1534 PART 5 Infectious Diseases

added indirect benefit of diminution of risk for HIV acquisition to the

female sexual partners of circumcised men.

In some studies, the use of oral contraceptives was associated with

an increase in incidence of HIV infection over and above that which

might be expected by not using a condom for birth control. This phenomenon may be due to drug-induced changes in the cervical mucosa,

rendering it more vulnerable to penetration by the virus. Adolescent

girls might also be more susceptible to infection upon exposure due

to the properties of an immature genital tract with increased cervical

ectopy or exposed columnar epithelium.

Oral sex is a much less efficient mode of transmission of HIV than is

anal intercourse or vaginal intercourse (Table 202-3). Multiple studies

have reported that the incidence of transmission of infection by oral

sex among couples discordant for HIV is extremely low. However, there

have been well-documented reports of HIV transmission that likely

resulted from fellatio or cunnilingus. Therefore, the assumption that

oral sex is completely safe is not warranted.

The association of alcohol consumption and illicit drug use with

unsafe sexual behavior, both homosexual and heterosexual, leads to an

increased risk of sexual transmission of HIV. Methamphetamine and

other so-called club drugs such as 3,4-methylenedioxymethamphetamine

(MDMA; also known as “ecstasy”), ketamine, gamma-hydroxybutyrate

(GHB), and inhaled nitrites (known as “poppers”), sometimes taken in

conjunction with PDE-5 inhibitors such as sildenafil (Viagra), tadalafil

(Cialis), or vardenafil (Levitra), have been associated with risky sexual

practices and increased risk of HIV infection, particularly among men

who have sex with men.

■ TRANSMISSION THROUGH INJECTION DRUG USE

HIV can be transmitted to injection drug users (IDUs) who are exposed

to HIV while sharing injection paraphernalia such as needles, syringes,

the water in which drugs are mixed, or the cotton through which drugs

are filtered. Parenteral transmission of HIV during injection drug

use does not require IV puncture; subcutaneous (“skin popping”) or

intramuscular (“muscling”) injections can transmit HIV as well, even

though these behaviors are sometimes erroneously perceived as low

risk. Among IDUs, the risk of HIV infection increases with the duration of injection drug use; the frequency of needle sharing; the number

of partners with whom paraphernalia are shared, comorbid psychiatric

conditions such as antisocial personality disorder; the use of cocaine

in injectable form or smoked as “crack”; and the use of injection drugs

in a geographic location with a high prevalence of HIV infection. As

noted in Table 202-3, the per-act risk of transmission from injection

drug use with a contaminated needle has been estimated to be approximately 0.6%.

■ TRANSMISSION BY TRANSFUSED BLOOD AND

BLOOD PRODUCTS

HIV can be transmitted to individuals who receive HIV-contaminated

blood transfusions, blood products, or transplanted tissue. The vast

majority of HIV infections acquired via contaminated blood transfusions, blood components, or transplanted tissue in resource-rich

countries occurred prior to the spring of 1985, when mandatory testing

of donated blood for HIV-1 was initiated. It is estimated that >90%

of individuals exposed to HIV-contaminated blood products become

infected (Table 202-3). Transfusions of whole blood, packed red

blood cells, platelets, leukocytes, and plasma are all capable of transmitting HIV infection. In contrast, hyperimmune gamma globulin,

hepatitis B immune globulin, plasma-derived hepatitis B vaccine, and

Rho

 immune globulin have not been associated with transmission of

HIV infection. The procedures involved in processing these products

either inactivate or remove the virus.

Currently, in the United States and in most developed countries,

the following measures have made the risk of transmission of HIV

infection by transfused blood or blood products extremely small: the

screening of blood donations for antibodies to HIV-1 and HIV-2 and

determination of the presence of HIV nucleic acid usually in minipools

of several specimens; the careful selection of potential blood donors

with health history questionnaires to exclude individuals with risk

behavior; and opportunities for self-deferral and the screening out of

HIV-negative individuals with serologic testing for infections that have

shared risk factors with HIV, such as hepatitis B and C and syphilis.

The chance of infection of a hemophiliac via clotting factor concentrates has essentially been eliminated because of standard screening

of blood together with the added layer of safety resulting from heat

treatment of the concentrates. It is currently estimated that the risk of

infection with HIV in the United States via transfused screened blood

is approximately 1 in 2 million units. Since nearly 21 million blood

components are transfused in the United States each year, completely

eliminating the risk of transfusion-related HIV transmission likely

will not be possible. Transmission of HIV (both HIV-1 and HIV-2) by

blood or blood products is still an ongoing threat in certain developing

countries where routine screening of blood is not universally practiced.

Furthermore, there have been reports in certain countries of sporadic

breakdowns in routinely available screening procedures in which contaminated blood was transfused, resulting in small clusters of patients

becoming infected.

■ OCCUPATIONAL TRANSMISSION OF HIV: HEALTH

CARE WORKERS, LABORATORY WORKERS, AND THE

HEALTH CARE SETTING

There is a small but definite occupational risk of HIV transmission to

health care workers and laboratory personnel and potentially others

who work with HIV-containing materials, particularly when sharp

objects are used. More than 300,000 health care workers are stuck with

needles or other sharp medical instruments in the United States each

year. The global number of HIV infections among health care workers

attributable to sharps injuries has been estimated to be 1000 cases

(range, 200–5000) per year. In the United States, a total of 58 documented cases of occupational HIV transmission to health care workers,

and 150 possible transmissions have been reported by the CDC. Since

1999, only one confirmed case (a laboratory technician sustaining a

needle puncture while working with a live HIV culture in 2008) has

been reported.

Exposures that place a health care worker at potential risk of HIV

infection are percutaneous injuries (e.g., a needle stick or cut with a

sharp object) or contact of mucous membrane or nonintact skin (e.g.,

exposed skin that is chapped, abraded, or afflicted with dermatitis)

with blood, tissue, or other potentially infectious body fluids. Large,

multi-institutional studies have indicated that the risk of HIV transmission following skin puncture from a needle or a sharp object that

was contaminated with blood from a person with documented HIV

infection is ~0.23% and after a mucous membrane exposure it is

~0.09% (see “HIV and the Health Care Worker,” below) if the injured

and/or exposed person is not treated within 24 hours with antiretroviral drugs. The risk of hepatitis B virus (HBV) infection following a

similar type of exposure is ~6–30% in nonimmune individuals; if a

susceptible worker is exposed to HBV, postexposure prophylaxis with

hepatitis B immune globulin and initiation of HBV vaccine is >90%

effective in preventing HBV infection. The risk of HCV infection following percutaneous injury is ~1.8% (Chap. 339).

