Category C Severely Symptomatic

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Children who have any condition listed in the 1987 surveillance ease definition for acquired immunodeficiency syndrome (with the exception of LIP)

Serious bacterial infections

Candidiasis, esophageal or pulmonary

Coccidioidomycosis

Cryptococcosis

Cryptosporidiosis

Cytomegalovirus disease

Encephalopathy

HSV infection

Histoplasmosis

Kaposi's sarcoma

Lymphoma, primary, in brain

Lymphoma

Mycobacterium tuberculosis

Mycobacterium, other species or unidentified species Mycobacterium avium complex or M. kansasii Pneumocystis carinii pneumonia Progressive multifocal leukoencephalopathy Salmonella

Toxoplasmosis of the brain with onset >1 month of age Wasting syndrome

Adapted from centers for Disease Control and Prevention Revised classification system for human immunodeficiency virus infection in children less than 13 years of age MMWR 1994;43:1.

therapy for OIs, and determine antiretroviral therapeutic strategies for primary HIV-1 infection. Once HIV-1 infection is confirmed by anti-HIV-1 antibody testing (ELISA) (with a confirmatory Western blot in adults), a complete

TABLE 44-5 -- CDC PEDIATRIC HUMAN IMMUNODEFICIENCY VIRUS CLASSIFICATION (1994)

Immunologic Categories

Age of Child

> 12 Months Cells/mm3 (Percent)

1 to 5 Years Cells/mm3 (Percent)

6 to 12 Years Cells/mm3 (Percent)

No evidence of suppression

>500 (

1500 (

1000 (225)

25)

25)

Evidence of moderate suppression

750 to 1499 (15 to 24)

500 to 999 (15 to 24)

200 to 499 (15 to 24)

Severe suppression

<750 (<15)

<500 (<15)

<200 (<15)

history should be obtained including a review of risk factors for HIV-1 exposure, drug and alcohol history, sexual history, travel history, and medical history. A complete baseline physical examination should be performed. Focused follow- up examinations are then recommended with attention directed to findings that indicate disease progression such as general appearance and weight loss, dermatological conditions (seborrheic dermatitis, folliculitis, dermatophytosis, Kaposi's sarcoma, bacillary angiomatosis), oral lesions (candidiasis, hairy leukoplakia, aphthous ulcers, periodontal disease), localized lymphadenopathy, splenomegaly and signs or symptoms of neurological/neuropsychiatric involvement (mood or affective disorders, psychomotor slowing, abnormal eye movements, hyperreflexia, change of gait).

Initial laboratory studies should include CD4+/CD8+ counts (absolute cell counts and percentages) and, if possible, HIV-1 RNA levels. CBC with differential count, electrolyte and liver function panel, hepatitis screen, reactive protein reagin (RPR) or VDRL, anti-toxoplasma IgG antibodies; purified protein derivative (PPD) with anergy panel, and chest x-ray should also be obtained. Ophthalmologics, dental, and gynecological examinations (including a PAP smear, chlamydia and gonorrhea studies) should be pursued. The stage of HIV-1 infection will then determine follow-up, prophylaxis, and therapeutic strategies.

In addition to declining CD4+ cell counts and CD4+/CD8+ lymphocyte ratios, other immunological markers of disease progression include elevated levels of serum beta- 2 microglobulin, neopterin, serum acid labile interferon, and decreased or absent levels of anti-p24 antibody. Virological indicators of disease progression are p24 antigenemia, HIV culture, quantitative polymerase chain reaction (PCR) of proviral DNA in cells or RNA in serum, the presence of syncytium-inducing strains of virus. Elevated erythrocyte sedimentation rate and decreased hematocrit values serve as nonspecific markers.

Newborns and young infants (up to 18 months of age) present special diagnostic challenges. Although the detection of anti-HIV-1-specific IgG antibody in peripheral blood in older children and adults is taken as proof of HIV- 1 infection, a positive antibody test in a well infant or young child is uninterpretable, as maternal IgG crosses the placenta and may persist for up to 18 months. Thus, a positive IgG antibody test only confirms the seropositivity of the mother. Direct evidence for HIV-1 infection may be sought by HIV-1 culture, PCR studies, HIV-1 RNA levels, and assays of circulating p24 in the peripheral blood. If the results of these studies are negative in the neonatal period, they should be repeated when the infant is 3 to 6 months of age. If they are again negative, an ELISA should be performed when the child is 15 to 18 months of age to document infection status.

