Case 2: Discussion

Acyclovir: Mechanism of Action

The drug acyclovir (Zovirax) does not have activity against viral pathogens until it is converted to the active
form acyclovir triphosphate. This process is initiated by the viral enzyme thymidine kinase; subsequently,
human cellular kinases perform the second and third phosphorylation steps to complete the process (Figure 1)
[1]. Acyclovir triphosphate, the active form of acyclovir, is present in 40- to 100-fold higher concentrations in
herpes simplex virus (HSV)-infected cells than in uninfected cells. Acyclovir triphosphate has a two-pronged
mechanism of action: (1) it competes with 2-deoxyguanosine triphosphate (dGTP) as a substrate for viral DNA
polymerase and (2) once it becomes incorporated into the replicating viral DNA, it acts as a chain terminator
because it does not have a terminal 3' hydroxyl group. In contrast, penciclovir, the active component of the
prodrug famciclovir (Famvir), does not act as a chain terminator because it has a terminal 3' hydroxyl group
that permits viral primer-template extension. Foscarnet (Foscavir) is a pyrophosphate analog that directly
inhibits viral DNA polymerase by reversibly blocking the pyrophosphate binding site of the viral polymerase (in
addition to inhibiting the cleavage of pyrophosphate from deoxynucleotide triphosphates).

Acyclovir: Mechanisms for Resistance

Acyclovir resistance can occur from one of four types of mechanisms: (1) absent production of viral thymidine
kinase (TK-negative mutants); (2) a partial decrease in the production of viral thymidine kinase (TK-partial
mutants); (3) altered viral thymidine kinase substrate specificity that results in phosphorylation of thymidine
but not acyclovir (TK-altered mutants); and (4) altered viral DNA polymerase (DNA polymerase mutants)
[3,4,5]. The herpes thymidine kinase is a 376-amino-acid protein encoded by the UL23 gene and the herpes
DNA polymerase is a larger protein (approximately 1,200-amino-acids long) and it is encoded by the
UL30 gene[6]. The DNA polymerase mutants result from a mutation in the HSV pol gene that causes a
decreased binding of acyclovir-triphosphate to viral DNA polymerase. Among the different types of resistance
mutations, the most common are the absent or decreased production of viral thymidine kinase (TK-negative
and TK-partial mutants) (Figure 2)[5,7]. Given that most assays can not easily differentiate low TK-partial
mutants from TK-negative mutants, some experts have referred to both of these mutants as TKdeficient mutants[5].

Background and Epidemiology

The first reported case of acyclovir-resistant HSV infection in a HIV-infected patient appeared in 1982[8].
Subsequent studies established that HIV-infected persons have a markedly higher incidence of acyclovirresistant HSV infection when compared with HIV-negative persons[9]. Most cases of acyclovir-resistant HSV
have involved HSV type 2[5,10]. Among HIV-infected individuals with acyclovir-resistant HSV infection, they
typically have advanced AIDS, a history of recurrent HSV infection, and significant prior treatment with
acyclovir, famciclovir, or valacyclovir (Valtrex)[9,11]. Rare reports have documented acyclovir-resistant HSV
infection in persons without prior treatment with acyclovir, famciclovir, or valacyclovir[5]. Person-to-person
transmission of acyclovir-resistant HSV has not been documented.

Clinical Manifestations
Although prior research in animal models suggested that thymidine kinase-negative HSV isolates have
decreased virulence[12], several reports have shown that acyclovir-resistant HSV can cause significant clinical
disease in humans[10,11,12,13]. Most HIV-infected persons who develop acyclovir-resistant HSV present with
gradually expanding, extensive, ulcerated lesions that fail to respond to conventional therapy[7,10,14]. These
lesions can develop anywhere on the body, but most often occur in the perianal (Figure 3) or oral area
(Figure 4). Less frequently, patients can develop raised, hypertrophic lesions (Figure 5). Mucocutaneous
dissemination rarely occurs[13]. One report described a patient with fatal acyclovir-resistant HSV
meningoencephalitis who developed acyclovir resistance during therapy of a persistent perirectal ulcer caused
by HSV[11].

