AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Over the past 25 years since the first cases of what we now recognize as human immunodeficiency virus (HIV) infection were identified in 1981, the number of children infected with HIV has increased dramatically in developing countries because of the number of HIV-infected women of childbearing age has risen. However, great advances have been made in the United States and in other industrialized nations to control transmission of the virus from mother to infant.

In the United States, universal prenatal HIV testing has been recommended to obstetricians since 1995. However, this testing was not mandatory in all states. In September 2006, the Centers for Disease Control and Prevention (CDC) released its Revised Recommendations for HIV Testing of Adults Adolescents, and Pregnant Women in Health-Care Settings. These new recommendations, which replaced its 1993 Recommendations for HIV Testing Services for Inpatients and Outpatients in Acute-Care Hospital Settings, advise routine HIV screening for adults, adolescents, and pregnant women in healthcare settings in the United States. They also recommend reducing barriers to HIV testing.

Before prenatal testing was common, diagnosing HIV infections in a woman after diagnosing it in her child was not unusual, and the diagnosis of acquired immunodeficiency syndrome (AIDS) in a previously healthy child was not rare.

Before 1985, one way in which children were infected was the transfusion of blood-products. Improved screening tests have eliminated such transmission. A common way adolescents become infected is by engaging in high-risk behaviors such as unprotected intercourse, male homosexual intercourse, and intravenous (IV) drug abuse

In pediatric patients, HIV infection progresses as it does in adults, though recent surveillance data from CDC suggests that patients who are aged 13-24 years when AIDS is diagnosed survive longer than older individuals do. Vertically transmitted HIV can cause rapidly progressive, chronically progressive, or adult-like disease in which a significant clinical latency period occurs before symptoms appear.

Pathophysiology

After HIV enters a host, trimeric gp120 glycoproteins that protrude from its lipoprotein bilayer envelope bind to CD4 cell-surface receptors and CCR5 or CXCR4 chemokine co-receptors. CD4 receptors are located on CD4⁺ T lymphocytes, monocytes, and macrophages. Juxtapositioned co-receptors are also needed for viral infection. The V3 region of the gp120 glycoprotein determines cellular tropism, and tropism is involved in syncytial formation. M-tropic (nonsyncytial) strains prefer the CCR5 co-receptor and are the primary causes of infection. Deficiency of CCR5 chemokine co-receptors is present in as many as 10% of Europeans and 20% of Ashkenazi Jews, and it appears to confer some protection against infection. After gp120 binds to the receptors, an associated gp41 transmembrane glycoprotein is inserted into the cell membrane and initiates cell-membrane fusion.

On entering the cell, the protease enzyme produces the reverse transcriptase and ribonuclease (RNAse) H enzymes responsible for synthesizing the single-stranded DNA (ssDNA) molecules and primers necessary to produce the complementary DNA strand. Because reverse transcriptase lacks proofreading machinery, considerable base-to-base variability results. The high mutation rate, combined with the high reproductive rate, results in substantial evolution and subsequent resistance to treatment.

Acute infection rapidly increases the viral load and causes a mild-to-moderate viremia. Although viral loads tend to diminish rapidly after acute infection in adults, they decrease slowly in vertically infected children and may not reach baseline levels until the children aged 4 or 5 years. Although infants possess numerous antigen-presenting and effector cells compared with adults, their cytokine production, proliferation, and cytotoxicity are reduced.

Envelope-specific cytotoxic T lymphocytes are less common in children who vertically acquire the disease than in children who acquire HIV by means of blood transfusion. Among those with vertically acquired disease, lymphocytes are least common in those with rapidly progressing disease. Precursors of cytotoxic T-lymphocyte that are specific to HIV type 1 (HIV-1) do not develop in significant number until the child is aged 1 year. In adults, antibodies to gp120 develop several months after the initial viremia occurs. The development of broadly neutralizing antibodies is associated with slowed disease progression in adults, children, and infants.

Frequency

United States

In 2002, an estimated 144-246 infants acquired HIV infection by means of vertical (mother-to-infant) transmission. Estimates from 1991 placed the peak of perinatally-transmitted HIV at 1651.

The HIV seroprevalence rate in pregnant women is as high as 0.3%. The seroprevalence of women infected with HIV is highest in the Northeast, followed by the South. Perinatal HIV transmission rates are 25% but as low as 2% in untreated women with viral loads of less than 100 copies/mL.

Although prophylactic interventions have reduced vertical transmissions, cases of perinatal HIV transmission continue to occur. This is largely because of missed opportunities for prevention, particularly among women who lack prenatal care or who are not being offered voluntary HIV counseling and testing during pregnancy. In many as 40% of the mothers of infants with perinatally acquired HIV infection, the HIV infection was not known before delivery.

In the United States, HIV infection is the 14th leading cause of death in young children. In 2004, 61 children with AIDS younger than 13 years died. Minority populations are overrepresented in this epidemic, and HIV infection is the 7th cause of death in the African American population. In the United States, most children with AIDS live in metropolitan areas.

HIV-1 is the most common cause of HIV infection in the Americas, in Europe, in Asia, and in Africa. HIV-1 subtypes differ by geographic region. HIV-1 subtype B is predominant in the United States, though non-B subtype HIV-1 infections are increasing.

International

Almost 40 million individuals are infected with HIV worldwide, and 90% of them are in developing countries. HIV has infected 4.4 million children and has resulted in the deaths of 3.2 million. Each day, 1800 children—the vast majority newborns—are infected with HIV. Approximately 7% of the population in sub-Saharan Africa is infected with HIV; these individuals represent 64% of the world's HIV-infected population. Furthermore, 76% of all women infected with HIV live in this region.

