CASE 77-3, QUESTION 6: P.Z. completes 21 days of foscarnet induction therapy. How can his CMV
retinitis be suppressed in the future?
The currently available antiviral agents used to treat CMV disease are not
curative. After induction therapy, chronic maintenance therapy is indicated for the
remainder of P.Z.’s life, unless immune reconstitution occurs as a result of HAART.
Effective suppressive regimens include parenteral or oral ganciclovir, parenteral
foscarnet, combined parenteral ganciclovir and foscarnet, and parenteral cidofovir.
The ganciclovir implant was also effective but is no longer manufactured (Table 77-
4). Oral valganciclovir is approved for both acute induction and maintenance
therapy, but the published clinical data are limited. In uncontrolled case series,
repeated intravitreal injections of ganciclovir, foscarnet, and cidofovir have been
shown to be effective for prophylaxis of CMV retinitis. However, because this
locally and does not protect the contralateral eye or other organ systems, it is
usually combined with oral valganciclovir.
Guidelines suggest that discontinuation of prophylaxis may be considered in
patients with CMV retinitis who are taking HAART with a sustained (>6 months)
increase in the CD4 count to greater than 100 to 150 and have remained disease-free
for more than 30 weeks. The decision to discontinue suppression should be based on
the magnitude and duration of the CD4 increase and viral load suppression, the
anatomic location of the retinal lesions, and the degree of vision loss.
who have had anti-CMV maintenance therapy discontinued should continue to
undergo regular ophthalmologic monitoring for early detection of CMV relapse as
well as for immune reconstitution uveitis.
Relapse or Refractory Cytomegalovirus Retinitis
CASE 77-3, QUESTION 7: After 5 months of maintenance therapy with foscarnet, a routine funduscopic
Most patients with CMV not receiving HAART while undergoing maintenance
12 For the first relapse, repeat induction therapy
followed by maintenance therapy with the same drug is beneficial in most patients.
Because P.Z. has tolerated foscarnet therapy thus far, he should receive another
course of induction therapy. After reinduction, P.Z. should receive a higher
maintenance dosage (120 mg/kg/day).
It is important to distinguish between relapse and refractory disease. Relapse, as
in the case of P.Z., is defined as the recurrence of clinically apparent viral activity
and is usually caused by a decline in immune function, insufficient delivery of drug
into the eye, or resistant CMV strains. Relapse can effectively be managed by repeat
induction therapy of the same drug. If the relapse is caused by a resistant virus, the
patient may benefit from a change in therapy. Ganciclovir-resistant CMV strains
occur by two mechanisms. DNA polymerase mutation at the UL54 gene is observed
in approximately 20% of ganciclovir-resistant strains. This mutation usually confers
resistance to cidofovir and, to a lesser extent, foscarnet.
CMV strains have UL97 mutations. UL97 mutations are incapable of
monophosphorylating ganciclovir. Cidofovir and foscarnet are appropriate
alternatives to treat strains with UL97 mutations. Patients who receive extensive
ganciclovir treatment (>6–9 months) may present with highly ganciclovir-resistant
strains containing UL54 and UL97 mutations.
83 Cidofovir may be considered in most
role in the clinical failure of these regimens is not known. Because of the different
mechanisms of action of ganciclovir and foscarnet, strains resistant to one drug may
retain sensitivity to the other.
84 Resistant or relapsing CMV retinitis may be treated
by the administration of local ocular therapy via intravitreal injection of ganciclovir
or foscarnet (see Local Treatment section).
Refractory CMV retinitis is defined by disease progression because of ineffective
therapy. This phenomenon is observed in two clinical situations: when the disease
persists with minimal or no response during induction therapy and when long-term
control is inadequate with maintenance therapy. Refractory CMV disease has been
defined in clinical trials as two relapses occurring within 10 weeks despite repeat
induction and maintenance therapy. Treatment options for refractory CMV retinitis
include reinduction with ganciclovir at higher dosages (7.5 mg/kg/dose every 12
hours, followed by maintenance doses of 10 mg/kg/day) or reinduction using
combination therapy (IV ganciclovir plus foscarnet).
