An academic circle’s focus has resulted in the appearance of three connected clusters on our map, which are HIV-1 protease (#0), integrase strand-transfer inhibitor (#3), and HIV-1 reverse transcriptase (#4), representing the four types of inhibitors in PIs, INSTIs, NRTIs, and NNRTIs, respectively.

HIV protease (PR) is the only protease of the virus that performs proteolysis of gag and gag-pol into all structural proteins (Ghosh et al., 2016). Therefore, numerous drugs, called PIs, have been developed. Most PIs that mimic the natural substrate of PR initially inhibit PR binding sites through competitive means (Wensing et al., 2010). Two generations of PIs, namely, indinavir, nelfinavir, lopinavir, and tipranavir, have been developed since saquinavir was first identified in 1995 (Ghosh et al., 2016). However, since PIs were first used in clinical settings, there is an opportunity for severe resistance mutations to be produced with this medication. According to a recent publication on PI mutations, the most prevalent mutation types are V82ACS, M46IL, 154MTV, and L76V. After receiving PI treatment for an extended period, one-third of patients develop significant resistance to the drug (Chimukangara et al., 2022). Consequently, although PIs are considered to have a high genetic barrier, more studies and advancements are needed for patient drug resistance testing.

By chelating divalent metal cations at the catalytic site of the enzyme, INSTIs block HIV-1 integrase, preferentially binding to the the active site of integrase with its cofactor over free integrase (Craigie, 2001; Zhao et al., 2022). The emergence of elvitegravir, bictegravir, dolutegravir, and raltegravir signifies that more substantial genetic barriers in INSTIs have been discovered (Max, 2019; Zhao et al., 2022). Clinical treatment is less potent when multiple mutations coexist, and the susceptibility to all INSTIs is reduced by more than 300 times (Cheung et al., 2022). Research has also revealed the side effects of INSTIs. Dolutegravir (DTG), for instance, has been linked to weight gain, neural tube abnormalities, and neuropsychiatric disorders (Scévola et al., 2020). Patients receiving elvitegravir and cobicstat may experience fatigue, malaise, and gastrointestinal symptoms (Lepik et al., 2018). As a result, we must consider how patients with infection and numerous mutations are treated and how these people are impacted by the side effects of these drugs, especially DTG.

NNRTIs and NRTIs inhibit viral replication by targeting the HIV reverse transcriptase process (Yoshida et al., 2021). Although NNRTIs are thought to be safe and well-tolerated medicines, increasing evidence suggests that they may be linked to gastrointestinal toxicity, skin responses, neuropsychiatric symptoms, hepatotoxicity, and metabolic abnormalities (Blas-Garcia et al., 2011; Reust, 2011). For NRTIs, some RT mutations, such as M184V, L74V, Q151M, and K65R, can lead to binding evasion while retaining the ability to recognize natural substrates; other mutations, such as M41L, D67N, K70R, cause enhanced phosphorolytic removal at the 3′-terminus of the primer after viral DNA binding by NRTIs, with others resulting in removal to overcome chain termination (Marcelin, 2006). Numerous novel chemicals and drug candidates have been created recently to address the problems of drug resistance and adverse reactions. As potent inhibitors of the novel HIV-1 NNRTI, diarylpyrimidines have been extensively synthesized in a variety of configurations (Huang et al., 2019; Liu et al., 2019). More investigations are required to develop more modern medications based on this kind of medication.

Pertaining to clusters 2 and 5, the presence of proviral DNA and spread of medication resistance may pose challenges to HIV control and treatment.

Proviral DNA, which is surrounded by two lengthy terminal repeats, is generated by copying of genomic RNA by reverse transcriptase (Mougel et al., 2009). ART cannot eradicate cells in which HIV-1 previral DNA is incorporated, which can act as a cell reservoir to store this DNA. As a result, these cell reservoirs may reseed the virus for reproduction when ART is discontinued (Linden and Jones, 2022). Since memory T cells have a lengthy half-life, the proviral DNA of the virus that has been integrated into CD4 T cells may retain drug resistance-related mutations. This attribute renders it an ideal target for the precursor DNA reservoir (Turriziani et al., 2010; Geretti et al., 2022). Therefore, one of the significant obstacles to curing HIV is the presence of drug-resistance wild-type previral DNA in memory T cells.

