Long-Term Successful Virological Suppression with Dolutegravir Monotherapy in the EARL-SIMPLIFIED Trial
August 1, 2023
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By Jake Scott, MD
Clinical Assistant Professor, Infectious Diseases and Geographic Medicine, Stanford University School of Medicine; Antimicrobial Stewardship Program Medical Director, Stanford Health Care Tri-Valley
SYNOPSIS: Dolutegravir monotherapy was demonstrated to be non-inferior as compared with combination antiretroviral therapy in EARLY-SIMPLIFIED, a randomized, controlled trial with long-term follow-up that included a highly selected group of people with HIV-1 infection.
SOURCE: West E, Zeeb M, Grube C, et al. Sustained viral suppression with dolutegravir monotherapy over 192 weeks in patients starting combination antiretroviral therapy during primary HIV infection (EARLY-SIMPLIFIED): A randomized, controlled, multi-site, non-inferiority trial. Clin Infect Dis 2023; Jun 20;ciad366. doi: 10.1093/cid/ciad366. [Online ahead of print].
West and colleagues conducted a randomized, open-label, non-inferiority trial that evaluated dolutegravir (DTG) monotherapy as compared with combination antiretroviral therapy (ART) for a selected group of persons living with human immunodeficiency virus type 1 (PLWH), with follow-up conducted during the randomized phase up to 96 weeks and until the study end at 192 weeks.1 This trial was an extension of an earlier pilot study (EARLY-SIMPLIFIED) conducted by Braun and colleagues, which had previously reported non-inferiority at week 48, with no virological failures in either group.2
Participants were recruited from multiple centers in Switzerland and included adults who had started combination ART (cART) within six months of the estimated date of human immunodeficiency virus (HIV) infection. The study also was restricted to patients who maintained virological suppression (HIV-1 ribonucleic acid [RNA] less than 50 copies/mL) while on at least 48 weeks of therapy, had no previous ART failure, no prior interruption of therapy, and no history of major integrase strand transfer inhibitor (INSTI)-resistant mutations nor hepatitis B infection.
The primary endpoint of the study was non-inferiority vs. cART based on virological failures in the DTG monotherapy group at 48, 96, 144, and 192 weeks. Virological failure was defined as at least two consecutive viral load measurements greater than 50 HIV-1 plasma RNA copies/mL over a period of at least 14 days. Secondary endpoints included CD4 T cell changes over time and between groups, differences in adverse events, weight change on DTG monotherapy, HIV deoxyribonucleic acid (DNA) reservoir size, and the occurrence of blips (defined as one viral load measurement between 50 and 400 HIV-1 RNA plasma copies/mL, followed by a value of ≤ 50 HIV-1 plasma RNA copies/mL within 30 days).
Participants were randomized in a 2:1 ratio to DTG monotherapy (n = 68, 67%) or cART (n = 33, 33%) and were assessed every three months. Baseline characteristics were well balanced. Median overall age was 42 years, 97% identified as male, 92% were Caucasian, and 84% were men who have sex with men (MSM). Median days from HIV infection until initiation of ART was 36 in the cART group (interquartile range [IQR], 29.0-113.0) and 38 (IQR, 27.5-73.0) in the DTG monotherapy group. Baseline median CD4 cell count was 669 (IQR, 545-881) and 730 (IQR, 610-920), and median CD4 cell count nadir was 329 (IQR, 269-442) and 377 (IQR, 263-496), respectively. Treatment was continued for an overall median of 3.60 (IQR, 1.96-5.98) years prior to study entry.
Thirteen (39.4%) participants in the cART group were on a DTG-based regimen at baseline, as compared with 33 (48.5%) in the DTG monotherapy group. Four participants in the monotherapy group and three in the cART group were excluded from the study due to various reasons. At 96 weeks, DTG monotherapy was shown to be non-inferior as compared with cART in the per-protocol analysis. There were no virological failures in either group; 64 out of 64 participants remained virally suppressed on DTG monotherapy and 30 out of 30 remained suppressed on cART. Non-inferiority also was demonstrated in the intention-to-treat analysis; 67 of 68 in the DTG monotherapy and 33 of 33 in the cART group were virally suppressed (1.47%; 95% confidence interval [CI], -100%, 7.59%). The one virological “failure” in the monotherapy group had been excluded during the pilot phase of the study after it had been discovered that the patient did not fulfill the definition of a primary HIV-1 infection and had been incorrectly enrolled in the study.
