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Relation Between Herpes Simplex Viruses and Human Immunodeficiency Virus Infections
Jessica L. Severson, MD;
Stephen K. Tyring, MD, PhD
Arch Dermatol. 1999;135:1393-1397.
ABSTRACT
The rates of herpes simplex virus (HSV) infection are rising, the highest prevalence being in the group infected with the human immunodeficiency virus (HIV). We review the relation between these 2 infections. The presence of genital ulcers increases the transmission of HIV, and the presence of HIV adversely affects the natural history of HSV infection. The detection and treatment of sexually transmitted diseases such as genital herpes actually decrease the rates of HIV infection in groups studied. The treatment of HSV in persons with HIV is challenging because the incidence of immunosuppression increases. Acyclovir resistance is more common in this group, but acyclovir use may prolong survival in some HIV-seropositive patients. Further studies are needed to determine whether persons with HIV disease should routinely be given HSV-specific therapy.
INTRODUCTION
Herpes simplex viruses (HSVs) are the most common cause of genital ulcer disease worldwide.1 Genital herpes is the most frequent sexually transmitted disease (STD) among persons seropositive for the human immunodeficiency virus (HIV),2 and most persons seropositive for HSV type 2 (HSV-2) have an intermittent reactivation of the virus on mucosal surfaces.3-4 In addition, disruption of the epithelial barrier and inflammation of HSV genital ulcers appear to increase the risk of HIV transmission. Acute or reactivated HSV infection may stimulate HIV replication, leading to the progression of HIV disease.5 On the other hand, HIV-induced immunosuppression results in alterations in the natural history of HSV. More severe HSV outbreaks and more frequent viral shedding are common in persons coinfected with HIV and HSV compared with those without HIV infection.
The treatment of HSV can be more challenging in HIV-infected patients. Higher doses of antiviral drugs may be required, and persons infected with HIV have an increased incidence of acyclovir-resistant HSV.6 This appears unrelated to acyclovir exposure because resistance is found in patients with no previous exposure to acyclovir, and rates of acyclovir resistance are lower in patients taking suppressive doses of acyclovir compared with those receiving therapeutic doses of the drug.7-12 In fact, a survival benefit has been shown13 when acyclovir is added to the medical regimen of HIV-positive patients. Further evidence14 suggests that HSV suppression with acyclovir indirectly lowers the HIV load, which is important in predicting the disease progression and response to antiretroviral therapy. These relationships may have implications for HIV control efforts, and intervening in these virus-virus interactions may modulate the progression of HIV infection. A consensus regarding the antiviral suppression of HSV in HIV-infected patients has not yet been reached. Further studies are needed to determine if HSV-specific antiviral therapy should be routinely added to the medical regimen of patients coinfected with HSV and HIV.
PREVALENCE OF COINFECTION WITH HSV AND HIV
Despite the widespread message in the 1980s and 1990s of the importance of safe sex in response to the HIV epidemic, the prevalence of HSV-2 infection in the United States has increased by 30% since 1976.15 Between 1988 and 1994, 45 million people were estimated15 to be seropositive for HSV-2. This corresponds to 1 of 5 people older than 12 years. The rates of HSV seropositivity in HIV-infected persons are even higher and vary geographically. A study16 in Baltimore, Md, showed HSV-2 seroprevalence of 81% among HIV-positive homosexual or bisexual men. In a study of HIV-positive heterosexual persons in south London, England, 43% of women and 38% of men had genital ulcers caused by HSV, antigens of which were detected by enzyme-linked immunosorbent assay.2 Serologic tests would have likely revealed higher percentages of HSV seropositivity. The prevalence of coinfection with HIV and HSV in Haitian women is 88%,17 and in prostitutes from Zaire, the prevalence is 95%.1
INCREASED TRANSMISSION OF HIV IN THE PRESENCE OF HSV
Many studies18-24 have found an association between the acquisition of HIV and the presence of genital lesions in the source contact. Other studies16-17,25-32 have specifically classified HSV as the cause of such genital lesions. It is estimated33 that ulcerative and nonulcerative STDs increase the risk of HIV transmission 3 to 5 times.
An increased viral load and the proximity of virions to cutaneous surfaces are factors that may lead to the increased transmission of HIV in the presence of HSV. Genital ulcers from HSV may facilitate the transmission of HIV through the reduced epithelial barrier and infiltration of CD4+ lymphocytes in herpetic lesions that are possible targets for HIV attachment and entry.5, 34-35 In addition, it is hypothesized36 that the antigenic stimulation of mucosal sites by the reactivation of HSV can increase HIV type 1 (HIV-1) replication on mucosal surfaces. Tetanus toxoid, influenza, and pneumococcal immunization is already known37-40 to transiently increase the plasma HIV-1 RNA concentration through the activation of T cells from antigenic stimulation. Schacker et al36 gave further evidence to support the hypothesis that genital herpes infection increases the efficiency of the sexual transmission of HIV-1. In their study, HIV-1 virions were consistently detected in genital ulcers caused by HSV-2 in HIV-seropositive men. In addition, the burst of HIV-1 virions that accompanies recurrent genital lesions may help explain the intermittent nature of the transmission of HIV-1 among stable sexual partners.41
INTERVENTION
Studies42-44 have shown that the treatment and prevention of STDs reduce HIV transmission. In rural Tanzania, improved STD treatment (including genital ulcers) reduced the HIV incidence by about 42% during 2 years of follow-up.42 Mertz et al45 studied the etiology of genital ulcers and the prevalence of HIV coinfection in 10 US cities, finding an average of 6% HIV seropositivity among patients with genital ulcers. They concluded that persons with genital ulcers should be the focus of HIV prevention activities.