27 Refractory CMV retinitis can
be treated with local ocular therapy via intravitreal injection of ganciclovir or
CASE 77-3, QUESTION 8: What is the role of intravitreal injections in CMV retinitis?
Intravitreal administration of ganciclovir or foscarnet through a small-gauge needle is
a method of selectively delivering the drug to the site of infection. Ganciclovir and
foscarnet doses of 0.2 to 2 mg and 1.2 to 2 mg, respectively, are administered 2 or 3
times per week for active disease, followed by weekly maintenance injections.
Potential complications of intravitreal injections include bacterial endophthalmitis,
vitreous hemorrhage, and retinal detachment. Intravitreal therapy is relatively
uncommon because intraocular implants are available. Importantly, in contrast to
systemic therapy, local instillation of a drug is associated with a higher risk of CMV
disease developing in the contralateral eye as well as extraocular sites (Table 77-3).
Intraocular Ganciclovir Implants
CASE 77-3, QUESTION 9: Is P.Z. a candidate for ganciclovir intraocular implants?
The ganciclovir implant (no longer manufactured) was a surgically implanted
reservoir of ganciclovir very effective in less severe vision loss, but ocular
complications including cataract, vitreous hemorrhage, and retinal detachment were
P.Z. should be reinduced with foscarnet therapy and maintained on a higher
foscarnet dose. Neither alternating regimens nor intravitreal administration of
antiviral agents is appropriate at present.
CASE 77-3, QUESTION 10: What is the role of valganciclovir for initial CMV prevention?
Valganciclovir has replaced oral ganciclovir, which is no longer marketed. This
agent yields an area under the curve approximately equivalent to that associated with
the IV administration of ganciclovir. The maintenance dosage is two 450-mg tablets
Data from clinical trials conducted with oral ganciclovir have been extrapolated to
valganciclovir, and all references in the OI treatment guidelines to oral ganciclovir
have been substituted with valganciclovir. The role of oral ganciclovir for primary
prophylaxis of CMV retinitis has been evaluated in two studies.
decreased the 1-year incidence of disease by approximately 50% in one study
86 These two studies had important differences in study
design that likely explains the disparate results. One cost-effectiveness study
estimated that oral ganciclovir prophylaxis would cost more than $1.7 million per
year of anticipated life expectancy.
88 Valganciclovir has not demonstrated a survival
advantage in patients with CD4 count less than 50 using it for CMV primary
12 These issues, in addition to adverse effects such as neutropenia and
anemia, the lack of proven survival benefit in HIV-infected patients, and the risk for
inducing CMV resistance, are concerns that should be addressed when deciding
whether to institute prophylaxis in
individual patients. Prophylaxis with valganciclovir is not recommended as the
standard of care (Table 77-2).
Clinical Presentation and Prognosis
QUESTION 1: A.S., aged 28, is infected with HIV. She weighs 48 kg. Her boyfriend was an IV drug user
who died of AIDS 2 years ago. She presents with a fever (103°F) and a 2-week history of “splitting
headaches.” Laboratory test results include the following:
A.S. is highly nonadherent and has not been to the clinic in more than a year, at which time she was
Lumbar puncture reveals the following CSF findings:
Cryptococcal antigen titer, 1:2,048 IU
Intracranial pressure (ICP), 24 cm H2O (normal, 8–22 cm H2O)
In the pre-HAART era, cryptococcosis developed in approximately 6% to 10% of
AIDS patients in the United States, with meningitis being the most common clinical
In the era of HAART and azole prophylaxis, a significant decline in
the incidence of cryptococcosis has been observed.
89 Based on a 2010 cohort study,
cryptococcosis is the second most common CNS infection associated with AIDS.
