TAG: The OI Report - herpes simplex

THE OI REPORT:
A Critical Review of the Treatment & Prophylaxis of
AIDS-Related Opportunistic Infections (OIs)

HERPES SIMPLEX VIRUS
by Paul Dietz

INTRODUCTION
Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) are members of the human herpesvirus family, which also includes cytomegalovirus (CMV), varicella zoster virus (VZV), Epstein-Barr virus (EBV), human herpesviruses 6 and 7, and Kaposi's sarcoma-associated herpesvirus, also known as human herpesvirus 8 (KSHV or HHV-8). HSV-1 and 2 are quite similar to each other in nature, though their modes of transmission and clinical manifestations differ.

HSV-1, the cause of the familiar cold sore, produces ulcerative lesions in and around the mouth and nostrils. It is transmitted through direct contact with infectious mucous membranes, usually by kissing or oral-genital contact. HSV-2 is transmitted through sexual contact, causing lesions on the penis in males, and around the vagina, cervix, vulva, and perineum in females. In both sexes, lesions in the perianal area and buttocks are common. Herpes sores may be accompanied by pain, itching, adenopathy (swelling of the lymph nodes), painful urination or defecation, fever, and fatigue. During primary infection, inflammation of the meninges can occur in 5-10% of patients.

HSV-1 and 2 are common in patients with HIV, often appearing among the earlier infections associated with AIDS. For some people with AIDS (PWAs), HSV remains asymptomatic or causes only occasional outbreaks. For others, HSV lesions may persist or continue to enlarge, exposing the patient to secondary infection and excruciating pain. In very severe cases, HSV may spread through the blood or cerebral spinal system to the esophagus, lung, eye, or brain. HSV lesions presenting for longer than a month, or the occurrence of HSV-related pneumonitis, bronchitis, or esophagitis in a person with HIV (or with no other apparent cause for immunodeficiency) are considered AIDS-defining (McGrath 1994). Though it occurs rarely, HSV-associated encephalitis (an infection of the brain) is a debilitating and life-threatening disease.

There is no cure for HSV, though the frequency and severity of attacks can be reduced through use of antiviral drugs such as acyclovir (Zovirax) or famciclovir (Famvir). However, the emergence of resistance to these drugs in immunocompromised patients may curtail the long-term effectiveness of these treatments. In such cases, alternative therapies include foscarnet or topical trifluridine, depending on the nature and severity of the HSV illness. Both are regarded as fairly safe and effective second-line treatments. Topical cidofovir and topical foscarnet are under investigation for this indication as well.

EPIDEMIOLOGY
HSV-1 is pervasive. In 1989, Johnson and colleagues reported that an estimated 70% of the adult U.S. population was infected with HSV-1 (Johnson 1989). Another study found that 46 of 68 (66%) HIV-infected patients with Pneumocystis carinii pneumonia (PCP) had antibodies to HSV-1 (Safrin 1991a). As a sexually transmitted disease, the epidemiology of HSV-2 closely resembles that of HIV, though genital herpes is much more common in women. Data from a San Francisco General Hospital trial in 1986 revealed that 77% of 68 patients with PCP tested positive for HSV-2 antibodies (Safrin 1991a). Without regard to type, herpes lesions are infectious from shortly before lesions develop to the point of full healing. The risk of transmitting HSV-2 can be reduced, though not prevented, with use of latex condoms. Once infected, patients should use good hygiene to reduce the chance of spreading the infection to other body parts. Topical antiseptic creams may help avoid superinfection of herpes lesions.

A report from the Fourth Conference on Retroviruses and Opportunistic Infections suggested that ulcerative herpes lesions are capable of aiding the sexual transmission of HIV. Schacker and colleagues tested 24 herpes ulcers from twelve HIV-infected men and found that 23 (96%) of the lesions contained large amounts of replication-competent HIV (Schacker 1997). The measured levels of HIV decreased after herpes treatment was initiated. The investigators suggested that these data provide biological evidence for the epidemiological association between HIV infection and genital herpes, and suggested studying the effect of acyclovir on genital HIV shedding.

