(Human Immunodeficiency Virus)
Ram, Yogev Ellen, Gould Chadwick - Nelson Pediatric 18th Ed. 2007
Advances in research and major improvements in the treatment and management of HIV infection have brought about a substantial decrease in the incidence of new HIV infections and AIDS in children born in the United States and Western Europe. Most HIV-infected children are born in developing countries. It is estimated that in 2004, 640,000 children <15>
ETIOLOGY.
The major external viral protein of HIV-1 is a heavily glycosylated gp120 protein that is associated with the transmembrane glycoprotein gp41; gp41 is very immunogenic and is used to detect HIV-1 antibodies in diagnostic assays; gp120 is a complex molecule that includes the highly variable V3 loop. This region is immunodominant for neutralizing antibodies. The heterogeneity of gp120 presents major obstacles in establishing an effective HIV vaccine. The gp120 glycoprotein also carries the binding site for the CD4 molecule, the most common host cell surface receptor of T lymphocytes. This tropism for CD4+ T cells is beneficial to the virus because it reduces the effectiveness of the host immune system. Other CD4-bearing cells include macrophages and microglial cells. Several chemokines serve as co-receptors for the envelope glycoproteins, permitting membrane fusion and entry into the cell. Most HIV strains have a specific tropism for 1 of the chemokines, including the fusion-inducing molecule CXCR-4, which has been shown to act as a co-receptor for HIV attachment to lymphocytes, and CCR-5, a β chemokine receptor that facilitates HIV entry into macrophages. Several other chemokine receptors (CCR-3) have also been shown in vitro to serve as virus co-receptors.
Other mechanisms of attachment of HIV to cells use non-neutralizing antiviral antibodies and complement receptors. The Fab portion of these antibodies attaches to the virus surface, and the Fc portion binds to cells that express Fc receptors (macrophages, fibroblasts), thus facilitating virus transfer into the cell. Other cell surface receptors, such as mannose-binding protein on macrophages and DC-specific C-type lectin (DC-SIGN) on dendritic cells, also bind to the HIV-1 envelope glycoprotein and increase the efficiency of viral infectivity. Following viral attachment, gp120 and the CD4 molecule undergo conformational changes, and gp41 interacts with the fusion receptor on the cell surface. Viral fusion with the cell membrane allows entry of viral RNA into the cell cytoplasm. This process involves accessory viral proteins (nef, vif) and binding of cyclophilin A (a host cellular protein) to p24. Viral DNA copies are then transcribed from the virion RNA through viral reverse transcriptase enzyme activity, and duplication of the DNA copies produces double-stranded circular DNA. The HIV-1 reverse transcriptase is error prone and lacks error-correcting mechanisms. Thus, many mutations arise, creating wide genetic variation in HIV-1 isolates even within an individual patient. The circular DNA is transported into the cell nucleus, where it is integrated into chromosomal DNA and referred to as the provirus. The provirus has the advantage of latency as it can remain dormant for extended periods. Integration usually occurs near active genes, which allow a high level of viral production in response to various external factors such as an increase in inflammatory cytokines (by infection with other pathogens) and cellular activation. Depending on the relative expression of the viral regulatory genes (tat, rev, nef), the proviral DNA may encode production of the viral RNA genome, which in turn leads to production of viral proteins necessary for viral assembly.
HIV-1 transcription is followed by translation. A capsid polyprotein is cleaved to produce, among others, the virus-specific protease (p10). This enzyme is critical for HIV-1 assembly. Several HIV-1 antiprotease drugs have been developed, targeting the increased sensitivity of the viral protease, which differs from the cellular proteases. The RNA genome is then incorporated into the newly formed viral capsid that requires zinc finger domains (p7) and the matrix protein (p17). As new virus is formed, it buds through specialized membrane areas, known as lipid rafts, and is released.
The diversity of HIV (groups M [main], O [outlier], N [non-M, non-O]) probably occurred from multiple zoonotic infections from primates in different geographic regions. Group M diversified to several subtypes (or clades A to H). In each region of the world, certain clades predominate. For example, clade B is found in the United States and South America, clade E in Thailand, and clade C in South Africa. Clades are mixed in some patients due to HIV recombination, and some crossing between groups (i.e., M and O) has been reported.
HIV-2 is known to cause infection in several monkey species. It is a rare cause of infection in children. It is most prevalent in Western Africa, but recently cases from Europe and Southern Asia have been reported. The diagnosis of HIV-2 infection is more difficult because the standard confirmatory assays (immunoblot) are HIV-1 specific and may give indeterminate results with HIV-2 infection. If HIV-2 infection is suspected, a specific immunoblot test that detects antibody to HIV-2 peptides should be used. In addition, the recently approved rapid tests should not be used in patients suspected to be HIV-2 infected because they test only for HIV-1. Third generation standard enzyme-linked immunosorbent assays (ELISA) should be used because they capture both HIV-1 and HIV-2.
EPIDEMIOLOGY.
