(See also Human Immunodeficiency Virus (HIV) Infection in Infants and Children Human Immunodeficiency Virus (HIV) Infection in Infants and Children Human immunodeficiency virus (HIV) infection is caused by the retrovirus HIV-1 (and less commonly by the related retrovirus HIV-2). Infection leads to progressive immunologic deterioration and... read more .)
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 in parts of West Africa. 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.
Epidemiology of HIV Infection
The World Health Organization (WHO) estimates (see UNAIDS: Global HIV & AIDS statistics — Fact sheet) that in 2021, approximately 38 million people worldwide, including 1.7 million children (< 15 years), were living with HIV; 54% were women and girls. Approximately 25.6 million (about 67%) of people living with HIV live in sub-Saharan Africa. In many sub-Saharan African countries, incidence of HIV infection is declining markedly from the very high rates of the 1990s; nevertheless, important gaps remain to meet the World Health Organization's Fast-Track strategy to end the AIDS epidemic by 2030.
In 2021, approximately 1.5 million people were newly infected with HIV, of whom approximately 860,000 (57%) were in sub-Saharan Africa. Among people living with HIV in 2021, approximately 85% knew their HIV status and 75% were accessing treatment. In 2021, approximately 650,000 people died from AIDS-related illnesses worldwide, compared to 1.9 million in 2004 and 1.4 million in 2010.
However, through international efforts, as of 2021, an estimated 28.7 million people living with HIV were accessing antiretroviral therapy (up from 7.8 million in 2010), dramatically reducing deaths and transmission in many countries (see UNAIDS: Global HIV & AIDS statistics — Fact sheet).
In the United States, at the end of 2019, an estimated 1,189,700 people ≥ 13 years were living with HIV, including an estimated 158,500 (13%) people whose infections had not been diagnosed. In 2020, over 30,600 people received an HIV diagnosis in the United States, and 20,758 cases were due to male-to-male sexual contact; data for 2020 should be interpreted with caution due to the impact of the COVID-19 pandemic on access to HIV testing, care-related services, and case surveillance activities. (See Centers for Disease Control and Prevention: HIV Statistics Center.)
HIV has spread in epidemiologically distinct patterns:
Heterosexual intercourse (affecting men and women about equally)
Men who have sex with men
Contact with infected blood (eg, through sharing needles; through transfusions before effective screening of donors)
Most HIV infections are transmitted through heterosexual contact, but risk factors vary according to region. For instance, transmission among men who have sex with men is usually the most common way infection occurs in high-resource countries, but people who inject drugs are disproportionally affected in Southern Asia.
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 young adults, creating millions of orphans. Factors associated with increased rates of spread include
Poverty and sexual violence
Lack of education
Health care systems that do not provide access to HIV testing and antiretroviral drugs
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 risk of specific opportunistic infections. In many countries with high rates of HIV infection, prevalence of latent tuberculosis Tuberculosis (TB) Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more and toxoplasmosis Histoplasmosis Histoplasmosis is a pulmonary and hematogenous disease caused by Histoplasma capsulatum; it is often chronic and usually follows an asymptomatic primary infection. Symptoms are those... read more in the general population is higher than that 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, incidence of coccidioidomycosis Coccidioidomycosis Coccidioidomycosis is caused by the fungi Coccidioides immitis and C. posadasii; it usually occurs as an acute, benign, asymptomatic or self-limited respiratory infection. The... read more , common in the Southwest, and histoplasmosis Histoplasmosis Histoplasmosis is a pulmonary and hematogenous disease caused by Histoplasma capsulatum; it is often chronic and usually follows an asymptomatic primary infection. Symptoms are those... read more , common in the Midwest, has increased because of HIV infection.
Human herpesvirus 8 infection, which causes Kaposi sarcoma Kaposi Sarcoma Kaposi sarcoma is a multicentric vascular tumor caused by herpesvirus type 8. It can occur in classic, AIDS-associated, endemic (in Africa), and iatrogenic (eg, after organ transplantation)... read more , is common among men who have sex with men but uncommon among other HIV patients in the United States and Europe. Thus, in the United States, > 90% of AIDS patients who have developed Kaposi sarcoma are men who have sex with men.
