Discontinuation of non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy: clinical implications in patients on CD4 T-cell-guided treatment interruption

Abstract

Ruiz and colleagues [1] found the frequent de novo selection of non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance in the group in their study on guided treatment interruptions (GTI) probably to be driven by the simultaneous interruption of all drugs in patients receiving NNRTI-containing regimens. They discouraged the inclusion of any drug with long plasma or low genetic barriers into GTI regimens because of the risk of the de novo selection of resistant mutations. Both United States and United Kingdom HIV treatment guidelines ackowledge the difficulty of knowing the exact duration of antiretroviral therapy cover required after stopping NNRTI, and the optimal interval between stopping efavirenz or nevirapine and other antiretroviral drugs is unknown. Their prolonged half-life leads to the detection of these drugs for 1–3 weeks after discontinuation [2,3], and the simultaneous interruption of all antiretroviral drugs in a regimen containing these agents may therefore result in functional monotherapy with the NNRTI. This in turn increases the risk of the selection of NNRTI-resistant mutations. Therefore some experts recommend stopping NNRTI while continuing other antiretroviral drugs for 5–7 days [4,5]. We describe our experience in eight patients who simultaneously interrupted all antiretroviral drugs (including NNRTI) during CD4 T-cell GTI and obtained a rapid return of plasma viraemia to undetectable levels after restarting the same regimen. A total of 46 white European patients were enrolled in the clinical study of CD4 T-cell GTI. Of these, 22 were on NNRTI-based antiretroviral therapy. The criteria used to stop antiretroviral therapy were a CD4 T-cell count of 500 cells/μl or greater and a plasma HIV-RNA level of less than 50 copies/ml for at least 3 years. Patients underwent laboratory evaluations 4 and 12 weeks after stopping antiretroviral therapy and then every 3 months. The criteria for restarting HAART were: (i) acute retroviral syndrome; (ii) patient's choice, independent of the CD4 T-cell count; (iii) pregnancy; (iv) the onset of HIV-related systemic symptoms (acute retroviral syndrome) or of opportunistic infections; (v) a CD4 T-cell count decline to less than 250 cells/μl. Four weeks after discontinuation, an antiretroviral genotyping test (TruGene HIV-1 genotyping assay) was performed to assess the presence of NNRTI-related point mutations. Fifteen patients restarted ART; eight of them (five women, median age 42 years, range 37–55) were on NNRTI (five on efavirenz and three on nevirapine). Four patients were antiretroviral naive and four antiretroviral experienced. Table 1 give details of the antiretroviral regimens, the date and length of interruption, and months of undetectable viral load reached after the reintroduction of the same regimen. Viraemia was undetectable again in all patients within 3 months of the reintroduction of antiretroviral therapy, and continues to be so.Table 1: Antiretroviral regimens, date and months of interruption, and time length of undetectable viral load after reintroduction of the same regimen.Genotypic resistance tests failed to reveal mutations conferring resistance to NNRTI in all patients (100%). Few data are available on the discontinuation of NNRTI-based therapy in order to avoid a monotherapy state and the potential evolution of drug-resistant variants. Two studies have documented how the duration of detectable levels of these drugs after discontinuation ranges from less than one week [4] to over 3 weeks [5], and the authors suggested continuing the nucleoside reverse transcriptase inhibitor backbone for a minimum of 5 days to a maximum of 14 days after the discontinuation of NNRTI in order to avoid the emergence of resistance. Some authors have also shown that certain host genetic polymorphisms, more common among African-American and Hispanic individuals [6,7], result in slower rates of clearance of these drugs. The optimal time sequence for staggered component discontinuation has, however, not been still determined. Our results, in a small number of individuals, indicate that white European patients with high CD4 T-cell numbers and undetectable plasma HIV-RNA levels can simultaneously discontinue all components of their antiretroviral regimen without developing point mutations conferring resistance to NNRTI. We hypothesized that the 4–7 day delay in viral rebound after therapy interruption, as shown by Neumann et al. [8], could explain our results. Perhaps the risk of developing NNRTI resistance when stopping all antiretroviral drugs simultaneously is more common when cessation occurs with a detectable plasma viraemia, as suggested by others [4].