Bictegravir/Emtricitabine/Tenofovir Alafenamide Versus Dolutegravir Plus Lamivudine for Switch Therapy in Patients with HIV-1 Infection: A Real-World Cohort Study

Abstract

Introduction

Bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) and dolutegravir plus lamivudine (DTG + 3TC) are well tolerated and effective in clinical trials. This study aimed to evaluate the safety and efficacy of these two schemes in a real-world setting and to obtain the first dataset for switching to BIC/FTC/TAF and DTG + 3TC in a Chinese population.

Methods

This retrospective single-center cohort study in China included participants who switched to DTG + 3TC or BIC/FTC/TAF between January 2020 and February 2023. The main endpoint was the proportion of participants with HIV-1 RNA levels of ≥ 50 copies/mL. Safety, tolerance, and the incidence of low-level viremia (LLV) were evaluated.

Results

A total of 525 participants were included, 454 of whom were included in the PP analysis. At week 48, the proportions of participants with HIV-1 RNA ≥ 50 copies/mL were 4.4% (10/225) for DTG + 3TC and 6.1% (14/229) for BIC/FTC/TAF; virological efficacy did not differ significantly between the two groups. Consistent results were obtained in an intent-to-treat (ITT) analysis. The incidences of LLV were 3.6% (7/193) and 4.9% (10/206), respectively. During the study, none of the participants stopped taking drugs because of a lack of efficacy or adverse reactions.

Conclusions

Both regimens are well tolerated and effective for switching HIV-1 infection therapy. However, the detection of genotypic drug resistance should be considered when baseline virological non-suppression is observed.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40121-023-00879-x.

Key Summary Points

Why carry out the study?

BIC/FTC/TAF and DTG + 3TC are potential therapies for HIV.

Both groups had excellent virological efficacy and immunological efficacy.

What was learned from the study?

The incidence of LLV was similar in the BIC/FTC/TAF and DTG + 3TC groups.

Changes in body weight, lipid metabolism, and liver and kidney function were similar, with good safety and tolerance.

Introduction

Advances in antiretroviral therapy (ART) over the past few decades have greatly extended the life expectancy of people living with HIV (PLWH) and transformed HIV infection into a manageable chronic disease [1]. In the past, standard ART involved two nucleoside reverse transcriptase inhibitors (NRTI) plus a core drug, such as a non-nucleoside reverse transcriptase inhibitor (NNRTI), boosted protease inhibitor (PI), or integrase strand transfer inhibitor (INSTI) [2]. With the extension of lifespan, PLWH need to be treated with drugs for decades and face not only chronic diseases related to age (e.g., hypertension, diabetes, and cardiovascular diseases) but also long-term drug damage to the body, osteoporosis, and liver and kidney damage [3–5]. Therefore, it is important to simplify the treatment by reducing the types of drugs, without sacrificing the virological efficacy, thus improving tolerance and safety [6].

Both bictegravir (BIC)/emtricitabine (FTC)/tenofovir alafenamide (TAF) and dolutegravir (DTG)/lamivudine (3TC) are recommended in treatment guidelines for initial and switch therapy in PLWH [7–10]. DTG is a potent integrase inhibitor with a high genetic barrier to resistance and is well tolerated by patients [11]. A large number of studies have proven the curative effect of a two-drug regimen consisting of DTG + 3TC; moreover, its curative effect is not inferior to those of three-drug regimens. In the GEMINI trials, DTG + 3TC and DTG + FTC/TAF showed similar rapid declines in plasma viral load, regardless of the baseline viral load [12]. The TANGO clinical trial showed that DTG + 3TC had a similar efficacy in maintaining virological suppression to that of a tenofovir alafenamide-based three-drug regimen [13]. Similarly, BIC is one of a new generation of integrase inhibitors; used in combination with FTC and TAF, it has shown high efficacy in large phase III randomized clinical trials as an initial treatment for ART-naïve patients and as a switching or treatment simplification strategy in treatment-experienced, virologically suppressed patients [14–17].

However, most studies on DTG + 3TC and BIC/FTC/TAF have focus on Europe and North America, with few real-world reports from China. The pharmacokinetics and pharmacodynamics of some ARTs may vary slightly by race [18]. Moreover, comparisons of the efficacy and safety of DTG + 3TC and BIC/FTC/TAF in real-world settings are lacking. To address this knowledge gap, we conducted a single-center study to compare the efficacy and safety of DTG + 3TC and BIC/FTC/TAF in Chinese ART-experienced patients. Unlike previous studies, we not only included patients with virological suppression but also included some patients with virological non-suppression.