The initial laboratory evaluations of children over age 18 months suspected of having HIV-1 infection should include HIV-1 serological testing (ELISA/Western blot), a complete blood count, and lymphocyte subsets (CD3, CD4, CD8 [and CD4:CD8 ratio]) enumeration. Other routine diagnostic tests, such as chest x-ray study, urine analysis, appropriate cultures for pathogens, a chemistry panel, and IgA, IgM, IgG levels may also be warranted.

Management. Early recognition and diagnosis of HIV- 1 infection is important to institute appropriate counseling, prevent further spread of the virus, limit the number of additional clinical and laboratory evaluations, to exclude possible other disorders. Thereafter, the mainstays of management of HIV-1 infection include antiretroviral therapy for primary HIV-1 infection and prophylaxis and treatment of OIs. [731 Drugs that treat HIV-1 infection attempt to interfere with the replication of HIV. Targeted points in the growth cycle of the virus include (1) blockage of viral entry (soluble CD4+ preparations); (2) prevention of transcription of RNA to DNA (reverse transcriptase inhibitors); (3) interference with translation (drugs acting on regulatory genes or their proteins); (4) inhibition of assembly (protease inhibitors); and (5) interruption of the release of virus (interferon) (see Fig. 44-5 (Figure Not Available) ).

At present there are nine antiretroviral agents licensed in the United States: zidovudine (ZDV, AZT), Retrovir; didanosine (ddI), Videx; dideoxycytidine (ddC), Hivid; stavudine (d4T), Zerit; and lamivudine (3TC), Epivir. These agents are nucleoside analogues that inhibit reverse transcriptase. Protease inhibitors include saquinavir, Invirase; indinavir, Crixivan; ritonavir, Norvir; and agouron, Nelfinavir, Viracept. Non-nucleoside reverse transcriptase inhibitors have also recently been introduced and include delavirdine and nevirapine. The primary goal of antiretroviral therapy is to maintain viral suppression for as long as possible. y Antiretroviral clinical trials show promising beneficial results. Effective treatment reduces plasma HIV RNA levels and increases CD4+ cell counts. Treatments offer the potential to delay onset of AIDS, prolong survival, and interrupt transmission. y Unfortunately, limitations have also been observed. Antiretrovirals do not completely inhibit viral replication, and HIV-1 disease progresses despite therapy. Studies show that treatment with antiretroviral drugs favors the fall of HIV RNA titers, the rise of CD4+ cell counts, the prolongation of time until HIV-1 related symptoms begin, and prolongation of survival. When to initiate primary HIV-1 therapy to an individual patient, however, remains unclear.

Recommendations for institution of antiretroviral therapy are guided by evaluation of the individual's clinical status and use of surrogate markers, such as CD4+ cell counts and plasma HIV-1 RNA levels.^ Some investigators

Figure 44-5 (Figure Not Available) Potential locations for treatment intervention in the life cycle of the HIV. The boxes depict the cellular signaling pathways used for replication by HIV. The first box indicates the cellular surface receptors; the second depicts the intracellular signals that transmit the first signal; the third pathway is assembled in response to second messenger signaling and includes protein-DNA and protein-RNA mtpraciReproduced with permission from Folks TM, Hart CE: The life cycle of human immunodeficiency virus type I. In DeVita VT, Hellman S, Rosenberg SA [eds]: AIDS: Biology, Diagnosis, Treatment and Prevention, 4th ed. Philadelphia, Lippincott-Raven, 1997, pp 29-43.)

suggest treatment before the onset of HIV-related symptoms when the CD4+ cell count falls to or below 500/ mm3 ; HIV RNA titer is 30,000 to 50,000 copies/ml; or CD4+ cell count is rapidly declining. Treatment may also be considered if the HIV RNA titer is greater 5000 copies/ mm 3 in those individuals whose CD4+ cell count is less than 500/mm3 .

