Efficacy and safety of doravirine/islatravir in heavily treatment-experienced participants living with HIV-1: results from a randomized trial

Abstract

Objective:

This study evaluated the efficacy (day 8) and safety (week 49) of doravirine/islatravir (DOR/ISL; 100 mg/0.75 mg) plus baseline antiretroviral therapy (ART) and optimized background therapy (OBT) in heavily treatment-experienced (HTE) adults living with detectable HIV-1 RNA.

Design and methods:

HTE adults with confirmed plasma viral load more than 500 copies/ml receiving a stable ART regimen for at least 3 months were randomly assigned 1 : 2 : 1 : 1 to receive once-daily ISL alone, DOR alone, DOR/ISL, or matching placebo for 7 days; at day 8, baseline ART was optimized and all participants received DOR/ISL and OBT through week 49. The primary efficacy endpoint was percentage of participants receiving DOR/ISL achieving at least 0.5 log₁₀ decline in viral load from baseline (day 1) to day 8. Secondary efficacy endpoints included HIV-1 RNA levels and CD4⁺ T-cell counts through week 49.

Results:

Thirty-five of the planned 100 participants were enrolled; most were White (57.1%) and men (77.1%) with median age of 50 years. From days 1 to 8, an at least 1.0 log₁₀ decrease in HIV-1 RNA was achieved in 85.7% of the DOR/ISL group compared with 0 in the placebo group. At week 49, HIV-1 RNA less than 50 copies/ml was achieved in 22 participants (71%) and the mean increase in CD4⁺ T-cell count was 87 cells/μl. Adverse events were reported in 29 participants (82.9%) through week 49; 9 (25.7%) were considered related to DOR/ISL.

Conclusion:

DOR/ISL plus OBT improved HIV-1 suppression in HTE adults living with HIV-1 and was generally well tolerated.

ClinicalTrials.gov:

NCT04233216.

Introduction

Heavily treatment-experienced (HTE) individuals comprise a small but important proportion of those living with HIV-1. In HTE individuals, extensive multidrug resistance and drug toxicity and/or intolerance result in the inability to construct an efficacious regimen that is fully active against HIV, with greater risks of transmission, disease progression, and death [1–3]. Combinations of antiretrovirals with distinct mechanisms of action, favorable safety profiles, few drug–drug interactions, and a lack of cross-resistance are, therefore, needed for those who are HTE.

Doravirine (DOR) is an approved nonnucleoside reverse transcriptase inhibitor (NNRTI) that noncompetitively inhibits reverse transcriptase [4]. Islatravir (ISL) is an investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI) that inhibits reverse transcriptase by multiple mechanisms of action, including inhibition of translocation and delayed chain termination [5–8]. A DOR/ISL fixed-dose combination not only has complementary mechanisms of action and resistance pathways, but also has few interactions with other antiretrovirals, making it a potentially useful regimen to add to optimized background therapy (OBT) in people with HIV who are HTE [9,10]. We evaluated the efficacy (day 8) and safety (week 49) of DOR/ISL (100/0.75 mg) plus baseline antiretroviral therapy (ART) and OBT in HTE adults living with detectable HIV–1 RNA.

Methods

Study design and study population

This randomized, two-part, phase 3 trial (MK-8591A-019; NCT04233216) was conducted at 26 centers in 14 countries: Australia, Canada, Chile, Colombia, France, Germany, Italy, Peru, Russia, South Africa, South Korea, Ukraine, United Kingdom, and the United States. It was anticipated that approximately 100 participants would be enrolled in the trial. The trial was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, Good Clinical Practice, and all applicable regulatory requirements. The first participant visit was in March 2020, and the last participant visit was in November 2023.

HTE persons living with HIV-1 (aged ≥12 years) were eligible if they had: been receiving the same ART regimen for at least 3 months; plasma HIV-1 RNA at least 500 copies/ml at screening and confirmed 10 days or less before randomization; at least triple-class resistant HIV-1 [including resistance to nucleos(t)ide reverse transcriptase inhibitors (NRTIs), NNRTIs, and either protease inhibitor or integrase strand transfer inhibitor (InSTI) classes]; and had two or less fully active antiretroviral drugs remaining among all available antiretroviral classes that could be effectively combined to form a viable regimen. Additional exclusion criteria are detailed in the Supplemental Material (see Supplemental Digital Content 1).

