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Chersich MF, et al. Efavirenz use during pregnancy and for women of child-bearing potential. AIDS Res Ther.

2006;3:11.

Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission.

Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health

and Interventions to Reduce Perinatal HIV Transmission in the United States.

https://aidsinfo.nih.gov/guidelines/html/3/perinatal-guidelines/0/#. Accessed August 7, 2017.

DeSantis M et al. Periconceptional exposure to efavirenz and neural tube defects. Arch Intern Med.

2002;162:355.

Fundaro C et al. Myelomeningocele in a child with intrauterine exposure to efavirenz [published correction

appears in AIDS. 2002;16:1443]. AIDS. 2002;16:299.

Saitoh A et al. Myelomeningocele in an infant with intrauterine exposure to efavirenz. J Perinatol. 2005;25:555.

World Health Organization. HIV transmission through breastfeeding.

http://www.who.int/nutrition/publications/HIV_IF_Transmission.pdf. Accessed May 28, 2011.

Truvada (emtricitabine/tenofovir disoproxil fumarate) [package insert]. Foster City, CA: Gilead Sciences, Inc.;

2013.

U.S. Public Health Service. Preexposure Prophylaxis for the Prevention of HIV Infection in the United States—

2014 Clinical Practice Guideline. U.S. Department of Health and Human Services and Center for Disease

Control. http://www.cdc.gov/hiv/pdf/PrEPguidelines2014.pdf. Accessed May 31, 2015.

Kuhar DT et al. Updated U.S. Public Health Service guidelines for the management of occupational exposures

to human immunodeficiency virus and recommendations for postexposure prophylaxis. Infect Control Hosp

Epidemiol. 2013;34(9):875–892.

HIV Prophylaxis Following Occupational Exposure. New York State Department of Health AIDS Institute.

www.hivguidelines.org. Updated October 2014. Accessed May 31, 2015.

HIV Prophylaxis Following Non-Occupational Exposure. New York: NY: New York State Department of

Health AIDS Institute. www.hivguidelines.org. Updated October 2014. Accessed May 31, 2015.

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Acquired immunodeficiency syndrome (AIDS) is characterized by the

gradual erosion of immune competence and the development of

opportunistic infections (OIs) and malignancies. A decline in OIs and

OI-related malignancies has been observed, which is associated with

highly active antiretroviral therapy (HAART).

Pneumocystis jiroveci pneumonia (PCP) should be treated with

trimethoprim–sulfamethoxazole (TMP-SMX). The patients intolerant of

sulfonamides should be treated with alternatives such as dapsone,

atovaquone, or pentamidine. Steroids should be used to treat patients

with moderate-to-severe diseases. Primary prophylaxis with these

agents is recommended for patients with CD4 counts less than 200.

Case 77-1 (Questions 1-5)

Toxoplasmosis typically occurs in patients with CD4 counts less than

100, and primary prophylaxis is indicated in these patients who are also

Toxoplasma immunoglobulin G (IgG)-positive. Alternatives for

prophylaxis include TMP-SMX, dapsone + pyrimethamine + leucovorin,

and atovaquone ± pyrimethamine + leucovorin. Treatment options

include sulfadiazine + pyrimethamine + leucovorin, clindamycin +

pyrimethamine + leucovorin, and TMP-SMX.

Case 77-2 (Questions 1, 3,

and 4)

Cytomegalovirus (CMV) typically causes retinitis in human

immunodeficiency virus (HIV)–infected patients with CD4 counts less

than 50. Primary prophylaxis is usually not indicated, and treatment

options include intravenous (IV) ganciclovir, valgancyclovir, IV

foscarnet, IV cidofovir, and intraocular ganciclovir implants.

Case 77-3 (Questions 1 and

2)

Cryptococcal meningitis occurs typically in patients with CD4 counts less

than 50, and primary prophylaxis is not typically recommended. First-line

treatment includes amphotericin + flucytosine for induction therapy with

subsequent addition of fluconazole for maintenance.