Rare HIV transmission after nonintact skin exposure has been documented, but the average risk for transmission by this route has not

been precisely determined; however, it is estimated to be less than the

risk for mucous membrane exposure. Transmission of HIV through

intact skin has not been documented. All health care workers experiencing a puncture wound or mucous membrane exposures involving

blood from a patient with documented HIV infection should be treated

prophylactically with combination antiretroviral therapy (ART). This

practice, referred to as postexposure prophylaxis or PEP, has dramatically reduced the occurrence of puncture-related transmissions of HIV

to health care workers.

In addition to blood and visibly bloody body fluids, semen and

vaginal secretions also are considered potentially infectious; however,

they have not been implicated in occupational transmission from

patients to health care workers. The following fluids also are considered potentially infectious: cerebrospinal fluid, synovial fluid, pleural

fluid, peritoneal fluid, pericardial fluid, and amniotic fluid. The risk for

1535CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

transmission after exposure to fluids or tissues other than HIV-infected

blood has not been quantified, but it is probably considerably lower

than the risk after blood exposures. Feces, nasal secretions, saliva,

sputum, sweat, tears, urine, and vomitus are not considered potentially

infectious for HIV unless they are visibly bloody. Rare cases of HIV

transmission via human bites have been reported, but not in the setting

of occupational exposure.

An increased risk for HIV infection following percutaneous exposures to HIV-infected blood is associated with exposures involving

a relatively large quantity of blood, as in the case of a device visibly

contaminated with the patient’s blood, a procedure that involves a

hollow-bore needle placed directly in a vein or artery, or a deep injury.

Factors that might be associated with mucocutaneous transmission of

HIV include exposure to an unusually large volume of blood and prolonged contact. In addition, the risk increases for exposures to blood

from untreated patients with high levels of HIV in the blood. Since the

beginning of the HIV epidemic, there have been rare instances where

transmission of infection from a health care worker to patients seemed

highly probable. Despite this small number of documented cases, the

risk of HIV transmission involving infected health care workers to

patients is extremely low in developed countries—in fact, too low to

be measured accurately. In this regard, several retrospective epidemiologic studies have been performed tracing thousands of patients of

HIV-infected dentists, physicians, surgeons, obstetricians, and gynecologists, and no cases of HIV transmission that could be linked to the

health care providers were identified other than the already identified

documented cases.

Breaches in infection control and the reuse of contaminated syringes,

failure to properly sterilize surgical instruments, and/or hemodialysis

equipment also have resulted rarely in the transmission of HIV from

patient to patient in hospitals, nursing homes, and outpatient settings.

Finally, these very rare occurrences of transmission of HIV as well

as HBV and HCV to and from health care workers in the workplace

underscore the importance of the use of universal precautions when

caring for all patients (see below and Chap. 142).

■ MOTHER-TO-CHILD TRANSMISSION OF HIV

HIV infection can be transmitted from an infected mother to her fetus

during pregnancy, during delivery, or by breast-feeding. This remains

a persistent form of transmission of HIV infection in certain developing countries. Virologic analyses of aborted fetuses indicate that HIV

can be transmitted to the fetus during the first or second trimesters of

pregnancy. However, maternal transmission to the fetus occurs most

commonly in the perinatal period. Two studies performed in Rwanda

and the Democratic Republic of Congo (then called Zaire) indicated

that among all mother-to-child transmissions of HIV, the relative proportions were 23–30% before birth, 50–65% during birth, and 12–20%

via breast-feeding.

In the absence of antiretroviral therapy for the mother during pregnancy, labor, and delivery, and for the fetus prophylactically following

birth, the probability of transmission of HIV from mother to infant/

fetus ranges from 15 to 25% in industrialized countries and from 25%

to 35% in developing countries. These differences may relate to the

adequacy of prenatal care as well as to the stage of HIV disease and

the general health of the mother during pregnancy. Higher rates of

transmission have been reported to be associated with many factors—

the best documented of which is the presence of high maternal levels

of plasma viremia, with the risk increasing linearly with the level

of maternal plasma viremia. It is very unlikely that mother-to-child

transmission will occur if the mother’s level of plasma viremia is <1000

copies of HIV RNA/mL of blood and extremely unlikely if the level is

<50 copies/mL. Increased mother-to-child transmission is also correlated with closer human leukocyte antigen (HLA) match between

mother and child. A prolonged interval between membrane rupture

and delivery is another well-documented risk factor for transmission.

Other conditions that are potential risk factors, but that have not been

consistently demonstrated, are the presence of chorioamnionitis at

delivery; STIs during pregnancy; illicit drug use during pregnancy;

cigarette smoking; preterm delivery; and obstetrical procedures such

as amniocentesis, amnioscopy, fetal scalp electrodes, and episiotomy.

Today, the rate of mother-to-child transmission has fallen to less than

1% in pregnant women who are receiving ART for their HIV infection.

Such treatment, combined with cesarean section delivery, has rendered

mother-to-child transmission of HIV an extremely unusual event in

the United States and other developed nations. In this regard, both

the United States Public Health Service and the World Health Organization guidelines recommend that all HIV-infected pregnant women

receive life-long ART for the health of the mother (regardless of plasma

HIV RNA copy number or CD4+ T-cell counts) as well as to prevent

perinatal transmission.

Breast-feeding is an important modality of transmission of HIV

infection in certain developing countries, particularly where mothers

continue to breast-feed for prolonged periods. The risk factors for

mother-to-child transmission of HIV via breast-feeding include detectable levels of HIV in breast milk, the presence of mastitis, low maternal

CD4+ T-cell counts, and maternal vitamin A deficiency. The risk of

HIV infection via breast-feeding is highest in the early months of

breast-feeding. In addition, exclusive breast-feeding has been reported

to carry a lower risk of HIV transmission than mixed feeding. In

developed countries, breast feeding of babies by an HIV-infected

mother is contraindicated since alternative forms of adequate nutrition, i.e., formulas, are readily available. In developing countries, where

breast-feeding may be essential for the overall health of the infant,

the continuation of ART in the infected mother during the period of

breastfeeding markedly diminishes the risk of transmission of HIV to

the infant. In fact, treatment of a pregnant woman with ART should be

provided for the benefit of the woman as much as for the prevention

of mother-to-child transmission and should be continued beyond the

pregnancy, for life.