Methods

Study Design and Participants

This was a real-world single-center, retrospective cohort study evaluating the efficacy and safety of switching to the DTG + 3TC vs. BIC/FTC/TAF regimen in adults living with HIV-1. The inclusion criteria were patients aged 18 years or older with confirmed HIV-1 infection who switched their prior ART regimen to DTG + 3TC or BIC/FTC/TAF between January 1, 2020 and March 30, 2022. Individuals were followed up until April 2023. The exclusion criteria were (1) pregnancy, (2) allergic history or high degree of sensitivity to any component or auxiliary material of the research drug, and (3) hepatitis B virus (HBV) infection in the DTG + 3TC group.

Procedures

Study visits were planned at baseline (when changing the regimen) and every 12 weeks thereafter. Routine blood, blood biochemistry, plasma HIV-RNA viral load (pVL), CD4⁺ cell counts and urine tests were performed at each follow-up visit. Genotypic drug resistance testing was not mandatory owing to financial constraints. Safety parameters, including adverse events (AEs) and serious AEs (SAEs), were assessed at each visit [19].

The data were extracted from case report forms (CRFs) and hospital laboratory systems. A CRF was used to collect baseline demographics and serial laboratory data, including the patient age, sex, weight, body mass index (BMI), CD4 cell count, HIV-1 RNA, prior ART, duration of ART before switching to DTG + 3TC or BIC/FTC/TAF, and fasting glucose and fasting lipids, which included triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). Information not available in CRFs was extracted from hospital laboratory systems and electronic medical records. The primary reason for switching to DTG + 3TC or BIC/FTC/TAF was extracted from medical records, if available. In addition, descriptions of AEs and adherence (measured by the proportion of days) were obtained from electronic medical records.

Definitions

Virological suppression (VS)

pVL < 50 copies/mL.

Virological non-suppression (VNS)

pVL ≥ 50 copies/mL.

Low-level viremia (LLV)

Baseline virological suppression and HIV-1 RNA between 50 and 200 copies/mL at 48 weeks [18].

ITT analysis

At least one dose of medicine was taken.

PP analysis

Follow-up of 48 ± 4 weeks was completed, and data were available at baseline and 48 ± 4 weeks.

Outcomes

The primary endpoint was the proportion of participants with VNS and VS 48 weeks after switching treatment (PP analysis). A sensitivity analysis was carried out using an ITT population. The secondary endpoints were (1) the rate of LLV; (2) safety and tolerability; and (3) change from baseline in the CD4 cell count, CD4/CD8, weight, BMI, renal biomarkers, liver markers, fasting lipids, and fasting glucose levels, PP analysis.

Ethics Approval and Informed Consent

This study conformed to the Declaration of Helsinki and was approved by the Ethics Committee of the Guiyang Public Health Treatment Center (202206). The Ethics Committee Board waived the requirement for written informed consent because this was a retrospective study, and all patient data were analyzed anonymously.

Statistical Analysis

Excel 2016 (Microsoft, Redmond, WA, USA) was used to input the data, and SPSS 23.0 (IBM, Armonk, NY, USA) was used for statistical analyses. Non-categorical variables were compared using the Student’s t test or Mann–Whitney U test, and categorical variables were compared using the χ² test or Fisher’s exact test. The Kolmogorov–Smirnov test was used to determine whether the numerical variables fit the assumption of normality. There are differences in baseline age, hypertension, diabetes, and pVL > 5 × 10⁵ copies/mL between the two groups. Therefore, we use multiple logistic regression to adjust these factors when analyzing the virological efficacy. Although there is no difference in CD4 and gender, we still include them in the model to balance the potential impact. For liver and kidney function, weight, and blood lipid, we use multiple linear regression model to adjust the influence of unbalanced factors. In addition to the aforementioned factors, we also include the baseline laboratory indicators of the two groups of participants in the model for analysis. In addition, the changes in immunological indexes at the 48th week were analyzed using covariance analysis (ANCOVA).

Results

Patient Characteristics

Between January 2020 and March 2022, 525 participants were screened, of whom 268 changed their ART scheme to BIC/FTC/TAF and 257 changed to DTG + 3TC (ITT). In the BIC/FTC/TAF group, 2 participants discontinued BIC/FTC/TAF for economic reasons, 1 participant died for non-drug related reasons, 24 participants were lost to follow-up (unrelated to efficacy issues or intolerance), and 12 participants had no data at 48 weeks. Finally, 229 participants were included in the PP analysis. In the DTG + 3TC group, 4 participants stopped ART, 4 participants died for non-drug related reasons, 18 participants were lost to follow-up (unrelated to efficacy issues or intolerance), and 6 participants had no data for 48 weeks. Finally, 225 participants were included in the PP analysis. For details, see Fig. 1.

