Mutations in HIV-1 Reverse Transcriptase during Therapy with Abacavir, Lamivudine and Zidovudine in HIV-1-Infected Adults with No Prior Antiretroviral Therapy
Authors: Ait-Khaled Mounir , Rakik Abdelrahim , Griffin Philip , Cutrell Amy , Fischl Margaret A , Clumeck Nathan , Greenberg Stephen B , Rubio Rafael , Peters Barry S , Pulido Federico , Gould Jayne , Pearce Gill , Spreen William , Tisdale Margaret , Lafon Steve ,   the CNA3003 International Study Team, Bellos NC , Brosgart CL , Jacobson S , Cooley TP , Hicks CB , Kumar P , Kraus PW , El-Sadr W , Pottage JC , Kessler HA , Santana JL , Torres RA , Casado JL , Gatell JM , Ocana I , Pena JM , Fisher MJ , Weber J , White D , West M , Hetherington S , Steel H , Ait-Khaled M , Verity L , Richardson C , Pearce G 
Published: April 2022

Objective To evaluate HIV-1 reverse transcriptase (RT) drug resistance in patients receiving abacavir, lamivudine and zidovudine therapy. Methods In a randomized, double-blind study, 173 anti-retroviral treatment-naive HIV-1-infected adults received abacavir/lamivudine/zidovudine or lamivudine/zidovudine for up to 48 weeks. After week 16, patients could switch to open-label abacavir/lamivudine/zidovudine, and those with plasma HIV-1 RNA (vRNA) >400 copies/ml could add other antiretrovirals. From weeks 16 to 48, samples with vRNA >400 copies/ml were collected for genotyping and phenotyping. Results At baseline, 90% of isolates were wild-type (WT). At week 16, vRNA was >400 copies/ml in seven of 72 (10%) patients receiving abacavir/lamivudine/zidovudine and in 41 of 66 (62%) receiving lamivudine/ zidovudine. At week 16, the genotypes in isolates from the abacavir/lamivudine/zidovudine group were M184V alone ( n=3 cases), WT ( n=3) and M184V plus thymidine analogue mutations (TAMs) ( n=1). The genotypes in isolates from the lamivudine/zidovudine group were M184V alone ( n=37), WT ( n=1) and M184V plus TAMs ( n=3). In the four cases where M184V plus TAMs were detected some mutations were present at baseline. Despite detectable M184V in 74% of patients on lamivudine/zidovudine, addition of abacavir with or without another antiretroviral therapy resulted in a reduction in vRNA, with 42 of 65 (65%) patients having week 48 vRNA <400 copies/ml (intent-to-treat with missing=failure). At week 48, the most common genotype was M184V alone in the abacavir/ lamivudine/zidovudine group (median vRNA 1–2 log10 below baseline), and M184V with or without TAMs in patients originally assigned to lamivudine/zidovudine. At week 48, phenotypic results were obtained for 11 isolates for patients from both arms, and all had reduced susceptibility to lamivudine but all remained sensitive to stavudine, all protease inhibitors and all non-nucleoside reverse transcriptase inhibitors. Three, three and two isolates had reduced susceptibility to abacavir, didanosine and zidovudine, respectively. Conclusions Abacavir retained efficacy against isolates with the M184V genotype alone. TAMs did not develop during 48 weeks of abacavir/lamivudine/zidovudine therapy and were uncommon when abacavir was added after 16 weeks of lamivudine/zidovudine therapy. Limited mutations upon rebound on this triple nucleoside combination allows for several subsequent treatment options.