Life Sciences

Checking the Status: The Evolutionary Explanations and Drug Resistance Prevalence to Dolutegravir for HIV Treatment (A Review)

Author: Evan Hall

  • Checking the Status: The Evolutionary Explanations and Drug Resistance Prevalence to Dolutegravir for HIV Treatment (A Review)

    Life Sciences

    Checking the Status: The Evolutionary Explanations and Drug Resistance Prevalence to Dolutegravir for HIV Treatment (A Review)

    Author:

Abstract

Drug treatment advancements for HIV have dramatically advanced since the virus’ identification in the early 1980s. Integrase strand transfer inhibitors (INSTIs) are one of seven HIV treatment drug classes currently utilized to create an undetectable viral count in blood samples of people living with HIV (PLWH). First generation INSTIs are documented with low barriers of genetic resistance, which indicates that the number of mutations to lead to a drug resistant mutation is low. The introduction of dolutegravir, a second generation INSTI, shows a higher barrier of genetic resistance that will reduce drug resistant mutations to INSTIs and increase the overall effectiveness of this class of HIV treatment. PLWH can be categorized based on whether they received treatment previously/currently or have never received treatment. Therapy naive and previously treated (successfully or unsuccessfully) patients for HIV report different rates of drug resistant mutations compared to actual resistance to dolutegravir, 0.4-31% and 0.1-67.2% respectively. Evolutionary considerations of genetic resistance, including epistatic interactions and point mutations, suggest both non-polymorphic and polymorphic mutations for these drug resistant mutations. An incomplete understanding of how evolutionary factors contribute to HIV drug resistance highlights the importance of conducting further research. This research may help improve the efficacy of second generation INSTIs in future treatment options for PLWH. This review describes the landscape of existing research on drug resistance prevalence for dolutegravir and possible evolutionary explanations on how these mutations arise in the first place, leading to implications in developing more robust treatment modalities.

How to Cite:

Hall, E., (2024) “Checking the Status: The Evolutionary Explanations and Drug Resistance Prevalence to Dolutegravir for HIV Treatment (A Review)”, University of Michigan Undergraduate Research Journal 17. doi: https://doi.org/10.3998/umurj.5510

130 Views

44 Downloads

Published on
08 Mar 2024
Peer Reviewed

Background

The human immunodeficiency virus (HIV) is a prominent retrovirus identified in 1983 that has no cure, yet it can be readily treated with the right combination antiviral therapy (cART) (Greene, 2007). At the end of 2021, the World Health Organization (WHO) estimated that 38.4 million people around the globe are living with HIV (WHO, 2022). UNAIDS set Ambition 2030 targets to end the ongoing HIV epidemic: (1) 95% of people living with HIV (PLWH) know their status; (2) 95% of people who know their status are receiving treatment; (3) 95% of those receiving treatment are virally suppressed (Ehrenkranz et al., 2021). PLWH who are virally suppressed reach a level of virus in the body that cannot be detected by laboratory tests. At these levels, HIV cannot be transmitted to other individuals, highlighting relevant campaigns such as undetectable equals untransmittable (U=U) and treatment as prevention.

HIV is a very mutable virus (Yeo et al., 2020). Viral mutations in the body and during seroconversions to infection increase due to error-prone replication cycles. Therefore, the HIV virus can develop drug-resistant mutations, decreasing the effectiveness of these medications in high active antiretroviral therapy (HAART) regimens. The strain of HIV in PLWH can be naturally resistant to certain drugs due to certain mutations in the virus or due to the development of acquired resistance over time in PLWH. In addition, there is evidence to suggest that people who inconsistently adhere to their medication can see increased rates of drug-resistant strains of HIV (Chen, Chen, & Kalichman, 2017). When PLWH and HIV providers encounter drug resistance, the range of medications to treat an HIV diagnosis may become limited, impacting the health outcomes of PLWH.

