1563CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

TABLE 202-11 NIH/CDC/IDSA 2013 Guidelines for the Prevention of Opportunistic Infections in Persons Infected with HIV

PATHOGEN INDICATIONS FIRST CHOICE(S) ALTERNATIVES

Recommended as Standard of Care for Primary and Secondary Prophylaxis

Pneumocystis jirovecii CD4+ T-cell count <200/μL Trimethoprim-sulfamethoxazole Dapsone 50 mg bid PO or 100 mg/d PO

or (TMP-SMX), 1 DS tablet qd PO or

Oropharyngeal candidiasis or Dapsone 50 mg/d PO +

or TMP-SMX, 1 SS tablet qd PO Pyrimethamine 50 mg/week PO +

Prior bout of PCP Leucovorin 25 mg/week PO

or

(Dapsone 200 mg PO +

Pyrimethamine 75 mg PO +

Leucovorin 25 mg weekly PO)

or

Aerosolized pentamidine, 300 mg via

Respirgard II nebulizer every month

or

Atovaquone 1500 mg/d PO

or

TMP-SMX 1 DS tablet 3×/week PO

May stop prophylaxis if CD4+ T-cell count

>200/μL for ≥3 months

Mycobacterium tuberculosis

Isoniazid sensitive Skin test >5 mm

or

Positive IFN-γ release assay

or

Prior positive test without treatment

or

Close contact with case of active pulmonary TB

Same with high probability of exposure to drugresistant TB

(Isoniazid 300 mg PO +

Pyridoxine 25 mg PO) qd × 9 months

or

Isoniazid 900 mg PO twice weekly

+ Pyridoxine 25 mg PO daily

× 9 months

Rifabutin (dose adjusted based on cART

regimen) or rifampin 600 mg PO qd

× 4 months

Drug resistant Consult local public health authorities

Mycobacterium-avium

complex

CD4+ T-cell count <50/μL unless ART

immediately initiated

Azithromycin 1200 mg weekly PO or

600 mg twice weekly PO

Rifabutin (dose adjusted based on cART

regimen)

or

Clarithromycin 500 mg bid PO

Prior documented disseminated disease Clarithromycin 500 mg bid PO +

Ethambutol 15 (mg/kg)/d PO

Azithromycin 500–600 mg/d PO +

Ethambutol 15 (mg/kg)/d PO

May stop prophylaxis once ART initiated

Toxoplasma gondii TOXO IgG antibody positive and CD4+ T-cell

count <100/μL

TMP-SMX 1 DS tablet PO qd TMP-SMX 1 DS 3× weekly PO

or

TMP-SMX, 1 SS PO daily

or

Dapsone 50 mg/d PO +

Pyrimethamine 50 mg weekly PO +

Leucovorin 25 mg weekly PO

or

(Dapsone 200 mg PO +

Pyrimethamine 75 mg PO +

Leucovorin 25 mg PO) weekly

or

Atovaquone 1500 mg PO daily ±

(Pyrimethamine 25 mg PO +

Leucovorin 10 mg PO) daily

Prior toxoplasmic encephalitis and CD4+ T-cell

count <200/μL

Sulfadiazine 2000–4000 mg in 2–4

divided doses daily PO +

Pyrimethamine 25–50 mg/d PO +

Leucovorin 10–25 mg/d PO

Clindamycin 600 mg q8h PO +

Pyrimethamine 25–50 mg/d PO +

Leucovorin 10–25 mg/d PO

or

TMP-SMX 1 DS tablet bid

or

(Continued)

1564 PART 5 Infectious Diseases

TABLE 202-11 NIH/CDC/IDSA 2013 Guidelines for the Prevention of Opportunistic Infections in Persons Infected with HIV

PATHOGEN INDICATIONS FIRST CHOICE(S) ALTERNATIVES

Atovaquone 750–1500 mg PO bid ±

(Pyrimethamine 25 mg/d PO +

Leucovorin 10 mg/d PO) or Sulfadiazine

2000–4000 mg/d (in 2–4 divided doses) PO

Toxoplasma gondii May stop prophylaxis if CD4+ T-cell count

>200/μL for ≥3 months

Varicella zoster virus Significant exposure to chickenpox or shingles

in a patient with no history of immunization or

prior exposure to either

Varicella zoster immune globulin, IM,

within 10 d of exposure (800-843-7477)

Acyclovir 800 mg PO 5 × day for 5–7 days

or

Valacyclovir 1 g PO tid for 5–7 days

Cryptococcus neoformans Prior documented disease Fluconazole 200 mg/d PO Itraconazole 200 mg/d PO

May stop prophylaxis if CD4+ T-cell count

>100/μL, no evidence of active fungal infection,

and HIV RNA levels <500 copies/mL for >3 months

Histoplasma capsulatum Prior documented disease or CD4+ T-cell

count <150 μL and high risk (endemic area or

occupational exposure)

Itraconazole 200 mg bid PO Fluconazole 400 mg/d PO

May stop prophylaxis after 1 year if CD4+ T-cell

count >150/μL and patient on cART for ≥6 months

Coccidioides immitis Prior documented disease or positive serology

and CD4+ T-cell count <250/μL if from a disease

endemic area. (For this indication prophylaxis

can be stopped if CD4+ T-cell count ≥250 for

6 months.)

Fluconazole 400 mg/d PO

Penicillium marneffei Prior documented disease

Patients with CD4+ T-cell counts <100 who live

or stay in northern Thailand, Southern China, or

Vietnam

Itraconazole 200 mg/d PO Fluconazole 400 mg PO once weekly

May stop secondary prophylaxis in patients on

ARV therapy with CD4+ T-cell count >100/μL for

≥6 months

Salmonella species Prior recurrent bacteremia Ciprofloxacin 500 mg bid PO for

≥6 months

Bartonella Prior infection Doxycycline 200 mg/d PO

or

Azithromycin 1200 mg weekly PO

or

Clarithromycin 500 mg bid PO

May stop if CD4+ T-cell count >200/μL for

>3 months

Cytomegalovirus Prior end-organ disease Valganciclovir 900 mg bid PO Cidofovir 5 mg/kg every other week IV +

Probenecid

or

Foscarnet 90–120 (mg/kg)/d IV

May stop prophylaxis if CD4+ T-cell count

>100/μL for 6 months and no evidence of active

CMV disease

Restart if prior retinitis and CD4+ T cells <100/μL

Immunizations Generally Recommended

Hepatitis B virus All susceptible (anti-HBc- and anti-HBsnegative) patients

Hepatitis B vaccine: 3 doses

Hepatitis A virus All susceptible (anti-HAV-negative) patients Hepatitis A vaccine: 2 doses

Influenza virus All patients annually Inactivated trivalent influenza virus

vaccine 1 dose yearly

Oseltamivir 75 mg PO qd

or

Rimantadine or amantadine 100 mg PO bid

(influenza A only)

Streptococcus pneumoniae All patients, preferably before CD4+ T-cell count

≤200/μL

Pneumococcal conjugated vaccine

(13) 0.5 mL IM × 1 followed in

8 weeks or more by pneumococcal

polysaccharide vaccine (23) if CD4+

T-cell count >200/μL

Patients initially immunized at a CD4+ T-cell

count <100/μL whose CD4+ T-cell count then

increases to>200/μL

Reimmunize

Human papillomavirus All patients 13–26 years of age HPV vaccine; 3 doses

(Continued)

(Continued)

1565CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

the incidence of these secondary infections has decreased dramatically

(Fig.  202-34). Overall, the clinical spectrum of HIV disease is constantly changing as patients live longer and new and better approaches

to treatment and prophylaxis are developed. In addition to the classic,

original AIDS-defining illnesses, patients with HIV infection also

have an increase in several serious non-AIDS illnesses, including

non-AIDS-related cancers and cardiovascular, renal, and hepatic disease. Non-AIDS events now dominate the disease burden for patients

with HIV infection successfully treated with ART (Table 202-4). In

developed countries, AIDS-related illnesses are responsible for only

~25% of deaths in patients with HIV infection. A similar percentage of

deaths are due to non-AIDS-defining malignancies, and cardiovascular

disease and liver disease each account for approximately 15% of deaths.

The physician providing care to a patient with HIV infection must be

well versed in general internal medicine as well as HIV-related opportunistic diseases. In general, it should be stressed that a key element of

treatment of symptomatic complications of HIV disease, whether they

are primary or secondary, is achieving good control of HIV replication

through the use of ART and instituting primary and secondary prophylaxis for opportunistic infections as indicated.