The initial portal of entry is the lungs, where the organism is normally contained by
an intact immune system. Cryptococcal disease typically develops in patients with
profound defects in cell-mediated immunity (i.e., CD4 counts, <50). Unlike bacterial
meningitis, cryptococcal CNS infection has a much more insidious onset; the most
common symptoms are fever and headache. Less frequent signs and symptoms
include nausea and vomiting, meningismus, photophobia, and altered mental status.
Focal neurologic deficits and seizures are observed in less than 10% of patients.
CSF glucose is decreased, whereas CSF proteins are usually elevated. CSF
cryptococcal antigen titer and CSF culture are frequently positive. These findings,
along with the clinical presentation, form the basis for the diagnosis. The overall
outcome is poor, with a mean survival of 5 months in patients not receiving HAART.
Relapse within 6 months occurs in 50% of patients who do not receive suppressive
therapy. Altered mental status at baseline, CSF WBC count of less than 20 cells/μL,
high CSF cryptococcal antigen titer (>1:1,000), and an elevated initial CSF opening
pressure of greater than 20 cm H2O have all been associated with a poor prognosis.
A.S.’s CD4 count is 92. She has a temperature of 103°F and has experienced
“splitting headaches” for about a week. Her clinical presentation is typical of an
AIDS patient with cryptococcal meningitis. The CSF WBC count of 10 cells/μL, high
cryptococcal antigen titer, and ICP greater than 20 cm H2O suggest a poor
If left untreated, cryptococcal meningitis is fatal.
CASE 77-4, QUESTION 2: How should A.S.’s acute cryptococcal meningitis be managed?
The current treatment recommended for cryptococcal meningitis is amphotericin B,
0.7 mg/kg/day IV, plus flucytosine (100 mg/kg/day) given PO in four divided doses
as induction therapy for 14 days. Once the patient is stable (e.g., afebrile, with the
resolution of symptoms), then consolidation therapy with oral fluconazole 400
mg/day for 8 weeks or until CSF cultures are sterile can be initiated. After
consolidation therapy, daily suppressive therapy with fluconazole 200 mg should be
continued indefinitely unless immune reconstitution occurs with HAART.
90 Lipidbased formulations of amphotericin B (specifically liposomal amphotericin, dosed as
4–6 mg/kg/day) are also effective.
Although the aforementioned regimen is highly effective, the ability to rapidly
reduce A.S.’s ICP will also significantly improve her clinical course. Removal of 10
to 20 mL of spinal fluid by repeat lumbar puncture is recommended for patients with
an ICP greater than 20 cm H2O (A.S.’s ICP is 24 cm H2O). An additional
intervention to consider reducing A.S.’s elevated ICP is the insertion of an
CASE 77-4, QUESTION 3: What is the evidence for adding flucytosine to amphotericin B in the acute
treatment of A.S.? What are the disadvantages of this combination?
Amphotericin B binds to sterols in the fungal cell membrane, resulting in leakage
of cytoplasmic contents. Flucytosine is an antimetabolite type of antifungal drug that
is activated by deamination within the fungal cells to 5-fluorouracil. It inhibits fungal
protein synthesis by replacing uracil with 5-flurouracil in fungal RNA, and it also
inhibits thymidylate synthase via 5-fluorodeoxy-uridine monophosphate, interfering
with fungal DNA synthesis. Flucytosine, a purine analog, is approximately 10%
converted to 5-fluorouracil, an antimetabolite, which is the mechanism for its
potential bone marrow toxicity.
