Chapter 41: Human Immunodeficiency Virus Infection

Pathogenesis & Transmission

Human immunodeficiency virus (HIV) is a retrovirus that enters and then integrates its nucleic acid into the DNA of cells of the immune system, including helper T lymphocytes (CD4 T lymphocytes), monocytes, and macrophages. The function and number of CD4 T lymphocytes and other affected cells are diminished by HIV infection, resulting in profound defects in cell-mediated and humoral immunity. HIV is found in blood, semen, preseminal fluids, rectal fluids, vaginal fluids, and breast milk, with transmission occurring via sexual contact, sharing contaminated needles, and perinatal transmission (in utero, peripartum, breast-feeding). Rarely, infants have acquired HIV from food premasticated by a person with HIV. Casual, classroom, or household contact with an HIV-infected person poses no risk of transmission in the absence of contact with blood or bloody secretions. Exposure resulting from accidental needle sticks or, rarely, mucosal exposure to blood may occur, mainly in health care settings.

At the time of exposure, HIV migrates to regional lymph nodes, replicates, and spreads to lymphoid tissues throughout the body. Based on nonhuman primate models, replicating virus is disseminated by 48 hours postinfection. Approximately 2 weeks after exposure, a high level of virus is detected in the bloodstream. In adults without therapy, the level of viremia declines concurrent with the appearance of an HIV-specific host immune response, and plasma viremia usually reaches a steady-state level about 6 months after primary infection. An asymptomatic period usually follows, lasting from 1 year to more than 12 years. However, ongoing viremia and immune activation causes injury to the immune system and other organs.

Infants with perinatal HIV infection have viremia that rises steeply after birth, reaching a peak at 1–2 months of age. In contrast with adults, infants have a gradual decline in plasma viremia that extends to age 4–5 years. Without treatment, up to 50% of infants will have rapid disease progression to AIDS or death by age 2 years.

HIV infection, in the absence of treatment, causes progressive immune incompetence with the hallmark loss of CD4 T-lymphocyte numbers, leading to conditions that meet the definition of acquired immunodeficiency syndrome (AIDS) and, eventually, death. AIDS is diagnosed when an HIV-infected individual develops any of the stage 3 opportunistic illnesses or other conditions listed in Table 41–1. In adults and children older than 6 years, the criteria for a diagnosis of AIDS also include an absolute CD4 T-lymphocyte count of 200 cells/μL or less.

Antiretroviral treatment (ART) inhibits virus replication and permits immune reconstitution. Cells with latent HIV infection persist and viral replication recurs if ART is interrupted; thus, treatment must be lifelong. Even with effective viral suppression, ongoing immune activation results in end-organ (eg, cardiovascular and central nervous system) damage consistent with premature aging. Nevertheless, HIV infection, once a terminal disease, is now a chronic condition for people with access to treatment.

Epidemiology

The World Health Organization (WHO) estimated in 2018 that there are 37.9 million adults and 1.7 million children living with HIV (https://www.who.int/hiv/data/2018_summary-global-hiv-epi-1.png?ua=1). Over 90% live in low- and middle-income countries, primarily sub-Saharan Africa and South and Southeast Asia. The annual number of new infections decreased by 36% between 2000 and 2017, but infection and mortality rates remain high. Among children younger than 15 years, there were 160,000 new infections and 100,000 deaths in 2018.