The World Health Organization (WHO) estimated that >39 million persons worldwide were living with HIV infection at the end of 2004, including 2.2 million children <15>500,000 and 9% in metropolitan areas with populations of 50,000–500,000.
Although adolescents (13–24 yr of age) with AIDS represent a minority of U.S. cases (approximately 5%), they constitute 1 of the fastest growing groups of newly infected persons in the country. Considering the long latency period between the time of infection and the development of clinical symptoms, reliance on AIDS case definition surveillance data severely under-represents the impact of the disease in adolescents. Based on a median incubation period of 8–12 yr, it has been estimated that 15–20% of all AIDS cases were acquired between 13 and 19 yr of age. Risk factors for HIV infection vary by gender in adolescents. The majority of teenaged males with AIDS who acquired HIV through sexual contact had male-to-male transmission. In contrast, more than half of adolescent females with AIDS were infected through heterosexual contact and ⅙ through IDU, compared with 8% and 6%, respectively, in teenaged males.
As in the pediatric population, adolescent racial and ethnic minority populations are over-represented, especially among females. In addition, a greater proportion of female adolescents have AIDS (male : female ratio 1.2 : 1) than do female adults >25 yr of age (male : female ratio 4.5 : 1).
Transmission.
Transmission of HIV-1 occurs via sexual contact, parenteral exposure to blood, or vertical transmission from mother to child. The primary route of infection in the pediatric population is vertical transmission, accounting for almost all new cases. Rates of transmission of HIV from mother to child have varied in different parts of the United States and among countries. The United States and Europe have documented transmission rates in untreated women between 12–30%. Transmission rates in Africa and Haiti are higher (25–52%). Perinatal treatment of HIV-infected mothers with anti-retroviral drugs has dramatically decreased these rates to <2%>4 hr duration of ruptured membranes and birthweight <2,500>50,000 copies/mL), some transmitting mothers in each group were asymptomatic or had a low, but detectable, viral load. Thus, in the USA it is recommended to consider cesarean section if the viral load is >1,000 copies/mL.
Transfusions of infected blood or blood products have accounted for 3–6% of all pediatric AIDS cases. The period of highest risk was between 1978 and 1985, before the availability of HIV antibody-screened blood products. Whereas the prevalence of HIV infection in individuals with hemophilia treated before 1985 was as high as 70%, heat treatment of factor VIII concentrate and HIV antibody screening of donors has virtually eliminated HIV transmission in this population. Blood donor screening has dramatically reduced, but not eliminated, the risk for transfusion-associated HIV infection. The rate of HIV transmission through antibody-screened blood in the USA is estimated to be approximately 1/60,000 transfused units. In many developing countries, screening of blood donors is not uniform, and the risk for transmitting HIV infection via transfusion is substantial.
Although HIV can be isolated rarely from saliva, it is in very low titers
PATHOGENESIS.
When the mucosa serves as the portal of entry for the HIV, the 1st cells to be infected are the dendritic cells. These cells collect and process antigens introduced from the periphery and transports them to the lymphoid tissue. HIV does not infect the dendritic cell but it binds to its DC-SIGN surface molecule, which allows the virus to survive until it reaches the lymphatic tissue. In the lymph node, the virus selectively binds to cells expressing CD4 molecules on their surface, primarily helper T lymphocytes (CD4 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. Individuals with homozygous CCR5 deletion mutation are highly protected from HIV infection. Usually, CD4 lymphocytes, recruited to respond to viral antigen, migrate to the lymph nodes where they 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), which accounts for the progressive loss of these cells' response and the subsequent loss of control of HIV replication. 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 flulike 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.
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 50% 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), which gradually causes deterioration of the immune system, evidenced particularly 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 in the lymphoid organs is greater than that 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 nodes in HIV disease serves to promote infection of new CD4 cells as well as subsequent viral replication within the cells. Viral replication in monocytes, which can be infected productively yet resist killing, explains 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 retroviral infection as the 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 during 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 due to a set point (controlled) replication. The other mechanism, the immune control, suggests that the development of an active immune response (whose magnitude is controlled by the amount of viral antigen) 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 anti-retroviral therapy, whereas the immune control mechanism emphasizes the importance of immune modulation treatment (cytokines, vaccines) to increase the efficiency of the immune response, which, in turn, slows disease progression.
A group of cytokines, such as 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, play 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 are called non-syncytium-inducing (NSI) viruses, which 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 it uses CXCR4 as its co-receptor. These isolates are called syncytium-inducing (SI) viruses. The switch from NSI to SI 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. This frees the virus 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, if untreated, a median survival time of 6–9 mo. 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, it 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 and peaks by 2–3 mo of age (median 750,000 copies/mL) and subsequently declines slowly. In contrast to the viral load in adults, the viral load in infants stays high for at least the 1st 2 yrs of life.
