Similar Efficacy, Safety, and Immune Improvement Through 96 Weeks in Individuals With Limited HIV-1 Treatment Options Using Twice-Daily Dolutegravir- or Fostemsavir-based Regimens

Abstract

Constructing suppressive regimens for individuals with multidrug-resistant HIV-1 can be challenging. Separate analyses of 96-week outcomes from the phase 3 VIKING-3 and BRIGHTE studies demonstrate that twice-daily dolutegravir-based and fostemsavir-based regimens each provide robust viral suppression, favorable safety profiles, and CD4+ T-cell count improvement in this population.

Clinical trial registration VIKING-3: ClinicalTrials.gov identification number, NCT01328041; URL, https://clinicaltrials.gov/study/NCT01328041; BRIGHTE: ClinicalTrials.gov identification number, NCT02362503; URL, https://clinicaltrials.gov/study/NCT02362503

Graphical Abstract

Graphical Abstract.

Alt text: Graphical abstract summarizing virologic response, immune outcomes, and safety profiles for dolutegravir-based regimens in the VIKING-3 study and fostemsavir-based regimens in the BRIGHTE study.

Constructing effective, safe antiretroviral therapy (ART) regimens for people with multidrug-resistant (MDR) HIV-1 remains challenging due to complex resistance mutations and limited therapeutic options [1–4]. Reduced efficacy can occur through accumulation of drug-resistant mutations driven by exposure to successive failed ART regimens [2]. Without potent, well-tolerated options, individuals face greater risks of virologic failure, immunologic decline, and HIV-related morbidity and mortality [5, 6]. Optimizing regimens for MDR HIV requires an individualized approach with 2 or 3 fully active agents based on resistance testing and treatment history [5, 7]. Agents with a high barrier to resistance can improve potency and durability, and adherence strategies can further reduce resistance development [5, 8]. Therapies with unique mechanisms of action and favorable resistance profiles are essential for durable virologic suppression (VS), robust immune recovery, and improved outcomes.

Dolutegravir is the benchmark of HIV treatment [9–12], including advanced HIV [13], due to its durable efficacy, favorable safety profile [14], and high barrier to resistance [8]. It is widely used [9, 11, 15] and recommended as the core agent in first- and later-line treatments [10–12]. Fostemsavir is a first-in-class attachment inhibitor indicated for MDR HIV in heavily treatment-experienced (HTE) populations [16]. The phase 3 VIKING-3 and BRIGHTE studies evaluated twice-daily dolutegravir- and fostemsavir-based regimens, respectively, in people with HIV with limited antiretroviral options [16, 17]. In VIKING-3, dolutegravir-based regimens showed robust antiviral activity and a good tolerability profile in a highly treatment-experienced population with advanced HIV through 24 weeks [17]. In BRIGHTE, fostemsavir-based regimens demonstrated a favorable safety profile with sustained VS and immunologic recovery through Week 240 [18].

To understand the impact of dolutegravir- and fostemsavir-based regimens in HTE populations, 96-week results from VIKING-3 (dolutegravir BID) are presented alongside 96-week results from BRIGHTE (fostemsavir).

METHODS

Study Populations

VIKING-3 (NCT01328041) included adults with MDR HIV who were HTE and on failing regimens containing raltegravir or elvitegravir, with ≥1 fully active antiretroviral available. BRIGHTE (NCT02362503) included adults with MDR HIV on failing regimens, with ≤2 fully active antiretroviral classes available (the randomized cohort, which had 1 to 2 fully active antiretrovirals, is the focus of this analysis) [16, 17]. See Supplementary Methods for details.

Patient Consent Statement

All participants provided written informed consent [16, 17]. See Supplementary Methods for ethics information.

Outcomes

Proportions of participants with VS by Snapshot (VIKING-3, HIV RNA <50 copies/mL; BRIGHTE, HIV RNA <40 copies/mL) and observed analysis (VIKING-3, HIV RNA <50 and <400 copies/mL; BRIGHTE, HIV RNA <40 and <400 copies/mL) were assessed through Week 96. For VIKING-3, observed analysis only was used after Week 48 (see Supplementary Methods). CD4+ T-cell count, CD4+/CD8+ ratio, and safety outcomes were assessed through Week 96. CD4+ T-cell percentage was assessed in BRIGHTE only. See Supplementary Methods for statistics.