Preventative measures can reduce the rate of perinatal transmission from 40% to less than 1%. New pediatric infections continue to occur in resource-limited settings due to inadequate access to care; approximately 80% of all pregnant women living with HIV globally received recommended treatment in 2017 (https://www.who.int/news-room/fact-sheets/detail/hiv-aids). In the United States, successful implementation of preventative interventions for perinatal HIV has made new perinatally acquired HIV cases rare (73 cases reported in 2017). In 2016, there were 2238 children younger than 13 years living with HIV in the United States, of whom the majority are foreign-born. Overall, there are approximately 10,000 people living with perinatally acquired HIV, some having reach their fourth decade as a result of highly effective treatment (https://www.cdc.gov/hiv/pdf/library/reports/surveillance/cdc-hiv-surveillance-report-2017-vol-29.pdf). By contrast, adolescents and young adults in the United States continue to be at risk of HIV acquisition; youth aged 13–24 years accounted for 21% (8164) of the 38,739 new HIV infections in 2017. The primary HIV exposure was male-to-male sexual contact, with the majority (87%) of the infections among gay and bisexual men, predominantly African American (51%) and Hispanic (25%) (https://www.cdc.gov/hiv/group/age/youth/index.html).

Prevention of Perinatal HIV Transmission

Key to prevention of perinatal HIV transmission is identification of pregnant women with HIV infection. Standard pregnancy care should include routine HIV testing early in gestation for all pregnant women (and their partners) and repeat testing in the third trimester if there have been risk factors for HIV acquisition, an illness consistent with acute HIV infection, or HIV seroprevalence is high (≥ 1/1000) among women delivering at the facility. For woman presenting in labor without previously documented HIV testing, HIV testing is recommended using assays that yield results within 60 minutes or less so that antiretrovirals (ARV) can be initiated for the mother during labor and/or for the infant immediately postpartum.

Maternal ART started before or early in pregnancy, in combination with infant ARV prophylaxis for 4–6 weeks postpartum, reduces the risk of transmission from 25%–40% to less than 1% with optimal maternal viral suppression. The choice of optimal ART during pregnancy is complex, and guidelines are updated frequently by the U.S. Department of Health and Human Services (https://aidsinfo.nih.gov/guidelines/html/3/perinatal/0). In addition, a consult line is available 24/7 for questions about prevention of perinatal HIV transmission (http://nccc.ucsf.edu/clinician-consultation/perinatal-hiv-aids/, 888-448-8765). Elective C-section prior to labor will also reduce transmission risk for women who have plasma viral load greater than or equal to 1000 copies/mL. Even if diagnosis of HIV is late, ARV medications given to women in labor and/or to infants as late as 48 hours postpartum reduce transmission by as much as 50%.

In resource-limited settings, breast-feeding increases survival and, therefore, breast-feeding is usually preferred to formula-feeding. Continuation of maternal ART or extended ARV prophylaxis given to the infant for the duration of breast-feeding markedly reduces transmission resulting from breast milk. Breast-feeding is not recommended in the United States where access to safe formula is readily available. However, a minority of women may choose to breast-feed for cultural or other reasons. In this scenario, attention to maternal adherence to ART and frequent monitoring of the mother for detectable plasma virus and of the infant for transmission is recommended. Several cases of HIV transmission have resulted from HIV-infected caregivers feeding children premasticated food; hence, families should be advised against this practice.

Prevention of Sexual Transmission

For individuals at risk of HIV acquisition through sexual contact, prevention efforts should integrate biomedical and behavioral methods. The FDA has approved the antiretroviral tenofovir/emtricitabine, a once daily, fixed-dose, single pill, for preexposure prophylaxis (PrEP) for adults and adolescents (https://www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2017.pdf). Combination ARV is also effective as PEP (https://stacks.cdc.gov/view/cdc/38856). These regimens are described in Chapter 44. The CDC publishes a compendium of evidence-based behavioral interventions for safer sex practices (https://www.cdc.gov/hiv/research/interventionresearch/compendium/rr/index.html).

On a public health level, a high priority for HIV prevention is widespread diagnosis and treatment of people living with HIV. Treatment of partners with HIV resulted in a 96% reduction in transmission to uninfected partners. Thus, treatment benefits the health of the individual with HIV and reduces the risk of transmission to others. Large studies of partners discordant for HIV demonstrate that there is effectively no risk of sexual transmission of HIV when the partner living with HIV on ART has a durably undetectable viral load (https://www.niaid.nih.gov/news-events/undetectable-equals-untransmittable). Broad recognition of this concept (termed Undetectable = Untransmittable), partnered with effective treatment, has the potential to markedly reduce the stigma associated with an HIV diagnosis.