■ TRANSMISSION OF HIV BY OTHER BODY FLUIDS

Although HIV can be isolated typically in low titers from saliva of a

small proportion of infected individuals, there is no convincing evidence that saliva can transmit HIV infection, either through kissing

or through other exposures, such as occupationally to health care

workers. Saliva contains endogenous antiviral factors; among these

factors, HIV-specific immunoglobulins of IgA, IgG, and IgM isotypes

are detected readily in salivary secretions of infected individuals. It has

been suggested that large glycoproteins such as mucins and thrombospondin 1 sequester HIV into aggregates for clearance by the host.

In addition, multiple soluble salivary factors inhibit HIV to various

degrees in vitro, probably by targeting host cell receptors rather than

the virus itself. Perhaps the best studied of these, secretory leukocyte

protease inhibitor (SLPI), blocks HIV infection in several cell culture

systems, and it is found in saliva at levels that approximate those

required for inhibition of HIV in vitro. In this regard, higher salivary

levels of SLPI in breast-fed infants were associated with a decreased risk

of HIV transmission through breast milk. It has also been suggested

that submandibular saliva reduces HIV infectivity by stripping gp120

from the surface of virions, and that saliva-mediated disruption and

lysis of HIV-infected cells occurs because of the hypotonicity of oral

secretions. Transmission of HIV by a human bite can occur but is a rare

event. Although virus can be identified, if not isolated, from virtually

any body fluid, there is no evidence that HIV transmission can occur

as a result of exposure to tears, sweat, or urine. However, there have

been isolated cases of transmission of HIV infection by body fluids

that may or may not have been contaminated with blood. Most of these

situations occurred in the setting of a close relative providing intensive nursing care for a person with HIV without observing universal

precautions, underscoring the importance of adhering to such precautions in the handling of body fluids and wastes from HIV-infected

individuals.

EPIDEMIOLOGY

■ HIV INFECTION AND AIDS WORLDWIDE

HIV infection/AIDS is a global pandemic, with cases reported from

virtually every country. At the end of 2020, an estimated 37.7 million

1536 PART 5 Infectious Diseases

individuals were living with HIV infection, according to the Joint

United Nations Programme on HIV/AIDS (UNAIDS). An estimated

95% of people living with HIV/AIDS reside in low- and middle-income

countries; ~50% are female, and 1.7 million are children <15 years.

The regional distribution of these cases is illustrated in Fig. 202-8.

The estimated number of people living with HIV—i.e., the global

prevalence—has increased nearly fivefold since 1990, reflecting the

combined effects of continued high rates of new HIV infections and

the life-prolonging impact of antiretroviral therapy (Fig. 202-9). In

2020, the global prevalence of HIV infection among persons 15–49

years of age was 0.7%, with rates varying widely by country and region

as illustrated in Fig. 202-10.

In 2020, an estimated 1.5 million new cases of HIV infection

occurred worldwide, including 150,000 among children <15 years;

about one-third of new infections were among people age 15–24 years.

Globally, members of certain high-risk populations are disproportionately affected by HIV infection. Sex workers; people who inject drugs;

transgender people; prisoners; gay men and other men who have sex

with men; the clients of sex workers; and the sexual partners of these

key populations accounted for 65% of all new HIV infections in 2020

(Fig. 202-11).

New HIV infections globally have fallen by 52% since their peak in

1997 (Fig. 202-9). Reductions in global HIV incidence likely reflect

progress with HIV prevention efforts and the increased provision to

HIV-infected people of antiretroviral therapy, which makes them much

less likely to transmit the virus to sexual partners. Among adults, the

estimated number of new infections declined by about 50% from 1997

to 2020. During the same period a ~70% reduction in HIV infections

among children <15 years was observed, progress due largely to the

increasing availability of antiretroviral medications to prevent the

transmission of HIV from mother to infant. An estimated 27.5 million

people globally were on antiretroviral therapy as of December 2020.

In 2020, global AIDS deaths totaled 680,000 (including 99,000 children <15 years), a 64% decrease since the peak in 2004 that coincides

with a rapid expansion of access to antiretroviral therapy (Fig. 202-12).

Since the beginning of the HIV pandemic, an estimated 36.3 million

persons globally have died of an AIDS-related illness.

The HIV epidemic has occurred in “waves” in different regions

of the world, each wave having somewhat different characteristics

depending on the demographics of the country and region in question and the timing of the introduction of HIV into the population.

Although the AIDS epidemic was first recognized in the United States

and shortly thereafter in Western Europe, it very likely began in

sub-Saharan Africa (see above), a region particularly devastated by the

epidemic.

The 20 countries of Eastern and Southern Africa are home to

about 6% of the world’s population but had 20.6 million people living with HIV in 2020, >50% of the global total (Fig. 202-8). Almost

all countries in the region have generalized epidemics, that is, their

national prevalence is >1%. In eight countries in the region, >10% of

the adult population age 15–49 has HIV infection (Fig. 202-10). South

Africa has the highest number of people living with HIV in the world

(7.8 million); Eswatini (formerly known as Swaziland) has the highest

adult HIV prevalence globally (26.8%). Recent data indicate declining HIV incidence and prevalence in many countries in the region,

although generally at levels that remain high. Heterosexual exposure is

the primary mode of HIV transmission in most countries in the region,

as is the case throughout sub-Saharan Africa. Women and girls account

for ~60 percent of all HIV infections in the region.

The 25 countries of Western and Central Africa are home to

4.7 million people living with HIV, of whom 410,000 are children. HIV

prevalence in most of the countries is relatively low compared with

East and Southern Africa. HIV prevalence among adults across the

region overall stands at 1.3% However, there is wide variation between

countries, ranging from 0.2% in Niger to 7.3% in Equatorial Guinea.