Diseases of the Respiratory System Acute bronchitis and sinusitis are prevalent during all stages of HIV infection. The most severe

cases tend to occur in patients with lower CD4+ T-cell counts. Sinusitis

presents as fever, nasal congestion, and headache. The diagnosis is made

by CT or MRI. The maxillary sinuses are most commonly involved;

however, disease is also frequently seen in the ethmoid, sphenoid, and

frontal sinuses. While some patients may improve without antibiotic

therapy, radiographic improvement is quicker and more pronounced

in patients who have received antimicrobial therapy. It is postulated

that this high incidence of sinusitis results from an increased frequency

of infection with encapsulated organisms such as H. influenzae and

Streptococcus pneumoniae. In patients with low CD4+ T-cell counts

one may see mucormycosis infections of the sinuses. In contrast to the

course of this infection in other patient populations, mucormycosis of

the sinuses in patients with HIV infection may progress more slowly. In

this setting aggressive, frequent local debridement in addition to local

and systemic amphotericin B may result in effective treatment.

Pulmonary disease is one of the most frequent complications of

HIV infection. The most common manifestation of pulmonary disease

is pneumonia. Three of the 10 most common AIDS-defining illnesses

are recurrent bacterial pneumonia, tuberculosis, and pneumonia due

to the unicellular fungus P. jirovecii. Other major causes of pulmonary

infiltrates include other mycobacterial infections, other fungal infections, nonspecific interstitial pneumonitis, KS, and lymphoma.

Bacterial pneumonia is seen with an increased frequency in patients

with HIV infection, with 0.8–2.0 cases per 100 person-years. Patients

with HIV infection are particularly prone to infections with encapsulated organisms. S. pneumoniae (Chap. 141) and H. influenzae

(Chap.  152) are responsible for most cases of bacterial pneumonia

in patients with AIDS. This may be a consequence of altered B-cell

function and/or defects in neutrophil function that may be secondary

to HIV disease (see above). Pneumonias due to S. aureus (Chap. 142)

and P. aeruginosa (Chap. 159) also are reported to occur with an

increased frequency in patients with HIV infection. S. pneumoniae

(pneumococcal) infection may be the earliest serious infection to

occur in patients with HIV disease. This can present as pneumonia,

sinusitis, and/or bacteremia. Patients with untreated HIV infection

have a six-fold increase in the incidence of pneumococcal pneumonia

and a 100-fold increase in the incidence of pneumococcal bacteremia.

Pneumococcal disease may be seen in patients with relatively intact

immune systems. In one study, the baseline CD4+ T-cell count at the

time of a first episode of pneumococcal pneumonia was ~300/μL. Of

interest is the fact that the inflammatory response to pneumococcal

infection appears proportional to the CD4+ T-cell count. Due to this

high risk of pneumococcal disease, immunization with the conjugated

pneumococcal vaccine followed by booster immunization with the

23-valent pneumococcal polysaccharide vaccine is one of the generally

recommended prophylactic measures for patients with HIV infection.

1993 1994 1995 1996 1997 1998

1995 1996 1997 1998

1992

Year of observation

Incidence/100 person-years No. of opportunistic infections

per 100 person-years

12

10

Esophageal candidiasis

8

6

4

2

0

12

10

8

6

4

2

0

Pneumocystis carinii pneumonia

Kaposi’s sarcoma

Cytomegalovirus disease

Cryptococcosis

Toxoplasmosis

Disseminated Mycobacterium avium complex

Cytomegalovirus retinitis

20

18

16

14

1999 2000 2001

A

B

CMV

PCP

MAC

FIGURE 202-34 A. Decrease in the incidence of opportunistic infections and

Kaposi’s sarcoma in HIV-infected individuals with CD4+ T-cell counts <100/μL from

1992 through 1998. (JE Kaplan et al: Epidemiology of human immunodeficiency

virus-associated opportunistic infections in the United States in the era of highly

active antiretroviral therapy. Clin Infect Dis 30Suppl1(s1):S5, 2000, with permission.)

B. Quarterly incidence rates of cytomegalovirus (CMV), Pneumocystis jirovecii

pneumonia (PCP), and Mycobacterium avium complex (MAC) from 1995 to 2001.

(Reproduced with permission from Palella FJ Jr et al; HIV Outpatient Study

Investigators. Durability and predictors of success of highly active antiretroviral

therapy for ambulatory HIV-infected patients. AIDS 16:1617, 2002.)

TABLE 202-11 NIH/CDC/IDSA 2013 Guidelines for the Prevention of Opportunistic Infections in Persons Infected with HIV

PATHOGEN INDICATIONS FIRST CHOICE(S) ALTERNATIVES

Recommended for Prevention of Severe or Frequent Recurrences

Herpes simplex Frequent/severe recurrences Valacyclovir 500 mg bid PO

or

Acyclovir 400 mg bid PO

or

Famciclovir 500 mg bid PO

Candida Frequent/severe recurrences Fluconazole 100–200 mg/d PO Posaconazole 400 mg bid PO

Abbreviations: ARV, antiretroviral; bid, twice daily; cART, combination antiretroviral therapy; DS, double-strength; IM, intramuscular; PCP, Pneumocystis jirovecii pneumonia;

PO, by mouth; qd, daily; SS, single-strength; TB, tuberculosis; tid, three times a day.

(Continued)

1566 PART 5 Infectious Diseases

This is likely most effective if given while the CD4+ T-cell count is

>200/μL and, if given to patients with lower CD4+ T-cell counts,

should be repeated once the count has been above 200 for 6 months.

Although clear guidelines do not exist, it also makes sense to repeat

immunization every 5 years. The incidence of bacterial pneumonia is

cut in half when patients quit smoking.

Pneumocystis pneumonia (PCP) is caused by the fungus P. jirovecii

and was once the hallmark of AIDS. It has dramatically declined in incidence following the development of effective prophylactic regimens and

the widespread use of ART. It is, however, still the single most common

cause of pneumonia in patients with HIV infection in the United States

and can be identified as a likely etiologic agent in 25% of cases of pneumonia in patients with HIV infection, with an incidence of about 1 case

per 100 person-years. Approximately 30% of cases of HIV-associated

PCP occur in patients who are unaware of their HIV status. The risk

of PCP is greatest among those who have experienced a previous bout

of PCP and those who have CD4+ T-cell counts of <200/μL. Overall,

79% of patients with PCP have CD4+ T-cell counts <100/μL and 95%

of patients have CD4+ T-cell counts <200/μL. Recurrent fever, night

sweats, thrush, and unexplained weight loss also are associated with

an increased incidence of PCP. For these reasons, it is strongly recommended that all patients with CD4+ T-cell counts <200/μL (or a CD4

percentage <15) receive some form of PCP prophylaxis. The incidence of

PCP is approaching zero in patients with known HIV infection receiving

appropriate ART and prophylaxis. In the United States, primary PCP is

now occurring at a median CD4+ T-cell count of 36/μL, while secondary

PCP is occurring at a median CD4+ T-cell count of 10/μL.

Patients with PCP generally present with fever and a cough that is

usually nonproductive or productive of only scant amounts of white

sputum. They may complain of a characteristic retrosternal chest

pain that is worse on inspiration and is described as sharp or burning.

HIV-associated PCP may have an indolent course characterized by

weeks of vague symptoms and should be included in the differential

diagnosis of fever, pulmonary complaints, or unexplained weight loss

in any patient with HIV infection and <200 CD4+ T cells/μL. The most

common finding on chest x-ray is either a normal film, if the disease

is suspected early, or a faint bilateral interstitial infiltrate. The classic

finding of a dense perihilar infiltrate is unusual in patients with AIDS.

In patients with PCP who have been receiving aerosolized pentamidine

for prophylaxis, one may see an x-ray picture of upper lobe cavitary

disease, reminiscent of TB. Other less common findings on chest x-ray

include lobar infiltrates and pleural effusions. Thin-section CT may

demonstrate a patchy ground-glass appearance. Routine laboratory

evaluation is usually of little help in the differential diagnosis of PCP.