Diagnosis
The first goal is to establish the diagnosis of HSV. If acyclovir resistance is suspected, testing for HSV should
include a viral culture of the sample, since resistance testing will require isolation of virus. Laboratory testing
for acyclovir resistance includes a variety of phenotypic assays, such as the plaque-reduction assay, dyeuptake assays, and viral DNA-inhibition assays[5]. Among these assays, the plaque reduction assay is the most
frequently used and resistance is characteristically defined as an IC50 greater than 2 ug/ml[5], with nonresistant isolates typically having an IC50 of approximately 0.1 ug/ml[3,12]. Within a single lesion,
heterogeneous virus populations may exist composed of susceptible and resistant strains.

Recommended Therapy
All of the drugs that require initial activation by HSV thymidine kinase (acyclovir, famciclovir, and valacyclovir)
generally produce ineffective results against HSV strains that have absent or decreased thymidine kinase
production. Drugs such as ganciclovir (Cytovene) and valganciclovir (Valcyte), that use a similar viral kinase
are also ineffective. Rarely, acyclovir-resistant HSV infections result from altered viral thymidine kinase and
these strains of HSV could theoretically respond to famciclovir. Because foscarnet does not require activation by
viral thymidine kinase, it retains activity against HSV strains with absent, partially reduced, or altered

production of thymidine kinase. Several clinical studies have shown foscarnet is the most effective drug in
treating acyclovir-resistant herpes simplex lesions and in these studies foscarnet was used at a dose at 40-60
mg/kg every 8 hours, with reduced dosage for renal insufficiency) for to 10 to 50 days[14,15,16]. The 2009
guidelines for the prevention and treatment of opportunistic infections recommend using foscarnet as first-line
therapy given at a dose of 80 to 120 mg/kg/day IV in 2 to 3 divided doses until a clinical response
has occurred[17]. The duration of therapy is usually at least 21 to 28 days (Figure 6).

Alternative Therapy

Cidofovir (Vistide), formerly HPMPC, is an antiviral compound that reaches the cell in a monophosphorylated
form whereby it is activated by cellular kinases. Because cidofovir does not require activation by a viral kinase,
it should theoretically have activity against acyclovir-resistant HSV infections. Several reports have suggested
that use of either topical cidofovir 0.3% or 1.0% gel applied once daily[18,19] or
intravenouscidofovir[20]were effective in the treatment of acyclovir-resistant HSV infections, but there are
insufficient data to make significant conclusions regarding the use of cidofovir for acyclovir-resistant HSV
infections. One AIDS Clinical Trial Group study reported fair responses to topical 1% ophthalmic trifluridine
solution (Viroptic) among patients with acyclovir-resistant HSV infections[21]. More recently, two reports have
described excellent clinical response with topical imiquimod (Aldara) 5% cream[22,23]. The 2009 opportunistic
infections guidelines note topical therapy with trifluridine, cidofovir, and imiquimod has been successful as
shown in case reports and these topical agents are listed as alternative therapies to foscarnet[17]. Topical
therapy may require prolonged application (at least 21 to 28 days)[17].

