Lysine for the Prevention and Treatment of Cutaneous Herpes Simplex Infections
Lysine for the Prevention and Treatment of Cutaneous Herpes Simplex Infections
July 1999; Volume 2: 73-76
By Philippe O. Szapary, MD and Michael D. Cirigliano, MD
More than 50% of the world’s population has recurrent cutaneous herpes simplex virus (HSV) infections.1 HSV is now the most common cause of genital ulceration in developed countries,2 and infection rates continue to rise in Europe and the United States. In the United States, viral subtype HSV-2 seroprevalence has risen from 16.4% (1976-1980) to 21.7% (1989-1991).2 Although clinical disease is self-limited, infection is lifelong and recurrences can cause significant psychosocial morbidity.
Treatment of cutaneous HSV infections usually involves topical or oral antivirals, along with avoidance of predisposing factors (especially stress, sunlight, and upper respiratory infections). Lysine, one of nine essential amino acids (AA), has gained popularity as a cheap and possibly effective agent in the treatment and prophylaxis of recurrent HSV infections. In fact, when taken orally at doses of 1,000-3,000 mg/d, lysine appears safe and effective in some patients as prophylaxis against recurrent cutaneous HSV infection.
History
L-lysine was first introduced in the United States in 1955 as monohydrochloride salt (LMH), a protein supplement for use in bread and cereal.3 In 1961, the FDA disallowed the use of LMH as an additive to white bread, diminishing food producers’ interest in lysine.3 However, LMH has been widely used as a protein supplement in farm animal feed (famously in Jurassic Park).
In the early 1980s, interest in LMH as prophylaxis for HSV infections increased in both the scientific and popular press with the publication of several positive clinical trials. Currently, LMH is readily available, with estimated sales of more than 100,000 lbs in 1992.3
Pharmacology
Free lysine is derived from the digestion of protein in the gut. Free lysine is then taken up by the liver where it is used either in protein synthesis or oxidative catabolism. Most free lysine is stored intracellularly in the skeletal muscle pool. Protein-bound lysine is methylated as a first step in the formation of L-carnitine, a protein used in muscle synthesis.3 Lysine is unique from the other eight indispensable AAs in that it is the most highly conserved.3 This means lysine is spared relative to other AAs and catabolized more slowly.
Mechanism of Action
Lysine has been recognized since 1952 as a potent inhibitor of viral replication.4 In 1958, researchers demonstrated that adding arginine to cultured HSV maintained optimum cell growth.5 In a landmark experiment, researchers found that omitting arginine from culture media decreased viral proliferation.6 On the other hand, omitting lysine increased proliferation, and when lysine was added to the culture media, it seemed to inhibit HSV replication. In a later study, newly HSV-infected cells switched from synthesizing more lysine-containing proteins to more arginine-containing proteins.7 From these studies, it was suggested that arginine may act as an inducer of viral capsid protein synthesis, while a predominance of lysine over arginine may act as a repressor or inhibitor.8
Clinical Trials
In addition to the first case report supporting an effect of lysine in 1974,9 12 other human studies were found searching the MEDLINE, CINHAL, Alt-HealthWatch, and IBIDS databases. Of the 13 studies, eight were distinct double-blind, randomized, placebo-controlled trials (DBRCT).1,10-16 The DBRCTs were all published in Western Europe (four trials) or the United States (four trials) between 1974 and 1987. The DBRCTs enrolled between 21 and 119 subjects with herpes labialis alone (three trials), or either herpes labialis or genitalis (five trials). There were no trials on patients with herpes genitalis alone.
Despite their titles, only two of the DBRCTs were exclusive treatment trials lasting four to five days. The other trials were 12- to 24-week prophylaxis trials in patients with at least three recurrences per year. Within the prophylaxis studies, lysine dosages ranged from 624-3,000 mg/d. Some of these trials merit special attention.
The initial excitement about lysine came from Griffith and his colleagues who reported more rapid control of outbreaks and reduced frequency of recurrences in a case series of 45 patients.8 Later, in a survey of 1,543 patients with recurrent cutaneous HSV, these same investigators found that 84% of lysine-treated patients reported less frequent recurrences.17 Overall, 88% of subjects felt lysine supplementation was effective in treating their HSV infection. Those results led to the publication of the most recent prophylaxis trial.
