Traditional Chinese Medicine for HIV-Associated Acute Herpes Zoster: A Systematic Review and Meta-Analysis of Randomized Trials

Background Herpes zoster (HZ) is a common infection in individuals with acquired immunodeficiency syndrome (AIDS) patients. Traditional Chinese medicine (TCM) has been used widely in clinical practice for HZ, which remains not supportive of evidence. This review aimed to evaluate the effectiveness and safety of TCM in treating HIV-associated HZ. Methods Nine electronic databases were searched for randomized controlled trials (RCTs) testing TCM in treating HIV-associated HZ. Data were extracted on citations, interventions, and outcomes, by two authors independently. For the quality evaluation, Cochrane risk-of-bias tool 2.0 was used. Meta-analyses were performed by Revman5.3 software. Effect estimation presented as risk ratio (RR) for dichotomous data and mean difference (MD) for continuous data with their 95% confidence interval (CI). Results Twelve RCTs (n = 644) were included; the majority of them had a high or unclear risk of bias. Meta-analysis showed that pain intensity (VAS 0–5) in the Chinese herbal medicine (CHM) group was lower than it in the drugs group (MD = −0.87, 95% CI [−1.69, −0.04], two trials, n = 93). Duration of herpes-related pain (days) of patients in the combination group was shorter than those in the drugs group (MD = −9.19, 95% CI [−16.73, −1.65], n = 144). The incidence of postherpetic neuralgia (PHN) in the combination group was lower than in the drugs group (RR = 0.49, 95% CI [0.25, 0.99], n = 202). As for cure rate (complete absence of pain and herpes), two trials showed that CHM was better than drugs (RR = 1.58, 95% CI [1.13, 2.22], n = 93), five trials showed combination treatment was better than drugs (RR = 1.40, 95% CI [1.08, 1.82], n = 224). The cure rate in the acupuncture group was more than that in the drugs group (RR = 1.99, 95% CI [1.18, 3.36], n = 120). Four trials reported adverse effects and found no serious adverse events occurred. Conclusion CHM and acupuncture demonstrate more benefits than drugs in pain relief, cure rate improvement, and incidence reduction of PHN. However, given the data limitation and TCM therapies' diversity, the conclusions need to be verified in future trials.


Background
Acquired immunodeficiency syndrome (AIDS) is an autoimmune disease caused by the human immunodeficiency virus (HIV). HIV destroys the human immune system, attacks helper T cells, infects B cells, and significantly decreases peripheral blood lymphocytes. Highly active antiretroviral therapy (HAART) is widely used for HIV infection. e treatment can effectively inhibit the replication of HIV transcription and reduce AIDS mortality; however, it can also lead to decreasing of CD4 + T cells and damage of the kidney and liver [1][2][3].
Herpes zoster, an acute infectious skin disease caused by the varicella-zoster virus (VZV), usually occurs between the earlier HIV infection stage and the period of AIDS [4]. e virus invades and is latent along the sensory nerve. When the body's immune function is weak, the latent virus replicates and spreads, resulting in HZ [5,6]. For patients with AIDS, HZ is more likely to occur and bring great pain due to its positron neuralgia, which greatly affects the quality of life [7,8]. e main drugs recommended in the China Guideline on the Diagnosis and Treatment of AIDS for HIV complicated with HZ include acyclovir, famciclovir, and valaciclovir [9].
Nevertheless, a series of reports remind us that acyclovir may lead to renal damage [10], and the use of ganciclovir in treating HZ may be controversial [11]. Due to intolerant pain, many patients seek traditional Chinese medicine (TCM) for relieving symptoms. TCM therapies often include herbal medicine (topical use and oral taking), acupuncture, and cupping. Since there have been a substantial number of clinical studies published, we, therefore, evaluated current clinical evidence from randomized trials on the effectiveness and safety of TCM in the treatment of HIV-associated herpes zoster.

Methods
is meta-analysis was performed following the PRISMA 2020 guidelines for systematic reviews and meta-analyses [12].