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 intercourse
Needle- or instrument-related: Sharing of blood-contaminated needles or exposure to contaminated instruments
Transfusion- or transplant-related
Vertical: Transmission from an infected mother to child during pregnancy, childbirth, or through breast milk
Sexual transmission of HIV
Sexual practices such as fellatio (oral sex done to a male) and cunnilingus (oral sex done to a female) appear to be relatively low risk but not absolutely safe (see table ). Risk does not increase significantly if semen or vaginal secretions are swallowed. However, open sores in the mouth may increase risk.
The sexual practices with the highest risks are those that cause mucosal trauma, typically intercourse. Anal-receptive intercourse poses the highest risk. Mucous membrane inflammation facilitates HIV transmission; sexually transmitted infections, such as gonorrhea Gonorrhea Gonorrhea is caused by the bacterium Neisseria gonorrhoeae. It typically infects epithelia of the urethra, cervix, rectum, pharynx, or conjunctivae, causing irritation or pain and purulent... read more , chlamydial infection Chlamydia and Mycoplasmal Mucosal Infections Sexually transmitted urethritis, cervicitis, proctitis, and pharyngitis (that are not due to gonorrhea) are caused predominantly by chlamydiae and less frequently by mycoplasmas. Chlamydiae... read more , trichomoniasis Trichomoniasis Trichomoniasis is infection of the vagina or male genital tract with Trichomonas vaginalis. It can be asymptomatic or cause urethritis, vaginitis, or occasionally cystitis, epididymitis... read more , and especially those that cause ulceration (eg, chancroid Chancroid Chancroid is infection of the genital skin or mucous membranes caused by Haemophilus ducreyi and characterized by papules, painful ulcers, and enlargement of the inguinal lymph nodes... read more , herpes Genital Herpes Genital herpes is a sexually transmitted infection caused by human herpesvirus 1 or 2. It causes ulcerative genital lesions. Diagnosis is clinical with laboratory confirmation by culture, polymerase... read more , syphilis Syphilis Syphilis is caused by the spirochete Treponema pallidum and is characterized by 3 sequential symptomatic stages separated by periods of asymptomatic latent infection. Common manifestations... read more ), increase the risk several-fold. 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 infected with HIV and/or with multiple concurrent sex partners, these practices increase the risk of HIV transmission.
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 (1, 2 Transmission references Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more ).
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.
HIV Transmission Risk for Several Sexual Activities
None (unless sores are present)
Body-to-body rubbing and massage
Using unshared inserted sexual devices (eg, sex toys)
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
Theoretical (extremely low risk unless sores are present)
Fellatio (oral sex done to a male) without ejaculation or if a condom is used
Cunnilingus (oral sex done to a female) if a barrier is used
Digital vaginal or anal penetration, with or without a glove
Use of shared but disinfected inserted sexual devices
Fellatio without a condom and with ejaculation
Cunnilingus if no barrier is used
Vaginal or anal intercourse if a condom is used correctly
Use of shared but not disinfected inserted sexual devices
Vaginal or anal intercourse with or without ejaculation if a condom is not used or is not used correctly
Needle- and instrument-related transmission
Risk of HIV transmission after skin penetration with a medical instrument contaminated with infected blood is on average about 1/300 without postexposure antiretroviral prophylaxis. Immediate prophylaxis probably reduces risk to < 1/1500. 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 infected health care practitioners who take appropriate precautions is unclear but appears minimal. In the 1980s, one dentist transmitted HIV to ≥ 6 of his patients by unknown means. However, extensive investigations of patients cared for by other physicians infected with HIV, including surgeons, have uncovered few other cases.
Vertical (maternal-child) transmission
HIV can be transmitted from mother to offspring
During pregnancy, transplacentally
Via breast milk
The overall cumulative risk of vertical transmission without antiretroviral medications is 35 to 45% (3 Transmission references Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more ).
Transmission rates can be reduced significantly by treating mothers with HIV infection with antiretroviral drugs while they are pregnant, in labor, and breastfeeding.
Cesarean delivery and treatment of the infant for several weeks after birth 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) (4 Transmission references Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more ).
