Efficacy and prognosis of transforaminal endoscopy in the treatment of lumbar disc herniation in patients infected with human immunodeficiency virus:a nonrandomized,controlled,2-year follow-up clinical study

Ming Lu,Chun-Hong Wang,Min Li,Tao Luo,Yong-Sui Lin,Wei-Li Zhou,Bao-Xue Sha,Ming-Xin Wang,De-Qiang Meng,Zhen-Chao Gao,Guang-Ling Yang,Xing-Cheng Zhao,Qiu Chen

Shanghai Public Health Clinical Center (South Branch,Zhongshan Hospital of Fudan University,Shanghai Public Health Clinical Center Affiliated to Fudan University),Shanghai,China

Abstract Background and objective:Transforaminal endoscopy has certain advantages over traditional surgeries (e.g.,intervertebral disc fusion) in the treatment of lumbar disc herniation,as it is associated with minimal trauma,clear surgical vision,and lower degree of bleeding.However,the therapeutic effects of transforaminal endoscopy on lumbar disc herniation in human immunodeficiency virus (HIV)-infected patients are poorly understood.The purposes of this study are to indicate the efficacy of transforaminal endoscopy in the treatment of lumber disc herniation in HIV-infected patients and compare the efficacy between transforaminal endoscopy and conventional lumbar disc fusion based on 2-year follow-up and prognosis turnover.Subjects and Methods:This is a prospective,single-center,non-randomized,controlled,2-year follow-up clinical study.Sixty HIV-infected patients with lumbar disc herniation who will receive treatment in the Shanghai Public Health Clinical Center will be included in this study.These patients will be divided into two groups according to the surgical treatment.Patients in the experimental group (n=30) will undergo nucleus pulposus enucleation under an intervertebral foramen endoscope,while patients in the control group (n=30) will undergo intervertebral disc fusion.All patients will be followed up postoperatively at 6,12,and 24 months.This study was approved by the Institutional Ethics Committee of Shanghai Public Health Clinical Center of China (approval No.[2020]2020-S122-02) on July 28,2020.All participants will be informed about the study protocol and will be asked to provide written informed consent.This study was designed on November 30,2018.Patient recruitment will be performed in the period between October 30,2020 and April 30,2021.The study outcomes will be analyzed between May 1,2023 and May 30,2023.The study will be terminated on June 30,2023.The primary outcome measure of this study is the change in the symptom improvement rate evaluated by the Japanese Orthopedic Association score at 24 months after the surgery.The secondary outcome measures include the changes in the symptom improvement rate evaluated by the Japanese Orthopedic Association score at 6 and 12 months after the surgery; pain improvement rate evaluated by the Visual Analogue Scale,and improvement in the quality of life evaluated by 36-Item Short Form Health Survey (SF-36) at 6,12,and 24 months,as well as the recurrence rate of lumbar disc herniation and the incidence of postoperative adverse reactions at 6,12,and 24 months after the surgery.Results:In our preliminary study ongoing between January 2016 and January 2018,86 patients were included and divided into two groups,i.e.,the experimental group (n=48; nucleus pulposus enucleation under intervertebral foramen endoscope) and the control group (n=38;intervertebral disc fusion).Six-month follow-up results revealed that the mortality of the experimental and control groups was 0 during and 6 months after the surgery,and no deaths occurred due to intervertebral foramen endoscope surgery or postoperative adverse reactions.Six-month follow-up results revealed that the improvement rate of the Japanese Orthopedic Association score and recurrence rate were comparable between the experimental and control groups,and no adverse reactions occurred.However,the improvement rate of the Visual Analogue Scale in the experimental group was higher than that in the control group (P ＜ 0.05).Conclusion: The results of this study can be used to indicate whether transforaminal endoscopy with minimal trauma in the treatment of lumbar disc herniation in HIV-infected patients is associated with better medium-and long-term surgical effects and prognosis as well as turnover than intervertebral disc fusion.The innovation of this study lies in a fact that the subjects are HIV-infected patients with lumbar disc herniation.Trial registration:This study was registered in the Chinese Clinical Trial Registry (registration number:ChiCTR2000037464) on August 28,2020.Study protocol:1.0.

