Primary Prevention of Opportunistic Infections in HIV-Infected Patients

8/8/2019 Primary Prevention of Opportunistic Infections in HIV-Infected Patients

1/14

Official reprint from UpToDatewww.uptodate.com

2010 UpToDate

AuthorJohn G Bartlett, MD

Section EditorMartin S Hirsch, MD

Deputy EditorBarbara H McGovern, MD

Primary prevention of opportunistic infections in HIV-infected patients

Last literature review version 18.2: Maio 2010 | This topic last updated: Outubro 15, 2009

INTRODUCTION HIV-related immunosuppression significantly increases the risk for acquiring opportunistic

infections due to bacteria, viruses, fungi, and protozoa. These opportunistic infections are a major source of

morbidity and mortality in HIV-infected patients.

Substantial advances in the prevention of opportunistic infections have been achieved. These strategies involve

prophylactic antibiotics, immunizations, and public health measures. The cost effectiveness of preventing infections

is variable, ranging from $16,000 per quality adjusted life-year saved for Pneumocystis carinii pneumonia to over

$300,000 for cytomegalovirus (table 1) [1].

The recommendations listed below largely reflect the 2009 NIH/CDC/IDSA Guidelines for Treatment and Prevention

of Opportunistic Infections in HIV-infected Adults and Adolescents [2]. The 2009 guidelines emphasize the primary

importance of antiretroviral therapy in reconstituting the immune system to reduce the risk of opportunistic

infections [2]. Several new infections have been added to the 2009 guidelines as well, including hepatitis B and

malaria. The prevention and treatment of these diseases are discussed elsewhere. (See "Epidemiology, clinical

manifestations, and diagnosis of hepatitis B in the HIV-infected patient" and "Treatment and prevention of hepatitis

B in the HIV-infected patient" and "HIV and malaria".)

The use of prophylactic antibiotics for primary prevention of the most common opportunistic infections will be

reviewed here (table 2). Clinical manifestations and treatment of specific opportunistic infections and secondary

prophylaxis are also discussed elsewhere. (See appropriate topics).

EPIDEMIOLOGY OF OPPORTUNISTIC INFECTIONS The widespread use of potent antiretroviral therapy

(ART) has led to a dramatic decline in the incidence of opportunistic infections [3]. In a cohort of 2410 patients

followed in seven centers in Switzerland in 1995-1997, the incidence of any OI decreased from 15.1 per 100

person-years in the 6 months before therapy to 7.7 in the first 3 months after starting treatment, 2.6 in the

following 6 months, and 2.2 per 100 person-years between 9 and 15 months [3]. In a multicenter study of more

than 8500 HIV-infected patients in the United States, the rates of OIs declined from 140 per 1000 person-years of

observation in 1995 to less than 20 per 1000 person-years of observation in 2007 [4]. Similar trends have been

noted in resource-limited settings. (See "The global human immunodeficiency virus pandemic".)

The lower rates of opportunistic infections have also been associated with a marked decline in mortality. One study

evaluated 31,620 HIV-infected patients to assess whether mortality differs by the specific type of AIDS-defining

event [5]. During a median follow-up period of 43 months, 2880 AIDS-defining events were diagnosed in 2262

patients; 1146 patients died. The following observations were made:

The most common diagnoses were esophageal candidiasis, Pneumocystis jirovecii pneumonia, and Kaposi

sarcoma.

Three categories of AIDS-defining events were identified based on the relative risk of death:

Severe: Non-Hodgkin's lymphoma and progressive multifocal leukoencephalopathy (HR, 7.3; 95% CI 5.55-9.48)

Moderate: Cryptococcosis, cerebral toxoplasmosis, AIDS dementia complex, and disseminated Mycobacterium

avium complex (HR, 2.35; 95% CI 1.8-3.1)

Mild: All other OIs (HR, 1.47; 95% CI 1.08-2.0)

These data suggest that in the era of potent ART, the risk of mortality is related to the specific AIDS-defining

event.

RESTORATION OF CELLULAR IMMUNITY

Effect of ART Restoration of immunity secondary to effective ART can also allow the safe discontinuation of

prophylaxis. However, attention still needs to be paid to the prevention of opportunistic infections among treatedpatients who do not attain adequate immunologic recovery, or in those who experience a decline in CD4 cell counts

after initial improvement [4].

Effect of interleukin 2 Two clinical trials demonstrated that although substantial CD4 cell count increases

occurred with concurrent administration of interleukin-2 with ART versus ART alone, no reduction of opportunistic

infections was demonstrated [6].