In part 1, eligible participants were randomly assigned 1: 2 : 1 : 1 to add ISL 0.75 mg, DOR 100 mg, DOR/ISL (100/0.75 mg), or placebo (all once daily) to their current ART at day 1 (that included one or more of an NRTI, NNRTI, protease inhibitor, InSTI, maraviroc, fostemsavir, ibalizumab, or enfuvirtide) until day 8 (see Figure, Supplemental Digital Content 2 – Study design). Randomization was stratified by age (<18 or ≥18 years) and, within the adult strata, the presence of M184V or M184I substitutions at screening. Randomization was implemented centrally using an interactive response technology system. Part 1 was conducted in a double-blind manner, so that all study drugs including placebo were packaged identically, and the participant, investigator, and sponsor personnel or delegate(s) involved in study drug administration or clinical evaluation of the participants, were unaware of drug assignments. Study participants and site personnel remained blinded to part 1 treatment, while sponsor personnel became unblinded to part 1 treatment at the time of the part 1 data analysis. Part 2 of the study was conducted in an open-label manner.

On day 8 (part 2), all participants received open-label DOR/ISL (100/0.75 mg once daily) plus (wherever possible) updated OBT through week 97 (see Figure, Supplemental Digital Content 2 – Study design). OBT options chosen by the investigator were selected from approved ARTs and driven by historic and baseline resistance, as well as safety, tolerability, access, and acceptability to the participant.

The US Food and Drug Administration placed a partial clinical hold on oral, once-daily DOR/ISL (100/0.75 mg) for HIV-1 treatment due to exposure-related decreases in CD4⁺ T-cell and total lymphocyte counts in some participants receiving ISL at the same or higher doses in other clinical studies. Following the clinical hold, participant enrollment was stopped on 13 December 2021. Participants who were already enrolled in the study continued study drug at the same dose with more frequent monitoring for specific decreases in CD4⁺ T-cell and total lymphocyte counts, and updated discontinuation criteria (≥30% decrease from the average baseline value for CD4⁺ T-cell or total lymphocyte count, observed on two consecutive measurements taken 3–4 weeks apart).

Efficacy assessments

Plasma HIV-1 RNA quantification was performed at the central laboratory using an Abbott Real Time PCR assay with a lower limit of detection of 40 copies/ml in plasma. Confirmation of viremia required two consecutive plasma HIV-1 RNA results of at least 200 copies/ml (at least 4 weeks apart) after a participant previously achieved HIV-1 RNA of less than 50 copies/ml. Plasma samples collected at day 1 (baseline), day 8, and samples with HIV-1 RNA at least 200 copies/ml for participants who were never suppressed at week 25, week 49, and week 97, as well as those that were collected either to confirm viremia or discontinuation, were sent for genotypic (GenoSure PRIme assay, Monogram Biosciences, San Francisco, California, USA) and phenotypic (PhenoSense assay, Monogram Biosciences, San Francisco, California, USA) testing. Viral resistance-associated substitutions were identified using the GenoSure PRIme assay conducted at Monogram Biosciences (San Francisco, California, USA). During the study, participants provided blood samples for measurement of CD4⁺ T-cell counts.

Safety assessments

Safety was evaluated through the monitoring of adverse events by the investigator. Following the clinical hold, more regular and frequent safety monitoring of total lymphocyte and lymphocyte subsets, including CD4⁺ T cells, CD8⁺ T cells, B cells, and natural killer cells, was conducted.

Statistical analyses

Sample size and power calculations were based on a sample size of 20 in the DOR/ISL (100/0.75 mg) group and, given the potential for a larger sample size, the calculations were expected to represent the minimum power. The power calculations were based on the futility rule, allowing for study discontinuation if 12 or more participants out of 20 who received DOR/ISL (100/0.75 mg) in part 1 failed to achieve an at least 0.5 log₁₀ decrease in HIV-1 RNA by the end of part 1.