Case 77-4 (Questions 1–5, 8)

Mycobacterium tuberculosis infects HIV-infected patients at any CD4

count, sometimes with an atypical presentation. Isoniazid for 9 months is

the preferred regimen for latent tuberculosis (TB) in HIV-infected

patients. Initial treatment in drug-susceptible TB is with rifampin (or

rifabutin) + isoniazid + pyrazinamide + ethambutol.

Case 77-5 (Question 1),

Case 77-6 (Question 1), and

Case 77-7 (Question 1)

Mycobacterium avium complex (MAC) can be localized to the lung or Case 77-8 (Questions 1, 5,

with disseminated infection in HIV-infected patients with CD4 counts

less than 50. Primary prophylaxis is indicated with either azithromycin or

clarithromycin. First-line treatment for acute infection consists of

clarithromycin (or azithromycin) + ethambutol ± rifampin (or rifabutin).

and 7)

INTRODUCTION

The AIDS is characterized by the gradual erosion of immune competence and the

development of OIs. Since the advent of HAART, AIDS-related mortality has

declined in the United States.

1

,

2 The overall 5-year survival probability after the first

OI diagnosis has increased dramatically from 7% in the pre-HAART to 65% in the

HAART era.

3 This decline in mortality has been associated with a decline in OIs and

an increase in noninfectious AIDS-related mortality.

4 Patients with HIV infection are

susceptible to an array of diseases, but most OIs are caused by a few common

pathogens, including P. jiroveci (carinii), CMV, fungi, and mycobacteria.

5

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The revised classification system for HIV infection and expanded surveillance

case definition for AIDS included stratification for the CD4 lymphocyte count, as

well as subgrouping by clinical categories (see Chapter 76, Pharmacotherapy of

Human Immunodeficiency Virus Infection, Tables 76-1 and 76-2). These AIDSdefining OIs may also occur in asymptomatic HIV-infected patients.

5

The Natural History of Opportunistic Infections

THE DECLINE OF THE CD4 LYMPHOCYTE

Within the immune system, the CD4 lymphocyte functions as a “helper cell” that

modulates the actions of the other key cellular components of the immune system. The

eventual loss of CD4 lymphocytes is the underlying pathophysiology that leads to

AIDS. (See Chapter 76, Pharmacotherapy of Human Immunodeficiency Virus

Infection, and comprehensive immunology texts for a more detailed explanation of

immune function and inflammation associated with HIV infection.) The infected CD4

lymphocyte can function normally for a time but eventually becomes dysfunctional, as

manifested by an abnormal response to soluble mitogens. It is this cellular functional

deficit, compounded by the eventual decline in the absolute number of CD4

lymphocytes which leads to OIs and neurologic dysfunctions. The CD4 lymphocyte

count declines gradually during several years in the untreated HIV- infected person.

The average rate of decline in CD4 lymphocyte cells (CD4 slope) is approximately

40 to 80 cells/μL/year in the absence of antiretroviral therapy. An accelerated

decline in the CD4 count occurs at 1.5 to 2 years, just before an AIDS-defining

diagnosis.

6 Without therapy, the course of infection averages approximately 10 years

from the time of initial infection to an AIDS-defining diagnosis.

The CD4 count dictates the need for OI prophylaxis, influences the differential

diagnosis of the OI, and is an independent indicator of prognosis. For these reasons,

the CD4 count has become a primary surrogate marker of immune suppression and

antiretroviral activity. HIV-1 ribonucleic acid (RNA) is the other clinical surrogate

marker, most predictive of survival and antiretroviral activity.

OIs range from relatively minor events (e.g., oral candidiasis or oral hairy

leukoplakia) to sight-threatening episodes of CMV retinitis or life-threatening PCP.

The risk for specific OIs varies with the degree of immunosuppression.