The HIV seroprevalence rate among pregnant women in South America is 0.3-5%; in sub-Saharan Africa, the range is 13-45%. In Europe, the HIV seroprevalence is greatest in western countries; France, Spain, and Italy have the highest incidences. Pregnant women in urban areas of these countries have a seroprevalence rate as high as 1%. Nonetheless, the epidemics in Eastern Europe and in Central Asia continue to grow; the number of people living with HIV in these regions reached an estimated 1.6 million in 2005—an increase of almost 20-fold in less than 10 years. The overwhelming majority of these people living with HIV are young; 75% of infections reported between 2000 and 2004 were in people younger than 30 years. In Western Europe, the corresponding percentage was 33%.

The magnitude of the AIDS epidemic in Asia is significant. Although national HIV infection levels are low in Asia compared with other continents (notably Africa), the populations of many Asian nations are so large that even low prevalences reflect large numbers of people are living with HIV. The seroprevalence rate in pregnant women is already 2%, and the vertical transmission rate is 24% without breastfeeding. Indian mothers infected with HIV routinely breastfeed and have transmission rates as high as 48%.

Perinatal transmission rates are relatively low in Europe and high in Africa, independent of treatment. Untreated women infect 13% and 40% of children in Europe and Africa, respectively. The rate of postnatal transmission in Africa and other developing countries is elevated because of the need to breastfeed.

HIV-1 is the most common cause of HIV infection in the Americas, Europe, Asia, and Africa. HIV type 2 (HIV-2) has caused epidemics in West Africa, though this virus is also found in European countries. HIV-1 subtypes differ by geographic region. Non-B subtypes are particularly prevalent in Africa and in Asia. The high transmission rate from Africa to Europe has increased the diversity of subtypes in Europe.

Mortality/Morbidity

The natural progression of vertically acquired HIV infection appears to have a trimodal distribution. Approximately 15% of children have rapidly progressive disease, and the remainder has either a chronic progressive course or an infection pattern typical of that observed in adults. Mean survival is about 10 years. In resource-poor nations, the progression to death accelerates. In some instances, close to 45-90% of HIV-infected children died by the age of 3 years. However, among children and adolescents, the start of combination therapy including protease inhibitors reduces the risk of death by an estimated 67%. Also, host genetics play an important role in HIV-1–related disease progression and neurologic impairment

The progression and prognosis of children with HIV infection is represented by using CDC classification system. This classification system is outlined in Prognosis.

Race

African American and Hispanic children are disproportionately affected. As of 2002, HIV infection was the 7th and 10th leading cause of death in African American children and in Hispanic teens, respectively. Approximately 62% of children with AIDS are African American.

Sex

Women of childbearing age are one of the fastest growing groups with AIDS; 20% of AIDS cases in adults occur in this group.

Age

• Vertical HIV infection occurs during 1 of 3 periods.
• • Period 1, before birth: The fetus can be hematologically infected by means of transmission across the placenta or across the amniotic membranes, especially if the membranes are inflamed or infected.
  • Period 2, delivery: Most vertical infections occur during delivery, and many factors affect the risk of infection during this period (see Deterrence/Prevention). In general, the longer and the greater amount of contact the neonate has with infected maternal blood and cervicovaginal secretions, the greater the risk of vertical transmission. Premature and low-birthweight neonates appear to have an increased risk of infection during delivery because of their reduced skin barrier and immunologic defenses.
  • Period 3, after birth: Postnatal vertical transmission occurs with the ingestion of HIV in the breast milk.
• The age of presentation can be highly variable in a high-risk child who was previously unidentified.
• • Children can be asymptomatic for many years, and the appearance of an opportunistic infection in a 10-year-old child or in an adolescent in whom AIDS is subsequently diagnosed is not rare.
  • Children who acquire HIV by means of nonvertical transmission may have an illness during the acute phase of the retroviral syndrome, or they may present many years later with opportunistic or recurrent infections.
  • Before 1985, contaminated blood products were the vehicles for transmission in many cases. Now, nonvertically transmitted HIV usually occurs by means of sexual contact and IV drug use.
• The CDC estimates that 50% of all new HIV infections in the United States occur among individuals aged 13-24 years. This is an important statistic that influences the mortality rates in young adults. For example, HIV is the 5th leading cause of death among African American women aged 20-24 years, and it is the principal cause of mortality in African American women aged 25-34 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Infection
• • Immunodeficiency should be suspected in individuals with recurrent bacterial infections (especially invasive infections, eg, bacteremia, meningitis, and pneumonia) and in those with unusual infections, such as those caused by the Mycobacterium avium-intracellulare complex (MAC).
  • Children with human immunodeficiency virus (HIV) infection often present with the common bacterial infections of childhood (eg, otitis media, sinusitis, pneumonia). These can be more frequent and more severe than similar infections in immunologically healthy children.
  • Recurrent fungal infections, such as candidiasis (thrush), that do not respond to standard antifungal agents suggest lymphocytic dysfunction.
  • Recurrent or unusually severe viral infections, such as recurrent or disseminated herpes simplex or zoster infection or cytomegalovirus (CMV) retinitis, are seen with moderate-to-severe cellular immune deficiency.
• Growth
• • Growth failure, failure to thrive, or wasting in the child may indicate HIV infection if other common metabolic and endocrine disorders do not appear to be the etiologies.
  • Growth failure, failure to thrive, or wasting in the patient with HIV infection may signify disease progression or underlying malnutrition.
• Development
• • Failure to attain typical milestones suggests a developmental delay. Such delays, particularly impairment in the development of expressive language, may indicate HIV encephalopathy.
  • The loss of previously attained milestones may signify a CNS insult due to progressive HIV encephalopathy or opportunistic infection.
  • In older children, behavioral abnormalities (eg, loss of concentration and memory) may indicate HIV encephalopathy.