A classic prospective study conducted in HIV-negative patients favored the use of
93 The protocol randomly assigned patients to receive either
amphotericin B monotherapy (0.4 mg/kg/day IV for 6 weeks followed by 0.8
mg/kg/day IV every other day for 4 weeks) or amphotericin B plus flucytosine (150
mg/kg/day PO divided every 6 hours) for 6 weeks. Fewer failures or relapses, more
rapid CSF sterilization, and less nephrotoxicity occurred in the combination group,
although overall mortality was not different. However, approximately one-fourth of
the patients in the combination arm developed leukopenia, thrombocytopenia, or
If flucytosine is chosen as adjunctive therapy, renal function and CBCs should be
monitored closely for these adverse effects. A.S. is at an increased risk of
granulocytopenia because of her HIV infection and her concomitant myelotoxic AZT
The comparative trial forming the basis for the current recommendations for the
treatment of acute cryptococcal meningitis in HIV-positive patients evaluated a
higher dose of IV amphotericin B (0.7 mg/kg/day) with or without flucytosine given
at a lower dose (25 mg/kg/dose PO every 6 hours) for 2 weeks.
evaluated 381 patients with an acute first episode of cryptococcal
meningitis. The second part of this trial randomly reassigned stable or improved
patients to either a fluconazole or an itraconazole treatment arm for an additional 8
weeks as consolidation therapy. Sixty percent and 51% of patients receiving
amphotericin B plus flucytosine, and amphotericin B alone, respectively, had sterile
CSF cultures at 2 weeks of therapy. No significant differences were noted between
groups in the percentage of patients who were culture-negative at 2 weeks.
Importantly, the addition of flucytosine to amphotericin B was not associated with a
significant increase in drug toxicities at 2 weeks. Fluconazole and itraconazole were
similar in efficacy. However, multivariate analysis revealed two factors that were
independently associated with a higher rate of CSF sterilization: the addition of
flucytosine and the randomization to fluconazole. A more recent trial randomized 299
patients to amphotericin B (1 mg/kg/day) for 4 weeks, amphotericin B (1 mg/kg/day)
plus flucytosine (100 mg/kg/day divided) for 2 weeks, or amphotericin B (1
mg/kg/day) plus fluconazole (400 mg bid) for 2 weeks. Patients receiving
amphotericin B and flucytosine had lower mortality rates and significantly increased
rates of yeast clearance from CSF. Rates of adverse events were similar between
groups with the exception of more frequent neutropenia in patients receiving a
combination therapy. The addition of fluconazole provided no survival benefit.
CASE 77-4, QUESTION 4: Could A.S. be treated with fluconazole instead of amphotericin B for acute
ergosterol, the fungal cell membrane becomes defective and loses its selective
permeability properties. Unlike itraconazole, fluconazole is well absorbed PO even
in the presence of an elevated gastric pH. Fluconazole has excellent CNS penetration
and a good safety profile, but it is likely a secondary choice in the initial treatment of
cryptococcal meningitis. In a prospective, randomized, multicenter trial, the National
Institute of Allergy and Infectious Diseases Mycoses Study Group and the AIDS
Clinical Trial Group compared amphotericin B with 200 mg/day of oral fluconazole
(after a 400-mg loading dose) for 10 weeks in 194 patients.
amphotericin B (mean dose, 0.4–0.5 mg/kg/day) and the possible addition of
flucytosine were left to the discretion of the individual investigators. Although the
overall mortality was similar (14% for amphotericin B vs. 18% for fluconazole),
more fluconazole-treated patients died during the first 2 weeks of treatment (15% vs.
8%; p = 0.25). Furthermore, the median time to the first negative CSF culture in the
successfully treated patients was shorter in the amphotericin B group compared with
fluconazole (16 vs. 30 days). In a small, prospective, randomized trial of 20 male
patients with AIDS, oral fluconazole (400 mg/day) for 10 weeks was compared with
IV amphotericin B (0.7 mg/kg/day for 1 week, followed by the same dose 3 times
weekly for 9 weeks) combined with flucytosine (150 mg/kg/day).
deaths in the fluconazole group and none in the amphotericin B group (p = 0.27).
