At week 24, the proportion of participants with HIV-1 RNA <50 copies/mL was 93.7% (419/447) in the DOR/3TC/TDF ISG and 94.6% (211/223) in the Baseline Regimen DSG (Fig. 2, Panel A). At week 48, HIV-1 RNA <50 copies/mL was maintained in 90.8% (406/447) of the DOR/3TC/TDF ISG (Fig. 2, Panel B), demonstrating that switching to DOR/3TC/TDF is noninferior to continuing the baseline regimen for 24 weeks [difference (95% CI), −3.8 (−7.9 to 0.3)]. Of the 209 participants in the Baseline Regimen DSG who switched to DOR/3TC/TDF at week 24, 198 (94.7%) had HIV-1 RNA <50 copies/mL at week 48 (see Supplemental Digital Content, http://links.lww.com/QAI/B313).
Across subgroups defined by demographics and baseline clinical characteristics, the antiretroviral efficacy of DOR/3TC/TDF at week 24 was comparable to that of the baseline regimen at week 24 (Fig. 3), consistent with the overall results. Virologic response rates in the DOR/3TC/TDF ISG were high regardless of the previous regimen: 93.0%, 100%, and 94.3%, respectively, in participants switched from boosted PIs, boosted elvitegravir, or NNRTIs. The efficacy of DOR/3TC/TDF at week 48 was also comparable to the baseline regimen at week 24 across demographics and baseline clinical characteristics (see Supplemental Digital Content, http://links.lww.com/QAI/B313).
Eleven participants in the DOR/3TC/TDF ISG had NNRTI resistance mutations at baseline: 10 (90.9%) were virologically suppressed at week 48, and 1 discontinued on day 29 (due to protocol deviation) with HIV-1 RNA <50 copies/mL. Thirteen participants in the Baseline Regimen DSG had NNRTI resistance mutations at baseline; 12 of these participants switched to DOR/3TC/TDF at week 24: 11 (91.7%) were virologically suppressed at week 48, and 1 discontinued on day 262 (due to noncompliance) with HIV-1 RNA <50 copies/mL on day 195 (last available measurement).
The proportion of participants with HIV-1 RNA ≥50 copies/mL was 1.8% in both treatment groups at week 24 (Figs. 2) and 1.6% in the DOR/3TC/TDF ISG at week 48 (the primary comparison time point), supporting the noninferiority of switching to DOR/3TC/TDF [difference −0.2 (−2.5 to 2.1) vs the baseline regimen at week 24]. The mean change from baseline in CD4+ T-cell count was minimal: +5 cells/mm3 in the DOR/3TC/TDF ISG and +18 cells/mm3 in the Baseline Regimen DSG at week 24, and +14 cells/mm3 in the DOR/3TC/TDF ISG at week 48.
Eight participants met criteria for PDVF: 6 in the DOR/3TC/TDF ISG, 1 in the Baseline Regimen DSG, and 1 in the DSG after switching to DOR/3TC/TDF; none of these participants had RT K103N, Y181C, and/or G190A mutations at baseline. Three participants with PDVF (2 in the DOR/3TC/TDF ISG and 1 in the Baseline Regimen DSG) had samples with HIV-1 RNA >400 copies/mL available for resistance testing. Neither ISG participant developed genotypic or phenotypic resistance to DOR, 3TC, or TDF. The DSG participant (who was receiving ritonavir-boosted DRV, FTC, and TDF) showed genotypic and phenotypic resistance to 3TC and FTC (conferred through RT M184M/I) at week 12. Viral drug resistance testing was also performed for 3 participants (1 in the DOR/3TC/TDF ISG and 2 in the Baseline Regimen DSG) who discontinued early without PDVF. None of these participants developed genotypic or phenotypic resistance to any component of the study therapy.
