Herpes Simplex Virus Lesions Research Articles

Frequent Recovery of HIV-1 From Genital Herpes Simplex Virus Lesions in HIV-1–Infected Men

Genital ulcer disease has been epidemiologically linked as a risk factor in the transmission of the human immunodeficiency virus 1 (HIV-1). While herpes simplex virus 2 (HSV-2) is the most common cause of genital ulcers, no study has systematically evaluated the frequency or titer of HIV-1 virus in HSV-2 lesions. To compare lesional HIV-1 RNA levels during and after genital HSV-2 reactivation and to evaluate the frequency, titer, and duration of HIV-1 RNA shedding in lesions due to HSV-2. Convenience sample. Sexually transmitted disease research clinic at the University of Washington, Seattle. Twelve HIV-infected men with a history of symptomatic HSV-2 infection who underwent daily sampling of genital lesions for HIV-1 RNA by polymerase chain reaction assay and HSV-2 by culture. Detection of lesional HIV RNA and HSV-2. HIV-1 RNA was detected from lesional swabs in 25 of 26 consecutively studied HSV-2 episodes and on 67% of days in which genital lesions were noted. The HIV-1 RNA titers in lesional swabs exceeded 10000 copies/mL of swab sample in 75% of samples (range, 2.2-3.2 x 10(5) copies/mL of swab sample). HIV-1 RNA in genital lesion swabs was seen in persons with high and low titers of plasma HIV-1 RNA and was not associated with plasma HIV-1 RNA levels. HIV-1 virions can consistently be detected in genital ulcers caused by HSV-2, which suggests that genital herpes infection likely increases the efficiency of the sexual transmission of HIV-1.

Erythema multiforme lesions are associated with expression of a herpes simplex virus (HSV) gene and qualitative alterations in the HSV-specific T-cell response.

A common form of erythema multiforme, herpes-associated erythema multiforme (HAEM), occurs following infection with herpes simplex virus (HSV). Here we report that HSV gene expression and the qualitative nature of the virus-specific T-cell responses are related to HAEM lesion development. Skin from HAEM lesions and 1-3 months healed HAEM lesional skin were positive for the viral DNA polymerase gene (Pol) by polymerase chain reaction. However, gene expression as determined by immunohistochemistry with Pol-specific antibody was seen only in HAEM lesions, suggesting that lesion development is associated with Pol gene expression. Similar HSV-specific T-cell lymphoproliferative responses were seen in peripheral blood mononuclear cells (PBMCs) from patients with acute or healed HAEM lesions or HSV lesions and from HSV-seropositive patients with unrelated inflammatory diseases. However, the T-cell receptor variable (V beta) chain repertoire of HSV-stimulated PBMCs obtained from HAEM lesions was altered; the prevalence of some families of variable chain (namely V beta 16 and V beta 19) was reduced, whereas the prevalence of others was increased (namely V beta 2 and V beta 7). V beta 2 cells were found in HAEM lesional skin positive for Pol antigen, suggesting that these cells home to viral antigen-positive skin.

In vivo production of cytokines and beta (C-C) chemokines in human recurrent herpes simplex lesions--do herpes simplex virus-infected keratinocytes contribute to their production?

Recurrent human herpes simplex lesions are infiltrated by macrophages and CD4 and CD8 lymphocytes, which secrete cytokines and chemokines. Vesicle fluid was examined by ELISA for the presence of cytokines and beta (C-C) chemokines. On the first day of the lesion, high concentrations of interleukin (IL)-1beta, and IL-6, moderate concentrations of IL-1alpha and IL-10, and low concentrations of IL-12 and beta chemokines were found; levels of macrophage inflammatory protein (MIP)-1beta were significantly higher than levels of MIP-1alpha and RANTES. At day 3, the concentrations of IL-1beta, IL-6, and MIP-1beta were lower, whereas the levels of IL-10, IL-12, and MIP-1alpha remained similar, and the level of tumor necrosis factor-alpha was now detectable. Herpes simplex virus infection of keratinocytes in vitro stimulated production of beta chemokines followed by IL-12 and then IL-10, IL-1alpha, IL-1beta, and IL-6, indicating a potential role for these events in early recruitment, activation, and interferon-gamma production of CD4 cells in herpetic lesions.