Physical

Few physical findings are specific to HIV infection, and many physical findings are caused by opportunistic infections. Lymphadenopathy, hepatomegaly, and splenomegaly are fairly common in HIV infection. Other findings may include those discussed below. 

• Anthropometric findings
• • Monitoring the patient's growth is one of the most important parts of the physical examination. Anthropometric measurements should be obtained at each visit.
  • Delayed growth in the head circumference is correlated with the development of underlying encephalopathy. However, normal head growth does not help in ruling out encephalopathy, and many patients with a normal head circumference may have radiographic or psychometric findings consistent with encephalopathy.
  • Fat redistribution syndrome in association with lipid abnormalities and insulin resistance is being described in HIV-infected children and adults. Presentations vary (eg, central adiposity vs peripheral fat wasting) and depend on factors such as race and age. Body habitus is altered because of lipoatrophy, lipohypertrophy, or both. Diverse diagnostic criteria have been used. Anthropometric measurements, such as skin-fold thickness and the waist-to-hip ratio, are useful to monitor the progression of changes. Technically sophisticated tools include bioelectrical impedance analysis (BIA), dual-energy X-ray absorptiometry (DEXA), CT, and MRI.
• Head, eyes, ears, nose, and throat (HEENT) findings
• • Parotid enlargement is observed in 30% of children with category C disease and in 15% of children with disease in other categories.
  • Tonsillar hypertrophy may be observed.
  • Aphthous ulcers may be observed.
  • Thrush in the oral cavity and posterior pharynx is observed in approximately 30% of HIV-infect children. In children with AIDS, the prevalence of thrush is correlated with a low CD4⁺ count. Thrush in the posterior pharynx may signify candidal esophagitis, especially in patients with feeding difficulties or retrosternal pain.
  • CMV retinitis occurs in 3.4% of children with CD4⁺ counts of less than 50 X 10⁹/L.
• Cardiac findings
• • Cardiomyopathy may be present.
  • Congestive heart failure may be present.
• Pulmonary findings
• • Lung examination is important, and good documentation of findings is required at each visit.
  • Chronic lung disease may produce baseline findings of crackles and decreased regional breath sounds.
  • Changes in the lung findings are important to note because pneumonia is common in children with HIV infection. Pneumonia may not be obvious during the examination, and many children have few symptoms. For example, Mycoplasma infection may not cause a high temperature, and Pneumocystis jiroveci infection may cause only tachypnea, fever, and hypoxemia.
  • Changing findings at lung examination may also signify worsening of chronic lung disease, lymphoid interstitial pneumonitis, or tuberculosis (TB).
• Abdominal findings
• • Hepatomegaly is observed in 70% and 45% of children with and children without AIDS, respectively.
  • Splenomegaly is observed in about 35% of children with HIV infection.
• Lymphatic findings
• • Generalized cervical, axillary, or inguinal lymphadenopathy is common and may be the first sign of initial infection during the asymptomatic phase of the disease. Generalized lymphadenopathy may not be present with well-controlled disease or end-stage AIDS. New shotty nodes may indicate that the disease has again progressed and that treatment failure has occurred.
  • A single large node may indicate lymphoma, and it may need to be examined with biopsy.
• Neurologic findings
• • Motor delay, hypotonia, hypertonia, and/or pyramidal-tract signs may indicate progressive HIV encephalopathy or opportunistic infection of the CNS.
  • Spastic diplegia and oral motor dysfunction are early signs of encephalopathy.
  • Acquired microcephaly with accompanying cerebral atrophy is a poor prognostic sign.
  • Subacute combined degeneration of the spinal cord with higher cortical dysfunction occurs in vitamin B-12 deficiency.
  • Ischemic and hemorrhagic strokes can occur in children with AIDS, but they seem to be related to infection or other mechanisms other than hypercoagulable states, as in the adult HIV-infected population.
• Skin findings
• • HIV dermatitis causes an erythematous papular rash and is observed in about 25% of children with HIV infection.
  • Vesicular lesions in a unilateral dermatomal distribution or in the oral, genital, or anal area may represent reactivation of herpes zoster.
  • Erythematous candidal dermatitis that does not respond to standard therapy may be present.
  • Bleeding or bruising of the mucous membranes and skin may be observed in children with HIV and immune thrombocytopenic purpura, though this is uncommon.
• Extremity findings
• • Digital clubbing may be observed as a result of chronic lung disease.
  • Nonpitting edema may result from hypoalbuminemia caused by HIV nephropathy or malnutrition.
  • Pitting edema may develop as a result of congestive heart failure.

Causes

Infection is due to HIV, a complex member of the Lentivirus genus of the Retroviridae family.

HIV-1 is the most common cause of HIV infection in the Americas, in Europe, in Asia, and in Africa. HIV-2 has caused epidemics in West Africa, although this virus is also found in European countries. HIV-2 disease progresses more slowly than HIV-1 disease, and HIV-2 is less transmissible than HIV-1.

HIV-1 subtypes differ by geographic region. HIV-1 subtype B is predominant in the United States. Non-B subtypes are particularly prevalent in Africa and Asia. The high transmission rate from Africa to Europe has increased the diversity of subtypes in Europe. Non-B subtype HIV-1 infections are increasing in the United States.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Idiopathic thrombocytopenic purpura

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

Detection of human immunodeficiency virus (HIV)

HIV detection is the first step in the laboratory workup.

