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Tim Niehues and Hermione Lyall

Children are not small adults. The HIV infection in childhood is different from the infection in adults with regard to transmission, the natural course of viral dynamics, maturity of the immune system and clinical manifestations. Several factors have to be considered when giving antiretroviral drugs to children: children may already have been exposed to AZT and other drugs in utero, the pharmacokinetics of the drugs are age-dependent and children require special attention to help with adherence.

More than 95 % of children are infected by perinatal transmission of the virus from the mother to the child (vertical infection). Transmission by transfusion, sexual transmission and drug abuse are much less prevalent. In most cases (75-90 %) HIV is transmitted peri- or intrapartum. Only a small proportion of children are infected in utero (10-25 %). Transmission by breastfeeding is important in resource-poor settings, but plays a minor role in developed countries, where breastfeeding by known HIV-infected mothers is strongly discouraged. The increasing knowledge about how HIV is vertically transmitted has led to highly effective interventions to prevent transmission and significant reduction of the transmission rate to less than 2 %. However, new infections in HIV-exposed children still occur

• if the HIV status of the mother is unknown;
• if prevention of transmission prophylaxis is incomplete;
• if the mother doesn't have access to transmission prophylaxis during pregnancy.

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At birth, viral load is usually low (< 10,000 copies/ml) and then rapidly rises within the first 2 weeks of life to values above 100,000 copies/ml and only slowly decreases after the age of 4-5 years. These viral dynamics are significantly different from the rapid increase and decrease of the viral load seen in untreated adults within a few months following the acute HIV infection (figure 1). In children, the higher viral load is associated with the somatic growth of the lymphatic system and the inability of the immature immune system in children to mount an HIV-specific response. When assessing the immune system in infants and children, it is very important to compare the child's CD4 count with the age-appropriate values (e.g. the mean CD4 count for a 6-month-old baby being 3.0 x 109/l). Lymphocyte counts are very high in infancy and decline to adult levels beyond 6 years of age (table 1). Figure 1: Differences in the natural course of viral load and anti-HIV immunity between adults and infants/toddlers The spectrum of clinical manifestations in HIV-infected children is different from that of adults. In adults, typical manifestations of the acute HIV seroconversion illness are: fever, sore throat, lymphadenopathy and a mononucleosis-like disease. HIV seroconversion illness has not been described in perinatally-infected children. Symptomatic disease presenting in childhood has been classified according to severity of symptoms (table 2). A new WHO staging has been proposed in 2006(http://www.who.int/hiv/pub/guidelines/en/index.html) . If antiretroviral therapy in children is effective, opportunistic infections become a rarity. However, in children who newly present with HIV (e.g. if HIV status in the mother is unknown and there was no transmission prophylaxis), opportunistic infections can still be observed. Table 1. 2006 WHO Human Immunodeficiency Virus Pediatric Classification System: Immune Categories Based on Age-Specific CD4 values Classification of HIV asociated immunodeficiency Age related CD4 Values < 11 months 12-35 months (%CD4+) 36 -59 months (%CD4+) >5 years (absolute number per mm3 or %CD4+) None or not significant >35 >30 >25 > 500 Mild 30-35 25-30 20-25 350-499 Advanced 25-29 20-24 15-19 200-349 Severe <25 <20 <15 <200 or <15% Table 2. WHO clinical staging of HIV/AIDS for children with confirmed HIV infection Clinical stage 1 Asymptomatic Persistent generalized lymphadenopathy Clinical stage 2 Unexplained persistent hepatosplenomegaly Papular pruritic eruptions Fungal nail infection Angular cheilitis Lineal gingival erythema Extensive wart virus infection Extensive molluscum contagiosum Recurrent oral ulcerations Unexplained persistent parotid enlargement Herpes zoster Recurrent or chronic upper respiratory tract infections (otitis media, otorrhoea, sinusitis or tonsillitis) Clinical stage 3 Unexplained moderate malnutrition or wasting not adequately responding to standard therapy Unexplained persistent diarrhoea (14 days or more) Unexplained persistent fever (above 37.5°C intermittent or constant, for longer than one month) Persistent oral candidiasis (after first 6-8 weeks of life) Oral hairy leukoplakia Acute necrotizing ulcerative gingivitis or periodontitis Lymph node tuberculosis Pulmonary tuberculosis Severe recurrent bacterial pneumonia Symptomatic lymphoid interstitial pneumonitis Chronic HIV-associated lung disease including brochiectasis Unexplained anaemia (<8 g/dl), neutropaenia (<0.5 × 109 per