HIV infection affects most of the immune system and disrupts its homeostasis (Fig. 268-2). In most cases, the initial infection is caused by low amounts of a single virus. Therefore, disease may be prevented by prophylactic drug(s) or vaccine. When the mucosa serves as the portal of entry for HIV, the 1st cells to be affected are the dendritic cells. These cells collect and process antigens introduced from the periphery and transport them to the lymphoid tissue. HIV does not infect the dendritic cell but binds to its DC-SIGN surface molecule, allowing the virus to survive until it reaches the lymphatic tissue. In the lymphatic tissue (e.g., lamina propria, lymph nodes), the virus selectively binds to cells expressing CD4 molecules on their surface, primarily helper T lymphocytes (CD4⁺ T cells) and cells of the monocyte-macrophage lineage. Other cells bearing CD4, such as microglia, astrocytes, oligodendroglia, and placental tissue containing villous Hofbauer cells, may also be infected by HIV. Additional factors (co-receptors) are necessary for HIV fusion and entry into cells. These factors include the chemokines CXCR4 (fusion) and CCR5. Other chemokines (CCR1, CCR3) may be necessary for the fusion of certain HIV strains. Several host genetic determinants affect the susceptibility to HIV infection, the progression of disease, and the response to treatment. These genetic variants vary in different populations. A deletion in the CCR5 gene that is protective against HIV infection (CCR5Δ32) is relatively common in whites but is rare in blacks. Several other genes that regulate chemokine receptors, ligands, histocompatibility complex, and cytokines have also been found to influence the outcome of HIV infection. Usually, CD4⁺ lymphocytes migrate to the lymphatic tissue in response to viral antigens and then become activated and proliferate, making them highly susceptible to HIV infection. This antigen-driven migration and accumulation of CD4 cells within the lymphoid tissue may contribute to the generalized lymphadenopathy characteristic of the acute retroviral syndrome in adults and adolescents. HIV preferentially infects the very cells that respond to it (HIV-specific memory CD4 cells), accounting for the progressive loss of these cells and the subsequent loss of control of HIV replication. The continued destruction of memory CD4+ cells in the gastrointestinal tract leads to reduced integrity of the gastrointestinal epithelium followed by leakage of bacterial particles into the blood and increased inflammatory response, which cause further CD4+ cell loss. When HIV replication reaches a threshold (usually within 3-6 wk from the time of infection), a burst of plasma viremia occurs. This intense viremia causes flu or mononucleosis-like symptoms (fever, rash, lymphadenopathy, arthralgia) in 50-70% of infected adults. With establishment of a cellular and humoral immune response within 2-4 mo, the viral load in the blood declines substantially, and patients enter a phase characterized by a lack of symptoms and a return of CD4 cells to only moderately decreased levels.

Figure 268-2 HIV life cycle and antiretroviral drug targets. Present antiretroviral drugs span 6 classes that target 5 unique steps in the HIV life cycle (binding, fusion, reverse transcription, integration, and proteolytic cleavage). The most common drugs used in resource-rich regions to target each step are shown. Extracellular virions enter their target cell through a complex 3-step process, which is (1) attachment to the CD4 receptor, (2) binding to the CCR5 or CXCR4 co-receptors, or both, and (3) membrane fusion. Maraviroc blocks CCR5 binding and enfuvirtide blocks fusion. The HIV reverse transcriptase enzyme catalyses transcription of HIV RNA into double-stranded HIV DNA, a step inhibited by nucleoside analogues and non-nucleoside reverse transcriptase inhibitors (NNRTIs). The HIV integrase enzyme facilitates incorporation of HIV DNA into host chromosomes and this step is inhibited by raltegravir and other integrase inhibitors. After transcription and translation of the HIV genome, immature virions are produced and bud from the cell surface. The HIV protease enzyme cleaves polypeptide chains, allowing the virus to mature. This last step is inhibited by HIV protease inhibitors.

(From Volberding PA, Deeks SG: Antiretroviral therapy and management of HIV infection, Lancet 376:49–60, 2010, Fig 1, p 50.)

Early HIV-1 replication in children has no apparent clinical manifestations. Whether tested by virus isolation or by PCR for viral nucleic acid sequences, fewer than 40% of HIV-1–infected infants demonstrate evidence of the virus at birth. The virus load increases by 1-4 mo, and almost all HIV-infected infants have detectable HIV-1 in peripheral blood by 4 mo of age.

In adults, the long period of clinical latency (up to 8-12 yr) is not indicative of viral latency. In fact, there is a very high turnover of virus and CD4 lymphocytes (more than a billion cells per day), gradually causing deterioration of the immune system, marked by depletion of CD4 cells. Several mechanisms for the depletion of CD4 cells in adults and children have been suggested, including HIV-mediated single cell killing, formation of multinucleated giant cells of infected and uninfected CD4 cells (syncytia formation), virus-specific immune responses (natural killer cells, antibody-dependent cellular cytotoxicity), superantigen-mediated activation of T cells (rendering them more susceptible to infection with HIV), autoimmunity, and programmed cell death (apoptosis). The viral burden is greater in the lymphoid organs than in the peripheral blood during the asymptomatic period. As HIV virions and their immune complexes migrate through the lymph nodes, they are trapped in the network of dendritic follicular cells. Because the ability of HIV to replicate in T cells depends on the state of activation of the cells, the immune activation that takes place within the microenvironment of the lymph nodes in HIV disease serves to promote infection of new CD4 cells as well as subsequent viral replication within these cells. Monocytes can be productively infected by HIV yet resist killing, explaining their role as reservoirs of HIV and as effectors of tissue damage in organs such as the brain.

Cell-mediated and humoral responses occur early in the infection. CD8 T cells play an important role in containing the infection. These cells produce various ligands (MIP-1α, MIP-1β, RANTES), which suppress HIV replication by blocking the binding of the virus to the co-receptors (CCR5). HIV-specific cytotoxic T lymphocytes (CTLs) develop against both the structural (ENV, POL, GAG) and regulatory (tat) viral proteins. The CTLs appear at the end of the acute infection, as viral replication is controlled by killing HIV-infected cells before new viruses are produced and by secreting potent antiviral factors that compete with the virus for its receptors (CCR5). Neutralizing antibodies appear later in the infection and seem to help in the continued suppression of viral replication during clinical latency. There are at least 2 possible mechanisms that control the steady-state viral load level during the chronic clinical latency. One mechanism may be the limited availability of activated CD4 cells, which prevent further increase in viral load. The other mechanism is development of an active immune response, which is influenced by the amount of viral antigen and limits viral replication at a steady state. There is no general consensus about which of these 2 mechanisms is more important. The CD4 cell limitation mechanism accounts for the effect of antiretroviral therapy, whereas the immune response mechanism emphasizes the importance of immune modulation treatment (cytokines, vaccines) to increase the efficiency of immune-mediated control. A group of cytokines that includes tumor necrosis factor-α (TNF-α), TNF-β, interleukin 1 (IL-1), IL-2, IL-3, IL-6, IL-8, IL-12, IL-15, granulocyte-macrophage colony-stimulating factor, and macrophage colony-stimulating factor plays an integral role in upregulating HIV expression from a state of quiescent infection to active viral replication. Other cytokines such as interferon-γ (IFN-γ), IFN-β, and IL-13 exert a suppressive effect on HIV replication. Certain cytokines (IL-4, IL-10, IFN-γ, TGF-β) reduce or enhance viral replication depending on the infected cell type. The interactions among these cytokines influence the concentration of viral particles in the tissues. Plasma concentrations of cytokines need not be elevated for them to exert their effect, because they are produced and act locally in the tissues. Thus, even during states of apparent immunologic quiescence, the complex interaction of cytokines sustains a constant level of viral expression, particularly in the lymph nodes.

Commonly HIV isolated during the clinical latency period grows slowly in culture and produces low titers of reverse transcriptase. These isolates use CCR5 as their co-receptor. By the late stages of clinical latency, the isolated virus is phenotypically different. It grows rapidly and to high titers in culture and uses CXCR4 as its co-receptor. The switch from CCR5-receptor to CXCR4 receptor increases the capacity of the virus to replicate, to infect a broader range of target cells (CXCR4 is more widely expressed on resting and activated immune cells), and to kill T cells more rapidly and efficiently. As a result, the clinical latency phase is over and progression toward AIDS is noted. The progression of disease is related temporally to the gradual disruption of lymph node architecture and degeneration of the follicular dendritic cell network with loss of its ability to trap HIV particles. The virus is freed to recirculate, producing high levels of viremia and an increased disappearance of CD4 T cells during the later stages of disease.