Nonquantitative detection of HIV is the first step in diagnosing infectivity. In adults and older children, enzyme-linked immunosorbent assay (ELISA) and Western blotting are used to initially detect HIV-specific antibodies. However, because maternal antibodies are present in neonatal blood, these tests are not used for diagnosis in patients younger than 2 years. A DNA polymerase chain reaction (PCR) and/or viral culturing are the standard detection methods in infants and young children.

HIV DNA PCR is used to detect HIV-1 provirus in mononuclear cells by using oligonucleotides directed at highly conserved regions of the viral genome. This test can be performed within 24 hours of infection and has a sensitivity and a specificity of 95% and 97%, respectively. Although it is more sensitive than viral culturing, the diagnostic performances of the 2 methods are equivalent.

Viral cultures are obtained by co-cultivating potentially infected and uninfected mononuclear cells together to promote viral replication. Every few days, the culture is assayed for HIV p24 antigen. Positive results on 2 sequential p24 antigen detection assays indicate infection. This technique requires a mean of 7-14 days to perform, but it may require as long as 28 days.

A positive virologic result should be confirmed with repeat virologic testing with a second specimen as soon as possible after the first result is available.

ELISA for HIV antibody, followed by a confirmatory Western blot (which has increased specificity), should be used to diagnose HIV infection in older children and adults.

Rapid HIV tests, which provide results in minutes, simplify and expand the availability of HIV testing. Their sensitivity is as high as 100%, but they must be followed with confirmatory Western blotting or immunofluorescence antibody testing, as with conventional HIV antibody tests. The U.S. Food and Drug Administration (FDA) has approved 4 rapid HIV screening tests that are available commercially in the United States, as listed below. Before the FDA approved of these tests, the most commonly used rapid HIV test was the Single-Use Diagnostic System (Murex SUDS; Abbott Diagnostics, Abbott Park, IL), which is no longer available.

1. OraQuick (and its newer version OraQuick Advance) Rapid HIV-1/2 Antibody Test (OraSure Technologies, Inc, Bethlehem, PA)
2. Reveal G3 Rapid HIV-1 Antibody Test (MedMira Laboratories, Inc, Halifax, Nova Scotia, Canada)
3. Uni-Gold Recombigen HIV Test (Trinity Biotech, Bray, Ireland)
4. Multispot HIV-1/HIV-2 Rapid Test (Bio-Rad Laboratories, Redmond, WA)

HIV RNA assays are used to detect extracellular viral RNA in the plasma and are as sensitive as HIV DNA PCR for early diagnosis of HIV infection in exposed infants. However, these are not the preferred methods of diagnosis in infants perinatally exposed because they may falsely indicate low viral loads in individuals who are HIV negative. Also, whether antenatal treatment of the mother with combination antiretrovirals and/or antiretroviral prophylaxis in the infant affects the sensitivity of RNA assays is unknown.

The FDA has approved the APTIMA HIV-1 RNA Qualitative Assay (Gen-Probe Incorporated, San Diego, CA). This assay enables people to learn with certainty whether are infected within a few days rather than up to 6 months, as with an HIV antibody test. Unlike some approved antibody tests, the APTIMA assay is intended to detect only HIV-1 and not HIV-2. The test could become a potential alternative to traditional Western blotting now used to confirm HIV-1 infection when screening results for HIV antibodies are positive. The APTIMA assay is approved for the diagnosis of primary HIV-1 infection for for confirming HIV-1 infection when antibody results are positive.

Quantification of viral load

The viral load can be quantified by using several HIV assays. The number of virions in the peripheral blood is an important indicator of disease activity and of the effectiveness of antiretroviral therapy (ART). A 5- or 3-fold change in the viral load is needed to reliably indicate a clinically significant change in children younger than 2 years or older than 2 years, respectively.

Certain viral-load tests are not sensitive to non-B subtypes of HIV-1. Therefore, viral loads can seem to be considerably reduced if these tests are used to process samples of non-B subtypes.

Reverse-transcription PCR (RT-PCR) and nucleic acid sequence—based amplification (NASBA) of plasma RNA reveal a viral load 2 times that obtained with the branched-chain DNA (bDNA) method. The former methods are sensitive to only HIV-1 subtype B viruses, whereas the bDNA method is sensitive to other HIV-1 subtypes. Switching test methods during treatment is not advised because their molecular technologies differ.

Initial infection is associated with high viral loads, especially in the neonate. In adults and adolescents with nonvertically acquired infections, the viral load rapidly decreases 6-12 months after the primary viremia. Neonates have high viral loads that persist throughout infancy; therefore, these values are hard to interpret in the first year of life. In children with vertically acquired infections, the load slowly declines after they are aged 1 year. The predictive value of specific HIV RNA concentrations for disease progression and death for an individual child is moderate.

Assays for viral resistance

Viral resistance may be present.

Both primary and secondary mutations can develop. Primary mutations alter the effectiveness of ART. Secondary mutations improve viral survival.

Both genotypic and phenotypic assays can be performed. Genotypic assays are fast and available, but they reveal only known mutations, and they cannot be used to predict complex interactions when several antiretroviral drugs (ARDs) are used together. Automated recombinant phenotypic assays are commercially available, but the results require additional time to be ready, and the tests are expensive. However, these assays can be used to detect complex interactions between ARDs and quasispecies, to perform in vitro drug trials, and to measure ART inhibitory concentrations.

Genotype or phenotype assays performed before a start or a change in therapy can help in preventing drug resistance.

Genotype and phenotype assays may not be useful for detecting minor quasispecies, and treatment failure occurs despite the use of these techniques.