The primary efficacy endpoint was the percentage of participants receiving DOR/ISL who achieved at least 0.5 log₁₀ decrease in HIV-1 RNA from baseline (day 1) to day 8. Efficacy analyses were based on the full analysis set population, which included 35 randomly assigned participants who received at least one dose of the study drug. Because target enrollment was not reached, hypothesis testing for efficacy was not conducted.

Primary safety endpoints were the percentage of participants who experienced adverse events and the percentage who discontinued treatment due to adverse events through week 49. Safety analyses were assessed in the all-participants-as-treated population, which included 35 randomly assigned participants who received at least one dose of study drug.

Secondary endpoints included mean change in HIV-1 RNA and the percentage of participants receiving DOR/ISL who achieved at least 1.0 log₁₀ decrease in HIV-1 RNA from baseline (day 1), viral resistance-associated substitutions, and mean change in CD4⁺ T-cell count from baseline for DOR/ISL, DOR, and ISL groups at day 8 in part 1, and overall at week 25, and week 49 in part 2. Data-as-observed approach was used in handling missing data in the analysis of participants living with HIV-1 RNA less than 50, less than 40, and less than 200 copies/ml over time.

In part 2, any changes to the OBT regimen due to lack of efficacy were imputed as failure using the US Food and Drug Administration snapshot approach. Changes to the OBT regimen for another reason (eg, pregnancy, delayed drug sourcing) were not imputed as failure.

Results

Study population

Because of the clinical hold, the original enrollment target of 100 participants was not met. One hundred and twelve participants were screened, of whom 35 were randomly assigned and received at least one dose of study drug (Fig. 1). The majority of participants were white (57.1%), men (77.1%), and aged at least 50 years (57.1%) (Table 1). For the overall group, the mean number of prior antiretroviral drugs at randomization was 13.1 (range 4–30). All participants were hepatitis C virus-negative. Most participants (68.6%) had baseline CD4⁺ T-cell counts 200 cells/μl or less. Median HIV-1 RNA at baseline was at least 4  log₁₀  copies/ml in all treatment groups (Table 1). Overall, 32 (91.4%) participants had prior exposure to at least six antiretroviral regimens (primarily those containing an NRTI, NNRTI, and/or protease inhibitor) with a median duration of exposure of at least 15  years. All participants had HIV-1 with triple-class genotypic resistance to NRTIs, NNRTIs, and protease inhibitors. Overall, 33 (94.3%) participants had M184V/I mutations at baseline. Genotypic (with amino acid substitutions) and phenotypic resistance to InSTIs were noted in 71.4 and 74.2% of participants, respectively. Resistance to ibalizumab, fostemsavir, maraviroc, and enfuvirtide was present in 4 (12.1%), 7 (21.2%), 18 (54.5%), and 6 (18.2%) participants, respectively.

Fig. 1.

Disposition of participants through week 49.

ART, antiretroviral therapy; D, day; DOR, doravirine; ISL, islatravir; PBO, placebo; W, week. ^aParticipants were randomly assigned to ISL plus ART, DOR plus ART, DOR/ISL plus ART, and placebo plus ART during the 7-day double-blinded period (part 1 of the study), and all participants were treated with DOR/ISL and OBT during the open-label period from day 8 through week 49 (part 2 of the study). ^bOther includes participants who were in screening when enrollment stopped or who were unable to complete study entry–related procedures due to other reasons.

Table 1.

Participant demographics and baseline characteristics.

