                   AIDS INFORMATION NEWSLETTER
                   Michael Howe, MSLS, Editor
                     AIDS Information Center
                VA Medical Center, San Francisco
                     (415) 221-4810 ext 3305
                        February 9, 1996

                Opportunistic Infections (Part XIX)

                          Herpesviruses

[Opportunistic Infections and Related Disorders; From AmFAR's
AIDS/HIV Treatment Directory, Vol. 7, No. 4 (January, 1995]

     PATHOGEN: Herpes simplex virus types 1 and type 2 (HSV-1,
HSV-2), varicella-zoster virus (herpes zoster, VZV) and human
herpesvirus 6 (HHV-6). 

     SITES OF INFECTION: Herpesviruses typically infect epithelial
and nerve tissues. Reactivation of these infections are common in
AIDS patients. Lesions resulting from HSV-1 most commonly affect
the mouth and lips, and those resulting from HSV-2 affect the
genitals and anus. VZV, the chicken-pox virus, resides in the nerve
roots adjacent to the spine; herpes zoster (shingles) represents
an acute re-activation of VZV. These lesions typically affect the
face and trunk.
     A recent report (Heng et al.) showed that in vitro
co-infection with HSV-1 allows HIV-1 to infect cells not normally
permissive to HIV-1 infection (in this case, keratinocytes which
do not express the CD4 receptor). The authors also noted unique
morphological and replicative characteristics of the virions in the
co-infected cells which suggested the presence of an HSV-1/HIV-1
hybrid virus. These data may support the concept of suppressive
treatment for herpes simplex in HIV-1 infected people.

     SYMPTOMS: Herpes simplex virus infection usually causes
painful blisters on an inflamed base; herpes zoster is a painful,
blistery rash that follows the path of a sensory nerve.

     DIAGNOSIS: By virus culture of the lesion or fluorescent
antigen testing.

     TREATMENT RESULTS, HERPES SIMPLEX: Oral acyclovir is approved
for the treatment of HSV-related syndromes and reduces the severity
and duration of HSV symptoms. Treatment of severe herpes zoster
infection may require hospitalization and treatment with
intravenous acyclovir or other antiherpetic agents.
     Preliminary data from a phase III study (ACTG 169) of BV ara-
U (40 mg once daily for 10 days) vs acyvlovir (800 mg five times
daily for 10 days) in localized zoster demonstrated superiority of
BV ara-U (Whitley and co-workers).  BV ara-U reduced the time to
cessation of new lesions and 100% crusting by one-half compared to
acyclovir.  Similar findings from a European study of the safety
and efficacy of BV ara-U were presented by Dehertogh et al.  BV-
ara-U (40 mg once daily) was compared with the standard acyclovir
dose of 800 mg 5 times daily among 137 HIV+ individuals.  This
study was halted when the second interim analysis revealed a
statistical difference between the two therapies in favor of BV
era-U.  Patients were followed for 6 months.  BV era-U reduced the
mean number of days to cessation of new lesion formation and time
to 100% crusting by one-third compared to acyclovir.  Time to
cessation of acute pain and time to resolution of postherpetic
neuralgia was not different between the two therapies.
     Bentley et al. recently reported that the absolute
bioavailability of acyclovir is substantially increased following
oral valaciclovir administration.  Twelve asymptomatic HIV+
participants were recruited to take part in an open label,
randomized, crossover study.  Subjects received either oral
valaciclovir (1000 mg) or IV acyclovir (350 mg as a 70 ml
infusion).  The mean absolute bioavailability of acyclovir from
oral valaciclovir was 54.2& (95% CI=49.4-59.5%).  The estimated
bioavailability of acyclovir from the ratio of urinary recovery was
52.8%.
     A multi-center study comparing acyclovir to BW256U87
(valaciclovir) for the treatment of recurrent anogenital herpes
simplex infection in HIV-infected patients is under way. A
multi-center double-blind study comparing valaciclovir to oral
acyclovir for frequently recurring herpes infection is under way.
     A multi-center randomized study comparing valaciclovir to oral
acyclovir for frequently recurring herpes infection is under way.