A new treatment for refractory herpes

Cidofovir gel heals herpes lesions that do not respond to acyclovir
For patients with herpes outbreaks that are unresponsive to oral acyclovir (Zovirax), the standard treatment
for this common viral infection, a new topical gel may offer relief. In a clinical trial of 30 people who had at
least one herpes lesion that failed to improve after 10 days of treatment with oral acyclovir, 30% of the study
participants who applied cidofovir gel to their lesions once daily showed complete healing of the lesions, and
another 20% had their lesions reduced to less than half the original size. By contrast, study participants who
used a placebo gel showed no clinical response at all. These results suggest that cidofovir gel may offer a
treatment option for patients whose herpes outbreaks cannot be controlled with acyclovir. The topical gel is
certainly an advance in terms of convenience, given that the current back-up treatment for unresponsive
herpes outbreaks, foscarnet, must be administered intravenously.
Advertisement

Lalezari J, Schacker T, Feinberg J, Gathe J, Lee S, Cheung T, Kramer F, Kessler H, Carey L, Drew WL, Boggs J,
McGuire B, Jaffe HS, Safrin S. A randomized, double-blind, placebo-controlled trial of cidofovir gel for the
treatment of acyclovir-unresponsive mucocutaneous herpes simplex virus infection in patients with
AIDS. Journal of Infectious Diseases1997; 176: 892-898.

More on how HIV enters cells

New discoveries may guide future research
In 1984, several scientists at the National Cancer Institute embarked on a project that many of their colleagues
considered a waste of time and resources. Their plan was to examine the DNA of individuals exposed to HIV, to
determine if there were genetic differences between individuals whose disease progressed slowly and those
known as rapid progressors. It took more than a decade for this "needle-in-a-haystack" research to bear fruit:
reports concerning cell-surface molecules that assist HIV in gaining entry into cells began to appear in the
literature in the mid-1990s (see "Genetic mutation appears to confer immunity to HIV," Vol. 2, No. 5, and "How
HIV penetrates CD4 cells," Vol. 2, No. 6).

It was well known that HIV used the CD4 receptor as a point of entry into cells, but other cites remained
unidentified until Dr. Stephen J. O'Brien and his colleagues at the Laboratory of Genomic Diversity at the
National Cancer Institute identified a protein receptor now called CKR5 or CCR5, found on T-lymphocytes, as a
target of HIV.
Investigators determined that mutant versions of the CCR5 protein existed, and they found that individuals
whose DNA codes for the mutant version of CCR5 make a protein that is "truncated," i.e. shorter than the
normal protein. This abbreviated version of CCR5 occurs in some, but by no means all, individuals who have
been exposed to HIV but have not been infected. The mutant version of the protein receptor is never found in
people who have been infected, however.
Some of the same researchers have amplified these original findings, and they will soon publish a paper
describing their results. This group analyzed a cohort of 3,003 patients with AIDS -- and this time they focused
their attention on another cell-surface protein, CCR2. Like CCR5, CCR2 ordinarily functions as a receptor for
chemokines, which are chemical signals that cells use to communicate. Unlike CCR5, CCR2 is not found with
increased frequency in individuals exposed to, but not infected by, HIV. However, people with the CCR2
mutation were found to have a slower course of disease progression.
In general, the presence of the altered CCR2 protein translated into a two-to-three-year postponement of the
median time to a diagnosis of AIDS. This finding was consistent among participants in several large studies,
including the Multicenter AIDS Cohort Study, the San Francisco City Cohort Study, and the Multicenter
Hemophilia Cohort Study. In all analyses, the mutant version of CCR2 was more prevalent in individuals whose
disease progressed slowly than it was in rapid progressors. The investigators estimate that 29% of long-term
survivors (those who do not progress to a diagnosis of AIDS for a decade or more after they are first infected)
owe their indolent disease course to the presence of these mutant surface proteins. These findings, according
to the authors, can be put to use in designing novel treatments to prevent cellular infection by HIV.
Smith MW, Dean M, Carrington M, Winkler C, Huttley GA, Lomb DA, et al. Contrasting genetic influence of
CCR2 and CCR5 variants on HIV-1 infection and disease progression. In press.