In high-resource countries, women with HIV infection are advised not to breastfeed (see Centers for Disease Control and Prevention: 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 living 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 AIDS in children is decreasing in many countries (see Human Immunodeficiency Virus (HIV) Infection in Infants and Children Human Immunodeficiency Virus (HIV) Infection in Infants and Children Human immunodeficiency virus (HIV) infection is caused by the retrovirus HIV-1 (and less commonly by the related retrovirus HIV-2). Infection leads to progressive immunologic deterioration and... read more ).
Transfusion- and transplant-related transmission
Screening of blood donors with tests for both antibody to HIV and HIV RNA has minimized risk of transmission via transfusion. Current risk of transmitting HIV via blood transfusion is estimated to be < 1/2,000,000 per unit transfused in the United States. However, in many high HIV burden countries, 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 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. Some cases of infection occurred in the early 1980s, before safeguards were introduced.
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.
1. 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
2. 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. 2016 Aug 9;316(6):667] [published correction appears in JAMA. 2016 Nov 15;316(19):2048]. JAMA 316(2):171-181, 2016. doi:10.1001/jama.2016.5148
3. 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
4. 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
Pathophysiology of HIV Infection
HIV attaches to and penetrates host T cells via CD4+ molecules and chemokine receptors (see figure ). 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 budded 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 Pathophysiology references Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more ). Hence, 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 (HTLV), is less common but can also cause serious disease.
Two main consequences of HIV infection are
Damage to the immune system, specifically depletion of CD4+ lymphocytes
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.
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 Pathophysiology references Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more ). Thus, HIV levels and resistance patterns in these compartments may vary independently from those in plasma.
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 Pathophysiology references Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more ). 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 AIDS (6, 7 Pathophysiology references Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more ).
Risk and severity of opportunistic infections, AIDS, and AIDS-related cancers Cancers Common in Patients with HIV Infection AIDS-defining cancers in patients infected with HIV are Kaposi sarcoma Lymphoma, Burkitt (or equivalent term) Lymphoma, immunoblastic (or equivalent term) Lymphoma, primary, of central nervous system read more are determined by 2 factors:
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 Pneumocystis jirovecii Pneumonia Pneumocystis jirovecii is a common cause of pneumonia in immunosuppressed patients, especially in those infected with human immunodeficiency virus (HIV) and in those receiving systemic... read more , toxoplasmic encephalitis CNS toxoplasmosis Toxoplasmosis is infection with Toxoplasma gondii. Symptoms range from none to benign lymphadenopathy, a mononucleosis-like illness, to life-threatening central nervous system (CNS) disease... read more , and cryptococcal meningitis Cryptococcal meningitis Subacute meningitis develops over days to a few weeks. Chronic meningitis lasts ≥ 4 weeks. Possible causes include fungi, Mycobacterium tuberculosis, rickettsiae, spirochetes, Toxoplasma... read more
CD4 count < 50/mcL: Increased risk of cytomegalovirus Cytomegalovirus (CMV) Infection Cytomegalovirus (CMV, human herpesvirus type 5) can cause infections that have a wide range of severity. A syndrome of infectious mononucleosis that lacks severe pharyngitis is common. Severe... read more (CMV) and Mycobacterium avium complex (MAC) infections Nontuberculous Mycobacterial Infections There are over 170 recognized species of mycobacteria, mostly environmental. Environmental exposure to many of these organisms is common, but most exposures do not cause infection and many infections... read more
For every 3-fold (0.5 log10) increase in plasma HIV RNA in untreated patients, risk of progression to AIDS or death over the next 2 to 3 years increases about 50% (6 Pathophysiology references Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more ).
Without treatment, risk of progression to AIDS is about 1 to 2%/year in the first 2 to 3 years of infection and about 5 to 6%/year thereafter. Eventually, AIDS almost invariably develops in untreated patients.
1. Ho DD, Neumann AU, Perelson AS, et al: Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 12;373(6510):123-6, 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):e00311-19, 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 1;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 and signs are often mistaken for infectious mononucleosis or benign, nonspecific viral syndromes and may include fever, malaise, fatigue, several types of dermatitis, sore throat, 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).