ACCELERATED PROGRESSION OF HIV DISEASE IN THE PRESENCE OF HSV
The plasma HIV load is important in predicting disease progression, the response to antiretroviral therapy, or both.46-47 In clinically latent HIV infection, acute or reactivated HSV infection may be involved in stimulating HIV replication, resulting in a progression to the acquired immunodeficiency syndrome (AIDS).48-49 A study by Mole et al50 demonstrated increased HIV RNA levels during active HSV infection. During an acute outbreak of HSV infection, the plasma HIV load increased a median of 3.4-fold, and in some patients, postoutbreak levels remained above preoutbreak baseline levels. The episode of acute HSV infection also increased HIV transcription, as evidenced by increased intracellular HIV gag messenger RNA. Kucera et al51 report that coinfection of human CD4+ cells with HSV and HIV results in a unidirectional accelerated replication of HIV.
Similarly, Heng et al5 found that the up-regulation of HIV-1 expression was induced by HSV, which may translate to increased plasma HIV-1 RNA levels. Their study documented in vivo reciprocal enhancement of viral replication associated with the coinfection of keratinocytes and macrophages by HIV-1 and HSV type 1 in patients with AIDS and nongenital HSV lesions. This observation may be evidence of the importance of including antiherpetic drugs as part of the overall treatment of patients with AIDS to avoid the excessive replication of HIV-1 in both CD4+-dependent and -independent targets.
ALTERATION IN NATURAL HISTORY AND RESPONSE TO THERAPY FOR HSV IN THE PRESENCE OF HIV
Clinical Manifestations and Viral Shedding of HSV
Herpes infections are more severe in immunocompromised patients. Multiple necrotic ulcers may appear in atypical locations. The outbreaks may progress to more extensive and more persistent lesions.52-54 There may be more frequent recurrences or chronic and nearly continuous ulcerations as HIV-related immunosuppression progresses.3, 55-56 Herpes simplex virus may also cause esophagitis and, rarely, pneumonitis or hepatitis in patients with AIDS.57
The prevalence of HSV-2 shedding is nearly 4 times greater in HIV-seropositive women than in HIV-seronegative women.3 Seventy-nine percent of viral shedding among HIV-seronegative women is asymptomatic, and overall shedding increases significantly as the CD4+ cell count decreases. Asymptomatic perianal shedding of HSV is common in patients with AIDS,58 even in those without a history of perianal lesions. Schacker et al4 found that 81% of HIV- and HSV-2–seropositive men shed HSV-2 and that most shedding was asymptomatic.
Treatment of HSV Infection in HIV-Seropositive Patients
A meta-analysis13 of 8 controlled randomized trials showed that acyclovir therapy offered a substantial survival benefit in patients with HIV infection. A survival advantage was seen specifically in studies5, 48-50 with high incidences of clinical herpesvirus infections. One possible explanation offered is that reducing the incidence of HSV and varicella-zoster virus infections may suppress bursts of HIV replication occurring during active herpesvirus infections. These studies were done before the availability of viral load measurement (HIV RNA), which may have offered more relevant prognostic information. Also, this analysis was conducted in the era of zidovudine monotherapy, preceding the widespread use of triple antiretroviral therapy. Apolonio et al59 analyzed survival rates in a cohort of HIV-1–infected men with a CD4+ lymphocyte count of less than 0.05x109/L (50/µL). One of the strongest factors affecting mortality included concurrent acyclovir and zidovudine use. The suppression of HSV reactivation may offer an additional benefit in reducing ongoing T-cell activation.37 Recently, HIV-infected patients receiving suppressive acyclovir therapy were found14 to have lower HIV RNA levels, as determined by reverse transcription–polymerase chain reaction, than patients not taking suppressive acyclovir.