RESULTS

VIKING-3

Demographics and Baseline Characteristics

VIKING-3 included 183 participants (Supplementary Table 1). The median age was 48 years, and most participants were assigned male sex at birth (77% [141/183]) and White (71% [130/183]). Baseline genotypic primary integrase resistance was detected in 67% (123/183) of participants; the most common antiretrovirals in initial optimized background therapy (OBT) were ritonavir-boosted darunavir (65% [119/183]) and tenofovir disoproxil fumarate/emtricitabine (60% [109/183]). The median (range) baseline CD4+ T-cell count was 140 (19–1100) cells/mm³.

Virologic Outcomes

In the intention-to-treat–exposed population, 69% (126/183) and 63% (116/183) of participants had HIV RNA <50 copies/mL (Snapshot) at Weeks 24 and 48, respectively. By observed analysis, proportions with virologic response were 84% (101/120; <50 copies/mL) and 93% (111/120; <400 copies/mL) at Week 96 (Figure 1A).

Figure 1.

(A), Virologic response by observed analysis, (B) change in median (IQR) CD4+ T-cell count, and (C) median CD4+/CD8+ ratio through Week 96 in participants receiving twice-daily dolutegravir-based regimens in VIKING-3. BL, baseline. ^aParticipants completed the study once dolutegravir became commercially available after Week 48. An observed analysis was used to avoid classifying these participants as non-responders under the Snapshot algorithm (ie, participants with missing data at each timepoint were excluded). ^bAnalysis not performed as CD8+ T-cell count data were not collected after Week 48.

Immunologic Outcomes

Improvements in CD4+ T-cell count and CD4+/CD8+ ratio were observed through Weeks 96 and 48, respectively. The median CD4+ T-cell count increase from baseline to Week 96 was 160 cells/mm³ (Figure 1B). The median CD4+/CD8+ ratio increased from 0.15 at baseline to 0.32 at Week 48 (CD8+ T-cell count not collected at Week 96; Figure 1C).

Safety

Through the end of the study, 92% (169/183) of participants experienced adverse events (AEs; Supplementary Table 2). Serious AEs occurred in 25% (46/183) of participants; 1% (2/183) were drug-related. Serious AEs were most commonly from the infections and infestations system organ class. Discontinuations due to AEs occurred in 4% (8/183) of participants.

BRIGHTE Randomized Cohort

Demographics and Baseline Characteristics

The randomized cohort included 272 participants (Supplementary Table 3). The median age was 48 years; most participants were assigned male sex at birth (74% [200/272]) and White (68% [185/272]). Baseline genotypic integrase resistance was detected in 43% (118/272) of participants. The most common antiretrovirals in initial OBT were dolutegravir (84% [229/272]) and darunavir (49% [134/272]). The median (range) baseline CD4+ T-cell count was 100 (0–1160) cells/mm³. Details on baseline susceptibility of dolutegravir and darunavir have been published previously [19].

Virologic Outcomes

In the intention-to-treat–exposed population, 60% (163/272) of participants had HIV RNA <40 copies/mL (Snapshot) at Week 96. By observed analysis, proportions with virologic response were 79% (170/214; <40 copies/mL) and 88% (189/214; <400 copies/mL) at Week 96 (Figure 2A).

Figure 2.

(A), Virologic response by observed analysis, (B) change in median (IQR) CD4+ T-cell count, and (C) median CD4+/CD8+ ratio through Week 96 in participants receiving fostemsavir-based regimens in the randomized cohort of BRIGHTE. Participants who discontinued the study, were on study but missing virologic data, or completed the study, were not included in observed analyses. BL, baseline.

Immunologic Outcomes

Improvements in CD4+ T-cell count and CD4+/CD8+ ratio were observed through Week 96. From baseline to Week 96, median CD4+ T-cell count increased by 175 cells/mm³ (Figure 2B), and mean CD4+ T-cell percentage increased by 8.4% (baseline mean, 10.6%). The median CD4+/CD8+ ratio increased from 0.14 at baseline to 0.36 at Week 96 (Figure 2C).

Safety

Through Week 96, 92% (249/272) of participants experienced AEs. Serious AEs occurred in 34% (92/272) of participants; 3% (9/272) were drug-related (Supplementary Table 4) [16]. Serious AEs were most commonly from the infections and infestations system organ class. Discontinuations due to AEs occurred in 5% (14/272) of participants.