Drug resistance can be precisely detected, and its extent of distribution can be determined by deep sequencing. Transmission of drug resistance occurs when an HIV-1 strain acquires one or more mutations linked to treatment resistance. Recent reports on global surveillance of HIV-1-transmitted drug resistance have shown that NNRTI and NRTI resistance is increasing in sub-Saharan Africa, NNRTI resistance is increasing in Latin America and the Caribbean, and NNRTI and PI resistance is generally increasing in North America (Rhee et al., 2020). This result demonstrates the importance of publishing study findings and monitoring global TDR. Ragonnet-Cronin and colleagues proved that clinical baseline diagnostic serum genotyping can be used for HIV TDR surveillance of treatment-naïve individuals (Ragonnet-Cronin et al., 2013) This achievement supports ongoing global TDR monitoring. Nichols et al. discovered a negative correlation between viral load and CD4+ T-cell count decline using ultradeep sequencing to evaluate the presence of minority patient TDR. This means that negative selection will affect a small percentage of the viral population’s transmission resistance (Nichols et al., 2014). This phenomenon is intriguing and merits further attention. The strains found in these samples may help in determining how to choose a drug for treatment-naïve individuals. Given that TDR may have an impact on antiretroviral therapy (Aghokeng et al., 2011), it is essential to monitor DRM status by deep sequencing while providing feedback to alter the first-line treatment plan and reduce HIV selection and transmission. Notably, the two studies mentioned above were carried out in settings with limited resources. As a result, more relevant studies in affluent areas must be conducted to obtain more persuasive results.

This section is mainly related to cluster 1. In cases in which first-line treatment fails virologically, second-line therapy—typically consisting of a PI combined with two NRTIs—is implemented (Hosseinipour et al., 2013). According to a related investigation, low adherence leads to severe treatment failure in locations with few resources (Ajose et al., 2012). Indeed, low adherence may be one factor contributing to second-line therapeutic failure, according to research performed by Mantshonyane (Mantshonyane et al., 2021). The index of first-line therapy adherence serves as a predictor of second-line therapy adherence (Ramadhani et al., 2014). Furthermore, it is thought that a patient’s weight may be associated with virologic failure (Salvi et al., 2022). If second-line therapy fails, third-line therapy needs to be attempted. One such medication combination that has been proven to be well tolerated is raltegravir, darunavir, and etravirine (Avihingsanon et al., 2022). Additionally, a better second-line alternative is a wise decision for clinical trials (Keene et al., 2021). Thus, prior to therapy, it is necessary to improve patient compliance. Further research is needed to determine the association between weight and virological failure. Future studies on better medicine combinations also need to be carried out.

This section is associated with cluster 6. This cluster’s form may be caused by the coinfection rate and severe mortality rate. When HIV and tuberculosis (TB) co-occur, the situation becomes more complex. Standard first-line treatment is virtually unavoidable for multidrug-resistant TB, which is resistant to isoniazid and rifampicin (Seung et al., 2015; Singh et al., 2020). Coinfection increases the rate at which TB progresses and increases the spread of drug-resistant TB (Khan et al., 2019). According to research by Anderson et al. on the mortality of drug-resistant TB patients, individuals with coinfections had an average 1.5-year shorter survival period than those with single infection (Anderson et al., 2022). The following coinfective variables are associated with mortality: BMI, mid-upper arm circumference, use of bedaquiline therapy, use of ART, and detectability of viral load (Bayowa et al., 2023). Moreover, coinfections increase the frequency of side effects such as depression, nephrotoxicity, and hearing loss (Lazarus et al., 2021). For patients who are coinfected, medical personnel should focus on these indices. Notably, the metabolic effects of many medications cannot be disregarded because HIV patients frequently receive multiple pharmacological treatments. Isoniazid combined with NNRTIs and PIs, for example, may increase associated toxicities (Mukonzo et al., 2019). Thus, additional research on the interactions between medications used to treat HIV and TB is needed. Furthermore, healthcare providers should avoid combining medications in a way that compromises drug metabolism.