HERPES ZOSTER AND ACYCLOVIR-RESISTANT HERPES SIMPLEX:

     The development of acyclovir-resistant herpes zoster has been
well documented in HIV-infected patients who were receiving
long-term acyclovir treatment (1 - 5 months). Foscarnet is the only
available agent in the U.S. shown to be effective for
acyclovir-resistant HSV infection and is used frequently for this
indication. Recent evidence reported by Safrin et al. (1994)
suggest that foscarnet-resistant HSV infections may be recognized
with increasing frequency.
     Erlich et al. treated 4 AIDS patients with severe acyclovir-
resistant HSV-2 disease with foscarnet (60 mg/kg IV every 8 hours)
for 12 to 50 days. Marked clinical improvement, marked clearing of
lesions, and eradication of HSV from mucous membranes were noted.
     Tan et al. treated 6 patients with acyclovir-resistant HSV
with foscarnet. Significant or complete healing of lesions occurred
in all patients by the end of day 14. Foscarnet maintenance
suppressed the recurrence of lesions for up to 10 weeks. Recurrent
lesions were successfully treated with a second induction course
of foscarnet. No significant renal or neurological toxicities were
seen. One patient developed persistent penile ulcerations.
     Safrin et al. treated 5 AIDS patients with acyclovir-resistant
varicella-zoster virus (VZV) with foscarnet (40 mg/kg IV three
times daily for more than 10 days). 4/5 patients had complete or
nearly complete healing of lesions. 2/4 had a relapse 7-14 days
after completing foscarnet therapy; isolates from both patients
showed susceptibility to acyclovir in vitro. One relapse patient
responded to intravenous acyclovir; one patient did not respond to
oral acyclovir (4,000 mg daily for 12 days).
     A randomized multicenter trial (ACTG 095) established that
foscarnet is superior to vidarabine (Ara-A) for acyclovir-resistant 
mucocutaneous HSV (Safrin et al.). Eight patients received
foscarnet (40 mg/kg IV three times daily) and 6 received vidarabine
(15 mg/kg IV daily). Lesion reduction and healing were observed in
foscarnet recipients after 10 - 24 days of therapy; no patient on
vidarabine healed. Recurrences in acyclovir-resistant HSV occurred
in all patients who had healed; the median time to relapse was 42.5
days after discontinuing foscarnet.
     Kessler et al. enrolled 26 AIDS subjects in an open-label
study (ACTG 172) of topical trifluridine (TFT) for ACV-resistant
chronic mucocutaneous HSV.  Interim data reported on 9 subjects
showed that 7/9 subjects responded to treatment.  Lesions
completely healed in 5/7 responders (mean duration to healing 32
days) and 2/7 had a partial response.  No toxicities were reported. 
Weaver et al. treated two AIDS patients with acyclovir-resistant
HSV with topical TFT solution.  TFT was applied three times daily;
all lesions healed completely within 11 to 34 days.
     Multi-center studies for herpes zoster are ongoing comparing
intravenous BV ara-U to intravenous acyclovir.
     Topical agents under investigation for the treatment of
acyclovir-resistant herpes simplex include HPMPC gel and foscarnet
cream.

REFERENCES: Bentley et al. Absolute bioavailability of acyclovir
is substantially increased following oral valaciclovir. Abstract
#PB0523, X Intl Conf AIDS, Japan, 1994.

Dehertogh et al. The safety and efficacy of sorivudine (BV ara-U)
for the treatment of zoster in HIV-infected adults. Abstract #A/7,
34th ICAAC, Orlando, 1994.

Erlich KS et al. Foscarnet therapy for severe acyclovir-resistant
herpes simplex virus type-2 infections in patients with AIDS. Ann
Int Med 110: 710-13, 1989.

     Heng M et al. Co-infection and synergy of human
immunodeficiency virus-1 and herpes simplex virus-1. Lancet 343:
255-260, 1994.