Symptoms during this relatively asymptomatic period may result from HIV directly or from opportunistic infections. The following are most common:
White plaques due to oral candidiasis
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 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 ). 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 Cancers Common in Patients with HIV Infection AIDS-defining cancers in patients infected with HIV are Kaposi sarcoma Lymphoma, Burkitt (or equivalent term) Lymphoma, immunoblastic (or equivalent term) Lymphoma, primary, of central nervous system read more ). In other patients, neurologic dysfunction may occur.
Evaluation may detect infections that do not typically occur in the general population, such as
Other fungal infections
Infections that also occur in the general population but suggest AIDS if they are unusually severe or frequently recur include
Acquired immune deficiency syndrome (AIDS)
AIDS is defined as HIV infection with one or more of the following:
A CD4+ cell percentage of ≤ 14% of the total lymphocyte count
AIDS-defining illnesses include
Serious opportunistic infections
Certain cancers (eg, Kaposi sarcoma Kaposi Sarcoma Kaposi sarcoma is a multicentric vascular tumor caused by herpesvirus type 8. It can occur in classic, AIDS-associated, endemic (in Africa), and iatrogenic (eg, after organ transplantation)... read more , non-Hodgkin lymphoma Non-Hodgkin Lymphomas Non-Hodgkin lymphomas are a heterogeneous group of disorders involving malignant monoclonal proliferation of lymphoid cells in lymphoreticular sites, including lymph nodes, bone marrow, the... read more ) to which defective cell-mediated immunity predisposes
Symptoms and signs reference
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 ). It may also be suspected in high-risk patients with symptoms that could represent acute primary HIV infection.
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 4th-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 one 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 4th-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 and is expensive.
The full testing sequence takes at least a day.
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 may 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.
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.
When HIV is diagnosed, the following should be determined:
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 x 0.3 x 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.
Baseline HIV genotype can be determined using a sample of blood; 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 infected with HIV 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 ).
Screening for HIV
Screening antibody tests or newer combination antigen/antibody tests should be offered routinely to adults and adolescents, particularly pregnant women, regardless of their perceived risk. For people at highest risk, especially sexually active people who have multiple 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 15 to 65 years and in younger adolescents and older adults who are at increased risk of infection (see US Preventive Services Task Force: HIV Screening). 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 drugs (antiretroviral therapy [ART], sometimes called highly active ART [HAART] or combined ART [cART])
(See also Antiretroviral Treatment of HIV Infection Antiretroviral Treatment of HIV Infection Because disease-related complications can occur in untreated patients with high CD4 counts and because less toxic drugs have been developed, treatment with antiretroviral therapy (ART) is now... read more .)
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 drugs 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 Treatment reference Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more ).
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.
The goal of ART can usually be achieved if patients take their medications > 95% of the time. 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 drug 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 drug 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 drugs. Genotypic and phenotypic assays are available and can help clinicians select a new regimen that should contain at least 2 and preferably 3 drugs 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 living 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 drugs, 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 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 two 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 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 drugs (eg, nevirapine) may remain high and thus increase the risk of resistance. Interruption may be necessary if intervening illnesses require treatment or if drug toxicity is intolerable or needs to be evaluated. After interruption to determine which drug is responsible for toxicity, clinicians can safely restart most drugs 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.
Pearls & Pitfalls
Prevention of opportunistic infections
(See also the United States Public Health Service and the HIV Medicine Association of the Infectious Diseases Society of America’s Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents.)
Effective chemoprophylaxis is available for many opportunistic infections and reduces rates of disease due to P. jirovecii, Candida, Cryptococcus, and MAC (Mycobacterium avium complex). If therapy restores CD4 counts to above threshold values for > 3 months, chemoprophylaxis can be stopped.
Primary prophylaxis depends on the CD4 count:
CD4 count < 200/mcL or oropharyngeal candidiasis (active or previous): Prophylaxis against P. jirovecii pneumonia is recommended. Double-strength trimethoprim/sulfamethoxazole (TMP/SMX) 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 Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked enzymatic defect common in people with African ancestry that can result in hemolysis after acute illnesses or intake of oxidant... read more ) 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: 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 drugs.
If latent tuberculosis Tuberculosis (TB) Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more 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, cryptococcal meningitis or pneumonia), oral fluconazole 100 to 200 mg once/day or 400 mg weekly is successful but is infrequently used because the cost per infection prevented is high and diagnosis and treatment of these infections are usually successful.