A mild leukocytosis is common, although this may not be obvious in

patients with prior neutropenia. Elevation of lactate dehydrogenase is

common. Arterial blood-gases may indicate hypoxemia with a decline

in Pao2 and an increase in the arterial-alveolar (a–a) gradient. Arterial

blood-gas measurements not only aid in making the diagnosis of PCP

but also provide important information for staging the severity of the

disease and directing treatment (see below). A definitive diagnosis

of PCP requires demonstration of the organism in samples obtained

from induced sputum, bronchoalveolar lavage, transbronchial biopsy,

or open-lung biopsy. PCR has been used to detect specific DNA

sequences for P. jirovecii in clinical specimens where histologic examinations have failed to make a diagnosis.

In addition to pneumonia, other clinical problems have been

reported in HIV-infected patients as a result of infection with P. jirovecii.

Otic involvement may be seen as a primary infection, presenting as a

polypoid mass involving the external auditory canal. In patients receiving aerosolized pentamidine for prophylaxis against PCP, one may

see a variety of extrapulmonary manifestations of P. jirovecii. These

include ophthalmic lesions of the choroid, a necrotizing vasculitis that

resembles Buerger disease, bone marrow hypoplasia, and intestinal

obstruction. Other organs that have been involved include lymph

nodes, spleen, liver, kidney, pancreas, pericardium, heart, thyroid, and

adrenals. Organ infection may be associated with cystic lesions that

may appear calcified on CT or ultrasound.

The standard treatment for PCP or disseminated pneumocystosis is

trimethoprim-sulfamethoxazole (TMP-SMX). A high (20–85%) incidence of side effects, particularly skin rash and bone marrow suppression, is seen with TMP-SMX in patients with HIV infection. Alternative

treatments for mild to moderate PCP include dapsone/trimethoprim,

clindamycin/primaquine, and atovaquone. IV pentamidine is the

treatment of choice for severe disease in the patient unable to tolerate

TMP-SMX. For patients with a Pao2 <70 mmHg or with an a–a gradient

>35 mmHg, adjunct glucocorticoid therapy should be used in addition

to specific antimicrobials. Overall, treatment should be continued for

21 days and followed by secondary prophylaxis. Prophylaxis for PCP is

indicated for any HIV-infected individual who has experienced a prior

bout of PCP, any patient with a CD4+ T-cell count of <200/μL or a

CD4 percentage <15, any patient with unexplained fever for >2 weeks,

and any patient with a recent history of oropharyngeal candidiasis. The

preferred regimen for prophylaxis is TMP-SMX, one double-strength

tablet daily. This regimen also provides protection against toxoplasmosis and some bacterial respiratory pathogens. For patients who cannot

tolerate TMP-SMX, alternatives for prophylaxis include dapsone plus

pyrimethamine plus leucovorin, aerosolized pentamidine administered

by the Respirgard II nebulizer, and atovaquone. Primary or secondary

prophylaxis for PCP can be discontinued in those patients treated with

ART who maintain good suppression of HIV (<50 copies/mL) and

CD4+ T-cell counts >200/μL for at least 3 months.

M. tuberculosis, once thought to be on its way to extinction in

the United States, experienced a resurgence associated with the HIV

epidemic (Chap. 173). Worldwide, approximately one-third of all

AIDS-related deaths are associated with TB, and TB is the primary

cause of death for 10–15% of patients with HIV infection. In the

United States ~5% of untreated AIDS patients have active TB. Patients

with HIV infection are more likely to have active TB by a factor of 100

when compared with an HIV-negative population. For an asymptomatic HIV-negative person with a positive purified protein derivative

(PPD) skin test, the risk of reactivation TB is around 1% per year. For

the patient with untreated HIV infection, a positive PPD skin test, and

no signs or symptoms of TB, the rate of reactivation TB is 7–10% per

year. Untreated TB can accelerate the course of HIV infection. Levels of

plasma HIV RNA increase in the setting of active TB and decline in the

setting of successful TB treatment. Active TB is most common in patients

25–44 years of age, in African Americans and Hispanics, in patients in

New York City and Miami, and in patients in developing countries. In

these demographic groups, 20–70% of the new cases of active TB are

in patients with HIV infection. The epidemic of TB embedded in the

epidemic of HIV infection probably represents the greatest health risk

to the general public and the health care profession associated with the

HIV epidemic. In contrast to infection with atypical mycobacteria such

as MAC, active TB often develops relatively early in the course of HIV

infection and may be an early clinical sign of HIV disease. In one study,

the median CD4+ T-cell count at presentation of TB was 326/μL.

The clinical manifestations of TB in HIV-infected patients are quite

varied and generally show different patterns as a function of the CD4+

T-cell count. In patients with relatively high CD4+ T-cell counts, the

typical pattern of pulmonary reactivation occurs: patients present with

fever, cough, dyspnea on exertion, weight loss, night sweats, and a chest

x-ray revealing cavitary apical disease of the upper lobes. In patients

with lower CD4+ T-cell counts, disseminated disease is more common.

In these patients the chest x-ray may reveal diffuse or lower-lobe bilateral reticulonodular infiltrates consistent with miliary spread, pleural

effusions, and hilar and/or mediastinal adenopathy. Infection may be

present in bone, brain, meninges, GI tract, lymph nodes (particularly

cervical lymph nodes), and viscera. Some patients with advanced HIV

infection and active TB may have no symptoms of illness, and thus

screening for TB should be part of the initial evaluation of every patient

with HIV infection. Approximately 60–80% of HIV-infected patients

with TB have pulmonary disease, and 30–40% have extrapulmonary

disease. Respiratory isolation and a negative-pressure room should be

used for patients in whom a diagnosis of pulmonary TB is being considered. This approach is critical to limit nosocomial and community

1567CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

spread of infection. Culture of the organism from an involved site

provides a definitive diagnosis. Blood cultures are positive in 15%

of patients. This figure is higher in patients with lower CD4+ T-cell

counts. In the setting of fulminant disease, one cannot rely on the

accuracy of a negative PPD skin test to rule out a diagnosis of TB. In

addition, IFN-γ release assays may be difficult to interpret due to high

backgrounds as a consequence of HIV-associated immune activation.

TB is one of the conditions associated with HIV infection for which

cure is possible with appropriate therapy. Therapy for TB is generally

the same in the HIV-infected patient as in the HIV-negative patient

(Chap. 173). Due to the possibility of multidrug-resistant or extensively

drug-resistant TB, drug susceptibility testing should be performed to

guide therapy. Due to pharmacokinetic interactions, adjusted doses of

rifabutin and/or changes in ART are required when treating TB in the

setting of HIV infection. Treatment is most effective in programs that

involve directly observed therapy. Initiation of ART and/or anti-TB

therapy may be associated with clinical deterioration due to immune

reconstitution inflammatory syndrome (IRIS) reactions. These are

most common in patients initiating both treatments at the same time,

may occur as early as 1 week after initiation of ART therapy, and are

seen more frequently in patients with advanced HIV disease. For

these reasons it is recommended that initiation of ART be delayed

in antiretroviral-naïve patients with CD4 counts >50 cells/μL until

2–4 weeks following the initiation of treatment for TB. For patients

with lower CD4 counts the benefits of more immediate ART outweigh

the risks of IRIS, and ART should be started as soon as possible in those

patients. Effective prevention of active TB can be a reality if the health

care professional is aggressive in looking for evidence of latent or active

TB by making sure that all patients with HIV infection receive a PPD

skin test or evaluation with an IFN-γ release assay. Anergy testing is not

of value in this setting. Since these tests rely on the host mounting an

immune response to M. tuberculosis, patients with CD4+ T-cell counts

<200 cells/μL should be retested if their CD4+ T-cell counts rise to persistently above 200. Patients at risk of continued exposure to TB should

be tested annually. HIV-infected individuals with a skin-test reaction

of >5 mm, those with a positive IFN-γ release assay, or those who are

close household contacts of persons with active TB should receive

treatment with 9 months of isoniazid and pyridoxine.

Atypical mycobacterial infections are also seen with an increased

frequency in patients with HIV infection. Infections with at least 12

different mycobacteria have been reported, including M. bovis and

representatives of all four Runyon groups. The most common atypical

mycobacterial infection is with M. avium or M. intracellulare species—

the Mycobacterium avium complex (MAC). Infections with MAC are

seen mainly in patients in the United States and are rare in Africa. It has

been suggested that prior infection with M. tuberculosis decreases the

risk of MAC infection. MAC infections probably arise from organisms

that are ubiquitous in the environment, including both soil and water.

There is little evidence for person-to-person transmission of MAC

infection. The presumed portals of entry are the respiratory and GI

tracts. MAC infection is a late complication of HIV infection, occurring predominantly in patients with CD4+ T-cell counts of <50/μL.