     Jacobson MA et al. Acyclovir-resistant varicella zoster virus
infection after chronic oral acyclovir therapy in patients with the
acquired immune deficiency syndrome (AIDS). Ann Int Med 112(3):
187-91, 1990.

     Kessler H et al. ACTG 172: treatment of acyclovir-resistant
(ACV-R) mucocutaneous herpes simplex virus (HSV) infection in
patients with AIDS: open label pilot study of topical trifluridine
(TFT). Abstract WeB1056, VIII Intl Conf AIDS, Amsterdam, 1992.

     Safrin S et al. Foscarnet-resistant herpes simplex virus
infection in patients with AIDS. JID 169: 193-6, 1994.

     Safrin S et al. A controlled trial comparing foscarnet with
vidarabine for acyclovir-resistant mucocutaneous herpes simplex in
acquired immunodeficiency syndrome. NEJM 325: 551-5, 1991.

     Safrin S et al. Foscarnet therapy in five patients with AIDS
and acyclovir-resistant varicella-zoster virus infection. Ann Int
Med 115(1): 19-21, 1991.

     Tan C et al. Foscarnet induction and maintenance therapy for
acyclovir-resistant herpes simplex infections in AIDS. VI Intl Conf
AIDS San Francisco, abstract #Th.B. 447, 1990.

     Weaver D et al. Topical trifluridine treatment of acyclovir-
resistant herpes simplex disease. 31st ICAAC, abstract #507, 1991.

     Whitley et al. ACTG 169: Evaluation of SQ 32,756 (BV era-U)
versus acyclovir in the treatment of localized herpes zoster in
HIV-infected patients. Oral presentation, 18th AIDS Clinical Trial
Group Meeting, Washington, DC, 1994.

OTHER REPORTS: Kaplowitz L et al. Prolonged continuous acyclovir
treatment of normal adults with frequently recurring genital herpes
simplex virus infection. JAMA 265(6): 747-751, 1991.

     Murphy M et al. Topical trifluridine for mucocutaneous
acyclovir-resistant herpes simplex II in AIDS patient. Lancet 340:
1040, 1992.

     Pottage J et al. Acyclovir resistant (ACV-R) herpes simplex:
susceptibility to alternative antiviral agents. Abstract PoB3238,
VIII Intl Conf AIDS, Amsterdam, 1992.

     Copyright (c) 1995 - American Foundation for AIDS Research
(AmFAR) - All Rights Reserved. Permission to reproduce for
non-profit use granted with the condition that the source and date
of the information be given, and that AmFAR be notified. Eric
Fretz, Treatment Information Services, AmFAR. DISTRIBUTED BY
GENA/aegis (714.248.2836 * 8N1/Full Duplex * v.34).  


               Herpes Simplex Virus Infections in
                     HIV-Infected Patients:
                 Clinical Course and Management

                      by Sharon Safrin, MD

[Susan Safrin is Assistant Professor, Department of Medicine,
Epidemiology and Biostatistics, University  of California, San
Francisco, and Chief, Herpes Virus Research Lab, San Francisco
General Hospital, California]

