Human Immunodeficiency Virus (HIV) Infection

By Edward R. Cachay, MD, MAS, University of California, San Diego School of Medicine

Reviewed/Revised May 2024

Epidemiology | Transmission | Pathophysiology | Symptoms and Signs |

Diagnosis | Screening for HIV | Treatment | Prognosis | Prevention | Key Points |
More Information

Human immunodeficiency virus (HIV) infection (infection with either HIV-1 or HIV-
2) destroys CD4+ lymphocytes and impairs cell-mediated immunity, increasing
risk of certain infections and cancers. Initial infection may cause nonspecific
febrile illness. Risk of subsequent manifestations—related to immunodeficiency—
is proportional to the level of CD4+ lymphocyte depletion. HIV can directly
damage the brain, gonads, kidneys, and heart, causing cognitive impairment,
hypogonadism, renal insufficiency, or cardiomyopathy. Manifestations range from
asymptomatic carriage of the virus to end-stage HIV (acquired immune deficiency
syndrome [AIDS]), which is defined by the presence of an AIDS-defining illness
(serious opportunistic infections or cancers) or a CD4 count 200/mcL. HIV
infection can be diagnosed by antibody, nucleic acid (HIV RNA), or antigen (p24)
testing. Screening should be routinely offered to all adults and adolescents ages
13 to 64. In addition, pregnant women should be tested for HIV early in each
pregnancy, even if they have been screened during previous pregnancies.
Treatment aims to suppress HIV replication by using combinations of ≥ 2
medications that inhibit HIV enzymes; treatment can restore immune function in
most patients if suppression of replication is sustained.

(See also Human Immunodeficiency Virus (HIV) Infection in Infants and Children.)

Human immunodeficiency virus (HIV) is a retrovirus. Retroviruses are enveloped RNA viruses defined by
their mechanism of replication via reverse transcription to produce DNA copies that integrate into the host
cell's genome.

There are 2 HIV types, HIV-1 and HIV-2. HIV-1 causes most HIV infections worldwide, but HIV-2 causes a
substantial proportion of infections, particularly in parts of West Africa (1). In some areas of West Africa,
both viruses are prevalent and may coinfect patients. HIV-2 appears to be less virulent than HIV-1.

HIV-1 originated in Central Africa in the first half of the 20th century, when a closely related chimpanzee
virus first infected humans. Epidemic global spread began in the late 1970s, and AIDS was recognized in
1981.
General reference

1. Campbell-Yesufu OT, Gandhi RT: Update on human immunodeficiency virus (HIV)-2 infection. Clin Infect Dis
52(6):780-787, 2011. doi: 10.1093/cid/ciq248

Epidemiology of HIV Infection

The following global HIV statistics were estimated by the World Health Organization (WHO) in 2022 (see
HIV Data and Statistics):

Global prevalence of HIV – 39 million

Children (0 to 14 years of age) with HIV – 1.5 million

People newly diagnosed with HIV infection – 1.3 million; since 2010, the number of people
acquiring HIV has been reduced by 38%, from 2.1 million

Mortality from HIV-related causes – 630,000; since 2010, HIV-related deaths have been
reduced by 51%, from 1.3 million

People with HIV receiving antiretroviral therapy – 29.8 million

People with HIV who know their status – 86% (76% of those who know their status are
receiving treatment and 71% have suppressed viral loads)

HIV infection is most prevalent in Africa, particularly in sub-Saharan Africa. WHO estimated 2022 statistics
in Africa include the following (see HIV Data and Statistics):

Prevalence – 25.6 million (90% knew their status, 82% were receiving treatment, and 76% had
suppressed viral loads)

People newly diagnosed with HIV infection – 660,000 (a decrease to 0.57 per 1000 uninfected
population from 1.75 per 1000 in 2010)

Morality from HIV-related causes – 380,000 (a decrease of 56% from 2010)

The most recent estimates for HIV (in people ≥ 13 years old) in the United States from 2021 include the
following (see U.S. Statistics: Fast Facts):

Prevalence – 1.2 million people (13% were not aware of their status)

People who acquired HIV – 32,100 (estimated new HIV infections declined 12% from 36,500 in
2017)

People who acquired HIV by subpopulation – Men who have sex with men (22,400 [70%]);
people who reported heterosexual contact (7,100 [22%]); people who inject drugs (2,500 ([8%])

HIV has spread through epidemiologically distinct routes:

Heterosexual intercourse (affecting men and women about equally)

Men who have sex with men

 Contact with infected blood (eg, through sharing of needles and via blood transfusions in the
absence of effective donor-screening measures)

Mother-to-child transmission
Most HIV infections are transmitted through heterosexual contact, but risk factors vary according to region
or national income level. For instance, in high-resource countries, transmission among men who have sex
with men is usually the most common way infection occurs, whereas people who inject drugs are
disproportionally affected in Central and Eastern Europe (1, 2).

In areas where heterosexual transmission is dominant, HIV infection follows routes of trade,
transportation, and economic migration to cities and spreads secondarily to rural areas. In Africa,
particularly southern Africa, the HIV epidemic has killed tens of millions of adults, creating millions of
orphans. Factors associated with increased rates of spread include

Poverty and sexual violence

Limited sexual education and awareness about HIV

Health care systems that do not provide access to HIV testing and antiretroviral medications

Stigmatization, criminalization, and discrimination against people with HIV

Many opportunistic infections that complicate HIV are reactivations of latent infections. Thus,
epidemiologic factors that determine the prevalence of latent infections also influence the risk of specific
opportunistic infections. In many countries with high rates of HIV infection, prevalence of latent
tuberculosis and toxoplasmosis in the general population is higher than in other countries. Dramatic
increases in reactivated tuberculosis and toxoplasmic encephalitis have followed the epidemic of HIV-
induced immunosuppression in these countries. Similarly, in the United States, the incidence of
coccidioidomycosis, common in the Southwest, and histoplasmosis, common in the Midwest, has
increased because of HIV infection.

Human herpesvirus 8 infection, which causes Kaposi sarcoma, is common among men who have sex with
men but uncommon among other patients with HIV in the United States and Europe. Thus, in the United
States, > 90% of people with HIV who have developed Kaposi sarcoma are men who have sex with men (3).

Epidemiology references

1. Vermund SH, Leigh-Brown AJ: The HIV epidemic: High-income countries. Cold Spring Harb Perspect Med
2(5):a007195, 2012. doi: 10.1101/cshperspect.a007195
2. Hamers FF, Downs AM: HIV in central and eastern Europe. Lancet 361(9362):1035-1044, 2003. doi:
10.1016/S0140-6736(03)12831-0
3. Bhutani M, Polizzotto MN, Uldrick TS, et al: Kaposi sarcoma-associated herpesvirus-associated malignancies:
Epidemiology, pathogenesis, and advances in treatment. Semin Oncol 42(2):223–246, 2015. doi:
10.1053/j.seminoncol.2014.12.027

Transmission of HIV Infection

Transmission of HIV requires contact with body fluids—specifically blood, semen, vaginal secretions, breast
milk, or exudates from wounds or skin and mucosal lesions—that contain free HIV virions or infected cells.
Transmission is more likely with the high levels of virions that are typical during primary infection, even
when such infections are asymptomatic. Transmission by saliva or droplets produced by coughing or
sneezing, although conceivable, is extremely unlikely.

HIV is not transmitted by contact that does not involve exchange of body fluids.

Transmission is usually

Sexual: Direct transmission through sexual activity

Needle- or instrument-related: Sharing of blood-contaminated needles or exposure to

contaminated medical instruments

Transfusion- or transplant-related

Vertical: Transmission from an infected mother to child during pregnancy, childbirth, or

through breast milk

Sexual transmission of HIV

The sexual practices with the highest risks are those that cause mucosal trauma (see table HIV
Transmission Risk for Several Sexual Activities. A systematic review reported the following risk of
transmission per sex act (1):

Receptive anal intercourse: 1 per 72 sex acts

Insertive anal intercourse: 1 per 909

Receptive penile–vaginal intercourse: 1 per 1250

Insertive penile–vaginal intercourse: 1 per 2500

Receptive or insertive oral sex: 0 to 4 per 10,000 exposures

Risk of transmission during oral sex does not increase significantly if semen or vaginal secretions are
swallowed. However, open sores in the mouth, bleeding gums, or oral contact with menstrual blood may
increase the risk (Oral Sex and HIV Risk ). Other practices that cause mucosal trauma include fisting
(inserting most or all of the hand into the rectum or vagina) and using sexual toys. When used during
intercourse with a partner with HIV infection, these practices increase the risk of HIV transmission.

Mucous membrane inflammation facilitates HIV transmission. Sores on the mouth, vagina, penis, or
rectum increase risk of transmission. Sexually transmitted infections, such as gonorrhea, chlamydia,
trichomoniasis, and especially those that cause ulceration (eg, chancroid, herpes, syphilis), increase the
risk several-fold.