Prevention Through Universal Precautions

Horizontal transmission (in the absence of sexual contact or injecting drug use) of HIV is exceedingly rare and is associated with exposure of nonintact skin or mucous membranes to HIV-infected blood or bloody secretions. Saliva, tears, urine, and stool are not infectious if they do not contain gross blood. Barrier protection (eg, latex or rubber gloves or thick pads of fabric or paper) should be used when possible contact with blood or bloody body fluids may occur. Objects that might be contaminated with blood, such as razors or toothbrushes, should not be shared. No special care is required for dishes, towels, toys, or bedclothes. Blood-soiled clothing may be washed routinely with hot water and detergent. Contaminated surfaces may be disinfected easily with a variety of agents, including household bleach (1:10 dilution), some commercial disinfectants (eg, Lysol), or 70% isopropyl alcohol.

The infant or child with HIV who is well enough to attend day care or school should not be treated differently from other children. The exception may be a toddler with uncontrollable biting behavior or bleeding lesions that cannot be covered adequately; in these situations, the child may be withheld from group day care. Families may choose to make the school health care provider and/or teacher aware of the diagnosis, but there is no legal requirement that any individual at the school or day care center be informed. The parents and child may prefer to keep the diagnosis confidential, because the stigma associated with HIV infection remains difficult to overcome. Because undiagnosed HIV-infected infants and children might be enrolled, all schools and day care centers should have policies with simple guidelines for using universal precautions to prevent transmission of HIV infection in these settings.

Management of the Perinatally HIV-Exposed Infant

Infants with perinatal HIV exposure receive ARV prophylaxis for 4–6 weeks, whether or not they have breast milk exposure. For infants born to women with optimal ART during pregnancy, monotherapy with zidovudine or nevirapine is sufficient; for infants at higher risk of transmission, prophylaxis with two ARV or empiric treatment with three ARV is recommended (details of regimens are found at https://aidsinfo.nih.gov/guidelines/html/3/perinatal/187/antiretroviral-management-of-newborns-with-perinatal-hiv-exposure-or-perinatal-hiv). During the period of ARV prophylaxis, some infants have reversible anemia or neutropenia that is usually not clinically significant. Viral nucleic acid tests to detect HIV in blood allow for presumptive and definitive determination of HIV infection status by age 4 weeks and 4 months, respectively. Early infant diagnosis allows for early initiation of ART, which reduces the otherwise high rate of early mortality among infants with perinatal HIV. Infants with HIV have a high risk of Pneumocystis jiroveci pneumonia (PCP), with the peak incidence at age 2–6 months. Thus, prophylaxis for P jiroveci pneumonia is given to infants born to HIV-infected mothers beginning at age 4–6 weeks and continuing until HIV infection has been excluded or until age 12 months for infants found to have HIV infection. PCP prophylaxis may be avoided for infants with negative HIV NAT at 2 and 4 weeks of age. Infants with ongoing HIV exposure via breast-feeding are recommended to continue PCP prophylaxis, at least until HIV infection has been excluded after cessation of breast-feeding.

Clinical Findings

Newborns with HIV infection rarely have symptoms or physical examination findings at birth or in the first months of life. However, 30%–80% of infected infants develop symptoms or signs within the first year of life. Hepatomegaly, splenomegaly, lymphadenopathy, parotitis, and recurrent respiratory tract infections are signs associated with slow progression. Severe bacterial infections, progressive neurologic disease, anemia, and fever are associated with rapid progression.

