Human Immunodeficiency Virus (HIV) Infection

Symptoms and signs of Human Immunodeficiency Virus (HIV) Infection

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 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, and cardiomyopathy. Manifestations range from asymptomatic carriage to acquired immune deficiency syndrome (AIDS), which is defined by serious opportunistic infections or cancers or a CD4 count of < 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. Treatment aims to suppress HIV replication by using combinations of ≥ 2 drugs that inhibit HIV enzymes; treatment can restore immune function in most patients if suppression of replication is sustained.  see also other disease

 

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. Several retroviruses, including 2 types of HIV and 2 types of human T-lymphotropic virus (HTLV), cause serious disorders in people.

 

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 HTLV-infected patients develop infections similar to those that occur in HIV-infected patients. HTLV-1 can also cause myelopathy/tropical spastic paraparesis.

 

Most cases are transmitted

 

From mother to child by breastfeeding

But HTLV-1 can be transmitted

 

Sexually

Through blood

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

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. (see also other disease )

 

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.

 

 

AIDS

AIDS is defined as one or more of the following:

 

HIV infection that leads to any of certain AIDS-defining illnesses

A CD4+ T lymphocyte ( helper cell) count of < 200/mcL

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

AIDS-defining illnesses are

·         Serious opportunistic infections

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

·         Neurologic dysfunction

·         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: 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 (previously known as Pneumocystis carinii) pneumonia

·         Pneumonia, recurrent

·         Progressive multifocal leukoencephalopathy

·         Salmonella septicemia (nontyphoid), recurrent

·         Toxoplasmosis of brain, onset at age > 1 month

·         Wasting syndrome attributed to HIV

See also Revised Surveillance Case Definition for HIV Infection.

 

Transmission of HIV Infection

Transmission of HIV requires contact with body fluids—specifically blood, semen, vaginal secretions, breast milk, saliva, 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 casual nonsexual contact as may occur at work, school, or home.

 

Transmission is usually

·         Sexual: Direct transmission through sexual intercourse

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

·         Maternal: Childbirth or breastfeeding

·         Transfusion- or transplant-related

Sexual transmission of HIV

Sexual practices such as fellatio and cunnilingus appear to be relatively low risk but not absolutely safe . 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, chlamydial infection, trichomoniasis, and especially those that cause ulceration (eg, chancroid, herpes, syphilis), 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 an HIV-infected partner and/or with multiple concurrent sex partners, these practices increase the risk of HIV transmission.(see also other disease)

 

In heterosexuals, risk is increased in the following:

 

Early and advanced stages of HIV infection when HIV concentrations in plasma and genital fluids are higher

Younger people

People with ulcerative genital diseases

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.

 

Recent evidence shows that HIV infected people in whom antiretroviral therapy has reduced their viral load below the current detectable level (virally suppressed) do not sexually transmit the virus to their partners. Undetectable virus equals an untransmittable virus.

 

 

 

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 injection drug users 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 HIV-infected physicians, including surgeons, have uncovered few other cases.

 

Maternal transmission

HIV can be transmitted from mother to offspring

Transplacentally

Perinatally

Via breast milk

Without treatment, risk of transmission at birth is about 25 to 35%.

 

HIV is excreted in breast milk, and breastfeeding by untreated HIV-infected mothers may transmit HIV to about 10 to 15% of infants who had previously escaped infection.

 

Transmission rates can be reduced dramatically by treating HIV-positive mothers 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.

 

Because many HIV-positive pregnant women are treated or take prophylactic drugs, the incidence of AIDS in children is decreasing 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 antibody to HIV and HIV RNA has minimized risk of transmission via transfusion. Current risk of transmitting HIV via blood transfusion is probably < 1/2,000,000 per unit transfused in the United States. However, in many developing 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.

 

Epidemiology of HIV Infection

HIV has spread in epidemiologically distinct patterns:

 

Men who have sex with men

Contact with infected blood (eg, through sharing needles in injection drug users; through transfusions before effective screening of donors)

Heterosexual intercourse (affecting men and women about equally)

In most countries, all patterns occur, but the first pattern (men who have sex with men) usually predominates in developed countries; the second pattern (contact with infected blood) predominates in Africa, South America, and southern Asia. (see also other disease )

 

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 that perpetuate spread include

 

Poverty and domestic violence

Poor education

Deficient systems of medical care that do not provide access to HIV testing and antiretroviral drugs

However, through international efforts, as of 2019, an estimated 25.4 million people living with HIV were accessing antiretroviral therapy, dramatically reducing deaths and transmission in many countries.

 

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 developing countries, prevalence of latent tuberculosis and toxoplasmosis in the general population is higher than that in developed 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, 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 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.

 

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.

 

Simplified HIV life cycle

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, 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.

 

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. see also other disease

 

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 be 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). 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 ( 5-6).