The majority of perinatally infected newborns (60–80%) in developed countries present with a 2nd pattern, that of a much slower progression of disease, with a median survival time of 6 yr. 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 by 2–3 mo of age (median 100,000 copies/mL) and 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 (long-term survivors) occurs in a small percentage (<5%) style="font-weight: bold; color: rgb(204, 0, 0);">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, interstitial pneumonia, 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. Symptoms 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 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 2 ). Category B (moderate symptoms) includes, for example, children with LIP, oropharyngeal thrush persisting for >2 mo, recurrent or chronic diarrhea, persistent fever for >1 mo, hepatitis, recurrent herpes simplex virus (HSV) stomatitis or HSV esophagitis or pneumonitis, disseminated varicella (i.e., with visceral involvement), cardiomegaly, or nephropathy (see Table 2 ). Category C (severe symptoms) includes, for example, children with 2 serious bacterial infections (sepsis, meningitis, pneumonia) in a 2 yr period, esophageal or lower respiratory tract candidiasis, cryptococcosis, cryptosporidiosis (>1 mo), encephalopathy, malignancies, disseminated mycobacterial infection, Pneumocystis pneumonia, cerebral toxoplasmosis (onset >1 mo of age), and severe weight loss.
TABLE 1 -- Pediatric HIV Classification for Children Younger Than 13 Years
| | IMMUNOLOGIC CATEGORIES | | | | | |||||
| | AGE-SPECIFIC CD4+ T-LYMPHOCYTE COUNT PERCENTAGE OF TOTAL LYMPHOCYTES[*] | CLINICAL CLASSIFICATIONS[†] | ||||||||
| | <12> | 1–5 yr | 6–12 yr | | | | | |||
| IMMUNOLOGIC DEFINITIONS | μ | % | μ | % | μ | % | N* | A* | B*[‡] | C*[‡] |
| 1: No evidence of suppression | ≥1500 | ≥25 | ≥1000 | ≥25 | ≥500 | ≥25 | N1 | A1 | B1 | C1 |
| 2: Evidence of moderate suppression | 750–1499 | 15–24 | 500–999 | 15–24 | 200–499 | 15–24 | N2 | A2 | B1 | C2 |
| 3: Severe suppression | <750 | <15 | <500 | <15 | <200 | <15 | N3 | A3 | B3 | C3 |
*N : No sign or symptom, A : Mild signs or symptoms, B : Moderate Signs or symptoms, C : Severe signs or symptoms
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 1994;43(RR-12):1–19. Red Book: 2006 Report of the Committee on Infectious Diseases, 27th ed. Elk Grove Village, IL, American Academy of Pediatrics, 2006, p 382.
| * | To convert values in ìL to Système International units (×109/L), multiply by 0.001. |
| † | Children whose HIV infection status is not confirmed are classified by using this grid with a letter E (for perinatally exposed) placed before the appropriate classification code (eg, EN2). |
| ‡ | Lymphoid interstitial pneumonitis in category B or any condition in category C is reportable to state and local health departments as acquired immunodeficiency syndrome (AIDS-defining conditions) (see Table 2 for further definition of clinical categories) |
TABLE 2 -- Clinical Categories for Children Younger Than 13 Years of Age with HIV infection
|
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 1994;43(RR- 12):1ndash;19.
Approximately 20% of AIDS-defining illnesses in children are recurrent bacterial infections caused primarily by encapsulated organisms such as Streptococcus pneumoniae and Salmonella ( Table 3 ). Other pathogens, including Staphylococcus, Enterococcus, Pseudomonas aeruginosa, and Haemophilus influenzae, and other gram-positive and gram-negative organisms may also be seen. Most of these infections are the result of HIV-related disturbances in humoral immunity. The most common serious infections are bacteremia, sepsis, and bacterial pneumonia, accounting for >50% of infections in HIV-infected children. Meningitis, urinary tract infections, deep-seated abscesses, and bone/joint infection 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.
Opportunistic infections 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, lacking prior immunity, often have a more fulminant course of disease. This principle is best illustrated by Pneumocystis carinii (jiroveci) pneumonia (PCP), the most common opportunistic infection in the pediatric population . The peak incidence of PCP occurs at age 3–6 mo, with the highest mortality rate in children <1>
TABLE 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 |
| Pneumocystic jiroveci pneumonia |
| Pneumonia, recurrent |
| Progressive multifocal leukoencephalopathy |
| Salmonella septicemia, recurrent |
| Toxoplasmosis of brain |
| Wasting syndrome attributable to HIV |
| CD4+ T-lymphocyte count <200/μ> |
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 1992;41(RR-17):1–19.
| Red Book: 2006 Report of the Committee on Infectious Disease, 27th ed. Elk Grove Village, IL, American Academy of Pediatrics, 2006, p 379. |
The classic clinical presentation of PCP 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. carinii (jiroveci) with appropriate staining of bronchoalveolar fluid lavage; rarely, an open lung biopsy is necessary.
The 1st line therapy for PCP is intravenous trimethoprim-sulfamethoxazole (TMP-SMZ) (15–20 mg/kg/day of TMP and 75–100 mg/kg/day of SMZ every 6 hr IV) with adjunctive corticosteroids if the Pao2 is <70>
Central Nervous System.