Secondary prophylaxis (after control of the initial infection) is indicated if patients have had the following:
Recurrent oral, vaginal, or esophageal candidiasis Candidiasis Candidiasis is infection by Candida species (most often C. albicans), manifested by mucocutaneous lesions, fungemia, and sometimes focal infection of multiple sites. Symptoms depend... read more ; coccidioidomycosis Coccidioidomycosis Coccidioidomycosis is caused by the fungi Coccidioides immitis and C. posadasii; it usually occurs as an acute, benign, asymptomatic or self-limited respiratory infection. The... read more ; or cryptococcal infections Cryptococcosis Cryptococcosis is a pulmonary or disseminated infection acquired by inhalation of soil contaminated with the encapsulated yeasts Cryptococcus neoformans or C. gattii. Symptoms... read more : Fluconazole is used.
Latent toxoplasmosis Toxoplasmosis Toxoplasmosis is infection with Toxoplasma gondii. Symptoms range from none to benign lymphadenopathy, a mononucleosis-like illness, to life-threatening central nervous system (CNS) disease... read more : 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).
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.
The CDC 2022 recommendations for vaccination of HIV-infected patients aged ≥ 19 years include the following:
Patients who have not received a conjugate pneumococcal vaccine Pneumococcal Vaccine Pneumococcal disease (eg, otitis media, pneumonia, sepsis, meningitis) is caused by some of the > 90 serotypes of Streptococcus pneumoniae (pneumococci). Vaccines are directed against... read more 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.
Patients at risk of hepatitis A or desiring protection from it should be given the hepatitis A vaccine Hepatitis A (HepA) Vaccine There are two hepatitis A vaccines; both provide long-term protection against hepatitis A. For more information, see Hepatitis A Advisory Committee on Immunization Practices Vaccine Recommendations... read more .
At the appropriate age, males and females should be given the human papillomavirus (HPV) vaccine Human Papillomavirus (HPV) Vaccine Human papillomavirus (HPV) infection is the most common sexually transmitted disease. HPV can cause skin warts, genital warts, or certain cancers, depending on the type of HPV. Vaccines are... read more to prevent HPV-related cervical and anal cancers.
Adults who have not been previously vaccinated with the meningococcal vaccine Meningococcal Vaccine The meningococcal serogroups that most often cause meningococcal disease in the United States are serogroups B, C, and Y. Serogroups A and W cause disease outside the United States. Current... read more should be given a 2-dose primary series of MenACWY ≥ 8 weeks apart and revaccinate every 5 years.
Patients who did not receive tetanus-diphtheria-pertussis vaccine Diphtheria-Tetanus-Pertussis Vaccine Vaccines that contain diphtheria toxoid, tetanus toxoid, and acellular pertussis help protect against diphtheria, tetanus, and pertussis, but they do not prevent all cases. For more information... read more (Tdap) as part of their completed tetanus-diphtheria vaccine Tetanus-Diphtheria Vaccine A vaccine for tetanus alone is available, but the tetanus vaccine is typically combined with those for diphtheria and/or pertussis. The vaccine for diphtheria is available only in combination... read more (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.
The varicella vaccine Varicella Vaccine Varicella vaccination provides effective protection against varicella (chickenpox). It is not known how long protection against varicella lasts. But, live-virus vaccines, like the varicella... read more may be given to patients with CD4 percentage ≥ 15% and CD4 count ≥ 200/mcL, but the vaccine is contraindicated in patients with CD4 percentage < 15% or CD4 count < 200/mcL.
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.
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 Routine vaccinations Human immunodeficiency virus (HIV) infection is caused by the retrovirus HIV-1 (and less commonly by the related retrovirus HIV-2). Infection leads to progressive immunologic deterioration and... read more and see table ).
Prognosis for HIV Infection
Risk of AIDS, 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%. 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 not infected with HIV (1 Prognosis references Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more ). 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 infected with HIV (termed long-term nonprogressors) remains 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 infected with HIV 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 living 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 (2 Prognosis references Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more ). However, HIV replication subsequently resumed (3 Prognosis references Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more ). 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 (4 Prognosis references Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more ).
