The Effect of 670-nm Low Laser Therapy on Herpes Simplex Type 1

Abstract

Objective: The purpose of this work was to study the effect of low-level laser therapy (LLLT) on the healing and relapse intervals in patients with recurrent labial herpes simplex infections. Background data: Several pharmaceuticals are available to reduce symptoms and improbé healing of labial herpes, but only LLLT has been reported to significantly influence the length of the recurrence period. Material and methods: In an initial study, 232 patients with herpes simplex type 1 virus symptoms were consecutively selected for either LLLT or conventional therapy, including acyclovir cream or tablets. One of the dentists was responsible for the diagnosis, a second dentist for the treatment, and and a third for the evaluation, to allow for a semi-blinded procedure. Patients in the laser group received 670-nm laser irradiation, 40 mW, 1.6 J, 2.04 J/cm², 51 mW/cm² per blister in the prodromal stage and 4.8 J in the crust and secondarily infected stages, plus 1.2 J at the C2–C3 vertebrae. Patients were monitored daily during the first week to control healing, and monthly for 1 year to check on recurrence. In a consecutive study, 322 patients receiving LLLT were followed during 5 years to observe the period of ocurrences. Results: An obvious effect of LLLT was found for both initial healing and for the length of the recurrence periods. Conclusions: LLLTof herpes simples virus 1 (HSV-1) appears to be an effective treatment modality without any observed side effects.

Introduction

H erpes simplex type 1 (HSV-1) is a common illness, mainly, but not solely, caused by the human herpes virus type 1 that generally presents as a primary lesion, with periods of latency and a tendency to relapse. According to the World Health Organization (WHO) an international prevalence of about 60% is observed.^1,2 Although painful and aesthetically bothersome, most HSV-1 attacks are occasional and will heal within<2 weeks without treatment. The major problems occur when there are recurrent attacks, sometimes as frequent as monthly. Exposure to intense ultraviolet (UV) radiation and stress are well-known triggers of an attack, and it can also appear at a certain stage of the menstruation cycle. Limited, but statistically significant, results have been shown with topical antivirals, such as acyclovir and penciclovir, improving healing times by ∼10%. Orally administrated antivirals, such as valaciclovir and famciclovir, have subsequently found clinical use. However, these two oral medications have different profiles in phase 3 studies. Famciclovir showed additional improvement of efficacy in terms of lesion healing time, but no effect on prevention of ulcerative lesions, whereas valaciclovir appeared to have similar efficacy to that of acyclovir cream in lesion healing, but some additional efficacy in prevention of ulcerative lesions.³

Low-level laser therapy (LLLT) has been used for decades to treat HSV-1, and the clinical results are reported to be promising. However, the literature on the method is scarce. Early in vitro studies^4,5 indicated that LLLT had an inhibiting effect on the proliferation of the virus. Clinical studies^6,7 showed that LLLT was as effective as traditional methods. An important aspect of LLLT was underlined by Schindl,⁸ showing that the relapse time increased after using LLLT. This effect is not observed with conventional methods.

The mechanisms behind the curative and prophylactic effects of LLLT are not well known. In an in vitro experiment by Eduardo,⁹ epithelial cells and HSV-1 virus in culture were studied. Cells were irradiated with 660 or 780 nm, using different dosages in four groups: (1) irradiation of uninfected epithelial cells; (2) epithelial cells irradiated prior to infection with the virus; (3) virus irradiated prior to infecting the epithelial cells; and (4) irradiation of HSV-1–infected cells. The irradiated epithelial cell growth was enhanced, but the only effect seen in cells infected with the virus was that the cell viability was prolonged if irradiated prior to infection. Therefore, prolongation of cell survival may be one of the mechanisms involved. These observations coincide with those by Donnarumma,¹⁰ hypothesizing that LLLT acts in the final stage of HSV-1 replication by limiting viral spread from cell to cell, and that laser therapy acts also on the host immune response, unblocking the suppression of pro-inflammatory mediators induced by accumulation of progeny virus in infected epithelial cells.

In an ear experimental model of HSV latency by Perrin,¹¹ it was observed that repeated exposure to infrared laser radiation of cervical ganglia following HSV inoculation appears to specifically hinder the establishment of virus latency in mice.

Materials and Methods

A pilot study was initially performed, in which 232 consecutive patients affected by the Herpes simplex type 1 virus were treated. All patients attended the clinic “Leonardo Fernández” in Cienfuegos, Cuba, during the period from January 2001 to January 2003. The objective was to determine the time of recurrence of the labial herpes in the groups, studied before and after treatment, and to evaluate the effectiveness of LLLT in the treatment of the infection itself. In order to obtain a homogeneous group of patients, cases with blisters outside of the actual lip areas were excluded. Both groups were interviewed before the study started, and were asked to indicate the number of HSV-1 outbreaks that they had per year.