2/14

PNEUMOCYSTIS Pneumocystis jirovecii (carinii) pneumonia remains the leading initial AIDS-defining illness and

an important cause of death in patients with AIDS. In the absence of antiretroviral therapy and prophylaxis, the

risk of pneumocystis pneumonia is 40 to 50 percent/year in patients with a CD4 count less than 100 cells/microL

[7]. The major reasons for prophylaxis failure are a CD4 count less than 50 cells/microL and non-adherence [8,9].

This topic is discussed in detail elsewhere. A brief summary is found below. (See "Prophylaxis against

Pneumocystis carinii (P. jirovecii) in HIV-infected patients".)

Who is at risk The most common risk factor for the development of PCP is a CD4 count


3/14

Discontinuation of prophylaxis Patients who experience immune reconstitution on ART with a rise in CD4 cell

count above 200 cells/microL for more than three months can usually safely discontinue PCP prophylaxis [24-26].

(See "Prophylaxis against Pneumocystis carinii (P. jirovecii) in HIV-infected patients", section on 'Discontinuation of

prophylaxis'.)

Prophylaxis should be reintroduced if the CD4 count decreases to 200/microL for more than three months. In one study of 199 patients,

discontinuation of primary prophylaxis resulted in no cases of either toxoplasma encephalitis or PCP [39].

Discontinuation of secondary prophylaxis is recommended when the CD4 count is >200 cells/mL x 3 months;

resumption of prophylaxis should occur if the CD4 count declines to the range of 100 to 200 cells/mm3 [ 2].


4/14

This issue is also discussed elsewhere. (See "Toxoplasmosis in HIV-infected patients", section on 'Prophylaxis'.)

MYCOBACTERIUM AVIUM COMPLEX Disseminated Mycobacterium avium complex infection is a significant

contributing factor to morbidity and mortality in late-stage AIDS [40]. (See "Mycobacterium avium complex (MAC)

infections in HIV-infected patients".)

Who is at risk The frequency of disseminated Mycobacterium avium complex (MAC) infection in patients with

AIDS in the absence of HAART is approximately 20 to 40 percent in patients with CD4 counts less than 50

cells/microL [41]. (See "Mycobacterium avium complex (MAC) infections in HIV-infected patients".)

Preventing exposure MAC is ubiquitous in the environment (food, water); no specific recommendations can be

made on avoidance of exposure.

Primary prophylaxis Primary prophylaxis against MAC infection should be given to all HIV-infected patients

with a CD4 cell count 32 microgram/mL) in 29 percent of the

clarithromycin failures and 25 percent of the breakthroughs in the combination arm. Rifabutin resistance (MIC >2.0


5/14

microgram/mL) was identified in two isolates, one from a patient receiving rifabutin and one from a patient

receiving clarithromycin.

Evaluation prior to prophylaxis Before prophylaxis with macrolides is initiated, blood cultures for MAC

isolation should be drawn if there is any suspicion of clinical disease. Cultures of respiratory and stool specimens

for MAC colonization are not recommended [2]. In patients initiating rifabutin, a chest x-ray should be obtained to

rule out active tuberculosis, since monotherapy with this medication would lead to resistance.

Discontinuation of prophylaxis Primary prophylaxis may be discontinued when HAART is associated with an

increase in CD4 cell count to >100/microL for more than three months [2].

Two randomized clinical trials confirm the safety of this approach as illustrated below:

A randomized, multicenter, double-blind trial compared continuing or stopping azithromycin prophylaxis in 520

AIDS patients whose CD4 counts had risen to >100/microL on two consecutive determinations in response to

HAART [52]. No patients in either group developed MAC infection during a median of 12 months of follow-up.

In another study (ACTG 362), 643 HIV infected subjects, whose CD4 cell counts rose from less than 50/microL

to above 100/microL, were randomly assigned to azithromycin (1200 mg once per week) or placebo [47]. After a

median follow-up of 16 months, two cases of MAC disease localized to the spine developed in the placebo group

compared to no cases in those randomized to azithromycin.

Primary prophylaxis should be reintroduced if the CD4 count decreases to !50 cells/microL [2].

HISTOPLASMA Histoplasmosis is the most prevalent endemic mycosis in the United States, especially the Ohioand Mississippi River Valleys. While most infections are asymptomatic or self-limited, immunosuppressed patients

may develop acute pulmonary infection or severe and progressive disseminated disease. (See "Diagnosis and

treatment of disseminated histoplasmosis in non-HIV-infected patients".)

Who is at risk The risk of histoplasmosis is 5 percent for patients with AIDS who reside in endemic areas and

who are not receiving antiretroviral therapy [53]. Disseminated disease is more common in patients with a CD4

count less than 150 cells/microL [54].

Preventing exposure Patients visiting endemic areas should be advised to avoid high-risk activities, such as

disturbing soil under bird roosting sites, demolishing old buildings, or exploring caves [55].