Expression of Herpes Simplex Virus DNA Fragments Located in Epidermal Keratinocytes and Germinative Cells Is Associated with the Development of Erythema Multiforme Lesions

Skin from acute and healed herpes simplex virus or herpes simplex virus-associated erythema multiforme (HAEM) lesions was examined by polymerase chain reaction with primers for DNA polymerase, ICP8, thymidine kinase (5' end of herpes simplex virus genome), and ICP27 (3' end of herpes simplex virus genome). The primers were herpes simplex virus specific and equally sensitive. The four herpes simplex virus genes were seen in acute herpes simplex virus lesions, but except for one patient, only polymerase (or polymerase and ICP8) were seen in 7-d healed lesional skin. Herpes simplex virus DNA was not seen 1-1.5 mo after healing. HAEM skins from 18 of 24 patients (75%) were positive for polymerase DNA and four of 24 (17%) were also positive for ICP8 or thymidine kinase DNA. Only one tissue (4%) was positive for polymerase, ICP8, and ICP27 DNA. Skin from healed HAEM lesions was still polymerase DNA positive 1-3 mo after lesion resolution. The polymerase DNA signal was in the basal and spinous cell layers of the epidermis and in the outer root sheath of the hair follicle. Polymerase RNA was identified by reverse transcriptase polymerase chain reaction in skin from acute, but not healed polymerase DNA positive HAEM lesions, suggesting that polymerase expression is associated with HAEM lesion development.

Herpes simplex virus-associated erythema multiforme in prepubertal children.

To examine clinical associations, evolution of the condition, and response to treatment of erythema multiforme (EM) in prepubertal children. A retrospective case series evaluation of children younger than 13 years with EM. Ambulatory care university hospital. Referral patients from pediatricians serving a population of 3.2 million. Results of treatment of each EM episode with topical acyclovir or oral acyclovir at a dose of 25 mg/kg per day and 6-month prophylaxis with oral acyclovir at a dose of 20 mg/kg per day were evaluated. Age at EM onset, preceding illness, and number and duration of episodes during a 3-year period were recorded. Twelve children (7 boys and 5 girls) in whom herpes simplex virus (HSV)-associated EM developed were evaluated. Preceding lesions were herpes labialis in 8 children and herpes facialis in 2 children. Two children had no obvious HSV lesion. The mean age at onset of disease was 8.1 years, and the mean time from the preceding HSV to the onset of skin lesions was 3.9 days (range, 0-11 days). Episodes of EM lasted a mean of 10.6 days. In 9 children, the EM was recurrent, with a mean of 2.6 episodes per year. All 12 children, including those with negative viral cultures for HSV or no HSV history had HSV detected in their target lesions by polymerase chain reaction amplification of DNA obtained from skin biopsy specimens. Six of 12 children were treated with oral acyclovir at a dose of 25 mg/kg per day for 1 or more individual episodes, without reduction in the episode. Three children underwent 6-month prophylaxis with oral acyclovir at a dose of 20 mg/kg per day and remained disease free during treatment. After discontinuation of the prophylactic treatment with acyclovir, 1 child relapsed at 4 months. The other 2 children had no further episodes during a 3-year period. The HSV-associated EM is a recurrent disease that can be precipitated by sun exposure and does not progress to Stevens-Johnson syndrome. Childhood HSV-associated EM may be unresponsive to treatment with oral steroids or oral or topical acyclovir. Frequent recurrences of EM may be abrogated by prophylactic treatment with acyclovir.

In vitro inactivation of herpes simplex virus by a biological response modifier, PSK