An estimated 43% of new infections in the region in 2020 occurred in

Nigeria, a large country with an HIV seroprevalence rate of 1.3%. As in

East and Southern Africa, heterosexual transmission accounts for most

HIV transmission in West and Central Africa.

The Middle East and North Africa region has one of the lowest

HIV prevalence rates in the world (<0.1%), although new infections

increased by 7% from 2010 to 2020. In 2020, an estimated 230,000

people were living with HIV in the region. Cases are largely concentrated among IDUs, men who have sex with men, and sex workers and

their clients.

In Asia and the Pacific, an estimated 5.8 million people were living

with HIV at the end of 2020. HIV infections in Asia and the Pacific

declined by 21% between 2010 and 2020, with reductions in Thailand

and Vietnam offset by increases in Pakistan and the Philippines. In this

region, HIV prevalence is highest in southeast Asian countries, with

wide variation in trends between different countries. Among countries

in Asia, only Thailand has an adult seroprevalence rate that reaches 1%.

Caribbean

330,000

Latin America

2.1 million

North America and Western and

Central Europe 2.2 million

Eastern Europe

and Central Asia

1.6 million

Middle East and

North Africa

230,000

a

Western and Central

Africa

4.7 million

Eastern and

Southern Africa

20.6 million

Asia and the

Pacific

5.8 million

FIGURE 202-8 Estimated number of adults and children living with HIV infection as

of December, 2020. Total: 37.7 million (30.2 million–45.1 million). (From Joint United

Nations Programme on HIV/AIDS [UNAIDS].)

People living with HIV infection

(millions)

New HIV infections

New HIV infections and deaths

Deaths due to AIDS

due to AIDS (millions)

People living with HIV

0

10

20

30

40

1990 1995 2000 2005 2010 2015 2020

0

1

2

3

4

FIGURE 202-9 Global estimates of HIV incidence, AIDS deaths, and HIV prevalence 1990–2020. (From UNAIDS.)

1537CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

However, the populations of many Asian nations are so large that even

low infection and seroprevalence rates result in large numbers of people living with HIV. In this regard, three populous countries—China,

India, and Indonesia—account for around three-quarters of all people

living with HIV in the region. Key populations (Fig. 202-11) and their

partners accounted for an estimated 94% of new HIV infections in the

region in 2020, and ~30% of new HIV infections were among young

people (age 15–24 years). Rising numbers of new infections among gay

men and other men who have sex with men are a major concern.

The HIV epidemic continues to expand in Eastern Europe and

Central Asia, with a 43% increase in annual new HIV infections

and  32% increase in AIDS deaths between 2010 and 2020. The

Russian Federation and Ukraine account for the majority of the

1.6 million people living with HIV in the region, where the epidemic

has been driven by injection drug use. Key populations and their sexual

partners account for the vast majority of new infections in the region.

Approximately 2.1 million people were living with HIV/AIDS in

Latin America at the end of 2020. The rate of new HIV infections

remained steady from 2010 to 2020. Brazil is home to the largest number of HIV-infected persons (930,000) in the region. In the Caribbean,

an estimated 330,000 people are living with HIV.

Approximately 2.2 million people were living with HIV/AIDS in

North America and Western and Central Europe at the end of 2020.

While modes of transmission vary greatly by country, HIV disproportionately affects men who have sex with men. In Western and Central

Europe, 11 countries saw HIV infections decline by more than 20%

from 2010 to 2020, while 16 countries, mostly in Central Europe, experienced increases or had limited declines in new HIV infections. North

America saw decreases in HIV diagnoses among gay and bisexual men

and heterosexuals and a small increase among people who inject drugs.

■ HIV INFECTION IN THE UNITED STATES

At the end of 2019, an estimated 1.2 million individuals in the United

States were living with HIV infection, ~13% of whom were unaware

of their infection. As illustrated in Fig. 202-13, only about 57% of

HIV-infected people in the United States have been able to negotiate

the steps in the HIV “care continuum,” from diagnosis, to entering into

care and receiving antiretroviral therapy, and ultimately to achieving a

suppressed viral load (see “Treatment,” below).

Nearly two-thirds of people living with HIV in the United States are

Black/African American or Hispanic/Latino, and ~60% are men who

have sex with men, according to CDC estimates. The HIV prevalence

rate among all individuals age 13 years or older in the United States

is ~0.4%. Approximately 1.4% of Black/African-American adults are

living with HIV in the United States, more than any other racial/ethnic

group.

The estimated annual number of new HIV infections in the United

States has fallen by more than two-thirds since its height in late 1980s

of about 130,000 per year. CDC data indicate that progress has stalled

in recent years, at about 34,000 to 38,000 new HIV infections each year.

The estimated distribution of incident HIV cases in 2019 is shown in

Fig. 202-14.

In the United States, the burden of HIV infection is not evenly distributed across states and regions. In most areas of the country, HIV is

concentrated in urban areas. In the southern United States, larger percentages of diagnoses are in smaller metropolitan and nonmetropolitan areas. HIV has disproportionately affected minority populations

in the United States in both urban and rural areas. Among those diagnosed with HIV (regardless of stage of infection) in 2019, 42% percent

were Blacks/African Americans, a group that constitutes only 13% of

the U.S. population. Hispanics/Latinos, 18% of the U.S. population,

accounted for 29% of new HIV diagnoses. The estimated rate of new

HIV diagnoses in 2019 by race/ethnicity per 100,000 population in the

United States is shown in Fig. 202-15.

Perinatal HIV transmission, from an HIV-infected mother to her

baby, has declined significantly in the United States, largely due to

the implementation of guidelines for the universal counseling and

voluntary HIV testing of pregnant women and the use of antiretroviral

therapy for pregnant women and newborn infants to prevent infection.

In 2019, 61 children were newly diagnosed with HIV infection in the

United States, down from a peak of ~1750 in 1991.

N/A

<1%

1–5%

5–10%

>10%

FIGURE 202-10 Adult HIV prevalence rates by country, 2020. Data are estimates for adults age 15–49 years. (From UNAIDS.)

Sex workers (11%)

People who

inject drugs (9%)

Clients of sex workers and

sex partners of all key

populations (20%)

Gay men and other

men who have sex

with men (23%)

Transgender people

(2%)

Remaining

population

(35%)

FIGURE 202-11 Global distribution of new HIV infections by population. Data for

2020. (Reproduced with permission from UNAIDS.)

