Pathogenesis

HIV is a lentivirus that infects humans chronically, progressively damaging the hosts’ immune systems. Two viral types have been characterized in humans: HIV type 1 (HIV-1) and HIV type 2 (HIV-2). Based on viral genetic sequences, HIV-1 isolates have been classified into three groups (M, N, and O). The majority of HIV-1 strains identified worldwide belong to group M. Group M (“main group”) is classified into a number of subtypes (also termed clades). The subtypes are designated by letters (A, B, C, D, F, G, H, J, and K).

HIV begins its life cycle after entry into the human body when it binds to CD4 receptors and one of two co-receptors (CCR5 or CXCR4) on CD4+ T-lymphocytes and other receptor-containing cells. Binding to appropriate receptors allows the virus to fuse with the host cell, releasing viral RNA and enzymes into the host cell. The genetic material of HIV is single-stranded RNA. The virus also contains three enzymes that are essential to its replication: reverse transcriptase, integrase, and protease. Reverse transcriptase converts the single-stranded RNA into double-stranded DNA. Reverse transcriptase is a “low-fidelity” enzyme, meaning it is prone to making errors. On average, it inserts the wrong base into the growing cDNA chain at least every 4000 bases, producing mutated viral quasispecies. Over time, each infected individual accumulates a number of quasispecies that become “archived” within the host genome. The existence of drug-resistant quasispecies also creates a therapeutic challenge.

After reverse transcription, the double-stranded DNA enters the host cell’s nucleus, where viral integrase facilitates its integration into the host DNA. The integrated HIV DNA is referred to as a provirus. The provirus can remain inactive for years. Activation of the cell induces transcription of proviral DNA into mRNA. The mRNA migrates into the cytoplasm, where viral proteins are produced by the host cell. The viral protease cleaves the large viral proteins into smaller pieces to create the infectious virus. Two viral RNA strands and the replication enzymes are then surrounded by a capsid of core proteins. The viral capsid acquires a glycopeptide-studded envelope during budding from the host cell. These HIV glycoproteins are necessary for the virus to bind to CD4 and co-receptors. The process of viral replication leads to death of the host cell.

As many as 10 billion HIV virions are produced daily in a single human host. Untreated people typically have 10³ to 10⁶ virions per milliliter of plasma. The concentration of virus in lymph nodes is usually two to three orders of magnitude higher than in plasma. The amount of virus in the plasma is measured using quantitative HIV RNA polymerase chain reaction (PCR) tests, also called “viral loads.” Antiretroviral treatment aims to halt HIV replication and get the viral load down to undetectable levels.

Diagnosis

Within 6 to 12 weeks of infection with HIV, people produce HIV-specific antibodies, detectable by commercially available assays. Adults and children older than 18 months of age are typically tested for HIV with antibody-based assays such as rapid HIV immunoassays (“rapid test” or enzyme immunoassay [EIA]) and enzyme-linked immunosorbent assay (ELISA). A positive rapid test or ELISA result is usually confirmed with a Western blot test. These antibody tests are positive in virtually all HIV-infected individuals after the first 3 months of infection. The period during which the person is HIV infected but does not have detectable antibodies is referred to as the window period. With the currently available antibody assays, antibodies to HIV are usually detectable by 4 to 6 weeks after infection.

Babies born to mothers with HIV are considered to be HIV exposed and need to undergo testing for HIV. HIV-exposed babies will have positive HIV antibody test results, even if the infants are not HIV infected. Maternal anti-HIV immunoglobulin G (IgG) antibodies cross the placenta and can be detected in babies born to mothers who carry the HIV antibodies. On average, maternal antibodies to HIV persist in the infants for the first 9 to 18 months of life. Therefore, virologic tests are used to confirm the presence of HIV infection in babies who are younger than 18 months of age. Most commonly, HIV DNA PCR or HIV RNA PCR is used for diagnosis during this time. Negative (DNA or RNA) PCR test results done at 1 month and 4 months of age can rule out HIV infection in perinatally HIV-exposed babies who are not breastfeeding. HIV viral culture and p24 antigen assays may also be done for diagnosis but are considered less sensitive and specific than RNA and DNA PCR tests. Early negative HIV virologic test results can be confirmed by obtaining a negative antibody-based test result around 18 months of age.