litre) and or chronic thrombocytopaenia (<50 × 109 per litre) Clinical stage 4 Unexplained severe wasting, stunting or severe malnutrition not responding to standard therapy Pneumocystis pneumonia Recurrent severe bacterial infections (such as empyema, pyomyositis, bone or joint infection or meningitis but excluding pneumonia) Chronic herpes simplex infection (orolabial or cutaneous of more than one month's duration or visceral at any site) Oesophageal candidiasis (or candidiasis of trachea, bronchi or lungs) Extrapulmonary tuberculosis Kaposi sarcoma Cytomegalovirus infection: retinitis or cytomegalovirus infection affecting another organ, with onset at age older than one month Central nervous system toxoplasmosis (after one month of life) Extrapulmonary cryptococcosis (including meningitis) HIV encephalopathy Disseminated endemic mycosis (coccidiomycosis or histoplasmosis) Disseminated non-tuberculous mycobacterial infection Chronic cryptosporidiosis (with diarrhoed) Chronic isosporiasis Cerebral or B-cell non-Hodgkin lymphoma Progressive multifocal leukoencephalopathy Symptomatic HIV-associated nephropathy or HIV-associated cardiomyopathy Diagnosis of HIV infection < 18 months of age The detection of anti-HIV antibodies does not prove an infection in infants. High titers of anti-HIV IgG are transferred transplacentally from mother to child. Maternal antibodies can be detected in children up to the age of 18 months. Therefore a direct method of detecting HIV is necessary. Identification by HIV DNA PCR is highly sensitive and specific. Detection of HIV can be achieved within the first 48 hours after birth in 38 % of infected children, and within the first 2 weeks in 93 % of children (Dunn 1995). Once a positive HIV PCR is found, a second independent blood sample should soon be taken for repeat PCR analysis. As diverse subtypes of HIV exist, it is advised to test paired samples from mother and infant by HIV DNA PCR. If the mothers virus is not amplified by the primer set used, then another set or another test can be used to avoid a false negative result in the infant. Cord blood is not useful for the diagnosis because maternal cells may be present and may cause a false positive test result. In general, the disappearance of maternal IgG antibodies to HIV needs to be documented before HIV infection can be definitely excluded in the HIV-exposed child. Tests with an increased sensitivity to detect HIV antibodies are not useful as they may detect maternal antibodies up to 28 months of age leading to anxiety and confusion in the affected families (Nastouli 2007). There is a WHO draft for diagnosing HIV in infants aimed at the developing world (http://www.who.int/hiv/paediatric/infantdiagnosis.pdf). Diagnosis of HIV infection > 18 months of age HIV infection is diagnosed in an analogous way to adults (see chapter "HIV Testing"). When to initiate antiretroviral therapy Keep the following facts in mind before starting antiretroviral therapy in children: § Treatment of HIV-infected children is usually not an emergency. § Take as much time as needed to decide whether to start with HAART or not. Commencing antiretroviral therapy too early risks possible long-term side effects and early exhaustion of the limited supply of antiretroviral drugs that can be safely used in children. Therefore, many experts defer treatment in asymptomatic children with a low viral load and without immunodeficiency. The indication for treatment is based on CD4 count, viral load and clinical criteria. There are new WHO guidelines for resource-poor settings (www.who.int/hiv/pub/guidelines/art/en/index.html) Table 3. PENTA recommendations on when to start antiretroviral therapy http://www.ctu.mrc.ac.uk/penta/guidelines.htm Infants 1. Clinical Start all infants with CDC stage B or C (AIDS) disease. 2. Surrogate marker Start all infants with CD4 % < 25-35 %. Strongly consider starting with a VL > 1 million copies/ml. Many experts treat all infants, whether symptomatic or not (with the aim of preventing HIV encephalopathy or other forms of disease progression). Children aged 1-3 years 1. Clinical Start all children with stage C disease. 2. Surrogate marker Start all children with a CD4 % < 20 %. Strongly consider starting with a VL > 250,000 copies/ml. Children aged 4-8 years 1. Clinical Start all children with stage C disease. 2. Surrogate marker data Start all children with a CD4 % < 15 %. Strongly consider starting with a VL > 250,000 copies/ml. Children aged 9-12 years 1. Clinical Start all children with stage C disease. 2. Surrogate marker data Start all children with CD4 < 15 %, but with less urgency than in a younger child. Strongly consider starting with a VL > 250,000 copies/ml. Adolescents aged 13-17 years 1. Clinical Start all adolescents with stage C disease. 