The incidence of CNS involvement in perinatally infected children is 50–90% in developing countries but lower in developed countries, with a median onset at 19 mo of age. This 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, 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.
Focal neurologic signs and seizures are unusual and may imply a comorbid pathologic process such as a CNS tumor, opportunistic infection, or stroke. CNS lymphoma may present with a new onset of 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; the overwhelming majority of these cases have the presence of serum IgG antitoxoplasma as a marker of infection. Other opportunistic infections of the CNS are rare and include CMV, JC virus (progressive multifocal leukoencephalopathy), HSV, and Cryptococcus or Coccidioides meningitis. 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, 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, historically occurring in approximately 25% of HIV-infected children. 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, which allows 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 may be accompanied by digital clubbing and symptomatic hypoxemia, which usually resolves with oral corticosteroid therapy. Several studies suggest that LIP is associated with 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 gram-negative bacteria may also be problematic; P. aeruginosa pneumonia occurs more commonly in severely symptomatic children (CDC C3 category) and is often associated with acute respiratory failure and death. Rarely, bronchiectasis can develop and cause recurrent secondary infections. PCP 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 has been reported with increasing frequency in HIV-infected children, although it is considerably more common in HIV-infected adults.
Cardiovascular System.
Subclinical cardiac abnormalities in HIV-infected children are common, persistent, and often progressive. A prospective study of young children with symptomatic HIV infection revealed that dilated cardiomyopathy and left ventricular hypertrophy were common; the 2 yr cumulative incidence of congestive heart failure was 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.
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 and ulcerations. 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. Lesions that have negative viral cultures may respond to thalidomide, which is currently investigational, or to short courses of prednisone. 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 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. The resulting malnutrition is associated with a grave prognosis and generally requires parenteral hyperalimentation.
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 or C, or MAC may lead to portal hypertension and liver failure. Several of the anti-retroviral drugs or other drugs such as didanosine, protease inhibitors, 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 glomeru losclerosis, 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 sulfonamides, and generally respond to withdrawal of the drug or to desensitization. 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 may be successful in treating the anemia.
Leukopenia occurs in almost ⅓ of untreated HIV-infected children, and neutropenia often occurs. In some cases, antineutrophil antibodies are the cause, and treatment with intravenous immunoglobulin (IVIG) has been successful. Multiple drugs used for treatment or prophylaxis for opportunistic infections such as PCP, MAC, and CMV or anti-retroviral drugs (zidovudine) may also cause leukopenia and/or neutropenia. In many cases, treatment with subcutaneous granulocyte colony-stimulating factor is successful.
Thrombocytopenia has been reported in 10–20% of patients. The etiology may be immunologic (i.e., circulating immune complexes or antiplatelet antibodies), or due to drug toxicity, or the cause may be unknown. Treatment with IVIG or anti-D offers temporary improvement in most cases. If ineffective, a 2–3 day course of high-dose steroids (30 mg/kg/day) may be an alternative. Anti-retroviral therapy may also reverse thrombocytopenia. Deficiency of clotting factors (factors II, VII, IX) is not rare in children with advanced HIV disease and is often easy to correct (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 occurred 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. Kaposi sarcoma, which is caused by human herpesvirus 8, occurs frequently among HIV-infected adults but is exceedingly uncommon among HIV-infected children.
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 lose maternal antibody between 6 and 12 mo of age and are known as seroreverters. Because a small proportion of uninfected infants continues 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 test (immunoblot or immunofluorescence assay) establishes the diagnosis of HIV infection.
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 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. Viral diagnostic assays, such as HIV DNA or RNA PCR, HIV culture, or HIV p24 antigen immune-dissociated p24 (ICD-p24), are considerably more useful in young infants, allowing a definitive diagnosis in most infected infants by 1–6 mo of age ( Table 4 ). By 4–6 mo of age, the HIV culture and/or PCR identify 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, may be more sensitive than DNA PCR for early diagnosis, but data are limited. HIV culture has similar sensitivity to HIV DNA PCR; however, it is more technically complex and expensive, and results are often not available for several weeks compared with 2–3 days for PCR. The p24 antigen assay is also highly specific and easy to perform, but it is less sensitive than the other virologic tests. It is not recommended for diagnosis of infection in infants
TABLE 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 p24 Ag | Less sensitive, false-positive results during 1 mo of life, variable results;not recommended |
| ICD p24 Ag | Negative test result does not rule out infection;not recommended |
| HIV culture | Expensive, not easily available, requires up to 4 wk to do test;not recommended |
| HIV RNA PCR | Not recommended for routine testing of infants and children younger than 18 mo of age, because a negative result cannot be used to exclude HIV infection definitively. Preferred test to identify non-B subtype HIV-1 infections. |
Red Book:2006 Report of the Committee on Infectious Diseases, 27th ed. Elk Grove Village, IL, American Academy of Pediatrics, 2006, p 386.
| Ag, antigen;ICD, immune complex dissociated;PCR, polymerase chain reaction. |
Viral diagnostic testing should be performed within the 1st 48 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 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 to maximize early detection of infected infants, if initiation of anti-retroviral therapy is desired. 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 effect of more intensive antiviral combinations (protease inhibitors) in pregnant women on the accuracy of the infant's viral tests 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 (the predominant type in the United States) are common, interpretation of a negative PCR test result should be done cautiously because the assay may not detect the particular subtype (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.