New formulation of saquinavir, Fortovase, has eight to nine times the bioavailability of
Invirase
Soft-gel capsules overcome principal therapeutic limitation of oldest protease inhibitor
When the first protease inhibitor, Hoffmann-La Roche's saquinavir, won F.D.A. approval in late 1995, it was
widely hailed as a major advance in the treatment of HIV infection. But clinicians soon discovered that the
drug's effectiveness was hampered by its low bioavailability: saquinavir had few side effects, even at high
doses, but it was hard to get enough of the drug into the bloodstream to suppress viral replication to
undetectable levels. As newer and better-absorbed protease inhibitors were approved
-- indinavir and ritonavir in 1996, nelfinavir in 1997 -- they supplanted saquinavir as first-line therapy.
Although saquinavir proved to be the least potent protease inhibitor when used alone or in combination with
nucleoside analogs, it works well in combination with ritonavir (see "Enhancing saquinavir levels with ritonavir,"
Vol. 3, No. 3). In patients who cannot tolerate the side effects of other, more powerful protease inhibitors -and in those who have failed their initial multidrug antiretroviral regimen -- the combination of saquinavir and
ritonavir offers an important therapeutic option. In this unique pairing ritonavir functions not only as an
antiretroviral agent but as a pharmacokinetic agent, one that increases the bioavailability of saquinavir by a
factor of 40.
The F.D.A. has now approved a new formulation of saquinavir -- a soft-gelatin capsule that has enhanced
phermacokinetic properties. The new formulation delivers 300% more saquinavir to metabolic sites than the
old formulation did, making this protease inhibitor a more appealing option for patients who are not doing well
on their current therapy.
Dr. Harold A. Kessler, author of "The Next Generation of Antiretroviral Agents -- An Update," in this issue,
and a member of the editorial advisory board of HIV Newsline, comments:
In a study presented at this year's ICAAC meeting, the soft-gel formulation of Roche Laboratories' protease
inhibitor was shown to reduce viral load to undetectable levels (400 copies/mL in this study) in 81% of patients

over 16 weeks of therapy when used in combination with ZDV and 3TC. During this same period the study
subjects' CD4 counts increased by 170 cells/mm 3.
These results were obtained in an open-label trial of 41 treatment-nave patients with viral loads greater than
10,000 copies/mL (mean: 63,408) and CD4 counts greater than 100 cells/mm 3 (mean: 412). Fortovase was
given at a dose of 1200 mg t.i.d. and the ZDV and 3TC were given at the currently recommended doses. The
soft-gel capsule formulation of saquinavir was generally well tolerated, with only two patients withdrawing from
the study due to adverse effects. The most common complaints were nausea, diarrhea, vomiting, and
headache.
Ongoing clinical trials are testing this new formulation of saquinavir in combination with nucleoside
analogs, NNRTIs, and other protease inhibitors. A number of studies have already established that the addition
of ritonavir to a saquinavir-containing regimen increases serum levels of the latter drug -- a synergistic effect
that translates into increased efficacy. It is reasonable to assume that regimens that combine ritonavir and the
soft-gel capsule formulation of saquinavir will provide even higher serum concentrations of active drug, leading
to even greater antiretroviral activity. Patients now taking ritonavir and Invirase can be safely switched to
ritonavir and Fortovase at the same dose, 400 mg b.i.d.