Table 95-1 summarizes the expected results of HIV diagnostic tests for HIV-exposed and -infected infants and adolescents. Children older than the age of 18 months would have the same test results as adolescents in the same infection or exposure category.

Clinical Manifestations of Hiv Infection

The process of HIV replication leads to depletion of CD4+ T lymphocytes. The degree of immunologic suppression is classified based on the number and percent of CD4+ T lymphocytes present in the bloodstream. In young children, the normal number of CD4+ T lymphocytes is much higher than in adults. Therefore, age-specific absolute CD4+ T lymphocyte count ranges should be used to determine the degree of immune suppression in children. CD4+ T lymphocyte percents change less with age and can be used instead of absolute counts to classify the degree of immune suppression in HIV-infected children (Table 95-2).

Along with depletion of CD4+ T lymphocytes, HIV infection leads to functional defects in existing CD4+ T-lymphocytes and defects in B-cell function. These combined immunosuppressive processes lead to a number of clinical manifestations. The most severe and common of these manifestations are outlined in Table 95-3. Opportunistic infections, cancers, hematologic aberrations, and other noninfectious manifestations are among the most severe AIDS-defining conditions.

Table 95-3 Selected Clinical Manifestations of HIV Infection

Severe Manifestations	Description
Pneumocystis jiroveci pneumonia	Definitive diagnosis via microscopy of induced sputum or BAL
Multiple or recurrent serious bacterial infections	Septicemia, pneumonia, meningitis, bone or joint infection, internal organ infections
Kaposi’s sarcoma	Characterized by pink or purple lesions on the skin and soft tissues; diagnosis is confirmed with biopsy
Lymphoma	Cerebral or B-cell non-Hodgkin’s lymphoma
Mycobacterial infections	Extrapulmonary mycobacterium tuberculosis infection and nontuberculous mycobacterial infections
HIV encephalopathy	Failure to attain or loss of developmental milestones or loss of intellectual ability, impaired brain growth, or acquired symmetric motor deficits lasting for >2 mo without a cause other than HIV
HIV wasting syndrome	Unexplained severe wasting, stunting, or severe malnutrition not adequately responding to standard therapy
Severe herpes simplex infections	Bronchitis, pneumonitis, esophagitis (or mucocutaneous ulcer persisting >1 mo)
Severe candidiasis	Esophageal or pulmonary (including bronchi and trachea)
Moderately Severe Manifestations
Single episode of serious bacterial infection	Septicemia, pneumonia, meningitis, bone or joint infection, internal organ infections
Lymphoid interstitial pneumonitis	Definitive diagnosis via biopsy but characterized by chronic bilateral reticulonodular interstitial pulmonary infiltrates and hypoxemia
Recurrent or chronic diarrhea	Persistent ≥14 days
Anemia, neutropenia, or thrombocytopenia persisting ≥30 days	Anemia: hemoglobin <8 g/dL Neutropenia: ANC <1000 cells/mm3 Thrombocytopenia: platelets <100,000 cells/mm3
Herpes zoster	At least two distinct episodes or more than one dermatome
Herpes simplex virus	Recurrent stomatitis (>two episodes in 1 year)
Complicated varicella	Disseminated or severe chicken pox
Candidiasis	Oropharyngeal lasting for >2 mo
Mild Manifestations
Lymphadenopathy	≥0.5 cm at more than two sites
Recurrent or persistent upper respiratory tract infections	Including sinusitis or otitis media
Hepatosplenomegaly	Unexplained, persistent
Mucocutaneous lesions	Extensive wart virus infection, extensive molluscum contagiosum, popular pruritic eruptions, recurrent oral ulcers

ANC, absolute neutrophil count; BAL, bronchoalveolar lavage.