Risk of transmission is increased in the early and advanced stages of HIV infection when HIV
concentrations in plasma and genital fluids are higher. Evidence shows that people with HIV infection
treated with antiretroviral therapy who have an undetectable viral load (virally suppressed) do not sexually
transmit the virus to their partners (2, 3).
Circumcision seems to reduce the risk of males acquiring HIV infection by about 50%, by removing the
penile mucosa (underside of foreskin), which is more susceptible to HIV infection than the keratinized,
stratified squamous epithelium that covers the rest of the penis.

TABLE

HIV Transmission Risk for Several Sexual Activities

Risk* Activity

Dry kissing

Body-to-body rubbing and massage

Using unshared inserted sexual devices (eg, sex toys)

None (unless sores are present) Genital stimulation by a partner but no contact with
semen or vaginal fluids

Bathing or showering together

Contact with feces or urine if skin is intact

Wet kissing

Receptive oral-penile sex without ejaculation or if a

condom is used

Oral-vaginal sex if a barrier is used

Theoretical (extremely low risk
unless sores are present) Oral-anal contact

Digital penetration of the vagina or anus, with or

without a glove

Needle- and instrument-related transmission

The risk of HIV transmission after skin penetration with a medical instrument contaminated with infected
blood is approximately 1/400 without postexposure antiretroviral prophylaxis (1). Postexposure
antiretroviral prophylaxis as soon as possible after exposure is recommended ( U.S. Guidelines for
Management of Occupational Exposures to HIV). Risk appears to be higher if the wound is deep or if blood
is inoculated (eg, with a contaminated hollow-bore needle). Risk is also increased with hollow-bore needles
and with punctures of arteries or veins compared with solid needles or other penetrating objects coated
with blood because larger volumes of blood may be transferred. Thus, sharing needles that have entered
the veins of other people is a very high risk activity.

Risk of transmission from clinicians with HIV infection who take appropriate precautions is unclear but
appears minimal (Surveillance of Occupationally Acquired HIV/AIDS ). However, extensive investigations of
patients cared for by other physicians with HIV infection, including surgeons, have uncovered few other
cases.

Vertical (mother-to-child) transmission

HIV can be transmitted from a mother to her fetus or newborn:

During pregnancy, transplacentally

During childbirth

Via breast milk

The overall cumulative risk of vertical transmission without antiretroviral medications is 35 to 45% (4).

Transmission rates can be reduced significantly by treating pregnant women with HIV infection with
antiretroviral drugs during pregnancy, labor, and breastfeeding.

Cesarean delivery reduces the risk and is preferred for pregnant women with HIV infection whose viral
loads are > 1,000 copies/mL at or near delivery, independent of antepartum antiretroviral therapy, or
whose levels are unknown (5).

Testing and prophylactic treatment of the infant also reduce the risk.

HIV is excreted in breast milk. The overall risk of transmission through breastfeeding is approximately
14%, reflecting varying durations of breastfeeding and plasma viral RNA concentrations (eg, risk is high in
women who become infected during pregnancy or during the period of breastfeeding) (6).

In high-resource countries, women with HIV infection are advised not to breastfeed (see CDC:
Breastfeeding and Special Circumstances). However, in resource-limited settings, breastfeeding is
associated with reduced infant morbidity and mortality due to malnutrition and infectious diseases. For
women with HIV in low-resource settings, the World Health Organization (WHO) recommends
antiretroviral treatment and adherence support combined with breastfeeding for at least 12 months (see
WHO: Guidelines on HIV and Infant Feeding).

Because many women with HIV infection and their infants are treated or take prophylactic antiretroviral
medications during pregnancy, the incidence of HIV in children has decreased significantly in many
countries (see Human Immunodeficiency Virus (HIV) Infection in Infants and Children).

Transfusion- and transplant-related transmission

Screening of blood donors with tests for both antibodies to HIV and HIV RNA has minimized the risk of
transmission via blood transfusion. Current risk of transmitting HIV via blood transfusion is estimated to
be < 1/2,000,000 per unit transfused in the United States (7). However, in many countries with a high
prevalence of HIV, where blood and blood products are not screened for HIV, the risk of transfusion-
transmitted HIV infection remains high.

Rarely, HIV has been transmitted via transplantation of organs from HIV-seropositive donors. Infection has
developed in recipients of kidney, liver, heart, pancreas, bone, and skin—all of which contain blood—but
screening for HIV greatly reduces the risk of transmission. HIV transmission is even more unlikely from
transplantation of cornea, ethanol-treated and lyophilized bone, fresh-frozen bone without marrow,
lyophilized tendon or fascia, or lyophilized and irradiated dura mater.

HIV transmission is possible via artificial insemination using sperm from HIV-positive donors. In the United
States, sperm washing is considered an effective method of reducing the risk of partner insemination from
a known HIV-positive sperm donor.

Transmission references
1. Patel P, Borkowf CB, Brooks JT, et al: Estimating per-act HIV transmission risk: A systematic review. AIDS
28(10):1509-1519, 2014. doi: 10.1097/QAD.0000000000000298
2. Rodger AJ, Cambiano V, Bruun T, et al: Risk of HIV transmission through condomless sex in serodifferent gay
couples with the HIV-positive partner taking suppressive antiretroviral therapy (PARTNER): Final results of a
multicentre, prospective, observational study. Lancet 393(10189):2428-2438, 2019. doi:10.1016/S0140-
6736(19)30418-0
3. Rodger AJ, Cambiano V, Bruun T, et al: Sexual activity without condoms and risk of HIV transmission in
serodifferent couples when the HIV-positive partner is using suppressive antiretroviral therapy [published
correction appears in JAMA 316(2):171-181, 2016. doi: 10.1001/jama.2016.5148. Erratum in: JAMA316(6):667.
Erratum in: JAMA 316(19):2048, 2016. PMID: 27404185
4. Newell ML, Coovadia H, Cortina-Borja M, et al: Mortality of infected and uninfected infants born to HIV-
infected mothers in Africa: A pooled analysis. Lancet 364(9441):1236-1243, 2004. doi:10.1016/S0140-
6736(04)17140-7
5. ACOG Committee Opinion No. 751 Summary: Labor and delivery management of women with human
immunodeficiency virus infection. Obstet Gynecol 32(3):803-804, 2018. doi: 10.1097/AOG.0000000000002821.
6. Dunn DT, Newell ML, Ades AE, Peckham CS: Risk of human immunodeficiency virus type 1 transmission
through breastfeeding. Lancet 340(8819):585-588, 1992. doi:10.1016/0140-6736(92)92115-v
7. Steele WR, Dodd RY, Notari EP, et al: HIV, HCV, and HBV incidence and residual risk in US blood donors before
and after implementation of the 12-month deferral policy for men who have sex with men. Transfusion
61(3):839-850, 2021. doi: 10.1111/trf.16250

Pathophysiology of HIV Infection

HIV attaches to and penetrates host T cells via CD4+ molecules and chemokine receptors (see figure
Simplified HIV Life Cycle). After attachment, HIV RNA and several HIV-encoded enzymes are released into
the host cell.

Viral replication requires that reverse transcriptase (an RNA-dependent DNA polymerase) copy HIV RNA,
producing proviral DNA; this copying mechanism is prone to errors, resulting in frequent mutations and,
thus, new HIV genotypes. These mutations facilitate the generation of HIV that can resist control by the
host’s immune system and by antiretroviral drugs.

Proviral DNA enters the host cell’s nucleus and is integrated into the host DNA in a process that involves
integrase, another HIV enzyme. With each cell division, the integrated proviral DNA is duplicated along with
the host DNA. Subsequently, the proviral HIV DNA can be transcribed to HIV RNA and translated to HIV
proteins, such as the envelope glycoproteins 41 and 120. These HIV proteins are assembled into HIV
virions at the host cell inner membrane and budded from the cell surface within an envelop of modified
human cell membrane. Each host cell may produce thousands of virions.

After budding, protease, another HIV enzyme, cleaves viral proteins, converting the immature virion into a
mature, infectious virion.

Simplified HIV Life Cycle

HIV attaches to and penetrates host T cells, then releases HIV RNA and enzymes into the host cell.
HIV reverse transcriptase copies viral RNA as proviral DNA. Proviral DNA enters the host cell’s
nucleus, and HIV integrase facilitates the proviral DNA’s integration into the host’s DNA. The host
cell then produces HIV RNA and HIV proteins. HIV proteins are assembled into HIV virions and bud
from the cell surface. HIV protease cleaves viral proteins, converting the immature virion to a
mature, infectious virus.