Dolutegravir is a second-generation integrase strand transfer inhibitor (INSTI) approved by the US Federal Drug Administration (FDA) in 2013 to treat HIV (Kandel & Walmsley, 2015). As it entered the global state, many HIV providers and public health officials promoted its potential to be a more effective medication than existing first-generation INSTIs, which are well-tolerated, are easy to take, and have decreased drug-drug interactions (Rhee et al., 2019). Furthermore, the greatest factor for dolutegravir’s success is its higher barrier to genetic resistance compared to first-generation INSTIs like raltegravir, reducing the chance of an individual needing to switch treatment regimen throughout their lifetime. Even with dolutegravir’s increased barrier to resistance, there is currently little understanding of the population-level prevalence of dolutegravir drug resistance and how drug resistance arises.

Drug Resistance Prevalence

Drug resistance is broadly outlined as the reduction in effectiveness of medications in treating a disease or conditions with prime examples coming from the fields of antimicrobial resistance in antibiotics and cancer medicine (Habboush & Guzman, 2022). PLWH can be categorized into two treatment categories: (1) therapy-naive patients and (2) previously treated patients (Colombo, Di Matteo, & Maggiolo, 2013; Tseng, Seet, & Phillips, 2015). Both therapy-naive and previously treated patients are individuals who have seroconverted, meaning the body has responded to HIV by creating antibodies. Importantly, therapy-naive patients contain a level of the virus in the body that is detectable for treatment response yet have never received treatment for HIV. Previously treated patients for HIV are individuals enrolled in previously successful or unsuccessful treatment regimens.

Research suggests that the rate of drug resistance for INSTIs in therapy-naive patients is 3.82%, while HIV in previously treated patients is resistant at 11% (Fan et al., 2022; Kamelian et al., 2019). For therapy-naive patients, the genotypes of the individual’s virus were screened for resistance-associated mutations (RAMs), which may suggest an individual’s inherent resistance to INSTIs. RAMs can be major or accessory. Major RAMs (Y143R/C/D/G and P145S) are shown to create actual drug resistance. Accessory RAMS (G140E, E157Q, and G163R) can, in combination and over time, lead to actual drug resistance. Among samples of therapy-naive patients in Cameroon, Mikaski et al. reported 5.4% major RAMs and 8.1% accessory RAMs (Mikasi et al., 2020). It is important to note that these samples were conducted for all INSTI mutations, not dolutegravir specifically. Áy et al. (2021) collected data on therapy-naive patients, which report different percentages of mutations, including 1 out of 249 (0.4%) to have major RAMs and 31% accessory RAMs. These dramatically different percentages may reflect population or geographically distinct prevalence of major and accessory RAMs associated with dolutegravir. These samples identify the critical role drug resistance screening plays in the larger rollout of dolutegravir and emphasize the research that must be conducted to pre-screening efforts.

There is markedly more research for drug resistance among previously treated patients. First-generation INSTIs have shown a plethora of drug resistance mutations leading to the increased failure of treatment regimens for HIV (Anstett et al., 2017). Data collected for drug resistance to dolutegravir are separated into two main outcomes for PLWH: (1) potential resistance from possible future mutations that can reduce the effectiveness of dolutegravir and (2) inherent resistance from existing mutations to dolutegravir in a specific HIV strain. Importantly, previously treated patients can be categorized based on their success or failure of previous treatment regimens. The range of actual resistance in PLWH was from 0.1–0.7% to 21.9% among those who are currently successfully virally suppressed under HAART (Kamelian et al., 2019; Engone-Ondo et al., 2021). These percentages greatly increased for PLWH who had previously or are currently failing first-generation INSTI treatment regimens, ranging from 29.6% to 67.2% showing resistance to dolutegravir (van Oosterhout et al., 2022; Engone-Ondo et al., 2021). Critically, 64–84.6% of HIV sequences screened show potential drug resistance mutations to dolutegravir among those who previously or are currently failing first-generation INSTIs (Fourati et al., 2015; Engone-Ondo et al., 2021). Saladini et al. (2012) reported that 59.8% of samples collected from previously treated patients harbored at least one of the resistance mutations for first- or second-generation INSTIs. Table 1 consolidates the patient and geographic population with the actual and potential resistance described in the source paper. Nonetheless, this does not indicate actual resistance, nor does it show treatment regimen failure for dolutegravir for PLWH.

