Abstract
Objective:
To compare the clinical effects of foscarnet sodium injection and interferon on human immunodeficiency virus (HIV)-infected patients complicated with herpes zoster.
Methods:
Ninety HIV-infected patients complicated with herpes zoster were divided into a treatment group and a control group that were both treated routinely first. Then the control group and treatment group were administered with interferon and foscarnet sodium injection respectively for four consecutive weeks.
Results:
After four weeks, the effective rates of the treatment and control groups were 95.6% and 80.0% respectively, which were significantly different (P < 0.05). The pain scores of the two groups were similar before treatment, but the scores of the treatment group were significantly lower than those of the control group two and four weeks after treatment (P < 0.05) as well as were significantly lower than those before treatment (P < 0.05). The numbers of CD4+ cells and the contents of IL-2 of both groups two and four weeks after treatment significantly exceeded those before treatment (P < 0.05), with significant inter-group differences also (P < 0.05). Two and four weeks after treatment, the treatment group scored significantly higher in physical activity, energy, sleep, social life and emotional reaction than the control group did (P < 0.05).
Conclusions:
HIV-infected patients are prone to being complicated with herpes zoster. Compared with interferon, foscarnet sodium injection better improves the clinical outcomes by effectively relieving pain and by regulating immune mediated inflammatory diseases, thus boosting the prognostic quality of life.
KEY WORDS: HIV infection, Herpes zoster, Foscarnet sodium, Interferon
INTRODUCTION
Currently, human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) have been severely endangering the whole world as public health issues.1,2 Epidemiological studies have shown that of about seven hundred thousand HIV-infected patients, approximately one hundred thousand ones suffered from AIDS that was mainly transmitted sexually or by intravenous drug injection.3-5 Herpes zoster, as an acute infectious skin disease induced by Varicella-Zoster virus (VZV), is typified by distribution of rash along peripheral nerve segments and neuralgia. During early infection, the virus lurks in the dorsal root neurons persistently, which, upon cellular immune dysfunction, is activated to induce ganglion inflammation, necrosis and acute skin damages.6
The patients with herpes zoster undergo long-term pain, depression and decrease in quality of life. There remain no eligible drugs for treating HIV plus herpes zoster, which are thus now routinely treated by anti-inflammation, infection prevention, disease course shortening and symptom-targeting strategies with antiviral agents, interferon, corticoids, transfer factors and B vitamins, etc.7 Interferon can inhibit virus from damaging nerves, control acute-phase symptoms and prevent postherpetic neuralgia, but it may lead to adverse reactions and high recurrence rates.8
With wide application of highly active anti-retroviral therapy in AIDS patients, anti-HIV treatment has obtained triumphs, and the transmission of HIV has been well controlled. However, resistant viruses have increased due to long-term individual use of a certain drug.9 Foscarnet sodium injection is a well-known, broad-spectrum antiviral agent. By directly binding to the pyrophosphate binding sites of RNA and DNA polymerases, foscarnet, as a non-nucleoside analog of pyrophosphate, non-competitively inhibits enzyme activity with nucleotide substrates.10 Besides, it selectively suppresses virus-specific DNA polymerase and well inhibits hepatitis B virus replication.11
In this study, we compared the clinical effects of foscarnet sodium injection and interferon on HIV-infected patients complicated with herpes zoster.
METHODS
Subjects
Ninety HIV-infected patients complicated with herpes zoster who were treated in our hospital from February 2008 to December 2013 were selected in this study.
Inclusion Criteria
In accordance with “Diagnostic criteria and principles of management of asymptomatic HIV/AIDS” (P. R. China, 2001 edition); expected survival rime > 1 year; with herpes and severe neuropathic pain within 1-7 days, without receiving antiviral or analgesic therapy; with written consent form to accept all possible therapies; 18-65 years old.
Exclusion standards
Severe liver and renal insufficiencies, or those complicated with severe primary cardiovascular, lung and hematopoietic system diseases; psychiatric patients; pregnant or lactating women; allergic to the drugs used herein; with primary immunodeficiency, hormone- or chemotherapy-induced secondary immunodeficiencies, or hematological diseases. Platelet count < 60×109/L. The patients were divided into a treatment group and a control group by random draw (n=45), and their gender, age, disease course, education time, body mass index and history of drug injection were similar (P > 0.05) (Table-I).
Table-I.