Fig. 1.

Flowchart for the inclusion of patients in the study

There were more male participants in the BIC/FTC/TAF group than in the DTG + 3TC group (88.1% vs. 76.3%, p < 0.001). In addition, the participants in the BIC/FTC/TAF group were younger [36 years (30–48 years) vs. 55 years (38–68 years), p < 0.001] than those in the DTG + 3TC group. The proportions of participants with CD4 < 500 cells/μL were 75.9% (195/257) in the DTG + 3TC group and 66.4% (178/268) in BIC/FTC/TAF group. Among the included participants, 70 did not show virological suppression (HIV-1 RNA ≥ 50 copies/mL), compared with 38 in the DTG + 3TC group, and 32 in the BIC/FTC/TAF group. Before conversion in the DTG + 3TC group, 2NRTI + INSTI were the main ART schemes, while 2NRTI + NNRTI were the main BIC/FTC/TAF schemes. As patients in the DTG + 3TC group were older, the prevalence of diabetes and hypertension in this group was higher than that in the BIC/FTC/TAF group (p < 0.001). Baseline characteristics and differences between groups are summarized in Table 1.

Table 1.

Characteristics of the study population

Characteristic	DTG + 3TC (n = 257)	BIC/FTC/TAF (n = 268)	p
Sex, n (%)
Male	196 (76.3)	236 (88.1)	< 0.001
Female	61 (23.7)	32 (11.9)
Age, median (IQR), year	55 (38–68)	36 (30–48)	< 0.001
BMI, mean ± SD, kg/m2	22.2 ± 2.8	22.2 ± 2.9	NS
Number of previous ART changes, median (IQR)	1 (1–2)	1 (1–2)	NS
Time from confirming HIV-1 to starting ART, median (IQR), days	20 (9–15)	22 (11–69)	NS
Time from confirming HIV-1 to replacement plan, median (IQR), years	3 (1–6)	4 (2–7)	NS
CD4+ cell count, cells/μL, n (%)
< 500	195 (75.9)	178 (66.4)	0.022
≥ 500	62 (24.1)	90 (33.6)
HIV-1 RNA, copies/mL, n (%)
< 50	219 (85.2)	236 (88.1)	NS
≥ 50	38 (14.8)	32 (11.9)
Previous ART, n (%)
2NRTI + INSTIa	132 (51.4)	88 (32.8)	< 0.001
2NRTI + NNRTI	93 (36.2)	142 (53)
Other	32 (12.4)	38 (14.2)
Reason for dressing change:
Side effects of previous ART	125 (48.6)	77 (28.7)	< 0.001
Patient’s own request	50 (19.5)	80 (29.8)
Simplification/optimization	32 (12.5)	5 (1.9)
Easy to take	25 (9.7)	76 (28.4)
Low potential for interaction	14 (5.5)	7 (2.6)
Reimbursement requirements	6 (2.3)	15 (5.6)
Other	5 (1.9)	8 (3)
Previous TDF-based regimen, n (%)	161 (62.6)	157 (58.6)	NS
Diabetes mellitus	27 (10.5)	4 (1.5)	< 0.001
Hypertension	39 (15.2)	14 (5.2)	< 0.001
AIDS-defining opportunistic illnesses	25 (9.7)	9 (3.3)	0.005

ART antiretroviral therapy, INSTI integrase strand transfer inhibitor, NRTI nucleoside reverse transcriptase inhibitor, NNRTI non-nucleoside reverse-transcriptase inhibitor, PI protease inhibitor, BMI body mass index, NS no significant difference, TDF tenofovir disoproxil fumarate

^aThe main regimen is TDF + 3TC + DTG

The most common reasons for switching to DTG + 3TC were side effects of the previous ART (48.6%), patient request (19.5%), and simplification/optimization (12.5%). The most common reasons for switching to BIC/FTC/TAF were patient request (29.8%), side effects of previous ART (28.7%), and easy to take (28.4%).