Before HAART was available, 3 distinct patterns of disease were described in children. Approximately 15-25% of HIV-infected newborns in developed countries present with a rapid disease course, with onset of AIDS and symptoms during the 1st few months of life and a median survival time of 6-9 mo if untreated. In resource-poor countries, the majority of HIV-infected newborns will have this rapidly progressing disease. It has been suggested that if intrauterine infection coincides with the period of rapid expansion of CD4 cells in the fetus, the virus could effectively infect the majority of the body’s immunocompetent cells. The normal migration of these cells to the marrow, spleen, and thymus would result in efficient systemic delivery of HIV, unchecked by the immature immune system of the fetus. Thus, infection would be established before the normal ontogenic development of the immune system, causing more severe impairment of immunity. Most children in this group have a positive HIV-1 culture and/or detectable virus in the plasma (median level 11,000 copies/mL) in the 1st 48 hr of life. This early evidence of viral presence suggests that the newborn was infected in utero. The viral load rapidly increases, peaking by 2-3 mo of age (median 750,000 copies/mL) and staying high for at least the 1st 2 yr of life.

The majority of perinatally infected newborns (60-80%) in developed countries present with a much slower progression of disease, with a median survival time of 6 yr representing the 2nd pattern of disease. Many patients in this group have a negative viral culture or PCR in the 1st wk of life and are therefore considered to be infected intrapartum. In a typical patient, the viral load rapidly increases, peaking by 2-3 mo of age (median 100,000 copies/mL) and then slowly declines over a period of 24 mo. The slow decline in viral load is in sharp contrast to the rapid decline after primary infection seen in adults. This observation can be explained only partially by the immaturity of the immune system in newborns and infants.

The 3rd pattern of disease occurs in a small percentage (<5%) of perinatally infected children referred to as long-term survivors (LTS), who have minimal or no progression of disease with relatively normal CD4 counts and very low viral loads for longer than 8 yr. Mechanisms for the delay in disease progression include effective humoral immunity and/or CTL responses, host genetic factors (e.g., HLA profile), and infection with attenuated (defective gene) virus. A subgroup of the LTS called “elite survivors” has no detectable viruses in the blood and may reflect different or greater mechanisms of protection from disease progression.

HIV-infected children have changes in the immune system that are similar to those in HIV-infected adults. CD4 cell depletion may be less dramatic because infants normally have a relative lymphocytosis. A value of 1,500 CD4 cells/mm³ in children <1 yr of age is indicative of severe CD4 depletion and is comparable to <200 CD4 cells/mm³ in adults. Lymphopenia is relatively rare in perinatally infected children and is usually only seen in older children or those with end-stage disease. Although cutaneous anergy is common during HIV infection, it is also frequent in healthy children <1 yr of age, and thus its interpretation is difficult to interpret in infected infants. The depletion of CD4 cells also decreases the response to soluble antigens such as in vitro mitogens phytohemagglutinin and concanavalin A.

Polyclonal activation of B cells occurs in most children early in the infection, as evidenced by elevation of IgA, IgM, IgE, and particularly IgG (hypergammaglobulinemia), with high levels of anti–HIV-1 antibody. This response may reflect both dysregulation of T-cell suppression of B-cell antibody synthesis and active CD4 enhancement of B-lymphocyte humoral response. As a result, antibody response to routine childhood vaccinations may be abnormal. The B-cell dysregulation precedes the CD4 depletion in many children, and may serve as a surrogate marker of HIV infection in symptomatic children in whom specific diagnostic tests (PCR, culture) are not available or are too expensive. Despite the increased levels of immunoglobulins, some children lack specific antibodies or protective antibodies. Hypogammaglobulinemia is very rare (<1%).

Central nervous system (CNS) involvement is more common in pediatric patients than in adults. Macrophages and microglia play an important role in HIV neuropathogenesis, and data suggest that astrocytes may also be involved. Although the specific mechanisms for encephalopathy in children are not yet clear, the developing brain in young infants is affected by at least 2 mechanisms. The virus itself may directly infect various brain cells or cause indirect damage to the nervous system by the release of cytokines (IL-1α, IL-1β, TNF-α, IL-2) or reactive oxygen from HIV-infected lymphocytes or macrophages.

Appropriate therapy with antiretroviral agents may result in immune reconstitution inflammatory syndrome (IRIS), which is characterized by an increased inflammatory response from the recovered immune system to subclinical opportunistic infections (e.g., tuberculosis, herpes simplex virus (HSV) infection, toxoplasmosis, CMV infection, cryptococcal infection). This condition is more commonly observed in patients with progressive disease and severe CD4⁺ T-lymphocyte depletion. Patients with IRIS develop fever and worsening of the clinical manifestations of the opportunistic infection or new manifestations (e.g., enlargement of lymph nodes, pulmonary infiltrates, etc.), typically within the 1st few weeks after initiation of antiretroviral therapy. Determining whether the symptoms represent IRIS, worsening of a current infection, a new opportunistic infection, or drug toxicity is often very difficult. If the syndrome does represent IRIS, adding nonsteroidal anti-inflammatory agents or corticosteroids may alleviate the inflammatory reaction, although the use of corticosteroids is controversial. The inflammation may take weeks or months to subside. In most cases, continuation of anti-HIV treatment while treating the opportunistic infection (with or without antiinflamatory agents) is sufficient. If opportunistic infection is suspected prior to initiation of antiretroviral therapy, appropriate antimicrobial treatment should be given first.

Clinical Manifestations

The clinical manifestations of HIV infection vary widely among infants, children, and adolescents. In most infants, physical examination at birth is normal. Initial symptoms may be subtle, such as lymphadenopathy and hepatosplenomegaly, or nonspecific, such as failure to thrive, chronic or recurrent diarrhea, respiratory symptoms, or oral thrush, and may be distinguishable only by their persistence. Whereas systemic and pulmonary findings are common in the USA and Europe, chronic diarrhea, wasting, and severe malnutrition predominate in Africa. Clinical manifestations found more commonly in children than adults with HIV infection include recurrent bacterial infections, chronic parotid swelling, lymphocytic interstitial pneumonitis (LIP), and early onset of progressive neurologic deterioration.

The HIV classification system is used to categorize the stage of pediatric disease by using 2 parameters: clinical status and degree of immunologic impairment (Table 268-1). Among the clinical categories, category A (mild symptoms) includes children with at least 2 mild symptoms such as lymphadenopathy, parotitis, hepatomegaly, splenomegaly, dermatitis, and recurrent or persistent sinusitis or otitis media (Table 268-2). Category B (moderate symptoms) includes children with LIP, oropharyngeal thrush persisting for >2 mo, recurrent or chronic diarrhea, persistent fever for >1 mo, hepatitis, recurrent (HSV) stomatitis, HSV esophagitis, HSV pneumonitis, disseminated varicella (i.e., with visceral involvement), cardiomegaly, or nephropathy (see Table 268-2). Category C (severe symptoms) includes children with opportunistic infections (e.g. esophageal or lower respiratory tract candidiasis, cryptosporidiosis (>1 mo), disseminated mycobacterial or cytomegalovirus infection, Pneumocystis pneumonia, or cerebral toxoplasmosis [onset >1 mo of age]), recurrent bacterial infections (sepsis, meningitis, pneumonia), encephalopathy, malignancies, and severe weight loss.

Table 268-1 PEDIATRIC HIV CLASSIFICATION FOR CHILDREN YOUNGER THAN 13 YEARS

Table 268-2 CLINICAL CATEGORIES FOR CHILDREN YOUNGER THAN 13 YEARS OF AGE WITH HIV INFECTION

CATEGORY N: NOT SYMPTOMATIC

Children who have no signs or symptoms considered to be the result of HIV infection or have only 1 of the conditions listed in category A.

CATEGORY A: MILDLY SYMPTOMATIC

Children with 2 or more of the conditions listed but none of the conditions listed in categories B and C.

• Lymphadenopathy (≥0.5 cm at more than 2 sites; bilateral at 1 site)

• Recurrent or persistent upper respiratory tract infection, sinusitis, or otitis media

CATEGORY B: MODERATELY SYMPTOMATIC

Children who have symptomatic conditions other than those listed for category A or C that are attributed to HIV infection.