Baseline clinical data.
| Group | Gender (male/female) | History of drug injection (case) | Age (years old) | Disease course (year) | Education time (year) | Body mass index (kg/m2) |
|---|---|---|---|---|---|---|
| Treatment group (n=45) | 25/20 | 21(46.7%) | 46.44±2.87 | 4.22±0.45 | 12.73±6.13 | 19.78±5.22 |
| Control group (n=45) | 24/21 | 20(44.4%) | 46.39±3.13 | 4.23±0.65 | 12.77±5.33 | 19.36±5.33 |
| χ2 | 0.078 | 0.50 | ||||
| t | 0.065 | 0.009 | 0.067 | 0.302 | ||
| P | >0.05 | >0.05 | >0.05 | >0.05 | >0.05 | >0.05 |
Treatment methods
Basic treatment
1.2 g reduced glutathione; 150 mg diammonium glycyrrhizinate, qd, intravenous infusion; oral administration of valacyclovir hydrochloride, 300 mg per time, bid; oral administration of vitamin B1, 10 mg, tid.
Control group
Based on the basic treatment, 50 million U IFN α-2b interferon (Jiangsu Chia Tai Tianqing Pharmaceutical Co., Ltd.) was intramuscular injected, qd.
Treatment group
Based on the basic treatment, 3.0 g foscarnet sodium injection (Jiangsu Chia Tai Tianqing Pharmaceutical Co., Ltd.) was intravenously infused, bid. Both groups were treated for four consecutive weeks, with seven days as a course of treatment. Serum and proteins were used to support treatment, but immunomodulators, jaundice-removing agents, other antiviral drugs or plasmapheresis were not employed.
Observation indices
Determination of therapeutic effects: Evaluation was performed four weeks after treatment. Markedly effective: Disappearance of rash and clinical signs (Rash means skin changes such as color, appearance, or texture; clinical signs mean pain, depression and decrease in quality of life), and significantly mitigated pain and itching; effective: disappearance of 30% rash, significantly decreased clinical signs, and mitigated pain and itching; ineffective: unable to reach the above standards.
Pain rating
Degree of pain was rated before as well as two and four weeks after treatment by visual analogous scale, with 0 being painless and 100 being the maximum pain that patients could imagine. The scale was completed by patients.
Investigation on quality of life
Nottingham health profile, which includes physical activity, energy, sleep, social life and emotional reaction, was used to investigate the patients two and four weeks after treatment. From 0 to 100, a higher score means better quality of life. The profile was highly reliable and valid.
Comparisons of inflammatory and immune cytokines
Before as well as two and four weeks after treatment, 5 mL of venous blood was collected and stored in a -20°C refrigerator after separating serum at low temperature. Interleukin-2 (IL-2) content was detected by polyclonal antibody-based sandwich ELISA according to the instructions of kit (Genzyme, USA). CD4+ cells were counted according to instructions by experienced personnel in our hospital.
Statistical analysis
All data were analyzed by SPSS 17.0. The categorical data were expressed as (x ± s), and intra-group and inter-group comparisons were performed by using t test and independent analysis of variance. The numerical data were compared by Chi-square analysis. P < 0.05 was considered statistically significant.
RESULTS
Clinical effects
Four weeks after treatment, the effective rate of the treatment group (95.6%) was significantly higher than that of the control group (80.0%) (P < 0.05) (Table-II).
Table-II.
Clinical effects (n).
| Group | Case No. | Markedly effective | Effective | Ineffective | Overall effective rate |
|---|---|---|---|---|---|
| Treatment group | 45 | 35 | 8 | 2 | 95.6% |
| Control group | 45 | 15 | 21 | 9 | 80.0% |
| χ² | 7.193 | ||||
| P | <0.05 |
Pain scores
The pain scores of the two groups were similar before treatment, but the scores of the treatment group were significantly lower than those of the control group two and four weeks after treatment (P < 0.05) as well as were significantly lower than those before treatment (P < 0.05) (Table-III).
Table-III.
Pain scores at different time points before and after treatment (point, x ± s).
| Group | Case No. (n) | Before | Two weeks after | Four weeks after |
|---|---|---|---|---|
| Treatment group | 45 | 80.44±7.13 | 12.87±5.33 | 6.89±3.12 |
| Control group | 45 | 80.65±6.09 | 34.17±5.11 | 20.11±4.01 |
| t | 0.028 | 22.863 | 14.992 | |
| P | >0.05 | <0.05 | <0.05 |
Changes of inflammatory and immune cytokines
The numbers of CD4+ cells and the contents of IL-2 of both groups two and four weeks after treatment significantly exceeded those before treatment (P < 0.05), with significant inter-group differences also (P < 0.05) (Table-IV).
Table-IV.