7

Asymptomatic patients with moderate immunosuppression (CD4 counts, 200–500)

may become infected with herpes viruses and Candida species or develop

pneumonia, enteric infection, and meningitis with more common pathogens. Massive

destruction of the immune system occurs when the CD4 count drops below 200,

which increases the risk of opportunistic pathogens (e.g., PCP), opportunistic tumors,

wasting, and neurologic complications. With a CD4 count of 50 to 100, invasive

candidiasis, cerebral toxoplasmosis, cryptococcosis, and various protozoal

infections are observed. When the CD4 count falls below 50, the patient is in an

advanced immunosuppressed state, which is associated with non-Hodgkin lymphoma,

CMV, and disseminated MAC ( Fig. 77-1). Without treatment, the median survival

associated with a CD4 count less than 200 is 3.1 years, and the time to an AIDSdefining infection ranges from 18 to 24 months.

7 With the implementation of HAART,

the 3-year probability of AIDS has dramatically declined; however, much of this

decline may be associated with the use of OI prophylaxis.

8

THE EFFECT OF OPPORTUNISTIC INFECTIONS ON VIRAL LOAD AND

SURVIVAL

Acute OIs upregulate HIV replication, resulting in higher HIV-1 RNA concentrations

in the plasma and lymphoid tissues of HIV-infected patients. This enhanced

replication is presumably caused by antigen-mediated activation of HIV-1 replication

in latently infected cells. To assess the impact of OIs on survival, data from a cohort

of 2,081 HIV-infected patients followed up (in the pre–protease inhibitor era) for a

mean of 30 months were analyzed.

9 CD4 counts and incidence of opportunistic

disease were used as independent variables. These investigators found that PCP,

CMV, MAC, esophageal candidiasis, Kaposi sarcoma (KS), non-Hodgkin

lymphoma, progressive multifocal leukoencephalopathy (PML), dementia, wasting

syndrome, toxoplasmosis, and cryptosporidiosis were independently associated with

death.

9 Additionally, data from a prospective longitudinal study of HIV infection in

homosexual men initiated in 1984 (Multicenter AIDS Cohort Study) demonstrated

that plasma HIV-1 RNA concentrations strongly predict the rate of decline in the

absolute CD4 count as well as clinical progression to AIDS and death.

10 More recent

investigations in the era of HAART have demonstrated that CD4 count is the

strongest prognostic factor in patients starting therapy.

8

Figure 77-1 Natural history of CD4 cell count in the average HIV-infected patient without antiretroviral therapy,

from the time of HIV transmissions to death. (Illustration by Mary Van, PharmD.)

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IMPACT OF ANTIRETROVIRAL AGENTS ON THE NATURAL HISTORY

OF OPPORTUNISTIC INFECTIONS

Reduction in the Incidence of Opportunistic Infections and Death

The introduction of protease inhibitors, combination therapy, prophylaxis therapy,

and improved medical care has reduced the incidence of OIs and death resulting from

AIDS in HIV-positive patients. HAART generally refers to an antiretroviral regimen

that can be expected to reduce the viral load in antiretroviral-naïve patients to less

than 50 copies/mL. A panel of experts convened by the US Department of Health and

Human Services and the Henry J. Kaiser Family Foundation recommended HAART

as the standard of care for all HIV-infected patients.

11 These potent antiretroviral

agents and effective management of OIs have led to an improved quality of life and

prolonged survival among HIV-infected US patients.

12 A significant decrease in the

incidence of OIs and death was first reported in 1996, when preliminary data

demonstrated that the addition of ritonavir to an existing reverse transcriptase

regimen in severely immunocompromised patients decreased the incidence of OIs

and death.

13 The steepest declines in the incidence of AIDS-defining OIs followed

this introduction of HAART, but the declines have also continued into the late-

HAART area.

14 A recent analysis demonstrated both a decline in opportunistic

infections (89–13.3 per 1,000 person-years) and opportunistic malignancies (23.4–

3.0 per 1,000 person-years) from 1994 to 2007.

2

CHANGES IN THE NATURAL HISTORY OF OPPORTUNISTIC

INFECTIONS

OIs result from long-standing immunosuppression from HIV infection.