Development of resistance to 1 or more of the drugs in a combination regimen is often the cause for viral rebound. Numerous clinical trials have demonstrated the clinical utility of ARD-resistance testing in selecting an alternate effective combination and in improving clinical outcomes.

Hematology

Hematologic laboratory values may be assessed.

The CD4⁺ lymphocyte count is a surrogate marker for disease progression and should be monitored closely. The CD4⁺ count should be obtained before therapy. A rapid decrease in the count, especially in infants younger than 1 year, is a poor prognostic sign and should prompt the start or alteration of therapy.

Consumptive thrombocytopenia is a common finding in children with HIV infection and may be observed in 10% of patients at initial diagnosis.

Anemia occurs in as many as 20% of patients at diagnosis and occurs in as many as 80% of patients at some time. Anemia can have many etiologies in HIV infected individuals and requires a workup as described in Medical Care.

A high mean corpuscular volume (MCV) is most commonly caused by zidovudine and can be used to verify compliance. Other medications also cause a high MCV, as well as vitamin B-12 and folate deficiencies.

Anemia continues to predict decreased survival even with highly active ART (HAART).

Pancytopenia results from folate deficiency, use of pharmaceutical agents, and infections with viruses such as parvovirus B19.

Neutropenia is observed in 10% of patients with early asymptomatic HIV infections and in 50% of patients with AIDS.

Blood smears may reveal large ovalocytes and hypersegmented polymorphonucleocytes in cases of folate deficiency.

Other clinical laboratory tests

Serum electrolytes should be monitored on a regular basis because medications or HIV infection may induce nephrotoxicity.

GI function should be monitored. Liver function can be impaired as a result of medication, HIV, or opportunistic infections. Transaminase levels should be monitored. Pancreatitis can be the result of medication, HIV or opportunistic infections. Amylase and lipase levels should be monitored.

Parotiditis (parotitis) is not uncommon, and amylase levels should be followed up if parotiditis is suspected or if the patient has a history of the condition.

Quantitative immunoglobulin levels should be followed up periodically. Hyperimmunoglobulinemia is associated with disease progression. Hypoimmunoglobulinemia is observed in end-stage disease and is associated with a poor prognosis.

Imaging Studies

• Brain CT scanning: Images may demonstrate degeneration of the white matter, atrophy, and/or calcifications of the basal ganglia with progressive HIV encephalopathy.
• Renal ultrasonography
• • HIV nephropathy increases the size and echogenicity of the kidneys, with a loss of cortical medullary differentiation.
  • Renal cysts are observed with an increased incidence.
• Renal CT scanning: Stasis of urine in the pyramids is observed in patients with HIV nephropathy. This finding, combined with characteristic renal ultrasound findings, is specific for HIV nephropathy.
• Renal scintigraphy with technetium-99m mercaptoacetyltriglycine (^99mTc MAG3)
• • Delayed elimination of the tracer and increased residual activity consistent with tubular dysfunction is observed in HIV nephropathy, and it is correlated with creatinine clearance.
  • Delayed uptake and elimination of the tracer indicates end-stage disease.
• Renal gallium scanning: Increased signal indicates inflammation in patients HIV nephropathy and is correlated with proteinuria.
• Abdominal ultrasonography: Calcifications in the liver, spleen, or kidney are observed with P jiroveci pneumonia (PCP) and with MAC, Bartonella, and/or Histoplasma infections.
• Abdominal CT scanning: Mesenteric adenopathy can be observed with MAC infections.

Histologic Findings

A lipid bilayer envelope surrounds the cylindrical core of HIV that contains the RNA genetic information and the machinery that promotes viral replication and integration during initial cellular infection. From the outside, the virion appears spherical, with a diameter of 110 nm.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Overview of ART

ART is the mainstay in human immunodeficiency virus (HIV) treatment.

The inadequacy of merely reducing the viral load has been realized in recent years. Quick suppression of the viral load with HAART substantially slows viral replication and prevents resistant mutations.

Most patients with vertically acquired HIV are treated regardless of their immune status. Most infants younger than 1 year should be treated aggressively. Pediatric HIV experts agree that infected infants with clinical symptoms of HIV disease or with evidence of immune compromise should be treated. However, treatment of asymptomatic infants with normal immunologic status (CD4⁺ cells ≥25%) is still controversial. Therapy may be deferred in children older than 1 year, but any progression of disease is an indication to begin HAART.

Initial therapy should be started with a combination of three drugs, including a backbone of 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor.

Initial NRTI combinations may include zidovudine with didanosine or lamivudine; didanosine plus lamivudine may also be used. Although experience with emtricitabine is relatively limited, it can be substituted for lamivudine, as it is similar to this latter drug and as it offers the convenience of once-daily administration.

Close monitoring to determine if the child is tolerating this new regimen and to answer any questions the caregiver may have are essential to the success of these therapies. At 4-8 weeks after the start of therapy, the CD4⁺ count and/or percentage and HIV RNA levels should be reassessed, and laboratory evaluations for toxicity should be done.

The main goal of therapy is to lower HIV RNA to undetectable levels, though not all infants will achieve. Some have a 10- or 5-fold decrease in the viral load.

Reduction in the mortality rate associated with perinatally acquired HIV-1 over the past 10 years is a result of improved ART. However, only triple combination therapy (as described above) appears to significantly reduce the relative hazard ratio of death, as compared with no treatment.

Drug interactions with ARDs

ARD regimens often contain 3 or more agents. In addition, other drugs are typically required to manage the numerous infectious and systemic consequences of AIDS. Therefore, the likelihood of drug interactions increases. The outcome of the drug interactions may reduce or eliminate the efficacy or increase the toxicity of 1 or both drugs. A thorough understanding of the mechanisms of interactions is essential to minimize or prevent adverse effects and to prevent inadequate treatment.