Numbers of CD4+ cells and IL-2 contents at different time points before and after treatment (x ± s).
| Group | Case No. (n) | Number of CD4+ cells (count/μl) | IL-2 content (ng/L) | ||||
|---|---|---|---|---|---|---|---|
| Before | Two weeks after | Four weeks after | Before | Two weeks after | Four weeks after | ||
| Treatment group | 45 | 109.37±45.33 | 302.76±60.27 | 338.65±59.09 | 445.22±90.37 | 879.68±78.03 | 1165.98±109.33 |
| Control group | 45 | 111.76±46.01 | 198.26±45.11 | 230.68±63.45 | 448.26±43.09 | 600.38±61.34 | 876.63±78.26 |
| t | 0.284 | 17.367 | 9.367 | 0.391 | 34.762 | 21.093 | |
| P | >0.05 | <0.05 | <0.05 | >0.05 | <0.05 | <0.05 | |
Evaluation on quality of life
Two and four weeks after treatment, the treatment group scored significantly higher in physical activity, energy, sleep, social life and emotional reaction than the control group did (P < 0.05) (Table-V).
Table-V.
Scores in quality of life at different time points before and after treatment (point, x ± s).
| Group | Case No. (n) | Two weeks after | Four weeks after | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Physical activity | Energy | Sleep | Social life | Emotional reaction | Physical activity | Energy | Sleep | Social life | Emotional reaction | ||
| Treatment group | 45 | 78.92±7.49 | 69.37±8.09 | 72.63±6.01 | 76.98±5.11 | 77.18±8.31 | 91.36±6.13 | 92.56±7.20 | 90.78±6.22 | 95.22±7.02 | 93.56±6.11 |
| Control group | 45 | 67.99±5.09 | 56.62±6.44 | 61.68±7.77 | 65.26±6.81 | 59.33±7.22 | 80.36±5.19 | 78.68±4.89 | 82.68±7.29 | 80.63±6.66 | 82.56±7.23 |
| t | 11.377 | 13.847 | 11.003 | 11.084 | 18.467 | 11.044 | 14.665 | 8.462 | 15.882 | 11.662 | |
| P | <0.05 | <0.05 | <0.05 | <0.05 | <0.05 | <0.05 | <0.05 | <0.05 | <0.05 | <0.05 | |
DISCUSSION
AIDS is a chronic infectious disease caused by HIV that belongs to the genus Lentivirus of the family Retroviridae and exists in most body fluids and tissues of HIV-infected and AIDS patients. This virus is mainly transmitted by sexual contact and blood in addition to mother-to-child transmission. Upon HIV invasion, the immune system of human body is attacked and inhibited from exerting protective effects.12 Moreover, along with the replication of immune cell DNA, this virus is also replicated and releases more viruses to infect more cells. Finally, many types of incurable infections and tumors are generated, which lead to inevitable death owing to the lack of eligible drugs.
On the other hand, herpes zoster is related with the immune status of human body, especially with the decrease in cellular immune function. Induced by VZV [with human herpes virus 3 (HHV3) as the main pathogen], herpes zoster is clinically manifested as local nerve involvement and obvious neuralgia.13 During onset, this virus is activated again because of decrease in resistance or cellular immune function, which inflames involved ganglia. Notably, HIV infection remarkably increases the risk of being injected with HHV3 simultaneously.
At present, viral infection is treated by interferon in most cases mainly by fighting against virus, cell proliferation and hepatic fibrosis as well as by regulating immunity. For instance, IFN α-2b can directly inhibit the replication of hepatitis B virus.14 Besides improving immune function, interferon can also enhance macrophage phagocytosis, the killing effect of cytotoxic T cells and the function of natural killer cells. Nevertheless, interferon only has short-term effects while being dose-dependent, accompanied by possible adverse reactions as a result. Foscarnet sodium is a congener of phosphonoacetic acid, and they are both the analogues of pyrophosphates. It has previously been held that foscarnet sodium was an inhibitor of herpes simplex virus DNA polymerase, with its antiviral activities verified against cells in vitro and against guinea pigs in vivo.15 After four weeks, the effective rates of the treatment and control groups were 95.6% and 80.0% respectively, which were significantly different (P < 0.05), suggesting that foscarnet sodium effectively relieved the herpes zoster symptoms.
HIV infection complicated with herpes zoster is mainly characterized by spontaneous, needle-like, burning-like, paroxysmal pain, being different from the persistent pain caused by lumbar diseases. Hence, pain scores are usually high. When the disease occurs, patients undergo insufferable burning and itching together with neuralgia, thus being sleep-deprived in extreme cases. Approximately 14.0% of herpes zoster develops into postherpetic neuralgia as neuropathic pain that will result in severe outcomes if not treated in time. Unlike interferon that exerts only short-term effects,16 foscarnet sodium, which is a totally synthesized small molecule compound, functions at the pyrophosphate binding site of viral DNA polymerase. It also prevents pain sequelae by rapidly inhibiting the congestion, edema and necrosis of ganglia and corresponding sensory fibers and by preventing desmoplasia. In this study, the pain scores of the two groups were insignificantly different before treatment, but the scores of the treatment group were significantly lower than those of the control group two and four weeks after treatment (P < 0.05) as well as were significantly lower than those before treatment (P < 0.05).