HIV-exposed but uninfected (HEU) infants are generally healthy, but a number of studies find higher morbidity and mortality compared with HIV-unexposed infants. Alterations in growth, neurocognitive development, immune function, and end-organ parameters are also reported in this population, although their clinical significance is under investigation. Some studies have found symptoms consistent with mitochondrial toxicity associated with perinatal ARV exposure; other studies have failed to confirm these findings. There is biological plausibility for this toxicity because the nucleoside analogue drugs used for PMTCT may cause mitochondrial toxicity. The benefit of prenatal and postnatal treatment to prevent HIV transmission outweighs the potential risk but ongoing studies are important to elucidate the effects of in utero and perinatal HIV and ARV exposure and to identify the safest regimens.

Laboratory Diagnosis

Infants born to HIV-infected mothers will have transplacental maternal HIV antibody regardless of their infection status. The median time to seroreversion with current antibody assays in uninfected infants is 13.9 months, and most uninfected infants become antibody negative by 18 months; in a minority of infants (approximately 14%), however, maternal antibody is detected until age 24 months. Therefore, early infant diagnosis must be made by direct detection of viral nucleic acid, either DNA or RNA, in blood. A recommended schedule of HIV NAT and antibody testing for infants is outlined in Table 41–2. Positive HIV NAT at any age requires a subsequent sample for confirmation to rule out a false positive, particularly for a test with low RNA copy number (< 5000 copies/mL).

HIV NAT is positive in blood at birth for the fraction of infants infected in utero, but negative for infants who acquire infection at birth. Most infected infants with either in utero or peripartum acquisition will have detectable HIV NAT by 2 weeks of life, over 95% will have detectable virus by 4 weeks, and virtually all by 4 months. Thus, infection can be “presumptively” excluded by negative HIV NAT at age 2 and 4 weeks. For the higher risk infant, receipt of combination ARV may inhibit detection of virus in blood and, hence, an additional NAT at age 8–10 weeks, 2–4 weeks after cessation of combination ARV, is performed for early identification of infection. Definitive evidence of absence of infection, if no breast-feeding, is defined by negative HIV NAT at age greater than or equal to 1 and 4 months (and at age 8–10 weeks if received combination ARV). Breast-fed infants may acquire HIV at any time until they are fully weaned, and virus may not be detected until several weeks or months after exposure. Therefore, breast milk-exposed infants should be tested at 6 weeks, 3 months, and 6 months after their last exposure.

For infants with negative NAT, many clinicians obtain HIV antibody testing at 12–24 months of age to demonstrate reversion to seronegative status. After age 24 months, diagnosis can be accomplished with the standard multitest algorithm used for adolescents and adults, screening with an HIV antibody/antigen test, with reactive tests followed by a confirmatory antibody test using a different detection platform.

Among adolescents and adults with primary HIV infection, nonspecific symptoms (eg, flu- or mild mononucleosis-like illness) beginning 2–4 weeks after exposure occur in 30%–90%, but they are frequently not severe enough to be brought to medical attention. This acute retroviral syndrome is described in more detail in Chapter 44. After acute infection, adolescents may be asymptomatic for several years, but during that time will have disease progression and the potential to transmit HIV to their sexual partners.

Laboratory Diagnosis

In the early weeks after acute infection HIV antibody may be absent, but HIV RNA and DNA are usually detected within a week of infection. Therefore, if acute infection is suspected, HIV NAT should be obtained in addition to antibody/antigen-based testing.

Current laboratory-based screening tests detect HIV-1 and HIV-2 antibody and HIV-1 p24 antigen. These tests are more sensitive for acute/early infection than earlier generation antibody tests because antigen may be detected in advance of antibodies (however, these tests still may be negative very early after acute infection). A second antibody test on the same sample using a different methodology is conducted to confirm the presence of antibodies because rare individuals have cross-reacting antibodies which result in a false-positive antibody test. If the initial test used detects both HIV antigen and anti-HIV antibody and the confirmatory test that detects only antibody is nonreactive, HIV NAT testing is indicated if acute HIV infection is a possibility, as antigen detection may precede antibody formation. Definitive diagnosis of HIV infection requires a positive result on a second sample obtained on a different occasion. Most patients will seroconvert by 6 weeks after exposure, but occasionally seroconversion does not occur for 3–6 months. Additional information about the use of available HIV diagnostic tests for a range of settings (clinics, community-based or field locations, home testing) is found at https://www.cdc.gov/hiv/testing/index.html.