Key words: foramen endoscope; intervertebral disc fusion; Japanese Orthopaedic Association score; lumbar disc herniation; non-randomized controlled trial; special infection carrier; Visual Analogue Scale

INTRODUCTION

Background

In the population infected with special pathogens,the incidence of postoperative infectious diseases and degenerative diseases increases due to the infectious environment in the patients' tissues.1-3In general lumbar disc surgery,including traditional intervertebral disc fusion and intervertebral foramen endoscopy,the latter has the advantages of minimal trauma,clear surgical vision,and smaller blood loss.However,it remains unclear whether intervertebral foramen endoscopy is associated with advantages in terms of postoperative curative effects,prognosis and turnover in human immunodeficiency virus (HIV)-infected patients with lumbar disc herniation.4-14HIV infection is very common in the population infected with special pathogens,15-17but there are only a few studies on lumbar disc herniation in the HIV-positive population.Moreover,the HIV does not invade the intervertebral disc or cause intervertebral disc herniation,and intervertebral disc herniation is often caused by external forces,leading to intervertebral disc involvement,worsened degeneration,and eventually even rupture of the annulus fibrosus.18,19

Therefore,external forces and poor living habits remain the main risk factors for intervertebral disc herniation.At present,only a few studies have addressed the treatment of intervertebral disc herniation in the HIV-infected population.We searched the PubMed database using the search terms"endoscope,lumbar disc herniation" to retrieve clinical studies on transforaminal endoscopy for the treatment of lumbar disc herniation published in September 2018.We found that endoscopic lumbar discectomy is suitable for the treatment of lumbar disc herniation,as is safe and effective (Table 1).12-14

Study objective

The purpose of this study is to evaluate the curative effects of transforaminal endoscopy in the treatment of lumbar disc herniation in HIV-infected patients using 2-year follow-up results,prognosis and turnover and to compare the curative effects between transforaminal endoscopy and traditional intervertebral disc fusion.

SUBJECTS AND METHODS

Study design

This is a prospective,single-center,non-randomized,controlled,2-year follow-up clinical trial.

Study setting

Shanghai Public Health Clinical Center,China.

Subjects

Prior to the release of recruitment information,the study protocol and recruitment advertisement were approved by the Institutional Ethics Committee of the Shanghai Public Health Clinical Center of China (approval No.[2020]2020-S122-02)on July 28,2020.The recruitment notice will be posted on the bulletin board of the Shanghai Public Health Clinical Center of China.Interested inpatients,outpatients,or their family members can contact the project manager via telephone.The participants will be screened according to the inclusion criteria and will be included in this study after having provided written informed consent.The researchers will treat the patients according to their diagnosis and treatment schedule,and regular follow-ups will be conducted.

Inclusion criteria

-Patients with clinically diagnosed lumbar disc herniation with imaging evidence,which meets the McCulloch's diagnostic criteria of lumbar disc herniation proposed in 198020;

-Over 50% secondary spinal stenosis rate as shown in lumbar magnetic resonance images;

-Patients agree to undergo transforaminal endoscopy and will not participate in other clinical trials in order not to influence the study outcomes;

-Meeting China's diagnostic criteria for HIV/acquired immunodeficiency syndrome (AIDS) and 2001 treatment principles; patients need to have all of the following conditionsin order to be diagnosed with AIDS:a) an epidemiological history,b) confirmed HIV antibody-positivity,c) serum HIV/RNA-positivity,d) one of any clinical manifestations.Patients can also be diagnosed with AIDS if HIV antibodies are confirmed in their blood or HIV-RNA is confirmed in the serum in addition to CD4+T lymphocytes ＜ 200/μL.