Two groups (study and control) were selected with 116 patients in each group, randomized to laser or control group by the SPSS computer program. One of the dentists was responsible for the diagnosis, a second dentist for the treatment, and and a third for the evaluation, to allow for a semi-blinded procedure. In the study group, the patients were offered treatment with a Lasermed 670 DL, a 670-nm diode laser (40 mW, 40 sec, 1.6 J, 2.04 J/cm², 51 mW/cm², spot size 0.79 cm², in non-contact mode; power measured at the Technical University of Cienfuegos) in the prodromal stage and in the stage of vesicles. In the crust stage and in lesions infected secondarily, 40 mW, 2 min, 4.8 J was used. All these patients also received radiation over the vertebrae C2–C3 (40 mW, 30 sec, 1.2 J), where the resident ganglion of the virus is reported to be located during the latent periods.¹¹

The control group was offered indicated treatment with antivirals (acyclovir cream and tablets) and other palliative therapies, such as an anesthetic cream and advice to avoid spicy and hot food. The patients were followed up during 1 year by monthly visits to the clinic. Patients not willing or able to come to the requested follow-ups were excluded from the study.

Pilot as well as recurrence studies were approved by the Scientific Committee of the Medical University of Cienfuegos, and a written consent was given by all participating patients. All therapies were free of charge for the patients.

Results

Pilot study

The outcome of the pilot study is illustrated in Tables 1 –3. In total, there were 84 occasions of recurrence in the laser group and 114 in the control group. After day 7 no patients in the laser group had any visible signs of HSV-1 blisters, whereas in the control group 77 patients still had vesicles, 29 had crust formation, and 10 had secondary infections. This confirms the curative effect on the clinical manifestation, and a clear trend toward reduction of the recurrence frequency.

Table 1.

Laser Group Recurrence Frequency

	Once a month	Every 2–3 months	Every 4–5 months	Every 6 months	Once a year	First time ever	No recurrence
Before treatment	9	26	58	12	7	4	0
After treatment	0	0	37	22	25	0	32

Distribution according to the frequency of annual recurrence of the labial herpes, before and after receiving treatment; n=116.

Table 2.

Recurrence Frequency for the Patients of the Control Group, Traditional Treatment

	Once a month	Every 2–3 months	Every 4–5 months	Every 6 months	Once a year	First time ever	No recurrence
Before treatment	7	24	56	14	9	6	0
After treatment	6	21	46	27	14	0	2

Distribution according to the annual recurrence frequency, before and after receiving treatment; n=116.

Table 3.

Recurrence Frequency Compared for the Patients of Both Groups

	Once a month	Every 2–3 months	Every 4–5 months	Every 6 months	Once a year	First time ever	No recurrence
Laser group	0	0	37	22	25	0	32
Control group	6	21	46	27	14	0	2

Distribution according to the annual recurrence frequency after receiving laser or traditional treatment.

Recurrence study

To follow up on these encouraging results, a new study was initiated in January 2004. Up until January 2006, 432 patients had been consulting at our clinic for HSV-1 occurrence. Out of this group, 322 patients were selected to be followed during 5 years in order to register the long-term incidence of recurrence. The study included 189 men and 133 women, ages ranging from 18 to 59. Exclusion criteria were inability to be reached during a 5-year follow-up and having perilabial blisters. The latter exclusion criterion was used to make the group more homogenous. After a detailed anamnesis, the patients were treated daily until they were clinically and subjectively asymptomatic. Patients in the prodromal stage were treated by 1.6 J per session, those in the blister stage by 4.8 J per session; parameters as in the pilot study. At all sessions, the region at the C2–C3 vertebrae was irradiated by 1.2 J, all in accordance with the experience from the pilot study. All patients were checked and interviewed annually by receiving home visits, all performed by the same dentist. Recurrences were also recorded if the patient came to the clinic on his/her own initiative for recurrence laser treatment. None of the 438 patients receiving LLLT in studies 1 and 2 reported any negative side effects, nor did any of the 110 patients not included in the study 2. Checking the available literature, no information about a possible difference in HSV-1 incidence in male and female patients was found. Clinically, the general feeling is that females are more likely to have labial HSV-1 attacks. This may, however, simply be because females in general are more keen to seek dentistry. We therefore performed an analysis by sex. Our data did not confirm the clinical impression. On the contrary, there was a tendency for more male relapses, especially in years 3 and 5.

Results of the recurrence study

Out of the 322 patients, the number of annual recurrences varied between 22 and 42, with the extreme exception of year 3. The increase in recurrence at year 3 remains to be understood. The number of relapses was as follows, with “m” indicating males and “f” indicating females: Year 1, 35 (21 m/14 f); year 2, 42 (23 m/19 f); year 3, 149 (98 m/51 f); year 4, 41 (20 m/21 f); year 5, 22 (10 m/12 f). Thirty-three patients (19 m/14 f) did not have one single recurrence after 5 years of observation.