First test for HIV resistance to nucleoside analogs is available

Genotypic assay can help clinicians determine treatment-induced resistance to nucleoside analogs
With so many therapeutic options now available to physicians and patients alike, the all-important question is:
Which particular combination of antiretroviral drugs will work best for a particular patient? Individuals who are
just beginning antiretroviral therapy can be expected to respond well to any of a number of multidrug
regimens. People who have tried many drug combinations over the years have fewer options -- because they
have, almost certainly, developed resistance to one or more of the drugs they were assigned.
The longer a patient has been on therapy -- and the more drugs that individual has tried and abandoned -- the
more important it is to know the patient's "resistance profile." Because no one drug has proven effective at
suppressing HIV for long, it is crucial to employ a combination of drugs that suppresses viral replication as
completely as possible for as long as possible with as few side effects as possible.
A test is now available that can help determine how resistant a viral isolate is to any of the nucleoside analogs.
Developed by Murex Technologies, the so-called LiPA HIV-1 RT genotypic resistance assay identifies nucleoside
analog-induced mutations in HIV DNA. These mutations indicate whether a patient's viral isolate has developed
resistance to AZT, ddI, ddC, or 3TC. Genotypic resistance to d4Tis not readily identified.
Dr. James O. Kahn, co-author of "The Problem of Protease Resistance," Vol. 3, No. 3, and a member of
the editorial advisory board of AIDS Care, comments:
Some researchers have cautioned clinicians against attaching too much significance to the information gained
from genotypic testing, because these assays read only a small portion of the DNA of HIV. Phenotypic assays,
which are still being developed, provide information regarding future treatment options for the viral isolate that
is assayed -- but these highly sophisticated tests are difficult to perform, expensive, and labor-intensive. Until
a less costly and more widely available phenotypic assay is developed, practitioners are limited to the
information that genotypic testing provides. This information may only be as good as an accurate history of a
patient's prior antiretroviral therapy.
The genotypic assay's main utility is in identifying drugs that will not be effective against the viral strains in a
particular person. Often, this information can also be obtained from a thorough history of prior anti-HIV
medication combined with knowledge, derived from viral-load monitoring and on-going clinical care, about a
patient's response to that treatment. A three-fold increase in viral load is generally accepted as an indicator
that antiretroviral therapy is failing.
Genotypic testing does have significant limitations. The treatment information suggested by the genetic
mutations that the assay reveals is not conclusive, and the LiPA HIV-1 RT test only identifies possible
resistance to nucleoside analogs, but not possible future treatment options. Until phenotypic testing can be
made faster and easier, and until tests are developed to identify mutations that indicate resistance to the

various protease inhibitors and NNRTIs, the information provided by first-generation genotypic assays will be of
limited value to clinicians and patients making decisions about changes in antiretroviral therapy.

HIV found in lymph tissue of patients with "undetectable" viral levels

A blow to hopes that HIV can be eradicated in some patients
Data presented at last October's ICAAC meeting in Toronto seem to seriously challenge hopes that HIV can be
eradicated through very early, very aggressive multidrug therapy. Dr. Robert Siliciano and his colleagues at
John Hopkins University examined the prevalence of, and decay dynamics in, resting CD4 cells that harbor HIV
DNA. Early estimates of the length of time needed to achieve eradication with a highly suppressive
antiretroviral regimen ranged from two to three years (see "Highlights of the 4th Conference on Retroviruses,"
Vol. 3, No. 1, pages 19-20). More recently this estimate has been increased to between 6 and 10 years, with
some investigators flatly declaring that eradication would never be possible.
What Siliciano found is that a tiny pool of latently infected lymphocytes -- less than 0.01% of resting CD4 cells
with a "memory" phenotype -- persist after as much as 30 months of HAART. While the majority of resting CD4
cells contain integrated HIV DNA that is defective and therefore harmless, a small but significant percentage of
these cells can be stimulated to produce infectious virus under certain laboratory conditions.
The Johns Hopkins team examined 22 patients who had been treated with protease inhibitor-containing HAART
regimens for 30 months or longer and who had maintained plasma HIV RNA levels below 200 copies/mL, the
lower limit of detection of most commercially available assays. The resting lymphocytes in these patients were
isolated and purified. Specimens from four patients proved inadequate for viral isolation, but the remaining 18
produced infectious virus when stimulated with radiation and phytohemaglutanin. "It is clear that replication of
competent virus can persist in these cells," Siliciano concludes, "and while we do not know the precise decay
characteristics of these cells, we do know that their half-life exceeds nine months."
Siliciano R. Latent reservoir of HIV. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy,
Toronto, Canada, 1997. Abstract S-36.
Dr. David Hardy, a member of the editorial advisory board of HIV Newsline, comments:
These findings serve as a sobering reminder of the highly invasive and insidious nature of HIV infection, and
they may cast cold water on the theory, advanced by Dr. David Ho and others, that it might be possible to
eliminate HIV entirely in at least some infected individuals, if their infection could be caught early enough and
treated aggressively enough. What makes Dr. Siliciano's data particularly dismaying is that he found no
correlation between the length of time his subjects were on HAART therapy and the number of infectious cells
they harbored -- suggesting that viral clearance and eventual eradication may not be functions of the length of
time a patient is on therapy.