Table 1:Three representative clinical studies on transforaminal endoscopy for treatment of lumbar disc herniation published during 2014-2016

Exclusion criteria

-Patients with coronary atherosclerosis and/or other basic diseases;

-Patients with stroke,malignant tumors,brain injury,and/or other diseases that can affect the follow-up examinations;

-Patients with surgical contraindications,including severe diabetes mellitus,liver disease,and abnormal coagulation function;

-Patients who do not agree to be treated with transforaminal endoscopic surgery;

-Patients with neuropsychiatric disorders;

-Patients with lumbar disc herniation and severe lumbar degenerative disease caused by other complex causes.

Grouping and blinding

Sixty HIV-infected patients with lumbar disc herniation will be divided into the experimental group (n=30; nucleus pulposus enucleation under intervertebral foramen endoscope) and the control group (n=30; intervertebral disc fusion).

Double-blind grouping and assignment concealment will not be performed.The evaluators who will be responsible for the Japanese Orthopaedic Association (JOA) score,Visual Analogue Scale (VAS) score,and Short Form-36 (SF-36)Questionnaire score will not be aware of the study protocol.

Surgical method

Experimental group

Patients will be placed in a prone position.An incision of the L5/S1 segment will be made at the intersection of the 10-14 cm lateral to the midline on the affected side and the superior edge of the iliac crest.The tissues around the incision,deep fascia,and superior articular process will be locally anesthetized with 1% lidocaine.Under fluoroscopic guidance,an 18G puncture needle will be inserted into the tip of the superior articular process of the corresponding segment and till the responsible intervertebral disc.Following this,a mixture of iohexol and methylene blue (3:1) will be injected into the intervertebral disc.After withdrawal of the puncture needle,the guide wire will be inserted into the intervertebral disc using the 18G puncture needle hole.The guide wire will be fixed and the 18G puncture needle will be withdrawn.An approximately 7-mm long incision will be made at the puncture point with a sharp knife.Along the guide wire,the first grade guide rod and catheter will be inserted.Then,along the first grade catheter,the first grade trephine will be inserted to cut the bone of the anterior part of the superior articular process to expand the intervertebral foramen.Next,the intervertebral foramen will be gradually expanded using the second grade and third grade trephine.After removal of the third grade trephine,a sleeve will be placed along the third grade catheter.Under fluoroscopic guidance,it will be ensured that the sleeve mouth will reach the position of the protruding nucleus pulposus.The herniated nucleus pulposus tissue will be removed under the endoscopic guidance.The nerve root will be released.Bipolar radiofrequency will be used for hemostasis at the bleeding point and ablation of the annulus fibrosus.After removal of the mirror and working channel,the incision will be sutured (Figure 1).The patients will remain in bed for 1 day after the surgery.They will be active under waist protection and exercise of the back muscle will be performed within the period of 1 month after the procedure.Rapid physical activity will need to be avoided within the period of 3 months after the surgery.

Control group

Considering the diseased segment as the center,a median straight incision crossing one normal vertebral segment above and below the diseased segment will be made along the spinous process.The intervertebral space will be exposed via the posterior medial incision.Hemilaminectomy will be performed on the affected side to remove the medial superior and inferior articular processes for decompression.The cauda equina will be pulled out and the superior and inferior nerve roots will be confirmed.The dural sac will be moderately pulled to the contralateral side.The reamer will be placed behind the intervertebral disc,and the center of the handle will be located in the midline.The intervertebral space will be gradually expanded to the appropriate height with a reamer.Under direct vision,the dural sac and nerve roots will be confirmed to be pulled away.An intervertebral cage of the appropriate size will be installed.Under a lateral X-ray fluoroscope,the cage will be confirmed to be wellplaced and fixed with pedicle screws after implantation of the unilateral pedicle screw rod.

Postoperative follow-up

All patients will be followed up via telephone or in-person clinical appointments at 6,12,and 24 months after the surgery.

Flow chart of clinical trial is shown inFigure 2.

Anti-HIV drug treatment

Highly active antiretroviral therapy (HAART) is currently the most important method to treat people living with HIV/AIDS.Improving medication compliance is crucial for ensuring HARRT efficiency.Zidovudine and Lamivudine tablets combined with Crixivan are mainly used for HAART throughout life in HIV-infected individuals.