• Anemia (hemoglobin <8 g/dL [<80 g/L]), neutropenia (white blood cell count <1,000/µL [<1.0 × 10⁹/L]), and/or thrombocytopenia (platelet count <100 × 10³/µL [<100 × 10⁹/L]) persisting for ≥30 days

• Bacterial meningitis, pneumonia, or sepsis (single episode)

• Candidiasis, oropharyngeal (thrush), persisting (>2 mo) in children older than 6 mo of age

• Cardiomyopathy

• Cytomegalovirus infection, with onset before 1 mo of age

• Diarrhea, recurrent or chronic

• Hepatitis

• Herpes simplex virus (HSV) stomatitis, recurrent (>2 episodes within 1 yr)

• HSV bronchitis, pneumonitis, or esophagitis with onset before 1 mo of age

• Herpes zoster (shingles) involving at least 2 distinct episodes or more than 1 dermatome

• Leiomyosarcoma

• Lymphoid interstitial pneumonia or pulmonary lymphoid hyperplasia complex

• Nephropathy

• Nocardiosis

• Persistent fever (lasting >1 mo)

• Toxoplasmosis, onset before 1 mo of age

• Varicella, disseminated (complicated chickenpox)

CATEGORY C: SEVERELY SYMPTOMATIC

• Serious bacterial infections, multiple or recurrent (i.e., any combination of at least 2 culture-confirmed infections within a 2 yr period), of the following types: septicemia, pneumonia, meningitis, bone or joint infection, or abscess of an internal organ or body cavity (excluding otitis media, superficial skin or mucosal abscesses, and indwelling catheter-related infections)

• Candidiasis, esophageal or pulmonary (bronchi, trachea, lungs)

• Coccidioidomycosis, disseminated (at site other than or in addition to lungs or cervical or hilar lymph nodes); cryptococcosis, extrapulmonary

• Cryptosporidiosis or isosporiasis with diarrhea persisting >1 mo

• Cytomegalovirus disease with onset of symptoms after 1 mo of age (at a site other than liver, spleen, or lymph nodes)

• Encephalopathy (at least 1 of the following progressive findings present for at least 2 mo in the absence of a concurrent illness other than HIV infection that could explain the findings): (1) failure to attain or loss of developmental milestones or loss of intellectual ability, verified by standard developmental scale or neuropsychologic tests; (2) impaired brain growth or acquired microcephaly demonstrated by head circumference measurements or brain atrophy demonstrated by CT or MRI (serial imaging required for children younger than 2 yr of age); or (3) acquired symmetric motor deficit manifested by 2 or more of the following: paresis, pathologic reflexes, ataxia, or gait disturbance

• HSV infection causing a mucocutaneous ulcer that persists for greater than 1 mo or bronchitis, pneumonitis, or esophagitis for any duration affecting a child older than 1 mo of age

• Histoplasmosis, disseminated (at a site other than or in addition to lungs or cervical or hilar lymph nodes)

• Kaposi sarcoma

• Lymphoma, primary, in brain

• Lymphoma, small, noncleaved cell (Burkitt), or immunoblastic; or large-cell lymphoma of B-lymphocyte or unknown immunologic phenotype

• Mycobacterium tuberculosis infection, disseminated or extrapulmonary

• Mycobacterium, other species or unidentified species infection, disseminated (at a site other than or in addition to lungs, skin, or cervical or hilar lymph nodes)

• Pneumocystis jiroveci pneumonia

• Progressive multifocal leukoencephalopathy

• Salmonella (nontyphoid) septicemia, recurrent

• Toxoplasmosis of the brain with onset after 1 mo of age

• Wasting syndrome in the absence of a concurrent illness other than HIV infection that could explain the following findings: (1) persistent weight loss >10% of baseline; (2) downward crossing of at least 2 of the following percentile lines on the weight-for-age chart (e.g., 95th, 75th, 50th, 25th, 5th) in a child 1 yr of age or older; OR (3) <5th percentile on weight-for-height chart on 2 consecutive measurements, ≥30 days apart; PLUS (1) chronic diarrhea (i.e., at least 2 loose stools per day for >30 days); OR (2) documented fever (for >30 days, intermittent or constant)

Modified from the Centers for Disease Control and Prevention: 1994 revised classification system for human immunodeficiency virus infection in children less than 13 years of age. Official authorized addenda: human immunodeficiency virus infection codes and official guidelines for coding and reporting ICD-9-CM, MMWR Recomm Rep 43(RR-12):1–19, 1994.

The immune classification is based on the absolute CD4 lymphocyte count or the percentage of CD4 cells (see Table 268-1). Age adjustment of the absolute CD4 count is necessary because counts that are relatively high in normal infants decline steadily until 6 yr of age, when they reach adult norms. If there is a discrepancy between the CD4 count and percentage, the disease is classified into the more severe category.

Infections

Approximately 20% of AIDS-defining illnesses in children are recurrent bacterial infections caused primarily by encapsulated organisms such as Streptococcus pneumoniae and Salmonella (Table 268-3) due to disturbances in humoral immunity. Other pathogens, including Staphylococcus, Enterococcus, Pseudomonas aeruginosa, Haemophilus influenzae, and other gram-positive and gram-negative organisms, may also be seen. The most common serious infections in HIV-infected children are bacteremia, sepsis, and bacterial pneumonia, accounting for >50% of infections in these patients. Meningitis, urinary tract infections, deep-seated abscesses, and bone/joint infections occur less frequently. Milder recurrent infections, such as otitis media, sinusitis, and skin and soft tissue infections, are very common and may be chronic with atypical presentations.

Table 268-3 1993 REVISED CASE DEFINITION OF AIDS-DEFINING CONDITIONS FOR ADULTS AND ADOLESCENTS 13 YEARS OF AGE AND OLDER

Candidiasis of bronchi, trachea, or lungs

Candidiasis, esophageal

Cervical cancer, invasive

Coccidioidomycosis, disseminated or extrapulmonary

Cryptococcosis, extrapulmonary

Cryptosporidiosis, chronic intestinal (>1 mo duration)

Cytomegalovirus disease (other than liver, spleen, or nodes)

Cytomegalovirus retinitis (with loss of vision)

Encephalopathy, HIV related

Herpes simplex: chronic ulcer(s) (>1 mo duration) or bronchitis, pneumonitis, or esophagitis

Histoplasmosis, disseminated or extrapulmonary

Isosporiasis, chronic intestinal (>1 mo duration)

Kaposi sarcoma

Lymphoma, Burkitt (or equivalent term)

Lymphoma, immunoblastic (or equivalent term)

Lymphoma, primary or brain

Mycobacterium avium complex or Mycobacterium kansasii infection, disseminated or extrapulmonary

Mycobacterium tuberculosis infection, any site, pulmonary or extrapulmonary

Mycobacterium, other species or unidentified species infection, disseminated or extrapulmonary

Pneumocystis jiroveci pneumonia

Pneumonia, recurrent

Progressive multifocal leukoencephalopathy

Salmonella septicemia, recurrent

Toxoplasmosis of brain

Wasting syndrome attributable to HIV

CD4⁺ T-lymphocyte count <200/µL (0.20 × 10⁹/L) or CD4⁺ lymphocyte percentage <15%

Modified from the Centers for Disease Control and Prevention: 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults, MMWR Recomm Rep 41(RR-17):1–19, 1992.

Opportunistic infections (OIs) are generally seen in children with severe depression of the CD4 count. In adults, these infections usually represent reactivation of a latent infection acquired early in life. In contrast, young children generally have primary infection and often have a more fulminant course of disease reflecting the lack of prior immunity. This principle is best illustrated by Pneumocystis jirovecii (formerly Pneumocystis carinii) pneumonia, the most common opportunistic infection in the pediatric population (Chapter 236). The peak incidence of Pneumocystis pneumonia occurs at age 3-6 mo in the setting of undiagnosed perinatally acquired disease, with the highest mortality rate in children <1 yr of age. Aggressive approaches to treatment have improved the outcome substantially. While the overall incidence of opportunistic infections has markedly declined since the era of combination antiretroviral therapy (ART), OIs still occur in patients with severe immunodepletion as the result of unchecked viral replication, which often accompanies poor ART adherence.