PATHOGENESIS
Soon after resolution of the primary symptoms, HSV assumes a latent status in the patient's sensory nerve endings and ganglia. In most cases, orolabial HSV establishes latency in the trigeminal root ganglia (face/jaw), while genital herpes establishes latency in the sacral plexus (genital/pelvis/buttocks area). Unlike HIV, HSV assumes both a clinical and cellular latency as the virus is believed to replicate at a lower rate during this period. The immune response appears to play an important role in driving HSV into its initial latent state and in maintaining HSV latency (McGrath 1994). The chronic immunodeficiency brought upon by HIV puts patients at increased risk of HSV reactivation. HSV replication is believed to be stimulated by a number of factors including fever (thus the term fever blister), sun exposure, concurrent viral infection, and possibly also localized trauma, hormonal changes, or stress (Erlich 1995).

DIAGNOSIS
The first incidence of HSV can be diagnosed through viral culture or Tzanck smear. Subsequent recurrences are often diagnosed by clinical examination. Serologic testing is not very useful since a large segment of the population has HSV antibodies indicating prior infection (Erlich 1995).

CLINICAL MANIFESTATIONS

HSV Esophagitis
HSV-1 esophagitis is characterized by extremely painful swallowing, sore throat, and retrosternal pain. Diagnosis is made by upper endoscopy with confirmatory biopsy for virus culture. Differential diagnosis should rule out esophageal candidiasis and CMV. HSV esophagitis responds well to oral acyclovir, though intravenous (IV) acyclovir may be used if throat pain impedes oral use (Erlich 1995).

HSV Proctitis
HSV-2 is a common cause of proctitis among sexually active individuals. Symptoms include anorectal pain, perianal lesions, painful urination and defecation, constipation, fever, and inguinal adenopathy (Goodell 1983). Diagnosis can often be made clinically, but should be confirmed with viral culture. Herpes proctitis generally responds well to treatment with oral acyclovir, though IV administration may be used for severe cases or where diarrhea may impede gastrointestinal absorption (Erlich 1995).

Ocular HSV Disease
Herpes simplex infections of the eye include keratitis, keratoconjunctivitis, uveitis, and keratouveitis. Serious cases can result in damage to the cornea. HSV-1 induced keratitis is "the principal infectious cause of blindness in the developed world" (Streilin 1997). Ophthalmic diagnosis requires differentiation from varicella-zoster virus. Herpetic keratitis may be treated with topical antiviral formulations of acyclovir or trifluridine (Klein 1988). Systemic therapy may be required to prevent recurrences.

HSV Encephalitis
Though rare, HSV encephalitis is a catastrophic and potentially fatal condition in PWAs (Fletcher 1992). Symptoms include headache, fever, nausea, lethargy, confusion and seizures possibly leading to coma and death. Some patients present with similar but milder symptoms resembling a benign meningitis. Until recently, HSV encephalitis was diagnosed by brain biopsy or serological testing of the cerebrospinal fluid for differentiation from toxoplasmosis, Cryptococcus neoformans, and lymphoma (Erlich 1995). However, the use of HSV DNA polymerase chain reaction (PCR) testing of the cerebrospinal fluid (CSF) is rapidly gaining acceptance and may have replaced brain biopsy as the preferred diagnostic method. In one study, PCR correctly diagnosed 53 of 54 patients with HSV encephalitis (Lakeman 1995). Proven cases of HSV encephalitis should be treated with IV acyclovir at 10 mg/kg every eight hours for at least ten days (Sasadeusz 1993). Foscarnet has not been well studied, but is known to penetrate the CNS (Raffi 1992). Treatment outcome appears to be related to the severity of disease, the person's age, and the state of consciousness at baseline (Whitley 1986). Despite treatment, the six-month mortality is 19%, with one-third of surviving patients suffering residual neurological damage (Sasadeusz 1993).

HSV Pneumonia
Though rare in patients with HIV, HSV-related pneumonia can be serious in immunocompromised patients if not properly diagnosed and treated. HSV pneumonia may result from the contiguous dissemination of HSV from the esophagus or from the visceral spread of HSV through the bloodstream. In 1982, Ramsey and colleagues isolated HSV from lung specimens of 20 patients who had died of respiratory insufficiency, though none of the patients had previously been diagnosed with HSV pneumonia (Ramsey 1982). Mucocutaneous herpes manifestations predated the pneumonia in 17 of 20 patients. Thus, clinicians may wish to consider HSV as a possible pathogen in patients with pneumonia and a history of HSV disease, especially if there is evidence of recent mucocutaneous HSV or visceral dissemination (Ramsey 1982). Diagnostic methods include culture from lung biopsy, histologic examination, and examination for virus antigen by immunofluorescence.

