Contemporary Antiretroviral Therapy Regimens in People With HIV Who Initiated Treatment in the Pre‐Antiretroviral Therapy Era

The treatment of HIV has evolved dramatically since the pre-antiretroviral therapy (ART) era, when monotherapy with zidovudine (AZT) or dual nucleoside reverse transcriptase inhibitors (NRTIs) therapy was commonly used [1]. A major milestone was the introduction of combination ART in 1996, consisting of two NRTIs plus a key drug, typically a protease inhibitor (PI). Currently, integrase strand transfer inhibitors-based regimen, such as dolutegravir/lamivudine (DTG/3TC) or bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF), as well as long-acting antiretroviral formulations like cabotegravir plus rilpivirine (CAB + RPV), can suppress HIV even in the presence of historical resistance mutations. Nevertheless, lamivudine (3TC) and emtricitabine (FTC) remain widely used, and resistance to these agents is still common [2]. Against this backdrop, we aimed to characterize current ART regimens among heavily treatment-experienced (HTE) people with HIV (PWH), focusing on individuals with over 30 years of continuous ART history. We retrospectively analyzed PWH who initiated antiretroviral drugs (ARVs) at IMSUT Hospital, Institute of Medical Science, The University of Tokyo, before 1996, and continued from April 2019 onwards. Eligible individuals had available HIV RNA data from both early ARVs, and the initiation of an effective three-drug regimen (3DR), and with confirmed virologic outcomes and the most recent ART regimens since April 2019, when B/F/TAF became available in Japan. Clinical data collected included age, the year of initial ARV initiation, HIV RNA levels at the start of effective 3DR, the presence of M184V/I mutations, history of ARV use, and the longitudinal history of ART regimens up to April 2025. Among 202 individuals who initiated ARVs before 1996, 23 remained in follow-up after April 2019. The median current age in 2025 was 64 years (range, 50–82). Initial regimens consisted of NRTI monotherapy in 8 individuals (6 with AZT) and dual NRTI therapy in 14 individuals (Table 1). Seventeen individuals (74%) had detectable viremia at the time of switching to two NRTIs plus a key drug after 1996, with a median HIV RNA of 19,500 copies/mL (range, 740–170,000), while six achieved virologic suppression even before the ART era (Table 2). The M184V mutation had been detected in 7 individuals (30%), and nearly half had prior exposure to 3TC with subsequent virological failure. Since 2019, the most recent regimens included TAF-based regimens in nine individuals and two-drug regimens (2DR) in 12 individuals. B/F/TAF was the most common TAF-based regimen, while DTG/3TC was the predominant 2DR, with one individual who received CAB + RPV (Table 1). Despite diverse treatment histories and prior resistance, all individuals maintained virologic suppression from April 2019 onward. In our cohort, the M184V mutation was detected in 30% of individuals. This relatively low detection rate may reflect the limited availability of resistance testing at that time, as commercial assays were not routinely performed. In addition, most pre-ART era regimens involved AZT, which is not associated with M184V, and none received 3TC monotherapy. These factors likely contributed to the lower observed prevalence [3]. Nevertheless, some individuals experienced viremia on 3TC without any documented resistance mutations, suggesting that 3TC alone was insufficient to fully suppress viral replication. Regarding current regimens, approximately 70% of individuals were on STR, about 40% received TAF-based regimens, and nearly 50% were on 2DR. Overall, most individuals used contemporary standard therapies such as B/F/TAF or DTG/3TC, with a subset on CAB + RPV. These findings suggest that even HTE PWH continue to access ART options with current standard-of-care practices [4, 5]. 3TC and FTC remain widely used, and M184V/I is still the most frequent NRTI- associated mutation. Evidence from Study 4030 shows that B/F/TAF maintains viral suppression even in the presence of M184I [2]. In our cohort, B/F/TAF remained active, indicating that M184I alone may not confer clinically significant resistance. Previous pooled analyses of six clinical trials with over 2000 virologically suppressed participants found pre-existing M184V/I in approximately 10% of cases [6]. Importantly, even when M184V/I coexisted with other resistance-associated mutations, switching to B/F/TAF achieved durable viral suppression in more than 98% of participants, without emergent resistance [6]. Importantly, these data were limited to virologically suppressed individuals already; the impact in treatment-naïve individuals remains less clear. This study has limitations. Of 202 individuals who initiated ARVs during the pre-ART era, only 23 individuals remained in follow-up, raising the possibility of survivor bias. HIV RNA quantification was not available until 1996, and the records of ARV use before that may be incomplete. Nevertheless, this cohort provides rare longitudinal data spanning three decades of continuous therapy in HTE individuals. Regarding treatment options for HTE, as of August 2025, lenacapavir is available in Japan, whereas ibalizumab and fostemsavir remained unapproved [7-9]. In summary, despite drug resistance and extensive treatment histories, these individuals are generally able to maintain virologic suppression with modern ART, underscoring the durability and effectiveness of contemporary regimens in HTE populations. Eisuke Adachi designed and conducted the study and was responsible for writing the manuscript. Eisuke Adachi, Shuhei Okuno, Yoshiaki Kanno, Michiko Koga, and Hiroshi Yotsuyanagi extracted clinical data, including characteristics of PWH and ART regimens, from the in-house database, which were subsequently curated by Eisuke Adachi. Ethics approval was granted by the ethics board of the Institute of Medical Science, University of Tokyo (2022-48-1128). Eisuke Adachi has received honoraria for lectures and advisory board participation from ViiV Healthcare K.K., Tokyo, Japan, ViiV Healthcare, London, UK, GlaxoSmithKline, Brentford, UK, and Gilead Sciences K.K., Tokyo, Japan, and Gilead Sciences Inc., Foster City, CA, USA. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.