Infected CD4+ lymphocytes produce > 98% of plasma HIV virions. A subset of infected CD4+ lymphocytes
constitutes a reservoir of HIV that can reactivate (eg, if antiviral treatment is stopped).
In moderate to heavy HIV infection, about 108 to 109 virions are created and removed daily. The HIV
average half-life in plasma is about 36 hours, about 24 hours intracellularly, and about 6 hours as an
extracellular virus. Every day, roughly 30% of the total HIV burden in an infected individual is turned over.
Also, 5 to 7% of CD4 cells turn over daily, and the entire pool of CD4 cells turns over every 2 days (1).
Hence, end-stage HIV infection (AIDS) results from a continuous and consistent replication of HIV, leading
to the virus and immune-mediated killing of CD4 lymphocytes. Further, the high volume of HIV replication
and high frequency of transcription errors by HIV reverse transcriptase result in many mutations,
increasing the chance of producing strains resistant to host immunity and drugs.

Infection with another type of retrovirus, human T-lymphotropic virus 1 (HTLV-1), is less common but can
also cause serious disease.

Immune system

Two main consequences of HIV infection are

Damage to the immune system, specifically depletion of CD4+ lymphocytes

Immune activation

CD4+ lymphocytes are involved in cell-mediated and, to a lesser extent, humoral immunity. CD4+
depletion may result from the following:

Direct cytotoxic effects of HIV replication

Cell-mediated immune cytotoxicity

Thymic damage that impairs lymphocyte production

Infected CD4+ lymphocytes have a half-life of about 2 days, which is much shorter than that of uninfected
CD4+ cells. Rates of CD4+ lymphocyte destruction correlate with plasma HIV level. Typically, during the
initial or primary infection, HIV levels are highest (> 106 copies/mL), and the CD4 count drops rapidly.

The normal CD4 count is about 750/mcL, and immunity is minimally affected if the count is > 350/mcL. If
the count drops below about 200/mcL, loss of cell-mediated immunity allows a variety of opportunistic
pathogens to reactivate from latent states and cause clinical disease.

The humoral immune system is also affected. Hyperplasia of B cells in lymph nodes causes
lymphadenopathy, and secretion of antibodies to previously encountered antigens increases, often
leading to hyperglobulinemia. Total antibody levels (especially IgG and IgA) and titers against previously
encountered antigens may be unusually high. However, antibody response to new antigens (eg, in
vaccines) decreases as the CD4 count decreases.

Abnormal elevation of immune activation may be caused in part by absorption of components of bowel
bacteria. Immune activation contributes to CD4+ depletion and immunosuppression by mechanisms that
remain unclear.

Other tissues
HIV also infects nonlymphoid monocytic cells (eg, dendritic cells in the skin, macrophages, brain microglia)
and cells of the brain, genital tract, heart, and kidneys, causing disease in the corresponding organ
systems.

HIV strains in several compartments, such as the nervous system (brain and cerebrospinal fluid) and
genital tract (semen, cervico-vaginal fluid), can acquire mutations and become genetically distinct from
those in plasma, suggesting that they have been selected by or have adapted to these anatomic
compartments (2–4). Thus, HIV levels and resistance patterns in these compartments may vary
independently from those in plasma.

Disease progression
During the first few weeks of primary infection, there are humoral and cellular immune responses:

Humoral: Antibodies to HIV are usually measurable within a few weeks after primary
infection; however, antibodies cannot fully control HIV infection because mutated forms of HIV
that are not controlled by the patient’s current anti-HIV antibodies are generated.

Cellular: Cell-mediated immunity is a more important means of controlling the high levels of
viremia (usually over 106 copies/mL) at first. But rapid mutation of viral antigens that are
targeted by lymphocyte-mediated cytotoxicity subvert control of HIV in all but a small
percentage of patients.

Plasma HIV virion levels, expressed as number of HIV RNA copies/mL, stabilize after about 6 months at a
level (set point) that varies widely among patients but averages 30,000 to 100,000/mL (4.2 to 5 log10/mL).
This variability depends on how host factors interact and impact HIV viral genetic diversity (5). The higher
this set point, the more quickly the CD4 count decreases to a level that seriously impairs immunity (<
200/mcL) and results in the opportunistic infections and cancers that define end-stage HIV (6, 7).

Risk and severity of opportunistic infections, end-stage HIV, and AIDS-related cancers are determined by 2
factors:

CD4 count

Exposure to potentially opportunistic pathogens

Risk of specific opportunistic infections increases below threshold CD4 counts of about 200/mcL for some
infections and 50/mcL for others, as in the following:

CD4 count < 200/mcL: Increased risk of Pneumocystis jirovecii pneumonia, toxoplasmic
encephalitis, and cryptococcal meningitis

CD4 count < 50/mcL: Increased risk of cytomegalovirus (CMV) and Mycobacterium aviuim
complex (MAC) infections

For every 3-fold (0.5 log10) increase in plasma HIV RNA in untreated patients, risk of progression to end-
stage HIV or death over the next 2 to 3 years increases about 50% (6).

Without treatment, risk of progression to end-stage HIV is about 1 to 2%/year in the first 2 to 3 years of
infection and about 5 to 6%/year thereafter. Eventually, end-stage HIV almost invariably develops in
untreated patients.

HTLV Infections

Infection with human T-lymphotropic virus (HTLV) 1 or 2 can cause T-cell leukemias and lymphomas,
lymphadenopathy, hepatosplenomegaly, skin lesions, and immunocompromise. Some patients with
HTLV infection develop infections similar to those that occur in patients with HIV infection. HTLV-1 can
also cause myelopathy/tropical spastic paraparesis .

Most cases are transmitted

From mother to child by breastfeeding

HTLV-1 can also be transmitted

Sexually

Through blood

Rarely, via transplantation of organs from HTLV-1 seropositive donors

Pathophysiology references

1. Ho DD, Neumann AU, Perelson AS, et al: Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1
infection. Nature 373(6510):123-126, 1995. doi: 10.1038/373123a0
2. Bednar MM, Sturdevant CB, Tompkins LA, et al: Compartmentalization, viral evolution, and viral latency of HIV
in the CNS. Curr HIV/AIDS Rep 12(2):262-271, 2015. doi:10.1007/s11904-015-0265-9
3. Mabvakure BM, Lambson BE, Ramdayal K, et al: Evidence for both intermittent and persistent
compartmentalization of HIV-1 in the female genital tract. J Virol 93(10):e00311-e00319, 2019.
doi:10.1128/JVI.00311-19
4. Ghosn J, Viard JP, Katlama C, et al: Evidence of genotypic resistance diversity of archived and circulating viral
strains in blood and semen of pre-treated HIV-infected men. AIDS (London, England). 18(3):447-457, 2004. doi:
10.1097/00002030-200402200-00011
5. Bartha I, McLaren PJ, Brumme C, et al: Estimating the respective contributions of human and viral genetic
variation to HIV control. PLoS Comput Biol 13(2):e1005339, 2017. Published 2017 Feb 9.
doi:10.1371/journal.pcbi.1005339
6. Lavreys L, Baeten JM, Chohan V, et al: Higher set point plasma viral load and more-severe acute HIV type 1
(HIV-1) illness predict mortality among high-risk HIV-1-infected African women. Clin Infect Dis 42(9):1333-9, 2006.
doi: 10.1086/503258
7. Lyles RH, Muñoz A, Yamashita TE, et al: Natural history of human immunodeficiency virus type 1 viremia after
seroconversion and proximal to AIDS in a large cohort of homosexual men. Multicenter AIDS cohort study. J
Infect Dis 181(3):872-80, 2000. doi: 10.1086/315339

Symptoms and Signs of HIV Infection

Initial HIV infection

Initially, primary HIV infection may be asymptomatic or cause transient nonspecific symptoms (acute
retroviral syndrome).

Acute retroviral syndrome usually begins within 1 to 4

weeks of infection and usually lasts 3 to 14 days. Symptoms Oral Candidiasis (Labial
and signs are often mistaken for infectious mononucleosis or Mucosa)
benign, nonspecific viral syndromes and may include fever,
malaise, fatigue, several types of dermatitis, sore throat, IMAGE

arthralgias, generalized lymphadenopathy, and septic

meningitis.

After the first symptoms disappear, most patients, even

without treatment, have no symptoms or only a few mild,
intermittent, nonspecific symptoms for a highly variable time
period (2 to 15 years).
© SPRINGER SCIENCE+BUSINESS
MEDIA
Symptoms during this relatively asymptomatic period may
result from HIV directly or from opportunistic infections. The
following are most common:

Lymphadenopathy Oral Candidiasis Due to

HIV
White plaques due to oral candidiasis

Herpes zoster
IMAGE

Diarrhea

Fatigue

Fever with intermittent sweats

Asymptomatic, mild-to-moderate cytopenias (eg, leukopenia,

anemia, thrombocytopenia) are also common. Some patients
experience progressive wasting (which may be related to © SPRINGER SCIENCE+BUSINESS
MEDIA
anorexia and increased catabolism due to infections) and
low-grade fevers or diarrhea.

Worsening HIV infection

When the CD4 count drops to < 200/mcL, nonspecific symptoms may worsen and a succession of AIDS-
defining illnesses develop.