Regarding the mechanisms, drug interactions are classified as pharmacokinetic or pharmacodynamic. Pharmacokinetic interactions alter drug absorption, distribution, or elimination (metabolism, excretion). Pharmacodynamic alterations manifest as additive, synergistic, or antagonistic drug effects. Several antiretroviral drugs may affect or be affected by absorption kinetics. Didanosine contains an aluminum and magnesium buffer that may affect the absorption of other drugs (eg, ciprofloxacin). Delavirdine is poorly absorbed when the pH of the GI tract increases.

Many ARD pharmacokinetic interactions alter the cytochrome P450 (CYP) metabolic enzyme system. Cytochromes are metabolic enzymes in the liver, and CYP denotes the specific enzyme. The CYP system is classified into families described with numbers. Three of these families are important in humans: CYP1, CYP2, and CYP3. Further delineation into subfamilies is denoted with a capital letter (eg, CYP3A). The nomenclature is completed with the description of individual proteins called isoenzymes, which are delineated with a second number (eg, CYP3A4).

Drugs may be substrates, inhibitors, and/or inducers of particular isoenzymes. Substrates are metabolized by means of the CYP system. They may also be classified as inhibitors (ie, those with reversible and competitive action that decreases metabolism) and/or inducers (ie, those with reversible and competitive action that increases metabolism). Inhibitors decrease hepatic metabolism of isoenzyme substrates (ie, increase serum concentrations), whereas inducers increase this metabolism (ie, decrease serum levels).

All currently approved protease inhibitors and NNRTIs are metabolized in the CYP system, principally by the 3A4 isoenzyme. Some also induce or inhibit CYP3A4, respectively decreasing or increasing serum levels of the 3A4 substrate. Strong inhibitors (eg, ritonavir) have been used in small doses to increase drug levels (eg, of the lopinavir-ritonavir combination), to enhance the efficacy of those drugs with a low enough dose to limit the risk of adverse effects.

The effects of NRTIs, protease inhibitors, and NNRTIs can be found in the supplementary material, Antiretroviral agents.

Drug interactions among antiretroviral agents may be used to increase and sustain serum levels of one another, enhancing efficacy and decreasing adverse effects (eg, Kaletra combination product of lopinavir and ritonavir). Other interactions may decrease levels, causing concern about sufficient efficacy. Supplementary material, Drug Interactions with Antiretroviral Agents, highlights these drug interactions and includes recommendations supported with sufficient data.

Abbreviations for antiretrovirals are listed in Drug Interactions with Antiretroviral Agents.

Common ARTs

Common antiretroviral therapies include the following regimens:

• Zidovudine plus lamivudine, didanosine, or emtricitabine plus lopinavir-ritonavir or nelfinavir
• Didanosine plus lamivudine or emtricitabine plus lopinavir-ritonavir or nelfinavir
• Zidovudine plus lamivudine, didanosine, or emtricitabine plus nevirapine or efavirenz
• Didanosine plus lamivudine or emtricitabine plus nevirapine or efavirenz

Avoid using the following drugs together:

• Zidovudine and stavudine: Zidovudine inhibits phosphorylation of stavudine, decreasing its effectiveness.
• Zalcitabine and didanosine, stavudine, or lamivudine: Lamivudine decreases phosphorylation of zalcitabine, whereas stavudine and didanosine have additive peripheral neuropathic effects.
• Lamivudine and emtricitabine: Both drugs have similar resistance patterns and no additive benefit.

Indications to change ART therapy include the following:

• Developmental regression
• New neurologic symptoms
• Growth failure
• Clinical disease progression
• Declining immunologic function
• Increasing viral load
• No decrease in viral load compared with that at therapy initiation

Treatment for patients at risk for vertical acquisition

Within 6-12 hours of the delivery of a neonate at risk, zidovudine therapy should be started after a baseline CBC count is obtained. Zidovudine should be continued until the infant is aged 6 weeks, when it may be discontinued if all DNA HIV PCR results are negative. If HIV infection is confirmed in the infant, zidovudine must be stopped immediately to abort monotherapy.

PCP prophylaxis should be started in all infants aged 6 weeks who were born to HIV-infected mothers. It should be continued until HIV infection has been ruled out.

DNA HIV PCR or viral cultures are used to detect infection during the first 18 months of a child's life. DNA HIV PCR is as accurate as and less costly than viral culture. DNA HIV PCR should be performed in neonates at birth and in infants at the ages of 1-2 weeks, 4-8 weeks, and 3-6 months. Within the first 48 hours, 14 days, and 4 weeks of life, 38%, 93%, and 96% of infected children, respectively, have positive HIV DNA PCR results. Any positive HIV DNA PCR finding should be confirmed with follow-up HIV DNA PCR before infection is diagnosed.

HIV infection can be ruled out if one of the following is true:

• DNA HIV PCR results are consistently negative in an infant older than 4 months in the absence of breastfeeding.
• Two DNA HIV PCR results obtained at least a month apart are negative in an infant older than 6 months.

Treatment for hematopoietic disturbances: thrombocytopenia

Thrombocytopenia is common in HIV infection, and platelet production generally decreases regardless of the platelet count. Immune-mediated platelet destruction develops in approximately 20% of children with HIV infection. In children with advanced disease, severe thrombocytopenia may need to be managed.