	ISL+ART (n = 7)	DOR+ART (n = 14)	DOR/ISL+ART (n = 7)	PBO+ART (n = 7)	Total (N = 35)
Sex [n (%)]
Male	5 (71.4)	10 (71.4)	6 (85.7)	6 (85.7)	27 (77.1)
Female	2 (28.6)	4 (28.6)	1 (14.3)	1 (14.3)	8 (22.9)
Age, median (range) (years)	44 (32–63)	54 (28–61)	55 (35–65)	43 (34–60)	52 (28–65)
Race [n (%)]
Asian	0	1 (7.1)	0	1 (14.3)	2 (5.7)
Black or African American	5 (71.4)	5 (35.7)	0	1 (14.3)	11 (31.4)
Multiplea	0	1 (7.1)	1 (14.3)	0	2 (5.7)
White	2 (28.6)	7 (50.0)	6 (85.7)	5 (71.4)	20 (57.1)
CD4+ T-cell counts [n (%)]
<50 cells/μl	2 (28.6)	6 (42.9)	2 (28.6)	2 (28.6)	12 (34.3)
≥50 to <200 cells/μl	2 (28.6)	5 (35.7)	2 (28.6)	3 (42.9)	12 (34.3)
≥200 cells/μl	3 (42.9)	3 (21.4)	3 (42.9)	2 (28.6)	11 (31.4)
Plasma HIV-1 RNA, median (range) (log10 copies/ml)	4.0 (2.7–5.3)	4.3 (2.5–5.7)	4.6 (2.9–5.1)	4.0 (3.6–5.3)	4.3 (2.5–5.7)
Prior exposure to baseline ART classes [n (%)]
NRTI	7 (100.0)	14 (100.0)	7 (100.0)	7 (100.0)	35 (100.0)
NNRTI	6 (85.7)	12 (85.7)	6 (85.7)	7 (100.0)	31 (88.6)
PI	7 (100.0)	14 (100.0)	7 (100.0)	7 (100.0)	35 (100.0)
HIV-1 with M184V/I [n (%)]	6 (85.7)	14 (100.0)	6 (85.7)	7 (100.0)	33 (94.3)
InSTI substitution [n (%)]	5 (71.4)	9 (64.3)	5 (71.4)	6 (85.7)	25 (71.4)
Ibalizumab resistance [n (%)]	2 (28.6)	1 (7.1)	1 (16.7)b	0	4 (12.1)c
Fostemsavir resistance [n (%)]	1 (14.3)	3 (21.4)	2 (33.3)b	1 (16.7)b	7 (21.2)c
Maraviroc resistance [n (%)]	3 (42.9)	8 (57.1)	3 (50.0)b	4 (66.7)b	18 (54.5)c
Enfuvirtide resistance [n (%)]	1 (14.3)	1 (7.1)	2 (33.3)b	2 (33.3)b	6 (18.2)c

ART, antiretroviral therapy; DOR, doravirine; InSTI, integrase strand transfer inhibitor; ISL, islatravir; NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTI, nucleos(t)ide reverse transcriptase inhibitor; PBO, placebo; PI, protease inhibitor.

^aIncludes American Indian or Alaska Native, Black or African American; American Indian or Alaska Native, White.

^bOne participant in the group had missing data.

^cN = 33 due to two participants with missing data.

All participants completed part 1 of the study. Overall, 31 participants (88.6%) modified their baseline ART regimen to OBT at day 8; the mean number of part 1 baseline ART stopped after day 8 was 1.71 (range 0–4) and the mean number of OBT started after day 8 was 1.83 (range 0–8). Five participants (14.3%) discontinued from the study by week 49. The most common reasons for discontinuation of study drug were loss to follow-up and participant withdrawal [two participants each (5.7%)]; one participant (2.9%) discontinued due to physician decision. Overall, 30 (85.7%) participants continued in the study through to week 49.

Efficacy

From day 1 to day 8, an at least 0.5 and at least 1 log₁₀ decrease in HIV-1 RNA were achieved in 85.7% of the DOR/ISL plus baseline ART group compared with 0% of the placebo plus baseline ART group (Fig. 2). The mean change in HIV-1 RNA of the DOR/ISL plus baseline ART group was −1.23 log₁₀ copies/ml [see figure, Supplemental Digital Content 3 – Mean change in HIV-1 RNA from (a) day 1 to day 8 in participants receiving ISL, DOR, DOR/ISL, or placebo plus baseline ART and (b) day 8 to week 25 and week 49 in participants receiving DOR/ISL plus OBT]. In the ISL plus baseline ART group, 28.6% of participants achieved an at least 0.5 log₁₀ decrease in HIV-1 RNA and 14.3% achieved an at least 1 log₁₀ decrease in HIV-1 RNA (Fig. 2). Meanwhile, in the DOR plus baseline ART group, 78.6% of participants achieved an at least 0.5 log₁₀ decrease in HIV-1 RNA and 50% achieved an at least 1 log₁₀ decrease in HIV-1 RNA (Fig. 2). In comparison, no participant in the placebo group achieved any decrease (Fig. 2).