The Centers for Disease Control and Prevention (CDC) recommends that HIV screening tests be conducted in routine health care settings with patient knowledge and right of refusal for patients aged 13–64 years and that all adults should be tested at least once for HIV during their lives (https://www.cdc.gov/hiv/guidelines/testing.html). The American Academy of Pediatrics recommends at least one-time testing for 16- to 18-year-old adolescents living in areas of high (≥ 0.1%) or unknown seroprevalence, irrespective of individual risk factors. In areas of lower seroprevalence, testing is encouraged for all sexually active adolescents and those with other risk factors for HIV infection. Point-of-care HIV antibody testing performed in the community and home HIV testing kits are strategies to increase access to testing for those at risk.

A. Clinical Findings

1. Disease staging

The CDC published revised disease staging for HIV-infected adults, adolescents, and children in 2014 (http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6303a1.htm) (Tables 41–1 and 41–3). Stages 1, 2, and 3 are determined by categories of age-adjusted absolute CD4 T-lymphocyte counts and percentages that indicate progressively severe immune suppression; stage 3 is defined as AIDS (see Table 41–3). AIDS is also diagnosed in individuals having one or more of the severe opportunistic illnesses or other serious conditions listed in Table 41–1. An individual’s staging may vary with time, improving or worsening depending on the outcome of the patient’s treatment course. The WHO has established a clinical staging system that is used widely outside the United States (WHO Consolidated guidelines on antiretroviral drugs for treatment and preventing HIV, Annex 10, found at https://www.who.int/hiv/pub/arv/arv-2016/en/). Risk of progression to AIDS or death for a child at specific ages can be determined with CD4 parameters and HIV viral load (tables for risk calculation found at https://aidsinfo.nih.gov/guidelines/html/2/pediatric-arv/440/appendix-c-supplemental-information).

2. Infections related to immunodeficiency

Bacteremia, especially due to Streptococcus pneumoniae, occurs at rates of 3 per 100 child-years without ART and decreases to 0.36 per 100 child-years with ART, but this remains approximately ten times higher than in HIV-uninfected children. Infections with M tuberculosis are a major cause of morbidity in countries with high rates of endemic tuberculosis (TB). Given the frequency of coinfection, diagnosis of M tuberculosis in a child is an indication for HIV testing. Likewise, children with HIV infection and their family members should have annual TB testing if there is potential for M tuberculosis exposure. Herpes zoster (shingles) occurs 10 times more frequently among untreated HIV-infected children compared with age-matched healthy children.

Late-stage immunodeficiency is accompanied by susceptibility to a variety of opportunistic pathogens. Pneumonia caused by P jiroveci is a common AIDS-defining diagnosis in children with unrecognized HIV infection who, therefore, are not receiving PCP prophylaxis. Symptoms are difficult to distinguish from those of viral or atypical pneumonia (see Chapter 43). Persistent candida mucocutaneous infections (oral, cutaneous, and vaginal) are common. Candida esophagitis occurs with more advanced disease. Cytomegalovirus (CMV) infections may result in disseminated disease, hepatitis, gastroenteritis, retinitis, and encephalitis. Disseminated infection with MAC, presenting with fever, night sweats, weight loss, diarrhea, fatigue, lymphadenopathy, hepatomegaly, anemia, and granulocytopenia, may occur in those who have CD4 T-lymphocyte counts below 50–100/μL. A variety of diarrheal pathogens that cause mild, self-limited symptoms in healthy persons may result in severe, chronic diarrhea in HIV-infected persons. These include Cryptosporidium parvum, Microsporidia, Cyclospora, Isospora belli, Giardia lamblia, and bacterial pathogens. Chronic parvovirus infection manifested by anemia can occur. In late-stage disease, prophylactic measures are recommended to prevent selected opportunistic infections (https://aidsinfo.nih.gov/guidelines/html/5/pediatric-oi-prevention-and-treatment-guidelines/0).