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 Durable power of attorney for health care Advance directives are legal documents that extend a person's control over health care decisions in the event that the person becomes incapacitated. They are called advance directives because... read more and wills, should be in place.
As patients near the end of life The Dying Patient Dying patients can have needs that differ from those of other patients. So that their needs can be met, dying patients must first be identified. Before death, patients tend to follow 1 of 3... read more , 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 AIDS makes good skin care difficult. The comprehensive support provided by hospice programs helps many patients because hospice providers are unusually skilled at symptom management, and they support caregivers and patient autonomy.
1. 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. Annals of Internal Medicine 169(2):87-96, 2018. doi: 10.7326/m16-2094
2. 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
3. Ledford, H: HIV rebound dashes hope of 'Mississippi baby' cure. Nature 2014. doi.org/10.1038/nature.2014.15535
4. 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 30;355 (22):2283–96, 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 AIDS 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 ).
Safer sex practices: People living with HIV who are not virally suppressed (ie, undetectable viral load) should practice safer sex behaviors that are essential to prevent the spread of the infection. Virally suppressed people living with HIV do not sexually transmit the virus to their partners (1 Prevention references Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more ). Safer sex practices should be used by a patient infected with HIV whose infection is not virally suppressed whether they have sex with partners who are not infected with HIV or with partners with HIV infection. Safer sex practices are 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 AIDS patients, as well as to 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 adolescents and adults 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 Vertical (maternal-child) transmission Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more 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 infected with HIV 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 Prevention of perinatal transmission Human immunodeficiency virus (HIV) infection is caused by the retrovirus HIV-1 (and less commonly by the related retrovirus HIV-2). Infection leads to progressive immunologic deterioration and... read more ). 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 FDA has issued guidance for deferral of blood donation, including deferral for 3 months after the most recent sexual contact for men who have had sex with another man and for women who have had sex with a man who has had sex with another man (see Revised Recommendations for Reducing the Risk of HIV Transmission by Blood and Blood Products, August 2020). 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 are not infected with HIV but are at high risk (eg, by having an HIV-infected sex partner) take an antiretroviral drug 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 (2 Prevention references Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more ). The CDC also recommends PrEP for those who inject drugs and report injection practices that place them at substantial risk of HIV Infection (2 Prevention references Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more ). The combination of tenofovir disoproxil fumarate plus emtricitabine (TDF/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 HIV-infected women treated with TDF/FTC. Use of PrEP to reduce the risk of HIV infection in people who user injection drugs is being studied. Long-acting antiretroviral agents are licensed in the United States and other countries to further improve PrEP in high-risk populations with poor medication adherence; however, their availability remains limited. For the current CDC recommendations, see Preexposure Prophylaxis for the Prevention of HIV Infection in the United States (2021 Update) – 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 health care practitioners 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 infected with HIV is unnecessary unless indicated by an 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 drugs given for 28 days (3 Prevention references Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more ). The drugs 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 raltegravir or dolutegravir. In patients with childbearing potential, raltegravir is preferred because dolutegravir is possibly teratogenic during the first trimester of pregnancy—this is under epidemiologic investigation. Alternative regimens include 2 NRTIs plus a protease inhibitor. For detailed recommendations, see the CDC's Updated Guidelines for Antiretroviral Postexposure Prophylaxis After Sexual, Injection Drug Use, or Other Nonoccupational Exposure to HIV—United States, 2016 (Updated May 2018) and Interim Statement Regarding Potential Fetal Harm from Exposure to Dolutegravir – Implications for HIV Post-exposure Prophylaxis (PEP).
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.
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 forthe prevention of HIV infection in the United States—2021 Update: a clinical practice guideline
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 [published online ahead of print, 2022 Dec 1]. JAMA. 2022;10.1001/jama.2022.22246. doi:10.1001/jama.2022.22246
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 living with HIV about safer sex.
Use postexposure and preexposure antiretroviral prophylaxis when indicated.
Give primary prophylaxis against opportunistic infections based on the CD4 count.
The following English-language resources may be useful. Please note that The Manual is not responsible for the content of these resources.
CDC 2022 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 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
Revised Recommendations for Reducing the Risk of HIV Transmission by Blood and Blood Products, 2020: 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