The average CD4+ T-cell count at the time of diagnosis is 10/μL. The

most common presentation is disseminated disease with fever, weight

loss, and night sweats. At least 85% of patients with MAC infection

are mycobacteremic, and large numbers of organisms can often be

demonstrated on bone marrow biopsy. The chest x-ray is abnormal

in ~25% of patients, with the most common pattern being that of a

bilateral, lower-lobe infiltrate suggestive of miliary spread. Alveolar or

nodular infiltrates and hilar and/or mediastinal adenopathy also can

occur. Other clinical findings include endobronchial lesions, abdominal pain, diarrhea, and lymphadenopathy. Anemia and elevated liver

alkaline phosphatase are common. The diagnosis is made by the culture of blood or involved tissue. The finding of two consecutive sputum

samples positive for MAC is highly suggestive of pulmonary infection.

Cultures may take 2 weeks to turn positive. Therapy consists of a macrolide, usually clarithromycin, with ethambutol. Some physicians elect

to add a third drug from among rifabutin, ciprofloxacin, or amikacin in

patients with extensive disease. Therapy is continued until resolution of

clinical signs and symptoms, negative cultures, and CD4+ T-cell counts

>100/μL for 3–6 months in the setting of ART. Primary prophylaxis

for MAC is indicated in patients with HIV infection and CD4+ T-cell

counts <50/μL not immediately starting ART. (Table 202-11). This may

be discontinued in patients in whom ART induces a sustained suppression of viral replication regardless of the change in CD4+ T-cell count.

Rhodococcus equi is a gram-positive, pleomorphic, acid-fast,

non-spore-forming bacillus that can cause pulmonary and/or disseminated infection in patients with advanced HIV infection. Fever and

cough are the most common presenting signs. Radiographically one

may see cavitary lesions and consolidation. Blood cultures are often

positive. Treatment is based on antimicrobial sensitivity testing.

Fungal infections of the lung, in addition to PCP, can be seen in

patients with AIDS. Patients with pulmonary cryptococcal disease

present with fever, cough, dyspnea, and, in some cases, hemoptysis.

A focal or diffuse interstitial infiltrate is seen on chest x-ray in >90%

of patients. In addition, one may see lobar disease, cavitary disease,

pleural effusions, and hilar or mediastinal adenopathy. More than half

of patients are fungemic, and 90% of patients have concomitant CNS

infection. Coccidioides immitis is a mold that is endemic in the southwest United States. It can cause a reactivation pulmonary syndrome

in patients with HIV infection. Most patients with this condition will

have CD4+ T-cell counts <250/μL. Patients present with fever, weight

loss, cough, and extensive, diffuse reticulonodular infiltrates on chest

x-ray. One may also see nodules, cavities, pleural effusions, and hilar

adenopathy. While serologic testing is of value in the immunocompetent host, serologies are negative in 25% of HIV-infected patients with

coccidioidal infection. Invasive aspergillosis is not an AIDS-defining

illness and is generally not seen in patients with AIDS in the absence

of neutropenia or administration of glucocorticoids. When it does

occur, Aspergillus infection may have an unusual presentation in the

respiratory tract of patients with AIDS, where it gives the appearance

of a pseudomembranous tracheobronchitis. Primary pulmonary infection of the lung may be seen with histoplasmosis. The most common

pulmonary manifestation of histoplasmosis, however, is in the setting

of disseminated disease, presumably due to reactivation. In this setting

respiratory symptoms are usually minimal, with cough and dyspnea

occurring in 10–30% of patients. The chest x-ray is abnormal in ~50%

of patients, showing either a diffuse interstitial infiltrate or diffuse small

nodules, and the urine will often be positive for Histoplasma antigen.

Two forms of idiopathic interstitial pneumonia have been identified

in patients with HIV infection: lymphoid interstitial pneumonitis (LIP)

and nonspecific interstitial pneumonitis (NIP). LIP, a common finding

in children, is seen in about 1% of adult patients with untreated HIV

infection. This disorder is characterized by a benign infiltrate of the lung

and is thought to be part of the polyclonal activation of lymphocytes

seen in the context of HIV and EBV infections. Transbronchial biopsy

is diagnostic in 50% of the cases, with an open-lung biopsy required

for diagnosis in the remainder of cases. This condition is generally

self-limited, and no specific treatment is necessary. Severe cases have

been managed with brief courses of glucocorticoids. Although rarely a

clinical problem since the use of ART, evidence of NIP may be seen in

up to half of all patients with untreated HIV infection. Histologically,

interstitial infiltrates of lymphocytes and plasma cells in a perivascular

and peribronchial distribution are present. When symptomatic, patients

present with fever and nonproductive cough occasionally accompanied

by mild chest discomfort. Chest x-ray is usually normal or may reveal a

faint interstitial pattern. Like LIP, NIP is a self-limited process for which

no therapy is indicated other than appropriate management of the

underlying HIV infection. HIV-related pulmonary arterial hypertension (HIV-PAH) is seen in ~0.5% of HIV-infected individuals. Patients

may present with an array of symptoms including shortness of breath,

fatigue, syncope, chest pain, and signs of right-sided heart failure. Chest

x-ray reveals dilated pulmonary vessels and right-sided cardiomegaly

with right ventricular hypertrophy seen on electrocardiogram. ART

does not appear to be of clear benefit, and the prognosis is quite poor

with a median survival in the range of 2 years.

1568 PART 5 Infectious Diseases

Neoplastic diseases of the lung including KS and lymphoma are discussed below in the section on neoplastic diseases.

Diseases of the Cardiovascular System Heart disease is a relatively common postmortem finding in HIV-infected patients (25–75%

in autopsy series). The most common form of heart disease is coronary

heart disease. In one large series the overall rate of myocardial infarction

(MI) was 3.5/1000 patient-years, 28% of these events were fatal, and MI

was responsible for 7% of all deaths in the cohort. In patients with HIV

infection, cardiovascular disease may be associated with classic risk

factors such as smoking, a direct consequence of HIV infection, or a

complication of ART. Patients with HIV infection have higher levels of

triglycerides, lower levels of high-density lipoprotein cholesterol, and a

higher prevalence of smoking than cohorts of individuals without HIV

infection. The finding that the rate of cardiovascular disease events was

lower in patients on antiretroviral therapy than in those randomized to

undergo a treatment interruption identified a clear association between

HIV replication and risk of cardiovascular disease. In one study, a baseline CD4+ T-cell count of <500/μL was found to be an independent

risk factor for cardiovascular disease comparable in magnitude to that

attributable to smoking. While the precise pathogenesis of this association remains unclear, it is likely related to the immune activation and

increased propensity for coagulation seen because of HIV replication.

Exposure to HIV protease inhibitors and certain reverse transcriptase

inhibitors has been associated with increases in total cholesterol and/

or risk of MI. Any increases in the risk of death from MI resulting from

the use of certain antiretrovirals must be balanced against the marked

increases in overall survival brought about by these drugs.

Another form of heart disease associated with HIV infection is a

dilated cardiomyopathy associated with congestive heart failure (CHF)

referred to as HIV-associated cardiomyopathy. This generally occurs

as a late complication of HIV infection and, histologically, displays

elements of myocarditis. For this reason, some have advocated it be

treated with IV immunoglobulin (IVIg). HIV can be directly demonstrated in cardiac tissue in this setting, and there is debate over whether

HIV plays a direct role in this condition. Patients present with typical

findings of CHF including edema and shortness of breath. Patients

with HIV infection may also develop cardiomyopathy as side effects of

IFN-α or nucleoside analogue therapy. These are reversible once therapy is stopped. KS, cryptococcosis, Chagas’ disease, and toxoplasmosis

can involve the myocardium, leading to cardiomyopathy. In one series,

most patients with HIV infection and a treatable myocarditis were

found to have myocarditis associated with toxoplasmosis. Most of these

patients also had evidence of CNS toxoplasmosis. Thus, MRI or doubledose contrast CT scan of the brain should be included in the workup of

any patient with advanced HIV infection and cardiomyopathy.