3. Organ system disease

HIV infection may directly affect a variety of organ systems and produce disease manifestations that include encephalopathy, pneumonitis, hepatitis, diarrhea, hematologic suppression, nephropathy, and cardiomyopathy. On average, HIV-infected children have lower than normal neuropsychological functioning which may not normalize when ART is started, despite suppression of viremia. Without ART, findings include acquired microcephaly, progressive motor deficit, ataxia, pseudobulbar palsy, and failure to attain (or loss of) developmental milestones.

Lymphoid interstitial pneumonitis, which is common in untreated children with HIV infection, is characterized by a diffuse peribronchial and interstitial infiltrate composed of lymphocytes and plasma cells. It may be asymptomatic or associated with dry cough, hypoxemia, dyspnea or wheezing on exertion, and clubbing of the digits. Children with this disorder frequently have enlargement of the parotid glands and generalized lymphadenopathy.

4. Malignancy

Children with HIV are at increased risk of malignancy. The most commonly occurring tumors are non-Hodgkin lymphomas, which may occur at unusual extranodal sites (central nervous system, bone, gastrointestinal tract, liver, or lungs). Human papillomavirus infection of the cervix is more likely to progress to neoplasia. Anal carcinoma due to human papillomavirus is also a concern. Kaposi sarcoma, a skin and mucous membrane malignancy that is common in HIV-infected men who have sex with men with advanced disease, is also observed among HIV-infected African children, but it is rare in children in the United States.

B. Laboratory Findings

The hallmark of HIV disease progression is decline in the absolute number and percentage of CD4 T lymphocytes and an increasing percentage of CD8 T lymphocytes. The CD4 T-lymphocyte values are predictive of the child’s risk of opportunistic infections. Healthy infants and children have CD4 T-lymphocyte numbers that are much higher than in adults; these gradually decline to adult levels by age 5–6 years. Hence, age-adjusted values must be used when assessing a child’s absolute CD4 T-lymphocyte count (see Table 41–3). CD4 T-lymphocyte percentage, which is less variable with age, is used when CD4 T-cell count is not available.

Hypergammaglobulinemia of IgG, IgA, and IgM is characteristic in untreated HIV. Late in the disease, some individuals may become hypogammaglobulinemic. Hematologic abnormalities (anemia, neutropenia, and thrombocytopenia) may occur due to effects of HIV disease or ART. Cerebrospinal fluid (CSF) may either be normal or may be associated with elevated protein and a mononuclear pleocytosis; HIV NAT may be positive in CSF.

C. Differential Diagnosis

HIV infection should be in the differential diagnosis for children being evaluated for immunodeficiency. Depending on the degree of immunosuppression, the presentation in HIV infection may be similar to that of B-cell (eg, hypogammaglobinemia), T-cell, or combined immunodeficiencies (eg, severe combined immunodeficiency) (see Chapter 33). HIV infection should also be considered in the evaluation of individuals with failure to thrive, developmental delay, chronic lung disease, and M tuberculosis infection. HIV infection presenting with generalized lymphadenopathy or hepatosplenomegaly may resemble infections with viruses such as Epstein-Barr virus or CMV in children or adolescents. Because blood tests are definitive for the diagnosis of HIV infection, the diagnosis can be readily established or excluded. In rare cases, HIV-infected people with hypogammaglobulinemia have falsely negative antibody tests but may be diagnosed with a nucleic acid-based test. Because recognized maternal or behavioral risk factors may not always be elicited, testing for HIV should be performed if the patient has signs consistent with HIV-associated disease even when the history or maternal testing early in pregnancy does not suggest increased risk.

