97: Human Immunodeficiency Virus

Two types of HIV cause disease in humans: HIV-1 and HIV-2. These are enveloped RNA cytopathic lentiviruses belonging to the family Retroviridae. Infection is most commonly secondary to HIV-1. HIV-2 is rare in the United States but more common in West Africa. HIV results in a broad spectrum of disease, with AIDS representing the most severe end of the clinical spectrum.

The Joint United Nations Program on HIV/AIDS estimated that 33.3 million people worldwide were infected with HIV-1 at the end of 2009. More than 95% of the total cases reside in developing countries. In the same year, an estimated 370,000 children contracted HIV during the perinatal and breast-feeding period, down from 500,000 in 2001 (down 24%). This drop reflects the fact that access to services for preventing the mother-to-child transmission (MTCT) of HIV has increased. On the other hand, the estimated number of children living with HIV increased to 2.5 million worldwide in 2009, mainly due to a decrease in AIDS-related mortality as antiretroviral drugs (ARDs) becomes more available. Currently, the Centers for Disease Control and Prevention (CDC) estimates that each year, 215–370 infants with HIV infection are born in the United States; this is a significant drop from 1650 in 1991.

HIV-1 is particularly tropic for CD4⁺ T cells and cells of monocyte or macrophage lineage. After infection of the cell, viral RNA is uncoated and a double-stranded DNA transcript is made. This DNA is transported to the nucleus and integrated into the host genome DNA. There is eventual destruction of both the cellular and humoral arms of the immune system. As well, HIV-1 gene products or cytokines elaborated by infected cells may affect macrophage, B-lymphocyte, and T-lymphocyte function. Hypergammaglobulinemia caused by HIV-induced polyclonal B-cell activation is often detected in early infancy. Disruption of B-cell function results in poor secondary antibody synthesis and response to vaccination. A small proportion (<10%) of patients will develop panhypogammaglobulinemia. Additionally, profound defects in cell-mediated immunity occur, allowing a predisposition to opportunistic infections such as fungus, Pneumocystis jiroveci pneumonia (PCP), and chronic diarrhea. The virus can also invade the central nervous system and produce psychosis and brain atrophy.

1. High-risk mother. Any infant born to a high-risk mother is at risk. High-risk mothers include intravenous (IV) drug users, hemophiliacs, spouses of hemophiliacs, spouses of bisexual males, those with a history of exchanging sex for money or drugs, sex partners of HIV-infected persons, and those who were diagnosed with sexually transmitted disease/sexually transmitted infection (STD/STI) during pregnancy. Several mechanisms/predisposing factors for viral transmission exist, including maternal disease state, fetal exposure to infected maternal body fluids, depressed maternal immune response, and breast-feeding. Maternal plasma HIV RNA level is the best single predictor of MTCT risk. Other risk factors include mode of delivery, duration of rupture of membranes (the risk increases with each hour increase in the duration), prematurity and low birthweight, cervical-vaginal viral load, low CD4⁺ cell count, maternal symptomatic HIV disease/AIDS, viral subtype, and host genetic factors. Most MTCT occurs intrapartum, with smaller proportions of transmission occurring in utero and postnatally through breast-feeding. MTCT may occur in utero, intrapartum, or postpartum through breast-feeding. Transplacental infection has been proven by evidence of infection in aborted first-trimester fetal tissues as well as isolation of HIV-1 in blood samples obtained within 48 hours of birth. Potential routes of infection include mixture of maternal and fetal blood and infection across the placenta when its integrity is compromised (eg, placentitis [syphilitic] and chorioamnionitis).

2. Blood transfusion. Screening of blood donors has reduced but has not totally eliminated the risk because some newly infected persons are viremic but seronegative for 2–4 months, and because some infected persons (5–15%) are seronegative. The current risk of transmission of HIV per unit transfused is 1 in 2 million. (See also Chapter 17.)