Herpes simplex virus (HSV) causes herpes genitalis, primary gingivostomatitis and recurrent herpes labialis. In order to elucidate in vivo mechanisms by which PSK, a biological response modifier, exerts a protective effect against HSV infection, we used an in vitro system to study whether PSK inactivated infectivity of HSV-type 1 (HSV-1) and HSV-type 2 (HSV-2) isolated from patients with herpes genitalis in addition to a laboratory-cultured strain of HSV type 1 (HSV-1-GC +). It was found that HSV-1-GC + was inactivated by PSK in a dose dependent fashion of concentrations of PSK and virus titers. Concentrations of PSK as low as 0.31 mg/ml was shown to inactivate the infectivity of HSV-1-GC +. Inactivation required at least 30 min of incubation at 37°C with maximal inactivation observed at 60 min incubation time. Similar to HSV-1-GC +, clinically isolated strains of HSV-2 were inactivated by PSK although clinically isolated strains of HSV-1 were resistant to PSK, compared with HSV-2. It was also shown that PSK-treated HSV retained the ability to adsorb to the cell membrane, but did not synthesize viral protein(s). These data illustrate that there is a biological difference in the sensitivity to PSK between HSV type 1 and type 2, and also suggest that PSK could inactivate HSV in lesions at peripheral sites of recurrent herpes.

Safety and efficacy of Virend ® for topical treatment of genital and anal herpes simplex lesions in patients with AIDS

Virend ® (SP-303), a new topical antiviral agent with activity against herpesvirus, was evaluated in a multicenter, double-blind, placebo-controlled Phase II study for safety and effectiveness against recurrent genital herpes lesions in patients with AIDS. The primary endpoints of this study were complete healing of lesions and time to healing. Patients had a history of recurrent genital or anogenital herpes with at least one lesion and positive HSV culture at enrollment. Participants received Virend ® (15% ointment; 24 patients) or matching placebo (21 patients) three times a day for 21 days. Excluding two patients in the Virend ® group who received an initial treatment but were lost to follow-up, 9 of 22 (41%) patients treated with Virend ® experienced complete healing of their lesions compared with three (14%) patients in the placebo group ( P = 0.053). Viral culture revealed that 50% of Virend ®-treated patients and 19% of placebo-treated patients became culture-negative during treatment ( P = 0.06). Based on these preliminary clinical findings, further evaluation of Virend ® for topical treatment of genital herpes in patients with AIDS is planned.

Postpartum endometritis caused by herpes simplex virus

Herpes simplex virus (HSV) is rarely the causative agent of endometritis and is usually found in association with pelvic inflammatory disease. Only one case of postpartum HSV endometritis has been reported. We describe two cases of herpes simplex postpartum endometritis. Neither patient had genital HSV lesions noted at the time of delivery. The first case developed after a preterm cesarean delivery in an 18-year-old primipara. She had persistent puerperal fever despite broad-spectrum anti-microbial treatment. The second case was a 16-year-old primipara whose vaginal delivery was complicated by severe postpartum endometritis. Vulvar and endometrial cultures were positive for HSV alone in both patients. Both infants died from disseminated HSV infection. Herpes simplex virus can cause clinical postpartum endometritis.

Preferential presentation of herpes simplex virus T-cell antigen by HLA DQA1*0501/DQB1*0201 in comparison to HLA DQA1*0201/DQB1*0201

The HLA DQA1 locus is polymorphic. Haplotypes containing HLA DQA1*0501, but not HLA DQA1*0201, together with HLA DQB1*0201 are associated with Grave's disease and celiac sprue. In this report, we demonstrate a functional correlate of DQA1 polymorphism. T cells infiltrating a herpes simplex virus (HSV) lesion from a HLA DQ 2,7 individual yielded a virusspecific CD4+ clone restricted by DQ2. Presentation of viral peptide and protein segregated with DQA1 allele, because cell lines bearing DQA1*0501/DQB1*0201 heterodimers presented antigen in proliferation and cytotoxicity assays much more efficiently than cell lines bearing DQA1*0201/DQB1*0201. Binding of viral peptide to cell lines bearing DQA1*0201, in comparison to DQA1*0501, was only moderately reduced and may not explain this effect. Truncation and substitution analyses of peptide binding and T-cell activation were performed to determine which viral peptide residues contacting TCR might therefore be presented in an altered conformation by DQA1*0201/DQB1*0201. Residues 432, 435, 437, 438, and 440 (position P1, P4, P6, P7, and P9) contributed to DQ2 binding, whereas residues 431, 433, 434, and 436 (positions P-1, P2, P3, and P5) contributed to TCR contact. Differential presentation of peptide by HLA DQ2 heterodimers varying at the DQA1 locus may have relevance to host defense and the pathogenesis of HLA DQ2-associated autoimmune diseases. Human Immunology 53, 195-205 (1997).