Fig. 2.

Proportion of participants who achieved at least 0.5 log₁₀ and at least 1.0 log₁₀ decreases in HIV-1 RNA by treatment group from day 1 to day 8.

ART, antiretroviral therapy; DOR, doravirine; ISL, islatravir; PBO, placebo.

In part 2 of the study, when all participants received DOR/ISL plus OBT, HIV-1 RNA less than 50copies/ml was achieved in 20 of 34 participants (58.8%) at week 25 and in 22 of 31 participants (71%) at week 49. The proportion of participants receiving DOR/ISL plus OBT who achieved at least 0.5 and at least 1 log₁₀ decrease in HIV-1 RNA from day 1 was 85.3 and 80.6% at week 25 and 67.6 and 71% at week 49 (see Figure, Supplemental Digital Content 4 – Proportion of participants receiving DOR/ISL plus OBT who achieved ≥0.5 and ≥1 log₁₀ decrease in HIV-1 RNA at week 25 and week 49). At week 49, seven participants with viremia (≥200 copies/ml) qualified for resistance testing; 2 (28.6%) had treatment-emergent viral resistance to DOR, 1 (14.3%) to ISL, and 2 (28.6%) to OBT. Substitutions at position V106A in reverse transcriptase were the most frequent treatment-emergent resistance-associated mutations (Table 2).

Table 2.

Treatment-emergent substitutions and viral resistance to doravirine, islatravir, or optimized background therapy at week 49.

	Number of participants [n (%)]	Treatment-emergent substitutions in RT (m)	OBT treatment-emergent substitutions in PR (m)	OBT treatment-emergent substitutions in IN (m)
Number of participants randomized (N)	35
Participants who discontinued by week 49	3 (8.6)	A98G (1), L234I (1), Y318F (1)	None	None
Participants who reached week 49	32 (91.4)
Participants with HIV-1 RNA ≥200 copies/ml at week 49	7 (20.0)a	A98G (1), D67N (1), K103S (1), K219E (1), M184V (1), M41L (1), N348I (1), V106A (2), V106I (1), V106M (1), V179I (2)	F53L (1), L90M (1), M36I (1)	None

DOR, doravirine; IN, integrase; ISL, islatravir; m, number of participants with the specified mutation or resistance; n, participants in the category; OBT, optimized background therapy; PR, protease; RT, reverse transcriptase.

^aNumber of participants who qualified for resistance testing (HIV-1 RNA ≥200 copies/ml); 2 (28.6%) had treatment-emergent viral resistance to DOR, 1 participant (14.3%) had treatment-emergent viral resistance to ISL, and 2 participants (28.6%) had treatment-emergent viral resistance to OBT.

At day 8, the mean increase in CD4⁺ T-cell count was greatest at 51 cells/μl in the DOR/ISL plus baseline ART group (Fig. 3a). In part 2, when all participants received DOR/ISL plus OBT, the mean increase in CD4⁺ T-cell count was 87 cells/μl at week 49 (Fig. 3b).

Fig. 3.

Mean change in CD4⁺ T-cell count from (a) day 1 to day 8 in participants receiving ISL, DOR, DOR/ISL, or placebo plus baseline ART and (b) day 8 to week 25 and week 49 in participants receiving DOR/ISL plus OBT.

ART, antiretroviral therapy; DOR, doravirine; ISL; islatravir, OBT, optimized background therapy; PBO; placebo.