After randomization had been lifted at 96 weeks, 18 participants in the cART group chose to switch to DTG monotherapy, and no participants in either group had documented virological failure as of the last study follow-up at week 192. There were no serious adverse events classified as related to any ART regimen in either group. Study drug-related adverse events were noted in 15 of 68 (22.1%) participants in the DTG monotherapy group and 10 of 33 (30.3%) in the cART group. Adherence, which was assessed during study visits by asking participants about missed doses and checking ART packets for the number of remaining pills, was 99.79% in the DTG monotherapy group and 99.62% in the cART group. Baseline latent HIV-1 DNA reservoir size, as measured by digital polymerase chain reaction (PCR), was low (≤ 2.0 log/106 peripheral blood mononuclear cells [PBMCs]) in both groups and decreases in size were similar while on the different study ART regimens. There was no statistical difference in blips between the groups.
COMMENTARY
The successful treatment of HIV infection depends on long-term, uninterrupted adherence to ART. The first drug approved for HIV infection was oral azidothymidine (AZT), which was shown in a study published in 1987 to significantly reduce mortality and opportunistic infections among people with advanced HIV, albeit with serious adverse effects.3 Monotherapy with AZT led to the rapid development of HIV resistance, however, which became a serious limitation. Combination therapy, which was shown to be more effective and less susceptible to resistance, eventually became the standard of care. While modern ART regimens have become better tolerated and simpler to take, minimizing antiretroviral regimen complexities, side effects, toxicity, and costs remain important goals. INSTI-based regimens that include either one or two nucleoside and nucleotide reverse-transcriptase inhibitors (NRTIs) currently are recommended as first-line initial therapy for most people with HIV infection.4-6 DTG, a second-generation INSTI given once daily, is highly potent and has an especially high barrier to resistance, a favorable pharmacokinetic/pharmacodynamic profile, an excellent tolerability and safety profile, and few drug-drug interactions. DTG plus lamivudine is the only two-drug regimen that currently is recommended and is limited to those with an HIV RNA level less than 500,000 copies/mL and without hepatitis B coinfection or historical resistance.
DTG monotherapy is not currently recommended due to virological failures with emergent INSTI-resistant mutations that had been reported in the three other DTG monotherapy randomized controlled trials (RCTs), DOMONO, DOLAM, and MONCAY.7-9 A meta-analysis of individual participant data from these three RCTs and from the initial pilot phase of the EARLY-SIMPLIFIED trial had shown a significantly increased risk of virological failure among those on DTG monotherapy (16 of 227 [7%]) as compared with those on combination ART (0 of 189) (risk difference 7%; 95% CI, 1% to 2%; P = 0.02; I2 = 51%).10 Risk factors for virological failure among those who received DTG monotherapy included initiation of combination ART at least 90 days after acute HIV infection, CD4 T cell nadir less than 350 cells/mm3, HIV RNA signal at baseline, and larger viral reservoir (HIV DNA copy greater than 2.7 log/106 PBMCs).
Five retrospective, single-center cohort studies of PLWH who had been switched to DTG monotherapy after long-term viral suppression have been published.11-16 Of the 171 individuals in these studies, six (3.5%) developed what was considered to be virological failure. One of these patients chose to discontinue DTG therapy, despite being virologically suppressed, because of reasons that were not deemed to be related to the drug. All five individuals who experienced detectable plasma HIV RNA (i.e., viral loads) while on DTG monotherapy previously had received an INSTI-containing ART.