TREATMENTS

Acyclovir (Zovirax™, Glaxo Wellcome)
Acyclovir is a well-established, safe and effective treatment for HSV-1 and 2. It is approved for the treatment and suppression of recurrent HSV. Acyclovir is available in topical, oral, and IV forms. IV acyclovir, however, is reserved for the treatment of HSV encephalitis, severe mucocutaneous disease, and where oral administration is not feasible (Sasadeusz 1993). Topical acyclovir is rarely used due to its limited effectiveness. Acyclovir has a favorable toxicity profile and has been used safely for over five years by a large number of patients. A minority of patients experience rash, nausea and loss of appetite. Reversible renal deterioration has been associated with high doses, and temporary neurotoxic symptoms such as disorientation, tremors, slurred speech, and seizures are infrequently associated with IV acyclovir (McGrath 1994). Acyclovir's disadvantage is its poor bioavailability (15% to 30%) which necessitates frequent dosing. CSF acyclovir concentrations average 50% of plasma levels.

Acyclovir (ACV) Dosages for HSV Infections in Immunocompromised Patient
Mild to moderate monocutaneous HSV-1 or 2 Oral ACV 200 mg 5 times daily or 400 mg 3 to 5 times daily
Severe or unrelenting monocutaneous HSV-1 or 2, or if oral absorption is dubious IV ACV 5 mg/kg every 8 hours
Visceral or disseminated HSV, or HSV encephalitis IV ACV 10 mg/kg every 8 hours.
Maintenance to suppress reactivation No uniform standard;400 mg twice or thrice daily is commonly prescribed.

(Fletcher 1992)

In patients with severe immunodeficiency, HSV may recur soon after discontinuation of therapy. In varying doses, acyclovir has been shown to reduce the frequency of recurrences (Straus 1984). Maintenance therapy is indicated for frequent or severe recurrences.

Acyclovir-resistant HSV occurs with significant frequency in HIV-infected and other immunocompromised patients. A retrospective study conducted at the University of Minnesota found acyclovir resistance in 7 of 148 (4.7%) immunocompromised patients with HSV (Englund 1990). A survey conducted at a major metropolitan hospital between 1992 and 1995 noted that 10% of HSV isolates demonstrated decreased susceptibility to acyclovir (Cotarelo 1996).

Most patients with acyclovir resistant HSV have profound immunosuppression (Balfour 1994). In one study, the median CD4 count in 25 HIV-positive patients with acyclovir-resistant HSV infection was 24 (Safrin 1991b). Taking acyclovir intermittently or in suboptimal doses may also encourage drug resistance (Balfour 1994). The FDA turned down Glaxo-Wellcome's application to market over-the-counter acyclovir, partly due to fear of encouraging the emergence of acyclovir-resistant HSV.

To act as an effective agent, acyclovir must first be triphosphorylated through a series of steps involving viral and cellular enzymes. The primary mechanism of acyclovir resistance is selection for virus deficient in thymidine kinase (Chatis 1992). Unfortunately, many other herpes drugs also require thymidine kinase for phosphorylation. As a result, acyclovir-resistant strains tend to be cross-resistant to ganciclovir, valacyclovir (the acyclovir prodrug), and famciclovir (the prodrug of penciclovir). This leaves few alternatives in the face of acyclovir resistance, though both foscarnet, cidofovir and trifluridine have shown activity against acyclovir-resistant HSV (Safrin 1991b; Kessler 1993; Lalezari 1996).

An algorithm for the treatment of acyclovir-resistant HSV was developed at a round-table symposium held in March 1993:

Increase the dosage of oral acyclovir to 800 mg 5 times a day if new lesions continue to form after 3 to 5 days of treatment at the standard dose listed above.

If there is no response after 5 to 7 days, and lesions are accessible, the panel recommended the addition of topical trifluridine every 8 hours until healing is complete. If lesions are not accessible, IV foscarnet at 60 mg/kg twice daily or 40 mg/kg thrice daily until complete healing.