In this trial, Griffith et al randomized 114 subjects to placebo or LMH 1,000 mg po tid with meals for six months.10 Although only 52 subjects completed the trial (46% dropout rate), researchers found that the lysine-treated group had 2.4 fewer HSV infections than the placebo-treated group (P < 0.05). In addition, lysine-treated patients reported that their lesions healed 2.1 days faster than placebo-treated patients (P < 0.05). More importantly, 74% of lysine-treated patients reported their treatment to be "effective" or "very effective" compared to 28% of placebo-treated patients. Problems with this study included the high dropout rate and the lack of intention-to-treat analysis.
These positive results are tempered by three essentially negative DBRCTs by a group of Danish investigators.11-13 Milman and colleagues found no effect of LMH 1,000 mg po at the onset of symptoms, followed by 500 mg bid for the following four days in the treatment of early cutaneous HSV infection in 119 patients.13 Later, in a prophylaxis trial, 1,000 mg of LMH po qd for 12 weeks also had no effect on recurrences nor rates of healing in 65 patients in a crossover DBRCT.12 These results were echoed by two other negative prophylaxis DBRCTs done by other investigators.14,15
Adverse Effects and Interactions
In the last 10 years, the FDA has become concerned over the safety of AA supplements in the wake of 24 reported deaths in 1988 from eosinophilia-myalgia syndrome linked to a contaminated batch of L-tryptophan.18 In 1992, the Life Sciences Research Office did not reach a conclusion on the safety of lysine, but stated that its use for HSV suppression was not associated with adverse effects.3
Multiple animal studies suggest that large doses of oral LMH have no adverse clinical, hematologic, or pathologic side effects.3 Some studies done in rat pups have shown that lysine-rich and arginine-poor diets cause growth retardation.3 Intravenous lysine has been associated with renal toxicity and death in rats at doses greater than 4 g/kg of body weight.3
Human studies of LMH have not reported any significant toxicity. At the highest doses of 3,000 mg/d, only a few cases of dyspepsia were noted.10 However, there is one report of tubulointerstitial nephritis which could have been caused by long-term use of 3 g LMH daily.19
There are no reported adverse interactions with LMH. Animal data suggest that LMH is safe in pregnancy and lactation.3 However, there are no human safety data on LMH in pregnancy or lactation.
Formulations and Dosing
LMH is readily available at pharmacies and health food stores as a generic preparation, usually sold as 500 mg tablets. Based on currently available data on prophylaxis, at least 1,000 mg of LMH should be taken daily. The data definitely suggest a dose-response relationship; a dose less than 1,000 mg was not effective in two studies,15,16 while doses of 1,248 mg and 3,000 mg appeared to decrease recurrences in two studies.10,16
Lysine can be found as part of combination preparations that often include echinacea and goldenseal. There are no published clinical trials on any lysine combination products. Topical lysine preparations have been studied in animals, but the benefits shown in animals have not been confirmed in human trials.20
Conclusions
Currently available data suggest that LMH is not effective in the treatment of acute cutaneous HSV infections. In acute infections, oral antivirals have proven efficacy, while the data for topical antivirals are less impressive.21
For prophylaxis, supplemental LMH at doses between 1,000-3,000 mg/d may decrease the frequency of recurrences. Even negative trials identified subgroups of patients who were particularly responsive to this intervention. Unfortunately, the available studies do not further characterize this group of responders. The oral antivirals shown in Table 1 are effective, and have been approved by the FDA for use as prophylactic agents. LMH, taken three times daily, is cheaper and has fewer side effects than oral antivirals. Increasing consumption of high lysine containing foods, such as meat, milk, fish, and eggs, has never been demonstrated to decrease recurrences.22 Long-term use of oral antivirals, however, raises the possibility of the development of HSV resistance.
| Table 1 | ||
| Comparison of currently available oral prophylactic therapies for cutaneous HSV infections | ||
| Product | Dose |
|
| L-lysine (LMH)
Acyclovir (Zovirax®) Valacyclovir (Valtrex®) Famcyclovir (Famvir®) |
500 mg 2 tablets po tid
400 mg 1 tablet po bid 1,000 mg 1 tablet po qd 250 mg 1 tablet po bid |
$113 $109 $95 |
|
*Based on Average Wholesale Price ____________________________________________________________________________ |
||
Recommendations
Patients with more than three outbreaks of cutaneous HSV per year may want to consider a trial of LMH, 1,000 mg po tid with meals as a non-toxic dietary supplement to decrease the frequency and severity of HSV infections. Patients with frequent outbreaks should avoid foods known to have a high arginine content such as chocolate, nuts, peas, and cereals.