2. Surrogate marker data Start all adolescents with an absolute CD4 count between 200 and 350 cells/mm3. In a meta analysis of 17 studies (Dunn D; HIV Paediatric Prognostic Markers Collaborative Study Group; HPPMC cohort) with 3,941 children who received no therapy or AZT monotherapy, viral load and CD4 cell counts proved to be independent prognostic markers for the end stage, AIDS or death (Dunn 2003). From this large cohort of children, a computer program has been generated which can be used to give the risk of progression to AIDS or death within 6/12 months according to the age and either CD4 count or viral load in the child ("PENTA Calculator" http://www.ctu.mrc.ac.uk/penta/hppmcs/calcProb.htm). Updated guidelines for treatment from Europe and the United States were published in 2004 (PENTA 2004 http://www.ctu.mrc.ac.uk/penta/; http://aidsinfo.nih.gov/guidelines/). The PENTA guidelines use the HPPMC cohort data to optimize timing of starting treatment at different ages, according to CD4 count / viral load, in order to maintain the 1-year risk of progression to AIDS at < 10 % and death at < 5 %. (tables 3, 4). Table 4. US Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection (http://aidsinfo.nih.gov/guidelines); A. Indications for Initiation of antiretroviral therapy in children < 12 months of age Clinical Category CD4 Cell Percentage Plasma HIV RNA Copy Number 1 Recommendation Symptomatic (Clinical category A, B, or C) OR < 25 % (Immune category 2 or 3) Any Value Treat Asymptomatic (Clinical category N) AND > 25 % (Immune category 1) Any Value Consider Treatment 2 1 Plasma HIV RNA levels are higher in HIV-infected infants than older infected children and adults. Because overall HIV RNA levels are high and overlap between infants who have and those who do not have rapid disease progression, HIV RNA levels may be difficult to interpret in infants < 12 months of age. 2 Because HIV infection progresses more rapidly in infants than older children or adults, some experts would treat all HIV-infected infants < 6 months or < 12 months of age, regardless of clinical, immunologic or virologic parameters. B. Indications for Initiation of Antiretroviral Therapy in Children > 1 Year of Age Clinical Category CD4+ Cell Percentage Plasma HIV RNA Copy Number Recommendation AIDS (C) OR < 15 % (Immune Category 3) Any value Treat Mild-Moderate Symptoms (A or B) OR 15-25 % 1 (Immune Category 2) OR > 100,000 copies/ml 2 Consider treatment Asymptomatic (N) AND > 25 % (Immune Category 1) AND < 100,000 copies/ml 2 Many experts would defer therapy and closely monitor clinical, immune, and viral parameters 1 Many experts would initiate therapy if CD4 cell percentage is between 15 to 20 %, and defer therapy with increased monitoring frequency in children with CD4 cell percentage 21 % to 25 %. 2 There is controversy among pediatric HIV experts regarding the plasma HIV RNA threshold warranting consideration of therapy in children in the absence of clinical or immune abnormalities; some experts would consider initiation of therapy in asymptomatic children if plasma HIV RNA levels were between 50,000 to 100,000 copies/ml. General considerations for treatment of HIV-infected children The treatment of children with antiretroviral drugs is becoming increasingly complex. A successful treatment requires an interdisciplinary approach to the children and their families. Antiretroviral therapy cannot be successful without good adherence to treatment. In the prospective PACTG 377, trial adherence was defined as having not missed a single medication dose over the last 3 days. According to this definition, only 70 % of children were found to be adherent (125 children within an observation period of 48 weeks; Van Dyke 2002). These data show that continuous motivation of children and their care providers is of high importance. The modalities of the daily intake of the medication need to be discussed in detail and adjusted to the daily and weekly routines of the family activities. Clear treatment goals need to be set, e.g. 90 % of the prescribed doses. Education of the patient and the family regarding the antiretroviral drugs is necessary. Sometimes a brief period of hospitalization at the start of antiretroviral therapy is useful to educate the patient and access the tolerability of the treatment regimen. Adherence is particularly problematic in adolescence. In this age group, adherence often needs a close follow up including other health care professions such as psychologists and social workers. Peer support may also be helpful for young people. Sometimes periods off ART, despite the risk of ill health, have to be accepted in this group of patients until the young person is ready to restart therapy themselves. A promising approach to increase adherence in children and adolescents is the availability of once-daily regimens: In the PACTG Study P1021 a once-daily regimen with Emtricitabine, Didanosine and Efavirenz was studied over >96 weeks in 37 treatment-naïve children (age 3 to 21 years) (McKinney 2007). This regimen resulted in a relatively high percentage of children having VL below detection limit (70% after 2 years), but unfortunately the study lacked a comparator arm, e.g a twice-daily regimen.Underdosing has been shown to be a problem in day to day practice (Menson, 2006). Dosing by weight instead of body surface area (given as an alternative in some old