1538 PART 5 Infectious Diseases

The rate of HIV-related deaths in the United States rose steadily

through the 1980s and peaked in 1995. Since then, the HIV death rate

has fallen fourfold (Fig. 202-16). This trend is likely due to several

factors, including improved prophylaxis and treatment of opportunistic infections, growing experience among the health professions in

caring for HIV-infected individuals, improved access to health care,

and a decrease in new infections. However, the most influential factor

clearly has been the increased use of combination antiretroviral therapy

(ART), generally administered in a combination of three or four agents.

PATHOPHYSIOLOGY AND PATHOGENESIS

The hallmark of HIV disease is a profound immunodeficiency resulting

primarily from a progressive quantitative and qualitative deficiency of

the subset of T lymphocytes referred to as helper T cells occurring in

a setting of aberrant immune activation. The helper subset of T cells

is defined phenotypically by the presence on its surface of the CD4

molecule (Chap. 349), which serves as the primary cellular receptor for

HIV. A co-receptor also must be present together with CD4 for efficient

binding, fusion, and entry of HIV-1 into its target cells (Figs. 202-3 and

202-4). HIV-1 uses two major co-receptors, CCR5 and CXCR4, for

fusion and entry; these co-receptors are also the primary receptors for

2000 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2001 2015 2016 2017 2018 2019 2020

60

50

40

30

20

10

0

2.5

2.0

1.0

1.5

0.5

0

Antiretroviral therapy coverage (%)

Number of AIDS-related deaths (million)

70

80 HIV treatment coverage (all ages) AIDS-related deaths (all ages)

FIGURE 202-12 Global antiretroviral therapy coverage and number of AIDS-related deaths, 2000–2020. (From UNAIDS).

87%

66%

50%

57%

100

90

80

70

60

50

40

30

20

10

0

Percent of all people living with HIV

Viral

Suppression

Retained in

Care

Receipt of

Care

Diagnosed

FIGURE 202-13 Estimated percentage of HIV-infected people engaged at selected

stages of the continuum of HIV care in the United States. Data for 2019. Receipt of

medical care defined as ≥1 test (CD4 count or viral load); retained in care, ≥2 tests

(CD4 or VL) ≥3 months apart in 2019; viral suppression, <200 copies/mL on the

most recent VL test. (From Centers for Disease Control and Prevention [CDC]: HIV

Surveillance Supplemental Report 26[No. 2], 2021.)

Male-to-male sexual

contact

23,100 infections (66%)

Injection drug use

2500 infections (7%)

Male-to-male sexual

contact and injection

drug use

1400 infections (4%)

Heterosexual contact

7800 infections (22%)

FIGURE 202-14 Estimated distribution of new HIV infections in the United States

by transmission category. Total: 34,800. Incidence estimate for 2019. (From CDC: HIV

Surveillance Supplemental Report 26 [No. 1], 2021.)

0 5 10 15 20 25 30 35 40

Black/African American

Hispanic/Latino

Multiple races

White

Asian

Rate/100,000 population

American Indian/

Alaska Native

Native Hawaiian/Other

Pacific Islander

FIGURE 202-15 Estimated rate of HIV infections (including children) diagnosed

during 2019 in the United States, by race/ethnicity (per 100,000 population).

(From CDC.)

1539CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

Deaths per 100,000 population

Year of death

1987

0

16

1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015 2017

14

12

10

8

6

4

2

18

FIGURE 202-16 Trends in annual age-adjusted rates of death due to HIV infection, United States, 1987–2018. Age distribution based on 2000 population. (From CDC.) CD4+ T lymphocyte count (cells/

µL)

1200 108

107

106

105

104

103

102

1100

1000

900

800

700

600

500

400

300

200

100

0

0 3 6 1 2 3 4 5 6 7 8 9 10 11

Weeks Years

Clinical latency

Primary

infection

Constitutional

symptoms

Opportunistic

diseases

Death ±Acute HIV syndrome

Wide dissemination of virus

Seeding of lymphoid organs

HIV RNA copies per mL plasma

9 12

FIGURE 202-17 Typical course of an untreated HIV-infected individual. See text for detailed description. (From G Pantaleo,

C Graziosi, AS Fauci: The Immunopathogenesis of Human Immunodeficiency Virus Infection. N Engl J Med 328:327, 1993.

Copyright © 1993 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.)

certain chemoattractant cytokines termed chemokines and belong to

the seven-transmembrane-domain G protein–coupled family of receptors. Multiple mechanisms responsible for cellular depletion and/or

immune dysfunction of CD4+ T cells have been demonstrated in vitro.

These include direct infection and destruction of these cells by HIV, as

well as indirect effects such as immune clearance of infected cells; cell

death associated with aberrant immune activation and inflammation,

including caspase 1–mediated pyroptosis prompted by tissue CD4+ T

cells undergoing abortive/nonproductive HIV infection; and immune

exhaustion due to persistent cellular activation with resulting cellular

dysfunction. Patients with CD4+ T-cell levels below certain thresholds

are at high risk of developing a variety of opportunistic diseases, particularly the infections and neoplasms that are AIDS-defining illnesses.

Some features of AIDS, such as Kaposi’s sarcoma and certain neurologic

abnormalities, cannot be explained completely by the immunodeficiency

caused by HIV infection, since these complications may occur prior to

the development of severe immunologic impairment.

The combination of viral pathogenic and immunopathogenic events

that occur during the course of HIV disease from the moment of initial

(primary) infection through the development of advanced-stage disease is complex and varied. It is important to appreciate that the pathogenic mechanisms of HIV disease are multifactorial and multiphasic

and are different at different stages of the disease. Therefore, it is essential to consider the typical clinical course of an untreated individual

with HIV to better appreciate these pathogenic events (Fig. 202-17).