References
1. Thein DJ, Hurt WC. Lysine as a prophylactic agent in the treatment of recurrent herpes simplex labialis. Oral Surg Oral Med Oral Pathol 1984;58:659-666.
2. Brugha R, et al. Genital herpes infection: A review. Int J Epidemiol 1997;26:698-709.
3. Flodin NW. The metabolic roles, pharmacology, and toxicology of lysine. J Am Coll Nutr 1997;16:7-21.
4. Miller CS, Foulke CN. Use of lysine in treating recurrent oral herpes simplex infections. Gen Dent 1984;32:490-493.
5. Thomas W, et al. Use of arginine to eliminate medium changes in tissue culture systems. Science 1958;127:591-592.
6. Tankersley RW. Amino acid requirements of herpes simplex virus in human cells. J Bact 1964;87:609-613.
7. Kaplan AS, et al. Synthesis of proteins in cells infected with herpesvirus. Relative amino acid content of various proteins formed after infection. Virology 1970;40:90-101.
8. Griffith RS, et al. A multicentered study of lysine therapy in herpes simplex infection. Dermatologica 1978;156:257-267.
9. Kagan C. Letter: Lysine therapy for herpes simplex. Lancet 1974;1:137.
10. Griffith RS, et al. Success of L-lysine therapy in frequently recurrent herpes simplex infection. Treatment and prophylaxis. Dermatologica 1987;175:183-190.
11. Milman N, et al. Failure of lysine treatment in recurrent herpes simplex labialis. Lancet 1978;2:942.
12. Milman N, et al. Lysine prophylaxis in recurrent herpes simplex labialis: A double-blind, controlled crossover study. Acta Derm Venereol 1980;60:85-87.
13. Milman N, et al. Lysine treatment of recurrent herpes simplex labialis. Ugeskr Laeger 1979;141:2960-2962.
14. DiGiovanna JJ, Blank H. Failure of lysine in frequently recurrent herpes simplex infection. Treatment and prophylaxis. Arch Dermatol 1984;120:48-51.
15. Simon CA, et al. Failure of lysine in frequently recurrent herpes simplex infection. Arch Dermatol 1985;121:167-168.
16. McCune MA, et al. Treatment of recurrent herpes simplex infections with L-lysine monohydrochloride. Cutis 1984;34:366-373.
17. Walsh DE, et al. Subjective response to lysine in the therapy of herpes simplex. J Antimicrob Chemother 1983;12:489-496.
18. Babal K. Nutrition review: The fall and rise of tryptophan. Nutr Sci News 1998;3:60-64.
19. Lo JC, et al. Fanconi’s syndrome and tubulointerstitial nephritis in association with L-lysine ingestion. Am J Kidney Dis 1996;28:614-617.
20. Ayala E, Krikorian D. Effect of L-lysine monohydrochloride on cutaneous herpes simplex virus in the guinea pig. J Med Virol 1989;28:16-20.
21. Poland JM. Current therapeutic management of recurrent herpes labialis. Gen Dent 1994;42:46-50.
22. Algert SJ, et al. Assessment of dietary intake of lysine and arginine in patients with herpes simplex. J Am Diet Assoc 1987;87:1560-1561.
Based on data from clinical trials, all the following conclusions can be drawn about L-lysine (LMH) except:
a. One must use at least 1,000 mg/d of LMH to prevent recurrences.
b. Only oral preparations used three times a day appear effective.
c. Patients generally believe LMH decreases their lesion frequency and severity.
d. LMH 1,000 mg per day taken within the first 48 hours of an outbreak will abort the outbreak.
All of the following can precipitate an outbreak of herpes labialis except:
a. milk.
b. chocolate.
c. sunlight.
d. upper respiratory tract infection.
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