7 For example,

before HAART, approximately 40% of all AIDS patients exhibited CMV retinitis,

with the most cases occurring at CD4 counts below 100. Since the implementation of

HAART, a decrease in the incidence and progression of CMV retinitis have been

noted.

15

,

16

Ironically, HAART has also been associated with a worsening or an unmasking of

occult OIs in patients with an advanced stage of AIDS. When antiretroviral therapy

strengthens the immune system, inflammatory symptoms in response to infection are

more clinically pronounced.

12 This syndrome has been referred to as immune

reconstitution inflammatory syndrome (IRIS). IRIS incidence is estimated to be 10%

to 40% in patients starting antiretroviral therapy, based primarily on retrospective

observational data.

17–20 During IRIS, there is typically a rapid increase in CD4

lymphocytes; however, this does not represent fully functional cells, but rather an

increase in memory subtypes.

The initiation of HAART typically results in an increase in CD4 lymphocytes and

a decrease in HIV-1 RNA to undetectable levels. This initial increase in CD4 T cells

after the initiation of therapy involves an increase in memory T cells with low

proliferation and a decrease in functional or effector cells. As a result, opportunistic

infections that are present in tissues are allowed to proliferate once the immune

system is recovering, allowing IRIS to occur.

21

IMPROVEMENT IN OR RESOLUTION OF OPPORTUNISTIC INFECTIONS

With the initiation of HAART, reports of improvement in or resolution of some OIs

can occur.

22–26 These OIs include KS,

26 PML,

24 CMV,

15

,

16 microsporidiosis,

cryptosporidiosis,

23 and molluscum contagiosum,

25 a viral infection caused by a

member of the Poxviridae family. Furthermore, there are reports of restored immunity

and clinical improvement in patients with chronic hepatitis B infection (not classified

as a CDC-defined AIDS indicator condition) with the initiation of HAART.

22

However, these infections were not eradicated, and in some cases, improvement was

only transient. Clinical resolution most likely results from immunologic

improvement, and the protective immunity against OI is sustained only as long as

HAART remains effective.

Pharmacotherapeutic Management of Opportunistic

Infections

Successful pharmacotherapeutic management of OIs requires an understanding of the

natural history of HIV-associated OIs, including the recognition that OIs occur with

declining CD4 lymphocyte counts, the clinical presentation of each disease,

diagnostic techniques, and effective treatment and preventive strategies. Management

issues, complicated by multiple-drug therapy for OIs and HIV suppression, include

adherence, toxicities, resistance, drug interactions, and cost. HIV-infected patients

are usually less tolerant to drugs such as flucytosine, TMP-SMX, and pyrimethamine;

however, alternative agents are available to overcome these barriers to treatment.

In 1995, the US Public Health Service (USPHS) and the Infectious Diseases

Society of America (IDSA) issued guidelines for the prevention of OIs in HIVinfected patients; these were revised in 1997,

27 1999,

28 and 2002.

29

Recommendations are included for preventing exposure to opportunistic pathogens,

preventing first episodes of disease by chemoprophylaxis or vaccination (primary

prophylaxis), and preventing disease recurrence (secondary prophylaxis).

Additionally, in 2004, the CDC published the first edition of guidelines for the

treatment of OIs.

30

In 2009, a combined set of guidelines for both prevention and

treatment of more than 30 opportunistic infections was developed.

12 The most recent

and any archived guidelines can be found at www.aidsinfo.nih.gov.

PRIMARY PROPHYLAXIS

Primary prophylaxis is defined as a therapy that is initiated before the appearance of

an OI in high-risk asymptomatic persons to prevent the initial occurrence of an

infection. Primary prevention of OIs is important, considering the inevitable immune

depletion associated with chronic HIV infection.

31 PCP and MAC prophylaxis have

significantly prolonged survival and delayed the onset of illness (see Prophylaxis

sections for both PCP and MAC).