The classic clinical presentation of Pneumocystis pneumonia includes acute onset of fever, tachypnea, dyspnea, and marked hypoxemia; in some children, more indolent development of hypoxemia may precede other clinical or x-ray manifestations. Chest x-ray findings most commonly consist of interstitial infiltrates or diffuse alveolar disease, which rapidly progresses. Nodular lesions, streaky or lobar infiltrates, or pleural effusions may occasionally be seen. Diagnosis is established by demonstration of P. jirovecii with appropriate staining of bronchoalveolar fluid lavage; rarely, an open lung biopsy is necessary.

The 1st line therapy for Pneumocystis pneumonia is intravenous trimethoprim-sulfamethoxazole (TMP-SMZ) (15-20 mg/kg/day of the TMP component every 6 hr IV) with adjunctive corticosteroids if the PaO₂ is <70 mm Hg while breathing room air. When the patient has improved, therapy with oral TMP-SMZ should be continued for a total of 21 days while the corticosteroids are weaned. Alternative therapy for Pneumocystis pneumonia includes intravenous administration of pentamidine (4 mg/kg/day). Other regimens such as TMP plus dapsone, clindamycin plus primaquine, or atovaquone are used as alternatives in adults but have not been widely used in children to date.

Atypical mycobacterial infection, particularly with Mycobacterium avium-intracellulare complex (MAC), may cause disseminated disease in HIV-infected children who are severely immunosuppressed. The incidence of MAC infection in ART-naïve children with <100 CD4 cells/mm³ has been estimated to be as high as 10%, but effective combination ART that results in viral suppression has made MAC infections rare. Disseminated MAC infection is characterized by fever, malaise, weight loss, and night sweats; diarrhea, abdominal pain, and rarely intestinal perforation or jaundice (due to biliary tract obstruction by lymphadenopathy) may also be present. Diagnosis is made by isolation of MAC from blood, bone marrow, or tissue; the isolated presence of MAC in the stool does not confirm a diagnosis of disseminated MAC. Treatment can reduce symptoms and prolong life but is at best only capable of suppressing the infection if severe CD4 depletion persists. Therapy should include at least 2 drugs: clarithromycin or azithromycin and ethambutol. A 3rd drug (rifabutin, rifampin, ciprofloxacin, levofloxacin, or amikacin) is generally added to decrease the emergence of drug-resistant isolates. Careful consideration of possible drug interactions with antiretroviral agents is necessary before initiation of disseminated MAC therapy. Drug susceptibilities should be ascertained, and the treatment regimen should be adjusted accordingly in the event of inadequate clinical response to therapy. Because of the great potential for toxicity with most of these medications, surveillance for adverse effects should be ongoing.

Oral candidiasis is the most common fungal infection seen in HIV-infected children. Oral nystatin suspension (2-5 mL qid) is often effective. Clotrimazole troches or fluconazole (3-6 mg/kg PO QD) are an effective alternative. Oral thrush progresses to involve the esophagus in as many as 20% of children with severe CD4 depletion, presenting with symptoms such as anorexia, dysphagia, vomiting, and fever. Treatment with oral fluconazole for 7-14 days generally results in rapid improvement in symptoms. Fungemia rarely occurs, usually in the setting of indwelling venous catheters, and up to 50% of cases may be caused by non-albicans species. Disseminated histoplasmosis, coccidioidomycosis, and cryptococcosis are rare in pediatric patients but may occur in endemic areas. Parasitic infections such as intestinal cryptosporidiosis and microsporidiosis and rarely isosporiasis or giardiasis are other opportunistic infections that cause significant morbidity. Although these intestinal infections are usually self-limiting in healthy hosts, they cause severe chronic diarrhea in HIV-infected children with low CD4 counts, often leading to malnutrition. Nitazoxanide therapy has been found to be partially effective at improving cryptosporidia diarrhea, but immune reconstitution with HAART is the most important factor for clearance of the infection. Albendazole has been reported to be effective against some microsporidia, and TMP-SMZ appears to be effective for isosporiasis.

Viral infections, especially with the herpesvirus group, pose significant problems for HIV-infected children. HSV causes recurrent gingivostomatitis, which may be complicated by local and distant cutaneous dissemination. Primary varicella-zoster virus (VZV) infection (chickenpox) may be prolonged and complicated by bacterial infections or visceral dissemination, including pneumonitis. Recurrent, atypical, or chronic episodes of herpes zoster are often debilitating and require prolonged therapy with acyclovir; in rare instances, VZV has developed resistance to acyclovir, requiring the use of foscarnet. Disseminated cytomegalovirus (CMV) infection occurs in the setting of severe CD4 depletion (<50 CD4 cells/mm³) and may involve single or multiple organs. Retinitis, pneumonitis, esophagitis, gastritis with pyloric obstruction, hepatitis, colitis, and encephalitis have been reported, but these complications are rarely seen if HAART is given. Ganciclovir (6 mg/kg bid IV) and foscarnet (60 mg/kg tid IV) are the drugs of choice and are often given together in children with sight-threatening CMV retinitis. An intraocular ganciclovir implant plus oral valganciclovir has also been efficacious in adults and older children with CMV retinitis. Measles may occur despite immunization and may present without the typical rash. It often disseminates to the lung or brain with a high mortality rate.

Respiratory viruses such as respiratory syncytial virus (RSV) and adenovirus may present with prolonged symptoms and persistent viral shedding. In parallel with the increased prevalence of genital tract human papillomavirus (HPV) infection, cervical intraepithelial neoplasia (CIN) and anal intraepithelial neoplasia (AIN) also occur with increased frequency among HIV-1–infected adult women compared with HIV-seronegative women. The relative risk for CIN is 5-10 times higher for HIV-1 seropositive women. Multiple modalities are used to treat HPV infection (Chapter 258), although none is uniformly effective and the recurrence rate is high among HIV-1–infected persons.

Central Nervous System

The incidence of CNS involvement in perinatally infected children is 50-90% in resource-limited countries but significantly lower in developed countries, with a median onset at 19 mo of age. Manifestations may range from subtle developmental delay to progressive encephalopathy with loss or plateau of developmental milestones, cognitive deterioration, impaired brain growth resulting in acquired microcephaly, and symmetric motor dysfunction. Encephalopathy may be the initial manifestation of the disease or may present much later when severe immune suppression occurs. With progression, marked apathy, spasticity, hyperreflexia, and gait disturbance may occur, as well as loss of language and oral, fine, and/or gross motor skills. The encephalopathy may progress intermittently, with periods of deterioration followed by transiently stable plateaus. Older children may exhibit behavioral problems and learning disabilities. Associated abnormalities identified by neuroimaging techniques include cerebral atrophy in up to 85% of children with neurologic symptoms, increased ventricular size, basal ganglia calcifications, and, less frequently, leukomalacia.

Fortunately, since the advent of HAART, the incident rate of encephalopathy has dramatically declined to as low as 0.08% in 2006. However, as HIV-infected children progress through adolescence and young adulthood, other subtle manifestations of CNS disease are evident, such as cognitive deficits, attention problems, and psychiatric disorders. Living with a chronic, often stigmatizing, disease, parental loss, and the requirement for lifelong pristine medication adherence compounds these issues, making it challenging for these youth as they inherit responsibility for managing their disease as adults.

Focal neurologic signs and seizures are unusual and may imply a co-morbid pathologic process such as a CNS tumor, opportunistic infection, or stroke. CNS lymphoma may present with new onset focal neurologic findings, headache, seizures, and mental status changes. Characteristic findings on neuroimaging studies include a hyperdense or isodense mass with variable contrast enhancement or a diffusely infiltrating contrast-enhancing mass. CNS toxoplasmosis is exceedingly rare in young infants, but may occur in HIV-infected adolescents and is typically associated with serum antitoxoplasma IgG as a marker of infection. Other opportunistic infections of the CNS are rare and include infection with CMV, JC virus (progressive multifocal leukoencephalopathy), HSV, Cryptococcus neoformans, and Coccidioides immitis. Although the true incidence of cerebrovascular disorders (both hemorrhagic and nonhemorrhagic strokes) is unclear, 6-10% of children from large clinical series have been affected.

Respiratory Tract

Recurrent upper respiratory tract infections such as otitis media and sinusitis are very common. Although the typical pathogens (S. pneumoniae, H. influenzae, Moraxella catarrhalis) are most common, but unusual pathogens such as P. aeruginosa, yeast, and anaerobes may be present in chronic infections and result in complications such as invasive sinusitis and mastoiditis.