In patients with HIV infection, certain syndromes are common and may require different considerations
(see table Common Manifestations of HIV Infection by Organ System). Some patients present with cancers
(eg, Kaposi sarcoma, B-cell lymphomas) that occur more frequently, are unusually severe, or have unique
features in patients with HIV infection (see Cancers Common in HIV-Infected Patients). In other patients,
neurologic dysfunction may occur.
Evaluation may detect infections that do not typically occur in the general population, such as

Disseminated mycobacterial infections

Pneumocystis jirovecii infection

Cryptococcus neoformans infection

Other fungal infections

Infections that also occur in the general population but suggest advanced HIV infection if they are
unusually severe or frequently recur include

Herpes zoster

Herpes simplex

Vaginal candidiasis

Invasive pneumococcal infections

Salmonella septicemia
Additional Manifestations of HIV Infection

Kaposi Sarcoma (AIDS Associated

 Kaposi Sarcoma

Oral Hairy Leukoplakia

Acquired immune deficiency syndrome

(AIDS)
TABLE
AIDS is defined as HIV infection with one or more of the
following: Common Manifestations
Associated With HIV Infection
One or more AIDS-defining illnesses (1) by Organ System

A CD4+ T lymphocyte (helper cell) count of <

200/mcL

A CD4+ cell percentage of ≤ 14% of the total lymphocyte count

AIDS-defining illnesses include

Serious opportunistic infections

Certain cancers (eg, Kaposi sarcoma, non-Hodgkin lymphoma) to which defective cell-
mediated immunity predisposes

Neurologic dysfunction

Wasting syndrome

AIDS-Defining Illnesses

Bacterial infections, multiple or recurrent*

Candidiasis of bronchi, trachea, or lungs

Candidiasis of esophagus

Cervical cancer, invasive†

Coccidioidomycosis, disseminated or extrapulmonary

Cryptococcosis, extrapulmonary

Cryptosporidiosis, chronic intestinal (lasting > 1 month)

Cytomegalovirus disease (other than liver, spleen, or lymph nodes), onset at age > 1 month

Cytomegalovirus retinitis (with loss of vision)

Encephalopathy attributed to HIV

Herpes simplex virus: chronic ulcers (lasting > 1 month) or bronchitis, pneumonitis, or esophagitis
(onset at age > 1 month)

Histoplasmosis, disseminated or extrapulmonary

Isosporiasis (cystoisosporiasis), chronic intestinal (lasting > 1 month)

Kaposi sarcoma

Lymphoma, Burkitt (or equivalent term)

Lymphoma, immunoblastic (or equivalent term)

Lymphoma, primary, of brain

Mycobacterium avium complex (MAC) or Mycobacterium kansasii, disseminated or extrapulmonary

Mycobacterium tuberculosis of any site, pulmonary, disseminated, or extrapulmonary

Mycobacterium, other species or unidentified species, disseminated or extrapulmonary

Pneumocystis jirovecii pneumonia

Pneumonia, recurrent†

Progressive multifocal leukoencephalopathy (PML)

Salmonella septicemia, recurrent

Toxoplasmosis of brain, onset at age > 1 month

Wasting syndrome attributed to HIV

 See also Centers for Disease Control and Prevention Morbidity and Mortality Weekly Report (MMWR):
Revised Surveillance Case Definition for HIV Infection, United States, 2014 .

* Only among children aged < 6 years

† Only among adults, adolescents, and children aged ≥ 6 years

Symptoms and signs reference

AIDS-Defining Illness:
1. Selik RM, Mokotoff ED, Branson, B, et al: Revised
Coccidioidomycosis
Surveillance Case Definition for HIV Infection—United States,
2014. MMWR63(RR03):1–10, 2014.
IMAGE

IMAGE COURTESY OF DR. EDWARD R.

CACHAY.

Diagnosis of HIV Infection

HIV antibody testing with or without HIV P24 antigen tests

Nucleic acid amplification assays to determine HIV RNA level (viral load)

HIV infection is suspected in patients with persistent, unexplained, generalized adenopathy or any of the
AIDS-defining illnesses (see sidebar AIDS-Defining Illnesses). It may also be suspected in high-risk patients
with symptoms that could represent acute primary HIV infection.

Diagnostic tests

Detection of antibodies to HIV is sensitive and specific except during the first few weeks after infection
(termed the "window period" of acute HIV infection). However, the HIV p24 antigen (a core protein of the
virus) is already present in the blood during most of this time and can be detected by assays.

Currently, a fourth-generation antigen/antibody combination immunoassay is recommended; it detects

antibodies to both HIV-1 and HIV-2 as well as the p24 HIV antigen. The laboratory version is probably
preferred over the point-of-care test for diagnosing early infection, but both can be done quickly (within 30
minutes). If the test result is positive, an assay to differentiate HIV-1 and HIV-2 and an HIV RNA assay are
done.

Earlier-generation enzyme-linked immunosorbent assay (ELISA) antibody assays are highly sensitive, but
because they do not test for antigen, they are not positive as early as the fourth-generation combination
test. Also, results are rarely false-positive. Positive ELISA results are therefore confirmed with a more
specific test such as Western blot. However, these tests have drawbacks:

ELISA requires complex equipment.

Western blot requires well-trained technicians, is expensive, and takes several days or weeks
for results to be available.

The full testing sequence takes at least a day.

Most settings use an HIV-1/HIV-2 differentiation assay as their preferred confirmatory test, replacing the
cumbersome Western blot. Additionally, HIV-1 Western blot assays do not reliably detect subtype O virus
prevalent in some African regions; if HIV-2 is being considered, a special HIV-2 Western blot needs to be
requested (1). Point-of-care tests using blood or saliva (eg, particle agglutination, immunoconcentration,
immunochromatography) can be done quickly (in 15 minutes) and simply, allowing testing in a variety of
settings and immediate reporting to patients. Positive results of these rapid tests should be confirmed by
standard blood tests (eg, ELISA with or without Western blot) in high-resource countries and repetition
with one or more other rapid tests in high HIV burden countries. Negative tests need not be confirmed.

If HIV infection is suspected despite negative antibody test results (eg, during the first few weeks after
infection), the plasma HIV RNA level should be measured. The nucleic acid amplification assays used are
highly sensitive and specific. HIV RNA assays require advanced technology, such as reverse transcription–
polymerase chain reaction (RT-PCR), which is sensitive to extremely low HIV RNA levels. Measuring p24 HIV
antigen by ELISA is less sensitive and less specific than directly detecting HIV RNA in blood.

Staging

HIV infection can be staged based on the CD4 count. In patients ≥ 6 years old, stages are as follows:

Stage 1: ≥ 500 cells/mcL

Stage 2: 200 to 499 cells/mcL

Stage 3: < 200 cells/mcL

The CD4 count after 1 to 2 years of treatment provides an indication of ultimate immune recovery; CD4
counts may not return to the normal range despite prolonged suppression of HIV.

Monitoring
When HIV is diagnosed, the following should be determined:

CD4 count

Plasma HIV RNA level

Both are useful for determining prognosis and monitoring treatment.

The CD4 count is calculated as the product of the following:

White blood cell count (eg, 4000 cells/mcL)

Percentage of white blood cells that are lymphocytes (eg, 30%)

Percentage of lymphocytes that are CD4+ (eg, 20%)

Using the numbers above, the CD4 count (4000 × 0.3 × 0.2) is 240 cells/mcL, or about 1/3 of the normal
CD4 count in adults, which is about 750 ± 250/mcL.

Plasma HIV RNA level (viral load) reflects HIV replication rates. The higher the set point (the relatively stable
virus levels that occur after primary infection), the more quickly the CD4 count decreases and the greater
the risk of opportunistic infection, even in patients without symptoms.

A baseline HIV genotype (blood test) can be ordered if the HIV viral load is > 500 copies/mL; availability of
this testing varies by location. HIV genotyping is used to identify mutations known to cause resistance to
certain antiretroviral drugs and to help select a drug regimen likely to be effective for a specific patient
with HIV infection.

Diagnosis of HIV-related conditions

Diagnosis of the various opportunistic infections, cancers, and other syndromes that occur in patients with
HIV infection is discussed elsewhere in THE MANUAL. Many have aspects unique to HIV infection.

Hematologic disorders (eg, cytopenias, lymphomas, cancers) are common and may be usefully evaluated
with bone marrow aspiration and biopsy. This procedure can also help diagnose disseminated infections
with MAC (Mycobacterium avium complex), M. tuberculosis, Cryptococcus, Histoplasma, human parvovirus
B19, P. jirovecii, and Leishmania. Most patients have normocellular or hypercellular marrow despite
peripheral cytopenia, reflecting peripheral destruction. Iron stores are usually normal or increased,
reflecting anemia of chronic disease (an iron-reutilization defect). Mild to moderate plasmacytosis,
lymphoid aggregates, increased numbers of histiocytes, and dysplastic changes in hematopoietic cells are
common.

