HIV drug resistance

25 November 2025

Key facts

  • The emergence of acquired resistance to dolutegravir (DTG) – the cornerstone of WHO recommended first- and second-line antiretroviral therapy (ART) – may be higher than anticipated, especially in people with heavy prior treatment experience.
  • Despite the emergence of resistance, DTG is a highly effective drug in HIV treatment, with more than 90% of patients achieving sustained viral suppression if adherent to treatment.
  • DTG resistance amplifies the urgent need to implement standardized surveys to characterize the prevalence and patterns of DTG resistance mutations and their associated clinical determinants.
  • As the use of DTG-based ART is scaled up, remaining vigilant in preventing and monitoring HIV drug resistance among infants newly diagnosed with HIV is imperative.
  • The prevalence of resistance to tenofovir is low among individuals who acquire HIV while receiving oral tenofovir-containing PrEP. However, the prevalence of tenofovir resistance is more than 10-fold higher if tenofovir-containing PrEP is initiated during undiagnosed acute HIV infection.
  • To stop HIV drug resistance: make optimal antiretroviral medicines available; retain patients in care and ensure adherence to treatment; increase access and use of viral load testing; and switch regimens rapidly in cases of confirmed treatment failure.

Overview

Over the past decade, the world has witnessed an unprecedented increase in the use of antiretroviral therapy (ART), which has saved the lives of tens of millions of people living with HIV. At the end of December 2024, 31.6 million people were accessing ART, up from 7.7 million in 2010 (1). Current WHO-recommended first-line regimens, which are dolutegravir-based, are highly effective: programmatic evidence from low- and middle-income countries shows that over 95% of adults retained in care achieve viral suppression within 6 to 24 months of treatment (2).

However, increased use of HIV medicines has been accompanied by the emergence of HIV drug resistance. HIV drug resistance is caused by changes in the genetic structure of HIV that affect the ability of medicines to block the replication of the virus.

Scope of the problem

All antiretroviral drugs, including those from newer drug classes, are at risk of becoming partially or fully inactive due to the emergence of drug-resistant virus. Surveillance of HIV drug resistance provides countries with evidence that can be used to optimize patient- and population-level treatment outcomes. Therefore, WHO recommends that countries routinely implement HIV drug resistance surveys in different populations, including adults, children and adolescents, and PrEP users diagnosed with HIV.

WHO’s brief 2024 HIV drug resistance report summarizes recent information, with a focus on HIV drug resistance in the era of integrase-strand transfer inhibitors for HIV prevention and treatment.

Acquired HIV drug resistance

Viral load suppression – the goal of HIV treatment – significantly contributes to preventing the emergence of HIV drug resistance. When viral load suppression is achieved and maintained, drug-resistant HIV is less likely to emerge.

As documented in WHO’s brief 2024 HIV drug resistance report, global data remain limited regarding emergence of HIV drug resistance to DTG; however, in published cohorts DGT resistance has been observed in up to 4.8% of participants without viral suppression. Recent studies supported by the United States President’s Emergency Plan for AIDS Relief in 4 low- and middle-income countries report prevalence estimates of DTG resistance among individuals receiving DTG-based ART with detectable viraemia ranging from 3.9% in people without viral suppression on ART for at least 9 months to 19.6% in people with heavy prior treatment experience. A modelling study from South Africa projects a rapid increase in HIV drug resistance to DTG associated with the failure of DTG-based ART, rising from 18% in 2023 to 42% by 2035, if mitigation measures are not adopted (3).

More data from standardized surveys of acquired HIV drug resistance and from longitudinal observational cohorts are needed from countries in all regions to provide enhanced insight into risk factors and patterns of drug resistance emergence among individuals exposed to DGT-based ART regimens.

WHO recommends that countries implement routine surveillance of acquired HIV drug resistance in adults, children and adolescents receiving ART either using a viral load laboratory-based method, an ART clinic-based method, or a sentinel survey approach. Which method is used depends upon national viral load testing coverage, the availability of deidentified demographic information, and funding.