Safety

Through week 49, adverse events were reported for most participants [29 (82.9%); see Table, Supplementary Digital Content 5 – Summary of drug-related adverse events (DRAEs) from day 1 through week 49]. Overall, the most frequently reported adverse events (>20%) were decreased lymphocyte count [3 (21.4%)], COVID-19 [3 (21.4%)], and decreased creatinine clearance [3 (21.4%)]. Seventeen participants (48.6%) experienced DRAEs, which were determined by the investigator to be attributable to DOR/ISL in 9 (25.7%), OBT in 4 (11.4%), and DOR/ISL plus OBT in 2 (5.7%) participants (see Table, Supplementary Digital Content 5). Overall, nine participants (25.7%) reported 11 DRAEs; of these, 5 DRAEs – including pruritus, feeling hot, night sweats, somnolence, and diarrhea – occurred in part 1 of the study. The most common DRAEs were diarrhea [6 (17.1%)] and decreased lymphocyte counts [3 (8.6%)]. Most DRAEs were grade 1 or 2 in severity and none were serious adverse events. Overall, eight participants (22.9%) reported adverse events that were grade 3 or 4 in severity through week 49. Few (n = 3; 8.6%) participants had grade 3 or 4 adverse events that were drug-related and discontinued study drug due to a DRAE (decreased CD4⁺ T-cell lymphocytes, decreased lymphocytes, and obesity).

Two participants (5.7%) had serious adverse events: one participant assigned to ISL plus baseline ART during part 1 had COVID-19-related pneumonia (grade 4) and sepsis (grade 4) at day 225 (week 33), and one participant assigned to DOR plus baseline ART during part 1 had a postoperative wound infection at day 214 (week 31). Neither event was considered drug-related. Three participants (8.6%) discontinued study drug due to an adverse event (decreased CD4⁺ T-cell lymphocyte count, decreased lymphocyte count, and weight gain, respectively); all of these events were considered drug-related. There were no pregnancies reported during the study.

At week 49, the mean percentage change (mean change) from baseline in total lymphocyte count was 21.2% (0.1 × 10⁹ cells/l). Additionally, there were general increases in the mean percentage change (mean change) from baseline in lymphocyte subsets: CD8⁺ T cells decreased by an average 19.9% (a decrease of 24 cells/μl), B cells increased by 97.6% (an increase of 59 cells/μl), and natural killer cells increased by 36.1% (an increase of 14 cells/μl).

Discussion

There has been a significant improvement in HIV treatment options over the past three decades [11,12]. Early antiretroviral regimens had many challenges including high pill burdens, inconvenient dosing schedules, treatment-limiting toxicities, and suboptimal virologic suppression [12]. Sequential monotherapy and failed virologic suppression have resulted in the emergence of multidrug resistance mutations for people with HIV [12]. Currently, treatment guidelines for HTE individuals living with HIV-1, multidrug resistance, and previous virologic failure recommend at least two fully active agents, with at least one agent having a high barrier to resistance; or three fully active drugs [13]. In this study, addition of DOR/ISL (100/0.75 mg) to an existing antiretroviral regimen was associated with decreased HIV-1 RNA levels in HTE adults living with HIV-1 and triple-class genotypic resistance. At day 8, the greatest virologic response was observed among those who received DOR/ISL (100/0.75 mg) plus baseline ART. Virologic suppression of HIV-1 was achieved and maintained in the 20 participants (63%) through 49 weeks of DOR/ISL plus OBT.

The virologic suppression rates observed with DOR/ISL in the current analysis were similar to observations from other similar studies of antiretroviral regimens in HTE individuals living with HIV-1 (including a DOR-containing regimen), where virologic suppression rates were able to be maintained at weeks 48, 96, and 240 [1,14,15].

In this study overall, there was an increase from baseline in average CD4⁺ T-cell counts; however, two participants who received DOR/ISL (100/0.75 mg) discontinued treatment due to decreases in CD4⁺ T-cell counts. No other clinically relevant safety findings were identified. Baseline CD4⁺ T-cell counts have been noted to be lower among HTE participants with multidrug-resistant HIV-1 and protocol-defined virologic failure [2]. Notably, decreased CD4⁺ T-cell counts may be observed in participants receiving DOR/ISL (100/0.75 mg) plus baseline ART, and it has been previously reported that HTE individuals living with HIV-1 are generally more likely to have CD4⁺ T-cell counts less than 200 cells/μl compared with non-HTE individuals [3]. Decreasing total lymphocyte and CD4⁺ T-cell counts have been observed across several clinical studies with ISL at doses of at least 0.75 mg once daily [16]. Due to these findings, a new clinical program with ISL 0.25 mg once daily is being studied based on phase 3 and modeling data in treatment-naive and virologically stable switch populations [17]. Ongoing studies are evaluating a once-daily oral combination of DOR 100 mg and ISL 0.25 mg (DOR/ISL, NCT05766501) for the treatment of HIV-1 infection [16]. However, this new clinical dose will not be investigated in HTE individuals living with HIV-1 as these individuals often harbor multidrug-resistant viruses with multiple NNRTI and NRTI resistance-associated substitutions that may not be adequately covered. While these substitutions can be covered at steady-state levels of ISL 0.25 mg, it takes several weeks to reach those levels. HTE individuals living with HIV may be underdosed during this period with the potential to select for resistance to ISL.