A variety of other cardiovascular problems are found in patients

with HIV infection. Pericardial effusions may be seen in the setting

of advanced HIV infection. Predisposing factors include TB, CHF,

mycobacterial infection, cryptococcal infection, pulmonary infection,

lymphoma, and KS. While pericarditis is quite rare, in one series 5%

of patients with HIV disease had pericardial effusions that were considered to be moderate or severe. Tamponade and death have occurred

in association with pericardial KS, presumably owing to acute hemorrhage. Nonbacterial thrombotic endocarditis has been reported and

should be considered in patients with unexplained embolic phenomena. IV pentamidine, when given rapidly, can result in hypotension as

a consequence of cardiovascular collapse.

Diseases of the Oropharynx and Gastrointestinal System

Oropharyngeal and GI diseases are common features of HIV infection.

They are most frequently due to secondary infections. In addition, oral

and GI lesions may occur with KS and lymphoma.

Oral lesions, including thrush, hairy leukoplakia, and aphthous ulcers

(Fig. 202-35), are particularly common in patients with untreated HIV

infection. Thrush, due to Candida infection, and oral hairy leukoplakia, presumed due to EBV, are usually indicative of fairly advanced

immunologic decline; they generally occur in patients with CD4+

T-cell counts of <300/μL. In one study, 59% of patients with oral candidiasis went on to develop AIDS in the next year. Thrush appears as a

white, cheesy exudate, often on an erythematous mucosa in the posterior oropharynx. While most commonly seen on the soft palate, early

lesions are often found along the gingival vestibule. The diagnosis is

made by direct examination of a scraping for pseudohyphal elements.

Culturing is of no diagnostic value, as patients with HIV infection may

have a positive throat culture for Candida in the absence of thrush.

Oral hairy leukoplakia presents as white, frondlike lesions, generally

along the lateral borders of the tongue and sometimes on the adjacent

buccal mucosa (Fig. 202-35). Despite its name, oral hairy leukoplakia

is not considered a premalignant condition. Lesions are associated

with florid replication of EBV. While usually more disconcerting as

a sign of HIV-associated immunodeficiency than a clinical problem

in need of treatment, severe cases of oral hairy leukoplakia have been

reported to respond to topical podophyllin or systemic therapy with

anti-herpesvirus agents. Aphthous ulcers of the posterior oropharynx

also are seen with regularity in patients with untreated HIV infection

(Fig. 202-35). These lesions are of unknown etiology and can be quite

painful and interfere with swallowing. Topical anesthetics provide

immediate symptomatic relief of short duration. The fact that thalidomide is an effective treatment for this condition suggests that the

pathogenesis may involve the action of tissue-destructive cytokines.

Palatal, glossal, or gingival ulcers may also result from cryptococcal

disease or histoplasmosis.

Esophagitis (Fig. 202-36) may present with odynophagia and

retrosternal pain. Upper endoscopy is generally required to make an

accurate diagnosis. Esophagitis may be due to Candida, CMV, or HSV.

While CMV tends to be associated with a single large ulcer, HSV infection is more often associated with multiple small ulcers. The esophagus

may also be the site of KS and lymphoma. Like the oral mucosa, the

esophageal mucosa may have large, painful ulcers of unclear etiology

that may respond to thalidomide. While achlorhydria is a common

problem in patients with HIV infection, other gastric problems are

generally rare. Among the neoplastic conditions involving the stomach

are KS and lymphoma.

Infections of the small and large intestine leading to diarrhea,

abdominal pain, and occasionally fever are among the most significant

GI problems in HIV-infected patients. They include infections with

bacteria, protozoa, and viruses.

Bacteria may be responsible for infections of the GI tract in patients

with HIV infection. Infections with enteric pathogens such as Salmonella, Shigella, and Campylobacter are more common in men who have

sex with men and are often more severe and more apt to relapse in

patients with HIV infection. Patients with untreated HIV have approximately a 20-fold increased risk of infection with S. typhimurium. They

may present with a variety of nonspecific symptoms including fever,

anorexia, fatigue, and malaise of several weeks’ duration. Diarrhea is

common but may be absent. Diagnosis is made by culture of blood

and stool. Long-term therapy with ciprofloxacin is the recommended

treatment. HIV-infected patients also have an increased incidence of

S. typhi infection in areas of the world where typhoid is a problem.

Shigella spp., particularly S. flexneri, can cause severe intestinal disease

in HIV-infected individuals. Up to 50% of patients with GI disease will

develop bacteremia. Campylobacter infections occur with an increased

frequency in patients with HIV infection. While C. jejuni is the strain

most frequently isolated, infections with many other strains have

been reported. Patients usually present with crampy abdominal pain,

fever, and bloody diarrhea. Infection may also present as proctitis.

Stool examination reveals the presence of fecal leukocytes. Systemic

infection can occur, with up to 10% of infected patients exhibiting bacteremia. Most strains are sensitive to erythromycin. Abdominal pain

and diarrhea may be seen with MAC infection, and patients with HIV

infection may have persistent diarrhea due to enteroaggregative E. coli.

Fungal infections may also be a cause of diarrhea in patients with

HIV infection. Histoplasmosis, coccidioidomycosis, and penicilliosis

have all been identified as a cause of fever and diarrhea in patients with

HIV infection. Peritonitis has been seen with C. immitis.

Cryptosporidia, microsporidia, and Isospora belli (Chap. 224) are

the most common opportunistic protozoa that infect the GI tract and

cause diarrhea in HIV-infected patients. Cryptosporidial infection may

1569CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

FIGURE 202-35 Various oral lesions in HIV-infected individuals. A. Thrush. B. Hairy leukoplakia. C. Aphthous ulcer. D. Kaposi’s sarcoma.

FIGURE 202-36 Barium swallow of a patient with Candida esophagitis. The flow of

barium along the mucosal surface is grossly irregular.

A B

C D

present in a variety of ways, ranging from a self-limited or intermittent

diarrheal illness in patients in the early stages of HIV infection to a

severe, life-threatening diarrhea in severely immunodeficient individuals. In patients with untreated HIV infection and CD4+ T-cell counts

of <300/μL, the incidence of cryptosporidiosis is ~1% per year. In 75%

of cases the diarrhea is accompanied by crampy abdominal pain, and

25% of patients have nausea and/or vomiting. Cryptosporidia may

also cause biliary tract disease in the HIV-infected patient, leading to

cholecystitis with or without accompanying cholangitis and pancreatitis secondary to papillary stenosis. The diagnosis of cryptosporidial

diarrhea is made by stool examination or biopsy of the small intestine.

The diarrhea is noninflammatory, and the characteristic finding is the

presence of oocysts that stain with acid-fast dyes. Therapy is predominantly supportive and marked improvements have been reported in the

setting of effective ART. Treatment with up to 2000 mg/d of nitazoxanide (NTZ) is associated with improvement in symptoms or a decrease

in shedding of organisms in about half of patients. Its overall role in the

management of this condition remains unclear. Patients can minimize

their risk of developing cryptosporidiosis by avoiding contact with

human and animal feces, by not drinking untreated water from lakes

or rivers, and by not eating raw shellfish.

Microsporidia are small, unicellular, obligate intracellular parasites

that reside in the cytoplasm of enteric cells (Chap. 224). The main

1570 PART 5 Infectious Diseases

species causing disease in humans is Enterocytozoon bieneusi. The

clinical manifestations are similar to those described for cryptosporidia

and include abdominal pain, malabsorption, diarrhea, and cholangitis.

The small size of the organism may make it difficult to detect; however,

with the use of chromotrope-based stains, organisms can be identified

in stool samples by light microscopy. Definitive diagnosis generally

depends on electron-microscopic examination of a stool specimen,

intestinal aspirate, or intestinal biopsy specimen. In contrast to cryptosporidia, microsporidia have been noted in a variety of extraintestinal

locations, including the eye, brain, sinuses, muscle, and liver, and they

have been associated with conjunctivitis and hepatitis. The most effective way to deal with microsporidia in a patient with HIV infection is

to restore the immune system by treating the HIV infection with ART.

Albendazole, 400 mg bid, has been reported to be of benefit in some

patients.

I. belli is a coccidian parasite (Chap. 224) most commonly found as

a cause of diarrhea in patients from tropical and subtropical regions.

Its cysts appear in the stool as large, acid-fast structures that can be

differentiated from those of cryptosporidia based on size, shape, and

number of sporocysts. The clinical syndromes of Isospora infection are

identical to those caused by cryptosporidia. The important distinction

is that infection with Isospora is generally relatively easy to treat with

TMP-SMX. While relapses are common, a thrice-weekly regimen of

TMP-SMX appears adequate to prevent recurrence.