Treatment

Before antiretroviral drugs were available, care for children with HIV focused on prevention and management of HIV-related complications and palliative care. When the first antiretroviral drugs became available in the early 1990s, significant clinical and immunologic benefits were seen. Initially, monotherapy was used. Later, two-drug combinations were introduced. Unfortunately, these had limited durability because viral mutations rapidly led to formation of resistance to the therapies. Currently, combinations of at least three drugs from two different drug classes are recommended for HIV treatment. These combinations are referred to as HAART. Excellent adherence to appropriate HAART regimens is associated with viral suppression, immunologic recovery, reduction in opportunistic infections and other disease manifestations, and improved survival.

Currently available antiretroviral therapies target various points in the HIV life cycle. The three oldest classes of antiretroviral drugs are nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). The first available antiretroviral therapies were in the NRTI drug class. NRTI’s are drugs whose chemical structure is a modified version of a natural nucleoside. NRTI’s interfere with the action of reverse transcription by causing premature termination of the proviral DNA chain. NNRTIs act as noncompetitive inhibitors of the HIV-1 reverse transcriptase by binding to the reverse transcriptase catalytic site. PIs block protease from cleaving HIV protein precursors, preventing formation of new infectious virions. HAART consisting of an NNRTI or a PI plus two NRTIs is recommended for treatment of antiretroviral-naïve children. In the United States and other high-resource settings, therapy choices are usually guided by viral resistance testing. When resistance to drugs in the NRTI, NNRTI, and PI classes occurs in children, newer drug classes are sometimes used.

Two newer commercially available drug classes exert activity against viral entry into the host cell by inhibiting viral fusion with the cell membrane or binding to the CCR5 co-receptor. A third drug class inhibits integration of proviral DNA into the human genome. None of these drugs is yet recommended for initial therapy of HIV-infected children because there are not yet sufficient data on pediatric dosing and safety. To allow for long-term effectiveness, three drugs to which the patient’s virus has not developed resistance should be given. Therefore, the newer drug classes are sometimes used in highly treatment-experienced children who otherwise have limited treatment options.

Figure 95-1 shows the life cycle as well as the targets of antiretroviral medications.

Table 95-4 describes key features of the antiretroviral medications most commonly used for treatment of children with HIV. To maintain long-term effectiveness, these drugs must be given in appropriate combinations and adherence to therapy must be excellent. Adherence is sometimes complicated by drug side effects. The PIs often cause gastrointestinal distress, particularly early in therapy, that make medication tolerance challenging. Many of the drugs have significant long-term effects, including hyperlipidemia, body habitus changes, and peripheral neuropathy. Careful monitoring by doctors who are experienced in the treatment of HIV allows for early detection of problems and appropriate adjustment of regimens to help ensure long-term therapeutic success.

For children with severe HIV-related immunosuppression, prophylactic medications should also be given to help prevent opportunistic infections. Common infections in children without HIV are also seen in children with HIV but frequently are more severe. Therefore, routine vaccination of HIV-infected children is essential. Table 95-5 outlines recommended strategies for primary prevention of infectious complications in children with HIV. After treatment of an opportunistic infection, long-term secondary prophylaxis is often given to prevent recurrence of disease, regardless of immunologic recovery.

Table 95-5 Primary Prophylaxis of Opportunistic Infection in HIV

Infection	Indications for Prophylaxis	Prevention Strategy
Pneumocystis jiroveci pneumonia	• <1 y: HIV infection or HIV exposure with uncertain HIV infection status • 2-5 y: CD4 <500 cells/mcL or <15% • 6+ y: CD4 <200 cells/mcL or <15%

TMP-SMX twice a day, 3 d/wk Tuberculosis Isoniazid daily for 9 mo Mycobacterium avium complex Azithromycin given weekly Vaccine-preventable illnesses All routine recommended childhood immunizations; defer varicella and MMR if CD4 <15%

MMR, mumps, measles, and rubella; TB, tuberculosis; TMP-SMX, trimethoprim−sulfamethoxazole.