Safety and Tolerability
During weeks 0–24, AEs were reported by 68.9% of the DOR/3TC/TDF ISG and 52.5% of the Baseline Regimen DSG. In both groups, the majority of participants with AEs rated the maximum intensity as mild (64.3% and 59.0%, respectively). The most frequently reported AEs were nasopharyngitis and headache (Table 2). AEs that were considered drug-related were reported during weeks 0–24 in 19.5% of the DOR/3TC/TDF ISG and 2.2% of the Baseline Regimen DSG; none of the specific drug-related AEs occurred in ≥2% of either group. Among participants in the DSG who switched to DOR/3TC/TDF at week 24, the AE profile during weeks 24–48 was similar to that reported for the DOR/3TC/TDF ISG during weeks 0–24 (Table 2).
Rates of serious AEs were low in both treatment groups during weeks 0–24 and during weeks 24–48 (Table 2). A total of 5 participants had serious AEs that were considered related to DOR/3TC/TDF: depression, increased lipase (grade 4), concurrent elevations in alanine aminotransferase (ALT) (grade 3) and aspartate aminotransferase (AST) (grade 2), concurrent elevations in amylase and lipase (both grade 4), and renal failure. The elevated ALT and AST resolved with no change in therapy. In the other 4 participants, the study drug was discontinued and the serious AEs resolved, except for increased lipase in 1 participant (see Supplemental Digital Content, http://links.lww.com/QAI/B313). No deaths were reported during the study among randomized participants.
Rates of treatment discontinuation due to AEs were low in both treatment groups during weeks 0–24 and during weeks 24–48 (Table 2). These events were considered related to DOR/3TC/TDF in 13 participants. The most common AEs causing discontinuation were increased transaminase levels (ALT, AST, or both; 4 participants) and increased lipase (3 participants, none with pancreatitis). Most AEs that led to discontinuation of DOR/3TC/TDF had resolved or were resolving at the last study contact (see Supplemental Digital Content, http://links.lww.com/QAI/B313).
In participants whose baseline regimen included a ritonavir-boosted PI, the mean change in fasting LDL-C and non-HDL-C from baseline to week 24 was significantly different (P < 0.0001) between the treatment groups (Fig. 4). Fasting cholesterol and fasting triglyceride levels were also substantially reduced among participants in the DOR/3TC/TDF ISG (Fig. 4). The mean change in the total cholesterol:HDL-C ratio was −0.44 in the DOR/3TC/TDF ISG and −0.57 in the Baseline Regimen DSG. Lipid-lowering therapy was started or changed (agent or dose) during the first 24 weeks of the study in 1.3% of participants receiving DOR/3TC/TDF and 2.7% receiving the baseline regimen.
The incidence of grade 3 or 4 laboratory abnormalities through week 24 was generally similar between the treatment groups (Table 2). Five participants in the Baseline Regimen DSG experienced a grade 3 increase in bilirubin; all 5 were receiving ritonavir-boosted atazanavir. The laboratory profile for the DSG after switching to DOR/3TC/TDF was similar to that for the ISG during weeks 0–24. No participants in either treatment group had laboratory values that met the criteria for potential drug-induced liver injury (ALT or AST ≥3 × ULN plus bilirubin ≥2 × ULN and alkaline phosphatase <2 × ULN).
This randomized, open-label, phase 3 trial demonstrated the efficacy and safety of switching from a stable antiretroviral regimen to a single-tablet, fixed-dose regimen of DOR/3TC/TDF in virologically suppressed adults with HIV-1 infection. Participants who received DOR/3TC/TDF for up to 48 weeks showed high rates of virologic suppression with low rates of virologic failure and discontinuation related to AEs. An open-label study design was chosen to reduce dosing complexity and to allow for evaluation of the acceptability of a single-tablet regimen. Because participants had been virologically suppressed for at least 6 months before enrollment, a treatment duration of 48 weeks after switching was considered important for evaluating the safety and tolerability of DOR/3TC/TDF and its durability in maintaining viral suppression. Because participants randomized to continue their baseline regimen might not be willing to wait 48 weeks before switching, this group was designated to switch at week 24. Thus, the primary efficacy analysis compared week 48 for DOR/3TC/TDF with week 24 for the baseline regimen. A secondary comparison was performed at week 24 for both treatment groups to assess the virologic response at the same duration of follow-up for both regimens.
