Six-Year Japanese Surveillance Finds Sustained HIV Suppression With Dolutegravir/Rilpivirine

A six-year post-marketing surveillance study in Japan found that a small group of people living with HIV who switched from other antiretroviral therapy regimens to dolutegravir/rilpivirine generally maintained viral suppression and stable CD4+ T-cell counts. Among 43 participants included in the safety analysis, three experienced four adverse drug reactions, all classified as non-serious. The longitudinal effectiveness analysis included 41 participants, most of whom remained below 50 HIV RNA copies per milliliter for three years after the switch, while their mean CD4+ T-cell count remained stable. The findings provide real-world evidence for the two-drug combination in a predominantly male Japanese population, but the small sample and specialized clinical setting limit how widely the results can be generalized.

Dolutegravir is an integrase strand-transfer inhibitor, and rilpivirine is a non-nucleoside reverse transcriptase inhibitor. Together, they form a two-drug maintenance regimen intended to replace a three-drug regimen in people whose plasma HIV-1 RNA is already controlled. Earlier open-label, randomized phase 3 studies known as SWORD-1 and SWORD-2 found dolutegravir/rilpivirine to be non-inferior to three-drug antiretroviral therapy over 48 weeks in participants receiving first- or second-line treatment who had maintained stable plasma HIV-1 RNA for at least six months before entering the studies. Subsequent reports found virologic suppression in 89% of participants at 100 weeks and 84% at 148 weeks. The fixed-dose combination was approved in the United States in 2017 and in the European Union and Japan in 2018.

Before the combination was approved in Japan, few domestic clinical studies had evaluated it, leaving limited evidence about long-term use in routine practice. The report presents the final analysis of six years of surveillance conducted through the HIV-Related Drug Cooperative Survey, a nationwide joint post-marketing program organized by manufacturers of HIV medicines under the supervision of Japan’s Ministry of Health, Labour and Welfare. Investigators obtained real-world clinical-use data from 17 specialized institutions that participated in the program and approved publication of participant information. The data-collection period ran from November 26, 2018, to November 26, 2024, while participant registration occurred between December 20, 2018, and March 31, 2022.

Participants received one tablet containing 50 mg of dolutegravir and 25 mg of rilpivirine, taken with or immediately after a meal according to the product instructions. A total of 44 people were registered. One participant who had no visit after the initial visit was excluded from the safety analysis, leaving 43 participants. Two additional participants were excluded from the effectiveness analysis because required before-and-after measurements of plasma HIV RNA and peripheral CD4+ T-cell counts were missing. Of the safety population, 42, or 97.67%, were Japanese and 39, or 90.70%, were men; the mean age was 53.3 years. The researchers did not conduct sex-based analyses because the safety group included only four women. Every participant had previously received other antiretroviral therapy and switched to dolutegravir/rilpivirine. Thirty-three participants, 76.74% of the safety group, received the combination for more than two years.

Safety was evaluated through adverse events judged by either the treating investigator or the study sponsor to have a possible causal relationship with treatment. When their seriousness assessments differed, the more severe classification was used. Four adverse drug reactions were reported in three participants, corresponding to 6.98% of the safety population. These consisted of increased weight in one person, hypertension in one, hyperuricemia in one, and aggravated hyperuricemia, recorded as condition aggravated, in the same participant with hyperuricemia. Weight increase appeared two days after treatment began, hypertension was recorded at day 393, and aggravated hyperuricemia at day 841. Hypertension had recovered, weight increase was recovering, and aggravated hyperuricemia had not recovered at the relevant assessment. None of the reactions was serious or corresponded to the important identified or potential risks listed in the Japanese risk-management plan, including depression.

Exploratory comparisons found statistically significant differences in adverse-reaction incidence when participants were grouped by treatment duration, baseline hepatic disorder, and baseline renal disorder, with reported p values of 0.003, 0.002, and 0.029, respectively. These are associations in a small observational dataset, not definitive risk estimates or evidence that the characteristics caused the reactions. The authors cautioned that no firm conclusions could be drawn because the sample was limited and only three participants experienced adverse drug reactions, with two events occurring in the same person. None of eight participants taking additional concomitant antiretroviral medicines developed a reaction, but the study could not isolate the effects of dolutegravir/rilpivirine from those of concomitant medications. Hypertension and hyperuricemia had also appeared in earlier Japanese post-marketing surveillance of other dolutegravir-containing products, but their frequencies could not be compared directly because the safety-assessment methods differed.