Study Type.
Randomized controlled trials (RCTs) were included without restriction on language, publication type, or blinding.

Participants.
Patients infected with HIV or diagnosed as AIDS and complicated with acute HZ at the same time will meet the main inclusion criterion, without the restriction on age, race, and nationality. But the duration of HZ should be less than three weeks [13].

Interventions. Trials testing any TCM therapies such as
Chinese herbal medicine (CHM) or acupuncture, moxibustion, and cupping with or without drugs (e.g., antiviral drugs, neurotrophic drugs, painkillers, and other common symptomatic treatments) were included. A combination of different TCM therapies as experimental treatment was also included.

Controls.
e controls included no treatment, placebo, or drugs therapy. If there were any drug therapy in the control group, it must stay the same as the intervention group.

Cointerventions.
If there were any cointerventions for HIV/AIDS, such as HAART or active antiretroviral therapy (ART), it should be the same between the control and intervention groups.

Outcomes
(1) Primary outcomes: indicators related to pain including pain intensity (VAS score and McGill score) and duration of pain, incidence of postherpetic neuralgia (PHN), cure rate by the end of treatment, cure defined as a complete absence of pain and herpes, and cure rate defined as the number of cured/ total number * 100% [14]

Screening.
All retrieved trials were managed using NoteExpress software. Initial screening was carried out based on inclusion/exclusion criteria after reading article titles and abstracts. e full-text screening was acquired and checked for eligibility before the final analysis. Two authors carried out back-to-back literature screening independently. Any disagreement was solved through discussions and consultation with a third author.

Data Extraction.
e extracted data were: (1) basic characteristics of included trials (first author, research topic, year of publication, etc.); (2) diagnosis information; (3) inclusion and exclusion criteria; (4) baseline characteristics; (5) control and intervention details; (6) primary outcome and their definitions, measuring time points, and follow-up; and (7) risk of bias components.

Quality Evaluation.
e methodological quality of included trials was evaluated by the risk of bias assessment tool 2.0 [15] developed by Cochrane Collaboration.
is tool assesses the risk of bias from five domains: randomization process, intended interventions, missing data, outcome measurement, and selective reporting (valid/invalid). Only if there are five domains assessed as low, the overall risk is low; otherwise, even if one domain considered as some concern/ high, the overall risk will turn in some concern/high. And if there were four or more domains assessed as some concerns, the overall risk will turn high.
Two authors (Y Jiang and RX Zheng) independently extracted data and assessed and verified the risk of bias. e results were cross-referenced, and any differences were resolved through discussion with the third author (J Li or JP Liu).
2.6. Data Analysis. Review Manager 5.3 software [16] was used for data pooling and statistical analysis. According to the inclusion criteria of intervention and control, trials were divided into four comparisons. Meta-analysis was conducted for each comparison according to different outcomes. Mean difference (MD) and 95% confidence interval (CI) were used for continuous outcomes, and relative risk (RR) was calculated with 95% CI for dichotomous outcomes.
e Cochran Q test and the I 2 statistics were used to examine the heterogeneity across the trials. e randomeffects model was used to estimate the size of the combined effects in the meta-analyses.
If P < 0.01 and the source of heterogeneity was unknown, descriptive analysis was used instead of meta-analysis. Subgroup analyses were conducted by different comparisons, such as CHM versus drugs, CHM + drugs versus drugs, acupuncture and moxibustion versus drugs, and so on, if the number of included studies is sufficient.
Due to the large variability of TCM and the different combination of TCM and drugs, ineradicable clinical heterogeneity of the treatment measures in the included studies, the random-effects model was used to combine the data. e related charts for meta-analysis should be carried out, such as forest and funnel plots.

Study Search.
In total, 448 trials (223 in Chinese and 225 in English) were searched; 139 were excluded before screening due to duplication; 272 were excluded at titles-abstracts screening; and 25 were excluded at full-text screening. Eventually, 12 trials were included in our review. e inclusion process and exclusion reasons for screening are shown in Figure 1.