HIV-associated neurologic syndromes can be differentiated via lumbar puncture with cerebrospinal fluid
analysis and central nervous system contrast-enhanced CT or MRI (see table Common Manifestations of
HIV Infection by Organ System).

Diagnosis reference

1. Centers for Disease Control and Prevention (CDC): Identification of HIV-1 group O infection—Los Angeles
county, California, MMWR Morb Mortal Wkly Rep 45(26):561-565, 1996.

Screening for HIV

Screening antibody tests or newer combination antigen/antibody tests should be offered routinely to
adults and adolescents, particularly pregnant women early in each pregnancy, regardless of their
perceived risk. For people at highest risk, especially sexually active people who have multiple sex partners
and who do not practice safe sex, testing should be repeated every 6 to 12 months. Such testing is
confidential and available, often free of charge, in many public and private facilities throughout the world.

Rapid tests have the advantage of offering preliminary test results at the initial encounter in less than 25
minutes. They are especially useful for people who are unlikely to return for their test results. People
receiving HIV testing should also be provided information on prevention, care, and treatment services.

In the United States, screening for HIV infection is recommended in all adolescents and adults aged 13 to
64 years and in younger adolescents and older adults who are at increased risk of infection (see Centers
for Disease Control and Prevention: Screening for HIV). Screening is also recommended in all pregnant
persons, including those who present in labor or at delivery whose HIV status is unknown.

The World Health Organization suggests that, in settings with a high HIV burden, HIV testing be done using
rapid antibody tests and enzyme immunoassays (see Consolidated Guidelines on HIV Testing services, July
2019).

Treatment of HIV Infection

Combinations of antiretroviral medications (antiretroviral therapy [ART], sometimes called

highly active ART [HAART] or combined ART [cART])

Chemoprophylaxis for opportunistic infections in patients at high risk

(See also Antiretroviral Treatment of HIV Infection.)

Treatment with ART is recommended for all patients, because disease-related complications can occur
even in untreated patients with high CD4 counts and because the toxicity of antiretrovirals has decreased
as new medications have been developed.

The benefits of ART outweigh the risks in every patient group and setting that has been carefully studied.
In the Strategic Timing of AntiRetroviral Treatment (START) study, 5472 treatment-naïve patients with HIV
infection and CD4 counts > 350 cells/mcL were randomized to start ART immediately (immediate initiation)
or to defer ART until their CD4 count decreased to < 250 cells/mcL (deferred initiation). Risk of AIDS-related
events (eg, tuberculosis, Kaposi sarcoma, malignant lymphomas) and non-AIDS–related events (eg, non-
AIDS cancer, cardiovascular disease) was lower in the immediate-initiation group (1).

A few exceptional patients can control their HIV strain without treatment; they maintain normal CD4
counts and very low blood levels of HIV (long-term nonprogressors) or normal CD4 counts and
undetectable blood levels of HIV (elite controllers). These patients may not require ART, but studies to
determine whether treating them is helpful have not been done and would be difficult because there are
few of these patients and they would likely do well not taking ART for long periods.

Antiretroviral therapy: General principles

ART aims to
 Reduce the plasma HIV RNA level to undetectable (ie, < 20 to 50 copies/mL)

Restore the CD4 count to a normal level (immune restoration or reconstitution)

A poor CD4 count response is more likely if the CD4 count at initiation of treatment is low (especially if <
50/mcL) and/or the HIV RNA level is high. However, marked improvement is likely even in patients with
advanced immunosuppression.

An increased CD4 count correlates with markedly decreased risk of opportunistic infections, other
complications, and death. With immune restoration, patients, even those with complications that have no
specific treatment (eg, HIV-induced cognitive dysfunction) or that were previously considered untreatable
(eg, progressive multifocal leukoencephalopathy), may improve. Outcomes are also improved for patients
with cancers (eg, lymphoma, Kaposi sarcoma) and most opportunistic infections.

Patients with most acute opportunistic infections benefit from early ART (initiated during the management
of the opportunistic infection). However, for some opportunistic infections, such as tuberculous meningitis
or cryptococcal meningitis, the evidence suggests that ART should be delayed (2 to 4 weeks in most cases)
until the first phase of antimicrobial therapy for these infections is finished because of the increased
frequency of adverse events and death.

Almost everyone who takes HIV medicine as prescribed can reach the goals of ART therapy usually within 6
months after starting treatment (Viral Suppression and an Undetectable Viral Load). However, maintaining
this degree of adherence is difficult. Partial suppression (failure to lower plasma HIV RNA levels to
undetectable levels) may select for single or multiple accumulated mutations in HIV that make viruses
partially or completely resistant to a single drug or entire classes of drugs. Unless subsequent treatment
uses drugs of other classes to which HIV remains sensitive, treatment is more likely to fail.

The success of ART is assessed by measuring plasma HIV RNA levels every 8 to 12 weeks for the first 4 to 6
months or until HIV levels are undetectable and every 6 months thereafter. Increasing HIV levels are the
earliest evidence of treatment failure and may precede a decreasing CD4 count by months. Maintaining
patients on failing medication regimens selects for HIV mutants that are more drug-resistant. However,
compared with wild-type HIV, these mutants appear less able to reduce the CD4 count, and failing
medication regimens are often continued when no fully suppressive regimen can be found.

If treatment fails, drug susceptibility (resistance) assays can determine the susceptibility of the dominant
HIV strain to all available medications. Genotypic and phenotypic assays are available and can help
clinicians select a new regimen that should contain at least 2 and preferably 3 medications to which the
HIV strain is more susceptible. The dominant HIV strain in the blood of patients who are taken off
antiretroviral therapy may revert over months to years to the wild-type (ie, susceptible) strain because the
resistant mutants replicate more slowly and are replaced by the wild type. Thus, if patients have not been
treated recently, the full extent of resistance may not be apparent through resistance testing, but when
treatment resumes, strains with resistance mutations often reemerge from latency and again replace the
wild-type HIV strain.

Many patients with HIV infection are taking complex regimens involving multiple pills to control the HIV
RNA level (viral load), but often, no conventional HIV RNA resistance tests were done when viral treatment
failed. With the availability of new co-formulated HIV medications, many patients could benefit from
simplification of their ART regimen, guided by HIV DNA archive genotype testing (GenoSure Archive). The
HIV DNA genotype archive provides HIV-1 antiretroviral drug resistance data when conventional HIV RNA
resistance testing cannot be done because patients have a low plasma HIV RNA level (< 500 copies/mL).
The HIV DNA archive genotype test analyzes integrated and unintegrated archived HIV-1 proviral DNA
embedded in host cells. The test amplifies cell-associated HIV-1 DNA from infected cells in whole blood
samples, then uses next-generation sequencing technology to analyze the HIV-1 polymerase region. The
positive predictive value of the HIV DNA archive resistance test results may enable clinicians to identify
HIV-resistance mutations that were previously unidentified and to select a potentially simpler regimen with
co-formulated drugs (≥ 2 drugs in a single pill).

Immune reconstitution inflammatory syndrome (IRIS)

Patients beginning ART sometimes deteriorate clinically, even though HIV levels in their blood are
suppressed and their CD4 count increases, because of an immune reaction to subclinical opportunistic
infections or to residual microbial antigens after successful treatment of opportunistic infections. IRIS
usually occurs in the first months of HIV treatment but is occasionally delayed. IRIS can complicate virtually
any opportunistic infection and even tumors (eg, Kaposi sarcoma) but is usually self-limited or responds to
brief regimens of corticosteroids.

IRIS has 2 forms:

Paradoxical IRIS, which refers to worsening symptoms due to a previously diagnosed infection

Unmasked IRIS, which refers to the first appearance of symptoms of an infection not
previously diagnosed

Paradoxical IRIS typically occurs during the first few months of HIV treatment and usually resolves on its
own. If it does not, corticosteroids, given for a short time, are often effective. Paradoxical IRIS is more likely
to cause symptoms and symptoms are more likely to be severe when ART is started soon after treatment
of an opportunistic infection is started. Thus, for some opportunistic infections, ART is delayed until
treatment of the opportunistic infection has reduced or eliminated the infection.

In patients with unmasked IRIS, the newly identified opportunistic infection is treated with antimicrobial
drugs. Occasionally, when the symptoms are severe, corticosteroids are also used. Usually, when
unmasked IRIS occurs, ART is continued. An exception is cryptococcal meningitis. Then ART is temporarily
interrupted until the infection is controlled.

Determining whether clinical deterioration is caused by treatment failure, IRIS, or both requires
assessment of the persistence of active infections with cultures and can be difficult.