Table 1:

Description of Actual and Potential Resistance from Current Literature Categorized by Patient and Geographic Populations

Source

Patient Population

Geographic Population

Actual Resistance

Potential Resistance

Kamelian et al., 2019

HAART-treated individuals

British Columbia, Canada

0.1–0.7% (1 to 7 per 1000)

Van Oosterhout et al., 2022

First-generation INSTI regimen failure

Malawi

29.6% (8 out of 27)

Fourati et al., 2015

First-generation INSTI regimen failure

France

13.9%

64%

Engone-Ondo et al., 2021

HAART-treated individuals; First-generation INSTI regimen failure

Semi-rural Gabon

21.9%; 67.2%

84.6% (among patients who failed first-generation INSTI regimen)

Evolutionary Explanation to Drug Resistance

HIV Drug Evasion

Drug resistance among HIV strains in PLWH can vary in their categorizations, including transmitted, acquired, or multi-class drug resistance (Pennings, 2013). Transmitted drug resistance indicates a viral strain that, when transmitted to another host, already contains drug-resistant mutations, while acquired drug resistance explains how an individual’s strain of HIV can mutate over time to confer drug-resistant mutations. Multi-class drug resistance describes strains of HIV that confer multiple mutations that evade more than one of the seven drug classes that target HIV. There is a stark geographic and socioeconomic influence of transmitted drug resistance, where the standard for patients in higher-income countries is to screen for genetic resistance before treatment begins. By conducting genetic screening, a provider can readily assess the feasibility of PLWH to receive some treatment over others. Acquired drug resistance appears to increase over time for a treated patient, indicating that although not all patients over time will develop resistance, a small subset of the population will develop drug resistance HIV virus strains. This type of resistance is notable for potential dolutegravir candidates who may have previously failed a first-generation INSTI in the same drug class. cART requires drugs from multiple classes, and when PLWH are limited in access to multiple drug classes, the course of treatment over a lifetime may become limited, creating future problems for maintaining viral suppression. Research suggests that drugs targeting viruses like HIV may have imperfect tissue penetrations and result in spatial monotherapy (Moreno-Gamez et al., 2015). These implications may stand to explain how some HIV strains in individuals adapt in environments where medication is not present.

Genetic exchange, re-assortment, and recombination of HIV could contribute to its adaptation at the population genetics level (Wilson et al., 2015). While the HIV virus on its own can mutate to adapt, the question of human adaptation to HIV drug resistance is largely unstudied, including the possible influences of linkage disequilibrium and epistatic interactions. Hence, there is an emphasis to assess standing genetic variation in new treatment initiation for PLWH to determine whether drug-resistant mutations are present.

First-Generation INSTIs

First-generation INSTIs are shown to have a low genetic barrier to resistance with the medications raltegravir and elvitegravir (Anstett et al., 2017). The field of virology and resistance in HIV have distinctly categorized the type of mutation from conventional evolutionary terminology. Non-polymorphic mutations are defined by a percentage of mutations occurring less than 1% of any subtype of HIV virus (Rhee, Tzou, & Shafer, 2021). Polymorphic mutations are sites with variable frequency by which the sequence of a gene is found in more than 1% of the population. The occurrence of drug resistance mutations among first-generation INSTIs appears to occur through the transmission of drug mutations rather than naturally arising resistance mutations in PLWH. Áy et al. (2021) characterize these drug-resistant mutations as non-polymorphic. In addition, Saladini et al. (2012) provide further evidence that first-generation INSTI naive patients did not have mutant strains that contained drug resistance mutations as natural polymorphisms. Two mutations (T124A & L101I) were detected among naive and treated patients, yet their prevalence was the same for either group. However, other research in Chinese populations has found polymorphic accessory mutations, which could cause low-level resistance to first-generation INSTIs (Yu et al., 2022).

Second-Generation INSTIs

The resistance profile of dolutegravir is extensively characterized by Rhee et al. (2019). The development of resistance mutations to dolutegravir has been observed in vivo and in samples from the populations (Fourati et al., 2015). Different mutations are categorized as directly impacting the effectiveness of dolutegravir and creating possible pathways that could lead to second-generation INSTI drug-resistant mutations.