Outcome measures

Primary outcome measure

-The change in symptom improvement rate evaluated by the JOA score at 24 months after the surgery:JOA scores range from 0 to 29 points21; or a lower JOA score indicates server dysfunction.Symptom improvement index=JOA score after treatment -JOA score before treatment.JOA score improvement rate=[(JOA score after treatment -JOA score before treatment)/29 -JOA score before treatment] × 100%.The symptom improvement index can reflect the improvement of lumbar function after the treatment relative to before the treatment.The JOA score improvement rate can be used to understand the clinical treatment efficacy.The JOA score improvement rate also corresponds to the criteria commonly used to evaluate treatment efficacy:JOA score improvement rate 100%,healed; 60%,highly effective; 25-60% effective;＜ 25%,ineffective.

Secondary outcome measures

- The change in the symptom improvement rate at 6 and 12 months after the surgery:the evaluation criteria are the same as above.

- Pain improvement rate evaluated by a VAS at 6,12,and 24 months after the surgery:VAS ranges from 0 to 10.A higher VAS indicates severer lumbar back pain.VAS scoring:0,no pain; ＜ 3,mild pain,tolerable; 4-6,pain that affects sleep,but tolerable; 7-10,gradually worsening pain that is unbearable.22VAS improvement rate (%):(VAS at the last follow up -VAS before treatment)/full score ×100%.Improvement in the quality of life evaluated by the SF-36 form at 6,12,and 24 months after surgery:the SF-36 form covers eight dimensions.The score of each item in each dimension will be summed up,and the total score of each dimension will be converted into a final score located between 0 and 100.A higher final score for each dimension indicates higher quality of life.

- Operation time,amount of blood loss,hospital days:shorter operation time,less blood loss,and a smaller number of hospital days indicate more effective treatment methods.- Recurrence rate of lumbar disc herniation at 6,12,and 24 months after the surgery:recurrence rate=the number of patients with recurrent lumbar disc herniation during the follow-up/total number of patients ×100%.23

- Incidence of adverse reactions at 6,12,and 24 months after surgery:adverse reactions include infection,vascular injury,nerve injury (epidural single or multiple nerve root injury,dural cauda equina nerve or nerve root injury; anesthetic drug-related injury),organ (such as ureter,bladder,ileum,appendix) injury,lumbar instability; cerebrospinal fluid fistula,or spinal pseudocyst.Incidence of adverse reactions=the number of patients with adverse reactions/total number of patients ×100%.

Schedule of primary and secondary outcome measures

Timing of primary and secondary outcome measures is shown inTable 2.

Adverse events

Adverse events include all causes of infection,nerve injury,and cardiovascular and cerebrovascular accidents.(1) All adverse events can only be recorded once,and only the first adverse event can be included.(2) Before the start of the trial,the research team members must be familiar with the subjects'medical records and the emergency plan for the prevention and treatment of their conditions.(3) In case of serious adverse events,the clinicians must report to the project manager and the office of drug clinical trial institution within 2 hours,and the office of drug clinical trial institution should report serious adverse events to the provincial food and drug administration department,ethics committee,as well as to the sponsor within 24 hours.(4) Clinical researchers should record the adverse events at the same time,including at least:description of adverse events,occurrence time,termination time,severity and occurrence frequency,and whether any treatment is needed,and if necessary,describe the used treatment.(5) Clinical researchers should treat the patients in accordance with the patients' conditions.The plan for the prevention and management of emergencies in medical treatment should be initiated when necessary.

Sample size

In accordance with our clinical experience and previous findings,24we hypothesized that after 24 months of the treatment duration,the JOA improvement rate in the experimental and control groups should be 93% and 83%,respectively.Assumingβ=0.2,power=80%,andα=0.05 (two-sided),an effective sample size ofn=165 was calculated using PASS 11.0 software (PASS,Kaysville,UT,RSA).Assuming a participant loss rate of 20%,we will require a sample size ofn=198 patients in this study.However,due to the limitation of our research institute,and considering the time factor of patient collection,n=30 patients/group will be included.Hence,a total of 60 patients will be included in the final analysis of the study outcomes.