guidelines) may result in underdosing and simply ongoing growth may not be adjusted for. This underlines the importance of frequent follow up especially for infants and toddlers on therapy when they are growing very fast and will need recalculation of their doses every 4-6 weeks. Particular genotypes are associated with hypermetabolism of of NNRTI's and PI's. Plasma levels of NNRTI's and PI's can be measured (pharmacologic drug monitoring) to detect interindividal differences in drug metabolism and lack of adherence. to exclude dosage that is too low and to prevent toxicity. Figure 2: Interdisciplinary care for children and families who are affected by HIV Obviously, regular physical examination and laboratory tests are necessary to monitor antiretroviral therapy in HIV children. Only a physician who is experienced in the care of HIV-infected children and the use of antiretroviral therapy will be able to provide adequate care. Before medication is initiated or changed, the decision should always be based on at least 2 independent blood samples. Infections and vaccinations may influence viral load and CD4 cell count. Therefore, it is not recommended to base decisions on data that have been gathered within 14 days of an infection or vaccination. Strategy At present, eradication of HIV cannot be achieved by the existing therapy. In some children, viral load remains below detection level for years and subsequently there are no more HIV-specific antibodies detectable in these children. Even in these children, ultra-sensitive assays can still detect HIV (Persaud 2004). Therefore risks and benefits of antiretroviral therapy have to be balanced in each child. Interruption or incomplete adherence may cause more harm than deferring the therapy. The decision to start antiretroviral therapy has fundamental consequences for the children and families. From this point on, it usually means that children need to take the medication for life. Structured treatment interruptions have not been tested in childhood and adolescence in controlled studies. A retrospective analysis of unplanned treatment interruptions in children demonstrated a significant decline of CD4 percentages by 6.6 % per year (Gibb 2004). PENTA (Pediatric European Network for Treatment of AIDS) is currently undertaking a randomised paediatric study of CD4 guided treatment interruptions (PENTA 11). Table 5 shows the current treatment concept for choosing antiretroviral drug combinations. In the American PACTG 338-study on 297 children, it has been shown that a PI-containing combination is more effective than a dual combination of 2 NRTI's. It appears useful to start with a combination that includes two substance classes (2NRTI's + PI or 2 NRTI's + NNRTI) in order to spare one or two substance classes for future change of antiretroviral therapy. If there is not full viral suppression on treatment, development of cross-resistance to NNRTIs and PIs is very likely. Therefore, sparing substance classes may be useful for a better long-term efficacy. It has been controversial whether all HIV infected infants should receive HAART. In the PACTG 256 study, an aggressive approach with inclusion of 3 substance classes (NRTI + NNRTI + PI) led to a highly effective and long-lasting virus load reduction (72 % of patients over 4 years), especially if therapy was started at an early age (< 3 months) (Luzuriaga 2004). Moreover, in the South African Study CHER, which examined the influence of early versus deferred HAART in infants, there is a much higher mortality in the deferred treatment arm (unpublished). Especially in the context of encephalopathy and high mortality rates these data suggest to start all infants on HAART what ever their CD4 count and whether or not they have any symptoms. Whether such early treatment in infancy needs to be continued long term beyond 1 or 2 years fo age is also being examined in the CHER trial. As there are only small numbers of children and adolescents with HIV in Europe it is highly recommended to include all children who receive antiretroviral therapy in multicenter clinical trials (e. g. PENTA (Pediatric European Network for Treatment of AIDS), http://www.pentatrials.org, Tel. Dr. Diana Gibb ++ 44 20 7670 4709; Lynda Harper ++ 44 20 7670 4791). The PENPACT 1 study with participation both of the PENTA and the PACTG group has now completed recruitment and results will be available in 2009 to This trial aims to answer the question whether initial therapy in children is more effective with 2 NRTI + PI or with 2 NRTI + NNRTI. Table 5. Treatment concept in HIV-infected children Regime Recommendation NRTI* 1 + NRTI 2 + PI** or NRTI 1 + NRTI 2 +NNRTI *** Include children in multicenter clinical trials (e.g. PENPACT 1) * = Nucleoside Reverse Transcriptase Inhibitor (Zidovudine (AZT), Didanosine (DDI), Lamivudine (3TC), Stavudine (D4T), Abacavir (ABC), Emtricitabine (FTV), Tenofovir). ** = Protease Inhibitor (Nelfinavir (NFV), Lopinavir/r (LPV/RTV), Atazanavir (ATV) Indinavir (IDV), Amprenavir (APV). Ritonavir as booster drug). *** = Non-nucleoside Reverse Transcriptase