Anstett et al. (2017) suggest that the increased resistance profile of dolutegravir is associated with a longer binding half-life, which maintains activity against more resistant first-generation strains. This further supports a theory of different binding properties to explain dolutegravir’s resistance profile (Garrido et al., 2011). However, the authors do not present an evolutionary mechanism for why this type of advantage is displayed by dolutegravir. Pham et al. (2021) offer that experiments conducted in their study show that deleterious effects of individual substitutions in the integrase codon region could lead to possible dolutegravir drug resistance. The studies listed in Table 2 largely characterize singular substitutions as a leading cause to genetic resistance, but some studies indicate that the epistasis can occur alongside these drug-resistant mutations. Epistasis occurs when the effect of a gene mutation is dependent on the presence or absence of mutations in or more other genes (Churchill, 2013; Garrido et al., 2011). Both Garrido et al. (2011) and Brenner et al. (2016) suggest that natural polymorphism in different HIV strain subtypes is partially responsible for drug resistance to dolutegravir for PLWH.

Table 2:

Description of Mutation and Mutation Types from the Current Literature

Source

Mutation

Mutation Type

Anstett et al., 2017

N155; Q148

Resistant; Pathways to Resistance

Pham et al., 2021

S153F or S153Y with R263K

Resistant

Garrido et al., 2011

T124A and L101I+T124A

Resistant

Brenner et al., 2016

G118R

Resistant

Saladini et al., 2012

L101I and T124A

Resistant

Rhee et al., 2019

R263K, G118R, N155H, Q148H/R; Q148 + G140 and/or E138

Resistant

George et al., 2018

T97A

Resistant

Ndashimye et al., 2018

E157Q

Pathways to Resistance

Conclusion

There is some prevalence in therapy-naive and previously treated patients of drug-resistant strains and mutations to the medication dolutegravir for PLWH. Most concerning is the high percentage of dolutegravir resistance among individuals currently taking or previously failing first-generation INSTIs, suggesting that alternative HIV medication routes may be necessary for these PLWH. Although resistance is prevalent, there is little research on the evolutionary mechanisms that may cause these drug-resistant mutations or strains. Broadly, first-generation INSTIs confer largely non-polymorphic mutations in creating dolutegravir drug resistance, while natural polymorphism is used as a primary explanation for the presence of drug-resistant mutations in second-generation INSTIs. Second-generation INSTI drug-resistant mutations appear to arise from individual substitutions with possible epistatic associations among some mutation locations.

These drug-resistant mutations against dolutegravir are critical in ending the HIV epidemic. INSTIs are quickly leading the charge on long-acting medications, while biomedical advancements in other HIV drug classes are lagging behind. Cabotegravir is a second-generation INSTI that is derived from dolutegravir and acts as a long-acting injectable medication versus a daily oral pill (Landovitz et al., 2021). If individuals do not have access to long-acting medications due to drug-resistant mutations limiting their drug class options, the treatment for PLWH may become challenging. Without further characterization and screening of drug-resistant mutations for second-generation INSTIs, potential biomedical advancements may face drug-resistant mutations in existing strains of HIV circulating in PLWH. Therefore, more research is needed to determine the evolutionary origins of drug-resistant mutations to INSTIs.

References

Anstett, K., Brenner, B., Mesplede, T., & Wainberg, M. A. (2017). HIV drug resistance against strand transfer integrase inhibitors. Retrovirology, 14(1), 36. https://doi.org/10.1186/s12977-017-0360-7https://doi.org/10.1186/s12977-017-0360-7

Áy, É., Pocskay, Á., Lakatos, B., Szlávik, J., Mezei, M., & Minárovits, J. (2021). Prevalence of resistance mutations associated with integrase inhibitors in therapy-naive HIV-positive patients in Hungary. Acta Microbiologica Et Immunologica Hungarica, 68(2), 87–91. https://doi.org/10.1556/030.2021.01433https://doi.org/10.1556/030.2021.01433

Brenner, B. G., Thomas, R., Blanco, J. L., Ibanescu, R. I., Oliveira, M., Mesplède, T., Golubkov, O., Roger, M., Garcia, F., Martinez, E., & Wainberg, M. A. (2016). Development of a G118R mutation in HIV-1 integrase following a switch to dolutegravir monotherapy leading to cross-resistance to integrase inhibitors. The Journal of Antimicrobial Chemotherapy, 71(7), 1948–1953. https://doi.org/10.1093/jac/dkw071https://doi.org/10.1093/jac/dkw071