Although their use is specifically approved by the Food and Drug Administration only in immunocompetent persons, famciclovir and valacyclovir hydrochloride appear safe and well tolerated for short- and long-term use in immunocompromised patients, including HIV-positive persons.60-61 Valacyclovir is effective in preventing HSV recurrences, and study results61 indicate that taking valacyclovir hydrochloride, 500 mg twice a day, offers better protection in HIV-positive patients than using acyclovir. Famciclovir is effective in suppressing symptomatic and asymptomatic HSV shedding and recurrences in HIV-infected patients.4, 62 Total HSV-2 shedding is decreased 81%, and the frequency of genital signs and symptoms is decreased 65%.4 Suppressive dosing with famciclovir (500 mg twice a day) has the same effectiveness as the use of acyclovir (400 mg 5 times a day) at a more convenient dosing regimen.62-63 Most of the patients who participated in suppression trials were taking highly active antiretroviral therapy.4, 62 The adverse effects of acyclovir, famciclovir, and valacyclovir are similar to those observed in immunocompetent persons. There is a possible relation between receiving high doses of valacyclovir hydrochloride (8 g/d for 1 year) and the incidence of thrombotic microangiopathy in immunocompromised patients.64 Recent studies4, 61-63 of the use of famciclovir and valacyclovir in immunocompromised patients have not reported any cases of thrombotic microangiopathy.
Although HSV outbreaks may be less frequent and less severe in patients taking highly active antiretroviral therapy, these patients continue to have outbreaks and asymptomatic viral shedding. Additional large studies are needed to determine if antiviral drugs specific for HSV should be routinely used in HIV-positive patients.
Acyclovir-Resistant HSV
The Centers for Disease Control and Prevention recently reported6 preliminary results from a national surveillance of acyclovir-resistant HSV. Of 1218 HSV isolates tested, 99.2% were sensitive to acyclovir. Of 140 isolates from HIV-positive patients, 6.4% were resistant to acyclovir. Resistance to acyclovir is caused by mutations in the viral thymidine kinase or DNA polymerase genes. These mutations result in decreased or absent HSV thymidine kinase production, altered affinity of the thymidine kinase for acyclovir triphosphate, or altered affinity of the HSV DNA polymerase for acyclovir triphosphate.
Acyclovir-resistant strains of HSV have been recovered from patients who have never been treated with acyclovir.7-9 In addition, the frequency of in vitro resistance has not changed from the time before the availability of acyclovir and does not appear increased among patients who received daily suppressive therapy for several years.10 Resistant HSV strains are more common in patients who receive therapeutic vs prophylactic antiviral therapy.11-12 Prophylactic HSV treatment reduces the number of replicating viruses,65 which is thought to decrease the likelihood of viral mutations. The increased incidence of acyclovir resistance in HIV-infected patients is probably due to an increased replication of HSV and decreased immunity in these patients. Therefore, taking anti-HSV drugs may likely decrease resistance by decreasing HSV replication.
Most acyclovir-resistant HSV isolates are susceptible to antiviral drugs that do not require activation by thymidine kinase.66-69 Foscarnet sodium (40 mg/kg intravenously every 8 hours) is approved by the Food and Drug Administration for the treatment of acyclovir-resistant HSV. Foscarnet is a pyrophosphate analogue that directly inhibits HSV DNA polymerase without requiring activation. Foscarnet also selectively inhibits in vitro the reverse transcriptase of HIV. Its use is limited, however, because it requires parenteral infusion and has substantial renal toxic effects.
Cidofovir is an antiviral agent that is phosphorylated to its active metabolite by host cellular enzymes rather than requiring virus-specific thymidine kinase. Cidofovir is a nucleotide analogue of deoxycytidine monophosphate with broad-spectrum anti–DNA virus activity. Cidofovir gel (0.3% or 1% gel daily for 5 days) has been evaluated70 for the treatment of acyclovir-unresponsive mucocutaneous HSV infection in patients with AIDS. Substantial benefits in lesion healing, virologic effect, and pain reduction are seen with cidofovir therapy.70 The drug has yet to receive approval and is not commercially available in a topical formulation.
CONCLUSIONS
The incidence of HSV infection continues to increase, and it affects most people seropositive for HIV. There is convincing evidence that the genital ulcers caused from HSV increase the risk of transmission of HIV. The treatment and prevention of STDs such as genital herpes may even help prevent HIV infection. More rigorous study designs are needed to confirm these possibilities. Recurrent HSV infection may accelerate the progression of HIV disease, and certainly, HIV-induced immunosuppression alters the reactivation of HSV. Antiviral therapies are safe and effective for episodic and suppressive treatment of HSV in HIV-infected persons; furthermore, suppressive therapy appears to offer a survival benefit in such persons. Since HSV reactivation and viral shedding exist, although to a lesser extent, in the less than 10% of HIV-infected persons in the world receiving highly active antiretroviral therapy, these persons may also benefit from suppressive therapy of HSV. The incidence of acyclovir resistance is increased in HIV-infected persons, although apparently not because of exposure to anti-HSV therapies but, rather, because of increased viral replication due to decreased immunity. Further studies are needed to determine if HSV-specific antiviral therapy should be routinely added to the medical regimen of patients coinfected with HSV and HIV.
AUTHOR INFORMATION
Accepted for publication June 4, 1999.
Corresponding author: Stephen K. Tyring, MD, PhD, Department of Dermatology, University of Texas Medical Branch, 301 University Blvd, Rte 1070, Galveston, TX 77555.
From the Departments of Dermatology, Microbiology and Immunology, and Internal Medicine, University of Texas Medical Branch, Galveston.
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