Interruption of antiretroviral therapy

Interruption of ART is usually safe if all drugs are stopped simultaneously, but levels of slowly metabolized
medications (eg, nevirapine, efavirenz) may remain high and thus increase the risk of resistance.
Interruption may be necessary if intervening illnesses require treatment or if medication toxicity is
intolerable or needs to be evaluated. After interruption to determine which drug is responsible for toxicity,
clinicians can safely restart most medications as monotherapy for up to a few days. NOTE: The most
important exception is abacavir; patients who had fever or rash during previous exposure to abacavir may
develop severe, potentially fatal hypersensitivity reactions with reexposure. Risk of an adverse reaction to
abacavir is 100-fold higher in patients with HLA-B*57:01, which can be detected by genetic testing.

Prevention of opportunistic infections

(See also the United States Public Health Service and the HIV
Pearls & Pitfalls
Medicine Association of the Infectious Diseases Society of
Patients who had an
America’s Guidelines for the Prevention and Treatment of
adverse reaction to abacavir
Opportunistic Infections in Adults and Adolescents With
should not be given the
HIV.)
medication again. If they are
reexposed to the
Effective chemoprophylaxis is available for many
medication, they may have
opportunistic infections and reduces rates of disease due to
a severe, potentially fatal
P. jirovecii, Candida, Cryptococcus, and MAC (Mycobacterium hypersensitivity reaction.
avium complex). If therapy restores CD4 counts to above Risk of an adverse reaction
threshold values for > 3 months, chemoprophylaxis can be to abacavir is 100-fold
stopped. higher in patients with HLA-
B*57:01, which can be
Primary prophylaxis depends on the CD4 count: detected by genetic testing.

CD4 count < 200/mcL or oropharyngeal candidiasis

(active or previous): Prophylaxis against P. jirovecii
pneumonia is recommended. Double-strength sulfamethoxazole/trimethoprim, SMX-TMP,
Cotrimoxazole tablets given once/day or 3 times/week are effective. Some adverse effects can
be minimized with the 3 times/week dose or by gradual dose escalation. Some patients who
cannot tolerate TMP/SMX can tolerate dapsone (100 mg once/day). Patients with glucose-6-
phosphate dehydrogenase (G6PD) deficiency are at risk for developing severe hemolysis with
dapsone use and, therefore, should be screened for G6PD deficiency before using dapsone.
For the few patients who cannot tolerate either drug because of a troublesome adverse effect
(eg, fever, neutropenia, rash), aerosolized pentamidine 300 mg once/month or atovaquone
1500 mg once/day can be used.

CD4 count < 50/mcL: Primary prophylaxis against disseminated MAC disease is not
recommended for adults and adolescents with HIV who immediately initiate ART. People with
HIV who are not receiving ART or who remain viremic on ART but have no current options for a
fully suppressive ART regimen should receive chemoprophylaxis against disseminated MAC
disease if they have CD4 counts <50 cells/mm3 (2). Prophylaxis against disseminated MAC
consists of azithromycin or clarithromycin; if neither of these drugs is tolerated, rifabutin can
be used. Azithromycin can be given weekly as two 600-mg tablets; it provides protection (70%)
similar to daily clarithromycin and does not interact with other medications.

If latent tuberculosis is suspected (based on tuberculin skin tests, interferon-gamma release assays, high-
risk exposure, personal history of active tuberculosis, or residence in a region with high tuberculosis
prevalence), regardless of CD4 count, patients should be given isoniazid 5 mg/kg (up to 300 mg) orally
once/day plus pyridoxine (vitamin B6) 10 to 25 mg orally once/day for 9 months to prevent reactivation.

For primary prophylaxis against some fungal infections (eg, esophageal candidiasis), oral fluconazole 100
to 200 mg once/day is successful but is infrequently used because the cost per infection prevented is high
and diagnosis and treatment of these infections are usually successful (3).

Secondary prophylaxis (after control of the initial infection) is indicated if patients have had the following:

Recurrent oral, vaginal, or esophageal candidiasis; coccidioidomycosis; or cryptococcal

infections: Fluconazole is used.

Histoplasmosis: Itraconazole is used.

Latent toxoplasmosis: This asymptomatic condition is indicated by serum antibodies (IgG) to

Toxoplasma gondii. TMP/SMX (in doses used to prevent P. jirovecii pneumonia) is used to
prevent reactivation and consequent toxoplasmic encephalitis. Latent infection is less
common (about 15% of adults) in the United States than in Europe and most high HIV burden
countries (up to 70 to 80% of adults).

P. jirovecii pneumonia

Herpes simplex infection

Aspergillosis (possibly)

Detailed guidelines for prophylaxis of fungal (including Pneumocystis), viral, mycobacterial, and toxoplasmic
infections are available at Clinical Info: Federally Approved Clinical Practice Guidelines for HIV/AIDS.

Immunization
The CDC 2024 recommendations for vaccination of patients aged ≥ 19 years with HIV infection include the
following:

Patients who have not received a conjugate pneumococcal vaccine or whose previous
vaccination history is unknown should be given PCV15 or PCV20; if PCV15 is given, follow with
PPSV23 ≥ 8 weeks after the PCV15 dose.

All patients should be given the influenza vaccine annually.

All patients should be given the hepatitis B vaccine.

Patients at risk of hepatitis A or desiring protection from it should be given the hepatitis A
vaccine.

At the appropriate age, males and females should be given the human papillomavirus (HPV)
vaccine to prevent HPV-related cervical and anal cancers.

Adults who have not been previously vaccinated with the meningococcal vaccine should be
given a 2-dose primary series of MenACWY ≥ 8 weeks apart and be revaccinated every 5 years.

Patients who did not receive tetanus-diphtheria-pertussis vaccine (Tdap) as part of their
completed tetanus-diphtheria vaccine (Td) series should be given Tdap for their next Td
 booster. For patients who are beginning or continuing their Td series and have not yet been
given Tdap, Tdap should be substituted for one of the Td boosters.

All patients should be given the recombinant zoster vaccine.

The varicella vaccine and the measles, mumps, and rubella (MMR) vaccine may be given to
patients with CD4 percentage ≥ 15% and CD4 count ≥ 200/mcL, but these vaccines are
contraindicated in patients with CD4 percentage < 15% or CD4 count < 200/mcL.

People with HIV should receive the full series of a COVID-19 vaccine, regardless of CD4 count
or viral load because the potential benefits outweigh potential risks (4).

Mpox vaccination is recommended for people with HIV at risk for MPox. The only Mpox
vaccine recommended for people with HIV is the modified vaccinia Ankara (Jynneos in the
United States), which is made from a highly attenuated, nonreplicating vaccinia virus and has
an excellent safety profile.
Generally, inactivated vaccines should be used. These vaccines are effective less often in patients who are
HIV-positive than in those who are HIV-negative.

Pregnant women with HIV should receive the routine vaccinations recommended during pregnancy.
Because live-virus vaccines are potentially dangerous for patients with severe immunosuppression, expert
opinion should be sought when dealing with patients at risk of primary varicella; recommendations vary
(see vaccination information in HIV in Infants and Children and see table Considerations for Use of Live
Vaccines in Children With HIV Infection).

Treatment references
1. INSIGHT START Study Group, Lundgren JD, Babiker AG, et al: Initiation of antiretroviral therapy in early
asymptomatic HIV infection. N Engl J Med 373 (9):795–807, 2015. doi:10.1056/NEJMoa1506816
2. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV:
Disseminated Mycobacterium Avium Complex Disease. Accessed May 7, 2024.
3. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV:
Cryptococcosis. Accessed May 7, 2024.
4. COVID Vaccine Guidance for COVID-19 and People With HIV: Accessed May 7, 2024.

Prognosis for HIV Infection

Risk of end-stage HIV, death, or both is predicted by the

CD4 count in the short term

Plasma HIV RNA level in the longer term

For every 3-fold (0.5 log10) increase in viral load, mortality over the next 2 to 3 years increases about 50%
(1-3). HIV-associated morbidity and mortality vary by the CD4 count, with the most deaths from HIV-related
causes occurring at counts of < 50/mcL. However, with effective treatment, the HIV RNA level decreases to
undetectable levels, CD4 counts often increase dramatically, and risk of illness and death falls but remains
higher than that for age-matched populations without HIV infection (4). Hence, prompt diagnosis of HIV
before the disease is too advanced and immediate initiation of HIV treatment are essential to prognosis.

Another, less well-understood prognostic factor is the level of immune activation as determined by
evaluating the expression of activation markers on CD4 and CD8 lymphocytes. Activation, which may be
caused by leakage of bacteria across the HIV-damaged colonic mucosa, is a strong prognostic predictor
but is not used clinically because this test is not widely available and antiretroviral therapy changes the
prognosis, making this test less important.

A subgroup of people with HIV (termed long-term nonprogressors) remain asymptomatic with high CD4
counts and low HIV levels in the blood without antiretroviral treatment. These people usually have
vigorous cellular and humoral immune responses to their infecting HIV strain as measured by assays in
vitro. The specificity of this effective response is shown by the following: When these people acquire a
superinfection with a second strain of HIV to which their immune response is not as effective, they convert
to a more typical pattern of progression. Thus, their unusually effective response to the first strain does
not apply to the second strain. These cases provide a rationale for counseling people with HIV infection
that they still need to avoid exposure to possible HIV superinfection through unsafe sex or needle sharing.