Inhibitor (Nevirapine (NVP), Efavirenz (EFV)). In the placebo-controlled American CNAA3006 study on children who had already received antiretroviral therapy, a triple NRTI therapy was shown to be more effective than a therapy consisting of 2 NRTI's (Saez-Llorens 2001). However, this study was carried out on children who were already on antiretroviral therapy and were not treatment naive. Data in adults suggest that a triple NRTI strategy is less effective than a therapy combination including PI or NNRTI. At present there are no data on triple NRTI therapy as initial therapy for children. Classes of Antiretrovirals In the following paragraphs the different antiretroviral classes that are currently used in children are introduced with emphasis on Pediatric issues and in particular daily dosage, relation to food intake (unless the drug can be taken independent of meals) and side effects. All drugs can lead to nausea, vomiting, fever, headache, diarrhea, rash and anorexia. Nucleos(t)ide analog reverse transcriptase inhibitors (NRTIs) NRTIs have been used for over 15 years in the treatment of HIV-infected children. The combination of 2 NRTIs as part of HAART is effective and well tolerated. Severe side effects are rare but potentially life-threatening, such as lactic acidosis and hepatic steatosis. Other side effects are neuromuscular dysfunction, cardiomyopathy, pancytopenia, pancreatitis and neuropathy. All of these effects are probably related to mitochondrial toxicity caused by NRTIs. Due to pharmacologic and antiviral antagonism as well as synergistic neurotoxicity, the following combinations are not recommended: AZT + D4T, DDI +D4T (not first line), and FTC + 3TC. The less mitochondrially toxic NRTI's include 3TC, ABC, FTC and TDF. Zidovudine (ZDV, AZT, Retrovir™) is available as syrup, capsules, tablets and concentrate for injection or intravenous infusion. Dosage is 180 mg/m² orally every 12 hours. Maximum dosage is 300 mg every 12 hours. Lamivudine (3TC, Epivir™) is available as oral solution and tablets. Dosage is 4 mg/kg every 12 hours, maximum dosage is 150 mg every 12 hours. In older children and adolescents (> 35 kg body weight) combination with Zidovudine (Combivir™) or Abacavir (KivexaTM/US: Epzicom™) can be used and daily pill burden reduced. In adults, lamivudine shows antiviral activity against hepatitis B virus. In HIV negative children with chronic Hepatitis B early initiation of Lamivudine appears to achieve a high HBe and HBs conversion rate(Choe 2007). There are no data in HBV and HIV coinfected children. A once-daily regimen in combination with abacavir has been shown to be as effective as twice daily (Bergshoeff, 2005) (PENTA 13 Trial). Didanosine (DDI, Dideoxyinosine, Videx™) is available as oral solution and tablets. Dosage is 200 mg/m2 once daily. Maximum dosage is 400 mg (body weight > 60 kg) or 250 mg (body weight < 60 kg). It should be taken on an empty stomach. NB need to dose adjust DDI with TDF Abacavir (ABC, Ziagen™) is available as oral solution and tablets. Dosage is 8 mg/kg every 12 hours, maximum dosage is 300 mg twice daily or 600 mg once daily. In the PENTA 5 trial, the NRTI back bone of ABC+3TC showed a better efficacy regarding viral load suppression than AZT+ABAC and AZT+3TC. There is a potential risk of a fatal hypersensitivity reaction. If ABC hypersensitivity occurs and the drug is stopped, it should not be restarted as, rarely, deaths have occurred in adults upon rechallenge HLA B5701 appears to be associated with hypersensitivity and HLA testing before starting ABC is useful, an alternative NRTI should be used in HLA B5701 positive children.In the PENTA 15 study the pharmacokinetics, feasibility and acceptability of dosing ABC or ABC in combination with 3TC once daily in children aged 3 months to <36 months is being assessed. Emtricitabine (FTC, Emtriva™) is available as capsules and oral solution. Dosage is 6 mg/kg is . The administration of capsules results in a 20 % higher plasma level. Emtricitabine can be given once daily. Maximum dosage is 200 mg once daily. Tenofovir (TDF, Viread™) is currently only available as tablets (300mg). In 18 children and adolescents between 6 and 16 years of age, a dosage of 200 mg/m² once daily was well tolerated (Hazra 2004). It should be taken with meals. There are no controlled trials regarding the efficacy of tenofovir in children. Tenofovir has been shown to have metabolic renal and bone side effects which may be significant for children and should be monitored closely. Tenofovir is also effective for treatment of HBV. In children co-infected with HIV and HVB who require treatment for HIV the NRTI backbone of TDF+FTC (Truvada) should be considered as this will be effective against both viruses. Stavudine (D4T, Zerit™) is available as oral solution and capsules. Dosage is 1 mg/kg every 12 hours. Maximum dosage is 40 mg every 12 hours. It should be taken on an empty stomach. D4T is not recommended for first-line therapy as it has a high risk of causing lipoatrophy. Non nucleoside reverse transcriptase inhibitors (NNRTIs) These drugs have a low