Statistical analysis

Data description

All data will be statistically analyzed using SPSS 22.0 software(IBM,Armonk,NY,USA).The number of patients completing the trial,and the number of dropouts will be analyzed.Demographics and baseline data in the experimental and control groups will be analyzed to evaluate the comparability of the two groups.Measurement data will be expressed as means,standard deviations,medians,minimum and maximum values,and upper and lower quartiles.Count data will be expressed as number of cases and percentages.

Table 2:Timing of primary and secondary outcome measures

Statistical methods

The JOA score,VAS,SF-36 form score,operation time,amount of blood loss,and hospital days will be compared using two-samplet-test (for normally distributed data) or the Mann-WhitneyUtest (for non-normally distributed data)between the experimental and control groups at each time point.The abovementioned parameters will be compared using repeated measures analysis of variance and Bonferoni test among different time points within the same group.JOA score improvement rate,VAS improvement rate,recurrence rate of lumbar disc herniation,and incidence of adverse reactions will be compared between the experimental and control groups using Pearson chi-square test.An inspection level ofα=0.05 (two-tailed) will be considered to indicate a significant difference.

Datasets

The included patients consist of the population assigned to the per-protocol set.The per-protocol set refers to the subjects who have completed the trial,meet the inclusion and exclusion criteria based on full-analysis set,have effective baseline values,have good compliance,and do not violate the clinical trial protocol and have completed the contents specified in the case report form.

Data collection and management

Data collection

All data will be collected in the case report forms.After accuracy and completeness confirmation,written records will be transferred to an electronic format using a double data entry strategy.

Data management

All collected data will be statistically analyzed by a professional statistician.The statistician will make a statistical analysis report,and the principle investigator will give a final report.The confirmed data documents will not be altered,and preserved for later use.Any unauthorized investigator will not have the right to review or use the data.All data dedicated to this study will be preserved by Shanghai Public Health Clinical Center of China.

Audits

Independent Data Monitoring Committee composition

The role and responsibilities of the Independent Data Monitoring Committee will be relative to the project steering committee,including doctors with related professional backgrounds,clinical pharmacologist and/or toxicologists,epidemiologists,statisticians,clinical trial managers,and ethics experts.

Investigator qualification

This study will be performed by senior attending physicians who have participated in this kind of surgery in 5-10 cases and who can perform standardized operations and are skillful in surgical instruments and equipment.The physicians who will be responsible for VAS,SF-36 form and JOA scoring should have received professional training and have rich scoring experience.

Monitoring

Monitors will visit the trial institute regularly or carry out clinical quality audit work according to the actual situation.Monitors will report the progress of the trial to the Independent Data Monitoring Committee every 2 months and update the trial progress in the registration database.

Compensation to patients

Patients included in the clinical trial will be monitored and followed up,and may undergo close examinations in our hospital without charge.

Ethics and dissemination

Ethics approval

This study was approved by the Institutional Ethics Committee of Shanghai Public Health Clinical Center of China (approval No.[2020]2020-S122-02) on July 28,2020 (Additional file 1).

This study will be performed in accordance with the requirements ofDeclaration of Helsinkiformulated by the World Medical Association.This study follows the requirements of Transparent Reporting of Evaluations with Nonrandomized Designs (TREND) (Additional file 2).

Informed consent

Participants will be informed of the study protocol and provide written informed consent(Additional file 3).

Dissemination policy

Resultswill be disseminated through presentations at scientific meetings and/or by publication in a peer-reviewed journal.Trial data will be published at www.figshare.com.

RESULTS

Results of a preliminary study involving 86 patients

Our team performed a preliminary study in Shanghai Public Health Clinical Center in the period between January 2016 and January 2018.In this preliminary study,we included 86 HIVinfected patients with lumbar disc herniation who received transforaminal endoscopy (48 patients in the experimental group and 38 patients in the control group).These patients were followed up for 6 months.

