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.

Response to efavirenz-containing regimens in previously antiretroviral-naive HIV-positive patients: the role of gender.

BACKGROUND: We investigated the role of gender on response to efavirenz (EFV)-containing regimens in previously antiretroviral-naive patients. METHODS: All previously antiretroviral-naive individuals from the Royal Free Hospital in London starting EFV from 1996 onward were included. Treatment failure was defined as the first of 2 consecutive viral load measurements >500 copies/mL more than 24 weeks after starting EFV. Standard survival methods were used to assess time to discontinuation and to treatment failure. RESULTS: Ninety-six women and 337 men were included. Women were mostly of black African ethnicity (64.6%) with a heterosexual risk (94.8%), whereas men were mostly white (66.8%; P < 0.0001) with a homosexual risk (71.2%; P < 0.0001). Women had lower CD4 counts when starting EFV (median [interquartile range [IQR] = 126 [36, 220] cells/mm for women vs. 190 [109, 268] cells/mm for men; P = 0.0003). After 48 and 96 weeks, 38.8% (95% confidence interval [CI]: 28.8% to 48.7%) and 56.3% (95% CI: 45.8% to 66.9%) of women had discontinued EFV compared with 28.3% (95% CI: 23.4% to 33.2%) and 41.8% (95% CI: 36.3% to 47.3%) of men (P = 0.005). The percentage experiencing failure by 48 and 96 weeks when ignoring treatment changes but censoring at the date of discontinuing all treatment was 1.3% (0.0%, 3.9%) and 4.4% (0.0%, 9.3%) for women compared with 3.8% (1.6%, 6.0%; P = 0.49) and 5.8% (3.0%, 8.6%) for men. Median (IQR) CD4 count increases at 48 weeks were +166 (+89, +239) cells/mm for women and +176 (+93, +263) cells/mm for men. CONCLUSIONS: Women seem to have comparable virologic and immunologic outcomes to first-line EFV-containing regimens compared with men, although they are more likely to discontinue the drug.

Treatment exhaustion of highly active antiretroviral therapy (HAART) among individuals infected with HIV in the United Kingdom: multicentre cohort study.

OBJECTIVES: To investigate whether there is evidence that an increasing proportion of HIV infected patients is starting to experience increases in viral load and decreases in CD4 cell count that are consistent with exhaustion of available treatment options. DESIGN: Multicentre cohort study. SETTING: Six large HIV treatment centres in southeast England. PARTICIPANTS: All individuals seen for care between 1 January 1996 and 31 December 2002. MAIN OUTCOME MEASURES: Exposure to individual antiretroviral drugs and drug classes, CD4 count, plasma HIV RNA burden. RESULTS: Information is available on 16,593 individuals (13,378 (80.6%) male patients, 10,340 (62.3%) infected via homosexual or bisexual sex, 4426 (26.7%) infected via heterosexual sex, median age 34 years). Overall, 10,207 of the 16,593 patients (61.5%) have been exposed to any antiretroviral therapy. This proportion increased from 41.2% of patients under follow up at the end of 1996 to 71.3% of those under follow up in 2002. The median CD4 count and HIV RNA burden of patients under follow up in each year changed from 270 cells/mm3 and 4.34 log10 copies/ml in 1996 to 408 cells/mm3 and 1.89 log10 copies/ml, respectively, in 2002. By 2002, 3060 (38%) of patients who had ever been treated with antiretroviral therapy had experienced all three main classes. Of these, around one quarter had evidence of "viral load failure" with all these three classes. Patients with three class failure were more likely to have an HIV RNA burden > 2.7 log10 copies/ml and a CD4 count < 200 cells/mm3. CONCLUSIONS: The proportion of individuals with HIV infection in the United Kingdom who have been treated has increased gradually over time. A substantial proportion of these patients seem to be in danger of exhausting their options for antiretroviral treatment. New drugs with low toxicity, which are not associated with cross resistance to existing drugs, are urgently needed for such patients.

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.