     Although herpes simplex virus (HSV) infections are not a major
cause of mortality in patients with human immunodeficiency virus
(HIV) infection, their frequent recurrence and propensity to
chronicity in such patients render them an important cause of
morbidity.  The prevalence of HSV-2 infection in the United States
has risen by nearly one third in the past two decades, with
estimates of the rate of infection in the general population now
22% (1).  Rates of HSV-2 infection have been correlated with level
of sexual activity in several studies (2,3) and they appear to be
particularly high among homosexual or bisexual men with HIV
infection (68% to 77%) (4-6).  Although the frequency of HSV-1
infection in HIV-infected persons does not appear to differ from
that found in the general population, reactivation of this virus
from latency may be responsible for recurrent labial or oral
ulcers.
     In multiple studies (5,6), the presence of HSV-2 infection has
been shown to be associated with a higher risk of acquiring HIV
infection; thus it appears that HSV-2 and HIV infections have a
bidirectional interaction, in which one exacerbates or predisposes
to the other.
     The course of HSV infection in the HIV-infected patient has
not been definitely studied.  However, anecdotal reports describe
episodes of anogenital HSV infection in HIV-infected patients to
be more frequent, more severe, and more prone to chronicity (7). 
The case definition of acquired immunodeficiency syndrome (AIDS)
was revised by the Centers for Disease Control in 1987 to include
"chronic mucocutaneous HSV lesions persisting for greater than 1
month, in the absence of other causes of immunodeficiency or in the
presence of serum antibody against HIV" (8).  A retrospective study
at San Francisco General Hospital was unable to document either a
greater frequency or greater severity of anogenital episodes of HSV
in patients having a first episode of Pneumocystis carinii
pneumonia (4).  However, a recent preliminary report described a
high incidence of asymptomatic shedding of HSV-2 in HIV-infected
gay men and the presence of asymptomatic reactivation of HSV-2 in
more than one bodily site simultaneously (9).
     Acyclovir, released in the United States in 1982, is widely
available for the management and suppression of HSV.  However, its
inability to eradicate the virus from its latent form in sensory
ganglia results in an inability to cure HSV infection.  In the
patient with severely impaired host defenses, HSV may cause
frequent painful recurrences that require repeated courses of
therapy with acyclovir; alternatively, acyclovir may be indicated
as a suppressive agent in the prevention of recurrences in those
with particularly frequent or severe outbreaks.  Additionally, the
possible enhancement of survival in patients with AID who receive
acyclovir in concert with zidovudine was suggested in recent
studies (10-12).

Clinical Manifestations

     Several authors have described HIV-infected patients with
severe anorectal ulcers that took longer to heal than expected
(7,13).  Chronicity of lesions in other sites has also been
described, usually n patients not treated with acyclovir (12).  In
such patients, inadequate host defenses prevented lesions from
healing without the aid of antiviral chemotherapy, such as
acyclovir, and chronic lesions, often with atypical appearances,
resulted (14).  A recent study demonstrated that HSV becomes a much
more prevalent cause of mucocutaneous ulceration as the CD4+ cell
count drops below 50 cells per milliliter.
     Increased severity of HSV lesions in the HIV-infected patient
has also been described (7,13).  This includes not only
mucocutaneous herpetic lesions, but also rare manifestations, such
as transverse myelitis and ventriculoencephalitis.  Isolated HIV-
infected patients with visceral dissemination of HSV have been
reported.
     HSV may cause proctitis, manifesting as fever, severe
anorectal pain, tenesmus, constipation, perianal ulceration,
difficulty in urination, and sacral parenthesis (16).  Esophagitis
due to HSV may cause odynophagia and painful oral and esophageal
ulcerations.

Diagnosis of HSV

     The "gold standard" method of diagnosis continues to be the
virus culture.  The sample is collected on cotton-tipped swabs by
directly sampling cells at the base of the lesion, then transmitted
to the laboratory in virus transport media.  The specimen should
be stored at 4 degrees C if a delay in transport to the laboratory
is expected.  HSV strains, once inoculated onto cell monolayers,
will replicate and cause a characteristic cytopathic effect in an
average of 48 to 72 hours.  Once a cytopathic effect is observed,
HSV is generally confirmed with fluorescent monoclonal antibodies
directed against type-specific antigens.  However, the long
turnaround time and relative expense of the virus culture have
motivated the investigation of more rapid methods.  In addition,
the sensitivity of the virus culture in detecting HSV decreases
with the age of the lesion, such that early vesicles yield the
highest detection rates.  Samples from recurrent lesions may have
lower rates of detection than those from primary HSV; one study
found a detection rate of only 53% from a single sample collected
from a recurrent genital HSV lesion (17).
     HSV antigen detection by direct fluorescent antibody (DFA)
testing is more rapid than, and approximately as sensitive as, the
virus culture in detecting HSV in clinical lesions.  However,
asymptomatic shedding of HSV in clinical lesions.  However,
asymptomatic shedding of HSV, which tends to cause a lower titer
of virus on the mucocutaneous surface, is less well detected by DFA
than by virus culture.
     The polymerase chain reaction (PCR) clearly shows high
sensitivity in the diagnosis of HSV, but it is not widely available
and is relatively expensive. HSV-PCR used to detect HSV in the
cerebrospinal fluid for the diagnosis of herpes encephalitis has
proved valuable in a number of recent studies (18) and is also
being studied for detection for asymptomatic shedding of virus from
mucocutaneous surfaces.
     Serologic detection of antibodies to HSV may be useful in
establishing the presence of HSV infection.  However, serologic
techniques that accurately determine HSV type are not yet
commercially available; the higher prevalence of HSV-1 than HSV-
2 infection in the general population and the frequency of cross-
reacting antigens between HSV-1 and HSV-2 render a positive
antibody test result for HSV from commercial kits useless in the
diagnosis of a genital or anal lesion for a given individual. 
Moreover, the duration of infection can not be determined
serologically, which compounds the difficulty in identifying HSV
as etiologic in a mucocutaneous lesion on the basis of a serologic
result.  Therefore, the greatest value of serologic testing, once
it is more readily available, may be in the diagnosis of
asymptomatic infection, in order to prevent both horizontal and
vertical transmission of HSV.