Virologic Response

Figure 2a shows the results of the PP analysis. At week 48, the VNS rates were 4.4% (10/225) in DTG + 3TC cohorts and 6.1% (14/229) in the BIC/FTC/TAF cohorts. The VS rates of the DTG + 3TC and BIC/FTC/TAF cohorts were 95.6% (215/225) and 93.9% (215/229), respectively; the incidences of LLV were 3.6% (7/193) and 4.9% (10/206), respectively. Among the participants with baseline VS, the VS rates of the DTG + 3TC and BIC/FTC/TAF cohorts were 95.9% (185/193) and 95.6% (197/206), respectively. Among the participants with baseline VNS, the VS rates of the DTG + 3TC and BIC/FTC/TAF cohorts were 93.8% (30/32) and 78.3% (18/23), respectively (p = 0.015). Figure 2b shows the results of the ITT analysis. These results were consistent with those of the PP analysis. Among the participants with baseline VNS, VS rates differed significantly between the DTG + 3TC (78.9%, 30/38) and BIC/FTC/TAF groups (56.3%, 18/32), p = 0.008. There were no significant differences in other parameters.

Fig. 2.

Virological outcomes at 48 weeks. Results of the A PP analysis and B ITT analysis. PP analysis: follow-up of 48 ± 4 weeks was completed, and data were available at baseline and 48 ± 4 weeks. ITT analysis: at least one dose of medicine was taken. VS virological suppression, VNS virological non-suppression, LLV low-level viremia. **p < 0.05, *p < 0.01

In the DTG + 3TC cohort, 10 participants had VNS at 48 weeks, including 8 participants with VS at baseline and 2 with VNS at baseline. Eight had pVL ranging from 50 to 200 copies/mL. One participant had a pVL of 3730 copies/mL; however, this participant skipped pills for 60 days. Another participant had a pVL of 14,300 copies/mL; this participant had skipped pills for 45 days. In the BIC/FTC/TAF cohort, 14 participants had VNS at 48 weeks, including 9 participants with VS at baseline and 5 with VNS at baseline. Twelve had pVL ranging from 50 to 200 copies/mL. One participant had a pVL of 386,000 copies/mL; this participant skipped pills for 90 days. Another participant had a pVL of 348 copies/mL. For details, see Supplementary Table S1.

Immunological Response and Clinical Outcomes

Figure 3 summarizes the changes in body mass index, weight, immune response, and biochemical indexes of patients after 48 weeks of switching to DTG + 3TC and BIC/FTC/TAF. In terms of immunological changes (Fig. 3a), in the DTG + 3TC group, CD4 increased by 24 cells/μL, and CD4/CD8 increased by 0.1. In the BIC/FTC/TAF group, CD4 and CD4/CD8 levels increased by 32 cells/μL and 0.1, respectively. After adjusting for the baseline sex, age, immunological parameters, and complications, there was no significant difference between the two groups.

Fig. 3.

Immunological and clinical outcomes at week 48. A Changes in CD4 cell count and CD4/CD8 at week 48. B Changes in BMI, weight, blood lipid, and glucose at week 48. C Changes in renal function and liver function at week 48. Data are according to the estimated average changes of CD4, CD4/CD8, weight, BMI, and blood biochemistry in each group at week 48 calculated using the multiple linear regression model, adjusted for the following covariates or factors: baseline pVL baseline CD4 cell count, age, weight, renal parameters, baseline fasting lipids, and previous ART. BMI body mass index, ALT alanine aminotransferase, AST aspartate aminotransferase, Creatinine clearance estimated with the Cockcroft–Gault equation, TC total cholesterol, TG triglyceride, HDL-C high density lipoprotein, LDL-C low density lipoprotein. **p < 0.05, *p < 0.01

Metabolic changes are shown in Fig. 3b. In the BIC/FTC/TAF group, the body weight increased by 2 kg, and the BMI increased by 0.7 kg/m². In the DTG + 3TC group, body weight increased by 1 kg, and BMI increased by 0.4 kg/m². Blood lipid parameters and fasting blood glucose did not differ from baseline substantially. After adjusting for the baseline sex, age, CD4, pVL, weight, or blood lipid parameters, ART containing TDF, and ART containing INSTI, there were no significant differences between the two groups.

The changes in liver function and renal function are shown in Fig. 3c. The changes in liver function were minimal, and the clinical significance was limited. In terms of renal function, after 48 weeks of treatment, the creatinine clearance rate of both groups decreased compared with the baseline, with a decrease in the BIC/FTC/TAF group of 11.7 mL/min (the median baseline value was 99.3 mL/min) and a decrease in the DTG + 3TC group of 4.1 mL/min (the median baseline value was 70.5 ml/min). There was no significant differences between the two groups after adjusting for the baseline age, sex, liver function parameters, renal function parameters, CD4, pVL, and ART containing TDF.

