Toward Ending HIV: Integrase Inhibitors Transform Treatment but Resistance and Inequities Persist

Two decades of relentless pharmacological innovation have transformed HIV from a uniformly fatal diagnosis into a manageable chronic infection for millions of people. Antiretroviral regimens are now simpler, less toxic and dramatically more effective, driving down deaths, new infections and the risk of onward transmission. Yet a new editorial in Frontiers in Epidemiology, introducing a Research Topic on HIV epidemiology and emerging drug resistance in the integrase strand transfer inhibitor (INSTI) era, argues that the path toward genuine epidemic control remains long and uneven. Seventeen manuscripts, primarily original research, reveal that while some countries have reached the UNAIDS target of 95 percent diagnosed, 95 percent treated and 95 percent virologically suppressed, most regions still have fewer than 75 percent of people on treatment achieving virological control.

The editorial, authored by Diego Ripamonti of Papa Giovanni XXIII Hospital in Bergamo, Maria Santoro and Francesca Ceccherini Silberstein of the University of Rome Tor Vergata, Joseph Fokam of CIRCB in Yaoundé, Cameroon, and Josep M. Llibre of CIBER Epidemiology and Public Health in Badalona, Spain, frames the collection around a central tension. The extensive roll-out of dolutegravir (DTG), a second-generation INSTI, across Africa has been followed by treatment-emergent resistance, largely because of the high prevalence of reverse transcriptase-associated mutations in those regions. Recent estimates place DTG-based antiretroviral therapy resistance rates in Sub-Saharan Africa between 3.9 and 19.6 percent, a range that threatens the durability of the region’s most important therapeutic advance.

Several studies in the collection deploy molecular epidemiology to map how HIV moves through populations. Gan and colleagues used molecular network technology based on HIV pol gene sequences to reveal transmission links among 1,162 men who have sex with men in Northeast China. By combining degree centrality and betweenness centrality, network measures that identify individuals with many connections or positions bridging transmission clusters, the team pinpointed people at high risk of onward transmission. Such targeting matters because undiagnosed people with HIV are the primary drivers of sustained transmission, and network analysis can direct interventions toward the individuals most likely to spread the virus.

Molecular phylogenetics also illuminated the history of epidemics in Eastern Europe and Central Europe. Kirpich and colleagues conducted the first systematic molecular epidemiology study of the HIV epidemic in Belarus, revealing two distinct epidemic waves spanning 1997 to 2005 and 2009 to 2018, each driven by different dominant modes of transmission. Reconstruction of HIV introduction routes confirmed linkages with neighboring Russia and Ukraine. In Hungary, Zsichla and colleagues analyzed partial pol sequences from 1,120 subjects collected between 2008 and 2024, finding that recent infections originate mainly from domestic transmission among men who have sex with men, with increasing introductions of non-B subtypes arriving from Eastern Europe.

Transmission risk is not determined by viral genetics alone but by virological status. He and colleagues surveyed 35,513 people with HIV in Zhejiang province, China, in 2022, categorizing sexual transmission risk across four plasma HIV RNA levels, from minimal risk among those below 50 copies per milliliter on antiretroviral therapy to high risk among those viremic off treatment. The vast majority, 88.6 percent, showed effective virological control on therapy with no transmission risk. However, people aged 16 to 24 years, men, heterosexuals and those with shorter follow-up had increased odds of being at risk, highlighting the need for more focused prevention education. Shi and colleagues tested contact tracing among 1,612 newly diagnosed people with HIV in Yunnan Province, identifying 2,226 close contacts of whom 17.8 percent tested positive for HIV, mostly newly diagnosed. Detection rates were higher among contacts identified by recently infected index cases, suggesting how tracing programs can be refined for efficiency.

Community viral load, the mean of individual plasma HIV RNA levels in a geographical area, serves as a measure of both the effectiveness of the HIV care cascade and the population’s transmission potential. Arsuffi and colleagues reported a retrospective longitudinal single-cohort study in northern Italy confirming improved virological control in the INSTI era, along with shifts in the composition of the top 10 percent of viral loads over time, increasingly including women and non-Italian individuals. Identifying subgroups with greater transmission potential allows more intensive monitoring where it is most needed. Meanwhile, Mayanja and colleagues examined peer education for oral pre-exposure prophylaxis in Uganda, implementing a randomized clinical trial with a qualitative component comparing health worker counselling alone against counselling plus monthly group peer education sessions for four months. They confirmed the negative impact of community perceptions on PrEP use as major social and cultural barriers among adolescent girls and young women, who remain major drivers of incident infections in Africa despite persistently low PrEP uptake, adherence and persistence.