Acyclovir:  Mechanism of Action

     Acyclovir is an acyclic guanosine analog formulated in
intravenous, oral, and topical preparations.  Activation by
phosphorylation is required for antiviral activity; catalysis by
a virus-encoded thymidine kinase accounts for the specificity of
antiviral effect in herpes-infected cells.  Following conversion
of acyclovir by the virus-specified thymidine kinase to its
monophosphate derivative, di- and triphosphorylation are catalyzed
by cellular enzymes, resulting in acyclovir triphosphate
concentrations that are 40 to 100 times higher in HSV-infected
cells than in uninfected cells (19).  Competition as a substrate
for the viral DNA polymerase by acyclovir triphosphate results in
both prevention of DNA elongation and chain termination.
     Because acyclovir is not phosphorylated efficiently by the
host cellular kinase, there is activation and accumulation of the
drug only in HSV-infected cells.  This results in sustained
intracellular inhibitions of HSV replication, causing a block in
the production of infectious HSV virions.  Ultimately, virus
shedding from the mucocutaneous surface ceases and herpetic lesions
subsequently heal.

Acyclovir:  Efficacy Against HSV Infection

     Acyclovir was initially studied as an intravenous preparation,
given in doses of 5 mg/kg every 8 hours, in patients with primary
genital herpes.  These studies demonstrated significant reductions
in the duration of viral shedding, itching and pain, time to
crusting and complete healing, and occurrence of new lesion
formation in patients randomized to receive acyclovir, compared
with those receiving placebo (20).  A statistically significant
benefit or oral acyclovir (200 mg five times daily) for the
treatment of primary genital herpes was demonstrated in a placebo-
controlled trial as well, with no evidence that administering
higher doses of oral acyclovir (eg, 4 g/d rather than 1 g/d)
provides any greater clinical benefit (22).
     Studies of oral acyclovir for the treatment of recurrent
genital herpes have confirmed similar benefits (21).  However, the
clinical benefit of treating immunocompetent patients with
recurrent genital herpes is relatively slight (eg, a decrease in
lesion healing time from an average of 6 to 5 days)(21).  A single
trial has suggested that the dosing regimen of 800 mg twice a day
is as effective as that of the ore inconvenient 200 mg five times
daily (23).  The dosage of 400 mg five times daily of oral
acyclovir was found in a placebo-controlled study to be effective
in limiting the duration of clinical lesions and of virus shedding
in homosexual men with first-episode herpes proctitis (24).
     Acyclovir is well tolerated by both immunocompetent and HIV-
infected hosts.  Although both neurologic and renal toxicities have
been described in association with high doses of acyclovir
administered intravenously, the drug has been more or less devoid
of serious side effects when appropriately administered either
orally or intravenously.  Additionally, no drug interactions of
note have been described to date.