3. Breast milk. Breast-feeding is the predominant means of postnatal HIV transmission to infants and accounts for an estimated one-third to one-half of all MTCT events in breast-feeding populations. According to a 2007 report from the World Health Organization (WHO), ∼200,000 infants worldwide become infected annually with HIV through breast-feeding. HIV-1 RNA and proviral DNA have been detected in both the cell-free and cellular portions of breast milk. Colostrum viral load appears to be particularly high. Risk from breast milk is highest when maternal primary infection occurs within the first few months after delivery. In areas where infant formula is accessible, affordable, safe, and sustainable, avoidance of breast-feeding has represented one of the main components of prevention efforts of MTCT of HIV-1 for many years. Complete avoidance of breast-feeding by HIV-1–infected women has been recommended by the American Academy of Pediatrics (AAP) and CDC and remains the only means by which prevention of breast-feeding transmission of HIV-1 can be absolutely ensured. In resource-limited countries where local sanitary conditions are poor and access to infant formulas is limited, the 2010 WHO guidelines recommend exclusive breast-feeding in combination with maternal or infant antiretroviral prophylaxis to minimize HIV transmission from the mother and to optimize the benefits of breast-feeding for the infant. Exclusive breast-feeding is associated with a lower risk of postnatal transmission compared to mixed breast-feeding and formula feeding. In areas where ARDs are available, infants should receive daily nevirapine prophylaxis until 1 week after human milk consumption stops.

4. Premastication. Possible transmission of HIV-1 by caregivers who premasticate food for infants has been described in 3 cases in the United States. HIV-1–infected caregivers should be asked and counseled not to premasticate food for infants.

Disease progression after vertical HIV-1 infection is highly variable.

1. Incubation period. The onset of symptoms is ∼12–18 months of age for untreated, perinatally infected infants in the United States; however, some may become ill in the first few months of life (15–20%).

2. Signs and symptoms. The newborn is usually asymptomatic or may have low birthweight, weight loss, or failure to thrive (if infected in utero). The frequency of different opportunistic pathogens among HIV-infected children decreased significantly with the application and widespread use of highly active antiretroviral therapy (HAART). In the pre-HAART era, serious bacterial infection, herpes zoster, disseminated Mycobacterium avium complex (MAC), PCP, and candidiasis were common. History of a previous AIDS-defining opportunistic infection was a predictor of developing a new infection. In the HAART era, descriptions of opportunistic infections among HIV-infected children have been limited because of the substantial decreases in morbidity and mortality among children receiving HAART. Nonspecific features of HIV infection include hepatosplenomegaly, lymphadenopathy, and fever. Neurologic disease may be either static (delayed attainment of milestones) or progressive, with impaired brain growth, failure to reach milestones, and progressive motor deficits. Common computed tomography (CT) scan findings include basal ganglia calcification and cortical atrophy. Cardiac abnormalities include pericardial disease, myocardial dysfunction, and dysrhythmias.

Diagnosis is based on suspicion of infection based on epidemiological risk or clinical presentation, and confirmation by different virologic assays in infants <18 months old or serologic tests if the infant is >18 months old.

1. All other causes of immunodeficiency must be excluded. These include both primary and secondary immunodeficiency states. Primary immunodeficiency diseases include DiGeorge or Wiskott-Aldrich syndromes, ataxia-telangiectasia, agammaglobulinemia, severe combined immunodeficiency, and neutrophil function abnormality. Secondary immunodeficiency states include those caused by immunosuppressive therapy, starvation, and lymphoreticular cancer.

2. Laboratory studies

   1. HIV serology. Antibodies against HIV-1 are found in all infants born to mothers with HIV infection because of transplacental passage of immunoglobulin G. HIV serology (enzyme-linked immunosorbent assay [ELISA] or Western blot) should not be used to diagnose HIV infection in infants <18 months of age.

