A Systematic Review of Second-Line Treatments in Antiviral Resistant Strains of HSV-1, HSV-2, and VZV

Drug-resistant variants of herpes simplex viruses (HSV) have been reported that are not effectively treated with first-line antiviral agents. The objective of this study was to evaluate available literature on the possible efficacy of second-line treatments in HSV and the use of second-line treatments in HSV strains that are resistant to first-line treatments. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a final search was conducted in six databases on November 5, 2021 for all relevant literature using terms related to antiviral resistance, herpes, and HSV. Eligible manuscripts were required to report the presence of an existing or proposed second-line treatment for HSV-1, HSV-2, or varicella zoster virus (VZV); have full-text English-language access; and potentially reduce the rate of antiviral resistance. Following screening, 137 articles were included in qualitative synthesis. Of the included studies, articles that examined the relationship between viral resistance to first-line treatments and potential second-line treatments in HSV were included. The Cochrane risk-of-bias tool for randomized trials was used to assess risk of bias. Due to the heterogeneity of study designs, a meta-analysis of the studies was not performed. The dates in which accepted studies were published spanned from 2015-2021. In terms of sample characteristics, the majority (72.26%) of studies used Vero cells. When looking at the viruses on which the interventions were tested, the majority (84.67%) used HSV-1, with (34.31%) of these studies reporting testing on resistant HSV strains. Regarding the effectiveness of the proposed interventions, 91.97% were effective as potential managements for resistant strains of HSV. Of the papers reviewed, nectin in 2.19% of the reviews had efficacy as a second-line treatments in HSV, amenamevir in 2.19%, methanol extract in 2.19%, monoclonal antibodies in 1.46%, arbidol in 1.46%, siRNA swarms in 1.46%, Cucumis melo sulfated pectin in 1.46%, and components from Olea europeae in 1.46%. In addition to this griffithsin in 1.46% was effective, Morus alba L. in 1.46%, using nucleosides in 1.46%, botryosphaeran in 1.46%, monoterpenes in 1.46%, almond skin extracts in 1.46%, bortezomib in 1.46%, flavonoid compounds in 1.46%, andessential oils were effective in 1.46%, but not effective in 0.73%. The available literature reviewed consistently supports the existence and potentiality of second-line treatments for HSV strains that are resistant to first-line treatments. Immunocompromised patients have been noted to be the population most often affected by drug-resistant variants of HSV. Subsequently, we found that HSV infections in this patient population are challenging to manage clinically effectively. The goal of this systematic review is to provide additional information to patients on the potentiality of second-line treatment in HSV strains resistant to first-line treatments, especially those who are immunocompromised. All patients, whether they are immunocompromised or not, deserve to have their infections clinically managed in a manner supported by comprehensive research. This review provides necessary information about treatment options for patients with resistant HSV infections and their providers.


Introduction And Background
Although antiviral agents, including acyclovir, ganciclovir, and foscarnet, hold a vital role in the clinical management of herpes virus infections, drug-resistant variants of herpes simplex viruses (HSV) have been reported that are not effectively treated with these drugs [1,2]. Immunocompromised patients have been reported to be the primary population to present with viral strains that have mutations conferring resistance [1,3]. The primary goal of this systematic review is to evaluate the available literature on the possible efficacy of second-line treatments in HSV strains that are resistant to first-line treatments.

Data Extraction
Of the included studies, articles that examined the relationship between viral resistance to first-line treatments and potential second-line treatments in HSV were included. A meta-analysis of the studies was excluded because of the nature of the study.
Main characteristics of studies included in the systematic review is shown in Table 1.

Comparison with Existing Literature
This systematic review provides additional information to patients on the potentiality of second-line treatment in HSV strains resistant to first-line treatments. The existing literature comparing medications as treatments for HSV primarily include acyclovir, ganciclovir, and foscarnet [1,2]. There has also been research that compares various plant extracts [24,110]. However, there is a paucity of research that compares greater than 100 second-line HSV interventions for efficacy, as our study has done.

Strengths and limitations
The primary strength of this study is the utilization of the most well-renowned methodology when conducting a systematic review. This included using a prospective protocol created to answer a specific research question, the risk of bias assessment applied to each article, and the summarized table of findings. An additional strength is the relatively large quantity of studies included within this review.
Limitations were that the literature search included language restrictions to only English articles. The search also included interventions for HSV-1, HSV-2, and VZV, and these differences were not considered when assessing efficacy of interventions. Various methodologies were utilized in studies meeting criteria and so the relationship of sample size and efficacy was not able to be successfully analyzed. Another limitation is that the relationship of severity of HSV infections and efficacy of the intervention was not studied.

Conclusions
Immunocompromised patients have been noted to be the population most affected by drug-resistant variants of HSV. Subsequently, we found that HSV infections within this patient population are challenging to manage clinically effectively. This systematic review provides additional information to patients on the potentiality of second-line treatment in HSV strains resistant to first-line treatments, especially for immunocompromised patients. This review is important as all patients, whether immunocompromised or not, deserve to have their infections clinically managed in a manner supported by comprehensive research. This review provides the necessary information about treatment options for patients with resistant HSV infections and their providers.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.