Durable HIV-1 suppression with indinavir after failing lamivudine-containing double nucleoside therapy: a randomized controlled trial

Objective: To assess the durability of the antiretroviral effect in plasma and cerebrospinal fluid (CSF) of antiviral therapy intensification, produce d by the addition of indinavir from week 12 onwards to the original regimen of zidovudine/lamivudine or stavudine/lamivudine, after 72 weeks of follow -up using an ultrasensitive HIV-1 RNA assay. To assess CSF concentrations o f indinavir at week 48. Design: In a prospectively, randomized, open, single-centre study, antiretr oviral-naive patients (CD4 cell count greater than or equal to 200 cells/mu l and a plasma HIV-1 RNA level greater than or equal to 10000 copies/ml) we re assigned to a combination of zidovudine/lamivudine or stavudine/lamivudi ne. Indinavir could be added to the double nucleoside analogue regimen from week 12 or thereafter in case the plasma HIV RNA level was insufficiently suppressed (> 500 copies/ml). Results: Forty-seven patients were enrolled (23 stavudine/lamivudine and 24 zidovudine/lamivudine), of whom 33 completed a follow-up of 72 weeks. Indi navir was added in 89% (42/47) of the patients. Only one discontinuation oc curred due to virological failure. At week 72, the median plasma HIV-1 RNA levels in the zidovudine/lamivudine group had decreased from 4.80 log(10) c opies/ml to < 500 copies/ml in 100% of patients and < 50 copies/ml in 86.6% of the patients. In the stavudine/lamivudine group the plasma HIV-1 RNA de creased from 4.98 log(10) copies/ml at baseline to <500 copies/ml in 100% o f patients and <less than>50 copies/ml in 66.7% of the patients. On an inte nt-to-treat basis these figures were 54.2 and 52.2% for zidovudine/lamivudi ne and stavudine/lamivudine, respectively, for the 50 copies/ml assay. The median CD4 cell count increased from 315 cells/mul, with 150 cells/mul in t he zidovudine/lamivudine arm, and from 290 cells/mul, with 310 cells/mul in the stavudine/lamivudine arm (P=0.0001). However, the percentage of CD4 ce lls did not differ in each group. In the zidovudine/lamivudine group 9/10 a nd 5/5, and in the stavudine/lamivudine group 11/11 and 6/6 had a CSF HIV-1 RNA level < 50 copies/ml at week 12 and 48, respectively. The CSF indinavi r concentration ranged from 50 to 170 ng/ml. Conclusion: The long-term HIV-1 suppression observed in this study is remar kable, as adding a single antiretroviral agent to a failing regimen goes ag ainst current notions of adequate therapy.