Comprehensive care of HIV-infected children must include psychosocial support to facilitate excellent lifelong adherence to therapy and overall health. Avoiding resistance to antiretroviral therapies requires excellent adherence to appropriate regimens. Age-appropriate counseling regarding the child’s HIV status and strategies to maintain health are essential. Counseling and support must be extended to the child’s entire family to ensure that the child’s environment will support excellent medication adherence and help the child achieve his or her life goals.

Prevention

One of the greatest successes in HIV medicine has been the development of therapies to prevent the mother-to-child transmission (MTCT) of HIV. Without any intervention, approximately 40% of babies born to breastfeeding HIV-infected mothers will be infected with HIV. When comprehensive preventive methods are adopted, the MTCT risk can be reduced to less than 2%.

Prevention of HIV infection in neonates begins with early identification of HIV infection in pregnant women. HIV testing during the first prenatal visit should be a part of routine prenatal care. This allows for early initiation (<28 weeks of gestation) of HAART to help prevent MTCT of HIV. Repeat HIV testing during the third trimester is recommended for women thought to be at “high risk” of HIV infection because the mother’s acquisition of HIV during pregnancy puts the child at especially high risk of infection around the time of delivery. After delivery, the perinatally HIV-exposed baby is often given AZT (Zidovudine) to further reduce the transmission risk. Additional antiretroviral drugs are sometimes given to the infant when the risk of perinatal infection is thought to be high (e.g., when the mother received no preventive therapy before delivery).

For women in resource-limited settings where HAART cannot be given for all HIV-infected pregnant women, a number of short-course antiretroviral options are considered. In settings where resources are most limited, a single dose of nevirapine is often given to the mother while she is in labor and to the infant right after birth. This single low-cost intervention can decrease the risk of HIV transmission by around 50%.

For women who are HIV infected, a number of nonpharmacologic interventions have proven to be valuable for the prevention of MTCT. Avoiding instrumentation (e.g., forceps and fetal scalp monitors) during deliveries also decreases MTCT risk. Cesarean section deliveries are recommended when the maternal HIV viral load is >1000 copies/mL at the time of delivery and resources are available for safe cesarean sections. Treating other sexually transmitted diseases (e.g., active herpes lesions) also decreases HIV transmission risk. Breastfeeding is another important mode of HIV transmission in some settings. Babies born to HIV-infected mothers therefore are usually recommended to formula feed when such feeding can be made affordable, feasible, accessible, safe, and sustainable.

Prevention of new HIV infections among adolescents is also a challenge in pediatrics. Although abstinence is a sure way to avoid sexual transmission of HIV, abstinence-only education has unfortunately proven to be an unsuccessful preventive approach. The consistent use of condoms is important for avoiding the spread of HIV and other sexually transmitted diseases among sexually active individuals. Male circumcision has also proven to be successful at decreasing the risk of HIV transmission.

Summary

HIV is a major worldwide cause of pediatric morbidity and mortality. Available therapies allow children who are born with HIV to maintain their health into adulthood. Unfortunately, only a minority of HIV-infected children worldwide currently have access to HIV treatment. Effective strategies for the prevention of MTCT of HIV are also available but are currently reaching only a minority of HIV-infected women worldwide.

Future Directions

A great deal of work needs to be done to expand prevention and treatment options in low-resource settings where the HIV prevalence is highest. New antiretroviral drugs and pediatric formulations of existing drugs are being developed to facilitate long-term effective treatment. Vaccine development is also a key area of research. The rapid mutation of HIV and its skill at evading antibodies and other immune responses makes it a particularly difficult target for preventive vaccines. Many researchers are also trying to create therapeutic vaccines that would improve the body’s ability to fight HIV, augmenting currently available antiretroviral therapies for individuals already infected with the virus.