LIP is the most common chronic lower respiratory tract abnormality reported to the Centers for Disease Control and Prevention (CDC); historically this occurred in approximately 25% of HIV-infected children, although the incidence has declined in the combination ART era. LIP is a chronic process with nodular lymphoid hyperplasia in the bronchial and bronchiolar epithelium, often leading to progressive alveolar capillary block over months to years. It has a characteristic chronic diffuse reticulonodular pattern on chest radiography rarely accompanied by hilar lymphadenopathy, allowing a presumptive diagnosis to be made radiographically before the onset of symptoms. There is an insidious onset of tachypnea, cough, and mild to moderate hypoxemia with normal auscultatory findings or minimal rales. Progressive disease presents with symptomatic hypoxemia, which usually resolves with oral corticosteroid therapy, accompanied by digital clubbing. Several studies suggest that LIP is a lymphyproliferative response to a primary Epstein-Barr virus infection in the setting of HIV infection.

Most symptomatic HIV-infected children experience at least 1 episode of pneumonia during the course of their disease. S. pneumoniae is the most common bacterial pathogen, but P. aeruginosa and other Gram-negative pneumonias may occur in end-stage disease and are often associated with acute respiratory failure and death. Rarely, severe recurrent bacterial pneumonia results in bronchiectasis. Pneumocystis pneumonia is the most common opportunistic infection, but other pathogens, including CMV, Aspergillus, Histoplasma, and Cryptococcus can cause pulmonary disease. Infection with common respiratory viruses, including respiratory syncytial virus, parainfluenza, influenza, and adenovirus, may occur simultaneously and have a protracted course and period of viral shedding from the respiratory tract. Pulmonary and extrapulmonary tuberculosis (TB) has been reported with increasing frequency in HIV-infected children in low-resource countries, although it is considerably more common in HIV-infected adults. Due to drug interactions between rifampin and ritonavir-based ART and poor tolerability of the combination of multiple drugs required, treatment of TB/HIV co-infection is particularly challenging in children.

Cardiovascular System

Subclinical cardiac abnormalities in HIV-infected children are common, persistent, and often progressive. Young children with symptomatic HIV infection often have dilated cardiomyopathy and left ventricular hypertrophy; the 2 yr cumulative incidence of congestive heart failure is almost 5%. Children with encephalopathy or other AIDS-defining conditions have the highest rate of adverse cardiac outcomes. Resting sinus tachycardia has been reported in up to 64% and marked sinus arrhythmia in 17% of HIV-infected children. Hemodynamic instability occurs more frequently with advanced HIV disease. Gallop rhythm with tachypnea and hepatosplenomegaly appear to be the best clinical indicators of congestive heart failure in HIV-infected children; anticongestive therapy is generally very effective, especially when initiated early. Electrocardiography and echocardiography are helpful in assessing cardiac function before the onset of clinical symptoms. There is increasing concern that premature cardiovascular disease will be seen in children who have disease- or treatment-related hyperlipidemia, and prospective studies will be needed to assess this risk.

Gastrointestinal and Hepatobiliary Tract

Oral manifestations of HIV disease include erythematous or pseudomembranous candidiasis, periodontal disease (e.g., ulcerative gingivitis or periodontitis), salivary gland disease (i.e., swelling, xerostomia), and rarely ulcerations or oral hairy leukoplakia. Gastrointestinal tract involvement is common in HIV-infected children. A variety of pathogens can cause gastrointestinal disease, including bacteria (Salmonella, Campylobacter, MAC), protozoa (Giardia, Cryptosporidium, Isospora, microsporidia), viruses (CMV, HSV, rotavirus), and fungi (Candida). MAC and the protozoal infections are most severe and protracted in patients with severe CD4 cell depletion. Infections may be localized or disseminated and affect any part of the gastrointestinal tract from the oropharynx to the rectum. Oral or esophageal ulcerations, either viral in origin or idiopathic, are painful and often interfere with eating. AIDS enteropathy, a syndrome of malabsorption with partial villous atrophy not associated with a specific pathogen, has been postulated to be a result of direct HIV infection of the gut. Disaccharide intolerance is common in HIV-infected children with chronic diarrhea.

The most common symptoms of gastrointestinal disease are chronic or recurrent diarrhea with malabsorption, abdominal pain, dysphagia, and failure to thrive (FTT). Prompt recognition of weight loss or poor growth velocity in the absence of diarrhea is critical. Linear growth impairment often correlates with the level of HIV viremia. Supplemental enteral feedings should be instituted, either by mouth or with nighttime nasogastric tube feedings in cases associated with more severe chronic growth problems; placement of a gastrostomy tube for nutritional supplementation may be necessary. The wasting syndrome, defined as a loss of >10% of body weight, is not as common as FTT in pediatric patients, but the resulting malnutrition is associated with a grave prognosis. Chronic liver inflammation evidenced by fluctuating serum levels of transaminases with or without cholestasis is relatively common, often without identification of an etiologic agent. Cryptosporidial cholecystitis is associated with abdominal pain, jaundice, and elevated gamma GT. In some patients, chronic hepatitis caused by CMV, hepatitis B, hepatitis C, or MAC may lead to portal hypertension and liver failure. Several of the antiretroviral drugs or other drugs such as didanosine, protease inhibitors, nevirapine, and dapsone may also cause reversible elevation of transaminases.

Pancreatitis with increased pancreatic enzymes with or without abdominal pain, vomiting, and fever may be the result of drug therapy (e.g., with pentamidine, didanosine, or lamivudine) or, rarely, opportunistic infections such as MAC or CMV.

Renal Disease

Nephropathy is an unusual presenting symptom of HIV infection, more commonly occurring in older symptomatic children. A direct effect of HIV on renal epithelial cells has been suggested as the cause, but immune complexes, hyperviscosity of the blood (secondary to hyperglobulinemia), and nephrotoxic drugs are other possible factors. A wide range of histologic abnormalities has been reported, including focal glomerulosclerosis, mesangial hyperplasia, segmental necrotizing glomerulonephritis, and minimal change disease. Focal glomerulosclerosis generally progresses to renal failure within 6-12 mo, but other histologic abnormalities in children may remain stable without significant renal insufficiency for prolonged periods. Nephrotic syndrome is the most common manifestation of pediatric renal disease, with edema, hypoalbuminemia, proteinuria, and azotemia with normal blood pressure. Cases resistant to steroid therapy may benefit from cyclosporine therapy. Polyuria, oliguria, and hematuria have also been observed in some patients.

Skin Manifestations

Many cutaneous manifestations seen in HIV-infected children are inflammatory or infectious disorders that are not unique to HIV infection. These disorders tend to be more disseminated and respond less consistently to conventional therapy than in the uninfected child. Seborrheic dermatitis or eczema that is severe and unresponsive to treatment may be an early nonspecific sign of HIV infection. Recurrent or chronic episodes of HSV, herpes zoster, molluscum contagiosum, flat warts, anogenital warts, and candidal infections are common and may be difficult to control.

Allergic drug eruptions are also common, in particular related to non-nucleoside reverse transcription inhibitors, and generally respond to withdrawal of the drug but also may resolve spontaneously without drug interruption: rarely, progression to Stevens-Johnson syndrome has been reported. Epidermal hyperkeratosis with dry, scaling skin is frequently observed, and sparse hair or hair loss may be seen in the later stages of the disease.

Hematologic and Malignant Diseases

Anemia occurs in 20-70% of HIV-infected children, more commonly in children with AIDS. The anemia may be due to chronic infection, poor nutrition, autoimmune factors, virus-associated conditions (hemophagocytic syndrome, parvovirus B19 red cell aplasia), or the adverse effect of drugs (zidovudine). In children with low erythropoietin levels, subcutaneous recombinant erythropoietin has been successful in treating the anemia.

Leukopenia occurs in almost 30% of untreated HIV-infected children, and neutropenia often occurs. Multiple drugs used for treatment or prophylaxis for opportunistic infections, such as Pneumocystis pneumonia, MAC, and CMV, or antiretroviral drugs (zidovudine) may also cause leukopenia and/or neutropenia. In cases in which therapy cannot be changed, treatment with subcutaneous granulocyte colony-stimulating factor may be necessary.