Drug resistance surveillance emerged as a technical cornerstone of the collection. Monitoring transmitted drug resistance is necessary to select appropriate regimens in different settings. Lv and colleagues reported a high prevalence of the V179D/E mutation, 14.8 percent, a polymorphic NNRTI-associated mutation conferring potential low-level resistance, among antiretroviral therapy-naive people with HIV in Guangzhou. Comparing people with pretreatment NNRTI resistance, unique presence of V179D/E and a no-resistance group, the team found this mutation may impair early virological response within the first year of therapy. Ouro-Medeli and colleagues used next-generation sequencing to assess transmitted resistance in 316 treatment-naive subjects in Togo in 2023. Although resistance to first-generation INSTIs was found in 17.2 percent of samples, no resistance mutations to dolutegravir or to protease inhibitors were detected, and mutations were found in only 0.6 percent and 6.3 percent for NRTIs and NNRTIs respectively. These findings confirm low levels of DTG resistance and support the ongoing systematic switch in the region.

The picture darkens in real-world treatment settings. Mac Asaga and colleagues reported a cross-sectional multicenter cohort of 412 subjects in tertiary care in Nigeria, mostly on NNRTI-based regimens. Alongside a high burden of advanced HIV disease, 38 percent with CD4 counts below 200 cells per milliliter, only 26.9 percent had viral loads below 1,000 copies per milliliter and just 10.4 percent below 40 copies per milliliter, with 86 percent of viremic subjects harboring drug-resistant HIV-1. Although tertiary care concentrates individuals with resistant virus and adherence issues, the findings confirm the need for genotyping at failure and for newer drugs in real life. Zewdu and colleagues studied 359 young children and adolescents in Ethiopia since the 2019 introduction of DTG-based regimens, finding that children below 10 years of age, particularly those without parents and with opportunistic infections, were at higher risk of virological failure. Zheng and colleagues analyzed persistent low-level viremia in 9,649 people with HIV on INSTI-sparing regimens in Guizhou Province from 2016 to 2022, finding virological failure rates ranging from 6.1 to 13.7 percent depending on the low-level viremia threshold, and highlighting the need for intensified detection and monitoring among middle-aged and older adults.

Simplification to single tablet regimens has expanded rapidly, reducing drug interactions and toxicity while enhancing adherence. Mengato and colleagues reported the multicenter retrospective observational MOSAICO study in 490 people with HIV on stable therapy across 20 Italian centers who switched to single tablet versus multi-tablet regimens between 2017 and 2019. At week 48, real-world effectiveness confirmed the durability of single tablet regimens, with INSTI-based regimens predominant among dual therapies. Yet Appiedu-Addo and colleagues reviewed persistent gaps that prevent developing regions from managing HIV as a chronic disease as western countries do, pointing to a double standard in virological suppression thresholds, with the World Health Organization accepting below 1,000 copies per milliliter versus below 50 copies per milliliter in western countries, and in access to newer antiviral classes including long-acting options for both treatment and prophylaxis.

Beyond virological control, the collection addresses comorbidities reshaping the lives of people with HIV. Hu and colleagues explored predictors of metabolic dysfunction-associated steatotic liver disease in 814 people with HIV on stable therapy at a Chinese tertiary care center between 2018 and 2025, finding the condition in 14 percent over a median follow-up of 2.8 years, driven largely by the lymphocyte-to-HDL cholesterol ratio rather than systemic inflammation markers. Huang and colleagues analyzed the global burden of syphilis among women of childbearing age from 1990 to 2021 using the Global Burden of Disease 2021 database, with the burden remaining significant in low- and middle-income countries where syphilis in pregnancy is associated with preventable maternal and child adverse events. The editorial concludes that stopping the HIV epidemic where the disease burden is highest will require more intensive virological monitoring in key subgroups, early genotyping at failure, and extended availability of modern antiretroviral classes and long-acting options for both therapy and prophylaxis. As long as these gaps persist, the editors warn, the 95-95-95 UNAIDS targets for 2030 will remain out of reach.

Subject of Research: Editorial: Towards control of the HIV epidemic: trends in epidemiology and emerging drug resistance in the integrase inhibitor era

Article Title: Editorial: Towards control of the HIV epidemic: trends in epidemiology and emerging drug resistance in the integrase inhibitor era

Article References: Ripamonti, D., Santoro, M., Fokam, J., Ceccherini Silberstein, F., & Llibre, J. M. (2026). Editorial: Towards control of the HIV epidemic: trends in epidemiology and emerging drug resistance in the integrase inhibitor era. Frontiers in Epidemiology, 6, Article 1991472. https://doi.org/10.3389/fepid.2026.1991472

Image Credits: AI Generated

DOI: 10.3389/fepid.2026.1991472

Keywords: Editorial, Towards, control, epidemic, trends, epidemiology, emerging, drug, resistance, integrase, inhibitor, scientific research