Richard D'Aquila | PubMed Health

PubMed2004

Effect of persistent moderate viremia on disease progression during HIV therapy.

OBJECTIVE: Although highly active antiretroviral therapy has been shown to lower plasma HIV-1 RNA in HIV infection, many patients do not reach the target goal of undetectable viremia. We evaluated whether risk of clinical progression varies by level of viral suppression achieved. DESIGN: Patients in the Collaborations in HIV Outcomes Research/United States cohort who maintained stable HIV-1 RNA levels of either <400, 400 to 20,000, or >20,000 copies/mL during a run-in period of at least 6 months were studied. Baseline was the first day after this period. METHODS: Proportional hazards models were used to quantify the relation between baseline HIV-1 RNA levels and risk of a new AIDS-defining diagnosis or death after adjusting for CD4 count, age, gender, ethnicity, study site, prior AIDS-defining diagnosis, and antiretroviral therapy history. RESULTS: Patients (N = 3010) were followed for up to 4.3 years after the 6-month run-in period, with 343 deaths or AIDS-defining diagnoses reported. The risk of a new AIDS-defining diagnosis or death was not significantly different in the 400 to 20,000- and <400-copies/mL groups (6% vs. 7%, hazard ratio [HR] = 1.0, 95% confidence interval [CI]: 0.7-1.4; P = 0.9) but was significantly higher in the >20,000-copies/mL group (26%, HR = 3.3, 95% CI: 2.5-4.4; P < 0.001 vs. the <400-copies/mL group). Median CD4 count changes during the first year of follow-up showed increases of 75 and 13 cells/mm for the <400- and 400 to 20,000-copies/mL groups, respectively, whereas the >20,000-copies/mL group had a decrease of 23 cells/mm. CONCLUSIONS: Patients who maintained baseline HIV-1 RNA levels of 400 to 20,000 copies/mL for at least 6 months preserved immunologic status and were no more likely to die or develop a new AIDS-defining diagnosis in the time frame studied than those with baseline levels <400 copies/mL. Patients with HIV-1 RNA levels >20,000 copies/mL at baseline had greater clinical and immunologic deterioration. These data suggest that maintenance of moderate viremia may confer clinical benefit not seen when viremia exceeds 20,000 copies/mL, and this should be taken into account when considering the risks and benefits of continuing failing therapy.

Adult↗

PubMed2004

Strategies to decrease viral load rebound, and prevent loss of CD4 and onset of resistance during structured treatment interruptions.

BACKGROUND: Toxicity and other drug adherence-related factors have contributed to decreased compliance to antiretroviral regimens amongst HIV-infected patients. Irregular therapy disruption causes loss of CD4 T cells, onset of drug resistance and rapid rebound of plasma viral load (VL). However, an appropriate choice of drugs and properly scheduled structured treatment interruptions (STIs) may limit VL rebound, maintain CD4 counts and minimize resistance. METHODS: We conducted a clinical study of STIs, RIGHT 901, involving 60 drug-naive patients with chronic HIV infection (CD4 >300, VL >10,000) randomized to receive didanosine-stavudine-indinavir (IDV group) or didanosine-stavudine-hydroxyurea (HU group), for 12 weeks. Subsequently, all patients were randomized again to start STI (short induction) or to continue the therapy for an additional 24 weeks before starting STI (long induction). Both groups underwent four STI cycles and then stopped therapy as long as viraemia remained below 10,000 copies/ml before reinitiating another four cycles of STI. RESULTS: During continuous therapy VLs were suppressed at similar rates in both the HU and IDV groups, while a blunted CD4 count was documented in the HU group. Following the first stop median VL rebounded close to baseline values in both groups, however, during the following STI median VL rebound decreased in the HU group, while in the IDV group VL continued to rebound to values close to baseline, and the difference between the two groups was statistically significant. Moreover, patients treated with HU had a constant and stable CD4 increase during STI, whereas CD4 counts fluctuated in the IDV group, with sharp falls during treatment interruptions and partial CD4 recovery following treatment restart. Even in the presence of IDV resistance predisposing mutations at baseline, no genotypic change in the protease sequence was observed during STI. A relevant mutation in the reverse transcriptase sequence (K70R) emerged in one patient interrupting treatment after 36 weeks of continuous therapy and in one patient after four STI cycles. Side effects (no major events) were similar among groups. CONCLUSIONS: An appropriate choice of STI schedule and regimens containing drugs less prone to resistance and/or able to prevent CD4 fluctuation may contribute to optimizing STI for chronically infected patients with respect to limiting viral rebound, improving CD4 counts and maintaining a resistance profile comparable to continuous highly active antiretroviral therapy.

Anti-HIV Agents↗