   2. Virologic assays. (HIV-1 DNA and RNA polymerase chain reaction [PCR].) These are considered the gold standard for diagnosis of HIV in infants and children <18 months. With the use of these tests, HIV infection may be diagnosed as early as the first day after birth in some infants and by 1 month of age in most infected infants. The HIV-1 DNA PCR assay is the preferred diagnostic tool. Amplification of proviral DNA allows detection of cells that harbor quiescent provirus as well as cells with actively replicating virus. Approximately 30% of infants with perinatal HIV infection have a positive DNA PCR in samples obtained by 48 hours of age. A positive result identifies infants who were infected in utero. The test routinely can detect 1–10 DNA copies. The test will be positive in 93 and 99% of all infected infants by 2 weeks and 1 month of age, respectively. HIV-1 RNA PCR assays detect plasma (cell-free) viral RNA by PCR amplification. These assays are available as either “standard” or “ultrasensitive,” and the lower limit of detection when using the ultrasensitive assays is in the range of 50–75 HIV-1 copies per milliliter of plasma. The reported sensitivity for RNA assays range from 25 to 50% within the first few days of life to 100% by 6–12 weeks of age. HIV-1 RNA assays are commonly used for quantifying the amount of virus present as one predictor of disease progression. They are used in follow-up testing of patients during treatment for HIV-1 infection. The first test result should be confirmed as soon as possible by a repeat virologic test on a second specimen because false-positive results can occur with both RNA and DNA assays. Zidovudine (ZDV) prophylaxis does not appear to alter the diagnostic sensitivity of either HIV DNA PCR or RNA assays. It is also established that HIV DNA PCR remains positive even in infected individuals receiving therapeutic HAART.

      Virologic assays should be performed within the first 48 hours after birth, at 14–21 days, between 1 and 2 months, and at 4–6 months of age. Cord blood should not be used because of the possibility of contamination with maternal blood. A positive virologic test confirmed at 2 weeks of age warrants a change in the recommended ZDV prophylactic monotherapy. HIV infection can be presumptively excluded in non–breast-fed infants with 2 or more negative virologic tests, with 1 test obtained at ≥14 days of age and 1 obtained at ≥4 weeks of age; or 1 negative virologic test obtained at ≥8 weeks of age; or 1 negative HIV antibody test obtained at ≥6 months of age. PCP prophylaxis is recommended for infants with indeterminate HIV infection status starting at 4–6 weeks of age until they are determined to be HIV uninfected or presumptively uninfected. Definitive exclusion of HIV infection in a non–breast-fed infant is based on 2 or more negative virologic tests, with 1 obtained at ≥1 month of age and one at ≥4 months of age; or 2 negative HIV antibody tests from separate specimens obtained at ≥6 months of age (in the absence of hypogammaglobulinemia). For both presumptive and definitive exclusion of HIV infection, the child must have no other laboratory (eg, no positive virologic test results or low CD4 count/percentage) or clinical evidence of HIV infection and not be breast-feeding. Many experts confirm the absence of HIV infection in infants with negative virologic tests by performing an antibody test at 12–18 months of age to document seroreversion to HIV antibody–negative status. The p₂₄ antigen assay is less sensitive than DNA or RNA PCR and is generally not recommended. Viral HIV-1 culture is labor intensive and poses a significant biohazard risk. It is largely supplanted by DNA and RNA PCR virologic assays.

   3. Rapid tests. A number of rapid tests for detection of HIV antibodies in blood, urine, or oral fluid have been licensed in the United States (www.fda.gov/cber/products/testkits.htm). These tests are comparable with enzyme immunoassays (EIAs) in both sensitivity (99.3–100%) and specificity (98.6–100%). As with routine EIAs, confirmation of positive results is necessary, but confirmation of a negative result is not. The rapid tests are valuable as a screening tool for pregnant women with no or limited prenatal care or for infants with unknown maternal HIV status. They have the potential to reduce MTCT, with immediate provision of antiretroviral prophylaxis and formula feeding to prevent postnatal transmission. They should be available in all hospitals providing delivery services in the United States. In 2012, a home HIV test received U.S. Food and Drug Administration (FDA) approval.

   4. Surrogate markers for disease. Immunologic abnormalities found in HIV-infected infants include hypergammaglobulinemia, a low CD4⁺ T-lymphocyte count, or a decreased CD4⁺ percentage.

3. Presence of a “marker” disease that indicates cellular immunodeficiency. Marker diseases include candidiasis, cryptococcosis, Mycobacterium avium infection, Epstein-Barr virus infection, PCP, strongyloidiasis, and Kaposi sarcoma. Cytomegalovirus (CMV) infection and toxoplasmosis are included if toxoplasmosis occurs >1 month after birth and CMV infection presents >6 months after birth.

Isolation precautions for all infectious diseases, including maternal and neonatal precautions, breast-feeding, and visiting issues, can be found in Appendix F.