Primary prophylaxis A trial comparing itraconazole 200 mg daily to placebo in 295 patients with HIV infection

and CD4 cell counts below 150/microL showed a significant reduction in the incidence of histoplasmosis in the

itraconazole group at a median follow-up of about one year (2.7 versus 6.8 percent) [56]. However, a survivalbenefit was not demonstrated.

The 2009 NIH/CDC/IDSA guidelines recommend consideration of prophylactic itraconazole (200 mg/day) for

patients with a CD4 count below 150/microL who are at high risk because of occupational exposure or who live in a

community with a hyperendemic rate of histoplasmosis (>10 cases/100 patient-years) [2].

Prophylaxis can be discontinued when the CD4 count is >150/mm3 for more than six months [2].

CANDIDA Mucosal candidal infections, such as oropharyngeal thrush and vaginitis, are commonly diagnosed in

HIV-infected patients; invasive esophageal candidiasis is an AIDS-defining diagnosis that occurs in more than 10

percent of immunosuppressed patients [57].

Preventing exposure These organisms are commonly found on skin and mucosal surfaces. No measures can

be undertaken to reduce exposure.Who is at risk The correlation between risk of mucosal disease and absolute CD4 cell count is not as clear as

in other opportunistic infections. Recurrent candida vaginitis is the most common HIV-related gynecological

presentation, but is also a common condition in women without HIV infection. Candida infections are also

associated with antibiotic use, including trimethoprim-sulfamethoxazole. The risk of candida esophagitis increases

in patients with a CD4 count less than 100 cells/microL and in those with oropharyngeal thrush.

Primary prophylaxis Studies of primary prophylaxis have found efficacy of itraconazole and fluconazole for the

prevention of mucosal candidal infections [56,58,59]. However, use of primary prophylaxis may also promote azole

resistance in Candida species by selecting resistant strains (especially C. tropicalis, C. glabrata, and C. krusei) or

by inducing resistance in the original strain of C. albicans [60]. The major risks for the induction of resistant strains

are fluconazole exposure and severe immunosuppression [61,62].

A randomized, double-blind, multicenter study of 636 HIV-infected patients with median CD4 counts of 40cells/microL compared a once-weekly regimen offluconazole (400 mg PO) to daily administration of fluconazole

(200 mg PO) and found equivalent efficacy in the prevention of fungal infections (8 versus 6 percent) [58]. There

was no placebo arm in the study. The daily regimen was more effective in preventing oral thrush. Once-weekly

dosing did not appear to increase fluconazole resistance, but only a small subset of patients had sensitivity testing

performed.


6/14

In a prospective, double-blind trial, 295 patients with advanced HIV infection were randomized to receive

itraconazole (200 mg daily) or placebo for prevention of mucosal and invasive fungal infections [56]. Prophylaxis

failure due to recurrent or refractory mucosal candidiasis occurred with similar frequency in patients receiving

itraconazole or placebo (15 versus 16 percent).

Lingering concerns regarding the potential induction of resistance with the use of primary prophylaxis led to

another randomized, open-label trial that compared oral fluconazole given 200 mg three times weekly (continuous

use) with fluconazole that was provided only for episodes of oropharyngeal or esophageal candidiasis (episodic

use) [63]. The primary endpoint was the time to development of fluconazole-refractory infection. A total of 829

patients were randomly assigned to the treatment arms. The study was significant for the following findings:

There was no difference in the clinical rates offluconazole-resistance between the two arms.

Continuous fluconazole was associated with fewer cases of oropharyngeal and esophageal candidiasis and fewer

invasive fungal infections, but not with improved survival, when compared to episodic treatment.

The authors concluded that the use of continuous fluconazole cannot be recommended due to the lack of a survival

benefit, but could be considered in certain individuals with frequent mucosal infections or in non-Western settings

where the rates of invasive fungal disease are much higher [64].

We do not recommend the routine use of systemic prophylaxis for the primary prevention of candida infections

despite studies showing effectiveness. The rationale for this recommendation is based on satisfactory response of

mucosal candidiasis in AIDS patients and concerns of emerging drug resistance balanced against the effectiveness

of therapy, the low associated mortality rate, and the cost of the drugs coupled with the risk of drug interactions.The alternative approach to systemic azoles for the treatment of oral thrush is the use of local antifungal therapy,

such as clotrimazole troches or nystatin pastilles.

CRYPTOCOCCUS Cryptococcosis most commonly presents as a meningoencephalitis with fever, malaise, and

headache. The lifetime rate for AIDS patients in the pre-HAART era was 5 to 10 percent for cryptococcosis (90

percent have cryptococcal meningitis) [65]. (See "AIDS-associated cryptococcal meningoencephalitis".)

