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2. Current Recommendations for Treatment of Pediatric HIV Infection
As a practical matter, except in the clinical research setting or as prophylaxis against vertical transmission, antiretroviral therapy rarely is initiated in the newborn period. Confirmation of the diagnosis of HIV infection in infancy requires time, and symptoms and signs rarely are present at birth or in the first few weeks of life. Nevertheless, with more widespread use of rapid diagnostic assays (e.g., HIV DNA PCR) it will be possible to initiate therapy earlier. Although there are no controlled studies, strong theoretical arguments favor initiation of treatment as early as possible in the newborn period to suppress early viral replication.
Current indications in the U.S. for antiretroviral therapy are shown in Table 5. Tables 6 and 7 outline the clinical symptoms and CD4+ lymphocyte count value thresholds that are used in determining a need for treatment. The concentration of plasma HIV RNA indicative of increased risk for disease progression is not well defined for young children. Regardless of age, any child with an HIV RNA concentration of >100,000 copies/mL is at high risk for mortality, and antiretroviral therapy should be initiated, regardless of clinical or immune status. HIV RNA concentrations in asymptomatic children aged >30 months that are the same as concentrations for which there are treatment recommendations for HIV-infected adults (e.g., >10,000-20,000 copies/mL) also may indicate the need to initiate treatment. In addition, any child with an HIV RNA concentration that demonstrates a substantial increase (more than a 0.7 log10 [fivefold] increase for children aged <2 years and more than a 0.5 log10 [threefold] increase for those aged >2 years) on repeated testing should be offered therapy, regardless of clinical or immunologic status or absolute plasma HIV RNA concentration.
Table 5. Indications for initiation of antiretroviral therapy in children with human immunodeficiency virus (HIV) infection*
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Clinical symptoms associated with HIV infection (i.e., clinical categories, A, B, or C [Table 6])
Evidence of immune suppression, indicated by CD4+ T-lymphocyte absolute number or percentage (i.e., immune category 2 or 3 [Table 7])
Age <12 months - regardless of clinical, immunologic, or virologic status For asymptomatic children aged >1 year with normal immune status, two options can be considered:
- Preferred Approach: Initiate therapy - regardless of age or symptom status
- Alternative Approach: Defer treatment in situations in which the risk for clinical disease progression is low and other factors (e.g., concern for the durability of response, safety, and adherence) favor postponing treatment. In such cases, the health-care provider should regularly monitor virologic, immunologic, and clinical status.
Factors to be considered in deciding to initiate therapy include the following:
- High or increasing HIV RNA copy number
- Rapidly declining CD4+ T-lymphocyte number or percentage to values approaching those indicative of moderate immune suppression (i.e., immune category 2 [Table 7])
- Development of clinical symptoms
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Table 6. 1994 Revised human immunodeficiency virus pediatric classification system: clinical categories*
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Category N: Not Symptomatic
Children who have no signs or symptoms considered to be the result of HIV infection or who have only one of the conditions listed in category A.
Category A: Mildly Symptomatic
Children with two or more of the following conditions but none of the conditions listed in categories B and C:
- Lymphadenopathy (>0.5 cm at more than two sites; bilateral-one site)
- Hepatomegaly
- Splenomegaly
- Dermatitis
- Parotitis
- Recurrent or persistent upper respiratory infection, sinusitis, or otitis media
Category B: Moderately Symptomatic
Children who have symptomatic conditions other than those listed for category A or category C that are attributed to HIV infection. Examples of conditions in clinical category B include but are not limited to the following:
- Anemia (<8 gm/dL), neutropenia (<1,000/mm3), or thrombocytopenia (<100,000/mm3) persisting >30 days
- Bacterial meningitis, pneumonia, or sepsis (single episode)
- Candidiasis, oropharyngeal (i.e., thrush) persisting for >2 months
- Cardiomyopathy
- Cytomegalovirus infection with onset before age 1 month
- Diarrhea, recurrent or chronic
- Hepatitis
- Herpes simplex virus (HSV) stomatitis, recurrent (i.e., more than two episodes within 1 year)
- HSV bronchitis, pneumonitis, or esophagitis with onset before age 1 month
- Herpes zoster (i.e., shingles) involving at least two distinct episodes or more than one dermatome
- Leiomyosarcoma
- Lymphoid interstitial pneumonia (LIP) or pulmonary lymphoid hyperplasia (PLH) complex
- Nephropathy
- Nocardiosis
- Fever lasting >1 month
- Toxoplasmosis with onset before age 1 month
- Varicella, disseminated (i.e., complicated chickenpox)
Category C: Severely Symptomatic
Children who have any condition listed in the 1987 surveillance case definition for acquired immunodeficiency syndrome, with the exception of LIP (which is a category B condition).
