Antiretroviral Long-Term Efficacy and Resistance of Lopinavir/Ritonavir Plus Lamivudine in HIV-1-Infected Treatment-Naïve Patients (ALTERLL): 144-Week Results of a Randomized, Open-Label, Non-Inferiority Study From Guangdong, China

Abstract

Dual therapy with lopinavir/ritonavir (LPV/r) plus lamivudine (3TC) has been demonstrated to be non-inferior to the triple drug regimen including LPV/r plus two nucleoside reverse transcriptase inhibitors (NRTIs) in 48-week studies. However, little is known about the long-term efficacy and drug resistance of this simplified strategy. A randomized, controlled, open-label, non-inferiority trial (ALTERLL) was conducted to assess the efficacy, drug resistance, and safety of dual therapy with LPV/r plus 3TC (DT group), compared with the first-line triple-therapy regimen containing tenofovir (TDF), 3TC plus efavirenz (EFV) (TT group) in antiretroviral therapy (ART)-naïve HIV-1-infected adults in Guangdong, China. The primary endpoint was the proportion of patients with plasma HIV-1 RNA < 50 copies/ml at week 144. Between March 1 and December 31, 2015, a total of 196 patients (from 274 patients screened) were included and randomly assigned to either the DT group (n = 99) or the TT group (n = 97). In the primary intention-to-treat (ITT) analysis at week 144, 95 patients (96%) in the DT group and 93 patients (95.9%) in the TT group achieved virological inhibition with plasma HIV-1 RNA <50 copies/ml (difference: 0.1%; 95% CI, -4.6-4.7%), meeting the criteria for non-inferiority. The DT group did not show significant differences in the mean increase in CD4⁺ cell count (247.0 vs. 204.5 cells/mm³; p = 0.074) or the CD4/CD8 ratio (0.47 vs. 0.49; p = 0.947) from baseline, or the inflammatory biomarker levels through week 144 compared with the TT group. For the subgroup analysis, baseline high viremia (HIV-1 RNA > 100,000 copies/ml) and genotype BC did not affect the primary endpoint or the mean increase in CD4⁺ cell count or CD4/CD8 ratio from baseline at week 144. However, in patients with genotype AE, the DT group showed a higher mean increase in CD4⁺ cell count from baseline through 144 weeks than the TT group (308.7 vs. 209.4 cells/mm³; p = 0.038). No secondary HIV resistance was observed in either group. Moreover, no severe adverse event (SAE) or death was observed in any group. Nonetheless, more patients in the TT group (6.1%) discontinued the assigned regimen than those in the DT group (1%) due to adverse events. Dual therapy with LPV/r plus 3TC manifests long-term non-inferior therapeutic efficacy, low drug resistance, good safety, and tolerability compared with the first-line triple-therapy regimen in Guangdong, China, indicating dual therapy is a viable alternative in resource-limited areas. Clinical Trial Registration: [http://www.chictr.org.cn], identifier [ChiCTR1900024611].

Keywords: antiretroviral therapy; efavirenz; inflammatory biomarker; lopinavir/ritonavir; randomized controlled study; simplified regimen.

FIGURE 1

Subject disposition of the study.

FIGURE 2

(A) Therapeutic response in the ITT and PP populations. The solid line represents no difference (dual treatment minus triple treatment) and the 15% non-inferiority margin. (B) Proportion of patients with HIV-1 RNA <50 copies/ml in ITT analysis. Proportions from two groups at different time points were tested for non-inferiority. p < 0.05 indicates that the dual treatment group is non-inferior to the triple treatment group. (C) Change in CD4⁺ count from baseline in ITT analysis. CD4⁺ counts from the two groups at different time points were tested with a Mann–Whitney U test. A p-value of less than 0.05 was considered significant. (D) Change in CD4/CD8 ratio from baseline in ITT analysis. CD4/CD8 ratios from the two groups at different time points were tested with a Mann–Whitney U test. A p-value less than 0.05 was considered significant.

FIGURE 3

(A) Therapeutic response in the ITT and PP populations in subgroups stratified by baseline HIV-1 RNA. Solid lines represent no difference (dual treatment minus triple treatment) and the 15% non-inferiority margin (B,C). (B) Proportion of patients with HIV-1 RNA <50 copies/ml; proportion of patients with a baseline HIV-1 RNA ≤100,000 copies/ml in ITT analysis. (C) proportion of patients with a baseline HIV-1 RNA >100,000 copies/ml in ITT analysis. Proportions obtained from two groups at different time points were tested for non-inferiority. A p < 0.05 indicates that dual treatment group is non-inferior to the triple treatment group (D,E). (D) Change in CD4⁺ count from baseline in patients with a baseline HIV-1 RNA ≤100,000 copies/ml in ITT analysis. (E) Change in CD4⁺ count from baseline in patients with a baseline HIV-1 RNA >100,000 copies/ml in ITT analysis. CD4⁺ counts from the two groups at different time points were tested with a Mann–Whitney U test. A p-value of less than 0.05 was considered significant (F,G). (F) Change in CD4/CD8 ratio from baseline in patients with a baseline HIV-1 RNA ≤100,000 copies/mL in ITT analysis. (G) Change in CD4/CD8 ratio from baseline in patients with a baseline HIV-1 RNA >100,000 copies/mL in ITT analysis. CD4/CD8 ratio from the two groups at different time points were tested with a Mann–Whitney U test. A p-value of less than 0.05 was considered significant.

FIGURE 4

(A) Therapeutic response in the ITT and PP populations in subgroups stratified according to genotype. Solid lines represent no difference (dual treatment minus triple treatment) and the 15% non-inferiority margin (B,C). (B) Proportion of patients with HIV-1 RNA <50 copies/ml and with AE genotype in ITT analysis. (C) Proportion of patients with HIV-1 RNA <50 copies/ml and with BC genotype in ITT analysis. Proportions from two groups at different time points were tested for non-inferiority. A p < 0.05 indicates that dual treatment group is non-inferior to the triple treatment group (D,E). (D) Change in CD4/CD8 ratio from baseline in patients with AE genotype in ITT analysis. (E) Change in CD4/CD8 ratio from baseline in patients BC genotype in ITT analysis. CD4⁺ counts from the two groups at different time points were tested with a Mann–Whitney U test. A p-value of less than 0.05 was considered significant (F,G). (F) Change in CD4⁺ count from baseline in patients with AE genotype in ITT analysis. (G) Change in CD4⁺ count from baseline in patients with BC genotype in ITT analysis. CD4/CD8 ratios from the two groups at different time points were tested with a Mann–Whitney U test. A p-value of less than 0.05 was considered significant.