Gammaglobulin prevents infections in patients with low CD4 counts

Monthly infusions reduce morbidity in advanced HIV disease
A team of researchers from New York's Cabrini Medical Center has conducted a small study which strongly
suggests that prophylactic treatment with intravenous gammaglobulin can significantly reduce the number of
infections experienced by people with CD4 counts below 100 cells/mm 3. The 18 people involved in this study
received infusions of gammaglobulin (40 mg/kg of body weight) once a month for 18 months. Over the course
of the study, 43 infections developed in the group receiving the gammaglobulin. During this same period 178
infections were noted in a control group of patients with similar clinical profiles who did not receive
gammaglobulin.
These results led the researchers to conclude that prophylactic treatment with intravenous gammaglobulin may
reduce mortality and improve quality of life for people with advanced HIV disease. Due to the relative
inexpensiveness of gammaglobulin treatment, this form of prophylaxis is also likely to reduce healthcare costs.

Fontana L, Castro C, Mullen M. Intravenous gammaglobulin in the prevention of infections in severely

immunocompromised AIDS patients. 1997 International Scientific Assembly of the American College of Chest
Physicians, New Orleans, 1997. Abstract 14S.

The immune system vs. HIV

Tipping the balance in favor of viral control
A group of researchers affiliated with Harvard Medical School has demonstrated that the immune system is
capable of mounting a vigorous and effective attack against HIV under certain circumstances -- and individuals
who manifest this response appear to be capable of keeping HIV at bay for long periods of time. So-called
long-term non-progressors, some of whom have virtually intact immune systems more than a decade after
they were infected with HIV, may benefit from the development of a type of T cell called a "cytotoxic T
lymphocyte," or CTL, that specifically attacks HIV. CTLs mount this attack by punching holes in the protective
membranes of HIV-infected cells, killing the cells and the virus within them.
According to Rosenberg and his colleagues, these HIV-specific CTLs persist in the body even after highly-active
antiretroviral therapy has reduced serum HIV RNA concentrations below the level of detection of the
commercially available assays. The persistence of surveillance CTLs is what is referred to as a "memory"
response.
The most important target of the CTLs, the Harvard researchers note, is p24 antigen, a protein in the core of
HIV. Indeed, there is an inverse correlation between viral load and the strength of the CTL response against
p24. On the other hand, the investigators found only a weak association between the strength of the CTL
response and the level of CD4 cells -- a finding that may help to explain why CD4 cells are not an especially
good surrogate marker for viral load.
This important piece of research has any number of tantalizing clinical implications. The investigators studied
three individuals who were identified and treated during the acute phase of HIV infection, a time when viral
proliferation is occurring at extraordinarily high levels. All three received HAART before they had developed
antibodies to the virus -- and because viral replication was largely suppressed during this period, all three
developed strong anti-HIV CTL responses.
The authors contrast these findings with data from patients who began HAART well after the period of acute
infection and who failed to develop anti-HIV CTL. The implication is that post-exposure HAART therapy, even if
it fails to eradicate the virus completely, may result in a more indolent form of HIV infection. In short, HAART
may tip the balance a bit more in favor of the immune system.
Although preliminary, these intriguing findings do strongly support the "hit early, hit hard" philosophy of
antiretroviral therapy. It may well be impossible to eradicate HIV in infected individuals (see the preceding item
in this Newsline section, "HIV found in lymph tissue of patients with 'undetectable' viral levels"). But that does
not mean that early, aggressive antiretroviral therapy cannot alter the course of HIV disease in some patients.
Larger clinical studies are clearly warranted, to investigate whether the immune response to HIV can be
significantly enhanced by HAART during the brief window of opportunity that follows acute exposure to the
virus.
Rosenberg SR, Billingsley JS, Caliendo AM, Boswell SL, Sax PE, Kalams SA, Walker BD. Vigorous HIV-1 specific
CD4+ cell responses associated with control of viremia. Science 1997; 218: 1447-50.