Infants born to HIV-infected mothers should be prescribed zidovudine (ZDV) prophylaxis. 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 anti-retroviral therapy). If the child is found to be HIV infected, CD4 and CD8 lymphocyte counts should be performed at 1 and 3 mo of age and 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.
TREATMENT.
The currently available therapy does not eradicate the virus and cure the patient; it only suppresses the virus for extended periods of time and changes the course of the disease to a chronic process. Decisions about anti-retroviral 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 anti-retroviral 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 anti-retroviral 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 anti-retroviral-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 anti-retroviral agents to which the patient has not been exposed previously and which are not cross-resistant to drugs with which the patient has been treated previously; (5) adherence to the complex drug regimens is crucial for a successful outcome.
Combination Therapy.
Anti-retroviral drugs licensed as of 2006 are categorized by their mechanism of action, such as the ability to inhibit the HIV reverse transcriptase or protease enzymes ( Table 5 ). 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). 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, which prevents viral DNA synthesis. Among the NRTIs, thymidine analogs (stavudine [d4T], zidovudine [ZDV]) are found in higher concentrations in activated or dividing cells, and nonthymidine analogs (didanosine [ddI], lamivudine [3TC]) have more activity in resting cells. Activated cells are thought to produce >99% of the population of HIV virons. In contrast, resting cells account for 1%
TABLE 5 -- Summary of Anti-retroviral Therapies (available in 2006)
| DRUG (TRADE NAMES, FORMULATIONS) | DOSING | SIDE EFFECTS | COMMENTS | |||||||||||||||||||||||||||||||||
| NUCLEOSIDE/NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIS) | Class adverse effects:Lactic acidosis with hepatic steatosis | | ||||||||||||||||||||||||||||||||||
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| Can be given with food.Serious hypersensitivity reaction occurs rarely;if hypersensitivity is suspected, do not rechallenge. | |||||||||||||||||||||||||||||||||
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| Same as for ddI | Combination with tenofovir increases ddI levels and risk for toxicity.Swallow capsules whole on empty stomach, 30 min before meals or 2 hr after meals | |||||||||||||||||||||||||||||||||||
| Emtricitabine | ||||||||||||||||||||||||||||||||||||
| Children ≥33 kg, adolescents and adults:200 mg capsule PO once daily or 240 mg (24 mL) oral solution q.d. |
| Closely monitor patients with hepatitis B co-infection. Can be given with food. | |||||||||||||||||||||||||||||||||
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| Drug interactions:Can be given with food.Should not be administered with ZDV. | |||||||||||||||||||||||||||||||||
| Zerit XR | ||||||||||||||||||||||||||||||||||||
| Capsule:75, 100 mg |
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| High fat meal increases absorption.Co-administration with ddI may increase ddI toxicity.Co-administration with atazanavir (ATV) may decrease ATV levels. Boosting with ritonavir (RTV) is required. | |||||||||||||||||||||||||||||||||
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| NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIS) | Class adverse effects:Rash—mild to severe, usually within first 6 wk.Discontinue the drug if severe rash (with blistering, desquamation, muscle involvement or fever) | |||||||||||||||||||||||||||||||||||
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| PROTEASE INHIBITORS | Class adverse effects:Hyperglycemia, hyperlipidemia (except atazanavir), lipodystrophy, increased transaminases, increased bleeding disorders in hemophiliacs.Can induce metabolism of ethinyl estradiol;use alternate contraception (other than estrogen-containing oral contraceptives).All undergo hepatic metabolism, mostly by CPY3A4, with many drug interactions! | |||||||||||||||||||||||||||||||||||
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| Liquid formulation contains vitamin E;supplemental vitamin E should not be given.Do not use liquid formulation <4> | |||||||||||||||||||||||||||||||||
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| Review drug interactions before initiating because ATV interacts with drugs using CYP3A4 for metabolism. Use with caution with cardiac conduction disease or liver impairment | |||||||||||||||||||||||||||||||||
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| Use with caution in sulfa-allergic individuals.Interacts with drugs utilizing CYP3A4 metabolism. | |||||||||||||||||||||||||||||||||
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| Adjust dose when used with NNRTIs and other protease inhibitors;interacts with drugs using CYP3A4 | |||||||||||||||||||||||||||||||||
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| Can inhibit human platelet aggregation:use with caution in patients at risk for increased bleeding (trauma, surgery, etc.) or in patients receiving concurrent medications which may increase the risk of bleeding. Contraindicated in patients with hepatic insufficiency or receiving concurrent therapy with amiodarone, cisapride, ergot alkaloids, benzodiazepines, pimozide. | |||||||||||||||||||||||||||||||||