Chen, Y., Chen, K., & Kalichman, S. C. (2017). Barriers to HIV medication adherence as a function of regimen simplification. Annals of Behavioral Medicine: A Publication of the Society of Behavioral Medicine, 51(1), 67–78. https://doi.org/10.1007/s12160-016-9827-3https://doi.org/10.1007/s12160-016-9827-3

Churchill G. A., Editor(s): Stanley Maloy, Kelly Hughes (2013) Brenner’s Encyclopedia of Genetics (Second Edition), Academic Press, 505–507, https://doi.org/10.1016/B978-0-12-374984-0.00482-4.https://doi.org/10.1016/B978-0-12-374984-0.00482-4

Colombo, G. L., Di Matteo, S., & Maggiolo, F. (2013). Antiretroviral therapy in HIV-infected patients: a proposal to assess the economic value of the single-tablet regimen. ClinicoEconomics and Outcomes Research: CEOR, 5, 59–68. https://doi.org/10.2147/CEOR.S38977https://doi.org/10.2147/CEOR.S38977

Ehrenkranz, P., Rosen, S., Boulle, A., Eaton, J. W., Ford, N., Fox, M. P., Grimsrud, A., Rice, B. D., Sikazwe, I., & Holmes, C. B. (2021). The revolving door of HIV care: Revising the service delivery cascade to achieve the UNAIDS 95–95–95 goals. PLoS Medicine, 18(5), e1003651. https://doi.org/10.1371/journal.pmed.1003651https://doi.org/10.1371/journal.pmed.1003651

Engone-Ondo, J. D., Mouinga-Ondémé, A., Lékana-Douki, S. E., Diané, A., Mamimandjiami, A. I., Banga, O., Ndong-Atome, G. R., & Aghokeng, A. F. (2021). High rate of virological failure and HIV drug resistance in semi-rural Gabon and implications for dolutegravir-based regimen efficacy. The Journal of Antimicrobial Chemotherapy, 76(4), 1051–1056. https://doi.org/10.1093/jac/dkaa537https://doi.org/10.1093/jac/dkaa537

Fan, W., Wang, X., Zhang, Y., Meng, J., Su, M., Yang, X., Shi, H., Shi, P., & Lu, X. (2022). Prevalence of resistance mutations associated with integrase inhibitors in therapy-naive HIV-positive patients in Baoding, Hebei province, China. Frontiers in Genetics, 13, 975397. https://doi.org/10.3389/fgene.2022.975397https://doi.org/10.3389/fgene.2022.975397

Fourati, S., Charpentier, C., Amiel, C., Morand-Joubert, L., Reigadas, S., Trabaud, M. A., Delaugerre, C., Nicot, F., Rodallec, A., Maillard, A., Mirand, A., Jeulin, H., Montès, B., Barin, F., Bettinger, D., Le Guillou-Guillemette, H., Vallet, S., Signori-Schmuck, A., Descamps, D., Calvez, V., … ANRS AC11 Resistance Study Group (2015). Cross-resistance to elvitegravir and dolutegravir in 502 patients failing on raltegravir: a French national study of raltegravir-experienced HIV-1-infected patients. The Journal of Antimicrobial Chemotherapy, 70(5), 1507–1512. https://doi.org/10.1093/jac/dku535https://doi.org/10.1093/jac/dku535

Garrido, C., Soriano, V., Geretti, A. M., Zahonero, N., Garcia, S., Booth, C., Gutierrez, F., Viciana, I., & de Mendoza, C. (2011). Resistance associated mutations to dolutegravir (S/GSK1349572) in HIV-infected patients–impact of HIV subtypes and prior raltegravir experience. Antiviral Research, 90(3), 164–167. https://doi.org/10.1016/j.antiviral.2011.03.178https://doi.org/10.1016/j.antiviral.2011.03.178