 

Risk and severity of opportunistic infections, AIDS, 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 avium complex (MAC) infections

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).

 

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.

 

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:

·         Lymphadenopathy

·         White plaques due to oral candidiasis

·         Herpes zoster

·         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 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 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

1.       Disseminated mycobacterial infections

2.       P. jirovecii infection

3.       Cryptococcus neoformans infection

4.       Other fungal infections

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

·         Herpes zoster

·         Herpes simplex

·         Vaginal candidiasis

·         Invasive pneumococcal infections

·         Salmonella septicemia

Manifestations of HIV Infection

 

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 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. see also other disease

 

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.

Newer 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 developed countries and repetition with one or more other rapid tests in developing 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.

 

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 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.

 

LAB TEST

HIV Viral Load    icon

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.

 

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.

 

HIV-related conditions

Diagnosis of the various opportunistic infections, cancers, and other syndromes that occur in HIV-infected patients 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, 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 contrast-enhanced CT or MRI (see table Common Manifestations of HIV Infection by Organ System).

 

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.

 

 

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).

 

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 HIV-infected people (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 HIV-infected people 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 cure was widely reported in an infant with transient eradication of replication-competent HIV after about 15 months of antiretroviral therapy. However, HIV replication subsequently resumed. 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 ( 2).

 

Treatment of HIV Infection

Combinations of antiretroviral drugs (antiretroviral therapy [ART], sometimes called highly active ART [HAART] or combined ART [cART])

Chemoprophylaxis for opportunistic infections in patients at high risk

 

Because disease-related complications can occur in untreated patients with high CD4 counts and because less toxic drugs have been developed, treatment with ART is now recommended for nearly all patients. 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.

 

ART can usually achieve its goals if patients take their drugs > 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.

 

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 until the first phase of antimicrobial therapy for these infections is finished because of the increased frequency of adverse events and death.

 

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 3 to 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.

 

HIV Antiretroviral Drug Resistance Testing, Genotypic     icon

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).

 

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 study, 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 damaging 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).

Counseling for parenteral drug users: 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 has been virtually eliminated by HIV testing, treatment with ART, and, in developed countries, use of breast milk substitutes. If pregnant women test positive for HIV, risk of mother-to-child transmission should be explained. Pregnant women who do not accept immediate treatment for their HIV infection should be encouraged to accept therapy to protect the unborn baby, 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 HIV-infected women 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 FDA has issued draft guidance for deferral of blood donation, including deferral for 12 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). However, use of sensitive HIV screening tests and deferral of donors of organs, blood, and blood products have not been implemented consistently in developing 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 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 injection drug users is being studied. Long-acting antiretroviral agents are also being studied to further improve PrEP in high-risk populations with poor medication adherence. For the current CDC recommendations, see Pre-Exposure Prophylaxis (PrEP).

Circumcision of men: In young African men, circumcision has been shown to reduce their risk of acquiring HIV infection from female partners during vaginal sex by about 50%; male circumcision is probably similarly effective elsewhere. 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 HIV-infected patients 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 (see table Postexposure Prophylaxis Recommendations).

 

 

Postexposure Prophylaxis (PEP) Recommendations         

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. 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 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 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.

 

Prevention of opportunistic infections

Effective chemoprophylaxis is available for many opportunistic infections and reduces rates of disease due to P. jirovecii, Candida, Cryptococcus, and MAC. 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) 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 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; 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 developing 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 ClinicalInfo.

 

Immunization

·         The CDC 2020 recommendations for vaccination of HIV-infected patients include the following:

·         Patients who have not received the conjugate pneumococcal vaccine (PCV13) or polysaccharide pneumococcal vaccine (PPSV23) should be given PCV13 followed by PPSV23 ≥ 8 weeks after PCV13.

·         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 ≥ 2 months apart.

·         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.

·         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.

 

The herpes zoster vaccine (for boosting immunity to prevent reactivation as zoster) could be useful in HIV-infected adults. The original live-attenuated zoster vaccine is contraindicated in patients with a weakened immune system and if the CD4 count is < 200/mcL. However, the newer recombinant zoster vaccine is not contraindicated in patients with HIV. The US Department of Health and Human Services recommends that adults with HIV age ≥ 50 years receive the recombinant zoster vaccine, but the Advisory Committee on Immunization Practices (ACIP) has yet to formally recommend vaccination to prevent herpes zoster in people with HIV (see CDC 2020 Adult Conditions Immunization Schedule).

 

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).

 

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 prenatal and perinatal maternal transmission.

·         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 safe sex, the importance of regular physical activity and a healthy diet, and stress management.

·         Use postexposure and preexposure antiretroviral prophylaxis when indicated.

·         Give primary prophylaxis against opportunistic infections based on the CD4 count.  see also other disease