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| *Modified from CDC. 1994 Revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR 1994;43(no. RR-12):1-10. |
Table 7. 1994 Revised human immunodeficiency virus pediatric classification system: immune categories based on age-specific CD4+ T-lymphocyte count and percentage*
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<12 mos |
1-5 yrs |
6-12 yrs |
| Immune Category |
No./ uL |
(%) |
No./ uL |
(%) |
No./ uL |
(%) |
Category 1
no suppression |
>1,500 |
(>25%) |
>1,000 |
(>25%) |
>500 |
(>25%) |
Category 2
moderate suppression |
750-1,499 |
(15%-24%) |
500-999 |
(15%-24%) |
200-499 |
(15%-24%) |
Category 3
severe suppression |
<750 |
(<15%) |
<500 |
(<15%) |
<200 |
(<15%) |
| *Modified from CDC. 1994 Revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR 1994;43(no. RR-12):1-10. |
Table 8 shows the antiretroviral regimens recommended by the U.S.-based Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children (available electronically at http://www.hivatis.org). Triple combination therapy is recommended for most HIV-infected infants and children because of its potential to produce long-term suppression of viral replication, preservation of immune function, and delay of disease progression. Based on clinical trials, the preferred regimens generally combine two nucleoside reverse transcriptase inhibitors with one protease inhibitor. Well-controlled pediatric studies of dual NRTI treatment regimens (e.g., ZDV plus 3TC, ZDV plus ddI, or d4T plus ddI) document the safety and efficacy of these therapies, as well. These two-drug regimens are suitable alternatives to triple combination therapy in many resource-constrained environments. Monotherapy of any kind, with the exception of ZDV for prevention of HIV vertical transmission, is not recommended.
Table 8. Recommended antiretroviral regimens for initial therapy for human immunodeficiency virus (HIV) infection in children
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Strongly Recommended
Evidence of clinical benefit and/or sustained suppression of HIV replication in clinical trials in HIV-infected adults and/or children. One highly active protease inhibitor plus two nucleoside analogue reverse transcriptase inhibitors (NRTIs)
- Preferred protease inhibitor for infants and children who cannot swallow pills or capsules: nelfinavir or ritonavir. Alternative for children who can swallow pills or capsules: indinavir.
- Recommended dual NRTI combinations: the most data on use in children are available for the combinations of zidovudine (ZDV) and dideoxyinosine (ddI) and for ZDV and lamivudine (3TC). More limited data are available for the combinations of stavudine (d4T) and ddI, d4T and 3TC, and ZDV and zalcitabine (ddC)Alternative for children who can swallow capsules: efavirenz plus 2NRTIs or efavirenz plus nelfinavir plus 1NRTI.
Recommended as an Alternative
Clinical trial evidence of suppression of HIV replication, but 1) durability may be less in adults and/or children than with strongly recommended regimens; or 2) the durability of suppression is not yet defined; or 3) evidence of efficacy may not outweigh potential adverse consequences (e.g., toxicity, drug interactions, cost, etc.).
- Nevirapine plus 2NRTIs
- Abacavir plus ZDV plus 3TC
Offer only in Special Circumstances
Clinical trial evidence of 1) limited benefit for patients; or 2) data re inconclusive, but may be reasonably offered in special circumstances.