George, J. M., Kuriakose, S. S., Dee, N., Stoll, P., Lalani, T., Dewar, R., Khan, M. A., Rehman, M. T., Grossman, Z., Maldarelli, F., & Pau, A. K. (2018). Rapid development of high-level resistance to dolutegravir with emergence of T97A mutation in 2 treatment-experienced individuals with baseline partial sensitivity to dolutegravir. Open Forum Infectious Diseases, 5(10), ofy221. https://doi.org/10.1093/ofid/ofy221https://doi.org/10.1093/ofid/ofy221

Greene W. C. (2007). A history of AIDS: looking back to see ahead. European Journal of Immunology, 37 Suppl 1, S94–S102. https://doi.org/10.1002/eji.200737441https://doi.org/10.1002/eji.200737441

Habboush, Y., & Guzman, N. (2022). Antibiotic Resistance. In StatPearls. StatPearls Publishing.

Kamelian, K., Lepik, K. J., Chau, W., Yip, B., Zhang, W. W., Lima, V. D., Robbins, M. A., Woods, C., Olmstead, A., Joy, J. B., Barrios, R., & Harrigan, P. R. (2019). Prevalence of human immunodeficiency virus-1 integrase strand transfer inhibitor resistance in British Columbia, Canada between 2009 and 2016: A longitudinal analysis. Open Forum Infectious Diseases, 6(3), ofz060. https://doi.org/10.1093/ofid/ofz060https://doi.org/10.1093/ofid/ofz060

Kandel, C. E., & Walmsley, S. L. (2015). Dolutegravir - a review of the pharmacology, efficacy, and safety in the treatment of HIV. Drug Design, Development and Therapy, 9, 3547–3555. https://doi.org/10.2147/DDDT.S84850https://doi.org/10.2147/DDDT.S84850

Landovitz, R. J., Donnell, D., Clement, M. E., Hanscom, B., Cottle, L., Coelho, L., Cabello, R., Chariyalertsak, S., Dunne, E. F., Frank, I., Gallardo-Cartagena, J. A., Gaur, A. H., Gonzales, P., Tran, H. V., Hinojosa, J. C., Kallas, E. G., Kelley, C. F., Losso, M. H., Madruga, J. V., Middelkoop, K., … HPTN 083 Study Team (2021). Cabotegravir for HIV prevention in cisgender men and transgender women. The New England Journal of Medicine, 385(7), 595–608. https://doi.org/10.1056/NEJMoa2101016https://doi.org/10.1056/NEJMoa2101016

Mikasi, S. G., Gichana, J. O., Van der Walt, C., Brado, D., Obasa, A. E., Njenda, D., Messembe, M., Lyonga, E., Assoumou, O., Cloete, R., Ikomey, G. M., & Jacobs, G. B. (2020). HIV-1 integrase diversity and resistance-associated mutations and polymorphisms among integrase strand transfer inhibitor-naive HIV-1 patients from Cameroon. AIDS Research and Human Retroviruses, 36(5), 450–455. https://doi.org/10.1089/AID.2019.0264https://doi.org/10.1089/AID.2019.0264

Moreno-Gamez, S., Hill, A. L., Rosenbloom, D. I., Petrov, D. A., Nowak, M. A., & Pennings, P. S. (2015). Imperfect drug penetration leads to spatial monotherapy and rapid evolution of multidrug resistance. Proceedings of the National Academy of Sciences of the United States of America, 112(22), E2874–E2883. https://doi.org/10.1073/pnas.1424184112https://doi.org/10.1073/pnas.1424184112

Ndashimye, E., Avino, M., Kyeyune, F., Nankya, I., Gibson, R. M., Nabulime, E., Poon, A. F. Y., Kityo, C., Mugyenyi, P., Quiñones-Mateu, M. E., & Arts, E. J. (2018). Absence of HIV-1 drug resistance mutations supports the use of dolutegravir in Uganda. AIDS Research and Human Retroviruses, 34(5), 404–414. https://doi.org/10.1089/AID.2017.0205https://doi.org/10.1089/AID.2017.0205

Pennings P. S. (2013). HIV drug resistance: Problems and perspectives. Infectious Disease Reports, 5(Suppl 1), e5. https://doi.org/10.4081/idr.2013.s1.e5https://doi.org/10.4081/idr.2013.s1.e5