genetic barrier to resistance. Within a few weeks suboptimal dosing or adherence can lead to cross-class resistance mutations affecting all available NNRTIs. NNRTIs exist in palatable liquid preparations which are easier for children to tolerate than the liquid PI solutions. It has to be kept in mind that single dose nevirapine exposure as part of the perinatal transmission prophylaxis may affect subsequent treatment response, if NNRTIs are used in an initial regimen for infants (Lockman 2007). Efavirenz (EFV, Sustiva™) is available as capsules and oral solution. Dosage is 200 mg (body weight 10-15 kg), 250 mg (15-20 kg), 300 mg (20-25 kg), 350 mg (25-33 kg), 400 mg (33-40 kg), 600 mg (> 40 kg) once daily. Maximum dosage is 600 mg once daily. It should be taken on an empty stomach. High fat meals should be avoided. When using the solution, a 20 % higher dosage than for capsules is necessary. Central nervous system symptoms (somnolence, insomnia, abnormal dreams, confusion, abnormal thinking, concentration, amnesia, agitation, depersonalization, hallucinations, euphoria) appear to be more common in adults than in children. Skin rash is observed in < 10 % of the patients and is rarely severe, it usually disappears within days despite continuation of efavirenz. Efavirenz may cause raised lipids in some patients. Nevirapine (NVP, Viramune™) is available as tablets and suspension. Dosage is 150 mg/m2 once daily for 14 days, followed by 150 mg/m2 every 12 hours, if liver function tests are normal. In a retrospective analysis, once-daily application - 300 mg/m2 after week 2 - was as effective as twice-daily (Verweel 2003). The most common side effect of nevirapine, in up to 16 % of children during the first weeks of treatment, is a skin rash, which may be quite severe (8 %) and require hospitalization. Life-threatening complications (Steven Johnson Syndrome, toxic epidermal necrolysis) are rare. Hepatotoxicity may also occur, and fatal cases have been reported in adults, but this appears to be less common in children. Protease inhibitors (PIs) All protease inhibitors can be used in combination with 2 NRTIs. PIs differ from each other in respect to their tolerability and side effects. As with adults, dyslipidemia is associated with the use of protease inhibitors (Lainka 2002). It includes elevated total cholesterol, triglycerides (TG), and low density lipoprotein cholesterol (LDL-c) and decreases in high density lipoprotein cholesterol (HDL-c) In lipodystrophy, there is a loss of subcutaneous fat (lipoatrophy) and/or a deposition of fat tissue subcutaneously or in visceral stores (lipohypertrophy) including the presence of dorsocervical fat accumulation ("buffalo hump") and increased waist-to-hip ratio. Lipoatrophy is marked by thinning of subcutaneous fat in the face, buttocks, and extremities associated with a prominent appearance of peripheral veins. The body habitus changes usually occur gradually over months to years. The exact prevalence of lipodystrophy in children is unknown and there are no clear diagnostic criteria. Lipodystrophy and dyslipidemia coexist, their interconnection is unclear. Other substance classes such as NRTIs (e.g. stavudine) and NNRTIs (efavirenz, not nevirapine) may also play a role in the pathogenesis of lipodystrophy. Insulin resistance is another side effect which may present with or without fasting hyperglycemia, with new onset diabetes mellitus and exacerbations of pre-existing diabetes. Moreover, PIs may influence bone mineral density and metabolism (Mora 2004). Taken together, the long-term consequences of PI-containing antiretroviral therapy for growth and development of the child are currently not known. Lopinavir / Ritonavir (LPV/r, Kaletra™) is a co-formulation of lopinavir and ritonavir, in which ritonavir acts as a pharmacokinetic enhancer (booster). It is available as capsules, tablets and oral solution. In therapy-naive and -experienced children, the combination of LPV/r and NRTI or NNRTI shows a high efficacy (Saez-Llorens 2003, Fraaij 2004). The dosage is 230-300mg/m2 (most centres use the higher dose) or 13 mg/kg lopinavir/3.25 mg/kg ritonavir twice daily (bodyweight 7 - < 15 kg), 11 mg/2.75 mg (15-50 kg), 533 mg/133 mg (> 50 kg). It should be taken with meals. The dosage of LPV/r may need to be increased by up to 30 % when combined with a NNRTI, and therapeutic drug monitoring is useful in this situation. Nelfinavir (NFV, Viracept™) is available as tablets and powder. It is well tolerated in most children. The dosage is 55 mg/kg every 12 hours, but in infants < 3 months 75 mg/kg every 12 hours is required. Maximum dosage is 1,250 mg every 12 hours. Some older children require 1,500 mg every 12 hours, more than the adult dose. Therapeutic drug monitoring is useful. In the PENTA 7 trial in newborns and infants below the age of 3 months, combination of nelfinavir with D4T and DDI was poorly absorbed with poor plasma levels and consequently poor viral load suppression (Aboulker 2004). It should be taken with meals. The most common side effect is diarrhea, which rarely causes discontinuation of