Thrombocytopenia has been reported in 10-20% of patients. The etiology may be immunologic (i.e., circulating immune complexes or antiplatelet antibodies) or less commonly due to drug toxicity, or the cause may be unknown. Antiretroviral therapy may also reverse thrombocytopenia in ARV-naïve patients. Treatment with intravenous immunoglobulin (IVIG) or anti-D offers temporary improvement in most patients already taking ARVs. If ineffective, a course of steroids may be an alternative, but consultation with a hematologist should be sought. Deficiency of clotting factors (factors II, VII, IX) is not rare in children with advanced HIV disease and is often easy to correct with vitamin K. A novel disease of the thymus has been observed in a few HIV-infected children. These patients were found to have characteristic anterior mediastinal multilocular thymic cysts without clinical symptoms. Histologic examination shows focal cystic changes, follicular hyperplasia, and diffuse plasmocytosis and multinucleated giant cells. Spontaneous involution occurs in some cases.

In contrast to the more frequent occurrence in adults, malignant diseases have been reported infrequently in HIV-infected children, representing only 2% of AIDS-defining illnesses. Non-Hodgkin lymphoma, primary CNS lymphoma, and leiomyosarcoma are the most commonly reported neoplasms among HIV-infected children. Epstein-Barr virus is associated with most lymphomas and with all leiomyosarcomas (Chapter 246). Kaposi sarcoma, which is caused by human herpesvirus 8, occurs frequently among HIV-infected adults but is exceedingly uncommon among HIV-infected children in resource rich countries (Chapter 249).

Diagnosis

All infants born to HIV-infected mothers test antibody-positive at birth because of passive transfer of maternal HIV antibody across the placenta during gestation. Most uninfected infants without ongoing exposure (i.e., who are not breast-fed) lose maternal antibody between 6 and 12 mo of age and are known as seroreverters. Because a small proportion of uninfected infants continue to test HIV antibody positive for up to 18 mo of age, positive IgG antibody tests, including the rapid tests, cannot be used to make a definitive diagnosis of HIV infection in infants younger than this age. The presence of IgA or IgM anti-HIV in the infant’s circulation can indicate HIV infection, because these immunoglobulin classes do not cross the placenta; however, IgA and IgM anti-HIV assays have been both insensitive and nonspecific and therefore are not valuable for clinical use. In any child >18 mo of age, demonstration of IgG antibody to HIV by a repeatedly reactive enzyme immunoassay (EIA) and confirmatory Western blot test establishes the diagnosis of HIV infection. Breast-fed infants should have antibody testing performed 12 wk following cessation of breast-feeding to identify those who became infected at the end of lactation by the HIV-infected mother. Certain diseases (e.g., syphilis, autoimmune diseases) may cause false-positive or indeterminate results. In such cases specific viral diagnostic tests (see later) have to be done.

Several rapid HIV tests are currently available with sensitivity and specificity better than those of the standard EIA. Many of these new tests require only a single step that allows test results to be reported within less than half an hour. Incorporating rapid HIV testing during delivery or immediately after birth is crucial for the care of HIV-exposed newborns whose HIV status was unknown during pregnancy. A positive rapid test has to be confirmed by Western blot testing. However, if 2 different rapid tests (testing different HIV-associated antibodies) are positive, there is no need for further verification with Western blot testing.

Viral diagnostic assays, such as HIV DNA or RNA PCR or HIV culture, are considerably more useful in young infants, allowing a definitive diagnosis in most infected infants by 1-6 mo of age (Table 268-4). By 3-4 mo of age, the HIV culture and/or PCR identifies all infected infants. HIV DNA PCR is the preferred virologic assay in developed countries. Almost 40% of infected newborns have positive test results in the 1st 2 days of life, with >90% testing positive by 2 wk of age. Plasma HIV RNA assays, which detect viral replication, are as sensitive as the DNA PCR for early diagnosis. HIV culture has similar sensitivity to HIV DNA PCR; it is more technically complex and expensive, and results are often not available for several weeks compared with 2-3 days for PCR.

Table 268-4 LABORATORY DIAGNOSIS OF HIV INFECTION

TEST	COMMENT
HIV DNA PCR	Preferred test to diagnose HIV-1 subtype B infection in infants and children younger than 18 mo of age; highly sensitive and specific by 2 wk of age and available; performed on peripheral blood mononuclear cells. False negatives can occur in non-B subtype HIV-1 infections
HIV culture	Expensive, not easily available, requires up to 4 wk to do test; not recommended
HIV RNA PCR	Less sensitive than DNA PCR for routine testing of infants, because a negative result cannot be used to exclude HIV infection definitively. Some assays preferred test to identify non-B subtype HIV-1 infections.

Ag, antigen; ICD, immune complex dissociated; PCR, polymerase chain reaction.

From Red book: 2009 report of the Committee on Infectious Diseases, ed 28, Elk Grove Village, IL, 2009, American Academy of Pediatrics, p 386.

Viral diagnostic testing should be performed within the 1st 12-24 hr of life. Almost 40% of HIV-infected children can be identified at this time. It seems that many of these children have a more rapid progression of their disease and deserve more aggressive therapy. In exposed children with negative virologic testing at 1-2 days of life, additional testing should be done at 1-2 mo of age and at 4-6 mo of age; some also favor testing at age 14 days as almost 90% of the infected infants can be identified and earlier initiation of antiretroviral therapy can be initiated. A positive virologic assay (i.e., detection of HIV by PCR, culture, or p24 antigen) suggests HIV infection and should be confirmed by a repeat test on a 2nd specimen as soon as possible. A diagnosis of HIV infection can be made with 2 positive virologic test results obtained from different blood samples.

Although the perinatal use of prophylactic zidovudine to prevent vertical transmission has not affected the predictive value of viral diagnostic testing, the more intensive antiviral combinations (protease inhibitors) in pregnant women do not affect the DNA PCR but the effect on the RNA PCR is unknown. HIV infection can be reasonably excluded if an infant has had at least 2 negative virologic test results with at least 1 test performed at ≥4 mo of age. In some parts of the world where non–subtype B are common (i.e., outside of the USA), interpretation of a negative PCR test result should be done with caution because the assay may not detect the particular subtype (e.g., group O). Close clinical monitoring with serologic testing (by 18 mo of age) or culture (if possible) is recommended. In older infants, 2 or more negative HIV antibody tests performed at least 1 mo apart past 6 mo of age in the absence of hypogammaglobulinemia or clinical evidence of HIV disease can reasonably exclude HIV infection. The infection can be excluded definitively if the same parameters are met when the infant is at least 18 mo of age.

Treatment

The currently available therapy does not eradicate the virus and cure the patient and instead suppresses the virus for extended periods of time and changes the course of the disease to a chronic process. Decisions about antiretroviral therapy for pediatric HIV-infected patients are based on the magnitude of viral replication (viral load), CD4 lymphocyte count or percentage, and clinical condition. Because antiretroviral therapy changes as new drugs become available, decisions regarding therapy should be made in consultation with an expert in pediatric HIV infection. Plasma viral load monitoring and measurement of CD4 values have made it possible to implement rational treatment strategies for viral suppression as well as to assess the efficacy of a particular drug combination. The following principles form the basis for antiretroviral treatment: (1) uninterrupted HIV replication causes destruction of the immune system and progression to AIDS; (2) the magnitude of the viral load predicts the rate of disease progression, and the CD4 cell count reflects the risk of opportunistic infections and HIV infection complications; (3) combinations of HAART, which include at least 3 drugs, should be the initial treatment. Potent combination therapy that suppresses HIV replication to an undetectable level restricts the selection of antiretroviral-resistant mutants; drug-resistant strains are the major factor limiting successful viral suppression and delay of disease progression; (4) the goal of sustainable suppression of HIV replication is best achieved by the simultaneous initiation of combinations of antiretroviral agents to which the patient has not been exposed previously and that are not cross-resistant to drugs with which the patient has been treated previously; and (5) adherence to the complex drug regimens is crucial for a successful outcome.

