidence interval, 1.12 to 1.41]; P<0.001). Other factors significantly associated with myocardial infarction were older age, current or former smoking, previous cardiovascular disease, and male sex, but not a family history of coronary heart disease. A higher total serum cholesterol level, a higher triglyceride level, and the presence of diabetes were also associated with an increased incidence of myocardial infarction. CONCLUSIONS: Combination antiretroviral therapy was independently associated with a 26 percent relative increase in the rate of myocardial infarction per year of exposure during the first four to six years of use. However, the absolute risk of myocardial infarction was low and must be balanced against the marked benefits from antiretroviral treatment.

Adult↗
PubMed2003

Access to antiretroviral treatment, incidence of sustained therapy interruptions, and risk of clinical events according to sex: evidence from the I.Co.N.A. Study.

Objectives of the study were to assess the differences between sexes in the likelihood of starting antiretroviral therapy (ART), in rates of sustained discontinuation from highly active antiretroviral therapy (HAART), and in clinical progression. In a multicenter cohort study (I.Co.N.A. Study), 2323 men and 1335 women previously naive to antiretrovirals were enrolled. As of September 2002, 807 women and 1480 men started ART. The median time to starting ART was 28 weeks for women and 17 weeks for men (P = 0.0003 by log-rank test). This difference was no longer significant after adjusting for either HIV RNA (P = 0.21) or CD4 count (P = 0.28) at enrollment. Women tend to start HAART less frequently than mono/dual ART after adjusting for potential confounders (odds ratio = 0.78, 95% confidence interval [CI]: 0.60-1.01; P = 0.06). Women who started HAART were 1.4 times more likely than men (95% CI: 1.00-1.99; P = 0.05) to interrupt at least 1 drug because of toxicity. Twenty-one percent of women and 19% of men interrupted HAART altogether for more than 3 months (P = 0.3). Clinical progression was observed in 53 women (22.6%) and 137 men (23.4%; P = 0.56). Risk of developing a clinical event was found to be no different between women and men (relative hazard = 0.84, 95% CI: 0.56-1.26; P = 0.40).

Acquired Immunodeficiency Syndrome↗
PubMed2003

Virological rebound after suppression on highly active antiretroviral therapy.

OBJECTIVE To determine the rate of virological rebound and factors associated with rebound among patients on highly active antiretroviral therapy (HAART) with previously undetectable levels of viraemia. DESIGN An observational cohort study of 2444 patients from the EuroSIDA study. METHODS Patients were followed from their first viral load under 400 copies/ml to the first of two consecutive viral loads above 400 copies/ml. Incidence rates were calculated using person-years of follow-up (PYFU), Cox proportional hazards models were used to determine factors related to rebound. RESULTS Of 2444 patients, 1031 experienced virological rebound (42.2%). The incidence of rebound decreased over time; from 33.5 in the first 6 months after initial suppression to 8.6 per 100 PYFU at 2 years after initial suppression (P < 0.0001). The rate of rebound was lower for treatment-naive compared with treatment-experienced patients. In multivariate models, patients who changed treatment were more likely to rebound, as were patients with higher viral loads on starting HAART. Treatment-naive patients were less likely to rebound. Among pretreated patients, those who were started on new nucleosides were less likely to rebound. CONCLUSION The rate of virological rebound decreased over time, suggesting that the greatest risk of treatment failure is in the months after initial suppression. Treatment-naive patients were at a lower risk of rebound, but among drug-experienced patients, those who added new nucleosides had a lower risk of rebound, as were patients with a good immunological response.

Adult↗
PubMed2003

Cardiovascular disease risk factors in HIV patients--association with antiretroviral therapy. Results from the DAD study.

OBJECTIVE: To determine the prevalence of risk factors for cardiovascular disease (CVD) among HIV-infected persons, and to investigate any association between such risk factors, stage of HIV disease, and use of antiretroviral therapies. DESIGN: Baseline data from 17,852 subjects enrolled in DAD, a prospective multinational cohort study initiated in 1999. METHODS: Cross-sectional analyses of CVD risk factors at baseline. The data collected includes data on demographic variables, cigarette smoking, diabetes mellitus, hypertension, dyslipidaemia, body mass index, stage of HIV infection, antiretroviral therapy. RESULTS: Almost 25% of the study population were at an age where there is an appreciable risk of CVD, with those receiving a protease inhibitor (PI) and/or non-nucleoside reverse transcriptase inhibitor (NNRTI) tending to be older. 1.4% had a previous history of CVD and 51.5% were cigarette smokers. Increased prevalence of elevated total cholesterol (> or = 6.2 mmol/l) was observed among subjects receiving an NNRTI but no PI [odds ratio (OR), 1.79; 95% confidence interval (CI), 1.45-2.22], PI but no NNRTI (OR, 2.35; 95% CI, 1.92-2.87), or NNRTI + PI (OR, 5.48; 95% CI, 4.34-6.91) compared to the prevalence among antiretroviral therapy (ART)-naive subjects. Subjects who have discontinued ART as well as subjects receiving nucleoside reverse transcriptase inhibitors had similar cholesterol levels to treatment-naive subjects. Higher CD4 cell count, lower plasma HIV RNA levels, clinical signs of lipodystrophy, longer exposure times to NNRTI and PI, and older age were all also associated with elevated total cholesterol level. CONCLUSION: HIV-infected persons exhibit multiple known risk factors for CVD. Of specific concern is the fact that use of the NNRTI and PI drug classes (alone and especially in combination), particularly among older subjects with normalized CD4 cell counts and suppressed HIV replication, was associated with a lipid profile known to increase the risk of coronary heart disease.

Adult↗