DOR/ISL plus OBT or ART was generally well tolerated. Most DRAEs were attributed to DOR/ISL but discontinuations due to adverse event and DRAE were infrequent, (overall, 8.6%). The majority of drug-related adverse events were grade 1 or 2 in severity and nonserious. At week 49, COVID-19 accounted for the most common infection. No deaths were reported during the study. These findings are consistent with a prior study of DOR in HTE individuals living with HIV-1, where switching to an InSTI-based regimen + DOR was shown to be well tolerated and efficacious [15].

Limitations of this study include the lack of a comparator group after day 8 and a relatively small sample size, with most participants being white and male. Additionally, because participant enrollment was stopped early, changes were implemented for the primary and secondary endpoints, since targeted recruitment numbers could not be reached.

In conclusion, the addition of DOR/ISL (100/0.75 mg) to current baseline antiretroviral regimens may provide virologic benefit to some highly treatment-experienced patients with triple-class resistance. In the current study, the combination of DOR/ISL with OBT provided sustained HIV-1 suppression in HTE individuals living with HIV-1 and was generally well tolerated through 49 weeks of treatment.

Acknowledgements

The authors thank the participants and investigators in the DOR/ISL clinical trial of HIV-1 treatment (MK-8591A-019). The authors acknowledge the many contributions of their colleagues at Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA. The authors thank Luisa M. Stamm of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA, for providing scientific guidance. Medical writing and/or editorial assistance was provided by Jared Cochran, PhD, and Claire Pouwels, BSc, of ApotheCom (Yardley, Pennsylvania, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA.

Data sharing: the data sharing policy, including procedures and restrictions, of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD), is available at https://externaldatasharing-msd.com/.

Author contributions: W.G., E.A.A., and T.C. contributed to the concept and design of the study. A.C., W.G., R.M., T.C., I.K., P.K., S.H., Y.Z., and E.A.A. contributed to the acquisition, analysis, and/or interpretation of data. Y.Z. performed the statistical analyses. The first draft was written by W.G., E.A.A., S.H., Y.Z., and T.C. All authors contributed to the critical revision of the manuscript for important intellectual content and approved the submission of the final draft.

Financial support: funding for this research was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA.

Conflicts of interest

Y.Z., T.C., E.A.A., and W.G. are current or former employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA, and may own stock and/or options in Merck & Co., Inc., Rahway, New Jersey, USA. A.C. has received research funding paid to his institution from Gilead, MSD, IgGenix, Balnaves Foundation, and ViiV Healthcare and received honoraria from Gilead Sciences, Merck & Co., Inc., Rahway, New Jersey, USA, and ViiV Healthcare. R.M. and I.K. have no conflicts of interest to disclose. P.N.K. has received research grants paid to her institution from Gilead Sciences, ViiV Healthcare, GSK, Merck & Co., Inc., Rahway, New Jersey, USA, and Theratechnologies; has received consulting fees from ViiV Healthcare, GSK, Gilead Sciences and Merck & Co., Inc., Rahway, New Jersey, USA; has served on advisory boards for Gilead Sciences, ViiV Healthcare, GSK, and Merck & Co., Inc., Rahway, New Jersey, USA; and own stock or hold stock options in Pfizer, Gilead Sciences, Johnson & Johnson, GSK, Moderna, and Merck & Co., Inc., Rahway, New Jersey, USA. S.H. has received honoraria from or has served on advisory boards for Merck & Co, Inc., Rahway, New Jersey, USA.