Eight of the 14 patients in the fluconazole group failed to respond to treatment,
whereas none in the amphotericin B group failed to respond. The mean duration of
positive CSF cultures was 41 days in the fluconazole group and 16 days in the
amphotericin B group (p = 0.02). These results, taken together, have led most
clinicians to choose amphotericin, with or without flucytosine, as initial treatment for
severe cryptococcal meningitis. Although increased doses of fluconazole have been
proposed, it is unknown whether these will result in improved outcomes. High doses
of fluconazole are being investigated further for patients in the developing world
where the use of IV amphotericin may not always be feasible. Considering the
severity of her meningitis, A.S. should be treated acutely with amphotericin and not
CASE 77-4, QUESTION 5: How long should treatment continue for A.S.’s cryptococcal meningitis?
Once A.S. completes 2 weeks of acute induction therapy with amphotericin B and
flucytosine, she should be switched, if stable, to oral fluconazole 400 mg/day for
consolidation therapy. Consolidation should be continued for an additional 8 to 10
weeks, followed by lifelong suppressive therapy with fluconazole 200 mg/day
CASE 77-4, QUESTION 6: Should A.S. receive maintenance therapy after successful treatment?
After induction and consolidation treatment of cryptococcal meningitis, A.S. and
all AIDS patients should receive maintenance therapy indefinitely, unless immune
reconstitution occurs as a result of HAART.
90 A higher relapse rate and a shorter
life expectancy have been observed in patients who did not receive chronic
97 Fluconazole (200 mg once daily) has emerged as the
suppressive treatment of choice. In a randomized, placebo-controlled trial of 61
AIDS patients, four recurrent cases of meningitis developed in the placebo group and
none in the fluconazole group.
98 A multicenter, comparative trial randomized patients
to receive either weekly amphotericin B 1 mg/kg/day IV or 200 mg/day of
99 Of 189 patients enrolled, 18% of the patients in the amphotericin B
group relapsed, compared with 2% in the fluconazole group. Serious toxicities were
more frequent in the amphotericin B group.
90 The newer triazole antifungals,
posaconazole and voriconazole, have limited experience as primary or maintenance
therapy for patients with cryptococcosis and are associated with many drug
interactions with antiretroviral therapy.
According to the OI guidelines,
12 adult and adolescent patients are at a low risk for
recurrence of cryptococcosis when they have completed a course of initial therapy,
remain asymptomatic, and have a sustained increase (e.g., >6 months) in their CD4
counts to at least 200 after HAART. Thus, discontinuing chronic maintenance therapy
among such patients is reasonable. Recurrences may occur, and some specialists
CD4 count decreases to less than 200.
CASE 77-4, QUESTION 7: What is the role of primary prophylaxis in cryptococcal meningitis?
Primary prophylaxis against cryptococcal disease in HIV-infected patients has
been studied in a few clinical trials.
In an open-label study, fluconazole (100
mg/day) was administered to all patients (329 HIV-infected patients) with CD4
counts less than 68. These results were compared with 337 historical controls from
100 Sixteen cases of cryptococcal meningitis occurred in the
historical controls (4.8%) compared with only one case in the fluconazole group
(0.3%). In a prospective, randomized AIDS Clinical Trial Group study, fluconazole
200 mg/day was compared with clotrimazole troches (10 mg 5 times a day) for
the prevention of fungal infections in 428 patients with advanced HIV disease.
After a median follow-up of 35 months, 32 cases of invasive fungal infection were
confirmed. Of these, the majority (17 of 32) were cryptococcosis: 2 cases in the
fluconazole group and 15 cases in the clotrimazole group. The greatest benefit
derived from fluconazole was observed in patients with CD4 counts of less than
101 However, no effect on survival was noted. A randomized, double-blind,
placebo-controlled trial of fluconazole 200 mg 3 times weekly versus placebo in
Ugandan adults with CD4 counts less than 200 found fluconazole prophylaxis to be
effective prophylaxis against cryptococcal disease, with 18 patients in the placebo
group developing cryptococcal disease versus one patient in the fluconazole group.