Furthermore, it is well-known that CD4+ cells play an important role in maintaining immune function as the center of immune response, and HIV mainly invades human CD4+ T lymphocytes by reducing their counts and by causing functional defects. HIV infection complicated with herpes zoster can decrease CD4+ cells by hindering their maturation, and lead to indirect damages by producing autoimmune response and by inducing the apoptosis of such cells. In the meantime, Th cell-assisted or mediated immune response functions are indirectly weakened, including decrease in IL-2 production and the failure of Th cells to activate specific antigens. Acute infection is typified by plummet in the number of CD4+ T lymphocytes, which may self-recover completely or partially in most patients without special treatment. Herein, the numbers of CD4+ cells and the contents of IL-2 of both groups two and four weeks after treatment significantly exceeded those before treatment (P < 0.05), with significant inter-group differences also (P < 0.05), indicating that foscarnet sodium effectively suppressed viral infection and proliferation by regulating immune and inflammatory mechanisms. Basic and clinical studies also showed that foscarnet sodium was able to well inhibit hepatitis B virus and the activities of T, B lymphocytes.17 In addition, most patients tolerate foscarnet sodium well, without undergoing renal function damages if given enough water therewith.18 In this study, the treatment group scored significantly higher in physical activity, energy, sleep, social life and emotional reaction than the control group did two and four weeks after treatment (P < 0.05).
In short, HIV-infected patients are prone to being complicated with herpes zoster. Foscarnet sodium injection, compared with interferon, better improves the clinical outcomes and prognostic quality of life by effectively alleviating pain and by regulating immune mediated inflammatory diseases.
Footnotes
Note: The first two authors contributed equally to this work.
Funding: None.
Conflicts of interest: The authors declare no conflicts of interest.
Authors’ Contribution
YYQ&XMP: Conceived, designed and did statistical analysis & editing of manuscript.
XJK & CXA: Did data collection and manuscript writing.
XMP: Did review and gave final approval of manuscript.
XMP: Takes the responsibility and is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
REFERENCES
- 1.Ghannad MS, Solgi G, Hashemi SH, Zebarjady-Bagherpour J, Hemmatzadeh A, Hajilooi M. Herpes simplex virus encephalitis in hamadan, iran. Iran J Microbiol. 2013;5(3):272–277. [PMC free article] [PubMed] [Google Scholar]
- 2.Piret J, Boivin G. Antiviral drug resistance in herpesviruses other than cytomegalovirus. Rev Med Virol. 2014;24(3):186–218. doi: 10.1002/rmv.1787. doi:10.1002/rmv.1787. [DOI] [PubMed] [Google Scholar]
- 3.Finn KM, Ginns LC, Robbins GK, Wu CC, Branda JA. Case records of the Massachusetts General Hospital. Case 20-2014. A 65-year-old man with dyspnea and progressively worsening lung disease. N Engl J Med. 2014;370(26):2521–2530. doi: 10.1056/NEJMcpc1400841. doi:10.1056/NEJMcpc1400841. [DOI] [PubMed] [Google Scholar]
- 4.Schaftenaar E, Verjans GM, Getu S, McIntyre JA, Struthers HE, Osterhaus AD, et al. High seroprevalence of human herpesviruses in HIV-infected individuals attending primary healthcare facilities in rural South Africa. PLoS One. 2014;9(6):e99243. doi: 10.1371/journal.pone.0099243. doi:10.1371/journal.pone.0099243. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Seang S, Boutolleau D, Burrel S, Regnier S, Epelboin L, Voujon D, et al. Long-term follow-up of HIV-infected patients once diagnosed with acyclovir-resistant herpes simplex virus infection. Int J STD AIDS. 2014;25(9):676–682. doi: 10.1177/0956462413518034. doi:10.1177/0956462413518034. [DOI] [PubMed] [Google Scholar]