EARLY-SIMPLIFIED enrolled a highly selected group of PLWH who had initiated combination ART soon after infection, maintained virological suppression, and therefore had a relatively high CD4 cell count nadir and limited latent HIV reservoir size. They also had no prior virological failure nor evidence of major INSTI-resistance mutations and had very high rates of ART adherence. All of these are factors that likely predict monotherapy treatment success, yet they are clearly an optimal set of characteristics that are not universal. While DTG monotherapy may be intriguing for carefully selected patients based on these data, advances in technologies to measure latent HIV reservoirs and detect resistance are needed, and further research into the risk of virological failure and clinical outcomes should continue.
REFERENCES
- West E, Zeeb M, Grube C, et al. Sustained viral suppression with dolutegravir monotherapy over 192 weeks in patients starting combination antiretroviral therapy during primary HIV infection (EARLY-SIMPLIFIED): A randomized, controlled, multi-site, non-inferiority trial. Clin Infect Dis 2023; June 20:ciad366. [Online ahead of print].
- Braun DL, Turk T, Tschumi F, et al. Noninferiority of simplified dolutegravir monotherapy compared to continued combination antiretroviral therapy that was initiated during primary human immunodeficiency virus infection: A randomized, controlled, multisite, open-label, noninferiority trial. Clin Infect Dis 2019;69:1489-1497.
- Fischl MA, Richman DD, Grieco MH, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med 1987;317:185-191.
- Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. HIV Clinical Guidelines: Adult and Adolescent ARV - What’s New in the Guidelines. Published March 23, 2023. https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-arv/whats-new
- Gandhi RT, Bedimo R, Hoy JF, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2022 recommendations of the International Antiviral Society-USA Panel. JAMA 2023;329:63-84.
- European AIDS Clinical Society. EACS Guidelines 2022. https://eacs.sanfordguide.com
- Wijting I, Rokx C, Boucher C, et al. Dolutegravir as maintenance monotherapy for HIV (DOMONO): A phase 2, randomised non-inferiority trial. Lancet HIV 2017;4:e547-e554.
- Blanco JL, Rojas J, Paredes R, et al. Dolutegravir-based maintenance monotherapy versus dual therapy with lamivudine: A planned 24 week analysis of the DOLAM randomized clinical trial. J Antimicrob Chemother 2018;73:1965-1971.
- Hocqueloux L, Raffi F, Prazuck T, et al. Dolutegravir monotherapy versus dolutegravir/abacavir/lamivudine for virologically suppressed people living with chronic human immunodeficiency virus infection: The Randomized Noninferiority MONotherapy of TiviCAY Trial. Clin Infect Dis 2019;69:1498-1505.
- Fournier AL, Hocqueloux L, Braun DL, et al. Dolutegravir monotherapy as maintenance strategy: A meta-analysis of individual participant data from randomized controlled trials. Open Forum Infect Dis 2022;9:ofac107.
- Katlama C, Soulié C, Caby F, et al. Dolutegravir as monotherapy in HIV-1-infected individuals with suppressed HIV viraemia. J Antimicrob Chemother 2016;71:2646-2650.
- Rojas J, Blanco JL, Marcos MA, et al. Dolutegravir monotherapy in HIV-infected patients with sustained viral suppression. J Antimicrob Chemother 2016;71:1975-1981.
- Gubavu C, Prazuck T, Niang M, et al. Dolutegravir-based monotherapy or dual therapy maintains a high proportion of viral suppression even in highly experienced HIV-1-infected patients. J Antimicrob Chemother 2016;71:1046-1050.
- Oldenbuettel C, Wolf E, Ritter A, et al. Dolutegravir monotherapy as treatment de-escalation in HIV-infected adults with virological control: DoluMono cohort results. Antivir Ther 2017;22:169-172.
- Lattuada E, Lanzafame M, Nicolè S, et al. Dolutegravir monotherapy in HIV-1-suppressed patients: A feasible regimen in real life. Int J STD AIDS 2018;29:206-207.
- Tebano G, Soulié C, Schneider L, et al. Long-term follow-up of HIV-infected patients on dolutegravir monotherapy. J Antimicrob Chemother 2020;75:675-680.
Dolutegravir monotherapy was demonstrated to be non-inferior as compared with combination antiretroviral therapy in EARLY-SIMPLIFIED, a randomized, controlled trial with long-term follow-up that included a highly selected group of people with HIV-1 infection.
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