(Balfour 1994)

Foscarnet (Foscavir™, Astra)
Foscarnet has in vitro activity against a number of human herpes viruses, including HSV-1 and 2, CMV, EBV, VZV, and also HIV (Sasadeusz 1993). Foscarnet is approved by the FDA for the treatment of CMV and for acyclovir-resistant herpes simplex in immunocompromised patients. Its side effects include nephrotoxicity (kidney disease), neutropenia, anemia, elevated liver enzymes, penile ulcers, hyperphosphatemia, hypocalcemia, and gastrointestinal intolerance (Safrin 1992).

Foscarnet was tested against vidarabine (ara-A) in ACTG 095, a randomized trial of 14 AIDS patients with acyclovir-resistant HSV. Foscarnet was found to be more effective and was associated with fewer adverse reactions (Safrin 1991b). Lesions healed in all eight patients assigned to receive foscarnet and in none of the six patients receiving vidarabine. Three patients receiving vidarabine had neurological abnormalities while no patient receiving foscarnet experienced any dose-limiting toxicities (Safrin 1991b). Resistance to foscarnet has also been documented (Hardy 1992).

In January 1996, Hardy and colleagues reported results from an open-label pilot study of topical foscarnet cream in 20 patients with acyclovir-resistant HSV. Side effects included skin ulcerations and fever. Of 15 patients reporting pain at baseline, 11 reported complete resolution and 2 reported partial resolution of pain. The median time to complete lesion healing was 44 days (Hardy 1996).

According to Astra Pharmaceuticals, further testing and development of foscarnet cream is under review pending ongoing analysis of trial data.

Foscarnet is available through a compassionate use program for patients with herpes simplex infection that does not respond to standard treatment with acyclovir. The cream formulation is likewise available to patients unable to tolerate IV foscarnet.

Trifluridine (Viroptic™, Glaxo Wellcome)
Trifluridine inhibits HSV by thymidine substitution and has activity against acyclovir-resistant strains. Ophthalmic trifluridine 1% solution is approved for the treatment of HSV keratitis and keratoconjunctivitis and can be used for mild cutaneous HSV that has stopped responding to treatment with acyclovir. In ACTG 172, Kessler and colleagues conducted an open-label study to evaluate the safety and efficacy of topical 1% trifluridine solution for the treatment of chronic acyclovir-resistant mucocutaneous HSV in 26 PWAs. Seven of 24 evaluable patients had complete healing of lesions within a median of seven weeks. An additional seven patients had at least a 50% reduction in lesion size with an estimated median time to 50 percent healing of 2.4 weeks. Seven patients (29%) discontinued treatment for failure to respond to therapy, and eight (33%) patients developed new lesions outside of the treatment area during the study, reflecting the local nature of this therapy. No dose-limiting toxicities were reported, though application of the solution and dressings to genital and perirectal regions three times a day was cumbersome and inefficient. However, given the limited options for the treatment of acyclovir-resistant herpes simplex disease, topical trifluridine may be a useful alternative for some patients (Kessler 1993).

Famciclovir (Famvir™, SmithKline Beecham)
Famciclovir is a nucleoside analogue which is converted to penciclovir in the body. In December 1995, the drug was approved for the treatment of genital herpes in immunocompetent patients. Famciclovir is more bioavailable than acyclovir (77% versus 30%) and has a longer intracellular half-life which allows for a twice daily dosing (Boyd 1988). Since famciclovir relies on viral thymidine kinase for processing, it is generally ineffective against acyclovir-resistant strains. In Europe, Famvir cream is approved for the treatment of herpes cold sores. Loveless and colleagues conducted three studies of 951 HIV-negative patients which compared various doses of famciclovir (250, 500, 750 mg thrice daily) to acyclovir 200 mg 5 times a day. There was no significant difference in the duration of viral shedding, time to healing, or reduction of symptoms in any of the arms. Both were equally tolerable (Loveless 1995). Schacker and colleagues compared 500 mg famciclovir twice daily with placebo for eight weeks in 48 HIV-infected individuals (45 men, three women) who experienced HSV-2 reactivation. Median CD4 count at entry was 384. By intent-to-treat, HSV-2 was isolated on 122/1114 (11%) placebo days versus 9/1071 (1%) of famciclovir days (relative risk, 0.15, p<0.001). "Breakthrough reactivations that occurred while patients were on famciclovir were infrequent, short, and often asymptomatic." Treated patients also experienced a shorter time to lesion healing. Unfortunately, this study made no comparison to acyclovir (Schacker 1996, 1998), as the sponsor apparently plans to promote Famvir's favorable dosing schedule rather than do further studies to establish equivalence or superiority of treatment. SmithKline Beecham plans to file a supplementary new drug application for Famvir for the treatment of acute herpes zoster and recurrent genital herpes in immunocompromised patients soon.