- 6.Drannik AG, Nag K, Sallenave JM, Rosenthal KL. Antiviral activity of trappin-2 and elafin in vitro and in vivo against genital herpes. J Virol. 2013;87(13):7526–7538. doi: 10.1128/JVI.02243-12. doi:10.1128/JVI.02243-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Leporrier J, Etienne M, Chapuzet C, Peytavin G, Bord S, Borsa-Lebas F, et al. Association of dolutegravir and rilpivirine, enhanced by foscarnet induction, in effective salvage antiretroviral therapy. Clin Virol. 2014;60(4):428–430. doi: 10.1016/j.jcv.2014.05.004. doi:10.1016/j.jcv.2014.05.004. [DOI] [PubMed] [Google Scholar]
- 8.Beňová A, Brichová M, Svozílková P, Kousal B, Jeníčková D, Heissigerová J, et al. Cytomegalovirus retinitis in HIV negative patients - retrospective study. Cesk Slov Oftalmol. 2013;69(6):227–234. [PubMed] [Google Scholar]
- 9.Fox JB, Shaw FE. Relationship of income and health care coverage to receipt of recommended clinical preventive services by adults - United States, 2011-2012. MMWR Morb Mortal Wkly Rep. 2014;63(31):666–670. [PMC free article] [PubMed] [Google Scholar]
- 10.Shahapur PR, Bidri RC. Recent trends in the spectrum of opportunistic infections in human immunodeficiency virus infected individuals on antiretroviral therapy in South India. J Nat Sci Biol Med. 2014;5(2):392–396. doi: 10.4103/0976-9668.136200. doi:10.4103/0976-9668.136200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Todesco E, Sayon S, Fourati S, Tubiana R, Simon A, Ktorza N, et al. Highly multidrug-resistant HIV: clonal analysis and therapeutic strategies. J Antimicrob Chemother. 2013;68(12):2882–2889. doi: 10.1093/jac/dkt272. doi:10.1093/jac/dkt272. [DOI] [PubMed] [Google Scholar]
- 12.Ehteshami M, Nijhuis M, Bernatchez JA, Ablenas CJ, McCormick S, de Jong D, et al. Formation of a quaternary complex of HIV-1 reverse transcriptase with a nucleotide-competing inhibitor and its ATP enhancer. J Biol Chem. 2013;288(24):17336–17346. doi: 10.1074/jbc.M112.433441. doi:10.1074/jbc.M112.433441. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Thompson MR, Sharma S, Atianand M, Jensen SB, Carpenter S, Knipe DM, et al. Interferon γ-inducible Protein (IFI) 16 Transcriptionally Regulates Type I Interferons and Other Interferon-stimulated Genes and Controls the Interferon Response to both DNA and RNA Viruses. J Biol Chem. 2014;89(34):23568–23581. doi: 10.1074/jbc.M114.554147. doi:10.1074/jbc.M114.554147. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Herold BC, Dezzutti CS, Richardson BA, Marrazzo J, Mesquita PM, Carpenter C, et al. Antiviral activity of genital tract secretions after oral or topical tenofovir pre-exposure prophylaxis for HIV-1. J Acquir Immune Defic Syndr. 2014;66(1):65–73. doi: 10.1097/QAI.0000000000000110. doi:10.1097/QAI.0000000000000110. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Nixon B, Fakioglu E, Stefanidou M, Wang Y, Dutta M, Goldstein H, et al. Genital herpes simplex virus type 2 infection in humanized HIV-transgenic mice triggers HIV shedding and is associated with greater neurological disease. J Infect Dis. 2014;209(4):510–522. doi: 10.1093/infdis/jit472. doi:10.1093/infdis/jit472. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Akinboro AO, Onayemi O, Mejiuni AD. Frequency, pattern, and extent of skin diseases in relation to CD4+cell count among adults with human immunodeficiency virus infection or acquired immunodeficiency syndrome in Osogbo, southwestern Nigeria. Int J Dermatol. 2014;53(4):416–424. doi: 10.1111/j.1365-4632.2012.05820.x. doi:10.1111/j.1365-4632.2012.05820.x. [DOI] [PubMed] [Google Scholar]
- 17.Siddiqi OK, Ghebremichael M, Dang X, Atadzhanov M, Kaonga P, Khoury MN, et al. Molecular diagnosis of central nervous system opportunistic infections in HIV-infected Zambian adults. Clin Infect Dis. 2014;58(12):1771–1777. doi: 10.1093/cid/ciu191. doi:10.1093/cid/ciu191. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Aissani B, Wiener HW, Zhang K, Kaslow RA, Ogwaro KM, Shrestha S, et al. A candidate gene approach for virally induced cancer with application to HIV-related Kaposi's sarcoma. Int J Cancer. 2014;134(2):397–404. doi: 10.1002/ijc.28351. doi:10.1002/ijc.28351. [DOI] [PMC free article] [PubMed] [Google Scholar]