KTP laser and neutral red phototherapy of human squamous cell carcinoma.

Neutral red (NR) is a cationic, nontoxic vital dye employed as a histologic stain for proliferating cells; it has been used clinically for photodynamic treatment of herpes simplex virus lesions. NR is selectively taken up and concentrated by mitotic cells, an important characteristic for more effective antineoplastic agents. In the present study, UCLA-SO-P3 human squamous carcinoma cells displayed minimal toxicity when incubated with up to 50 microg/ml NR in the absence of light. However, cells incubated with greater than 0.5 microg/ml NR followed by exposure to KTP laser light at 532 nm exhibited nearly 100% tumor cell death. The degree of cell toxicity was proportional to NR dose and laser light fluence. This study demonstrates that NR is an excellent cancer cell photosensitizer in vitro, and, after adding additional in vivo preclinical testing, may prove to be a useful agent in photodynamic destruction of head and neck tumors.

Asymptomatic Perianal Shedding of Herpes Simplex Virus in Patients With Acquired Immunodeficiency Syndrome

To determine the frequency of asymptomatic perianal shedding of herpes simplex virus (HSV) in adult patients with acquired immunodeficiency syndrome (AIDS). Cross-sectional study. A 1000-bed, state-supported hospital in Brazil that provides comprehensive health care. Eighty-two consecutively hospitalized patients with AIDS (Centers for Disease Control and Prevention class C). Specimens for HSV culture were obtained with premoistened swabs of the perianal region at approximately 7-day intervals during the hospitalization of each patient. After the specimens were inoculated into cultures of human foreskin and Vero cells, supernatants of cultures showing the cytopathic effect characteristic of HSV infection were tested for virus in a confirmatory immunoenzymatic assay. Typing of HSV was performed by polymerase chain reaction amplification of HSV-1- and HSV-2-specific DNA polymerase sequences. On early into the study, 12 (15%) of 82 patients had perianal ulceration and 70 did not. None of the patients in the latter group developed perianal ulcers during the study period, but HSV was isolated at least once from 17 (24%) of them. Nine of the 17 asymptomatic perianal shedders had a mean of 3 perianal swabs collected before the first HSV isolation, and 11 (65%) of 17 had a total of 18 perianal swabs collected 8 to 62 days after the HSV isolation. All postpositive samples were negative for HSV except 1 obtained from a patient 13 days after the first positive sample. Twelve of the 17 asymptomatic perianal shedders of HSV were followed up clinically for 8 to 62 days after the first episode of shedding and none developed perianal ulceration. We conclude that asymptomatic perianal shedding of HSV is common in patients with AIDS, even among those without a history of perianal HSV lesions. This shedding appears to be short-lived, intermittent, and not associated with early subsequent development of perianal ulcers. These findings present a new perspective on the natural course of perianal HSV infection in patients with AIDS.

High frequency of CD8+ cytotoxic T-lymphocyte precursors specific for herpes simplex viruses in persons with genital herpes.

Herpes simplex virus (HSV)-specific CD8+ cytotoxic T lymphocytes (CTL) have rarely been detected in humans, presumably because of virus-induced mechanisms that downregulate major histocompatibility complex class I expression. We have developed a method that has allowed us to consistently demonstrate HSV-specific CD8+ precursor CTL (pCTL) from HSV type 1- and 2-seropositive persons. Major histocompatibility complex-restricted HSV-specific CD8+ pCTL were found in 10 consecutively tested HSV type 1- and 2-seropositive subjects at frequencies ranging from 1 in 21,000 to 1 in 300 (median, 1 in 6,000) versus a pCTL frequency of 1 in 100,000 in HSV-seronegative donors. These results suggest that CD8+ CTL are important effector cells in resolving HSV lesions.