Acyclovir as a Suppressive Agent to Prevent Recurrences of HSV

     Placebo-controlled trials have demonstrated a marked reduction
in the number of episodes of recurrent genital herpes in patients
taking daily suppressive doses of acyclovir (either 400 mg twice
a day or 200 mg three times a day)(25,26).  A regimen of 800 mg
once daily also appear promising in one small study(27).  In
immunocompetent hosts, there is no evidence of an increased
frequency of acyclovir-resistant HSV strains emerging in those
taking acyclovir daily in subinhibitory concentrations(25,28) and
the safety of this regimen has been documented for periods of
ingestion of as long as 6 years(29).  However, at least 50% of
patients of patients on suppressive daily therapy will continue to
have at east one outbreak annually(25), and the rate of recurrence
may increase to base-line levels once suppressive therapy is
discontinued(26).  In addition, daily chemosuppression with
acyclovir does not appear to prevent asymptomatic virus
shedding(30), such that transmission to uninfected contacts would
still be possible.

New Agents Under Study to Manage HSV Infection

     Famciclovir, a guanine analog, has excellent in vitro activity
against HSV and a prolonged intracellular half-life that allows
longer intervals between oral dosing(31).  Preliminary results from
a recent study suggest that twice-daily dosing of famciclovir is
effective in suppressing recurrences of genital herpes (32); its
effectiveness for the treatment of recurrent HSV is currently under
study.  Valaciclovir, the L-valine ester of acyclovir, reaches
serum levels that approximate those achieved with intravenous
administration of acyclovir, by virtue of enhanced oral
bioavailability and a rapid metabolic conversion to acyclovir once
ingested (33).  In preliminary studies, it appears to be as
effective as acyclovir for the management of recurrent genital
herpes and as well tolerated, requiring only twice-daily dosing
(34).

Resistance to Acyclovir:  Prevalence and Clinical Presentation

     Acyclovir and the antiherpes treatment modalities under study
are limited by their virostatic nature, failing to eradicate virus
latent in the paraspinous ganglia.  Additionally, we have come to
appreciate that acyclovir-resistant mutant strains of HSV tend to
arise by selection of mutant viruses within clinical lesions(35). 
Although the prevalence of acyclovir-resistant HSV has not been
fully studied, it is likely that a subpopulation of resistant
mutants is generally present in all clinical lesions.  Although the
prevalence of acyclovir-resistant HSV has not been fully studied,
it is likely that a subpopulation of resistant mutants is generally
present in all clinical lesions.  Although not clinically
significant in the immunocompetent host, they may ultimately
predominate because of unopposed replication, with resultant
progressive and persistent lesions(36).
     Beginning in 1982, reports in the medical literature described
patients with hematologic malignancies or congenital
immunodeficiencies who has nonhealing lesions despite therapy with
acyclovir; tested strains from such lesions demonstrated in vitro
resistance to acyclovir(37,38).  Similar acyclovir-resistant HSV
lesions were subsequently described in HIV-infected patients
(36,39,40).  The cumulative number of such patients reported in
the medical literature to date is at least 80.  The most frequent
site of involvement in HIV-infected patients is the perianal area,
whereas the orofacial region is more commonly involved in hosts
with other types of immunodeficiencies and acyclovir-resistant HSV
infection.  Nevertheless, virtually any mucocutaneous site may be
involved, and either HSV-1 or HSV-2 may be etiologic.  Although
systemic or visceral dissemination is rare, a recent case report
described a fatal meningoencephalitis due to acyclovir-resistant
HSV-2 infection in a patient with AIDS(41).
     Although horizontal (ie, person-to-person) transmission has
not been documented to date, it has been implicated in the first
reported case of an immunocompetent person with acyclovir-resistant
HSV infection(42).  Analogously, transmission of zidovudine-
resistant HIV-1 virus has been cited in several recent reports
(43,33).  Thus, we need to target the problem of antiviral
resistance in HSV for both preventive and therapeutic strategies.