A. Specific Measures

1. Principles of HIV treatment

Studies in young infants and adults support initiation of ART early after infection to prevent HIV progression, and current US and WHO guidelines recommend ART for all individuals soon after diagnosis. For children, initiation of ART is urgent for those with stage 3 clinical or CD4 T-cell parameters or younger than 12 months (irrespective of CD4 count). Older children with less advanced infection are also recommended to start treatment but with more time allowed to prepare the family for successful adherence to treatment. The goal of ART is suppression of viral replication (plasma virus < 20–75 copies/mL), resulting in an increase in CD4 T-lymphocyte count and reconstitution of immune function (or maintenance, if baseline parameters are within normal limits). HIV has a high spontaneous mutation rate allowing emergence of drug resistance with single-drug treatment; therefore, combinations of three drugs, including two drugs with different mechanisms of action, are standard. Optimally, children initiating ART will have laboratory monitoring at 2–4 weeks and then every 3–4 months to confirm viral suppression. If plasma virus becomes consistently detectable (> 200 copies/mL), the underlying cause must be determined (eg, poor adherence or viral resistance), and, if necessary, a change in the medication combination is made. Latent HIV persists in long-lived resting cells, the so-called viral reservoir, and cessation of ARV treatment results in resumption of viremia. Therefore, treatment for HIV with currently available modalities must be lifelong.

Strict adherence to the prescribed treatment is critical. A wide range of issues may impact adherence, including pill burden, dosing frequency, and tolerability, as well as psychosocial factors such as developmental stage, mental health of child and caregiver, HIV knowledge, and beliefs about treatment. Programs and services that enhance adherence are essential adjuncts of any HIV treatment regimen.

2. Antiretroviral medications

There are numerous ARV medications approved by the U.S. Food and Drug Administration (FDA) categorized into five different drug classes for the treatment of HIV. Many of the drugs have pediatric indications for older children, but pharmacokinetic data and administration forms appropriate for infants and toddlers are more limited. The drug classes and mechanism of action of each class are described briefly in Table 41–4. Recommended regimens vary by age but will generally include two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) plus one drug from another class. Fixed dose formulations including two or three drugs at adult dosages in a single pill have become common and offer simplified regimens, often a once-daily pill, for adolescents. Guidelines for the treatment of HIV developed by US national working groups of pediatric HIV specialists are published and updated frequently at: http://www.aidsinfo.nih.gov and WHO recommendations are found at: http://www.who.int/hiv/pub/guidelines/en/.

3. Complications of antiretroviral medications

ART may result in a range of adverse effects. Each medication has specific toxicities which are described in detail in the Guidelines for Use of ARV in Pediatric HIV Infection, Tables 15a–15k (found at https://www.aidsinfo.nih.gov/contentfiles/lvguidelines/PedARV_TablesOnly.pdf). Common adverse events are gastrointestinal distress, hematologic toxicity (anemia, neutropenia), elevated liver enzymes, dyslipidemia (elevated LDL-cholesterol and triglycerides). Less common are glucose intolerance and abnormal fat distribution (lipodystrophy). Reduced bone mineral content and renal dysfunction may result from drug effects as well as from direct effects of HIV. Several drugs (eg, nevirapine, abacavir) have been associated with severe hepatitis, usually occurring in the first 6 weeks of treatment, and may occur in the context of a systemic hypersensitivity reaction. These events may be life-threatening if not identified early or upon rechallenge with the same medication. The nucleoside and nucleotide analogues have low-level affinity for the human mitochondrial DNA polymerase. Therefore, these analogues may be incorporated into mitochondrial DNA, which is one mechanism that may lead to adverse effects. Mitochondrial toxicity can result in lactic acidosis, a rare, but potentially fatal, complication. During the initial weeks of treatment, immune restoration may lead to worsening or unmasking of underlying infection with other organisms such as M tuberculosis, an event termed immune reconstitution inflammatory syndrome (IRIS).

