Multidrug-resistant HIV: Is there a role for structured treatment interruption?

Structured treatment interruption (STI) before initiating a new antiretroviral regimen is one strategy for improving virological response in patients with multidrug-resistant HIV-1 infection. However, there are conflicting data concerning the effectiveness of STI, and its role has not been established. The results of several recent studies, described below, are noteworthy (Table).

Ananworanich and associates¹ studied 430 HIV-infected patients who had CD4⁺ cell counts of greater than 350/µL and HIV RNA levels of less than 50 copies/mL. The participants were randomly assigned to continued antiretroviral therapy or STI.

STI was associated with a drug savings of about 62%. An HIV RNA level of less than 50 copies/mL was achieved in about 91% of the STI group and in 92% of the continuous treatment group. No AIDS-defining events occurred.

Diarrhea and neuropathy were more common in the continuous treatment group, while candidiasis was more common in the STI group. The authors concluded that antiretroviral therapy can be safely interrupted, provided CD4⁺ cells counts are monitored.¹

However, more disturbing findings were reported by Lawrence and associates,² who described the final results of the Community Programs for Clinical Research on AIDS (CPCRA-064) Study. In this study, 274 patients who had multidrug-resistant HIV-1 treatment failure were randomly assigned to a 4-month STI, followed by an optimized antiretroviral regimen or an immediate change to an optimized regimen.² The median follow-up was 37 months.

After STI, the 2 groups did not differ in HIV-1 RNA response or measures of disease progression. CD4⁺ cell count improved significantly more in the non-STI group than in the STI group; these differences were documented at 0 to 4 months, 4 to 12 months, 12 to 24 months, and after 24 months.

Discouraging findings also have been reported by Benson and colleagues,³ who conducted a prospective trial of 41 patients with HIV infection that was resistant to multiple drug classes. The participants were randomly assigned to a 16-week STI, followed by optimized antiretroviral therapy or immediate antiretroviral therapy without STI. Optimized therapy was based on genotypic and phenotypic susceptibility testing and the patient's antiretroviral therapy history.

At 48 weeks, the 2 groups did not differ significantly with respect to the proportion of patients with HIV-1 RNA level of less than 400 copies/mL (19% in the STI group and 33% in the non-STI group). The groups also did not differ in median changes from baseline in CD4⁺ cell counts and HIV-1 RNA levels.

At the end of STI, standard genotypes demonstrated near-complete reversion to wild-type virus in a minority of patients. Virus with resistance to 3 drug classes reemerged even when antiretroviral therapy included only 1 or 2 drug classes. Single-genome sequencing showed that each genome encoded resistance mutations for 3 drug classes.

The authors concluded that STI before the reinitiation of optimized therapy does not lead to improved virological or immunological responses compared with the immediate initiation of optimized therapy in patients with multidrug-resistant infection.³ They attributed the failure of STI to the persistence of resistant viral variants, despite the reversion to wild-type virus in plasma after STI.

More encouraging news has been reported by Jacobson and associates,⁴ who found evidence that cycles of brief STIs can enhance host control of viral replication. In this setting, the STI cycles are delivering pulses of exposure to autologous HIV-1 RNA antigens to the host immune system.

They studied 97 patients who were receiving stable antiretroviral therapy and had HIV-1 RNA levels of less than 50 copies/mL and CD4⁺ cell counts of greater than 400/µL. After treatment interruption, plasma HIV RNA levels rose, usually within 2 to 4 weeks. Patients who underwent cycles of STI were more likely to achieve a stable HIV RNA level of less than 1000 copies/mL than were patients who received continuous antiretroviral therapy. Moreover, there was relative preservation of CD4⁺ cell counts in patients who underwent STI.

In contrast, immunization with ALVAC-HIV vCP1452 (an attenuated canarypox virus loaded with consensus sequences of HIV genes) did not affect HIV RNA level.

References:

1.

Ananworanich J, Gayet-Ageron A, Le Braz M, et al. CD4-guided scheduled treatment interruptions compared with continuous therapy for patients infected with HIV-1: results of the Staccato randomized trial.

Lancet.

2006;368:459-465.

2.

Lawrence J, Hullsiek KH, Thackeray LM, et al. Disadvantages of structured treatment interruption persist in patients with multidrug-resistant HIV-1: final results of the CPCRA 064 Study.

J Acquir Immune Defic Syndr.

2006;43:169-178.

3.

Benson CA, Vaida F, Havlir DV, et al. A randomized trial of treatment interruption before optimized antiretroviral therapy for persons with drug-resistant HIV: 48-week virologic results of ACTG A5086.

J Infect Dis.

2006;194:1309-1318.

4.

Jacobson JM, Bucy RP, Spritzler J, et al. Evidence that intermittent structured treatment interruption, but not immunization with ALVAC-HIV vCP1452, promotes host control of HIV replication: the results of AIDS Clinical Trials Group 5068.

J Infect Dis.

2006;194:623-632.