Baseline information

There were no significant differences in baseline data,with the exception of sex,between the experimental and control groups (P＞ 0.05).Patients' parameters in these two groups were comparable (Table 3)

Outcome measure results at postoperative 6 months

The mortality rate of patients during and 6 months after the surgery was 0.No one died of transforaminal endoscopy or postoperative adverse reactions.The recurrence rate of lumbar disc herniation and JOA score improvement rate [(JOA score before treatment -JOA score after treatment)/JOA score before treatment ×100%] were similar between the experimental and control groups.No adverse reactions were observed in both groups.However,the VAS improvement rate in the experimental group was significantly higher than that in the control group (P＜ 0.05;Table 4).

DISCUSSION

Previous contributions and problematic questions in this field

Lumbar disc herniation is a common disease among patients admitted to the department of orthopedics,25-30and it inevitably occurs in the special infection population.The incidence of orthopedics-related diseases in the special infection population is increasing year by year.1-3

Table 3:Comparisons of patients' baseline data between two groups

Table 4:Outcome measures during the surgery and at postoperative 6 months

Novelty of this study

This study takes HIV-infected patients with lumbar disc herniation as subjects to investigate the curative effects,prognosis,and turnover associated with transforaminal endoscopy in the treatment of lumbar disc herniation.To the best of our knowledge,there are only a few related studies.The Shanghai Public Health Clinical Center as the diagnosis and treatment center for special infection diseases provides the patient source for performing transforaminal endoscopy treatment of lumbar disc herniation in HIV-infected patients.

Study limitations

Randomization will not be used and double-blinding evaluation will not be performed in this study.The patient cohort size is relatively small.Outcome measures include basic parameters.There is lack of qualitative data such as imaging index of the intervertebral disc to validate the outcome measures.Multi-center,large-sample,randomized controlled trials are needed to validate the findings of this study.

Clinical significance

Findings of this study will help indicate whether transforaminal endoscopy treatment of lumbar disc herniation in HIV-infected patients is a better therapeutic strategy (also in terms of prognosis and turnover) compared to standard surgeries.

TRIAL STATUS

Date of registration:August 28,2020.

Recruitment time:October 30,2020 to April 30,2021.

Study completed:June 30,2023.

Trial status:Not yet recruiting.

Additional files

Additional file 1:Hospital Ethics Approval (Chinese).

Additional file 2:TREND Checklist.

Additional file 3:Informed Consent Form (Chinese).

Author contributions

Study design:MLu and MLi; patient recruitment:MLi,TL,WLZ,BXS; data collection and sorting and statistical analysis:MLi,DQM,ZCG,CHW,GLY,and XCZ; literature retrieval and analysis:TL,MXW; study implementation:MLu; study supervision and coordination:QC; final approval of this manuscript for publication:all authors.

Conflicts of interest

The authors have no conflicts of interest to declare.

Financial support

None.

Institutional review board statement

The study protocol conformed to the ethical guidelines of theDeclaration of Helsinkiand relevant ethical requirements for human body research.This study was approved by Institutional Ethics Committee of Shanghai Public Health Clinical Center of China (approval No.[2020]2020-S122-02) on July 28,2020.

Declaration of patient consent

The authors certify that they will obtain all appropriate patient consent forms.In the form,the patients will give their consent for patients'images and other clinical information to be reported in the journal.The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity,but anonymity cannot be guaranteed.

Reporting statement

This manuscript was prepared in accordance with the Transparent Reporting of Evaluations with Nonrandomized Designs (TREND)statement.

Biostatistics statement

The statistical methods of this study were reviewed by the biostatistician of Shanghai Public Health Clinical Center Affiliated to Fudan University,China.

Copyright license agreement

The Copyright License Agreement has been signed by all authors before publication.

Data sharing statement

Individual participant data that underlie the results reported in this article,after deidentification (text,tables,figures,and appendices).Data will be available immediately following publication,with no end date.Resultswill be disseminated through presentations at scientific meetings and/or by publication in a peer-reviewed journal.Anonymized trial data will be available indefinitely at www.figshare.com.

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Externally peer reviewed.

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