CMV colitis was once seen as a consequence of advanced immunodeficiency in 5–10% of patients with AIDS. It is much less common

with the advent of ART. CMV colitis presents as diarrhea, abdominal

pain, weight loss, and anorexia. The diarrhea is usually nonbloody,

and the diagnosis is achieved through endoscopy and biopsy. Multiple

mucosal ulcerations are seen at endoscopy, and biopsies reveal characteristic intranuclear and cytoplasmic inclusion bodies. Secondary

bacteremias may result as a consequence of thinning of the bowel wall.

Treatment is with either valganciclovir/ganciclovir or foscarnet for

3–6 weeks. Relapses are common, and maintenance therapy is typically necessary in patients whose HIV infection is poorly controlled.

Patients with CMV disease of the GI tract should be carefully monitored for evidence of CMV retinitis.

In addition to disease caused by specific secondary infections,

patients with HIV infection may also experience a chronic diarrheal

syndrome for which no etiologic agent other than HIV can be identified. This entity is referred to as AIDS enteropathy or HIV enteropathy. It is most likely a direct result of HIV infection in the GI tract

and improves with ART. Histologic examination of the small bowel

in these patients reveals low-grade mucosal atrophy with a decrease

in mitotic figures, suggesting a hyporegenerative state. Patients often

have decreased or absent small-bowel lactase and malabsorption with

accompanying weight loss.

The initial evaluation of a patient with HIV infection and diarrhea

should include a set of stool examinations, including culture, examination for ova and parasites, and examination for Clostridium difficile

toxin. Approximately 50% of the time this workup will demonstrate

infection with pathogenic bacteria, mycobacteria, or protozoa. If the

initial stool examinations are negative, additional evaluation, including

upper and/or lower endoscopy with biopsy, will yield a diagnosis of

microsporidial or mycobacterial infection of the small intestine ~30%

of the time. In patients for whom this diagnostic evaluation is nonrevealing, a presumptive diagnosis of HIV enteropathy can be made if the

diarrhea has persisted for >1 month. An algorithm for the evaluation of

diarrhea in patients with HIV infection is given in Fig. 202-37.

Rectal lesions are common in HIV-infected patients, particularly

the perirectal ulcers and erosions due to the reactivation of HSV

(Fig. 202-38). These lesions may appear quite atypical, as denuded skin

without vesicles. They typically respond well to treatment with valacyclovir, famciclovir, or foscarnet. Other rectal lesions encountered in

patients with HIV infection include condylomata acuminata, KS, and

intraepithelial neoplasia (see below).

Hepatobiliary Diseases Diseases of the hepatobiliary system are

a major problem in patients with HIV infection. It has been estimated

that approximately 15% of the deaths of patients with HIV infection

are related to liver disease. While this is predominantly a reflection of

the problems encountered in the setting of co-infection with hepatitis B

or C, it is also a reflection of the hepatic injury, ranging from hepatic

steatosis to hypersensitivity reactions to immune reconstitution, that

can be seen in the context of ART.

The prevalence of co-infection with HIV and hepatitis viruses varies by geographic region. In the United States, ~90% of HIV-infected

individuals have evidence of infection with HBV; 6–14% have chronic

HBV infection; 5–50% of patients are co-infected with HCV; and

co-infections with hepatitis D, E, and/or G viruses are common.

Among IV drug users with HIV infection, rates of HCV infection

Treat

Treat

History and physical

Stool culture for enteric pathogens

Stool for ova and parasites x 3

Stool for Clostridium difficile toxin

No suspicion of colitis Suspicion of colitis

Upper endoscopy

and biopsy Diagnosis Colonoscopy

and biopsy

Diagnosis

No diagnosis

No diagnosis

HIV-Associated Enteropathy

FIGURE 202-37 Algorithm for the evaluation of diarrhea in a patient with HIV

infection. HIV-associated enteropathy is a diagnosis of exclusion and can be made

only after other, generally treatable, forms of diarrheal illness have been ruled out.

FIGURE 202-38 Severe, erosive perirectal herpes simplex in a patient with AIDS.

1571CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

range from 70 to 95%. HIV infection has a significant impact on the

course of hepatitis virus infection. It is associated with approximately a

threefold increase in the development of persistent hepatitis B surface

antigenemia. Patients infected with both HBV and HIV have decreased

evidence of inflammatory liver disease. The presumption that this is

due to the immunosuppressive effects of HIV infection is supported

by the observations that this situation can be reversed, and one may

see the development of more severe hepatitis following the initiation

of effective ART. In studies of the impact of HIV on HBV infection,

four- to tenfold increases in liver-related mortality rates have been

noted in patients with HIV and active HBV infection compared to

rates in patients with either infection alone. There is, however, only

a slight increase in overall mortality rate in HIV-infected individuals

who are also hepatitis B surface antigen (HBsAg)–positive. IFN-α is

less successful as treatment for HBV in patients with HIV co-infection.

Lamivudine, emtricitabine, adefovir/tenofovir/entecavir, and telbivudine alone or in combination are useful in the treatment of hepatitis B

in patients with HIV infection. It is important to remember that all the

above-mentioned drugs also have activity against HIV and should not

be used alone in patients with HIV infection, to avoid the emergence of

quasispecies of HIV resistant to these drugs. For this reason, the treatment of hepatitis B infection in a patient with HIV infection should

always be done in the setting of ART, and alterations in ART need to

take into account that the current regimen is also treating HBV. HCV

infection is more severe in the patient with HIV infection; it does not

appear to affect overall mortality rates in HIV-infected individuals

when other variables such as age, baseline CD4+ T-cell count, and

use of ART are taken into account. In the setting of HIV and HCV

co-infection, levels of HCV are approximately tenfold higher than in

the HIV-negative patient with HCV infection. There is a 50% higher

overall mortality rate with a five-fold increased risk of death due to

liver disease in patients chronically infected with both HCV and HIV.

Use of directly acting agents for the treatment of HCV leads to cure

rates approaching 100%, even in patients with HIV co-infection. Successful treatment of HCV in HIV-infected patients decreases mortality.

Hepatitis A virus infection is not seen with an increased frequency

in patients with HIV infection. It is recommended that all patients

with HIV infection who have not experienced natural infection be

immunized with hepatitis A and/or hepatitis B vaccines. Infection with

hepatitis G virus, also known as GB virus C, is seen in ~50% of patients

with HIV infection. For reasons that are currently unclear, there are

data to suggest that patients with HIV infection co-infected with this

virus have a decreased rate of progression to AIDS.

A variety of other infections also may involve the liver. Granulomatous hepatitis may be seen as a consequence of mycobacterial or

fungal infections, particularly MAC infection. Hepatic masses may be

seen in the context of TB, peliosis hepatis, or fungal infection. Among

the fungal opportunistic infections, C. immitis and Histoplasma capsulatum are those most likely to involve the liver. Biliary tract disease

in the form of papillary stenosis or sclerosing cholangitis has been

reported in the context of cryptosporidiosis, CMV infection, and KS.

When no diagnosis can be made, the term AIDS cholangiopathy is used.

Hemophagocytic lymphohistiocytosis of the liver has been seen in the

setting of Hodgkin’s disease and may occur prior to diagnosis of the

underlying neoplasm.

Many of the drugs used to treat HIV infection are metabolized by

the liver and can cause liver injury. Fatal hepatic reactions have been

reported with a wide array of antiretrovirals including nucleoside

analogues, nonnucleoside analogues, and protease inhibitors. Nucleoside analogues work by inhibiting DNA synthesis. This can result in

toxicity to mitochondria, which can lead to disturbances in oxidative

metabolism. This may manifest as hepatic steatosis and, in severe cases,

lactic acidosis and fulminant liver failure. It is important to be aware

of this condition and to watch for it in patients with HIV infection

receiving nucleoside analogues. It is reversible if diagnosed early and

the offending agent(s) discontinued. Nevirapine has been associated

with at times fatal fulminant and cholestatic hepatitis, hepatic necrosis,

and hepatic failure. Indinavir may cause mild to moderate elevations

in serum bilirubin in 10–15% of patients in a syndrome similar to

Gilbert’s syndrome. A similar pattern of hepatic injury may be seen

with atazanavir. In the patient receiving ART with an unexplained

increase in hepatic transaminases, strong consideration should be

given to drug toxicity.