Based on the proportion of participants with HIV-1 RNA <50 copies/mL at week 24, switching to DOR/3TC/TDF was comparable with continuation of the baseline regimen (93.7% vs 94.6%). After an additional 24 weeks, virologic suppression was maintained in 90.8% of participants receiving DOR/3TC/TDF, demonstrating the noninferior efficacy of DOR/3TC/TDF at week 48 compared with the baseline regimen at week 24. The difference in response rates for the primary comparison was mainly due to missing data for nonvirologic reasons (7.6% vs 3.6%), including discontinuations due to AEs. This imbalance reflects, in part, the opportunity for additional events to occur in the DOR/3TC/TDF ISG because of the longer evaluation period (48 weeks).
After this trial began, the recommended primary endpoint in FDA guidance for HIV switch trials18 was changed to HIV-1 RNA ≥50 copies/mL, which was a secondary endpoint in this trial. Switching to DOR/3TC/TDF was comparable with continuation of the baseline regimen with respect to this endpoint: 1.8% of both groups had HIV-1 RNA ≥50 copies/mL at week 24, as did 1.6% of the DOR/3TC/TDF ISG at week 48.
The results for both virologic suppression and virologic rebound in this trial are similar to the week 48 results of other open-label switch trials, such as the STRIIVING study of abacavir/dolutegravir/lamivudine (83% with HIV-1 RNA <50 copies/mL, <1% with HIV-1 RNA ≥50 copies/mL),19 the EMERALD study of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (94.9% and 2.5%, respectively),20 and the GS-US-380-1878 study of bictegravir/emtricitabine/tenofovir alafenamide (92% and 2%, respectively).21
Very few participants (7/676) met the criteria for PDVF after switching to DOR/3TC/TDF, and no viral resistance to DOR was identified in the participants whose samples could be tested. At study entry, 24 participants had virus with NNRTI resistance mutations K103N, Y181C, and/or G190A; of the 23 who switched to DOR/3TC/TDF, 21 remained suppressed through week 48 and 2 discontinued early for other reasons but were suppressed at their last study visit. These clinical findings are consistent with the in vitro activity of doravirine.
Switching to DOR/3TC/TDF demonstrated a superior lipid profile compared with continuation of a ritonavir-boosted PI-based regimen, with a statistically significant difference between the treatment groups for both LDL-C and non-HDL-C at week 24 (P < 0.0001). Previous studies have shown that DOR is lipid neutral in treatment-naive adults,15,16 whereas boosted PIs are associated with increased lipid levels.22 This trial shows that switching from a boosted PI to DOR/3TC/TDF improves lipid profiles.
DOR/3TC/TDF was generally well tolerated for up to 48 weeks, with no deaths and low rates of serious AEs and discontinuation due to AEs. Compared with participants who continued their baseline regimen, participants who switched to DOR/3TC/TDF had higher rates of any AE (68.9% vs 52.5%) and of treatment-related AEs (19.5% vs 2.2%) at week 24. The higher AE rates in the DOR/3TC/TDF group are not unexpected because these participants switched to a new treatment regimen, whereas participants in the Baseline Regimen group continued on the same therapy they had received for at least 6 months before entering this trial. In addition, because the participants were not blinded to whether they received the new regimen, ascertainment bias may have contributed to the difference in AE rates. Other antiretroviral switch studies have also found that participants who switched to a new regimen reported more drug-related AEs than those who continued their previous regimen, particularly when the trial was not blinded.19–21,23
Despite the high incidence of AEs reported, only 2% of participants (13/656) discontinued DOR/3TC/TDF because of AEs that were considered treatment related. Overall, the safety profile of DOR/3TC/TDF in treatment-experienced participants who switched to this regimen was consistent with the safety profile observed in the treatment-naive trials, DRIVE-FORWARD and DRIVE-AHEAD,15,16 although the rate of drug-related AEs in the current trial (19.5%) was lower than in treatment-naive participants (31%).