Pretreatment HIV drug resistance

Drug resistance can be found in some people before they begin treatment. This type of resistance can either be transmitted at the time of infection or acquired during previous treatments.

WHO recommends surveillance of HIV drug resistance in adults initiating or reinitiating ART and in treatment naive infants initiating ART to inform optimal selection of first-line regimens.

According to the WHO’s brief 2024 HIV drug resistance report, 11 countries reported data to WHO on the prevalence of pretreatment HIV drug resistance to DTG among adults initiating ART. Only one country detected DTG at a very low prevalence of 0.2%, which was attributed to a rare non-polymorphic integrase mutation. However, these surveys were conducted before DTG was introduced or during the early stages of transition in these countries and thus cannot provide evidence of an absence of DTG resistance in populations initiating or reinitiating ART as scale-up and maintenance on DTG-based ART continues.

The levels of pretreatment rilpivirine (RPV) resistance among individuals initiating ART without previous exposure to ARV drugs ranged from 0.0% (95% CI 0.0–9.4%) in Tajikistan in 2016 to a high of 16.6% (95% CI 11.2–24.0%) in Eswatini. These data suggest that if RPV were to be used in combination with cabotegravir as a long-acting ART, pretreatment HIV drug resistance testing would be needed in some settings to identify those without RPV drug resistance because pretreatment RPV drug resistance mutations are a risk factor for failure to suppress viral load among people treated with long-acting cabotegravir in combination with RPV.

To date, very limited data are available from national surveys assessing HIV drug resistance among infants after introducing DTG-containing regimens. One documented case of DTG resistance was identified in a treatment-naive infant whose mother had been taking DTG-based ART (4). This case underscores the importance of strengthening surveillance efforts in infants and ensuring effective management of high maternal viral loads during pregnancy and breastfeeding to prevent transmission of resistant HIV strains.

The surveillance of HIV drug resistance among treatment-naive infants newly diagnosed with HIV remains highly relevant in the era of DTG-based ART, and accelerated implementation of these surveys is needed. Moreover, effective management of high viral loads among pregnant and breastfeeding women is critical to prevent transmitting HIV to infants.

Pre-exposure prophylaxis for HIV prevention

Many people living in situations considered high risk for exposure to HIV take medicines to reduce the chance of acquiring the disease. WHO recommends pre-exposure prophylaxis (PrEP) be offered as an additional choice for HIV prevention.

HIV infection is infrequent among individuals taking PrEP. However, among people becoming HIV infected despite the use of PrEP, the emergence of drug resistance is common. Drug resistance can reduce HIV treatment options due to the overlapping resistance profiles between antiretroviral drugs used for both PrEP and treatment.

In a literature review published in WHO’s 2024 HIV drug resistance report, of 310 reported seroconversions occurring while on oral tenofovir-containing PrEP between 2020 and 2023 in clinical settings, 20% had tenofovir or lamivudine drug resistance, with the prevalence of drug resistance more than 10-fold higher if PrEP was initiated during undiagnosed infection.

Long-acting PrEP options, such as cabotegravir and lenacapavir, represent important advances in HIV prevention. Long-acting cabotegravir, administered every two months, is highly effective. However, individuals acquiring HIV while using long-acting cabotegravir may carry virus resistant to DTG, a key component of WHO’s preferred ART regimens (5). In contrast, lenacapavir, delivered every six months, does not have predicted cross-resistance to current WHO-recommended regimens should a breakthrough infection occur. Most known lenacapavir-associated resistance mutations also have reduced replication capacity, limiting their potential for sustained transmission (6). While resistance mutations could emerge with both products, HIV infections remain extremely rare when long-acting PrEP is used as prescribed.

For the dapivirine vaginal ring, Phase 3 trials found no significant difference in resistance to non-nucleoside reverse transcriptase inhibitors between the dapivirine vaginal ring and placebo groups. While systemic resistance appears unlikely due to low absorption, the selection of drug resistance in the genital tract cannot be excluded.

To monitor the effectiveness of HIV medicines used for both treatment and prevention, WHO recommends that countries implement nationally representative surveys to monitor the levels of HIV drug resistance among people initiating treatment, people receiving treatment and among people using PrEP who acquire HIV.