- Two NRTIs
- Amprenavir plus 2NRTIs or abacavir
Not Recommended
Evidence against use because of overlapping toxicity and/or because use may be virologically undesirable.
- Any monotherapy*
- d4T and ZDV
- ddC and ddI
- ddC and d4T
- ddC and 3TC
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| *Except for ZDV chemoprophylaxis administered to HIV-exposed infants during the first 6 weeks of life to prevent perinatal HIV transmission; if an infant is identified as HIV-infected while receiving ZDV prophylaxis, therapy should be changed to a combination antiretroviral drug regimen. |
Decisions regarding changes in antiretroviral therapy can be complex (Table 9), particularly when there is discordance between virologic, immunologic, and clinical indicators of treatment failure. In general, any change should include substitution of at least two drugs. Substitution of single agents can lead to rapid emergence of viral resistance.
Table 9. Considerations for changing antiretroviral therapy for human immunodeficiency virus (HIV) infected children
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Virologic Considerations*
- Less than a minimally acceptable virologic response after 8-12 weeks of therapy. For children receiving antiretroviral therapy with two nucleoside analogue reverse transcriptase inhibitors (NRTIs) and a protease inhibitor, such a response is defined as a <10-fold (1.0 log10) decrease from baseline HIV RNA levels. For children who are receiving less potent antiretroviral therapy (i.e., dual NRTI combinations), an insufficient response is defined as a less than five-fold (0.7 log10) decrease in HIV RNA levels from baseline
- HIV RNA not suppressed to undetectable levels after 4-6 months of antiretroviral therapy†
- Repeated detection of HIV RNA in children who initially responded to antiretroviral therapy with undetectable levels§
- A reproducible increase in HIV RNA copy number among children who have had a substantial HIV RNA response but still have low levels of detectable HIV RNA. Such an increase would warrant change in therapy if, after initiation of the therapeutic regimen, a greater than threefold (0.5 log10) increase in copy number for children aged >2 years and a greater than fivefold (0.7 log10) increase is observed for children aged <2 years
Immunologic Considerations
- Change in immunologic classification (Table 7).
- For children with CD4+ T-lymphocyte percentages of <15% (i.e., those in immune category 3), a persistent decline of five percentiles or more in CD4+ cell percentage (e.g., from 15% to 10%).
- A rapid and substantial decrease in absolute CD4+ T-lymphocyte count (e.g., a >30% decline in <6 months)
Clinical Considerations
- Progressive neurodevelopmental deterioration
- Growth failure defined as persistent decline in weight-growth velocity despite adequate nutritional support and without other explanation
- Disease progression defined as advancement from one pediatric clinical category to another (e.g., from clinical category A to clinical category B).**
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*At least two measurements (taken 1 week apart) should be performed before considering a change in therapy.
†The initial HIV RNA level of the child at the start of therapy and the level achieved with therapy should be considered when contemplating potential drug changes. For example, an immediate change in therapy may not be warranted if there is a sustained 1.5 to 2.0 log10 decrease in HIV RNA copy number, even if RNA remains detectable at low levels.
§More frequent evaluation of HIV RNA levels should be considered if the HIV RNA increase is limited (e.g., if when using an HIV RNA assay with a lower limit of detection of 1,000 copies/mL, there is a <0.7 log10 increase from undetectable to approximately 5,000 copies/mL in an infant aged <2 years).
Minimal changes in CD4+ T-lymphocyte percentile that may result in change in immunologic category (e.g., from 26% to 24%, or 16% to 14%) may not be as concerning as a rapid substantial change in CD4+ percentile within the same immunologic category (e.g., a drop from 35% to 25%).
**In patients with stable immunologic and virologic parameters, progression from one clinical category to another may not represent an indication to change therapy. Thus, in patients whose disease progression is not associated with neurologic deterioration or growth failure, virologic and immunologic considerations are important in deciding whether to change therapy. |
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