the drug. To facilitate the administration of nelfinavir, the tablets can be crushed or readily dissolved in water. In the PENTA 5 study, nelfinavir powder was only poorly tolerated. In May 2007 a contamination of NFV with a genotoxic/carcinogenic agent ethyl mesylate (also known as methane sulfonic acid ethylester) occurred, which is a by-product of manufacture and was found in some batches of nelfavinavir manufactured in Europe. Children were either switched to an other agent or NFV from the manufacturer in the US was imported. International registeries of children in Europe treated with Nelfinavir, or exposed to Nelfinavir whilst in utero are going to be set up to follow children for any side effects of possible exposure. Amprenavir (APV, Agenerase™) is not recommended for children < 4 years of age. It is available as capsules and oral solution. Capsule dosage is 20 mg/kg every 12 hours, for the oral solution 22.5 mg/kg every 12 hours. The maximum dosage is 1,200 mg every 12 hours. The dosage of amprenavir needs to be increased by 30 % in case of combination with NNRTI. In 5 children, who were intensively pretreated, amprenavir in combination with delavirdine showed good efficacy (Engelhorn 2004). The most common side effects are nausea, vomiting, diarrhea and headaches. The prodrug of amprenavir is fosamprenavir, which is currently used for antiretroviral therapy in adults at a dosage of 1,400 mg twice daily (without ritonavir) or 1,400 mg + ritonavir 200 mg once daily. It should be taken with meals. There is no pediatric dose. The drug is currently under investigation for use in HIV-infected children. Fosamprenavir is usually prescribed with ritoanvir boosting to increase bioavailable levels. Ritonavir (RTV, Norvir™) is available as oral solution or capsules. However, most children do not tolerate the taste of the oral solution. The dosage is 350-400 mg/m² every 12 hours, maximum dosage 600 mg every 12 hours. It should be taken with meals. Today, ritonavir is almost exclusively used as a drug to boost other protease inhibitors, and for this purpose, the dosage is 75 mg/m² every 12 hours. Indinavir (IDV, Crixivan™) is available as capsules. Dosage is 500 mg/m² every 12 hours in combination with ritonavir 750 mg/m² every 12 hours. It should be taken on an empty stomach. Side effects include nephrolithiasis, especially at high plasma levels. Saquinavir (SQV, Invirase™ hard gel capsule or Fortovase™ softgel capsule). Dosage in children is unknown. There is very limited experience with 50 mg/kg every 12 hours. Saquinavir should only be used in combination with ritonavir because of poor bioavailability. It should be taken with meals. Atazanavir (ATV, Reyataz™) is available as capsules. It should be taken with meals. Atazanavir could be an interesting drug for use in children in the future, because of its once-daily application and lower incidence of dyslipidemia. At present, there is no approved dosage for children. Phase I and II studies are underway. Some patients develop jaundice. Better levels of atazanivir are obtained with ritonivir boosting. Tipranavir (TPV, Aptivus™ ) is available as 250mg soft gel capsules. It should be taken with meals. At present, there is no approved dosage for children and it has been associated with significant hepatotoxicity in adults. Phase I and II studies in children are being conducted. Fusion inhibitors Fusion inhibitors prevent the fusion of the virus with the target cell. In adults, randomized studies have proven an effect of T-20 (the first drug of this substance class) within salvage treatment protocols. Enfuvirtide (T-20, Fuzeon™) can be used in children older than 6 years of age. The drug is injected subcutaneously at a dosage of 2 mg/kg every 12 hours. A study with 14 children showed no severe side effects, but after a 2-year treatment duration only 6 out of 14 children stayed on this therapy (Church 2004). Reasons for treatment discontinuations were aversion to injections, local injection site reactions, inefficient viral load suppression, thrombocytopenia and edema. There are no controlled studies on the use of T-20 in children. Drug interaction There are a great number of interactions, which may complicate antiretroviral therapy when it is co-administered with other drugs. In particular, tuberculosis and atypical mycobacterial treatment may interact with ART, so close monitoring and expert advice should be sought. Monitoring of therapy efficacy and therapy failure A good treatment response is documented by a permanent suppression of the viral load below the detection limit. Not all children achieve complete viral suppression, and development of resistance is not uncommon due to the selection pressure of the anti-HIV immune response as well as antiretroviral therapy. There is no commonly used definition of treatment failure in children treated with antiretroviral drugs. Therefore, it is also not certain when to change antiretroviral therapy. In the PENPACT 1 study, this important question is being addressed: children are randomized to change a failing treatment at either low or high