WHO response

Minimizing the emergence and spread of HIV drug resistance is a critical aspect of the broader global response to antimicrobial resistance (AMR). WHO’s new Integrated drug resistance action framework for HIV, hepatitis B and C and sexually transmitted infections, 2026–2030 provides a unified roadmap to prevent, monitor and respond to drug resistance across these disease areas.

Building on WHO’s Global action plan on HIV drug resistance 2017–2021, the new framework aligns with the Global Health Sector Strategies on, respectively, HIV, viral hepatitis and sexually transmitted infections for the period 2022–2030 and the AMR agenda, and outlines 5 strategic objectives:

  1. prevention and response: implement high-impact, people-centred interventions to prevent infections and to prevent, detect and respond to drug resistance;
  2. monitoring and surveillance: strengthen national surveillance systems and use routine data to assess service quality and guide interventions to prevent drug resistance;
  3. research and innovation: close knowledge gaps and promote research to develop and deliver effective tools to minimize drug resistance;
  4. laboratory capacity: expand robust laboratory systems to monitor treatment outcomes and conduct drug resistance surveillance; and
  5. governance and enabling mechanisms: ensure country ownership, community engagement, coordinated action and sustainable financing.

The framework emphasizes integrated, multisectoral action and supports countries in aligning drug resistance responses with broader AMR strategies and health system strengthening efforts.

 

References

  1. Global HIV statistics – fact sheet 2025. Geneva: Joint United Nations Programme on HIV/AIDS; 2025 (https://www.unaids.org/sites/default/files/2025-07/2025_Global_HIV_Factsheet_en.pdf).
  2. Girón-Callejas, A., Lorenzana, R., Pickles, M. et al. High HIV viral suppression among adults receiving WHO-recommended first-line dolutegravir-based antiretroviral therapy in low- and middle-income countries: a systematic review and meta-analysis of programmatic evidence. AIDS Res Ther 22, 91 (2025). https://doi.org/10.1186/s12981-025-00788-8
  3. Loosli T, Han N, Hauser A, Josi J, Ingle SM, van Sighem A et al. Predicted dolutegravir resistance in people living with HIV in South Africa during 2020–35: a modelling study. Lancet Glob Health. 2025;13(4):e698–706 (https://doi.org/10.1016/S2214-109X(24)00553-9)
  4. Bamford A, Hamzah L, Turkova A. Paediatric antiretroviral therapy challenges with emerging integrase resistance. Curr Opin HIV AIDS. 2024 Nov 1;19(6):323-329. doi: 10.1097/COH.0000000000000876. Epub 2024 Jul 5. PMID: 38967797; PMCID: PMC11451947 (https://pmc.ncbi.nlm.nih.gov/articles/PMC10552825/pdf/aids-37-2097.pdf)
  5. Ahluwalia AK, Inzaule S, Baggaley RC, Vitoria M, Schaefer R, Schmidt HA, Rodolph M, Giron A, Jordan MR. Characterization of dolutegravir drug resistance in persons diagnosed with HIV after exposure to long-acting injectable cabotegravir for preexposure prophylaxis. AIDS. 2022 Nov 1;36(13):1897-1898. doi: 10.1097/QAD.0000000000003322. PMID: 36172874; PMCID: PMC9594132 (https://pmc.ncbi.nlm.nih.gov/articles/PMC9594132/)
  6. van Zyl G, Prochazka M, Schmidt HA, Orrell C, Schapiro JM, McCluskey SM, Vitoria M, Kantor R, Parikh UM, Rodolph M, Jordan MR, Shafer RW. Lenacapavir-associated drug resistance: implications for scaling up long-acting HIV pre-exposure prophylaxis. Lancet HIV. 2025 Oct;12(10):e732-e736. doi: 10.1016/S2352-3018(25)00128-6. Epub 2025 Jun 18. PMID: 40543515; PMCID: PMC12435527 (https://pmc.ncbi.nlm.nih.gov/articles/PMC12435527/)