There was no difference in all-cause mortality between the groups.
Fluconazole resistance has been reported in HIV-infected patients receiving a
In addition to the potential for resistance, other concerns include
the lack of survival benefits associated with prophylaxis, the possibility of drug
interactions, and cost. In light of these concerns, the guidelines currently do not
recommend primary prophylaxis for this disease (Table 77-1).
High-dose fluconazole alone (800–2,000 mg/day for up to 6 months) has been
compared with high-dose fluconazole and flucytosine (100–150 mg/kg/day for 4
weeks) in multiple clinical trials.
103–105 These studies have shown that the
combination of fluconazole and flucytosine is superior to fluconazole alone in terms
of both survival and CSF culture clearance. The combination of fluconazole and
Additionally, higher doses of fluconazole in these settings (1,800–2,000 mg/day) may
be the best option for patients owing to the limitations of obtaining and administering
count was 120 cells/μL, and his viral load was 5,200 copies/mL.
TB is the second leading cause of mortality caused by infection worldwide—
second only to HIV—with 9 million infections in 2013 and 1.5 million deaths.
Low- to middle-income countries account for 95% of deaths from M. tuberculosis.
Of the cases in 2013, 480,000 patients developed multidrug-resistant TB. In the
United States, 9,582 cases of TB occurred in 2013, which was a 3.6% decline in the
number of cases when compared with 2012.
107 The recognized link between HIV and
TB, along with an increase in clinical and public health resources, has subsequently
resulted in a decline in the incidence of TB in the United States.
C.J. presents with fever, cough, night sweats, and a right middle lobe infiltrate
with hilar adenopathy, consistent with TB. Furthermore, his HIV status in
combination with his incarceration increases the probability of M. tuberculosis
infection, including multidrug-resistant isolates. C.J. will be started with the standard
four-drug regimen: isoniazid, rifampin (or rifabutin), pyrazinamide, and ethambutol.
(See Chapter 68, Tuberculosis, for a more comprehensive approach to TB treatment,
lack of cavitary lesions in C.J. still consistent with M. tuberculosis infection?
HIV-infected patients with CD4 counts less than 200 commonly present with
extrapulmonary TB, along with or in the absence of pulmonary disease. These
extrapulmonary sites include lymph nodes, bone marrow, spleen, liver, CSF, and
12 The chest radiograph in HIV-infected patients may reveal hilar or
mediastinal adenopathy or localized infiltrates in the middle or lower lung fields.
In HIV-infected patients, it is unusual to see typical apical infiltrates or
cavitations. Furthermore, concomitant PCP may confuse the interpretation of chest
radiographs. Finally, anergy (a state of immune unresponsiveness) is common in HIV
disease. Thus, definitive diagnosis of TB rests on positive cultures from sputum or
other tissue and body fluid specimens.
12 Unlike many other AIDS-related
opportunistic infections, CD4 count is not a reliable predictor of an increased risk
for TB diseases, and patients can have relatively high CD4 counts at the time of TB
HIV-INFECTED PERSONS: DRUG-SUSCEPTIBLE TUBERCULOSIS
to the clinic in 48 hours. His PPD has been negative in the past, and he has demonstrated delayed
treated for latent TB considering his known exposure to TB?
Current guidelines recommend 9 months of isoniazid prophylaxis (300 mg/day PO)
plus pyridoxine (50 mg/day PO) for all HIV-infected persons who have at least a 5-
mm induration reaction to PPD and no evidence of active TB (negative chest
radiograph and no clinical symptoms), unless otherwise contraindicated and
regardless of Bacillus Calmette–Guerin vaccination status.
Bacillus Calmette–Guerin vaccine to HIV-infected persons is contraindicated
because of the potential to cause disseminated disease.
reaction in HIV-infected persons is considered positive.
failures have been reported, although this finding has not been systematically studied.