Combination Therapy

Antiretroviral drugs licensed as of 2010 are categorized by their mechanism of action, such as preventing viral entrance into CD4⁺ T cells, inhibiting the HIV reverse transcriptase or protease enzymes, or inhibiting integration of the virus into the human DNA. Within the reverse transcriptase inhibitors, a further subdivision can be made: nucleoside (or nucleotide) reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) (see Fig. 268-2). The NRTIs have a similar structure to the building blocks of DNA (e.g., thymidine, cytosine). When incorporated into DNA, they act like chain terminators and block further incorporation of nucleosides, preventing viral DNA synthesis. As of 2010, 7 NRTIs were licensed in the USA (Table 268-5). Among the NRTIs, thymidine analogs (e.g., stavudine [d4T], zidovudine [ZDV]) are found in higher concentrations in activated or dividing cells, and nonthymidine analogs (e.g., didanosine [ddI], lamivudine [3TC]) have more activity in resting cells. Activated cells are thought to produce >99% of the population of HIV virions. In contrast, resting cells account for <1% of the population but may serve as a reservoir for HIV. Suppression of replication in both populations is thought to be an important component of long-term viral control. NNRTIs (i.e., nevirapine, efavirenz, etravirine) act differently than the NRTIs. They attach to the reverse transcriptase and restrict its motility, reducing the activity of the enzyme. The protease inhibitors (PIs) are potent agents that act farther along the viral replicative cycle. As of 2010, 9 PIs were licensed in the USA, but only 5 of these agents (ritonavir, nelfinavir, fosamprenavir, tipranavir, and lopinavir) have pediatric formulations (e.g., liquid or powder) (see Table 268-5). The PIs bind to the site where the viral long polypeptides are cut to individual, mature, and functional core proteins that produce the infectious virions before they leave the cell. The virus entry into the cell is a complex process that involves cellular receptors and fusion. Several drugs have been developed to prevent this process. The fusion inhibitor, enfuvirtide, which binds to viral gp41, causes conformational changes that prevent fusion of the virus with the CD4⁺ cell and entry into the cell. Maraviroc is an example of a selective CCR5 co-receptor antagonist that blocks the attachment of the virus to this chemokine (an essential process in the viral binding and fusion to the CD4⁺ cells). Integrase inhibitors like raltegravir block the enzyme that catalyzes the incorporation of the viral genome into the host’s DNA.

Table 268-5 SUMMARY OF ANTIRETROVIRAL THERAPIES AVAILABLE IN 2009

While the principal site of viral replication is lymphoid tissue, sanctuary sites such as the CNS may harbor residual virions with the potential to be a source of local or persistent disease. Impaired penetration of drugs to these compartments could result in development of resistance. Although data on CNS penetration of antiviral agents are presently limited, ZDV, d4T, and 3TC appear to achieve inhibitory concentrations in the CNS. Nevirapine also penetrates the CSF, but protease inhibitors are actively transported out of the CNS, thereby limiting their potential efficacy at this site.

By targeting different points in the viral life cycle and stages of cell activation and by delivering drug to all tissue sites, maximal viral suppression may be feasible. Combinations of 3 drugs, a thymidine analog NRTI (ZDV) and a nonthymidine analog NRTI (3TC) to suppress replication in both active and resting cells and a protease inhibitor (lopinavir/ritonavir or nelfinavir) or an NNRTI (efavirenz) have been shown to produce prolonged viral suppression. Less potent combinations such as triple NRTIs (abacavir, zidovudine, lamivudine) may be considered in special situations when there are concerns about significant drug interactions or adherence to a complex drug regimen. Combination treatment increases the rate of toxicities (see Table 268-5), and complex drug-drug interactions exist among many of the antiretroviral drugs. Many protease inhibitor drugs are inducers or inhibitors of the cytochrome P450 system and are therefore likely to have serious interactions with multiple drug classes, including nonsedating antihistamines and psychotropic, vasoconstrictor, antimycobacterial, cardiovascular, analgesic, and gastrointestinal drugs (cisapride). Whenever new medications are added to an antiretroviral treatment regimen, especially a protease inhibitor–containing regimen, a pharmacist and/or HIV specialist should be consulted to address possible drug interactions. The inhibitory effect of ritonavir (a protease inhibitor) on the cytochrome P450 system has been exploited, and small doses of the drug are added to several other protease inhibitors (lopinavir, tipranavir, atazanavir) to slow their metabolism by the P450 system and to improve their pharmacokinetic profile. This strategy provides more effective drug levels with less toxicity and less frequent dosing.

Adherence

Adherence to the medications schedules and dosages is fundamental to antiretroviral therapy success. Therefore, assessment of the likelihood of adherence to treatment is an important factor in deciding whether and when to initiate therapy. Numerous studies have shown that compliance of <90% results in less successful suppression of the viral load. In addition, several studies have documented that almost half of the pediatric patients surveyed were nonadherent to their regimen. Poor adherence to prescribed medication regimens results in subtherapeutic drug concentrations and enhances development of resistance. Several barriers to adherence are unique to children with HIV infection. Combination antiretroviral regimens are often unpalatable and require extreme dedication on the part of the caregiver and child; a reluctance to disclose the child’s disease to others reduces social support; there may be a tendency to skip doses if the caregiver is not around or when the child is in school. Adolescents have other issues that reduce adherence. Denial of their infection, unstructured lifestyle, wishing to be the same as their peers, depression, anxiety, and alcohol and substance abuse are just a few of the barriers for a long-term adherence in this growing population. These and other barriers make participation of the family in the decision to initiate therapy essential. Intensive education on the relationship of drug adherence to viral suppression, training on drug administration, frequent follow-up visits, peer support, pager messaging, and commitment of the caregiver and the patient (despite the inconvenience of adverse effects, dosing schedule, and so on) are critical for successful antiviral treatment.

Initiation of Therapy

HIV-infected children with symptoms (clinical category A, B, or C) or with evidence of immune dysfunction (immune category 2 or 3) should be treated with antiretroviral therapy, regardless of age or viral load (see Tables 268-1 and 268-2). Children <1 yr of age are at high risk for disease progression, and immunologic and virologic tests to identify those likely to develop rapidly progressive disease are less predictive than in older children. Therefore, such infants should be treated with antiretroviral agents as soon as the diagnosis of HIV infection has been confirmed, regardless of clinical or immunologic status or viral load. Data suggest that HIV-infected infants who are treated before the age of 3 mo control their HIV infection better than infants whose antiretroviral therapy started later than 3 mo of age. Some of these infants even become HIV seronegative and lose their HIV specific immune response.

There is still a debate on when to start therapy in children older than 1 yr of age. Most guidelines recommend deferring treatment if the CD4 is ≥25% in children 1-5 yr of age or the CD4 count is above 350-500 cells/mm³ in children >5 yr of age, with a viral load of <100,000 copies/mm³ because there are concerns regarding drug adherence, safety, and durability of antiretroviral response. These children should be monitored regularly for evidence of virologic, immunologic, or clinical progression, at which point therapy should be initiated as long as potential adherence issues are addressed. Some clinicians advocate treating such children to prevent the inevitable immunologic deterioration that will otherwise occur.

Dosing

Data on antiretroviral drug dosages for neonates are often limited. Because of the immaturity of the neonatal liver, premature infants and newborns often require an increase in the dosing interval of drugs primarily cleared through hepatic glucuronidation. Children are usually treated with higher doses (per kg weight) than adults due to reduced absorption or increased elimination.

Adolescents should have antiretroviral dosages prescribed on the basis of Tanner staging of puberty rather than on the basis of age. Pediatric dosing ranges should be used during early puberty (Tanner stages I, II, and III), whereas adult dosing schedules should be followed in adolescents in late puberty (Tanner stages IV and V).

Changing Antiretroviral Therapy

Therapy should be changed when the current regimen is judged ineffective as evidenced by increase in viral load, deterioration of the CD4 cell count, or clinical progression. Development of toxicity or intolerance to drugs is another reason to consider a change in therapy. When a change is considered, the patient and family should be reassessed for adherence problems. Because adherence is a major issue in this population, resistance testing (while on antiretroviral medications) is important in identifying adherence issues (e.g., detectable virus sensitive to current drugs) or development of resistance (e.g., evidence of resistance mutations to given drugs). In both situations, other contributing factors such as poor absorption, incorrect dose, or drug-drug interactions should be carefully reviewed. While considering possible new drug choices, potential cross-resistance should be addressed. In addition, few patients who have virologic failure may still demonstrate improved CD4 cell counts (discordant response). Impaired replication ability of the resistant virus and enhanced cytotoxic T lymphocyte (CTL) effects are some of the reasons for this discordant response. In these patients, delay in changing therapy may be considered as long as the immunologic benefit is evident. Ideally, when a decision is made to change the antiretroviral therapy, all drugs should be changed. However, in many situations (previous antiretroviral experience, intolerance, toxicity) this is not possible, and, therefore, at least 2 drugs should be changed based on the resistance mutation genotype (if available) or previous regimen used.