DISCUSSION

Dolutegravir- and fostemsavir-based regimens each provided robust VS and improvement in CD4+ T-cell count and CD4+/CD8 + ratio up to 96 weeks in populations with MDR HIV. VIKING-3 results demonstrate the benefit of dolutegravir for individuals with first-generation integrase inhibitor resistance and limited treatment options, with 84% of participants with available data achieving VS at Week 96. Median CD4+ T-cell count increased by 160 cells/mm³ by Week 96, supporting a robust immunologic response. In BRIGHTE, 79% of participants with available data receiving fostemsavir achieved VS, with improvement in the immune landscape observed at Week 96 (175 cells/mm³ increase in median CD4+ T-cell count; 8.4% increase in mean CD4+ T-cell percentage). Dolutegravir-based and fostemsavir-based regimens were generally well-tolerated with few safety-related discontinuations.

Assessing viral resistance in clinical trials is inherently challenging [20]. In BRIGHTE, fostemsavir-based regimens were combined with physician-selected OBT based on individual genotypic and phenotypic resistance profiles, with dolutegravir used in 84% of participants, 75% BID [16]. Most participants in BRIGHTE had raltegravir resistance, and dolutegravir demonstrated efficacy in individuals with raltegravir resistance in VIKING-3. The broad use of dolutegravir in BRIGHTE is likely a reflection of its high barrier to resistance [8], antiviral potency, favorable safety profile [17], and compatibility with other antiretrovirals in populations with limited treatment options. Dolutegravir is a well-established antiretroviral used globally and recommended as a core component of many first- and later-line ART regimens [9–12, 15, 21].

Dolutegravir and fostemsavir are commonly used for MDR HIV [1] due to their favorable safety [16, 17] and drug-drug interaction profiles [22, 23]. Additionally, dolutegravir remains the only second-generation integrase inhibitor approved for people with integrase resistance [24]. The pharmacologic profiles of dolutegravir and fostemsavir support use in individuals taking multiple concomitant medications, potentially reducing the risk of AEs and interactions that could affect adherence and efficacy. As a result, these agents may provide clinical flexibility in the setting of polypharmacy, enabling sustained VS and immune recovery in individuals with complex needs and limited options, potentially improving long-term outcomes and quality of life.

Fostemsavir-based regimens have demonstrated durable VS and sustained immune recovery, with 74% of participants with baseline CD4+ T-cell counts <50 cells/mm³ achieving counts ≥200 cells/mm³ at Week 240 [18], an improvement which correlated with fewer AIDS-defining events [23]. Additionally, a plateauing response was observed across key biomarkers independently associated with disease progression that are typically elevated in HIV [25, 26]. This stabilization may indicate a dampening of systemic inflammatory burden. These findings support the long-term efficacy of fostemsavir with improvement in immune function irrespective of geography, race, age, or sex in this diverse cohort [27].

Limitations of VIKING-3 and BRIGHTE include the lack of a comparator group and the confounder of highly individualized background therapies required by these cohorts. These limitations are inherent to the complex treatment needs of this population. Although not intended as comparative studies, there are differences between VIKING-3 and BRIGHTE. VIKING-3 was conducted from 2011 to 2015, and BRIGHTE was initiated in 2015 and recently presented findings at 7 years (Week 336) [26]. Some BRIGHTE participants may have participated in VIKING-3 and would have greater treatment experience at the start of BRIGHTE [28]. Baseline characteristics differed between studies, with immunosuppression at baseline being more pronounced in participants from BRIGHTE. Nonetheless, in both studies, participants showed immune improvement despite profound baseline immunosuppression.

In individuals with limited antiretroviral options, BID dolutegravir- and fostemsavir-based regimens demonstrated efficacy, safety, and CD4+ T-cell count recovery through Week 96. Mortality was low in VIKING-3 (n=2) and BRIGHTE (n=12; randomized cohort) despite 56% and 85% of participants, respectively, having prior AIDS-defining events. Twice-daily dolutegravir is established as a core agent for people with MDR HIV [3]. Fostemsavir is also an effective and well-tolerated treatment option in this population. These data provide valuable insights into the long-term durability and tolerability of these antiretrovirals, informing clinical decision-making for managing individuals with limited therapeutic options.

Supplementary Data

Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.