Treatment of Patients With Acyclovir-Resistant HSV Infection

     Acyclovir-resistant HSV infection should be suspected in any
immunocompromised patient in whom mucocutaneous lesions of HSV fail
to show signs of reepithelialization after 7 to 10 days of oral (
1 g/d) or intravenous ( 15 mg/kg/d) acyclovir).  Antiviral
susceptibility testing is available in several reference
laboratories around the country, and should be considered either
in concert with a change in antiviral therapy or as a preliminary
step when such a change is contemplated.  In addition, an increase
in the dose of oral acyclovir (eg, to 4 g/d) should be instituted
in the patient failing to respond to lower doses, in an effort to
overcome the drug's poor bioavailability(45).
     Although three mechanisms of resistance to acyclovir have been
described and documented in vitro(46), the vast majority of
clinical isolates are resistant to acyclovir on the basis of
deficiency activity of thymidine kinase, the enzyme required for
triphosphorylation and activation of acyclovir.  An occasional
clinical isolate with resistance to acyclovir due to alteration in
thymidine kinase substrate affinity (47) or to altered DNA
polymerase activity(48,49) has also been described.  Antiviral
agents with mechanisms of action different from those of acyclovir,
or those that act at different lock on the DNA polymerase gene, are
therefore sought as alternative therapies.
     Certain antiviral agents are not generally useful in patients
with resistance to acyclovir.  Thymidine kinase-deficient strains
of HSV are cross-resistant to ganciclovir, for example, such that
a substitution of ganciclovir in a patient failing to respond to
acyclovir is unlikely to be beneficial(36).  Although in vitro
susceptibility to vidarabine is maintained in thymidine kinase-
deficiency, acyclovir-resistant strains of HSV, the drug has not
been effective in the treatment of patients with acyclovir-
resistant HSV infections to date(39,40,50).  AIDS Clinical Trials
Group (ACTG) protocol 095, a randomized trial comparing the
nucleoside analog vidarabine to the pyrophosphate analog foscarnet
for the treatment of acyclovir-resistant HSV infection in patients
with AIDS, found lack of efficacy of vidarabine and an association
of that drug with neurologic an myeloid toxicities(50).
     A small pilot study examined the effectiveness of topical
therapy with BW- 348U87, a ribonucleotide reductase inhibitor, in
combination with acyclovir for the therapy of acyclovir-resistant
HSV infection in AIDS patients.  BW 348U87 potentiates the activity
of acyclovir and retains activity against acyclovir-resistant
mutants of HSV in vitro(51).  However, for unclear reasons, this
therapy failed to induce healing in the 10 patients studied(52). 
Another small pilot study, recently completed, evaluated the
bioflavonoid SP-303, a plant extract that appears to inhibit
attachment of HSV to cells, as a topical therapy for the same
indication.  Unfortunately, none of the nine patients studied
achieved healing with the therapy(53).
     Therapeutic trials with foscarnet have met with greater
success.  The drug is a direct inhibitor of the viral DNA
polymerase and thus retains in vitro activity against thymidine
kinase mutants resistant to acyclovir.  Complete healing of
acyclovir-resistant lesions of HSV has been reported in both
uncontrolled(40,54,55) and controlled(50) studies using intravenous
foscarnet in doses of 40 mg/kg every 8 hours.  Preliminary evidence
suggests that a dosage of 60 mg/kg every 12 hours may be used as
well.  Several potential toxicities are associated with foscarnet,
including azotemia, hypercalcemia, hypocalcemia, hyperphosphatemia,
hypophosphatemia, anemia, seizures, and penile ulcers; however,
administration of a lower dosage for HSV than for cytomegalovirus
infections (40 mg/kg every 8 hours versus 60 mg/kg every 8 hours)
and administration of saline hydration in association with
infusions and careful titration of dosage according to calculated
creatinine clearance have resulted in few instances of dose-
limiting toxicity.  Complete healing has been achieved in
approximately 87% of patients reported in the literature, with a
median time of 13.5 days in one controlled study(50). 
Nevertheless, foscarnet's requirement for intravenous
administration, the need for frequent serum monitoring for
toxicity, and its expense mean that the search for other
alternative therapies for patients with acyclovir-resistant HSV
infection must continue.  In addition, reports of patients with
foscarnet-resistant HSV infection have recently appeared in the
literature(56).
     Several other strategies have been evaluated in a preliminary
manner as therapies for patients with acyclovir-resistant HSV
infection.  Continuous infusion of acyclovir resulted in complete
healing of acyclovir-resistant HSV lesions after approximately 6
weeks in a total of five patients with AIDS(57).  Monitoring of
serum levels of acyclovir is necessary in patients receiving
continuous infusions, to avoid toxicity and to achieve optimum
efficacy, and such testing is not readily available.  The topical
application of trifluorothymidine (TFT), a nucleoside analog that
is currently licensed as an ophthalmic solution for the treatment
of patients with herpes keratitis, has resulted in complete healing
in several patients with acyclovir-resistant HSV infection(58,59). 
Also, a single report demonstrated in vitro synergism as well as
clinical response in three patients receiving the combination of
TFT and interferon-alpha(60).
     The nucleotide analog cidofovir [HPMPC ([(s)-1-(3-hydroxy-2-
phosphonylmethoxy)propyl]-cytosine)] is currently under study for
the treatment of resistant HSV infection.  It retains in vitro
activity against thymidine kinase-deficiency and DNA polymerase
mutants of acyclovir-resistant HSV, and it induced complete healing
when applied topically in two recently reported patients(61,62). 
A placebo-controlled randomized trial is currently in progress. 
Unfortunately, acyclovir-resistant HSV infection seems destined to
recur.  In one study(50), although the majority (70%) of same-site
recurrences following the successful healing of acyclovir-resistant
HSV lesions with foscarnet were susceptible rather than resistant
HSV lesions with foscarnet were susceptible rather than resistant
to acyclovir, all patients had an eventual recurrence of acyclovir-
resistant HSV infection at a median of 43 days after healing. 
Strategies for the prevention of recurrence, including chronic
suppressive foscarnet administration and chronic suppressive use
of acyclovir, have not yet been studied.