Additional preferred regimens in instances of questionable compliance include
isoniazid 900 mg twice weekly plus pyridoxine 50 mg twice weekly for 9 months,
both administered under direct observed therapy. Persons who cannot take isoniazid
or who have been exposed to a known isoniazid-resistant strain should use either
rifampin or rifabutin alone for 4 months as alternatives, being mindful of potential
drug interactions with antiretroviral therapy.
irrespective of age, PPD results, or prior course of chemoprophylaxis, should be
given chemoprophylaxis if they are in close contact with persons who have active
TB. Prophylaxis also should be given for anergic, HIV-infected persons who have
been in contact with patients known to have active TB.
latent TB is begun, active TB needs to be ruled out. K.D. should undergo chest
radiography and clinical evaluation to rule out active disease. The CDC no longer
recommends routine anergy testing in these patients.
All ritonavir- and cobicistat-boosted
Fosamprenavir Consider alternative
Atazanavir Rifabutin 150 mg daily
Nevirapine Use caution at usual
Efavirenz Rifabutin 450–600 mg
Etravirine Rifabutin 300 mg daily
Rilpivirine Increase rilpivirine dose
Maraviroc Maraviroc 300 mg BID
Raltegravir No change in dosing Raltegravir 800 mg BID
Dolutegravir No change in dosing Dolutegravir 50 mg BID
Elvitegravir/cobicistat/tenofovir/emtricitabine Do not coadminister Do not coadminister
BID, twice a day; CYP3A4, cytochrome P-450 3A4.
HIV-INFECTED PERSONS: PROTEASE INHIBITORS, NONNUCLEOSIDE
REVERSE TRANSCRIPTASE INHIBITORS, CCR5 ANTAGONISTS, AND
QUESTION 1: F.C., a 36-year-old HIV-infected woman, diagnosed 6 months ago, was found to have active
TB (pulmonary infiltrates on chest radiographs, sputum AFB stain and culture positive, and culture
300 cells/μL. What factors must be considered when selecting TB therapy for F.C.?
The use of protease inhibitors in the treatment of HIV-infected patients coinfected
with TB increases the potential for drug interactions with rifamycin derivatives
(rifampin and rifabutin). Because the rifamycins are potent inducers of the hepatic
cytochrome P-450 system (e.g., CYP3A4), they can induce metabolism of the
protease inhibitors, resulting in subtherapeutic levels. Conversely, the protease
inhibitors elevate rifamycin serum levels by inhibiting their metabolism and
increasing toxicities, such as rifabutin-associated uveitis (inflammation of the uveal
tract of the eye; see Chapter 68, Tuberculosis).
According to recent guidelines, rifampin should not be coadministered with any
standard protease inhibitors (boosted or not with ritonavir or cobicistat), etravirine,
nevirapine, rilpivirine, or elvitegravir.
108 Rifampin may be used with efavirenz at
the standard 600-mg once-daily dose with close monitoring for virologic response to
antiviral therapy. Some clinicians recommend an 800-mg dose of efavirenz for
patients weighing greater than 60 kg.
108 When using rifampin with raltegravir, the
recommended dose of raltegravir is 800 mg BID, and patients should be monitored
closely for virologic response. Coadministration of rifampin and maraviroc is not
recommended, but if necessary, maraviroc
should be dosed 600 mg BID (or, if coadministered with a strong CYP3A
inhibitor, maraviroc, 300 mg BID).
11 Dolutegravir should be dosed 50 mg twice
daily if combined with rifampin.
11 Rifabutin should be given at 50% of the usual dose
(i.e., reduced from 300 to 150 mg/day or 300 mg 3 times a week) with ritonavir- or
cobicistat-boosted protease inhibitors.
11 Rifabutin should be given with efavirenz at
dosages of 450 to 600 mg/day. Rifabutin can be used in full doses with nevirapine,
etravirine, and rilpivirine; however, the rilpivirine dose should be increased to 50
If etravirine is coadministered with a ritonavir-boosted protease
inhibitor, rifabutin should not be coadministered.