Discussion

These two studies confirm that HSV-1 outbreaks can be relieved and shortened by using LLLT, and that the number of relapses decreases. An analysis of the available literature verifies our positive clinical observations. In the early literature an in vitro study by Gilioli et al.⁴ showed a stimulating effect on the virus itself. Tardivo⁵ observed the behavior of cells infected with HSV-1 under a GaAs laser, 30 mW. Doses of 4 and 12 J were given. A lesser cytopathic effect was noted in the irradiated cells than in the control cells, more evident at 4 J. The two cell lines were incubated for 7 days and frozen, and the released viruses were inoculated in a new culture. An absence of cytopathic effect was noted in the cells infected with viruses derived from the cultures that received 12 J initially.

One of the first clinical reports on the use of LLLT for HSV-1 appeared in 1983, and indicated that 647 nm, 50 mW, 3 J/cm² had a positive effect on HSV-1, but less on HSV-2.⁶

Vélez-González et al.⁷ treated 60 patients with herpes simplex in the oral (HSV-1) or genital (HSV-2) area. Three groups in each category received (1) 200 mg acyclovir orally plus placebo laser; (2) placebo acyclovir and HeNe laser light at 8 J/cm²; or (3) acyclovir and HeNe. Relapses in the lips and face were significantly reduced in the group treated with HeNe laser plus acyclovir, as compared with the groups treated with acyclovir or HeNe only. The number of relapses per year before and after treatment was 5.2/2.8 for group I, 7.83/1.16 for group II, and 7.28/1.28 for group III. There was no significant difference between the latter groups. However, healing time was shorter in the group that received a combination of treatments. The effects on the HSV-2 groups were lower for all three treatment modalities.

However, the use of LLLT to suppress infections caused by HSV 1 and 2 was evaluated by Ferreira et al.¹² after one to five applications. A gradual reduction in replication of HSV 1 as well as 2 was observed, with 68.4% and 57.3% inhibition, respectively, after five applications.

An important aspect of LLLT for HSV-1 has been described by Schindl et al.⁸, namely, the possibility of treating patients with recurrent herpes labialis even during the symptom-free period. Fifty patients with recurrent herpes labialis infections (at least once a month for>6 months) were treated with 690 nm, 80 mW laser, energy density 48 J/cm², in a double-blind study. Patients received daily irradiations for 2 weeks, 10 sessions in all. The treatment was given during a recurrence-free period and the irradiation was given at the site of the original herpes labialis infection. If both lips had been involved, both upper and lower lips were treated. Patients were monitored for 52 weeks. The mean recurrence-free interval in the laser group was 37.5 weeks (range, 2–52 weeks), and in the placebo group 3 weeks (range, 1–20 weeks). No side effects were noted.

LLLT has been used as a single treatment modality and in combination with other modalities. Tzonko et al.¹³ used 630 nm, 100 mW/cm² in a group of 32 patients, and the same treatment for another group of 32 patients in combination with the photosensibilizer Granofurin H. Both groups showed positive results, but the addition of Granofurin H provided the best outcome. Sperandio et al.¹⁴, Marotti et al.,¹⁵ and de Carvalho et al.¹⁶ report that photoactivated disinfection (PAD) can be a viable method of treating HSV-1. The blister is dyed with methylene blue, and irradiated with red laser light. Bello-Silva et al.¹⁷ used Er:YAG to open and drain large blisters, and then followed up with 660-nm LLLT. Almeida-Lopes et al.¹⁸ have shown that HSV-1 can be treated advantageously by irradiation of the involved lymph nodes only.

The cellular mechanism behind the reported result is partly unknown. The positive effects of LLLT on pain¹⁹ and inflammation²⁰ are well documented and are likely a part of the mechanism. However, the prolonged relapse time cannot be explained by these factors. From the studies of Eduardo,⁹ Donnarumma,¹⁰ and Almeida-Lopes¹⁸ it can be hypothesized that the main effect of the laser light is more a stimulation of the immune system than an inhibitory effect on the virus.

In this study, a wavelength of 670 nm in the red part of the spectrum was used, and fairly low energies were applied. Other wavelengths and generally higher energies are also reported in the literature. Therefore, it seems that the treatment is not wavelength sensitive or very sensitive to the amount of energy applied.

Irradiation over the C2–C3 vertebrae has so far only been reported in an animal study,¹¹ and our study did not make an effort to establish the specific effect of this additional irradiation. The low energy used and the rather weak penetration of the 670-nm wavelength are both probably on the outskirts of the actual therapeutic window.

Given the high number of patients included in both studies, and the high level of improvement, no statistical analysis was considered.

Taking the lack of side effects and the prolongation of the relapse time into consideration, LLLT appears to be an attractive alternative to presently used treatment modalities.

Conclusions

LLLT appears to be a safe, inexpensive, and effective treatment modality for the treatment of HSV-1, with advantages over pharmaceutical methods. The main advantage over the latter is the prolongation of the recurrence period. Further studies on the underlying mechanisms are warranted.

Footnotes

Author Disclosure Statement

No conflicting financial interests exist. The research was self-funded by the authors and their clinic.

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