32

,

33

The guidelines strongly recommend primary prophylaxis against PCP,

toxoplasmosis, M. tuberculosis, and MAC. Vaccinations to prevent Streptococcus

pneumoniae, hepatitis B virus, hepatitis A virus, varicella zoster virus (VZV), and

influenza virus infection are generally recommended for all HIV-infected patients.

Primary prophylaxis for fungal infections (Cryptococcus neoformans and

Histoplasma capsulatum), CMV, and bacterial infections are not routinely

recommended for most patients, except in unusual circumstances (Table 77-1).

Discontinuation of Primary Prophylaxis Therapy

HAART has diminished the incidence of several OIs.

16

,

23

,

26 Therefore, it may be

possible to discontinue prophylactic OI therapy when CD4 counts rise above the

threshold associated with the risk for infection. These data have been particularly

encouraging in patients who had PCP prophylaxis discontinued with an increase in

CD4 counts.

12

In one observational PCP prophylaxis study, no episodes of PCP were

observed after the discontinuation of primary and secondary PCP prophylaxis.

34

These studies suggest that patients who respond to HAART with a sustained increase

in CD4 count can have their primary prophylaxis safely discontinued. The OI

prophylaxis guidelines suggest that primary PCP prophylaxis may be discontinued for

patients on HAART when the CD4 count is greater than 200 for at least 3 months.

Primary prophylaxis for MAC may also be discontinued when the CD4 count

increases to greater than 100.

12

In addition, the guidelines suggest discontinuing

primary prophylaxis for toxoplasmosis when the CD4 count increases to greater than

200 for at least 3 months.

12

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Table 77-1

Primary Prophylaxis of Opportunistic Infections in HIV-Infected Adults and

Adolescents

Preventive Regimens

Pathogen Indication First Choice Alternatives

D/C

Prophylaxis

Strongly Recommended as Standard of Care

Pneumocystis

jiroveci

(carinii)

CD4 count <200 or

oropharyngeal candidiasis

TMP-SMX, 1 DS

PO daily or TMPSMX 1 SS PO daily

TMP-SMX 1 DS TIW

Dapsone 50 mg BID or

100 mg/day; dapsone 50

mg daily + pyrimethamine

50 mg QW + leucovorin 25

mg PO QW; aerosolized

pentamidine 300 mg QM

via Respirgard II nebulizer,

atovaquone 1,500 mg PO

daily; atovaquone 1,500 mg

PO + pyrimethamine 25

mg PO + leucovorin 25 mg

PO daily

Patients on

HAART with

sustained CD4

>200 cells for

≥3 months may

discontinue

PCP

prophylaxis.

Reintroduce if

CD4 <200.

Mycobacterium tuberculosis

Isoniazid-sensitiv+eDiagnostic test for TB

with no evidence of active

TB, no prior treatment OR

− Diagnostic test for TB,

close contact with person

with active TB and no

personal active TB OR

History of untreated or

inadequately treated TB

and no evidence of active

TB

Isoniazid 300 mg PO

daily OR isoniazid

900 mg PO BIW × 9

months both with

pyridoxine 50 mg PO

daily

Rifampin 600 mg PO daily

× 4 months or rifabutin

dose adjusted for

antiretroviral therapy × 4

months

Drugresistant TB

Same; high probability of

exposure to

isoniazid-resistant

tuberculosis

Choice of drugs

requires consultation

with public health

authorities

None

Toxoplasma

gondii

IgG antibody to

Toxoplasma and CD4

count <100

TMP-SMX, 1 DS

PO daily

TMP-SMX, 1 SS PO daily;

TMP-SMX 1 DS PO

TIW; dapsone 50 mg PO

daily + pyrimethamine 50

mg PO QW + leucovorin

25 mg PO QW; dapsone

200 mg PO QW +

pyrimethamine 75 mg PO

QW + leucovorin 25 mg

PO QW; atovaquone 1,500

mg PO daily with or

without pyrimethamine 25

mg PO daily + leucovorin

10 mg PO daily

Patients on

HAART with

sustained CD4

>200 for ≥3

months may

discontinue

toxoplasmosis

prophylaxis.

