Viral efficacy maintained and safety parameters improved with a reduced dose of stavudine: a pilot study.

OBJECTIVES: Stavudine (d4T) is a potent but potentially toxic nucleoside reverse transcriptase inhibitor that is still widely used in developing countries. This study's aim was to determine the efficacy and safety profile of lower-dose d4T. METHODS: Multi-centre, open-label, single-arm, pilot, 48-week study in French patients weighing >60 kg with viral load <400 HIV-1 RNA copies/mL who were receiving d4T 40 mg twice daily and then switched to 30 mg twice daily. The primary endpoint was the proportion with plasma viral load <400 copies/mL at week 24. Secondary endpoints included the proportion with <50 copies/mL at weeks 24 and 48, changes in mitochondrial DNA, CD4 cell count and pharmacokinetics, and clinical and laboratory safety. RESULTS: Fifty-seven patients enrolled. Baseline CD4 count was 584 cells/microL; viral loads were <400 copies/mL and <50 copies/mL in 100% and 89%, respectively. Prior antiretroviral drug exposure was 6.9 years, d4T exposure was 6.3 years. Fifty-six out of 57 (98%) patients had viral load <400 copies/mL and 51 (89%) had viral load <50 copies/mL at week 24. Median CD4 count increased by 63 cells/microL at week 48 (P=0.006). At 48 weeks, total cholesterol decreased by 0.24 mmol (P=0.02), high-density lipoprotein cholesterol by 0.15 mmol (P=0.0001) and alanine aminotransferase by 5.74 mg/dL (P=0.01). Paired baseline DNA and week 24 RNA mutations were unchanged. Mitochondrial DNA (copies/cell) content increased from 672+/-254 to 682+/-269. d4T area under the plasma concentration time curve (AUC) decreased by 31% (P=0.003) and C(max) by 44% (P=0.004). Clinical and laboratory parameters improved or were unchanged. CONCLUSIONS: Reduced-dose d4T is effective with improved safety parameters.

GENOPHAR: a randomized study of plasma drug measurements in association with genotypic resistance testing and expert advice to optimize therapy in patients failing antiretroviral therapy.

OBJECTIVES: To evaluate the benefits of therapeutic drug monitoring (TDM) in association with genotypic resistance testing and expert advice to optimize therapy in multiexperienced patients infected with HIV-1. METHODS: Patients with a viral load>1000 HIV-1 RNA copies/mL and an unchanged antiretroviral therapy regimen over the last 3 months were randomized into two groups: a genotypic group (G) and a geno-pharmacological group (GP). Treatment was selected by an expert committee according to genotypic resistance testing (the G and GP groups) and TDM (the GP group) at week 4. Treatment could be modified at each visit according to toxicity, poor virological response and TDM. Results of TDM were withheld from the G group until week 12. The primary endpoint of the study was the percentage of patients with viral load<200 copies/mL at week 12. RESULTS: A total of 134 patients were randomized in the study, with 67 in each group, and included in the intent-to-treat (ITT) analysis. At baseline, median values were as follows: viral load (log(10) copies/mL): G=4.1, GP=4.0; CD4 cell count (cells/microL): G=292, GP=294; and number of prior drugs: G=7, GP=8. The median number of resistance mutations was five in the G group [nucleoside reverse transcriptase inhibitors (NRTIs)=three; non-nucleoside reverse transcriptase inhibitors (NNRTIs)=one; protease inhibitors (PI)=one] and seven in the GP group (NRTI=four; NNRTI=two; PI=one). At week 8, treatment was adjusted according to the TDM in 13 of the 67 patients in the GP group (19%). By ITT missing equal failure analysis at week 12, and after only one intervention according to plasma concentration results, a viral load<200 copies/mL was achieved in 30 of the 67 patients (45%) in the G group and in 29 of the 67 patients (43%) in the GP group (not significant). In the multivariate analysis, only prior exposure to at least two PIs at baseline gave a poor response to subsequent antiretroviral therapy. At week 24, a viral load<200 copies/mL was achieved in 35 of the 67 patients (52%) in the G group and in 40 of the 67 patients (60%) in the GP group. CONCLUSIONS: A statistically significant benefit of using TDM was not found in this short-term study where patients appeared to be adherent. However, combining genotypic resistance testing with the use of an expert committee to monitor subsequent therapy individually in patients with multiple resistance mutations was associated with high antiviral efficacy.

Long-lasting recovery in CD4 T-cell function and viral-load reduction after highly active antiretroviral therapy in advanced HIV-1 disease.

BACKGROUND: Highly active antiretroviral therapy (HAART) decreases viral load and increases CD4 T-cell counts in patients with advanced HIV-1 infection. Whether HAART can improve CD4 T-cell function, and the biological characteristics affecting immune reconstitution, remain unclear. We undertook an open prospective pilot study to address these issues. Both treatment-naïve and previously treated patients were included. METHODS: 20 patients (seven naïve, 13 previously treated) were treated with one protease inhibitor and two reverse-transcriptase inhibitors and followed up for 12 months. We measured CD4-cell proliferation in response to cytomegalovirus and tuberculin antigens and counted subsets of CD4 cells at baseline and months 1, 3, 6, 9, and 12. Patients who had no antigen-specific reactivity at baseline but developed it while receiving HAART were classified as immunological responders. FINDINGS: Four patients had antigen-specific reactivity at baseline compared with 14 at month 12 (p <0.001). Between month 3 and month 12 viral load fell by a median of 1.5 log copies/mL from baseline (4.6 log copies/mL) and CD4-cell count increased by a median of 63/microL (from 93/microL). Ten patients (six of seven naïve, four of 13 previously treated) were immunological responders. They differed significantly from the ten non-responders in that their viral-load reduction was sustained for 12 months, the increase in CD4 count was greater, and they showed an early increase in memory CD4 T cells with an increase of naïve T cells. INTERPRETATION: HAART can induce sustained recovery of CD4 T-cell reactivity against opportunistic pathogens in severely immunosuppressed patients. This recovery depends not on baseline values but on the amplitude and duration of viral-load reduction and the increase of memory CD4 T cells.