Adverse Events

There were 28 (10.9%) and 23 (8.6%) AEs reported in the DTG + 3TC and BIC/FTC/TAF groups, respectively. The most common AEs in the DTG + 3TC group were dizzy/headache (1.2%), fatigue (1.2%), and edema of the lower extremities (1.2%). The most common AEs in the BIC/FTC/TAF group were itchy skin (2.6%), abdominalgia/diarrhea (2.2%), and arthralgia (1.5%). No AEs led to drug withdrawal from the study. There were more SAEs in the DTG + 3TC group than in the BIC/FTC/TAF group (8.9% vs. 3%, p = 0.007), and the SAEs in both groups were non drug-related hospitalizations and death (Supplementary Table S2). In the DTG + 3TC group, there was one reported case of drug-related insomnia. In the BIC/FTC/TAF group, one case of diarrhea and one case of rapid weight gain were reported to be drug-related (Table 2).

Table 2.

Overview of adverse events associated with DTG + 3TC and BIC/FTC/TAF in the cohort

Adverse events	DTG + 3TC (n = 257)	BIC/FTC/TAF (n = 268)	p
All adverse events	28 (10.9%)	23 (8.6%)	0.455
Itchy skin	1 (0.4%)	7 (2.6%)
Dizzy/headache	3 (1.2%)	1 (0.4%)
Arthralgia	2 (0.8%)	4 (1.5%)
Insomnia	1 (0.4%)	3 (1.1%)
Abdominalgia/diarrhea	2 (0.8%)	6 (2.2%)
Rapid weight gain	0 (0)	1 (0.4%)
Fatigue	3 (1.2%)	1 (0.4%)
Edema of lower extremity	3 (1.2%)	0 (0)
Serious adverse events	23 (8.9%)	8 (3%)	0.007
Drug-related adverse event			–
Diarrhea	0 (0)	1 (0.4%)
Rapid weight gain	0 (0)	1 (0.4%)
Insomnia	1 (0.4%)	0 (0)

BIC/FTC/TAF bictegravir/emtricitabine/tenofovir alafenamide, DTG + 3TC dolutegravir plus lamivudine

Discussion

To the best of our knowledge, this is the largest cohort study for the comparison of DTG + 3TC and BIC/FTC/TAF in China. Patients who were and were not virologically suppressed were included. Several clinical trials have shown the effective maintenance of viral suppression after a switch to DTG + 3TC in individuals on a first-line ART regimen that contained three or more ARVs [13, 20–22]. In the TANGO trial, 93.2% of patients maintained virologic suppression at 48 weeks after switching to DTG + 3TC. The rate of virologic suppression at 48 weeks of three- or four-drug therapies based on TAF was 93% [13]. In the SALSA study, rates of virologic suppression at 48 weeks in the DTG + 3TC and 3-/4-drug regime groups were 94% and 93%, respectively [20]. Our research confirms the results of these clinical trials using real-world data; at 48 weeks, VS rates were 95.9% (DTG + 3TC) and 95.6% (BIC/FTC/TAF) in the group with baseline VS. Furthermore, regardless of baseline VS, the VS rates using DTG + 3TC or BIC/FTC/TAF for 48 weeks were 95.6% and 93.9%, respectively, and were 93.8% and 78.3% (p < 0.05), respectively, in the subgroup with baseline VNS. Although the VS ratio of the DTG + 3TC group was higher than that of BIC/FTC/TAF group, the sample size for this subgroup was very small and the clinical significance of this result is limited. We do not expect the VS of DTG + 3TC to be better than that of BIC/FTC/TAF among the participants with baseline VNS.

There is little research on the incidence of INSTI LLV. We report that the incidences of LLV in the BIC/FTC/TAF and DTG + 3TC groups at 48 weeks were 3.6% and 4.9% (p > 0.05), respectively, consistent with the results of a large LLV cohort in Taiwan Province, in which the incidences in BIC and DTG cohorts were 6.2% and 3.8%, respectively (p = 0.08). Whether LLV with pVL between 50 and 199 copies/mL leads to subsequent virological failure (VF) remains controversial. Several studies have shown that LLV with pVL between 50 and 199 copies/mL is associated with VF [23–26], including studies in South Africa [25] and the USA [26]. However, the vast majority of PLWH included in those cohorts received NNRTI-based regimens. This differs from the integrase-based scheme used in our study; therefore, these results should be interpreted with caution. A multicenter study including more than 100,000 people showed that LLV with pVL between 50 and 199 copies/mL was not related to VF [27], and a study of INSTI found that LLV with pVL between 50 and 199 copies/mL was not related to VF [20].