Skin preps; herpes simplex lesions; size of instrument sets; surgical masks; irrigation solutions

AORN JournalVolume 62, Issue 3 p. 439-441 Department Skin preps; herpes simplex lesions; size of instrument sets; surgical masks; irrigation solutions Julie Thompson RN, MSN, CNOR, Julie Thompson RN, MSN, CNOR Perioperative nursing specialist Center for Nursing PracticeSearch for more papers by this author Julie Thompson RN, MSN, CNOR, Julie Thompson RN, MSN, CNOR Perioperative nursing specialist Center for Nursing PracticeSearch for more papers by this author First published: September 1995 https://doi.org/10.1016/S0001-2092(06)63587-4Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume62, Issue3September 1995Pages 439-441 RelatedInformation

Frequency and reactivation of nongenital lesions among patients with genital herpes simplex virus

To determine the frequency, recurrence patterns, and host factors associated with nongenital herpes simplex virus lesions. In this cohort study at a referral clinic, 457 patients with first episodes of genital herpes were prospectively observed to evaluate the anatomic sites of herpetic lesions at the first and subsequent visits. Of these patients, 73 had primary genital herpes simplex virus (HSV) type 1, 326 had primary first episode genital HSV-2, and 58 had HSV-1 infection prior to acquisition of genital HSV-2. The median follow-up was 63 weeks. Nongenital lesions at the time of acquisition of genital herpes were observed in 25%, 9%, and 2% of patients with primary HSV-1, primary HSV-2, and nonprimary HSV-2, respectively. Half of the patients with concurrent genital and nongenital lesions subsequently had recurrences at a nongenital site. Twenty patients (6.5%) whose primary genital HSV-2 infection involved only the genitalia subsequently developed nongenital recurrences, primarily on the buttocks (12) and legs (4). Nongenital recurrences, especially buttock recurrences, tended to be less frequent but of longer duration than genital recurrences. Overall, 21% of patients with primary genital herpes will have or will subsequently develop a nongenital recurrence. Among patients with HSV-1, nongenital lesions tended to occur more often on the hand and face, whereas HSV-2 lesions appeared more often on the buttocks. Buttock lesions due to HSV recur less frequently but last longer than genital lesions.

Dosing considerations for oral acyclovir following neonatal herpes disease

Herpes simplex virus lesions recur in 8-30% of infants who receive a course of parenteral antiviral therapy for an initial infection. Long-term acyclovir is used by some clinicians to prevent recurrent Herpes simplex disease. We describe nine infants who were treated with doses of oral acyclovir which were chosen to achieve 2-h post-plasma concentrations of > or = 2 micrograms/ml. Eight infants had Herpes simplex encephalitis and one had multiple recurrences of dermal and ocular disease. The target plasma concentration was chosen in order to attain acyclovir cerebrospinal fluid distribution (< or = 50% plasma) for an estimated ID30 of Herpes simplex II strains of 0.1-0.5 microgram/ml. One of nine patients failed to achieve the target plasma acyclovir concentration. One of nine patients developed symptomatic recurrence of the central nervous system disease and none of the remaining eight patients experienced recognized dermal or neurologic recurrence of Herpes simplex disease. Renal and neurologic status were routinely monitored and no signs of acyclovir toxicity were observed. Plasma concentration of acyclovir > or = 2 micrograms/ml may be achieved with average oral doses of 1340 mg/m2/dose (1000-1740 mg/m2/dose) given at 12-h intervals.

Cutaneous Ultraviolet Radiation Inhibits Herpes Simplex Virus-Induced Lymphoproliferation in Latently Infected Subjects

Exposure of herpes simplex virus (HSV) latently infected subjects to ultraviolet irradiation (UVR) (1 minimum erythema dose, 90% body surface) caused a significant inhibition of HSV and phytohemagglutinin-induced lymphoproliferation. The inhibition was observed on Day 3 post-UVR and lasted at least 9 days. UVR-induced downregulation of HSV-specific lymphoproliferation was associated with increased levels of activated transforming growth factor β However, the relationship between UVR-induced immune downregulation and the development of recurrent HSV lesions was incomplete.

The incidence of herpes simplex virus labialis after cesarean delivery

Epidural and subarachnoid opioids have been associated with the development of oral herpes simplex lesions. Because of this risk, some anesthesiologists avoid neuraxial morphine in parturients with a history of herpes simplex virus labialis. When we began using neuraxial opioids for analgesia after cesarean delivery, we did not see any increased incidence of facial lesions. To confirm this impression, we studied 357 consecutive parturients presenting for elective or emergent cesarean delivery between 1 December 1989 and 27 June 1990. The women received spinal, epidural, or general anesthesia. Two hundred and one women received either spinal or epidural morphine, the remaining 156 parturients received only systemic opioids for postoperative analgesia. An investigator saw each patient daily until discharge. Only 11 patients (3%) developed oral lesions while hospitalized. None of these women had severe lesions. Neuraxial morphine did not increase the risk of labial lesions significantly (3.5% vs. 2.6%). Despite published data to the contrary, we found no correlation between neuraxial morphine and the risk of facial herpes virus lesions in women after cesarean delivery. We offer patients the option of neuraxial morphine for analgesia after cesarean delivery despite any history of oral herpes lesions.