The results of timeline and landscape view analyses are shown in Figures 10, 11, respectively, revealing how hot research topics change over time and aiding in comprehending the evolution of the field. The largest cluster in our study, cluster 0, indicates that protease, or PI, is consistently the main focus of academic circles. Investigation of medications and their underlying mechanisms remains a primary focus, and steady advancements have been made. Cluster 2 had a low update status for the past 3 years, which might mean that the spread of medicine resistance has been limited. Cluster 3 displays a rise in keywords between 2021 and 2022, suggesting recent advancements in the subject. Little change in the coinfection resistance of pulmonary TB has been observed, revealing that further research in this field is necessary. Since there have been no recent new keywords for cluster 4, further innovation in this area is needed. The number of keywords in other clusters has increased recently, implying that these disciplines have been steadily developing. Furthermore, controlling HIV infection remains a challenging task despite technological advancements. In addition, INSTI drugs have been extensively used in clinical treatment to reduce HIV replication, resulting in countless clinical reports that have produced a wealth of novel findings, including mutations, side effects, and development of related, more potent new drugs.

The burst results reveal that tenofovir alafenamide (TAF), DTG, and RPV are the three most potent medications. TAF functions by obstructing the catalytic site of HIV reverse transcriptase (Li et al., 2022), which has been the initial therapeutic option for HIV-1 (Ueaphongsukkit et al., 2021). Although TAF, the prodrug of tenofovir, is thought to have superior effects on bone mineral density and kidney function, subsequent studies have revealed that it can still exert some nephrotoxicity (Gupta et al., 2019; Ueaphongsukkit et al., 2021). Nevertheless, TAF-containing regimens are thought to provide safe and effective viral suppression for children and teenagers. This is a helpful reminder since there are few available drugs (Agwu et al., 2014; O'Rourke et al., 2023). As a tricyclic carbamoyl pyridone analog, DTG is absorbed and spread through cerebrospinal fluid and impairs the HIV integrase-DNA complex through chemical synthesis (Kandel and Walmsley, 2015). Antiretroviral therapy with two-drug regimens is practical and appealing owing to the decreased medium- and long-term toxic effects, its intricacy, and the associated expenses (Antinori et al., 2019). R263K, G118R, N155H, and Q148H/R/K are mutations associated with DTG, particularly G118R and R263K (Tao et al., 2023). Significant weight gain and neuropsychiatric symptoms are two of its related side effects (Kolakowska et al., 2019; Eckard and McComsey, 2020). RPV is the e-isomer of dapivirine and is found in the diarylpyrimidine dapivirine (Li et al., 2022). Due to its safety, RPV has been demonstrated to be the preferred choice for treatment-naïve patients, and the mutations that cause the RPV to lose effectiveness are K103N and M184I/V (Putcharoen et al., 2013). Nonetheless, derivatives developed based on RPV are an excellent choice for combating these mutations (Smith et al., 2016). Moreover, studies have shown that the therapeutic impact of rilpivirine with DTG and lamivudine with DTG is comparable to that of conventional three-drug regimens (Fida et al., 2020). Therefore, drug combination techniques relying on TAF should be widely used in clinical practice, and more studies on the adverse effects of TAF are necessary. There is potential for creating novel medications including RPV.

Because our map contains the term “children” as a burst, the drug resistance of these young people presents a novel potential situation requiring further exploration. NNRTI-based regimens were the initial choice for this group (Agwu et al., 2014). The number of adolescent HIV patients will increase as a result of the growing number of pediatric patients. There is less drug pressure due to restricted drug selection, which lowers the rate of mutation in this population (Agwu et al., 2014). Nevertheless, according to research from China, significant mutations affect approximately 73.1% of patients. NRTI, NNRTI, and dual-class resistance are responsible for 48.4, 63.4, and 38.7% of cases, respectively (Yan et al., 2022). This outcome demonstrates that because children have been treated for an extended period, the rate of mutations in this group has increased recently. A recent report on use of RPV for treatment of HIV-positive adolescents revealed that while the effectiveness of RPV decreased with prolonged use, its safety remained stable (Lombaard et al., 2022). In addition, TAF-containing regimens have been demonstrated to be a not-to-be-ignored strategy for children (O'Rourke et al., 2023). When second-line ART is begun in children, their CD4+ T lymphocyte count increases, and their mortality and loss to follow-up decrease (Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) Global Cohort Collaboration, 2020). Consequently, treating drug resistance in children is positively impacted by prompt medication modifications. More research should be conducted on regimens to prevent children from becoming drug resistant.