■ EARLY EVENTS IN HIV INFECTION: PRIMARY

INFECTION AND INITIAL DISSEMINATION OF VIRUS

Using rectal or vaginal mucosal transmission in nonhuman primates

as a model, the earliest events (within hours) that occur following

exposure of HIV to the mucosal surface

determine whether an infection will be

established or aborted as well as the

subsequent course of events following

infection. Although the mucosal barrier

is relatively effective in limiting access

of HIV to susceptible targets in the submucosal tissue, the virus can cross the

barrier by transport on Langerhans cells,

an epidermal type of DC, just beneath

the surface or through microscopic rents

in the mucosa. Significant disruptions in

the mucosal barrier as seen in ulcerative

genital disease facilitate viral entry and

increase the efficiency of infection. Virus

then seek susceptible targets, which are

primarily CD4+ T cells that are spatially

dispersed in the mucosa. This spatial

dispersion of targets provides a significant obstacle to the establishment of

infection. Such obstacles account for the

low efficiency of sexual transmission of

HIV (see “Sexual Transmission,” above).

Both “partially” resting CD4+ T cells

and activated CD4+ T cells serve as early

amplifiers of infection. Resting CD4+ T

cells are more abundant; however, activated CD4+ T cells support productive

1540 PART 5 Infectious Diseases

infection and thus generate larger amounts of virus. For infection to

become established, the basic reproductive rate (R0

) must become

equal to or greater than 1, i.e., each infected cell would infect at least

one other cell. Once infection is established, the virus replicates in

lymphoid cells in the mucosa, the submucosa, and to some extent

the lymphoreticular tissues that drain the gut or genital tissues. For a

variable period ranging from a few to several days, the virus is typically

not detected in the plasma. This period is referred to as the “eclipse”

phase of infection. As more virus is produced within several days to

weeks, it is disseminated, first to the draining lymph nodes and then

to other lymphoid compartments where it has easy access to dense

concentrations of CD4+ T-cell targets, allowing for a burst of high-level

plasma viremia that is readily detectable by currently available assays

(Fig. 202-18). The gut-associated lymphoid tissue (GALT) is a target of

HIV infection and the location where large numbers of CD4+ T cells

(usually memory cells) are infected and depleted, both by direct viral

effects and by activation-associated apoptosis. Once virus replication

reaches this threshold and virus is widely disseminated, infection is

firmly established throughout the lymphoid tissues of the body and

persists for the life of the individual. It is important to point out that

the efficiency of initial infection of susceptible cells may vary somewhat with the route of infection. Virus that enters directly into the

bloodstream via infected blood or blood products (i.e., transfusions,

use of contaminated needles for injection drugs, sharp-object injuries,

maternal-to-fetal transmission either intrapartum or perinatally, or

sexual intercourse where there is enough trauma to cause bleeding)

is likely first cleared from the circulation to the spleen and other

lymphoid organs, where primary focal infections begin, followed by

wider dissemination throughout other lymphoid tissues as described

above.

It has been demonstrated that sexual transmission of HIV is the

result of a single infectious event and that a viral genetic bottleneck

exists for transmission with selective transmission of certain viruses.

In this regard, certain characteristics of the HIV envelope glycoprotein

have a major influence on transmission, at least in subtype A and C

viruses. Transmitting viruses, often referred to as “founder viruses,”

are usually underrepresented in the circulating viremia of the transmitting partner and are less-diverged viruses with signature sequences

including shorter V1–V2 loop sequences and fewer predicted N-linked

glycosylation sites relative to the major circulating variants. These

viruses are almost exclusively R5 strains and are usually sensitive to

neutralizing antibody. Once replication proceeds in the newly infected

partner, the founder virus diverges and accumulates glycosylation sites,

becoming progressively more resistant to neutralization (Fig. 202-19).

The acute burst of viremia and wide dissemination of virus in primary HIV infection may be associated with an acute HIV syndrome,

which occurs to varying degrees in ~50% of individuals within 2 to

4 weeks of initial infection (see below). This syndrome is usually associated with millions of copies of HIV RNA per milliliter of plasma that

last for several weeks. Acute mononucleosis-like symptoms are well

correlated with the presence of high levels of plasma viremia. Virtually

all patients develop some degree of plasma viremia during primary

infection, which contributes to virus dissemination throughout the

lymphoid tissue, even though they may remain asymptomatic or not

recall experiencing symptoms. The initial level of plasma viremia in

primary HIV infection does not necessarily determine the rate of

disease progression; however, the set point of the level of steady-state

plasma viremia after ~1 year correlates with the rate of disease progression in the untreated patient and with immunologic and virologic

aberrancies that persist in the treated patient. The strikingly high levels

of viremia observed in many patients during acute HIV infection is felt

to be associated with a higher likelihood of transmission of the virus

to others by a variety of routes including sexual transmission, shared

needles and syringes, and mother-to-child transmission intrapartum,

perinatally, or via breast milk.

DC

Crossing

the

barrier

Infected

cell

Infected

activated

CD4+ T cell

Activated

CD4+ T cell

Macrophage

“Resting”

CD4+ T cells

Lamina propria Lymphoid tissue

Regulatory

T cells

Late-responding CTLs

HIV

virions

Sustained

HIV

production

Partial

control

Immune

activation

Establishment

of lymphoidtissue viral

reservoir

Dissemination

of virus

Hours Days Weeks Years

Infected “resting”

CD4+ T cells

PD-1+CD8+

 T cells

FIGURE 202-18 Summary of early events in HIV infection. See text for detailed description. CTLs, cytolytic T lymphocytes; HIV, human immunodeficiency virus. (Adapted

from AT Haase: Nat Rev Immunol 5:783, 2005.)

Founder

Replicating virus

FIGURE 202-19 As HIV diverges from founder to chronically replicating virus,

it accumulates N-linked glycosylation sites. See text for detailed description.

(Adapted from CA Derdeyn et al: Science 303:2019, 2004; B Chohan et al: J Virol

79:6528, 2005; and BF Keele et al: Proc Natl Acad Sci USA 105:7552, 2008.)