The platelet count may transiently increase with IV immunoglobulin (IVIG), interferon (IFN)-alfa, corticosteroids, or anti-Rh immunoglobulin. IVIG is the treatment of choice. Regimens include IVIG 1-2 g/kg/day for 2-5 days. Three million units of IFN-alfa administered 3 times per week increases the platelet count in 50% of adults after 3 weeks. A 4-week course of prednisone 1-2 mg/kg followed by a 2- to 4-week taper is an alternative, but the immunosuppressive adverse effects must be considered carefully.

Anti-Rh immunoglobulin is useful in Rh-positive patients who have not undergone splenectomy, and it is relatively inexpensive. A 1- to 2-g decrease in the hemoglobin level occurs and must be considered. %his effect limits use of this therapy in patients with anemia. In most patients, 25 mcg/kg administered IV on 2 consecutive days with repeated doses of IV anti-Rh or intramuscular (IM) anti-D every 2-4 weeks increases the platelet count. As an alternative, 6-13 mcg/kg IM administered every week also produces a reasonable increase in the platelet count.

More permanent therapy than these are treatment with zidovudine or danazol or splenectomy. In most adults, high-dose zidovudine can reverse HIV-related idiopathic thrombocytopenia purpura (HIV-ITP). Treatment of HIV infection, especially with zidovudine, appears to improve the platelet count and platelet production. In adults, danazol 400-800 mg every day increases the platelet count in 1-2 months. Splenectomy is an effective long-term treatment. Although splenectomy is not associated with an increased mortality rate, the risk of fulminant infections with encapsulated bacteria increases.

Iatrogenic anemia is not uncommon, and HIV infection often suppresses bone marrow, serum erythropoietin levels, and responses of the bone marrow to erythropoietin. An infectious or neoplastic agent may cause new-onset anemia. A standard workup for anemia should be performed along with a determination of the erythropoietin level, reticulocyte count, and indirect bilirubin level.

A high reticulocyte count indicates a good bone marrow response. When accompanied by a high indirect bilirubin level, hemolytic anemia should be suspected. In the setting of glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, sulfonamides, dapsone, or oxidant drugs can cause iatrogenic erythrocyte hemolysis. A low indirect bilirubin level indicates a response to acute blood loss or recent replacement of a necessary cofactor.

Disseminated intravascular coagulation and thrombotic thrombocytopenic purpura can cause hemolytic anemia and are associated with thrombocytopenia and fragmented RBCs on smears.

Although the prevalence of erythrocyte autoantibodies is high in HIV-infected patients, especially those with hypergammaglobulinemia, the rate of hemolysis by this mechanism is low.

Hemophagocytic syndrome occurs when macrophages in the bone marrow phagocytose erythrocytes.

A low reticulocyte count indicates bone marrow suppression or ineffective erythropoiesis. Vitamin B-12 or folic acid deficiency produces a high MCV and indirect bilirubin level. Patients with HIV are especially at risk for these deficiencies because of poor nutrition and poor small-bowel function. As many as 33% of patients with HIV have a negative vitamin B-12 balance. Folic acid deficiency causes the production of large oval erythrocytes, hypersegmented polymorphonucleocytes, and pancytopenia. Vitamin B-12 deficiency causes subacute combined degeneration of the spinal cord with high cortical dysfunction. Before treatment is started with supplemental parenteral vitamin B-12 and enteral folic acid, serum folate and vitamin B-12 levels must be measured.

A low or normal indirect bilirubin value suggests secondary myelosuppression.

A high MCV indicates iatrogenic pharmaceutical suppression of erythropoiesis. A low MCV suggests iron deficiency anemia. A normal MCV suggests HIV anemia, anemia related to chronic disease, an infectious etiology, or neoplastic marrow invasion.

Parvovirus B19 and many pharmaceutical agents cause neutropenia in addition to anemia.

Ancillary hematologic laboratory tests may help clarify the differential diagnosis, and an investigation of an infectious etiology may be warranted if the CD4⁺ count is low.

Several etiologies may be involved, resulting in laboratory values that may not be correlated with a particular type of anemia. Clinical evaluation and correlation with laboratory values is necessary. Bone marrow biopsy may be necessary if laboratory and clinical findings are inconclusive.

Serum erythropoietin levels of less than 500 IU/L and anemia due to bone marrow suppression as a result of infection, inflammation, or pharmaceutical agents should be managed with erythropoietin. Other causes of anemia must be ruled out and managed before erythropoietin is given. Erythropoietin should be started at a dosage of 100 U/kg given subcutaneously 3 times per week; this may be increased to 200 U/kg/dose. After the hematocrit returns to normal, dosing should be decreased to once every week or every other week to maintain a stable hematocrit. Adverse effects include pain at the injection site and fever. Supplemental iron should always be given with erythropoietin therapy.

Treatment for hematopoietic disturbances: neutropenia

Neutropenia is relatively common in advanced disease and creates a clinically significant risk for infection. In 25% of patients with moderate neutropenia, bacterial infections develop, most often within 24 hours of the onset of neutropenia. The following myelosuppressive drugs—especially zidovudine, trimethoprim-sulfamethoxazole, and ganciclovir—can induce neutropenia:

• Zidovudine
• Lamivudine
• Didanosine
• Stavudine
• Ganciclovir
• Valganciclovir
• Foscarnet
• Flucytosine
• Amphotericin
• Sulfonamides
• Trimethoprim, trimethoprim-sulfamethoxazole
• Pyrimethamine
• Pentamidine

Infectious agents such as parvovirus B19 can cause myelosuppression, as can invasive neoplastic processes of the marrow.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) are used to treat neutropenia and to promote granulocyte production and function. GM-CSF has more adverse effects than G-CSF, and it promotes viral replication. However, GM-CSF does not increase the viral load if it is used with ART.