Co-infection and synergy of human immunodeficiency virus-1 and herpes simplex virus-1

The human immunodeficiency virus (HIV-1) uses the CD4 molecule, expressed by T helper cells and activated macrophages, as a receptor for entry into host cells. In tissues co-infected with herpes simplex type 1 (HSV-1), HIV-1 virions were observed to infect keratinocytes, which, because they lack the CD4 molecule, are normally incapable of being infected by HIV-1. Although a number of other viruses have been reported to enhance HIV-1 viral transcription in vitro, this is the first in-vivo report to our knowledge of reciprocal enhancement of viral replication associated with co-infection of keratinocytes and macrophages by HIV-1 and HSV-1 in patients with AIDS and non-genital herpes simplex lesions. The virions in the co-infected cells were larger, morphologically atypical, and appear to be hybrids; most contain the HIV-1 envelope necessary for infectivity. The increased viral load and the proximity of the virions to the cutaneous surface may lead to increased risk of transcutaneous transmission of both viruses. These findings point to the need for incorporation of suppressive treatment for herpes simplex in the treatment of AIDS.

Concurrent oral cytomegalovirus and herpes simplex virus infection in association with HIV infection: A case report

Recurrent oral herpes simplex virus lesions are common in both immunocompetent and immunocompromised persons. In contrast, cytomegalovirus-associated intraoral lesions are rarely seen, even in the immunocompromised host. We report a case of concurrent oral herpes simplex virus and cytomegalovirus infection, appearing as an ulcerative lesion of the labial mucosa in a patient with acquired immunodeficiency syndrome. Herpes simplex virus type 1 was shown to be present in the lesion by culture tests, histopathologic examination, immunohistochemistry findings and a direct immunofluorescence assay, and cytomegalovirus by histopathologic examination and immunohistochemistry findings. We deduce that the lesion was due to concurrent herpes simplex virus-1 and cytomegalovirus infection. The patient responded well to 2 weeks of treatment with a high dose of acyclovir.

Foscarnet treatment of acyclovir-resistant herpes simplex virus infection in patients with acquired immunodeficiency syndrome: Preliminary results of a controlled, randomized, regimen-comparative trial

Herpes simplex virus (HSV) resistant to acyclovir can produce persistent mucocutaneous ulcerative disease in patients with the acquired immunodeficiency syndrome (AIDS). The incidence of clinically significant acyclovir-resistant HSV disease has dramatically increased since the advent of the AIDS epidemic. The primary mechanism of acyclovir resistance is induction of viral mutants defective or deficient in thymidine kinase, the viral-encoded enzyme, which catalyzes the rate-limiting step in the triphosphorylation of acyclovir to its active form (acyclovir triphosphate). Foscarnet, a potent inhibitor of HSV DNA polymerase, does not require phosphorylation for its antiviral activity. This compound has been found to be effective in the treatment of acyclovir-resistant HSV infection by several investigators. A recently completed dose-comparative trial of foscarnet in AIDS patients with acyclovir-resistant HSV has confirmed the safety and efficacy of two doses of foscarnet (40 mg/kg every 8 or 12 hours) in the treatment of this disease, as well as providing preliminary evidence supporting the utility of foscarnet maintenance therapy in delaying recurrence of HSV lesions. Analysis of data from this trial has been complicated by the tremendous variability in lesion size at initiation of therapy, making any statistically valid comparison of treatment regimens almost impossible. A further trial in AIDS patients with acyclovir-resistant HSV infection has been designed to define better the role of foscarnet maintenance and, in light of evidence that a significant proportion of initial recurrences are due to acyclovir-sensitive HSV, to examine the potential utility of acyclovir maintenance following foscarnet induction therapy.