1541CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

■ ESTABLISHMENT OF CHRONIC INFECTION

Persistence of Virus Replication HIV infection is unique

among human viral infections. Despite the robust cellular and humoral

immune responses that are mounted following primary infection (see

“Immune Response to HIV,” below), once infection has been established the virus succeeds in escaping complete immune-mediated

clearance, paradoxically seems to thrive on immune activation, and is

never eliminated completely from the body. Rather, a chronic infection

develops and persists with varying degrees of continual virus replication in the untreated patient for a median of ~10 years before the

patient becomes clinically ill (see “Advanced HIV Disease,” below). It is

this establishment of a chronic, persistent infection that is the hallmark

of HIV disease. Throughout the often-protracted course of chronic

infection, virus replication can invariably be detected in untreated

patients by widely available molecular assays that measure copies of

virion-associated HIV RNA in plasma (copies per milliliter). Levels

of virus vary greatly in most untreated patients, usually ranging from

fewer than 50 to greater than a million copies of HIV RNA per milliliter

of plasma. Studies using highly sensitive molecular techniques have

demonstrated that even in treated patients in whom plasma viremia is

suppressed to below detection (lower limit, 20–50 copies of HIV RNA

per milliliter depending on assay kit manufacturer) by ART, there is

a continual low level of virion production in the majority of infected

patients. In other human viral infections, with some exceptions, if the

host survives, the virus is completely cleared from the body and a state

of immunity against subsequent infection develops. HIV infection very

rarely kills the host during primary infection. Certain viruses, such

as HSV (Chap. 192), are not completely cleared from the body after

infection, but instead enter a latent state; in these cases, clinical latency

is accompanied by microbiologic latency. This is not the case with HIV

infection as described above. Chronicity associated with persistent

virus replication can also be seen in certain cases of HBV and HCV

infections (Chap. 341); however, in these infections the immune system is not a target of the virus.

Escape of HIV from Effective Immune System Control

Inherent to the establishment of chronicity of HIV infection is the

ability of the virus to evade adequate control and elimination by both

the cellular and humoral immune responses. There are several mechanisms whereby the virus accomplishes this evasion. Paramount among

these is the establishment of a sustained level of replication associated

with the generation of viral diversity via mutation and recombination.

The selection of mutants that escape control by CD8+ cytolytic T lymphocytes (CTLs) is critical to the propagation and progression of HIV

infection. The high rate of virus replication associated with inevitable

mutations also contributes to the inability of antibody to neutralize

and/or clear the autologous virus. Furthermore, for reasons that remain

unclear, the humoral immune system does not readily produce classic

neutralizing antibodies against the HIV envelope and does so only after

years of persistent virus replication and after the infection is firmly

established (see below). Extensive analyses of sequential HIV isolates

and host responses have demonstrated that viral escape from B-cell and

CD8+ T-cell responses occurs early after infection and allows the virus

to stay one step ahead of effective immune responses. Virus-specific

CD8+ CTLs expand greatly during primary HIV infection, and they

likely represent the high-affinity responses that would be expected to

be most efficient in eliminating virus-infected cells; however, viral control is generally incomplete as viral replication persists at relatively high

levels in the majority of individuals. In addition to viral escape from

CTLs through high rates of mutation, it is thought that the initially

strong immune response becomes qualitatively dysfunctional owing to

the overwhelming immune activation associated with persistent viral

replication, leading to immune “exhaustion” that affects both arms

of adaptive immunity. Several studies have indicated that exhaustion

of HIV-specific CD8+ T cells during prolonged immune activation

is associated with upregulation of several inhibitory receptors, such

as the programmed death (PD) 1 molecule (of the B7-CD28 family

of molecules), T-cell immunoreceptor with Ig and ITIM domains

(TIGIT), T-cell immunoglobulin and mucin domain–containing

molecule 3 (Tim-3), and lymphocyte activating gene 3 (Lag-3), collectively referred to as immune-checkpoint receptors. Upregulation of

these surface proteins restricts polyreactivity and proliferative capacity,

functional attributes of CD8+ T cells that are essential for effective

killing of pathogens. Another mechanism contributing to the evasion

by HIV of immune system control is the downregulation of HLA class I

molecules on the surface of HIV-infected cells by the viral proteins Nef,

Tat, and Vpu, resulting in the lack of ability of CD8+ CTLs to recognize

and kill infected target cells. Although this downregulation of HLA

class I molecules would seem to favor elimination of HIV-infected cells

by natural killer (NK) cells, this latter mechanism does not remove

HIV-infected cells effectively (see below). Another potential means of

escape of HIV-infected cells from elimination by CD8+ CTLs is the

sequestration of infected cells in immunologically privileged sites such

as the central nervous system (CNS), as well as the low frequency of

virus-specific CD8+ CTLs in areas of lymphoid tissues, namely germinal centers, where HIV actively replicates.

The principal targets of neutralizing antibodies against HIV are the

envelope proteins gp120 and gp41. HIV employs at least three mechanisms to evade neutralizing antibody responses: hypervariability in

the primary sequence of the envelope, extensive glycosylation of the

envelope, and conformational masking of neutralizing epitopes. Several studies that have followed the evolution of the humoral immune

response to HIV from the earliest points after primary infection indicate that the virus continually mutates to escape the emerging antibody

response such that the sequential antibodies that are induced do not

neutralize the currently autologous virus. Broadly neutralizing antibodies capable of neutralizing a wide range of primary HIV isolates in vitro

occur in only about 20% of HIV-infected individuals, and, when they

do occur, 2 to 3 years of infection with continual virus replication are

generally required to drive the affinity maturation of the antibodies.

Unfortunately, by the time these broadly neutralizing antibodies are

formed, they are ineffective in containing the virus currently replicating in the patient. Persistent viremia also results in exhaustion of B cells

like the exhaustion reported for CD8+ T cells, adding to the defects in

the humoral response to HIV.

CD4+ T-cell help is essential for the integrity of both humoral and

cell-mediated antigen-specific immune responses. HIV preferentially

infects activated CD4+ T cells including HIV-specific CD4+ T cells,

and so this loss of viral-specific helper T-cell responses has profoundly

negative consequences for the immunologic control of HIV replication. Furthermore, this loss occurs early in the course of infection, and

animal studies indicate that 40–70% of all memory CD4+ T cells in

the GALT are eliminated during acute infection. During chronic HIV

viremia, CD4+ T cells also exhibit evidence of exhaustion, including

by upregulation of the cytotoxic T lymphocyte–associated antigen 4

(CTLA-4), also a member of the B7-CD28 family.

Finally, the escape of HIV from immune-mediated elimination

during primary infection allows the formation of a pool of latently

infected CD4+ T cells, referred to as the viral reservoir, that may not be

recognized or completely eliminated by virus-specific CTLs or by ART

(see below). Thus, despite a potent immune response and the marked

downregulation of virus replication following primary HIV infection,

HIV succeeds in establishing a state of chronic infection with a variable

degree of persistent virus replication. During this period most patients

make the clinical transition from acute primary infection to variable

periods of clinical latency or smoldering disease activity (see below).