It is not certain which initial antiretroviral agent or combination of agents should be used. The specific initial antiretroviral treatment should be based on an assessment of the potency, expected duration of benefit, resistance, toxicity, potential interactions with other medications, ease of use, and cost. y These medications are extraordinarily expensive and have certain common and distinct side effects (.iTabl.§..44.-.§ ). Because this information is rapidly changing, clinicians should review yearly updates on therapy

TABLE 44-6 -- COMPLICATIONS OF TREATMENT WITH SPECIFIC ANTIRETROVIRAL AGENTS

Zidovudine ddl ddC

Stavudine (d4T) Lamivudine (3TC)

Anemia, neutropenia, nausea, anorexia, fatigue, insomnia, headache, myalgia, myopathy Pancreatitis, peripheral neuropathy, hyperamylasemia, hyperuricemia, transaminase elevations Peripheral neuropathy (dose-dependent), pancreatitis, rash, stomatitis, gastrointestinal disturbances Peripheral neuropathy, arthralgia, myalgia, anemia, asthenia, gastrointestinal complaints, headache, insomnia Pancreatitis, paresthesias, peripheral neuropathy, rash, cough, headache, dizziness, fatigue, hair loss, insomnia recommendations. It is recommended that initial therapy for antiretroviral-naive patients consist of two nucleoside analogues that act on the transcription of viral RNA to DNA. Such combinations include ZDV/ddI, ZDV/zalcitabine and ZDV/lamivudine, as clinical trials indicate that combination therapy is more effective than monotherapy with ZDV. Monotherapy with ddI or stavudine is also an option for those patients who cannot tolerate or refuse ZDV. Stavudine (d4T) is another alternative, as is stavudine combined with ddI. In vitro studies show that resistance can develop to all these agents within 6 to 12 months of use. The clinical significance is uncertain. It should be remembered that nucleoside analogues are active against replicating HIV, and not latent provirus.

The development of the protease inhibitor class of therapy, aimed at inhibiting the assembly of active viral products, has provided further treatment options, including their use with double nucleoside therapy as discussed above. [75] Efficacy and toxicity data are still limited. In choosing this regimen, consideration must be given to side effects and cross-resistance among drugs. In addition, these agents must also be administered at optimal dosages, because a reduction in dosage may lead to the development of resistance. Protease inhibitors (ritonavir, indinavir, and saquinavir) are all metabolized in the liver by the cytochrome p450 oxidase enzymes. Therefore, competition and interaction with other drugs metabolized by the cytochrome p450 system must be taken into consideration. Non-nucleoside reverse transcriptase inhibitors combined with other regimens are currently under clinical investigations and data are limited.

The goal of antiretroviral therapy is to maintain viral suppression as long as possible. Unfortunately, clinical experience has shown that over time therapy has a diminished

benefit. The optimum choice of secondary treatment is often a major dilemma. Many factors must be taken into consideration, for example, the patient's previous antiretroviral regimen, length of time the antiretroviral was taken, toxicities encountered, as well as side effects or toxicities of the new agent. Development of resistance to antiretroviral agents is a major problem, especially when protease inhibitors are administered as monotherapy or when not taken by the patient as directed. Skipped doses, drug holidays, and irregular dosing rapidly leads to the development of resistance.

There is still relatively limited published data concerning antiretroviral therapy for children with HIV-1 infection. In clinical trials, children treated with ZDV had improvement in weight gain and growth, stabilization of CD4 counts, a reduction in serum and CSF p24 antigen levels, decrease in immunoglobulin levels, and improvement or stabilization of cognitive function. At the time of this writing, the number of therapeutic agents available for the treatment of HIV-1 infection and its complications is limited. ZDV and ddI are the only antiretroviral agents approved by the FDA for treatment of HIV infection in children under age 13. The agents listed above for adult use are available at the present time for investigational use in pediatric patients. Protease inhibitors are also under investigation in pediatric clinical trials, as are protease inhibitors in combination with other antiviral agents. The optimal time to initiate antiretroviral therapy in children is unknown. At present, antiretroviral therapy is recommended for children who either have evidence of significant immunodeficiency or defined HIV-associated symptoms. It is recommended that initial therapy should begin with ddI or ddI in combination with ZDV with the caveat that combination therapy may carry a greater risk of toxicity.

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