1. Prevention. MTCT can take place in utero, during labor, at delivery, and postnatally through breast-feeding. Before the widespread use of MTCT interventions (described later), transmission rates in the United States ranged from 16 to 30%. More recently, MTCT has dropped below 1–2%.

   1. Identification of HIV infection in pregnant women and newborns. A prerequisite for the application of successful MTCT interventions is identifying mothers who are HIV positive. The CDC issued revised guidelines in 2006 regarding HIV testing in pregnant women. The guidelines recommended that HIV screening be included in the routine panel of prenatal screening tests for all pregnant women. HIV screening is recommended after the patient is notified that testing will be performed unless the patient declines (opt-out screening). Separate written consent for HIV testing should not be required, and a general consent for medical care should be considered sufficient to encompass consent for HIV testing. Repeat screening in the third trimester is recommended in certain jurisdictions with elevated rates of HIV infection among pregnant women. The AAP and American College of Obstetricians and Gynecologists (ACOG) issued a recommendation similar to the CDC with all organizations supporting routine testing and the opt-out strategy. Most guidelines now state that health care providers have a responsibility not only to offer, but also to recommend, antenatal HIV testing. The benefits of antenatal HIV testing extend beyond the potential to reduce vertical transmission risk and include the opportunity to evaluate the infected woman's health status, to initiate HAART if required, and to allow the woman to reduce the risk of transmitting HIV to her sexual partner. For a newborn infant whose mother's HIV infection status is unknown, the newborn infant's physician should perform rapid HIV antibody testing on the mother or the infant (with appropriate consent). Test results should be reported to the physician as soon as possible to allow effective ARD prophylaxis, ideally within 12 hours. In some states, rapid testing of the neonate is required by law if the mother has refused to be tested.

   2. Antiretroviral prophylaxis and treatment. Antiretroviral drugs (ARDs) are prescribed to HIV-infected pregnant women to treat their own disease and to decrease MTCT of HIV. For optimal prevention of perinatal HIV transmission, combined antepartum, intrapartum, and infant antiretroviral prophylaxis are recommended. The ACTG 076 trial published in 1994 showed that an intensive regimen of oral ZDV given prenatally, intrapartum, and postpartum decreased perinatal transmission risk by two-thirds when compared with placebo. Widespread implementation of trial regimen led to sharp decreases in perinatal HIV transmission. Furthermore, since the late 1990s, most HIV-infected women in the United States have been prescribed combination regimens, which further reduced the risk. Widespread use of HAART, which is usually composed of 3 antiretrovirals from 2 drug classes, has substantially reduced MTCT rates to below 1–2%. Antiretroviral therapy or prophylaxis should be recommended to all pregnant HIV-infected women regardless of plasma HIV RNA copy number or CD4⁺ cell count. According to the 2007 Public Health Service Task Force recommendations, HAART should be considered the standard of care for all pregnant women with HIV infection, even those who do not require treatment for their own health. Regimens for prophylaxis against perinatal HIV transmission should include a 3-drug combination from 2 classes of antiretroviral drugs. The use of ZDV alone is controversial but may be considered for those women initiating prophylaxis with plasma HIV RNA levels <1000 copies/mL on no therapy. ZDV should be included in the antenatal antiretroviral regimen unless there is severe toxicity or documented resistance. ZDV rapidly crosses the placenta, providing protective drug levels for the fetus. Clinical trial data clearly demonstrate the efficacy and safety of ZDV in reducing the risk of perinatal HIV transmission. Lamivudine (3TC) is the preferred drug to be used in combination with ZDV. Both drugs are usually given together (Combivir) as 1 pill twice daily. Lopinavir/ritonavir (LPV/r) is the preferred protease inhibitor with a favorable safety profile for the mother and the fetus. The details of what combination drugs to use in pregnancy are outlined by guidelines released by the U.S. Department of Health and Human Services. These guidelines are updated regularly and are available online at (http://aidsinfo.nih.gov/ContentFiles/PerinatalGL.pdf).