References

1.  Johnson RE, Lee F. Hadgu A, et al. US genital herpes trends
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          BETA News Briefs: Foscarnet Approved to Treat
               Acyclovir-Resistant Herpes Simplex
                      by Ronald Baker, PhD

[BETA (Bulletin of Experimental Treatments for AIDS) No. 26,
September 1995; published by San Francisco AIDS Foundation, BETA
Subscription Services, Infocom Group, 1250 45th Street, Suite 200,
Emeryville, CA 94608-2924.]

     FDA on July 6, 1995 gave marketing approval to foscarnet
(Foscavir) for the treatment of acyclovir-resistant herpes simplex
virus (HSV) in immunocompromised individuals, such as people with
AIDS. Foscavir is also FDA-approved for the treatment of CMV
retinitis (see above). "Immunocompromised patients with
HSV-resistant infections are often debilitated and suffer great
pain," according to Henry Balfour, MD, of the University of
Minnesota Health Sciences Center.
     "Foscarnet therapy [via injection] should be initiated within
7-10 days of clinical acyclovir failure and continued for at least
10 days or until the lesions are completely healed," said Balfour. 
     Patients who do not have adequate insurance coverage may call
1-800-488-3247 for reimbursement information. Foscavir is
distributed by Astra USA, Inc. of Westborough, Massachusetts, a
subsidiary of Astra AB of Sweden.

     DISTRIBUTED FOR GENA by AEGIS/San Juan Capistrano -
714.248.2836: Copyright (c) 1994 - Bulletin of Experimental
Treatments for AIDS (BETA), a quarterly publication of the San
Francisco AIDS Foundation (SFAF).  Reproduced with permission. 
Reproduction of this article (other than one copy for personal
reference) requires written consent from the SFAF.  For
subscription information contact the BETA Subscription Office at
1.800.959.1059 or 1.510.549.4300, or via the internet at
beta@sfsuvax1.sfsu.edu. 

     For more information about herpesviruses, see: Bowers M.
Herpesviruses. Bulletin of Experimental Treatments for AIDS (BETA).
December, 1995, pp. 33-37.


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