Characteristics of the Included Trials.
e general information of included trial is presented in Table 1. e trials were published between 2000 and 2014 and were conducted in China. e participants in the trials were mainly male, while only three trials were female-dominated [18,21,28].
ere were 644 participants: 348 in the control group and 196 in the intervention group. Only one trial [26] reported cointervention as HAART but no further details.
TCM therapies contain oral taken herbal granules, herbal medicine for external use, Chinese herbal injection and acupuncture, or moxibustion. Drugs included antiviral agents, nonsteroidal antipyretic and painkillers, neurotrophic agents, and painkillers with the administration as injection, oral use, and external use ( Table 2).

Methodological
Quality. Among 12 included trials, none had a low risk of bias. Seven trials had some concern of risk of bias, and the other five trials had a high risk of bias. Details regarding downgrading are provided in Figure 2. Although four studies [19, 21-23, 25, 27] did not specify randomization, from the same group with the studies that did specify randomization [17,18,20,24,26]. us, researchers identified these ten trials with a low risk of bias in domain 1 (Additional file 4-1). We could not get access to the trial protocols, and no trial indicated registration information. erefore, we evaluated deviations from the intended interventions (domain 2, Additional file 4-2) with some concern. No trials reported missing data, and the number of randomized participants was consistent with that in statistical analyses. us, all trials were identified with low in domain 3 (Additional file 4-3). No objective outcomes were used in seven trials [17,18,[24][25][26][27][28], and the outcome measurement is likely to be influenced by lack of blinding. Domain 4 in seven trials [17,18,[24][25][26][27][28] were identified with high (Additional file . No registered protocol of the included trials was mentioned, so the authors determined to evaluate the selective bias of other trials with some concern (domain 5, Additional file 4-5; Figure 2). And the percentage figure for risk of bias is presented in Additional file 3.

Analysis of Overall Effects.
Data from ten trials were included in meta-analyses, focusing on five classes of outcomes, and the results are shown as follows.
Duration of pain: Five trials from two comparisons reported time of pain; it showed a significant reduction in CHM + drugs group in the duration of pain (MD −9.19 days, 95% CI [−16.73, −1.65], four trials), then in drugs group [20,[23][24][25]. And in the acupuncture and moxibustion +drugs group, the reduction in the duration of pain was also more than in the drugs group (MD −5.87 days, 95% CI [−7.85, −3.89], one trial) [27] (Table 3).

Incidence of Postherpetic Neuralgina.
ree trials [19,22,23] reported the incidence of PHN and showed a benefit of CHM + drugs in reducing the incidence of PHN (RR 0.49, 95% CI [0.25, 0.99]), compared with drugs (Table 3).  Table 3). [17,18,23,24]. Two trials compared CHM with drugs, and both treated intervention group with Long Dan Xie Gan granules + Ruyi Jinhuang paste and control group with acyclovir. One of them [17] reported no drug-related adverse reaction. e other one [18] said a few cases underwent abnormal liver function, but not an exact number, with no abnormal index in routine blood, urine, and kidney function test.

Four Trials Reported Adverse Effects
Two trials compared CHM + drugs with drugs. One trial [24] reported no drug-related adverse reaction. Intervention treatment of this trial was Long Dan Xie Gan granules or Ba Zhen formula + ganciclovir + unknown AA for external use + compound glycyrrhizin injection + BCG-PSN + vitamin B12 + calamine. At the same time, the control group was treated with all the same as the intervention group except CHM. One trial [23] reported three cases of slightly dizzy (intervention group: two cases and control group: one case) after the first dose of intravenous antiviral drugs but all of the cases with no abnormal index in routine blood, urine, liver function, and kidney function test. e intervention of this trial is with Long Dan Xie Gan formula or Chu Shi Wei Ling formula + Sanhuang wash lotion + valacyclovir + acyclovir, and the control is with valacyclovir + acyclovir.