   3. Safety of antiretroviral drugs (ARDs) during pregnancy. There are limited human safety data on the antenatal use of ARDs. Efavirenz is a category D drug and thus contraindicated in pregnancy. Women are at increased risk of nevirapine (NVP)-related hepatotoxicity. Lactic acidosis is a relatively uncommon side effect of nucleoside reverse-transcriptase inhibitor (NRTI) drugs. HAART in pregnancy may increase the risk of gestational diabetes, preeclampsia, and premature delivery. Although animal studies suggest an increased risk of malformations associated with the use of certain ARDs, to date there appears to be no increased risk of congenital malformations associated with HAART exposure in pregnancy according to a registry's data (www.apregistry.com). ZDV treatment in infants is associated with a transient anemia. In utero exposure to HAART was shown to result in mild but statistically significant hematologic abnormalities like neutropenia and thrombocytopenia.

   4. Mode of delivery. Data from individual patient meta-analysis and a randomized controlled trial confirmed that cesarean section (CS) performed before labor and rupture of membranes reduces MTCT by 50–80%, independent of the use of antiretroviral therapy or ZDV prophylaxis. The ACOG and the Department of Health and Human Services (DHHS) Panel on Treatment of HIV Infected Pregnant Women and Prevention of Perinatal Transmission recommend early CS for HIV-infected women with plasma viral loads of more than 1000 copies/mL. Elective CS is associated with a higher rate of postpartum complications among HIV-infected women than vaginal delivery. The added benefit of elective CS on reducing risk of MTCT in women with low-plasma HIV RNA loads (<1000 copies/mL) is uncertain, and most experts now recommend that women in this category can be offered vaginal delivery. The use of invasive procedures in labor (eg, amniocentesis, fetal scalp electrodes, operative vaginal delivery, and episiotomy) should be avoided because of the potential risk for enhanced transmission.

   5. Postdelivery. Amniotic fluid and blood should be cleaned thoroughly. The infant should be isolated with the same precautions as for hepatitis B (blood and secretion precautions). Zidovudine (ZDV) is used. See dose in Chapter 148. Among infants whose mothers did not receive any ARDs before onset of labor, the current recommendation for neonatal postexposure prophylaxis is a 2-drug regimen of ZDV for 6 weeks with 3 doses of nevirapine during the first week of life (at birth, 48 hours, and 96 hours of life) rather than ZDV alone. Serial virologic studies should be obtained as discussed previously. The HIV-infected mother may be coinfected with other pathogens that can be transmitted from mother to child, such as cytomegalovirus, herpes simplex virus, hepatitis B, hepatitis C, syphilis, toxoplasmosis, or tuberculosis. Infants born to mothers with such coinfections should undergo appropriate evaluations as indicated to rule out transmission of additional infectious agents. Breast-feeding must be discouraged. Both mother and infant should have prescriptions for the HIV drugs when they leave the hospital, and the infant should have an appointment for a postnatal visit at 2–4 weeks of age to monitor medication adherence, obtain virologic testing (HIV DNA PCR), and screen the infant for anemia from ZDV.

   6. Treatment of infected patients. Management of HIV-1 infection is an area of medicine that is changing rapidly. Current treatment recommendations for HIV-1–infected children are available online (http://aidsinfo.nih.gov) and are continuously updated. ARDs therapy is indicated for all HIV-1–infected infants <12 months of age as soon as infection is confirmed, irrespective of clinical symptoms, immune status, or viral load. The principal objectives of therapy are to suppress viral replication maximally, to restore and preserve immune function, to reduce HIV-associated morbidity and mortality, to minimize drug toxicity, to maintain normal growth and development, and to improve quality of life. Aggressive therapy is warranted in the youngest children who are at greatest risk of rapid disease progression. In general, combination ARDs therapy with at least 3 drugs is recommended. Drug regimens most often used include 2 nucleoside analogue reverse-transcriptase inhibitors (NRTIs) plus either a protease inhibitor or a nonnucleoside reverse-transcriptase inhibitor (NNRTI). ARDs resistance testing (viral genotyping) is recommended before starting treatment, because infected infants may acquire resistant virus from their mothers. Suppression of the virus to undetectable levels is the desired goal. Early diagnosis and aggressive treatment of opportunistic infections may prolong survival and should be strongly pursued.