| FUSION INHIBITORS | ||||||||||||||||||||||||||||||||||||
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| Give subcutaneously in the upper arm, anterior leg or abdomen (maximum:90 mg/dose).Severity of adverse effects increased if give intramuscularly Injection sites should be rotated | |||||||||||||||||||||||||||||||||
| COMBINATION PRODUCTS | These combinations can be used in adolescents at appropriate Tanner stage (Tanner stages IV and V) and weight (>40 kg). | | ||||||||||||||||||||||||||||||||||
| Atripla | ||||||||||||||||||||||||||||||||||||
| Each tablet contains 600 mg Efavirenz, 200 mg emtricitabine, and 300 mg tenofovir disoproxil fumarate | ||||||||||||||||||||||||||||||||||||
| Adult dose:1 tablet | ||||||||||||||||||||||||||||||||||||
| Combivir | ||||||||||||||||||||||||||||||||||||
| Each tablet contains 300 mg AZT + 150 mg | ||||||||||||||||||||||||||||||||||||
| 3TC | ||||||||||||||||||||||||||||||||||||
| Adult dose:1 tablet | ||||||||||||||||||||||||||||||||||||
| Epzicom | ||||||||||||||||||||||||||||||||||||
| Each tablet contains 300 mg 3TC + 600 mg | ||||||||||||||||||||||||||||||||||||
| ABC | ||||||||||||||||||||||||||||||||||||
| Adult dose:1 tablet | ||||||||||||||||||||||||||||||||||||
| Trizivir | ||||||||||||||||||||||||||||||||||||
| Each tablet contains 300 mg AZT + 150 mg | ||||||||||||||||||||||||||||||||||||
| 3TC + 300 mg ABC | ||||||||||||||||||||||||||||||||||||
| Adult dose:1 tablet | ||||||||||||||||||||||||||||||||||||
| Truvada | ||||||||||||||||||||||||||||||||||||
| Each tablet contains 200 mg FTC + 300 mg | ||||||||||||||||||||||||||||||||||||
| TDF | ||||||||||||||||||||||||||||||||||||
| Adult dose:1 tablet | ||||||||||||||||||||||||||||||||||||
| Antiretroviral drugs often have significant drug-drug interactions, with each other and with other classes of medicines, which sho uld be reviewed before initiating any new medication. The information in this table is not all-inclusive. Updated and additional information on dosing, drug-drug interactions, and toxicities is available on the AIDSinfo website at http://www.aidsinfo.nih.gov |
By targeting different points in the viral life cycle and stages of cell activation, and delivering drug to all tissue sites, maximal viral suppression may be feasible. Combinations of 3 drugs (thymidine analog NRTI [ZDV], 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. Although not ideal, less potent combinations such as triple NRTIs (abacavir, zidovudine, lamivudine), dual NRTIs, or ritonavir with stavudine may be considered in special situations when there are concerns about adherence to a complex drug regimen or when the patient and/or family prefer a simplified alternative regimen. Combination treatment increases the rate of toxicities (see Table 5 ), and complex drug-drug interactions exist among many of the anti-retroviral drugs. Most NNRTI and protease inhibitor drugs are inducers or inhibitors of the cytochrome P450 system. The protease inhibitors are particularly 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 anti-retroviral treatment, 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, indinavir, saquinavir) to slow their metabolism by the P450 system and to improve their pharmacokinetic profile. This provides more effective drug levels with less toxicity and, often, less frequent dosing.
Adherence.
Assessment of the likelihood of adherence to treatment is an important factor in deciding whether and when to ini tiate therapy. Numerous studies have shown that compliance of <80–90%>
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 anti-retroviral therapy, regardless of age or viral load (see Tables 1 and 2 [1] [2]). Children <1>
Some clinicians advocate treating asymptomatic children ≥1 yr of age to prevent immunologic deterioration. When there are concerns regarding drug adherence, safety, and durability of anti-retroviral response, some providers elect to delay treatment in the immunologically normal child with a viral load of <100,000>
Inflammatory immune reconstitution syndromes have been described for children and adults, and represent the paradoxical emergence of transient to severe inflammation-mediated symptoms as immune function is restored with anti-retroviral therapy. Most of these syndromes are associated with mycobacterial infections, especially M. tuberculosis, and have also been reported with P. carinii, Toxoplasma, hepatitis B and hepatitis C viruses, CMV, and other pathogens. Immune reconstitution syndromes are characterized by fever and worsening of the clinical manifestations of the opportunistic infection or new manifestations, typically within the 1st few weeks after initiation of anti-retroviral therapy, although they may occur up to several months after the initiation. Determining whether the symptoms represent worsening of a current infection or a new opportunistic infection, an immune reconstitution syndrome, or drug toxicity is often very difficult. If the syndrome does represent an immune reactivation syndrome, adding nonsteroidal anti-inflammatory agents or corticosteroids to alleviate the inflammatory reaction is appropriate. The inflammation may take weeks or months to subside.