Main Finding.
Sixteen trials of HIV-associated herpes zoster were found, but 4 trials focused on postherpetic neuralgia. Only 12 RCTs (n � 644) focused on acute herpes zoster were included in this review. ose trials represent both genders and cover all ages. All trials were published Reports of included studies (n = 12) * Studies that showed significant inconsistencies in describing the use of randomization and blinding methods were also considered not to be true RCTs.
? Figure 2: Risk of bias assessment of including trials using Rob2 tool. Domains: D1: bias arising from the randomization process, D2: bias due to deviations from intended intervention, D3: bias due to missing outcome data, D4: bias in the measurement of the outcome, and D5: bias in the selection of the reported result. between 2000 and 2014 and were conducted in China. CM treatment includes oral taken granules of CHM, external use CHM, injection of CHM and acupuncture, and moxibustion. Due to the limitation and the small sample size of each included trial, we cannot draw firm conclusions relating TCM therapy in treating patients with HIV-associated acute herpes zoster. Compared with drugs, CHM + external use demonstrated positive effects in improving cure rate and alleviating pain (VAS). CHM + drugs are much better than drugs on improving cure rate, shortening the duration of pain, reducing the incidence of PHN, and improving cure rate and quality of life (WHOQOL-100) at the end of treatment. Acupuncture and moxibustion demonstrated positive effects in alleviating pain (VAS), shortening the duration of pain, and improving the cure rate at the end of treatment. Four included trials reported the outcome of adverse events; two reported nonserious adverse events.

Comparison with Other Studies.
e correlative factor for HIV-associated HZ is usually around hypoimmunity and immunosuppression, which are hard to fix. Compared with drugs, four systematic reviews suggested positive effects of TCM therapy. Wet cupping [29], Long Dan Cao (Gentiana scabra Bunge.) single herb formula [30], and acupuncture [31] may decrease the rate of PHN. Acupuncture using independently [31] and acupuncture plus moxibustion [32] may reduce the VAS score of pain. Gentiana scabra Bunge. formula (Long Dan Cao single herb formula) could also shorten the pain duration [30].
e clinical significance of those study results is yet to be established, and high-quality evidence with rigorous research methods is still insufficient.

Limitations.
e measures of the control group of integrative medicine were inconsistent, which might be because of the unregulated drug use. And the number of included trials and the number of sample sizes were small; the trial scale was limited; and the general quality was low. Most of the included trials did not describe the specific randomization method, did not use the blind method, and evaluated outcome indicators mainly consisted of doctor evaluation or patient self-rating scale, which was highly subjective. erefore, the meta-analysis results can only indicate the partial effect of CHM and AM on HIVassociated HZ, and the reliability of the conclusions obtained is limited.

Implications for Clinical Practice and Further Research.
Our review suggests that TCM may be a potential alternative therapy for the treatment of HIV-associated HZ. Still, most of the included trials have modified the original formula

100.0%
Risk of bias legend Domains: D1: Bias arising from the randomization process D2: Bias due to deviations from intended intervention D3: Bias due to missing outcome data D4: Bias in the measurement of the outcome D5: Bias in the selection of the reported result  erefore, clinicians should add and subtract some herbs according to physical signs in clinical practice to improve clinical symptoms. e included trials were limited by the small sample size and relatively low methodological quality. We hope that in the future, with the support of a more rigorous methodology, more multicenter clinical trials of CHM treatment of HIV/AIDS-associated HZ will be carried out with large sample size, especially RCT trials. More high-quality evidence will help verify the effectiveness of CM and integrative medicine treatment and provide more reliable support for this clinical problem.
In terms of basic research, the research on the components of CHM, the effective mechanism of acupuncture and moxibustion therapy, and the interaction between Chinese and drugs still need to be further explored to provide an experimental basis for clinical research on this topic.

Conclusion
Low certainty of evidence showed that Chinese herbal remedies and acupuncture might be beneficial in relieving pain for HIV-associated HZ and appears to be safe. Further research with a higher quality of evidence is still needed before the clinical recommendation of TCM therapies.