The appearance of “open-label” and NGS indicates the research frontiers of DRMs. With its high-throughput, fast sequencing, next-generation sequencing has revolutionized genomic research (Levy and Boone, 2019). In contrast to classical Sanger sequencing, which detects substitutions, small insertions, and deletions, NGS does not require extra assays to collect mutation data; instead, mutation data are obtained through NGS. In addition, increasing the sequencing depth can increase the sensitivity of NGS (Behjati and Tarpey, 2013). With its high throughput for HIV-1, NGS can sequence full-length genomes while identifying HIV-1 genotypes with low levels of medication resistance (Metzner, 2022). In a high-throughput manner, NGS can detect 1% or fewer minor mutations, making it the first choice for HIV superinfection (Redd et al., 2013). Nonetheless, several of the steps of the NGS workflow, such as the sample type, PCR amplification, and initial material, are susceptible to bias. Moreover, there are difficulties with clinical care, especially in settings with few resources. It is challenging to popularize NGSs in these places because of infrastructure and equipment needs, cost, logistics, and supply chains (Ávila-Ríos et al., 2020). Furthermore, similar to previous sequencing platforms, the high throughput of NGS relies on both the amount and quality of the initial template input, meaning that NGS alone cannot identify low copy numbers in genomes (Munyuza et al., 2022). Therefore, further NGS optimization studies must be performed, as should maintaining the NGS supply chain and logistics in low-income areas and improving NGS usage training for medical personnel working in these locations.

After individuals complete the double-blind phase of the trial for a novel medication, they are offered the opportunity to participate in the open-label extension phase to obtain data on the drug’s long-term safety and tolerability (Taylor and Wainwright, 2005). Open-label studies differ from double-blind studies in that both the participants and investigators are aware of the true administration. For 96 weeks, an open-label, randomized, noninferiority trial examined the efficacy of therapeutic therapy or pharmacological combination virology in children and adolescents. Comparing the DTG group to the standard-care group, it was demonstrated that the former had reduced rates of death and virological failure, optimized CD4 count results, no drug-resistant mutations with first-line therapy, and fewer mutations with second-line therapy (Turkova et al., 2021). This finding indicates that DTG outperformed standard care in terms of inhibitory efficacy for younger patients. Open-label studies, as opposed to double-blind studies, often acquire data on the incidence rate of side effects and the effects of a new drug to track the impact of prolonged therapy. Regardless, open-label practices have several drawbacks. In open-label studies, there may be ethical problems as well as ascertainment bias, which can affect the objectivity of the study. To obtain more accurate results, a study should involve a double-blind or even triple-blind study.

As DRM barriers can be found through recent bursts, we believe that “accumulation,” “sex,” and “pretreatment drug resistance (PDR)” have been hindrances and troublesome in recent years. Accumulation of deleterious mutations is caused by elevated turnover of lymphocytes (Galvani, 2005). This may result in fewer therapeutic alternatives available, the possibility of DRM spread, and the acceleration of the immune system’s aging process (Galvani, 2005; Villabona-Arenas et al., 2016). Since accumulation is nonlinear, selection is restricted to genetic variation (Maldarelli et al., 2013), and additional investigation is required to ascertain the causes of such selection. Pretreatment mutation testing must be performed in locations where antiretroviral therapy (ART) is used for an extended period, and more research into the process and conditions for mutation accumulation is needed.

The commonly used NNRTIs efavirenz and nevirapine are typically the cause of pretreatment drug resistance (PDR) (Ndashimye and Arts, 2019), which is frequently followed by acquired drug resistance and greater risk of virologic failure (Parikh and Mellors, 2012). Although PDR is uncommon, it has increased in the last several years (Kiros et al., 2023). Transmission of the related mutations K103NS and E138A still occurs (García-Morales et al., 2021). Notably, high-incidence patient groups of PDR include men who have sex with men (MSM), sex workers, and inmates (Macdonald et al., 2020). MSM are especially susceptible to HIV transmission through sexual activity, as HIV can be spread through rectal anal contact without the use of a condom. Bacterial sexually transmitted infections may also be a contributing factor by facilitating HIV transmission (Macdonald et al., 2020). As a result, these groups need to receive more attention, and appropriate coping strategies must be outlined to address the rising PDR.