Preventing exposure No recommendations can be made regarding avoidance of exposure. There is no

evidence that exposure to pigeon droppings increases the risk of cryptococcosis.

Who is at risk The majority of cases of cryptococcal infection occur in patients with a CD4 count


7/14

main risk factors for disease include a CD4 count


8/14

RECOMMENDATIONS OF WHEN TO INITIATE PROPHYLAXIS Preventive measures against opportunistic

infections can include avoidance of certain exposures, good hygiene, and the use of prophylactic medications.

Specific recommendations are governed by the degree of immunosuppression and the risk of disease, which varies

for each pathogen.

The need for primary prophylaxis is stratified below by CD4 cell count thresholds. Dosing recommendations and

alternative therapies are found under each specific infection in "Recommendations for individual pathogens" below.

Primary prophylaxis

CD4 counts


9/14

In the patient who is intolerant or allergic to the above two regimens, we suggest atovaquone (1500 mg once

daily) with or without pyrimethamine/leucovorin (Grade 2C). Monotherapy with dapsone, pyrimethamine,

azithromycin, or clarithromycin is not recommended.

In pregnant women, we recommend trimethoprim-sulfamethoxazole for the prophylaxis of toxoplasmosis

starting in the second trimester (Grade 2C). Pyrimethamine is teratogenic and should not be used during

pregnancy.

Patients who are seronegative for toxoplasma should be counseled to avoid eating undercooked meats (eg,

lamb, beef, pork) and to use gloves when cleaning cat litter boxes.

Mycobacterium avium complex

We recommend the use of macrolides rather than rifabutin for the primary prophylaxis of MAC infection in

patients with a CD4 count less than 50 cells/microL (Grade 1A). Given issues of dosing, drug interactions, and

resistance, we suggest prophylaxis with weekly azithromycin rather than daily clarithromycin (Grade 2C). (See

'Mycobacterium avium complex' above.)

Ifazithromycin is not tolerated, clarithromycin should be initiated. If neither macrolide is tolerated, then

rifabutin can be considered an alternative. However, caution should be exercised when using either of these

medications in light of known drug interactions with both clarithromycin and rifabutin. (See 'Mycobacterium avium

complex' above.)

Azithromycin may be used during pregnancy. Clarithromycin is a teratogen in animals and should not be used

during pregnancy. Experience with rifabutin is limited.

Before prophylaxis with macrolides is initiated, blood cultures for MAC isolation should be drawn if there is any

suspicion of clinical disease. In patients initiating rifabutin, a chest x-ray should be obtained to rule out active

tuberculosis.

Histoplasmosis

We suggest the use ofitraconazole (200 mg daily) for the prophylaxis of histoplasmosis in patients with a CD4

count


10/14

products when needed.

Cryptosporidium

We suggest NOT administering prophylaxis for cryptosporidium (Grade 2C). (See 'Cryptosporidium' above.)

Use of UpToDate is subject to the Subscription and License Agreement.


11/14

GRAPHICS


12/14

Cost-effectiveness of preventing AIDS-related opportunistic infections

Infection Drug

Cost per year for the

drug

Cost per

QALY*

Pneumocystis cariniipneumonia

Trimethoprim-sulfamethoxazole

$25 $16,000

Mycobacterium aviumcomplex

Azithromycin $1450 $35,000

Clarithromycin $2455 $58,000

Rifabutin $2140 $74,000

Fungal infections Fluconazole $2472 $100,000

Cytomegalovirus Oral ganciclovir $15,600 $314,000

QALY: quality-adjusted life-year saved.From Freedberg, KA, Scharfstein, JA, Seage, GA, et al, JAMA 1998;

279:130.


13/14

Prophylaxis against opportunistic infections in patients with AIDS

Infection Preferred drug Indications

Pneumocystiscariniipneumonia

Trimethoprim-sulfamethoxazole(double-strength tablet daily)

CD4 count


14/14

Pneumocystis pneumonia prophylaxis

Drug Dosage Adverse reactions

Preferred regimen for both primary and secondary prophylaxis

TMP-SMX 1 DS tablet daily Fever, rash, neutropenia,gastrointestinal upset,transaminase elevationOR

1 DS tablet three timesper week

OR

1 SS tablet daily

Alternative regimens

Atovaquone suspension 1500 mg orally oncedaily

Gastrointestinal distress, rash

Dapsone 50 mg twice daily Fever, rash, gastrointestinalupset, methemoglobinemia,hemolytic anemia (check forG6PD deficiency)

OR

100 mg daily

In patients who are IgG seropositive fortoxoplasmosis AND are HIV-positive with a CD4count

Primary Prevention of Opportunistic Infections in HIV-Infected Patients

Documents

Transcript of Primary Prevention of Opportunistic Infections in HIV-Infected Patients