Among the 41 participants in the effectiveness analysis, the mean plasma HIV RNA concentration at baseline was 1.3 log copies per milliliter, equivalent to 20 copies per milliliter. Most remained below 1.7 log copies per milliliter, corresponding to 50 copies per milliliter, throughout the three years after switching. One participant had a value of 1.7 log copies per milliliter at baseline and another reached that value at 21 months. The mean peripheral CD4+ T-cell count was 563.3 cells per cubic millimeter, with a standard deviation of 207.2 cells per cubic millimeter, and remained stable over the three-year period. The proportion of participants with counts of at least 500 cells per cubic millimeter ranged from 30.8% to 100% during follow-up. One man had a count below 200 cells per cubic millimeter at nine months, but his HIV RNA remained below 20 copies per milliliter during the three years and he experienced no adverse drug reaction.

The regimen has no activity against hepatitis B virus, an important distinction because Japanese guidance recommends screening for hepatitis B before starting antiretroviral therapy and selecting agents active against both viruses for people with co-infection. Three participants had concomitant hepatitis B at baseline, but no events related to hepatitis B infection or reactivation were reported throughout surveillance. Plasma HIV RNA and CD4+ T-cell counts were measured at baseline and every three months using each institution’s established methods. Missing data were not imputed, and the longitudinal results therefore reflect available measurements rather than a complete dataset. Fisher’s exact test and the chi-square test were used for comparisons of dichotomous variables and variables with three or more categories, respectively, with a two-sided significance level of 5% and no adjustment for multiple comparisons.

Several limitations constrain the interpretation and generalizability of the findings. The cohort included only 44 registered participants at 17 specialized facilities, and its composition—predominantly Japanese men with a mean age above 50—may not represent the full diversity of people living with HIV in Japan. Survey forms did not always contain consistent laboratory data, potentially resulting in missing or overlooked abnormal results, and information on treatment discontinuation was not comprehensively captured. The study followed people who were already virologically suppressed and switching regimens rather than evaluating treatment initiation in people with uncontrolled HIV. The report also counted reactions considered potentially attributable to treatment, whereas many clinical studies report all adverse events regardless of causality, limiting direct comparisons with trial results. The analysis was primarily descriptive, and the small number of events prevents firm conclusions about the exploratory associations involving treatment duration or baseline hepatic and renal disorders.

Within those boundaries, the final six-year report supports the real-world safety and effectiveness of dolutegravir/rilpivirine as a two-drug maintenance option for selected people in Japan whose HIV RNA was controlled before the switch. Most participants maintained suppression and stable CD4+ T-cell counts, while serious or potentially important treatment-related adverse reactions were not observed. The result extends earlier phase 3 evidence into Japanese clinical practice over six years of surveillance, with detailed effectiveness follow-up reported for three years. It does not establish that the regimen is equally safe or effective for every population, nor does it resolve the small exploratory associations involving hepatic or renal disorders. Rather, the report provides a carefully bounded real-world signal that can inform physicians treating the limited group of people who received the combination through the national cooperative program.

Subject of Research: Real-world safety and effectiveness of dolutegravir/rilpivirine maintenance therapy in a small Japanese cohort living with HIV.

Article Title: Safety and Effectiveness of Dolutegravir/Rilpivirine in Japanese People Living with HIV: Final Report of 6-Year Post-marketing Surveillance Study

Article References: Sebata, A., Nagao, T., Matsukawa, T., Yoshikawa, Y., Fukuda, A., & Wang, D. (2026). Safety and Effectiveness of Dolutegravir/Rilpivirine in Japanese People Living with HIV: Final Report of 6-Year Post-marketing Surveillance Study. Advances in Therapy. https://doi.org/10.1007/s12325-026-03812-z

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03812-z

Keywords: HIV, Dolutegravir, Rilpivirine, Antiretroviral therapy, Post-marketing surveillance, Viral suppression, CD4+ T cells, Adverse drug reactions, Japan, Real-world evidence, Safety, Effectiveness