The virological efficacy of DTG + 3TC and BIC/FTC/TAF has been proven in individuals who are ART-naïve and virologically suppressed with another regimen [12–17, 21, 22]. However, little is known about switching to DTG + 3TC or BIC/FTC/TAF in patients with virological non-suppression. In this study, effective viral suppression was detected in patients who switched from another protocol to DTG + 3TC (n = 32) or BIC/FTC/TAF (n = 23). At the end of follow-up, in the DTG + 3TC groups, 93.8% of patients (30/32) achieved VS (one patient had poor compliance, skipping pills for 45 days; one patient had 74 copies/mL) and in the BIC/FTC/TAF groups, 78.3% of patients (18/23) achieved VS (one patient had 348 copies/mL; other patients had between 50 and 200 copies/mL). Although most patients achieved VS in an analysis of clinical outcomes, the sample size of this subgroup was small and there was little information about drug resistance mutations. Although a large-scale observational study confirmed that DTG + 3TC was effective, regardless of the existence of M184V mutation, the research subjects all showed VS; however, the effect of a short duration of previous virological suppression in individuals with M184V on DTG + 3TC response remains troubling. Therefore, genotypic resistance tests should be carried out for patients with baseline VNS who switch to DTG + 3TC or BIC/FTC/TAF [28].

In this study, we observed that after 48 weeks of conversion, the estimated serum creatinine clearance rate decreased to some extent in both groups, consistent with the trends observed in the TANGO and SALSA studies [13, 21]. The BIC/FTC/TAF group showed a greater decline. However, after accounting for factors showing baseline differences between groups by a multiple regression, there were no significant differences between the two groups. Therefore, we think that the effects of DTG + 3TC and BIC/FTC/TAF on renal parameters are equivalent. We did not detect significant differences between DTG + 3TC and BIC/FTC/TAF in weight, lipid parameters (TC, TG, HDL-C, and LDL-C), and fasting blood glucose. This is similar to the results reported by Degroote and others at the CROI Conference in 2023 [29].

The overall AEs in the two groups were similar; however, the incidence of SAEs was higher in the DTG + 3TC group, which was characterized by an older age and higher frequency of non-drug-related hospitalization.

This study had several limitations. First, this was a retrospective study, which may lead to selection bias. This may affect the results, even though multiple regression was used to correct confounding factors and minimize bias. Second, safety incidents were all self-reported, and may be underreported. Finally, this was a single-center study that lasted for only 48 weeks, limiting the ability to extrapolate.

Conclusions

This study proved that the virological efficacy, immunological efficacy, and LLV incidence were similar after switching to DTG + 3TC and BIC/FTC/TAF for 48 weeks. Both regimens are well tolerated and safe. However, when VNS exists at baseline, genotypic drug resistance detection should be fully considered.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Lin Gan, Xiaoxin Xie, and Yanhua Fu contributed to the conception and design of the research. Xiaoyan Yang, Shujing Ma, and Linghong Kong collected all required data. Lin Gan and Xiaoyan Yang analyzed data and draw tables. Chunli Song, Yebing Song, and Tingting Ren helped perform analyses with constructive discussions. Lin Gan wrote the original draft. Hai Long and Lin Gan were responsible for the study design and analysis plan and carried out the data monitoring. All authors agreed on the submission of the manuscript to the journal and reviewed and agreed on all versions of the article before submission, during revision, the final version accepted for publication, and significant changes introduced at the proofing stage. All authors had access to the study data and took responsibility for the integrity of the data and accuracy of the data analysis.

Funding

This work was supported by the Science and Technology Foundation of Guizhou Province (Qian Kehe support [2021] 055).The journal’s Rapid Service fee was funded by the authors.

Data Availability Statement

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of Interest

Lin Gan, Xiaoxin Xie, Yanhua Fu, Xiaoyan Yang, Shujing Ma, Linghong Kong, Chunli Song, Yebing Song, Tingting Ren and Hai Long has nothing to disclose.

Ethics Approval

This study conformed to the Declaration of Helsinki and was approved by the Ethics Committee of the Guiyang Public Health Treatment Center. The Ethics Committee Board waived the requirement for written informed consent because this was a retrospective study, and all patient data were analyzed anonymously.