Pancreatic injury is most commonly a consequence of drug toxicity,

notably that secondary to pentamidine or dideoxynucleosides. While

up to half of patients in some series have biochemical evidence of

pancreatic injury, <5% of patients show any clinical evidence of pancreatitis that is not linked to a drug toxicity.

Diseases of the Kidney and Genitourinary Tract Diseases of

the kidney or genitourinary tract may be a direct consequence of HIV

infection, due to an opportunistic infection or neoplasm, or related to

drug toxicity. Overall, microalbuminuria is seen in ~20% of untreated

HIV-infected patients; significant proteinuria is seen in closer to

2%. The presence of microalbuminuria has been associated with an

increase in all-cause mortality. HIV-associated nephropathy (HIVAN)

was first described in IDUs and was initially thought to be IDU nephropathy in patients with HIV infection; it is now recognized as a true

direct complication of HIV infection. Although most patients with this

condition have CD4+ T-cell counts <200/μL, HIV-associated nephropathy can be an early manifestation of HIV infection and is also seen in

children. Over 90% of reported cases have been in African-American

or Hispanic individuals; the disease is not only more prevalent in these

populations but also more severe and is the third leading cause of endstage renal failure among African Americans age 20–64 in the United

States. Proteinuria is the hallmark of this disorder. Edema and hypertension are rare. Ultrasound examination reveals enlarged, hyperechogenic kidneys. A definitive diagnosis is obtained through renal

biopsy. Histologically, focal segmental glomerulosclerosis is present in

80%, and mesangial proliferation in 10–15% of cases. Prior to effective

antiretroviral therapy, this disease was characterized by relatively rapid

progression to end-stage renal disease. Patients with HIV-associated

nephropathy should be treated for their HIV infection. Treatment with

angiotensin-converting enzyme (ACE) inhibitors and/or prednisone,

60 mg/d, also has been reported to be of benefit in some cases. The

incidence of this disease in patients receiving adequate ART has not

been well defined; however, the impression is that it has decreased in

frequency and severity. It is the leading cause of end-stage renal disease

in patients with HIV infection.

Among the drugs commonly associated with renal damage in

patients with HIV disease are pentamidine, amphotericin, adefovir,

cidofovir, tenofovir, and foscarnet. Switching from TDF to TAF may

lead to a decrease in renal injury from tenofovir. TMP-SMX may

compete for tubular secretion with creatinine and cause an increase

in the serum creatinine level. The pharmacokinetic booster cobicistat,

a component of several fixed-drug ART formulations, inhibits renal

tubular secretion of creatinine leading to increased serum creatinine

levels without a true decline in glomerular filtration rate. Sulfadiazine

may crystallize in the kidney and result in an easily reversible form of

renal shutdown, while indinavir or atazanavir may form renal calculi.

Adequate hydration is the mainstay of treatment and prevention for

these latter two conditions.

Genitourinary tract infections are seen with a high frequency in

patients with HIV infection; they present with skin lesions, dysuria,

hematuria, and/or pyuria and are managed in the same fashion as

in patients without HIV infection. Infections with HSV are covered

below (“Dermatologic Diseases”). Infections with T. pallidum, the

etiologic agent of syphilis, play an important role in the HIV epidemic.

In HIV-negative individuals, genital syphilitic ulcers as well as the

ulcers of chancroid are major predisposing factors for heterosexual

transmission of HIV infection. While most HIV-infected individuals

with syphilis have a typical presentation, a variety of formerly rare

clinical problems may be encountered in the setting of dual infection.

Among them are lues maligna, an ulcerating lesion of the skin due

to a necrotizing vasculitis; unexplained fever; nephrotic syndrome;

and neurosyphilis. The most common presentation of syphilis in the

HIV-infected patient is that of condylomata lata, a form of secondary

syphilis. Neurosyphilis may be asymptomatic or may present as acute

1572 PART 5 Infectious Diseases

meningitis, neuroretinitis, deafness, or stroke. The rate of neurosyphilis

may be as high as 1% in patients with HIV infection, and one should

consider a lumbar puncture to look for neurosyphilis in all patients

with HIV infection and secondary syphilis. As a consequence of the

immunologic abnormalities seen in the setting of HIV infection, diagnosis of syphilis through standard serologic testing may be challenging.

On the one hand, a significant number of patients have false-positive

Venereal Disease Research Laboratory (VDRL) tests due to polyclonal

B-cell activation. On the other hand, the development of a new positive VDRL may be delayed in patients with new infections, and the

anti–fluorescent treponemal antibody (anti-FTA) test may be negative

due to immunodeficiency. Thus, dark-field examination of appropriate

specimens should be performed in any patient in whom syphilis is suspected, even if the patient has a negative VDRL. Similarly, any patient

with a positive serum VDRL test, neurologic findings, and an abnormal

spinal fluid examination should be considered to have neurosyphilis

and treated accordingly, regardless of the CSF VDRL result. In any

setting, patients treated for syphilis need to be carefully monitored

to ensure adequate therapy. Approximately one-third of patients with

HIV infection will experience a Jarisch-Herxheimer reaction upon

initiation of therapy for syphilis.

Vulvovaginal candidiasis is a common problem in women with HIV

infection. Symptoms include pruritus, discomfort, dyspareunia, and

dysuria. Vulvar infection may present as a morbilliform rash that may

extend to the thighs. Vaginal infection is usually associated with a white

discharge, and plaques may be seen along an erythematous vaginal

wall. Diagnosis is made by microscopic examination of the discharge

for pseudohyphal elements in a 10% potassium hydroxide solution.

Mild disease can be treated with topical therapy. More serious disease

can be treated with fluconazole. Other causes of vaginitis include Trichomonas and mixed bacteria.

Diseases of the Endocrine System and Metabolic Disorders

A variety of endocrine and metabolic disorders are seen in the context

of HIV infection. These may be a direct consequence of HIV infection,

secondary to opportunistic infections or neoplasms, or related to medication side effects. Between 33 and 75% of patients with HIV infection

receiving thymidine analogues or protease inhibitors as a component

of ART develop a syndrome often referred to as lipodystrophy, consisting of elevations in plasma triglycerides, total cholesterol, and apolipoprotein B, as well as hyperinsulinemia and hyperglycemia. Many

of the patients have been noted to have a characteristic set of body

habitus changes associated with fat redistribution, consisting of truncal

obesity coupled with peripheral wasting (Fig. 202-39). Truncal obesity

is apparent as an increase in abdominal girth related to increases in

mesenteric fat, a dorsocervical fat pad (“buffalo hump”) reminiscent

of patients with Cushing’s syndrome, and enlargement of the breasts.

The peripheral wasting, or lipoatrophy, is particularly noticeable in the

face and buttocks and by the prominence of the veins in the legs. These

changes may develop at any time ranging from ~6 weeks to several

years following the initiation of ART. Approximately 20% of the patients with HIV-associated

lipodystrophy meet the criteria for the metabolic

syndrome as defined by The International Diabetes Federation or The U.S. National Cholesterol

Education Program Adult Treatment Panel III.

The lipodystrophy syndrome has been reported

in association with regimens containing a variety

of different drugs, and while initially reported

in the setting of protease inhibitor therapy, it

appears that similar changes can also be induced by

protease-sparing regimens. It has been suggested

that the lipoatrophy changes are particularly severe

in patients receiving the thymidine analogues stavudine and zidovudine. Current treatment guidelines avoid these drugs and recommend drugs with

fewer of these side effects. National Cholesterol

Education Program (NCEP) guidelines should be

followed in the management of these lipid abnormalities (Chap. 400), and consideration should be

given to changing the components of ART with

avoidance of thymidine analogues (azidothymidine and stavudine) and offending protease inhibitors. Due to concerns regarding drug interactions,

the most utilized lipid-lowering agents in this

setting are gemfibrozil and atorvastatin. In addition, lactic acidosis is associated with ART. This is

most often seen with nucleoside analogue reverse

transcriptase inhibitors and can be fatal.

Patients with advanced HIV disease may

develop hyponatremia due to the syndrome of

inappropriate antidiuretic hormone (vasopressin)

secretion (SIADH) because of increased free-water

intake and decreased free-water excretion. SIADH

is usually seen in conjunction with pulmonary

or CNS disease. Low serum sodium may also be

due to adrenal insufficiency; a concomitant high

serum potassium should alert one to this possibility. Hyperkalemia may be secondary to adrenal

insufficiency; HIV nephropathy; or medications,

particularly trimethoprim and pentamidine.