Monitoring Antiretroviral Therapy

Children need to be seen within 1 to 2 wk after initiation of new antiretroviral therapy to assure compliance and to screen for potential side effects. Virologic and immunologic surveillance (using HIV RNA copy number and CD4 lymphocyte count or percentage) as well as clinical assessment should be performed regularly during antiretroviral therapy. Initial virologic response (i.e., at least a 5-fold [0.7 log₁₀] reduction in viral load) should be achieved within 4-8 wk of initiating antiretroviral therapy. The maximum response to therapy usually occurs within 12-16 wk but may be later (24 wk) in very young infants. Thus, HIV RNA levels should be measured at 4 wk and 3-4 mo after therapy initiation. Once an optimal response has occurred, viral load should then be measured at least every 3-6 mo. If the response is unsatisfactory, another viral load should be performed as soon as possible to verify the results before a change in therapy is considered. The CD4 cells respond more slowly to successful treatment and, therefore, can be monitored less frequently. Potential toxicity should be monitored closely for the 1st 8-12 wk, and if no clinical or laboratory toxicity is documented, a follow-up visit every 3-4 mo is adequate. Monitoring for potential toxicity should be tailored to the drugs taken. These toxicities include hematologic complications (e.g., ZDV); hypersensitivity rash (e.g., EFV); lipodystrophy (e.g., redistribution of body fat seen with NRTIs, protease inhibitors); hyperlipidemia (elevation of cholesterol and triglyceride concentrations), hyperglycemia and insulin resistance, and mitochondrial toxicity leading to severe lactic acidosis (e.g., D4T, ddI), ECG abnormalities (e.g., atazanavir, lopinavir), abnormal bone mineral metabolism (e.g., tenofavir), and hepatic toxicity including severe hepatomegaly with steatosis.

Resistance to Antiretroviral Therapy

Young children are at greater risk than adults for developing resistance because they have higher viral loads than adults and are more limited by which ARV options are available. The high mutation rate of HIV (mainly due to the absence of error-correcting mechanisms) severely impairs the success of antiretroviral therapy. Failure to reduce the viral load to <50 copies/mL increases the risk for developing resistance. Even effectively treated patients do not completely suppress viral replication, and persistence of HIV transcription and evolution of envelope sequences continues in the latent cellular reservoirs. The accumulation of resistance mutations progressively diminishes the potency of the antiretroviral therapy and challenges the physician to find new regimens. For some drugs (e.g., nevirapine, 3TC) a single mutation is associated with resistance, while for other drugs (e.g., ZDV, lopinavir) several mutations are needed before resistance develops. Testing for drug resistance, especially when devising a new regimen, is becoming the standard of care. Two types of tests are available. The phenotypic assay measures the virus susceptibility in various concentrations of the drug, and the genotypic assay predicts the virus susceptibility from mutations identified in the HIV genome isolated from the patient. Several studies have shown that treatment success was higher in patients whose antiretroviral therapy was guided by genotype or phenotype testing.

Supportive Care

Even before antiretroviral drugs were available, a significant impact on the quality of life and survival of HIV-infected children was achieved when supportive care was given. A multidisciplinary team approach is desirable for successful management. Close attention should be paid to nutritional status, which is often delicately balanced and may require aggressive enteral supplementation; Painful oropharyngeal lesions and dental caries may interfere with eating, and thus routine dental evaluations and careful attention to oral hygiene should be encouraged. Paradoxically, an increasing number of adolescents with perinatally-acquired or behavioral risk-acquired disease are obese. Some teens experience ARV-related central lipo-accumulation, but others have poor dietary habits and inactivity as the cause of their obesity, in parallel to epidemic obesity in the USA. Development should be evaluated regularly with provision of necessary physical, occupational, and/or speech therapy. Recognition of pain in the young child may be difficult, and effective nonpharmacologic and pharmacologic protocols for pain management should be instituted.

Infants born to HIV-infected mothers should receive ZDV prophylaxis for 4-6 weeks +/− additional ART to prevent transmission. Guidelines for such prophylaxis are updated at least yearly and can be accessed at http://www.aidsinfo.nih.gov/default.aspx. A complete blood count, differential leukocyte count, and platelet count should be performed at 4 wk of age to monitor ZDV toxicity. If the child is found to be HIV-infected or if the HIV status is not clear, these tests should be continued every 1-3 mo to assess the hematologic effect of the disease or its treatment (prophylactic TMP-SMZ and antiretroviral therapy). If the child is found to be HIV infected, baseline laboratory assessment (e.g., CD4 count, HIV RNA, CBC, chemistries) should be done. Viral load and CD4 lymphocyte counts should be performed at 1 and 3 mo of age and should be repeated every 3 mo. The frequency of the test should be increased (every 4-6 wk) if the CD4 lymphocyte count or percentage declines rapidly.

All HIV-exposed and infected children should receive standard pediatric immunizations. In general, live oral polio vaccine should not be given (Fig. 268-3). The risk and benefits of rotavirus vaccination should be considered in infants born to HIV-infected mothers. Because <1% of these infants in developed countries will develop HIV infection, the vaccine should be given. In other situations, the considerable attenuation of the vaccine’s strains should be taken into account and unless the infant has clinical symptoms of AIDS or CD4 <15%, vaccination seems to be appropriate. Other live bacterial vaccines (e.g., bacillus Calmette-Guérin [BCG]) should be avoided due to the high incidence of BCG-related disease in HIV-infected infants. Varicella and measles-mumps-rubella (MMR) vaccines are recommended for children who are not severely immunosuppressed (i.e., CD4 cell percentage ≥15%), but neither varicella nor MMR vaccines should be given to severely immunocompromised children (i.e., CD4 cell <15%). Of note, prior immunizations do not always provide protection, as evidenced by outbreaks of measles and pertussis in immunized HIV-infected children. Durability of vaccine-induced titers is often short, especially if vaccines are administered when the child’s CD4 cell is <15%, and re-immunization when the CD4 count has increased (i.e., >15%) may be indicated.

Figure 268-3 Routine childhood immunization schedule for HIV-infected children.

Prophylactic regimens are integral for the care of HIV-infected children. All infants between 4-6 wk and 1 yr of age who are proven to be HIV-infected should receive prophylaxis to prevent Pneumocystis jiroveci infection regardless of the CD4 count or percentage (see Tables 268-6 and 268-7). Infants exposed to HIV-infected mothers should receive the same prophylaxis until they are proven to be noninfected; however, prophylaxis does not have to be initiated if there is strong presumptive evidence of noninfection (i.e., non–breast-fed infant with 2 negative HIV PCR tests at >14 days and 4 wk of age, respectively). When the HIV-infected child is >1 yr of age, prophylaxis should be given according to the CD4 lymphocyte count (Table 268-6). The best prophylactic regimen is 150 mg/m²/day of trimethoprim component of TMP/SMZ given as 1-2 daily doses 3 days per wk. For severe adverse reactions to TMP/SMZ, alternative therapies include dapsone, atovaquone, or aerosolized pentamidine.

Table 268-6 RECOMMENDATIONS FOR PCP PROPHYLAXIS AND CD4 MONITORING FOR HIV-EXPOSED INFANTS AND HIV-INFECTED CHILDREN, BY AGE AND HIV INFECTION STATUS

AGE/HIV INFECTION STATUS	PCP PROPHYLAXIS	CD4 MONITORING
Birth to 4-6 wk, HIV exposed	No prophylaxis	None
HIV infection reasonably excluded*	No prophylaxis	None
4-6 wk to 4 mo, HIV exposed	Prophylaxis	3 mo
6 wk to 1 yr HIV-infected or indeterminate	Prophylaxis	6, 9, and 12 mo
1-5 yr, HIV infected	Prophylaxis if:	Every 3-4 mo^†
1-5 yr, HIV infected	CD4 <500 cells/µL or <15%
> 6 yr, HIV infected	Prophylaxis if:	Every 3-4 mo^†
> 6 yr, HIV infected	CD4 <200 cells/µL or <15%^‡