Dosing.
Data on anti-retroviral 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.
Adolescents should have anti-retroviral dosages prescribed on the basis of Tanner staging of puberty rather than on the basis of age. During early puberty (Tanner stages I, II, and III), pediatric dosing ranges should be used, whereas adolescents in late puberty (Tanner stages IV and V) should follow adult dosing schedules.
Changing Anti-Retroviral 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. While considering possible new drug choices, potential cross-resistance should be addressed. In addition, few patients who have virologic failure may still demonstrate elevated 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 should be considered as long as the immunologic benefit is evident. Ideally, when a decision is made to change the anti-retroviral therapy, all drugs should be changed. However, in many situations (previous anti-retroviral 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 Anti-Retroviral Therapy.
Virologic and immunologic surveillance (using HIV RNA copy number and CD4 lymphocyte count or percentage) as well as clinical assessment should be performed regularly in children taking anti-retroviral therapy. Initial virologic response (i.e., at least 5-fold [0.7 log10] reduction in viral load) should be achieved within 4 wk of initiating anti-retroviral therapy. The maximum response to therapy usually occurs within 12–16 wk. 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 2–3 mo is adequate. Several toxicities have caused increasing concern regarding anti-retroviral use (especially protease inhibitors). These toxicities include hematologic complications, hypersensitivity rash, lipodystrophy (e.g., redistribution of body fat), hyperlipidemia (elevation of cholesterol and triglyceride concentrations), hyperglycemia and insulin resistance, mitochondrial toxicity leading to severe lactic acidosis, abnormal bone mineral metabolism, and hepatic toxicity including severe hepatomegaly with steatosis.
Resistance to Anti-Retroviral Therapy.
The high mutation rate of HIV (mainly due to the absence of error-correcting mechanisms) severely impairs the success of anti-retroviral therapy. Failure to reduce the viral load to <50>
Supportive Care.
Even before the new anti-retroviral 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 nutrition status, which is often delicately balanced and may require aggressive preemptive intervention (nasogastric or gastric feedings or parenteral nutrition) to achieve adequate caloric and protein intake. Painful oropharyngeal lesions and dental caries are frequent and may interfere with eating; routine dental evaluations and careful attention to oral hygiene should be encouraged. 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 pharmacologic and nonpharmacologic protocols for pain management should be instituted, especially during the terminal phase of the disease.
All HIV-exposed and infected children should receive standard pediatric immunizations. In general, live oral polio vaccine and live bacterial vaccines (BCG) should not be given ( Fig. 2 ). Varicella and measles-mumps-rubella (MMR) vaccines are recommended for children in immune categories 1 and 2, but neither varicella nor MMR vaccines should be given to severely immunocompromised children (immune category 3). Of note, prior immunizations do not always provide protection, as evidenced by outbreaks of measles and pertussis in immunized HIV-infected children.
TABLE 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 | 1 mo |
| 4–6 wk to 4 mo or HIV exposed 4–12 mo | Prophylaxis | 3 mo |
| HIV-infected or indeterminate | Prophylaxis | 6,9, and 12 mo |
| HIV infection reasonably excluded[*] | No prophylaxis | None |
| 1–5 yr, HIV infected | Prophylaxis if: | Every 3–4 mo[†] |
| | CD4 count is <500> | |
| 6–12 yr, HIV infected | Prophylaxis if: | Every 3–4 mo[‡] |
| | CD4 count is <200>[§] | |
Primary prophylaxis against opportunistic infections may be discontinued if patients have experienced sustained (>6 mo duration) immune reconstitution with HAART. Even if patients have had opportunistic infections such as PCP or disseminated MAC, it may also be possible to discontinue prophylaxis if immune reconstitution has been sustained.
Some experts recommend IVIG to prevent recurrent serious bacterial infections for symptomatic HIV-infected children who (1) have suffered from at least 2 documented serious bacterial infections within 1 yr, (2) have laboratory-documented inability to make antigen-specific antibodies, or (3) are hypogammaglobulinemic. The dose is 400 mg/kg every 4 wk.
All HIV-exposed children should have skin testing (5TU PPD) for tuberculosis at 1 yr of age and be retested every 2 yr. If the child is living in close contact with a person with tuberculosis, he or she should be tested more frequently. To reduce the incidence of other potential infections, parents should be counseled about (1) the importance of good handwashing, (2) avoiding raw or undercooked food (Salmonella), (3) avoiding drinking or swimming in lake or river water or being in contact with young farm animals (Cryptosporidium), and (4) the risk of playing with pets (Toxoplasma and Bartonella from cats, Salmonella from reptiles).
Because of the frequent changes in these guidelines, physicians providing care to few HIV-exposed or infected children should periodically consult physicians with expertise in pediatric HIV infection.
PROGNOSIS.
