Reply to Comment on “Prevalence of Naturally Occurring HIV-1 Capsid Inhibitor Resistance-related Mutations in Antiretroviral Therapy-naïve and -Experienced Individuals in Taiwan”

To the  Editor—We appreciate the thoughtful comments and the opportunity to clarify the intentions and context of our study titled “Prevalence of Naturally Occurring HIV-1 Capsid Inhibitor Resistance-related Mutations in Antiretroviral Therapy-naïve and -Experienced Individuals in Taiwan.” The primary objective of our investigation was to examine capsid protein mutations in a cohort of people with human immunodeficiency virus (HIV) (PWH) in Taiwan, prior to the introduction of the first HIV-1 capsid inhibitor, lenacapavir, in the country. Our motivation stemmed from a frequently cited—but unsubstantiated—assertion heard at international meetings: that PWH without prior exposure to lenacapavir do not harbor resistance to this agent. Alongside 2 other studies [1, 2] referenced in our article, our findings demonstrated the presence of naturally occurring capsid inhibitor resistance-related mutations even in treatment-naïve populations.

We acknowledge the limitations of a retrospective study conducted within a single geographic region. However, the publication of our findings was intended to raise awareness of the potential existence of such mutations in nature. In anticipation of concerns regarding clinical relevance, we limited our analysis to previously reported mutations associated with resistance to focus on the most interpretable and evidence-based targets. This should not be interpreted as implying that other mutations are unimportant. Rather, due to the lack of appropriate laboratory infrastructure, we were unable to investigate novel variants independently. We believe that the responsibility for identifying and characterizing additional significant mutations should also be shared by pharmaceutical manufacturers, who are likewise in a position to evaluate the genetic barrier of their products in comparison to other available antiretroviral agents.

Regarding the inclusion of the capsid region in routine HIV-1 genotypic resistance testing, we refrained from taking a definitive stance in the manuscript, recognizing that the decision is highly dependent on local resources and public health priorities. Given the relatively low prevalence of these mutations observed to date, routine screening may not currently be cost-effective. Nevertheless, as the clinical use of capsid inhibitors expands, we propose that periodic surveillance sampling, including capsid region sequencing, could be a practical future approach to inform local treatment strategies.

As for the clinical significance of specific mutations such as Q67H or Q67R, we agree that their relatively low prevalence at present may limit the feasibility and necessity of launching dedicated prospective trials. Establishing a centralized standard for monitoring these mutations may likewise be premature. However, we concur that these mutations merit longitudinal monitoring to assess their persistence and potential selection dynamics should capsid inhibitors become more widely used.

We are grateful for the feedback and welcome continued discussion regarding preemptive surveillance and resistance testing strategies for emerging antiretroviral therapies.