Pham, H. T., Alves, B. M., Yoo, S., Xiao, M. A., Leng, J., Quashie, P. K., Soares, E. A., Routy, J. P., Soares, M. A., & Mesplède, T. (2021). Progressive emergence of an S153F plus R263K combination of integrase mutations in the proviral DNA of one individual successfully treated with dolutegravir. The Journal of Antimicrobial Chemotherapy, 76(3), 639–647. https://doi.org/10.1093/jac/dkaa471https://doi.org/10.1093/jac/dkaa471

Rhee, S. Y., Grant, P. M., Tzou, P. L., Barrow, G., Harrigan, P. R., Ioannidis, J. P. A., & Shafer, R. W. (2019). A systematic review of the genetic mechanisms of dolutegravir resistance. The Journal of Antimicrobial Chemotherapy, 74(11), 3135–3149. https://doi.org/10.1093/jac/dkz256https://doi.org/10.1093/jac/dkz256

Rhee, S. Y., Tzou, P. L., & Shafer, R. W. (2021). Temporal trends in HIV-1 mutations used for the surveillance of transmitted drug resistance. Viruses, 13(5), 879. https://doi.org/10.3390/v13050879https://doi.org/10.3390/v13050879

Saladini, F., Meini, G., Bianco, C., Monno, L., Punzi, G., Pecorari, M., Borghi, V., Di Pietro, M., Filice, G., Gismondo, M. R., Micheli, V., Penco, G., Carli, T., De Luca, A., Zazzi, M., & ARCA Collaborative Group (2012). Prevalence of HIV-1 integrase mutations related to resistance to dolutegravir in raltegravir naïve and pretreated patients. Clinical Microbiology and Infection: The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases, 18(10), E428–E430. https://doi.org/10.1111/j.1469-0691.2012.03917.xhttps://doi.org/10.1111/j.1469-0691.2012.03917.x

Tseng, A., Seet, J., & Phillips, E. J. (2015). The evolution of three decades of antiretroviral therapy: challenges, triumphs and the promise of the future. British Journal of Clinical Pharmacology, 79(2), 182–194. https://doi.org/10.1111/bcp.12403.https://doi.org/10.1111/bcp.12403

van Oosterhout, J. J., Chipungu, C., Nkhoma, L., Kanise, H., Hosseinipour, M. C., Sagno, J. B., Simon, K., Cox, C., Hoffman, R., Steegen, K., Matola, B. W., Phiri, S., Jahn, A., Nyirenda, R., & Heller, T. (2022). Dolutegravir Resistance in Malawi’s National HIV Treatment Program. Open Forum Infectious Diseases, 9(5), ofac148. https://doi.org/10.1093/ofid/ofac148https://doi.org/10.1093/ofid/ofac148

World Health Organization. (2022, July). HIV. The Global Health Observatory. https://www.who.int/data/gho/data/themes/hiv-aids#:~:text=Globally%2C%2038.4%20million%20%5B33.9%E2%80%93,considerably%20between%20countries%20and%20regions.https://www.who.int/data/gho/data/themes/hiv-aids#:~:text=Globally%2C%2038.4%20million%20%5B33.9%E2%80%93,considerably%20between%20countries%20and%20regions.https://www.who.int/data/gho/data/themes/hiv-aids#:~:text=Globally%2C%2038.4%20million%20%5B33.9%E2%80%93,considerably%20between%20countries%20and%20regionshttps://www.who.int/data/gho/data/themes/hiv-aids#:~:text=Globally%2C%2038.4%20million%20%5B33.9%E2%80%93,considerably%20between%20countries%20and%20regions

Yeo, J. Y., Goh, G. R., Su, C. T., & Gan, S. K. (2020). The determination of HIV-1 RT mutation rate, its possible allosteric effects, and its implications on drug resistance. Viruses, 12(3), 297. https://doi.org/10.3390/v12030297https://doi.org/10.3390/v12030297

Yu, F., Li, Q., Wang, L., Zhao, H., Wu, H., Yang, S., Tang, Y., Xiao, J., & Zhang, F. (2022). Drug resistance to HIV-1 integrase inhibitors among treatment-naive patients in Beijing, China. Pharmacogenomics and Personalized Medicine, 15, 195–203. https://doi.org/10.2147/PGPM.S345797https://doi.org/10.2147/PGPM.S345797