Hypokalemia may be seen in the setting of tenofovir or amphotericin therapy. Adrenal gland disease

may be due to mycobacterial infections, CMV

A B

C

FIGURE 202-39 Characteristics of lipodystrophy. A. Truncal obesity and buffalo hump. B. Facial wasting.

C. Accumulation of intraabdominal fat on CT scan.

1573CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

disease, cryptococcal disease, histoplasmosis, or ketoconazole toxicity.

Iatrogenic Cushing’s syndrome with suppression of the hypothalamicpituitary-adrenal axis may be seen with the use of local glucocorticoids

(injected or inhaled) in patients receiving ritonavir or cobicistat. This

is due to inhibition of the hepatic enzyme CYP3A4 by ritonavir leading

to prolongation of the glucocorticoid half-life.

Thyroid function may be altered in 10–15% of patients with HIV

infection. Both hypo- and hyperthyroidism may be seen. The predominant abnormality is subclinical hypothyroidism. In the setting

of ART, up to 10% of patients have been noted to have elevated

thyroid-stimulating hormone levels, suggesting that this may be a manifestation of immune reconstitution. Immune-reconstitution Graves’

disease may occur as a late (9–48 months) complication of ART. In

advanced HIV disease, infection of the thyroid gland may occur with

opportunistic pathogens, including P. jirovecii, CMV, mycobacteria,

Toxoplasma gondii, and Cryptococcus neoformans. These infections

are generally associated with a nontender, diffuse enlargement of the

thyroid gland. Thyroid function is usually normal. Diagnosis is made

by fine-needle aspirate or open biopsy.

Depending on the severity of disease, HIV infection is associated

with hypogonadism in 20–50% of men and is lowest in the setting of

ART. While this is generally a complication of underlying illness, testicular dysfunction may also be a side effect of ganciclovir therapy. In

some surveys, up to two-thirds of patients report decreased libido and

one-third complain of erectile dysfunction. Androgen-replacement

therapy should be considered in patients with symptomatic hypogonadism. HIV infection does not seem to have a significant effect on the

menstrual cycle outside the setting of advanced disease.

Immunologic and Rheumatologic Diseases Immunologic and

rheumatologic disorders are common in patients with HIV infection

and range from excessive immediate-type hypersensitivity reactions

(Chap. 347) to an increase in the incidence of reactive arthritis

(Chap.  355) to conditions characterized by a diffuse infiltrative

lymphocytosis. The occurrence of these phenomena is an apparent paradox in the setting of the profound immunodeficiency and

immunosuppression that characterizes HIV infection and reflects the

complex nature of the immune system and its regulatory mechanisms.

Drug allergies are the most significant allergic reactions occurring

in HIV-infected patients and appear to become more common as the

disease progresses. They occur in up to 65% of patients who receive

therapy with TMP-SMX for PCP. In general, these drug reactions are

characterized by erythematous, morbilliform eruptions that are pruritic, tend to coalesce, and are often associated with fever. Nonetheless,

~33% of patients can be maintained on the offending therapy, and thus

these reactions are not an immediate indication to stop the drug. Anaphylaxis is extremely rare in patients with HIV infection, and patients

who have a cutaneous reaction during a single course of therapy can

still be considered candidates for future treatment or prophylaxis with

the same agent. The one exception to this is the nucleoside analogue

abacavir, where fatal hypersensitivity reactions have been reported

with rechallenge. This hypersensitivity is strongly associated with the

HLA-B5701 haplotype, and a hypersensitivity reaction to abacavir

is an absolute contraindication to future therapy. For other agents,

including TMP-SMX, desensitization regimens are moderately successful. While the mechanisms underlying these allergic-type reactions

remain unknown, patients with HIV infection have been noted to have

elevated IgE levels that increase as the CD4+ T-cell count declines. The

numerous examples of patients with multiple drug reactions suggest

that a common pathway is involved.

HIV infection shares many similarities with a variety of autoimmune diseases, including a substantial polyclonal B-cell activation that

is associated with a high incidence of antiphospholipid antibodies, such

as anticardiolipin antibodies, VDRL antibodies, and lupus-like anticoagulants. In addition, HIV-infected individuals have an increased

incidence of antinuclear antibodies. Despite these serologic findings,

there is no evidence that HIV-infected individuals have an increase in

two of the more common autoimmune diseases, i.e., systemic lupus

erythematosus and rheumatoid arthritis. In fact, it has been observed

that these diseases may be somewhat ameliorated by the concomitant

presence of HIV infection, suggesting that an intact CD4+ T-cell limb

of the immune response plays an integral role in the pathogenesis

of these conditions. Similarly, there are anecdotal reports of patients

with common variable immunodeficiency (Chap. 344), characterized by hypogammaglobulinemia, who have had a normalization of

Ig levels following the development of HIV infection, suggesting a

possible role for overactive CD4+ T-cell immunity in certain forms

of that syndrome. The one autoimmune disease that may occur with

an increased frequency in patients with HIV infection is a variant of

primary Sjögren’s syndrome (Chap. 354) in which patients with HIV

infection develop a syndrome consisting of parotid gland enlargement,

dry eyes, and dry mouth. This condition is associated with lymphocytic

infiltrates of the salivary gland and lung. One also can see peripheral

neuropathy, polymyositis, renal tubular acidosis, and hepatitis. In

contrast to Sjögren’s syndrome, in which the lymphocytic infiltrates

are composed predominantly of CD4+ T cells, in patients with HIV

infection the infiltrates are composed predominantly of CD8+ T cells.

In addition, while patients with Sjögren’s syndrome are mainly women

who have autoantibodies to Ro and La and who frequently have

HLA-DR3 or B8 MHC haplotypes, HIV-infected individuals with this

syndrome are usually African-American men who do not have anti-Ro

or anti-La and who most often are HLA-DR5. This syndrome appears

to be less common with the increased use of effective ART. The term

diffuse infiltrative lymphocytosis syndrome (DILS) is used to describe

this entity and to distinguish it from Sjögren’s syndrome.

Approximately one-third of HIV-infected individuals experience

arthralgias; furthermore, 5–10% are diagnosed as having some form

of reactive arthritis, such as Reiter’s syndrome or psoriatic arthritis

as well as undifferentiated spondyloarthropathy (Chap. 355). These

syndromes occur with increasing frequency as the competency of

the  immune system declines. This association may be related to an

increase in the number of infections with organisms that may trigger

a reactive arthritis with progressive immunodeficiency or to a loss

of important regulatory T cells. Reactive arthritides in HIV-infected

individuals generally respond well to standard treatment; however,

therapy with methotrexate has been associated with an increase in the

incidence of opportunistic infections and should be used with caution

and only in severe cases.

HIV-infected individuals also experience a variety of joint problems without obvious cause that are referred to generically as HIV- or

AIDS-associated arthropathy. This syndrome is characterized by subacute oligoarticular arthritis developing over a period of 1–6 weeks

and lasting 6 weeks to 6 months. It generally involves the large joints,

predominantly the knees and ankles, and is nonerosive with only a

mild inflammatory response. X-rays are nonrevealing. Nonsteroidal

anti-inflammatory drugs are only marginally helpful; however, relief

has been noted with the use of intraarticular glucocorticoids. A second

form of arthritis also thought to be secondary to HIV infection is called

painful articular syndrome. This condition, reported as occurring in as

many as 10% of AIDS patients, presents as an acute, severe, sharp pain

in the affected joint. It affects primarily the knees, elbows, and shoulders; lasts 2–24 h; and may be severe enough to require narcotic analgesics. The cause of this arthropathy is unclear; however, it is thought

to result from a direct effect of HIV on the joint. This condition is

reminiscent of the fact that other lentiviruses, in particular the caprine

arthritis-encephalitis virus, are capable of directly causing arthritis.

A variety of other immunologic or rheumatologic diseases have

been reported in HIV-infected individuals, either de novo or in association with opportunistic infections or drugs. Using the criteria of

widespread musculoskeletal pain of at least 3 months’ duration and the

presence of at least 11 of 18 possible tender points by digital palpation,

11% of an HIV-infected cohort containing 55% IDUs were diagnosed

as having fibromyalgia (Chap. 366). While the incidence of frank

arthritis was less in this population than in other studied populations

that consisted predominantly of men who have sex with men, these

data support the concept that there are musculoskeletal problems that

occur as a direct result of HIV infection. CNS angiitis and polymyositis

also have been reported in HIV-infected individuals. Septic arthritis is