In summary, switching to DOR/3TC/TDF was noninferior to continuation of the previous regimen in virologically suppressed adults with HIV-1, with high rates of virologic suppression and low rates of virologic rebound. No resistance to DOR developed in either treatment group. DOR/3TC/TDF demonstrated a favorable safety profile over 48 weeks of treatment, and switching to DOR/3TC/TDF was associated with a favorable lipid profile compared with a boosted-PI regimen. These results show that switching to once-daily DOR/3TC/TDF is an effective and generally well-tolerated option for maintaining viral suppression in patients considering a change in therapy.
The authors thank all the patients who participated in this study. The contributions of the investigators and their staff are also gratefully recognized. Primary investigators (by country): Argentina—W. Belloso, P.E.Cahn, I. Cassetti, and S.H.Lupo; Australia—J. McMahon, R. Finlayson, M. Bloch, and T. Read; Austria—A. Zoufaly, A. Rieger, and B. Haas; Belgium—L. Vandekerckhove, E. Florence, S. DeWit, I. Derdelinckx, and B. Vandercam; Canada—F. Smaill, S. Walmsley, B. Conway, and J. Szabo; Colombia—J. Onate Gutierrez; Denmark—J. Gerstoft, N. Weis, O. Larsen, and H. Nielsen; France—J-M. Molina, F. Raffi, J. Reynes, and Y. Yazdanpanah; Germany—J. Rockstroh, M. Bickel, H. Jaeger, A. Baumgarten, J. Bogner, K. Arasteh, and W. Kern; Guatemala—E. Rojas Alvarado; Israel—Z. Sthoeger, M. Chowers, K. Riesenberg, E. Shahar, I. Levy, H. Elinav, and D. Turner; Italy—A. Antinori, A. Chirianni, G. Di Perri, A. Lazzarin, M. Andreoni, G. Migliorino, G. Angarano, G. Rizzardini, A. D'Arminio Monforte, and R. Cauda; Korea—S. W. Kim and J. Y. Choi; Mexico—J. Andrade, G. Reyes Teran, and B. Crabtree Ramirez; New Zealand—A. Pithie; Peru—R. Infante; Poland—A. Horban, W. Halota, and J. Gasiorowski; Puerto Rico—G. Ortiz-Lasanta; Russian Federation—E. Voronin, A. Yakovlev, S. Kizhlo, V. Pokrovsky, F. Nagimova, and I. Khaertynova; Spain—E. Negredo Puigmal, J. Mallolas, J. Arribas Lopez, R. Rubio Garcia, V. Estrada, J. Iribarren Loyarte, and F. Gutierrez Rodero; Switzerland—M. Cavassini, J. Fehr, and A. Rauch; United Kingdom—M. Nelson, C. Orkin, M. Gompels, I. Williams, A. Clarke, M. Johnson, G. Schembri, A. Ustianowski, and N. Fearnley; United States—D. Asmuth, K. Vigil, D. Berger, K. Casey, G. Crofoot, D. Cunningham, C. Dietz, D. Goldstein, J. Flamm, L. Gorgos, C. Hare, W. Henry, M. Jain, T. Jefferson, M. Johnson, D. Klein, P. Kumar, J. Lalezari, J. Sims, R. Novak, G. Pierone, D. Prelutsky, S. Schrader, D. Sweet, D. Riedel, O. Osiyemi, P. Tebas, W. Robbins, D. Parenti, W. Towner, R. Nahass, and J. Morales-Ramirez.
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