Tenofovir/emtricitabine/elvitegravir/cobicistat should not be coadministered with
rifabutin; however, no dose adjustment is needed when combined with dolutegravir
11 Sequential treatment of TB followed by HIV treatment is not
12 Three clinical trials have demonstrated a reduction in mortality and
HIV-related diseases when antiretrovirals are given during TB treatment.
Discontinuing the protease inhibitor for F.C. is not an option considering the rapid
viral replication and the risk of developing resistant isolates, especially considering
that she recently was started on protease inhibitor therapy and is clinically
responsive. A reduced dose of rifabutin (150 mg daily or 300 mg 3 times per week)
is recommended when coadministered with atazanavir + ritonavir. Considering that
F.C. is receiving atazanavir + ritonavir, she will be treated with a rifabutin-based
regimen. She will receive isoniazid, rifabutin, pyrazinamide, and ethambutol daily
for 8 weeks followed by isoniazid and rifabutin daily or 3 times weekly for 6
MYCOBACTERIUM AVIUM COMPLEX DISEASE
woman with mild hepatosplenomegaly. Pertinent laboratory test results include the following:
WBC count, 3,500 cells/L, with 68% neutrophils, 2% bands, 22% lymphocytes, and 8% monocytes
Absolute CD4 count, 25 cells/μL
Aspartate transferase, 135 international units/L
Alanine aminotransferase, 95 international units/L
Alkaline phosphatase, 186 international units/L
Disseminated MAC infection is common in end-stage AIDS patients. On autopsy,
MAC organisms are observed in the lungs and multiple other bodily tissues.
predominant organism in HIV-positive patients is M. avium (>95% of typeable
12 The risk of developing disseminated MAC infection is highest in patients
with a CD4 count less than 50.
12 Poor prognostic indicators include prior OI, high
plasma HIV RNA levels, previous colonization of the respiratory or GI tract with
MAC, and reduced in vitro lymphoproliferative immune responses to M. avium
M. avium is a ubiquitous organism found in food, water, soil, and house dust. The
most likely portal of entry is either the GI or respiratory tract. Common presenting
symptoms associated with MAC infection include fever, night sweats, anorexia,
malaise, profound weight loss (>10% body weight), anemia, lymphadenopathy, and
12 M.E.’s fevers, drenching night sweats, poor appetite, 20-pound weight
loss, and mild hepatosplenomegaly are consistent with MAC infection. In particular,
her CD4 count of 25 puts her at a risk for this OI.
have documented the presence of MAC?
Disseminated MAC is best diagnosed by peripheral blood cultures. However,
initial testing often includes AFB on a blood smear.
12 Conventional culture methods
using solid media may have a turnaround time of as long as 8 weeks; however,
radiometric broth systems signaling the release of carbon 15-labeled CO2
mycobacteria may detect bacterial growth in 7 to 10 days.
organism (M. tuberculosis vs. atypical mycobacteria) by conventional biochemical
methods may take weeks to months. Techniques using DNA probes make diagnosis
possible within several hours.
113 Quantitative blood cultures have been useful to
monitor the effects of drug therapy but may not be practical on a routine clinical
basis. Radiometric broth methods also may provide in vitro drug susceptibility in
another 7 to 10 days. Even with the availability of all of these laboratory tests,
results generally are not available for 2 to 3 weeks. In view of this lag time, empiric
therapy should be initiated as quickly as possible. Although MAC is typically
isolated from blood, the organism can also be demonstrated via acid-fast smears of
lymph node, liver, or bone marrow biopsies. Because these organs are rich in
monocytes (the target cells for MAC infection), the organism load may be high (up to
DRUG SUSCEPTIBILITY AS A BASIS FOR TREATMENT
CASE 77-8, QUESTION 3: Should M.E.’s therapy be based on in vitro drug susceptibility results?
Correlation between in vitro drug susceptibility results and clinical efficacy has
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