Cure of HIV infection has not been thought possible, and thus lifelong drug treatment is considered
necessary. Patients with HIV infection should be urged to take their antiretroviral drugs consistently. An
instance of a possible functional cure was widely reported in an infant with transient eradication of
replication-competent HIV after about 15 months of antiretroviral therapy (5). However, HIV replication
subsequently resumed (6). Periodic HIV treatment interruption is also detrimental. In a large international
clinical trial, risk of opportunistic infection or death from any cause, particularly from premature coronary
artery disease, cerebrovascular events, or liver and kidney disorders, was significantly higher when
antiretroviral therapy was taken episodically (guided by the CD4 count) than when it was taken
continuously (7).

End-of-life care

Although antiretroviral therapy has dramatically increased life expectancy for patients with AIDS, many
patients still deteriorate and die. Death may result from the following:

Inability to take ART consistently, resulting in progressive immunosuppression

Occurrence of untreatable opportunistic infections and cancers

Liver failure due to hepatitis B or C

Accelerated aging and age-related disorders

Non-AIDS–related cancers that occur at a higher rate in patients with otherwise well-controlled
HIV infection

Death is rarely sudden; thus, patients usually have time to make plans. Nonetheless, patients should
record their plans for health care early, with clear instructions for end-of-life care. Other legal documents,
including powers of attorney and wills, should be in place.
As patients near the end of life, clinicians may need to prescribe drugs to relieve pain, anorexia, agitation,
and other distressing symptoms. The profound weight loss in many people during the last stages of HIV
makes good skin care difficult. The comprehensive support provided by hospice programs helps many
patients because hospice providers are skilled at symptom management, and they support caregivers and
patient autonomy.

Prognosis references

1. Mellors JW, Kingsley LA, Rinaldo CR, et al: Quantitation of HIV-1 RNA in plasma predicts outcome after
seroconversion. Ann Internal Med 122(8):573-579, 1995. doi: 10.7326/0003-4819-122-8-199504150-00003
2. Mellors JW, Rinaldo CR, Gupta P, et al: Prognosis in HIV-1 infection predicted by the quantity of virus in
plasma. Science 272(5265):1167-1170, 1996. doi:10.1126/science.272.5265.1167
3. Welles SL, Jackson JB, Yen-Lieberman B, et al: Prognostic value of plasma human immunodeficiency virus type
1 (HIV-1) RNA levels in patients with advanced HIV-1 disease and with little or no prior zidovudine therapy. AIDS
Clinical Trials Group Protocol 116A/116B/117 Team. J Infect Dis 174(4):696-703, 1996.
doi:10.1093/infdis/174.4.696
4. Park LS, Tate JP, Sigel K, et al: Association of viral suppression with lower AIDS-defining and non-AIDS-defining
cancer incidence in HIV-infected veterans: A prospective cohort study. Ann Intern Med 169(2):87-96, 2018.
doi:10.7326/m16-2094
5. Persaud D, Gay H, Ziemniak C, et al: Absence of detectable HIV-1 viremia after treatment cessation in an
infant. N Engl J Med 369(19):1828-1835, 2013. doi:10.1056/NEJMoa1302976
6. Ledford H: HIV rebound dashes hope of 'Mississippi baby' cure. Nature 2014.
doi.org/10.1038/nature.2014.15535
7. Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren J, et al:
CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 355(22):2283-2296, 2006. doi:
10.1056/NEJMoa062360

Prevention of HIV Infection

Vaccines against HIV have been difficult to develop because HIV surface proteins mutate easily, resulting in
an enormous diversity of antigenic types. Nonetheless, various vaccine candidates are under investigation,
and a few have shown promise in clinical trials. At the present time, there is no effective HIV vaccine.

Prevention of transmission

Vaginal microbicides (including antiretroviral drugs) inserted before sexual contact have thus far proved
ineffective, and some appear to increase risk for women, perhaps by causing cellular damage and thus
decreasing natural barriers to HIV.

Effective measures include the following:

Public education: Education is effective and appears to have decreased rates of infection in
some countries, notably Thailand and Uganda. Because sexual contact accounts for most
cases, teaching people to avoid unsafe sex practices is the most relevant measure (see table
HIV Transmission Risk for Several Sexual Activities).

Safer sex practices: People with HIV who are not virally suppressed (ie, do not have an
undetectable viral load) should practice safer sex behaviors that are essential to prevent the
spread of the infection. Virally suppressed people with HIV do not sexually transmit the virus
to their partners (1). Safer sex practices should be used by a patient with HIV whose infection
is not virally suppressed regardless of who they have sex with. Safer sex practices are also
advised when both partners are HIV-positive and one or both partners are not virally
suppressed; unprotected sex between people with virally unsuppressed-HIV infection may
expose a person to resistant or more virulent strains of HIV. In addition, safer sex practices
help to prevent transmission of other viruses (eg, cytomegalovirus, Epstein-Barr virus, herpes
simplex virus, hepatitis B virus) that cause severe disease in end-stage HIV patients, as well as
help to prevent transmission of syphilis and other sexually transmitted infections (STIs),
including concerning infections such as multi-drug–resistant gonorrhea and sexually
transmitted Neisseria meningitidis. Condoms offer the best protection. Oil-based lubricants
should not be used because they may dissolve latex, increasing the risk of condom failure.
(See also the Center for Disease Control and Prevention (CDC) information on HIV
Transmission.)

Counseling for people who use parenteral drugs: Counseling about the risk of sharing
needles is important but is probably more effective if combined with provision of sterile
needles and syringes to reduce transmission of HIV and other bloodborne viruses that are
acquired by sharing contaminated injecting equipment, treatment of drug dependence, and
rehabilitation.

Confidential testing for HIV infection: Testing should be offered routinely to sexually active
adolescents and adults ages 13 to 75 in virtually all health care settings. To facilitate routine
testing, some states no longer require written consent or extensive pre-test counseling.

Counseling for pregnant women: Mother-to-child transmission has been virtually eliminated
by HIV testing, treatment with ART, and, in high-resource countries, use of breast milk
substitutes. If pregnant women are known to have HIV infection or test positive for HIV, they
should be counseled about the risk of mother-to-child transmission. Pregnant women with
HIV infection should be encouraged to accept therapy to prevent infection of the fetus or
newborn, typically beginning at about 14 weeks gestation. Combination therapy is typically
used because it is more effective than monotherapy and less likely to result in drug resistance.
Some drugs can be toxic to the fetus or woman and should be avoided. If women meet criteria
for ART, they should begin a regimen tailored to their history and stage of pregnancy and
continue it throughout pregnancy. Cesarean delivery can also reduce risk of transmission.
Regardless of the antepartum regimen used or mode of delivery, all women with HIV infection
should be given IV zidovudine during labor, and after birth, neonates should be given oral
zidovudine, which is continued for 6 weeks after delivery (see also Prevention of Perinatal
Transmission). Some women choose to terminate their pregnancy because HIV can be
transmitted in utero to the fetus or for other reasons.
Screening of blood and organs: Transmission by blood transfusion is still remotely possible
in the United States because antibody results may be false-negative during early infection.
Currently, screening blood for antibody and p24 antigen is mandated in the United States and
probably further reduces risk of transmission. Risk is reduced further by asking people with
risk factors for HIV infection, even those with recent negative HIV antibody test results, not to
donate blood or organs for transplantation. The Red Cross has issued guidance for deferral of
blood donation, including deferral for having had a new sex partner or more than one sex
partner in the previous 3 months and having engaged in anal sex in the last 3 months (see
American Red Cross Blood Donation Eligibility Criteria: Alphabetical ). However, use of
sensitive HIV screening tests and deferral of donors of organs, blood, and blood products have
not been implemented consistently in high HIV burden countries.

Preexposure prophylaxis with antiretrovirals (PrEP): In PrEP, people who do not have HIV
infection but are at high risk (eg, by having a sex partner with HIV) take an antiretroviral
medication daily to reduce their risk of infection. The CDC recommends PrEP for sexually
active adults and adolescents weighing ≥ 35 kg (77 lb) who report sexual behaviors that place
them at substantial risk of HIV infection . The CDC also recommends PrEP for those who inject
drugs and report injection practices that place them at substantial risk of HIV Infection . The
combination of tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC) or tenofovir
alafenamide-emtricitabine (TAF-FTC) can be used. Use of PrEP does not eliminate the need to
use other methods of reducing risk of HIV infection, including using condoms and avoiding
high-risk behaviors (eg, needle sharing). Data concerning infants of HIV-negative mothers
taking TDF/FTC PrEP during pregnancy are incomplete, but currently, no adverse effects have
been reported in children born to women with HIV infection treated with TDF/FTC. Use of PrEP
to reduce the risk of HIV infection in people who use injection drugs is being studied. Long-
acting antiretroviral agents (ie, cabotegravir LA, an injectable integrase inhibitor that is
administered every 8 weeks, is indicated for PrEP in adults and adolescents weighing at least
35 kg). . For the current CDC recommendations, see Preexposure Prophylaxis for the
Prevention of HIV Infection in the United States – Clinical Practice Guideline.