Drug-Drug Interactions: An Update

Use caution when mixing protease inhibitors and anticonvulsants
The addition of protease inhibitors to combination therapy has revolutionized the fight against HIV. It
has also complicated the care of people with HIV. The increased use of combination antiretroviral

therapy has led, predictably enough, to an increase in the number of adverse drug-drug interactions
seen in people taking these multidrug regimens. Sometimes these adverse interactions occur when
antiretrovirals are taken in combination. (We know, for example, that the NNRTI nevirapine reduces
serum concentrations of some protease inhibitors.) More often these adverse interactions occur when
antiretrovirals are taken in combination with agents used to combat AIDS-related opportunistic
infections -- such as the drugs used to fighttuberculosis (see "Guidelines for the Administration of
Protease Inhibitors and Rifampin in HIV-Positive Patients with Tuberculosis," Vol. 3, No. 5).
Last February we alerted readers to the dangers of taking a protease inhibitor in combination with
rifampin or rifabutin (see "Drug-interaction warnings," in AIDS Care,Vol. 1, No. 1, page 6). Because
all of these drugs are metabolized at the same location in the liver, both rifampin of rifabutin increase
the speed at which protease inhibitors are processed by the liver -- causing the amount of protease
inhibitor in the bloodstream to drop below effective levels, thereby promoting the development of
drug-resistant viral strains.
More recently, warnings have been issued about possible interactions between the protease inhibitors
and the three most popular anticonvulsant drugs: carbamazepine, phenobarbital, and phenytoin. In
theory, anyway, using any of these anticonvulsants with a protease inhibitor may reduce the amount
of the protease inhibitor circulating in the body, and this may allow suppressed HIV to rebound.
Conversely, the use of protease inhibitors -- particularly ritonavir and nelfinavir -- may cause serum
levels of the anticonvulsants, particularly carbamazepine, to rise to toxic levels.
Practitioners who treat people with HIV should therefore confer with a neurologist before prescribing
an anticonvulsant to one of their patients. It may be preferable to use either of two other
anticonvulsants, gabapentin and lamotrigine, since they are not metabolized at the same place in the
liver -- but neither is approved by the F.D.A. for single-agent use as an anticonvulsant. Of the
protease inhibitors, indinavir is predicted to have the most minimal interaction with any of the
anticonvulsants.
Brooks J, Daily J, Schwamm L. Protease inhibitors and anticonvulsants. AIDS Clinical Care 1997; 9:
87.

Delavirdine and fluconazole can be taken together without adjusting

doses
Concerns about potential drug-drug interactions have made some practitioners wary about
prescribing delavirdine, one of the two F.D.A.-approved non-nucleoside reverse-transcriptase
inhibitors, in combination with fluconazole, an antifungal agent used to combat many common
opportunistic infections, chiefly oral candidiasis. However, a study recently published in Antimicrobial
Agents and Chemotherapy has shown that the two drugs can be taken together, and that no
adjustment is necessary to the dosage of either drug.
Borin MT, Cox SR, Herman BD, Carel BJ, Anderson RD, Freimuth WW. Pharmacokinetics of
delavirdine in human immunodeficiency virus-positive patients.Antimicrob Agents and
Chemother 1997; 41: 1892-7.