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.
appears in AIDS. 2002;16:1443]. AIDS. 2002;16:299.
World Health Organization. HIV transmission through breastfeeding.
http://www.who.int/nutrition/publications/HIV_IF_Transmission.pdf. Accessed May 28, 2011.
Control. http://www.cdc.gov/hiv/pdf/PrEPguidelines2014.pdf. Accessed May 31, 2015.
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.
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.
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.
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.
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.
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.
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).
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.
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
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.
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
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
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.
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
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.
THE EFFECT OF OPPORTUNISTIC INFECTIONS ON VIRAL LOAD AND
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
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.
investigations in the era of HAART have demonstrated that CD4 count is the
strongest prognostic factor in patients starting therapy.
from the time of HIV transmissions to death. (Illustration by Mary Van, PharmD.)
IMPACT OF ANTIRETROVIRAL AGENTS ON THE NATURAL HISTORY
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
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-
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.
CHANGES IN THE NATURAL HISTORY OF OPPORTUNISTIC
OIs result from long-standing immunosuppression from HIV infection.
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
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
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
17–20 During IRIS, there is typically a rapid increase in CD4
lymphocytes; however, this does not represent fully functional cells, but rather an
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.
IMPROVEMENT IN OR RESOLUTION OF OPPORTUNISTIC INFECTIONS
With the initiation of HAART, reports of improvement in or resolution of some OIs
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.
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
Pharmacotherapeutic Management of Opportunistic
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
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
In 2009, a combined set of guidelines for both prevention and
treatment of more than 30 opportunistic infections was developed.
and any archived guidelines can be found at www.aidsinfo.nih.gov.
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).
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.
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
In one observational PCP prophylaxis study, no episodes of PCP were
observed after the discontinuation of primary and secondary PCP prophylaxis.
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.
In addition, the guidelines suggest discontinuing
primary prophylaxis for toxoplasmosis when the CD4 count increases to greater than
Primary Prophylaxis of Opportunistic Infections in HIV-Infected Adults and
Pathogen Indication First Choice Alternatives
Strongly Recommended as Standard of Care
PO daily or TMPSMX 1 SS PO daily
Isoniazid-sensitiv+eDiagnostic test for TB
MAC CD4 count <50 after ruling
Rifabutin, 300 mg PO daily Patients on
HBV Allsusceptible (anti-HBcnegative) patients
HAV Allsusceptible (anti-HAVnegative) patients at an
Not Recommended for Most Patients; Indicated for Use Only in Unusual Circumstances
Bacteria Neutropenia G-CSF 510 mg/kg
CD4 count <50 Fluconazole 100–200
stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; HAART, highly active
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