Circumcision of men: Data from young African men show that circumcision reduces the risk
of acquiring HIV infection from female partners during vaginal sex by about 50%; male
circumcision is probably similarly effective in other male-patient populations. Whether male
circumcision reduces HIV transmission from HIV-positive men to women or reduces the risk of
acquiring HIV from an infected male partner is unknown.

Universal precautions: Medical and dental clinicians should wear gloves in situations that
may involve contact with any patient’s mucous membranes or body fluids and should be
taught how to avoid needlestick accidents. Home caregivers of patients with HIV infection
should wear gloves if their hands may be exposed to body fluids. Surfaces or instruments
contaminated by blood or other body fluids should be cleaned and disinfected. Effective
disinfectants include heat, peroxide, alcohols, phenolics, and hypochlorite (bleach). Isolation of
patients with HIV infection is unnecessary unless indicated by an active opportunistic infection
(eg, tuberculosis).
 Treatment of HIV infection: Treatment with ART lowers the risk of transmission.

Postexposure prophylaxis (PEP)

Potential consequences of exposure to HIV have prompted the development of policies and procedures,
particularly preventive treatment, to decrease risk of infection to health care workers.

Preventive treatment is indicated after

Penetrating injuries involving HIV-infected blood (usually needlesticks)

Heavy exposure of mucous membranes (eye or mouth) to infected body fluids such as semen,
vaginal fluids, or other body fluids containing blood (eg, amniotic fluid)

Body fluids such as saliva, urine, tears, nasal secretions, vomitus, or sweat are not considered potentially
infectious unless they are visibly bloody.

After initial exposure to blood, the exposed area is immediately cleaned with soap and water for skin
exposures and with antiseptic for puncture wounds. If mucous membranes are exposed, the area is
flushed with large amounts of water.

The following are documented:

Type of exposure

Time elapsed since exposure

Clinical information (including risk factors and serologic tests for HIV) about the source patient
for the exposure and the person exposed

Type of exposure is defined by

Which body fluid was involved

Whether exposure involved a penetrating injury (eg, needlestick, cut with sharp object) and
how deep the injury was

Whether the fluid had contact with nonintact skin (eg, abraded or chapped skin) or mucous
membrane

Risk of infection is about 0.3% (1:300) after a typical percutaneous exposure and about 0.09% (1:1100)
after mucous membrane exposure. These risks vary, reflecting the amount of HIV transferred to the
person with the injury; the amount of HIV transferred is affected by multiple factors, including viral load of
the source and type of needle (eg, hollow or solid). However, these factors are no longer taken into
account in PEP recommendations.

The source is qualified by whether it is known or unknown. If the source is unknown (eg, a needle on the
street or in a sharps disposal container), risk should be assessed based on the circumstances of the
exposure (eg, whether the exposure occurred in an area where injection drug use is prevalent, whether a
needle discarded in a drug-treatment facility was used). If the source is known but HIV status is not, the
source is assessed for HIV risk factors, and prophylaxis is considered.
The goal is to start PEP as soon after exposure as possible if prophylaxis is warranted. CDC recommends
providing PEP within 24 to 36 hours after exposure; a longer interval after exposure requires the advice of
an expert.

Use of PEP is determined by risk of infection; guidelines recommend antiretroviral therapy with ≥ 3
antiretroviral medications given for 28 days (2). The medications should be carefully selected to minimize
adverse effects and provide a convenient dosing schedule and thus encourage PEP completion. Preferred
regimens include a combination of 2 nucleoside reverse transcriptase inhibitors (NRTIs) and an integrase
inhibitor, either bictegravir-emtricitabine-tenofovir alafenamide or dolutegravir in combination with either
tenofovir disoproxil fumarate-emtricitabine (TDF/FTC) or tenofovir alafenamide-emtricitabine (TAF/FTC). An
alternative integrase-inhibitor-based regimen is raltegravir (400 mg twice daily) and either TDF/FTC or
TAF/FTC administered once daily. In rare occasions where an integrase inhibitor-based regimen cannot be
used, TDF/FTC or TAF/FTC can be combined with the boosted protease inhibitor darunavir. (For detailed
recommendations, see The 2022 Recommendations of the International Antiviral Society—USA Panel:
Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults.)

If the source’s virus is known or suspected to be resistant to ≥ 1 drug, an expert in antiretroviral therapy
and HIV transmission should be consulted. However, clinicians should not delay PEP pending expert
consultation or drug susceptibility testing. Also, clinicians should provide immediate evaluation and face-
to-face counseling and not delay follow-up care.

In patients who may become or are pregnant, first-line postexposure prophylaxis regimens are similar to
those for nonpregnant patients, including TDF/FTC or TAF/FTC once daily plus either dolutegravir (50 mg
once daily) or raltegravir (400 mg twice daily). Bictegravir-emtricitabine-tenofovir alafenamide is generally
avoided in pregnant women and persons of childbearing potential who are not on effective contraception
because there are limited data on its use during pregnancy (3).

Prevention references

1. Rodger AJ, Cambiano V, Bruun T, et al: Sexual activity without condoms and risk of HIV transmission in
serodifferent couples when the HIV-positive partner is using suppressive antiretroviral therapy. JAMA 316(2):171-
81, 2016. doi:10.1001/jama.2016.5148
2. Centers for Disease Control and Prevention: US Public Health Service: Preexposure prophylaxis for the
prevention of HIV infection in the United States—2021 Update: A clinical practice guideline. Accessed May 13,
2024.
3. Gandhi RT, Bedimo R, Hoy JF, et al: Antiretroviral drugs for treatment and prevention of HIV infection in
adults: 2022 Recommendations of the International Antiviral Society-USA Panel. JAMA 329(1):63-84, 2023.
doi:10.1001/jama.2022.22246

Key Points

HIV infects CD4+ lymphocytes and thus interferes with cell-mediated and, to a lesser
extent, humoral immunity.
 HIV is spread mainly by sexual contact, parenteral exposure to contaminated blood or
transplanted tissue or organs, and vertical transmission (in utero, during childbirth, or
through breastfeeding).

Frequent viral mutations combined with immune system damage significantly impair
the body's ability to clear the HIV infection.

Various opportunistic infections and cancers can develop and are the usual cause of
death in untreated patients.

Diagnose using antibody tests, and monitor by measuring viral load and CD4 count.

Treat with a combination of antiretroviral drugs, which can restore immune function to
nearly normal in most patients if they take the drugs consistently.

Periodically counsel patients with HIV about safer sex.

Use postexposure and preexposure antiretroviral prophylaxis when indicated.

Give primary prophylaxis against opportunistic infections based on the CD4 count.

More Information

The following English-language resources may be useful. Please note that THE MANUAL is not responsible
for the content of these resources.

CDC 2024 Immunization Schedule: Recommended adult immunization schedule by medical condition and other
indications
Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents: Drug-Drug Interactions:
Information regarding pharmacokinetic (PK) drug-drug interactions between antiretroviral (ARV) drugs and
concomitant medications that are common and may lead to increased or decreased drug exposure
Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents
Guidelines on Post-Exposure Prophylaxis for HIV and the Use of Co-Trimoxazole Prophylaxis for HIV-Related
Infections Among Adults, Adolescents and Children: Recommendations for a public health approach - December
2014 supplement to the 2013 consolidated ARV guidelines
National Institutes of Health's AIDSInfo: HIV-related research information from the NIH’s Office of AIDS
Research (OAR), the National Institute Of Allergy and Infectious Diseases (NIAID), and the U.S. National Library of
Medicine (NLM)
CDC: Post-Exposure Prophylaxis (PEP): Resources for providers and consumer regarding the use of antiretroviral
drugs after a single high-risk event to stop HIV seroconversion
Primary Care Guidelines for the Management of Persons Infected with Human Immunodeficiency Virus: 2020
Update by the HIV Medicine Association of the Infectious Diseases Society of America: Evidence-based
guidelines for the management of people infected with HIV
Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HIV and
Recommendations for Postexposure Prophylaxis (PEP): Updated recommendations regarding HIV PEP regimens
and the duration of HIV follow-up testing for exposed personnel
American Red Cross Blood Donation Eligibility Criteria: Alphabetical: Revised guidance document providing
blood establishments that collect blood or blood components, including Source Plasma, with revised donor
deferral recommendations for individuals with increased risk for transmitting HIV infection

Human Immunodeficiency Virus (HIV) Infection Antiretroviral Treatment of HIV Infection