G-CSF is started at a dosage of 5 mcg/kg/day, and it is given until neutropenia resolves. Titration to once or twice per week is typical. Adverse effects of G-CSF are minimal and include bone pain and elevations in lactate dehydrogenase (LDH) and alkaline phosphatase levels. GM-CSF is started at a dosage of 5 mcg/kg/d given subcutaneously for 5 days and then titrated to effect. Adverse effects include flulike symptoms, myalgias, bone pain, fatigue, and fever.

Surgical Care

• Children who require long-term parenteral medication may need a central venous access line. Placement of subcutaneous ports are common in children requiring long-term parenteral therapy, but the risks of placing such a line should be weighed against the possible need for recurrent replacement because of repeated line infections.
• Gastrostomy placement may be necessary in children who cannot take oral medications or who cannot achieve adequate nutrition by mouth. Gastrostomy tubes are well tolerated, and they are often more comfortable than nasogastric or nasojejunal tubes.
• A biopsy sample should be taken from enlarged lymph nodes of undetermined cause, especially if they are singular, hard, nonmotile, or unaccompanied by generalized lymphadenopathy.

Consultations

• An infectious disease specialist is usually the primary care provider who coordinates the care of the other specialists.
• In general, assembling a team of specialists is the best approach for managing the medical care of a child with HIV infection.
• A human development specialist, a nutritionist, a psychologist, and a case manager should be involved in the treatment of every child with HIV infection.
• A cardiologist, an endocrinologist, a gastroenterologist, a nephrologist, a neurologist, a pulmonologist, and mental health specialists should be consulted when necessary.

Diet

• Malnutrition with an accompanying failure to thrive is not uncommon in children infected with HIV.
• The patient's dietary habits should be reviewed on a regular basis, and a nutritional specialist should be involved in the patient's treatment.
• Poor appetite results in poor nutritional intake. Appetite stimulants can be useful.
• High-energy, high-protein nutritional supplements are commonly needed. Caretakers must be instructed to avoid giving the child any food or water that has a high risk of being contaminated with any infectious agent. HIV and accompanying opportunistic infections can worsen GI symptoms.
• Nasogastric, nasojejunal, and/or gastrostomy tubes may be needed to support the patient's nutritional and fluid status.
• Parenteral hyperalimentation may be necessary when the patient's GI tract cannot support substantial feedings.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Antiretroviral agents inhibit reverse transcriptase. Therefore, they cause chain termination when they are incorporated into a growing viral strand. ARDs are used in combination for the treatment of human immunodeficiency virus (HIV) infection and for postexposure prophylaxis (PEP). Agents in this class are NRTIs (eg, zidovudine, abacavir, didanosine, lamivudine, stavudine, zalcitabine), protease inhibitors (eg, indinavir, nelfinavir, ritonavir, saquinavir), NNRTIs (eg, delavirdine, efavirenz, nevirapine), and fusion inhibitors (eg, enfuvirtide). ARDs that inhibit reverse transcriptase act by preventing spread of the virus to uninfected cells, whereas protease inhibitors act during a late stage of viral replication, preventing the maturation of the viral particle to an infective form.

Zalcitabine (Hivid) is currently being phased out of distribution by its manufacturer, and it will no longer be available.

Monotherapy with an antiretroviral has failed to produce sustained clinical benefits, such as improved survival. This failure is partly due to the development of drug-resistant variants of HIV. Resistance develops rapidly during monotherapy, and cross-resistance among related drugs is reported.

Combination therapy with ARDs (a strategy analogous to the treatment of TB and other infectious diseases) has improved efficacy, minimized toxicity, and delayed drug resistance.

Initial therapy should be started with a combination of 3 drugs, including a backbone of 2 NRTIs plus an NNRTI or a protease inhibitor.

Treatment guidelines from the CDC change constantly. The most current guidelines may be viewed at the AIDS Info Web site, a service of the U.S. Department of Health and Human Services.

In addition, the CDC recently updated its recommended basic and expanded HIV PEP regimens. For details, see the Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HIV and Recommendations for Postexposure Prophylaxis. An overview of these recommendations for PEP is summarized below.

• Basic PEP 2-drug regimen - Zidovudine plus lamivudine, zidovudine plus emtricitabine, tenofovir plus lamivudine, or tenofovir plus emtricitabine
• Alternative basic PEP regimen - Lamivudine plus stavudine, lamivudine plus didanosine, emtricitabine plus stavudine, or emtricitabine plus didanosine
• Expanded PEP regimen - Basic PEP regimen plus lopinavir-ritonavir
• Alternative expanded PEP regimen - Basic PEP regimen plus 1 of the following:
  
  
  • Atazanavir with or without ritonavir
  • Fosamprenavir with or without ritonavir
  • Indinavir with or without ritonavir
  • Saquinavir with or without ritonavir
  • Nelfinavir
  • Efavirenz

Use of nevirapine for PEP is generally not recommended because of a risk of early onset rash and severe hepatotoxicity.

For additional information, see the supplementary material about Antiretroviral Agents, Drug Interactions with Antiretroviral Agents, and Use of Antiretroviral Drugs in Pregnancy.

Drug Category: NRTIs

These are nucleoside or nucleotide (nucleotide reverse transcriptase inhibitor [NtRTI]) analogs with antiviral activity. They are indicated for the treatment of HIV infection, and they delay the progression of the disease.

Drug Category: NNRTIs

NNRTIs inhibit both DNA- and RNA-directed polymerase functions of HIV-1 reverse transcriptase. The different sites of action of nonnucleoside and nucleoside inhibitors suggests potential synergistic effects of these agents and their potential activity against nucleoside-resistant HIV strains.

Drug Category: Protease inhibitors