Application and resistance of integrase inhibitors in antiviral therapy

Since the first anti AIDS virus drug was approved for marketing in 1987, there have been five categories, more than 30 drugs and drug mixtures, which have brought good news to AIDS patients. These major breakthroughs in AIDS drugs have made AIDS a “chronic infectious diseases”. However, with the widespread use of antiviral drugs, HIV drug resistance has become an important factor affecting the effectiveness of AIDS prevention and control and the prevalence of the disease.
Most first-line treatment options worldwide use a combination of nucleoside reverse transcriptase inhibitors (NRTIs) and non nucleoside reverse transcriptase inhibitors (NNRTIs). Integrative enzyme chain transfer inhibitors (INSTIs) have the advantages of safety, good tolerability, rapid inhibition of virus replication, strong antiviral activity, and high genetic resistance barrier. They are currently the most effective antiviral drugs, including Latiravir (RAL), Etiravir (EVG), Dotitravir (DTG), Bixigevir (BIC), and Cabotevir (CAB).
The principle of action of integrase inhibitors
Integrative enzyme inhibitors block the catalytic activity of integrase to prevent viral DNA from integrating into the human genome. The integrase has three functional domains: the N-terminal region that binds to Zn+, the catalytic core region, and the C-terminal region that binds to host DNA (Figure 1).
The action of integrases mainly involves two steps: 3 ‘end processing and 5’ end chain transfer. (Figure 2)
(1) 3 ‘end processing: HIV double stranded DNA is cleaved of two nucleotides at the 3’ end by integrase, forming a pre integration complex (PIC);
(2) 5 ‘end chain transfer: After PIC enters the nucleus, integrase makes an interlaced incision on the DNA of the host cell chromosome, and then embeds HIV DNA into the host DNA.
INSTIs inhibit chain transfer by competitively binding to the enzyme binding site of target DNA, not only replacing the 3 ‘end of viral DNA from the active site, but also chelating divalent ions (Mg2+or Mn2+) necessary for integrase activity, thereby preventing the virus from forming covalent bonds with host DNA and inhibiting viral DNA incorporation into the host genome [2].
Application scope of integrase inhibitors
In 2018, WHO issued guidelines, suggesting that DTG based programs should be the first choice for adults and children as first-line antiviral treatment programs [3], and the domestic AIDS Diagnosis and Treatment Guidelines (2018) also recommended that programs containing INSTIs be used as first-line treatment programs [4]. As of July 2022, 108 countries worldwide have transitioned to using DTG as the first-line antiviral treatment for adults and adolescents (Figure 3), and 60 countries have adopted DTG as the first-line antiviral treatment for infants and children (Figure 4) [5]. The Chinese AIDS Diagnosis and Treatment Guidelines (2021) for the first time included DTG in the preferred ART scheme for HIV infected pregnant women, and DTG and RAL were also included in the preferred treatment scheme for children [6].
The issue of resistance to integrase inhibitors
Although the resistance rate of integrase inhibitors is currently low, there are still some reports of resistance site mutations. A study conducted in Italy in 2018 showed that among 179 patients receiving RAL treatment, 21 patients were detected with major resistance sites, and the mutation rate of resistance sites was 11.7%. These resistance mutation sites are mostly N155H, Q148H/R, Y143C/S, and T66A/I/T. A 2020 study on drug resistance among men who have sex with men in the United States showed that 11 out of 138 individuals (8.0%) with viral loads>1000 copies/ml exhibited high resistance to EVG, including 4 individuals who also showed high resistance to RAL and moderate resistance to DTG and BIC. A study from Africa in 2021 found that 11 out of 34 individuals treated with INSTI developed resistance mutations, with the main mutation sites being E138K, N155H, S147G, and Q148R. In addition, survey results in some foreign regions have also shown [10] that mutations in major resistance sites can be detected in patients who have not received INSTIs treatment, including S147G, G163K, E138T, E138E/K, and T66T/I. Preliminary domestic investigation results indicate that the transmission resistance rate of INSTIs in the pre-treatment population in China is at a low level, but some cases of primary resistance to INSTIs have also been found. For example, a study in Yunnan [11] showed that high resistance to RAL and EVG appeared in the population who did not receive INSTIs, but the resistance rate was relatively low at 1.7%; Studies in Ganzhou, Hunan and other places have also found one case of drug resistance in a patient treated with INSTI [12] – [13]. In addition, although the long-acting formula PrEP provides a more convenient way of administration and is beneficial for improving compliance, if HIV exposure occurs in the later stage of PrEP treatment, the long half-life may lead to the development of drug resistance.
Initially, INSTAs were self funded medications, which placed a significant financial burden on HIV patients. In 2019, Anhui Province became the first province to include DTG and RAL in INSTIs in the provincial medical insurance. In June 2023, the National Free Antiviral Treatment Manual for AIDS (Version 2023), which included docetavir sodium in the national free drugs for conditional use, eased the economic burden of HIV patients.
Currently, INSTIs are being expanded for clinical antiviral therapy and prevention before and after exposure. DTG, as a second-generation drug, has a higher genetic resistance barrier and is currently the more recommended INSTI. CAB, as a long-acting drug, provides HIV patients with a simplified and more convenient choice through oral or intramuscular injection, and may become a new trend in drug use in the future.
Although INSTIs have a high genetic resistance barrier, the prevalence of resistance to INSTIs in China is currently at a low level. However, the impact of resistance to INSTIs on the efficacy of antiviral therapy remains an important challenge that cannot be avoided.