The improved understanding of the pathogenesis of HIV infection in children and the availability of more effective anti-retroviral drugs has changed the prognosis considerably. In developed countries where early diagnosis leads to prompt anti-retroviral therapy, progression of the disease to AIDS and the mortality rate have diminished. HIV-infected children live longer with improved quality of life. Even with only partial reduction of viral load, children may have both significant immunologic and clinical benefits. In general, the best prognostic indicators are the sustained suppression of plasma viral load and CD4+ lymphocytes. If determinations of viral load and CD4 lymphocytes are available, the results can be used to evaluate prognosis. It is unusual to see rapid progression in an infant with a viral load <100,000>100,000 copies/mL) over time is associated with greater risk for disease progression and death. CD4 lymphocyte percentage is another prognostic indicator, and the mortality rate is higher in patients with a CD4 lymphocyte percentage of <15%.>30% of such children dying before age 3 yr of age. In contrast, lymphadenopathy, splenomegaly, hepatomegaly, lymphoid interstitial pneumonitis, and parotitis are indicators of a better prognosis.
PREVENTION.
Interruption of perinatal transmission from mother-to-child has been achieved by administering ZDV chemoprophylaxis (200 mg every 8 hr) to the pregnant woman (started as early as 4 wk of gestation) and continued during delivery (2 mg/kg loading dose IV followed by 1 mg/kg/hr IV) and in the newborn for the 1st 6 wk of life (2 mg/kg every 6 hr PO). In the developed world, such therapy has been documented to decrease the rate of perinatal HIV-1 transmission to <8%.>1,000 copies/mL should be counseled about the potential benefit of cesarean section in reducing the risk for vertical transmission.
Retrospective data suggest that even if a mother has received no anti-retroviral therapy during gestation or delivery, the 6-wk component of the ZDV prophylactic regimen instituted for the newborn as soon as possible after delivery (preferably within 12–24 hr of birth) results in a significant reduction of transmission rate. Full-term infants should be given oral ZDV at a dose of 2 mg/kg every 6 hr for 6 wk. Reduced dosages are used for preterm infants (see Table 5 ).
A study evaluating the efficacy of oral nevirapine, a non-nucleoside reverse transcriptase inhibitor, given once to women in labor and once to the infant during the 1st 48–72 hr of life, capitalizes on the prolonged half-life of this drug. In Africa it has been shown to reduce perinatal transmission by 50%, providing a simple and highly cost-effective regimen for resource-poor countries. For women living in resource-constrained settings, the WHO has recommended that pregnant women be treated with an anti-retroviral regimen appropriate for their own health if possible. For those who do not meet indications for or have no access to therapy, a regimen known to prevent vertical HIV-1 transmission should be offered, such as ZDV from 28 wk of pregnancy plus a single dose of nevirapine (SD NVP) during labor and 1 wk of ZDV therapy for the neonate. International studies are under way to determine optimal approaches to interruption of perinatal transmission in breast-fed infants. Studies in non-breast-feeding pregnant women in Thailand have shown that 3rd trimester ZDV with SD NVP in labor with 7 days of ZDV ± SD NVP to the infant was associated with a transmission rate of 3%.
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Here is a great herbal doctor who cured me of Hepatitis B. his name is Dr. Imoloa. I suffered Hepatitis B for 11 years, I was very weak with pains all over my body my stomach was swollen and I could hardly eat. And one day my brother came with a herbal medicine from doctor Imoloa and asked me to drink and I drank hence there was no hope, and behold after 2 week of taking the medicine, I started feeling relief, my swollen stomach started shrinking down and the pains was gone. I became normal after the completion of the medication, I went to the hospital and I was tested negative which means I’m cured. He can also cure the following diseases with his herbal medicine...lupus, hay fever, measles, dry cough, diabetics hepatitis A.B.C, mouth ulcer, mouth cancer, bile salt disease, fol ate deficinecy, diarrhoea, liver/kidney inflammatory, eye cancer, skin cancer disease, malaria, chronic kidney disease, high blood pressure, food poisoning, parkinson disease, bowel cancer, bone cancer, brain tumours, asthma, arthritis, epilepsy, cystic fibrosis, lyme disease, muscle aches, fatigue, muscle aches, shortness of breath, alzhemer's disease, acute myeloid leukaemia, acute pancreatitis, chronic inflammatory joint disease, Addison's disease back acne, breast cancer, allergic bronchitis, Celia disease, bulimia, congenital heart disease, cirrhosis, constipation, fungal nail infection, fabromyalgia, (love spell) and many more. he is a great herbalist man. Contact him on email; drimolaherbalmademedicine@gmail.com. You can also reach him on whatssap- +2347081986098.
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ReplyDeleteI was diagnosed as HEPATITIS B carrier in 2013 with fibrosis of the
liver already present. I started on antiviral medications which
reduced the viral load initially. After a couple of years the virus
became resistant. I started on HEPATITIS B Herbal treatment from
ULTIMATE LIFE CLINIC (www.ultimatelifeclinic.com) in March, 2020. Their
treatment totally reversed the virus. I did another blood test after
the 6 months long treatment and tested negative to the virus. Amazing
treatment! This treatment is a breakthrough for all HBV carriers.