The HIV Reservoir: Obstacles to the Eradication of Virus A

pool of latently infected, resting CD4+ T cells that serves as at least

one component of the persistent reservoir of virus exists in virtually

all HIV-infected individuals, including those who are receiving ART.

Such cells carry an integrated form of HIV DNA in the genome of the

host and can remain in this state until an activation signal drives the

expression of HIV transcripts. Only a small fraction of the latently

infected cells in the viral reservoir contain replication-competent virus,

with the overwhelming majority of cells containing defective proviruses incapable of a full replication cycle. However, upon activation of

the reservoir variable degrees of sustained virus replication invariably

1542 PART 5 Infectious Diseases

occur. This form of latency is to be distinguished from preintegration

latency, in which HIV enters a resting CD4+ T cell and, in the absence

of an activation signal, reverse transcription of the HIV genome occurs

to a certain extent but the resulting proviral DNA fails to integrate into

the host genome. This period of preintegration latency may last hours

to days, and if no activation signal is delivered to the cell, the proviral

DNA loses its capacity to initiate a productive infection. If these cells

do become activated prior to decay of the preintegration complex,

reverse transcription proceeds to completion and the virus continues

along its replication cycle (see above and Fig. 202-20).

The pool of cells that are in the postintegration state of

latency is established early during primary HIV infection.

Despite the suppression of plasma viremia to <50 copies

per milliliter by potent regimens of ART administered over

several years, this pool of latently infected cells persists and

can give rise to replication-competent virus upon cellular

activation ex vivo. Modeling studies built on projections

of decay curves have estimated that in such a setting of

prolonged viral suppression, it would require many years

to the entire life of the host for the pool of latently infected

cells to be eliminated. This has not been documented to

occur spontaneously in any patients very likely because

the latent viral reservoir is long-lived and is continually

replenished by the low levels of persistent virus replication

that may remain below the limits of detection of current

assays (see below) as well as by the expansion by proliferation of the pool of latently infected cells (Fig. 202-20), even

in patients who for the most part are treated successfully.

Reservoirs of HIV-infected cells, latent or otherwise, can

exist in a number of compartments including the lymphoid

tissue, peripheral blood, and the CNS (likely in cells of

the monocyte/macrophage lineage) as well as in other unidentified

locations. Over the past several years attempts have been made to

eliminate HIV in the latent viral reservoir using agents that activate

resting CD4+ T cells and/or reinitiate viral expression without systemic

activation during the course of ART; however, such attempts, referred

to as “shock and kill,” have been unsuccessful. Thus, this persistent

reservoir of infected cells remains a major obstacle to the goal of eradication of virus from infected individuals and hence a classic “cure,”

despite the favorable clinical outcomes that have resulted from ART.

Consequently, intense efforts are being directed toward investigating

the feasibility of achieving ART-free HIV remission through passive

transfer of long-acting broadly neutralizing antibodies and therapeutic

agents that could enhance the host immune responses against the virus.

Viral Dynamics The dynamics of viral production and turnover

have been quantified using mathematical modeling in the setting of

the administration of reverse transcriptase and protease inhibitors

to HIV-infected individuals in clinical studies. Treatment with these

drugs resulted in a precipitous decline in the level of plasma viremia,

which typically fell by well over 90% within 2 weeks. It was determined

on the basis of modeling the kinetics of viral decline and the emergence

of resistant mutants during therapy that 93–99% of the circulating virus

originated from recently infected, rapidly turning over CD4+ T cells

and that ~1–7% of circulating virus originated from longer-lived cells,

likely monocytes/macrophages. A negligible amount of circulating

virus originated from the pool of latently infected cells (Fig. 202-21).

It was also determined that the half-life of a circulating virion was

~30–60 min and that of productively infected cells was 1 day. Given

the relatively steady level of plasma viremia and of infected cells, it

appears that extremely large amounts of virus (~1010–1011 virions) are

produced and cleared from the circulation each day. In addition, data

suggest that the minimal duration of the HIV-1 replication cycle in

vivo is ~2 days. Other studies have demonstrated that the decrease in

plasma viremia that results from treatment with ART correlates closely

with a decrease in virus replication in lymph nodes, further confirming

that lymphoid tissue is the main site of HIV replication and the main

source of plasma viremia.

The level of steady-state viremia, called the viral set point, at ~1 year

following acquisition of HIV infection has important prognostic implications for the progression of HIV disease in the untreated patient. It

has been demonstrated that, as a group, untreated HIV-infected individuals who have a low set point at 6 months to 1 year following infection progress to AIDS much more slowly than do individuals whose set

point is very high at that time (Fig. 202-22).

Clinical Latency versus Microbiologic Latency With the exception of certain long-term nonprogressors and “elite controllers” of HIV

replication, the level of CD4+ T cells in the blood inevitably decreases

Resting CD4+ T cell

CTLs

Cytopathic

effect of

virus

Virus spread

Resting latently infected

CD4+ memory T cells

Degradation

of unintegrated

HIV DNA

Resting CD4+ T cell

Preintegration latency

(unstable) T-cell activation

(Ag, cytokines)

T-cell activation

(Ag, cytokines)

Postintegration

latency (stable)

T-cell activation

(Ag, cytokines)

Active Virus Replication

FIGURE 202-20 Generation of latently infected, resting CD4+ T cells in HIVinfected individuals. See text for details. Ag, antigen; CTLs, cytolytic T lymphocytes.

(Courtesy of TW Chun.)

Circulating

HIV virions

Half life ~30–60 min

Latently infected

CD4+ T cells

Uninfected

CD4+ T cells

CD4+ T cells

infected with

defective viruses

Longer-lived

cells

≤1%

93–99%

1–7%

Uninfected,

activated

CD4+ T cells

Rapidly turning over

infected CD4+ T cells

Half life 1.0 day

Replication cycle ~2 days

FIGURE 202-21 Dynamics of HIV infection in vivo. See text for detailed description. (Adapted

from Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD: HIV-1 dynamics in vivo: virion

clearance rate, infected cell life-span, and viral generation time. Science 271:1582, 1996.)