2. General supportive care

   1. Intravenous immune globulin (IVIG). HIV-infected infants who have recurrent, serious bacterial infections (like bacteremia, meningitis, or pneumonia) are appropriate candidates for routine IVIG prophylaxis (400 mg/kg/dose every 28 days). Trimethoprim-sulfamethoxazole prophylaxis may provide comparable protection.

   2. Immunization

      1. Active immunization. All routine infant immunizations should be given to HIV-1–exposed infants. If HIV-1 infection is confirmed, then guidelines for the HIV-1–infected child should be followed. Children with HIV-1 infection should be immunized as soon as is age appropriate with inactivated vaccines. Trivalent inactivated influenza vaccine (TIV) should be given annually. Additionally, live virus–containing measles-mumps-rubella (MMR) and varicella vaccines should be given to asymptomatic HIV-1–infected children and those with appropriate CD4 percentages (ie, CD4+ T-lymphocyte count >15% in children). Rotavirus vaccine may be given to HIV-1–exposed and HIV-1–infected infants. Measles-mumps-rubella-varicella (MMRV) vaccine should not be administered to HIV-infected infants because of lack of safety data in this population. The immunologic response to these vaccines in HIV-1–infected children may be less robust and less persistent than in immunologically normal children. Members of households in which a child has HIV-1 infection can receive MMR vaccine. Yearly influenza immunization is recommended to all household members 6 months of age or older. Immunization with varicella vaccine of siblings and susceptible adult caregivers of patients with HIV-1 infection is encouraged.

      2. Passive immunization. HIV-1–infected children exposed to measles should receive intramuscular immune globulin (IG) prophylaxis regardless of immunization status. Additionally, children with HIV-1 infection who sustain wounds classified as tetanus prone should receive tetanus immune globulin regardless of immunization status. Finally, for chickenpox or shingles exposure, HIV-infected children without a history of previous chickenpox or varicella vaccination should receive varicella zoster immune globulin (VariZIG) or, if not available, IVIG within 10 days after exposure.

   3. Nutrition. Close nutritional monitoring should be part of the routine care of these children.

   4. Pneumocystis jiroveci prophylaxis. CDC guidelines state that all infants born to HIV-infected women receive prophylaxis for 1 year beginning at 4–6 weeks regardless of CD4+ lymphocyte count. If HIV infection is excluded, then prophylaxis can be stopped. The drug of choice for this is trimethoprim-sulfamethoxazole. The need for prophylaxis after 1 year can be determined by the degree of immunosuppression as determined by CD4+ T-lymphocyte count.

   5. Other aspects of supportive care. Neurodevelopmental supportive services include preschool early intervention programs and school-based developmental disability programs. Aggressive management and protocols for pharmacologic and nonpharmacologic pain management should be used.

In developed countries, 2 patterns of symptomatic infection have been recognized in children who are not treated. Some children become symptomatic quickly and die before 4 years of age, with a median age of death of 11 months (15–20%, termed rapid progressors). The majority (80–85%) of untreated children, on the other hand, have delayed onset of milder symptoms and survive beyond 5 years of age (termed slow progressors). Only a minority of patients remain asymptomatic by 8 years. Clinical and laboratory factors associated with poor prognosis include being born to mothers with low CD4⁺ counts or high viral load (ie, >100,000 copies/mL), high virus copy number in the cord blood, and early manifestation of symptoms (opportunistic infections, encephalopathy, severe wasting, and hepatosplenomegaly). Use of HAART has substantially reduced both mortality and morbidity and improved quality of life in HIV-infected children. Children with HIV infection acquired through blood transfusion tend to have a prolonged asymptomatic period. In the United States, mortality in HIV-infected children has declined from 7.2 per 100 person years in 1993 to 0.8 per 100 person years in 2006. In resource-limited developing countries, before the use of ARDs, the prognosis is much worse with one study showing 89% of the infected children having died by 3 years of age, 10% having been in HIV disease category B or C, and only ∼1% having remained without HIV symptoms. With availability of ARDs to some developing countries, the prognosis is significantly improving. Recent studies from South Africa showed that implementation of a national antiretroviral treatment program resulted in 1 year and 3 year mortality rates of 4.6 and 7.7%, respectively.