Restart if CD4

<100–200

MAC CD4 count <50 after ruling

out active infection

Azithromycin, 1,200

mg PO QW;

clarithromycin 500

mg PO BID;

azithromycin 600 mg

PO BIW

Rifabutin, 300 mg PO daily Patients on

HAART with

sustained CD4

>100 for ≥3

months may

discontinue

MAC

prophylaxis.

Restart if CD4

<50

VZV Preexposure prevention:

Patients with CD4 ≥200

who have not been

vaccinated, have no history

of varicella or herpes

zoster or who are

seronegative for VZV

Postexposure prevention:

Significant exposure to

chicken pox or shingles for

patients who are

susceptible

Preexposure:

Primary varicella

vaccination, two

doses administered 3

months apart

Postexposure

prevention: VZIG

125 international

units per 10 kg

(maximum of 635

international units)

IM administered 96

hours after exposure

Usually Recommended

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Streptococcus

pneumoniae

Regardless of CD4 count

followed by:

If CD4 >200

If CD4 <200

For individuals who have

previously received

PCV13 0.5 mL × 1

PPV23 0.5 mL IM

at least 8 weeks

after PCV13

PPV23 can be

offered at least 8

None

PPV23 weeks after

receiving PCV13 or

can wait until CD4

≥200

One dose of PCV13

should be given at

least 1 year after the

last receipt of

PPV23

HBV Allsusceptible (anti-HBcnegative) patients

Hepatitis B vaccine

three doses

None

HPV Females aged 13–26 years

Males aged 13–26 years

HPV quadrivalent

vaccine 0.5 mL IM

at Months 0, 1–2,

and 6 OR

HPV bivalent

vaccine 0.5 mL IM

at Months 0, 1–2,

and 6

HPV quadrivalent

vaccine 0.5 mL IM

at Months 0, 1–2,

and 6

Influenza

virus

All patients (annually

before influenza season)

Inactivated influenza

vaccine per

recommendation for

the season (note, live

attenuated influenza

vaccine is

contraindicated in all

HIV-infected

patients)

HAV Allsusceptible (anti-HAVnegative) patients at an

increased risk for HAV or

patients with chronic liver

disease (including HBV or

HCV)

Hepatitis A vaccine;

two doses

None

Not Recommended for Most Patients; Indicated for Use Only in Unusual Circumstances

Bacteria Neutropenia G-CSF 510 mg/kg

SC daily × 24 weeks

or GM-CSF 250

mg/m

2 SC × 24

weeks

None

Cryptococcus

neoformans

CD4 count <50 Fluconazole 100–200

mg PO daily

Itraconazole 200 mg PO

daily

Histoplasma

capsulatum

CD4 count <100, endemic

geographic areas

Itraconazole 200 mg

PO daily

None

CMV CD4 count <50 and CMV

antibody–positive

Valganciclovir 900

mg PO daily

None

BID, twice a day; BIW, twice weekly; CMV, cytomegalovirus; DS, double strength; G-CSF, granulocyte colony-

stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; HAART, highly active

antiretroviral therapy; HAV, hepatitis A virus; HBc, hepatitis B core; HBV, hepatitis B virus; HPV, human

papillomavirus; IM, intramuscularly; INH, isoniazid; MAC, Mycobacterium avium complex; PCV13, 13-valent

pneumococcal conjugate vaccine; PO, orally; PPV23, 23-valent pneumococcal polysaccharides vaccine; QM,

monthly; QW, weekly; RIF, rifampin; SC, subcutaneously; SS, single strength; TIW, three times a week; TMPSMX, trimethoprim–sulfamethoxazole; TST, tuberculin skin test; VZIG, varicella zoster immune globulin; VZV,

varicella zoster virus.

Source: Panel on Opportunistic Infections in HIV-infected Adults and Adolescents. Guidelines for prevention and

treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the

National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America.

https://aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent-oi-prevention-and-treatmentguidelines/.

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