INVESTIGATIONAL HSV TREATMENTS

Cidofovir (HPMPC, Vistide™, Gilead Sciences)
Cidofovir -- a nucleotide analogue -- has broad spectrum of activity against several viruses. Approved in 1996 for the treatment of CMV, cidofovir is phosphorylated by cellular rather than viral enzymes and has shown in vitro activity against acyclovir-resistant HSV (DeClerq 1993). In vitro, HPMPC is not as effective as trifluridine or foscarnet against acyclovir-resistant strains (Kessler 1993). Moreover, mucocutaneous outbreaks of herpes simplex have been noted in patients receiving intravenous cidofovir for treatment of CMV (Wohl 1997).

In January, 1996 Lalezari and colleagues reported results of a Phase I/II randomized, double-blind, placebo-controlled trial of topical cidofovir gel in PWAs with mucocutaneous herpes simplex unresponsive to acyclovir. A total of 30 patients received either placebo or cidofovir gel at 0.1% or 0.3% concentrations for five days. By day 15, one-half of those treated with the gel had experienced a greater than 50% reduction in the size of lesions. However, complete responses were seen in only 3 of 11 patients receiving the low concentration and in just three of nine (33%) patients receiving the high concentration gel (Lalezari 1996). Based on these data, Gilead applied to the FDA for approval to market cidofovir gel for refractory herpes simplex infection in PWAs. Cidofovir gel, now known under the brand name ForvadeTM, is currently available from the manufacturer, under a compassionate use program, to patients with mucocutaneous herpes simplex who have failed conventional therapy with acyclovir.

CONTRAINDICATED TREATMENTS

Valacyclovir (Valtrex™, Glaxo Wellcome)
Valacyclovir -- the prodrug of acyclovir -- yields greater bioavailability than its metabolite. Oral administration of 1,000 mg of valacyclovir thrice daily yields plasma concentrations comparable to intravenous acyclovir. Since valacyclovir is converted to acyclovir inside the body, it is not active against thymidine kinase deficient, acyclovir-resistant strains (Easterbrook 1994).

Fife and colleagues compared valacyclovir (100 mg twice daily) against acyclovir (200 mg 5 times a day) in a 643 HIV-negative patient study for the treatment of primary genital HSV. Duration of HSV shedding, pain, and symptoms and time to healing were similar in the two groups (Fife 1995, 1997).

A Phase I trial conducted in HIV-positive patients with CD4 counts less than 150 established a generally favorable safety profile for valacyclovir (Jacobson 1994). Nausea, vomiting, and abdominal pain were reported as well as a few cases of neutropenia. Valacyclovir, however, carries a warning against its use in immunocompromised patients because of its association with hemolytic uremic syndrome / thrombotic thrombocytopenic purpura (bursting blood vessels in the kidneys) as seen in ACTG 204, a study comparing valacyclovir to acyclovir for CMV prophylaxis HIV-positive patients (FDA Data 1996, Feinberg 1998). Ironically, the ACTG is continuing studies in HIV-positive children (ACTG 253).

*

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Acyclovir (ACV) Dosages for HSV Infections in Immunocompromised Patient
Mild to moderate monocutaneous HSV-1 or 2	Oral ACV 200 mg 5 times daily or 400 mg 3 to 5 times daily
Severe or unrelenting monocutaneous HSV-1 or 2, or if oral absorption is dubious	IV ACV 5 mg/kg every 8 hours
Visceral or disseminated HSV, or HSV encephalitis	IV ACV 10 mg/kg every 8 hours.
Maintenance to suppress reactivation	No uniform standard;400 mg twice or thrice daily is commonly prescribed.