B. General Measures

1. Immunizations

Inactivated vaccines are recommended, as they are safe and generally immunogenic in HIV-infected children. The use of LAV depends on the child’s immune stage and particular vaccine. Generally, LAV are not recommended for children with severe immunosuppression, defined as CD4 T-lymphocyte percentage less than 15% at any age and/or a CD4 T-lymphocyte count less than 200 cells/μL at age greater than or equal to 5 years. However, for children with CD4 T-lymphocyte parameters that exceed those values for at least the preceding 6 months, rotavirus, measles-mumps-rubella, and varicella-zoster virus LAV are recommended. Yellow fever vaccine may be given to stage 1 individuals and may also be considered for children in stage 2. Bacille Calmette-Guérin (BCG), oral polio, smallpox, and live typhoid vaccines should not be given to HIV-infected people, irrespective of stage. Based on studies demonstrating diminished magnitude or durability of vaccine-induced immune responses, additional doses are recommended for particular vaccines. Vaccine responses are more robust with higher CD4 T-lymphocyte counts and suppressed plasma virus. Therefore, for children who were immunized prior to establishment of effective ART, reimmunization should be considered and is specifically recommended for measles-mumps-rubella vaccine. Children with HIV have higher rates of disease from pneumococcus, Haemophilus influenzae type b, and meningococcus; therefore, recommendations for high-risk groups for these vaccines apply. Details of modified recommendations for children with HIV infection are provided in Table 41–5 (CDC guidance for vaccines indicated for children based on medical indications https://www.cdc.gov/vaccines/schedules/hcp/imz/child-indications.html).

2. Psychosocial support and mental health

Evaluation and support for psychosocial needs of HIV-affected families is imperative. As with other chronic illnesses, HIV infection affects all family members and also carries additional social stigma. Emotional concerns and financial needs, which are more prominent than medical needs at many stages of the disease process, influence the family’s ability to comply with a medical treatment regimen. HIV-infected children often have comorbid mental health conditions. Rates of attention-deficit/hyperactivity disorder range from 20% to 50% in various studies. Hospital admissions for mental health disorders are more frequent among HIV-infected children. In one study, dual diagnosis of HIV and a mental health disorder occurred in 85% of adolescents who acquired HIV infection through high-risk behaviors. Ideally, care should be coordinated by a team of caregivers that is familiar with HIV disease and its comorbidities, newest therapies, and community resources.

Evidence-based care guidelines are published by the U.S. Department of Health and Human Services and are updated frequently (http://aidsinfo.nih.gov/). The guidelines establish best practices for prevention, initiation of treatment, choice of ARV, monitoring frequency, and prophylaxis for opportunistic infections, and the HIV/AIDS Bureau (HAB) of Human Resources and Services Administration has established quality performance measures based on these guidelines (http://hab.hrsa.gov/deliverhivaidscare/habperformmeasures.html). In addition, a major quality emphasis is on monitoring success of the continuum care at local and national levels. This continuum describes the percentage of people living with HIV in a defined community who have completed the sequential stages in successful HIV care: (1) diagnosis, (2) linkage to care, (3) engagement and retention in care, (4) prescription of ART, and, finally, (5) viral suppression. Many countries have endorsed the UNAIDS goals that 90% of those living with HIV know their diagnosis, 90% of those diagnosed be engaged in care, and 90% of those engaged in care have a viral load below 200 copies/mL, the so-called 90 / 90 / 90 target. Several US national quality groups collect and publish data across clinics on these cascade outcomes, thereby setting national metrics and providing technical assistance to HIV programs (in+care Campaign at http://www.incarecampaign.org/; National Quality Center at https://targethiv.org/cqii).