viral rebound (> 1,000 or > 30,000 copies/ml) Alternatively, therapy failure can be defined by a decrease in CD4 cell counts, e.g. a decrease by at least a third of the absolute CD4 cell number in less than 6 months. In children with relatively low CD4 cell counts of less than 15 %, a decrease by more than 5 % may already be significant for therapy failure. The use of clinical criteria, such as toxicity of the drugs, a progression within the CDC classification, an increased susceptibility to infections, encephalopathy and failure to thrive, may all indicate treatment failure. Many children with multi-disciplicnary support do now manage to maintain longterm (> 5 years) viral suppression on first line therapy, and the longer this can be maintained on first line therapy the better. Indeed over the last few years as more treatments have become available for children they have been increasingly successful with treatment. The most common cause of treatment failure is insufficient adherence, which can be found in up to 25-30 % of children. Assessment of adherence may be difficult as questionnaires may not be reliable. Determination of plasma levels and resistance tests (e.g. reoccurrence of wild type) are other options to assess adherence and monitor antiretroviral therapy more effectively. Change of therapy There are no systematic data on how and when to change therapy in HIV-infected children. The suppression of viral load that can be reached by a second or third regimen depends on the preceding therapy and the resistance status. The longer and more intensive pretreatment has been, the lower the viral load reduction that can be expected. When a new antiretroviral drug combination is introduced, the age of the child, the availability of appropriate formulations (e.g. solution for infants), side effects and interactions with other drugs are all taken into account. At present, it is unclear whether dyslipidemia and lipodystrophy can be influenced by a change from a PI-containing regimen to an NNRTI-containing HAART (McComsey 2003). In adults, randomized and prospective trials have shown that a change of antiretroviral therapy guided by resistance tests leads to a better treatment response. In children there is a smaller prospective study (Englund 2004). Usually, the initial treatment regimen contains a double NRTI backbone (e.g. AZT + 3TC or AB C + 3TC). When changing therapy, it appears useful to introduce a backbone with two new NRTI's and one new substance class into the treatment combination. A mega-HAART therapy combining five to six antiretroviral drugs has not been systematically investigated in children. In single cases, it may be useful to introduce up to five drugs if treatment failure has occurred despite multiple different drug regimens. Supportive therapy and prophylaxis Opportunistic infections have become rare in perinatally infected children who experience immune reconstitution with successful HAART. In most of these HIV infected children respiratory and other infections are not more common than in healthy children. HIV infected children who are treated with HAART and who are clinically stable can even be given live varicella virus vaccine and show a specific response, which is an impressive sign of successful immune reconstitution (Armeninan, 2006). In the vast majority of stable treated children treatment with i.v. immunoglobulins and PCP prophylaxis is no longer required (Nachman 2005b). However, there are still life-threatening infections and deaths from HIV, if perinatal HIV infection is unrecognised or HAART has not yet led to immune reconstitution. A description of such infections in adults is given in other chapters of this book. An excellent and detailed guide for treatment of children with opportunistic infections can be found at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5314a1.htm. Conclusion In many aspects, HIV infection in children is different from HIV infection in adults. The ongoing growth and development of children, their viral dynamics and immaturity of the immune system result in a different response to HIV in children compared to adults. This has important consequences for diagnosis and treatment of HIV in children. The aim of the therapy is to reach maximum efficacy while avoiding long-term side effects. Sustained success in the treatment of children with HIV infection can be achieved by: § a multidisciplinary approach; § standardized treatment protocols; § participation in multicenter trials; § development of new drugs and strategies for children. In developed countries, the clinical picture of HIV infection in children has now changed from an often fatal to a treatable chronic infection. This picture is entirely different in developing countries, where the majority of children do not have access to HAART (Prendergast 2007). According to the WHO, 380,000 children died from HIV infection or its sequelae in the year 2006, a disease that can be treated and, more importantly, prevented. References 1. Aboulker JP, Babiker A, Chaix ML, et al.; Paediatric European Network for Treatment of AIDS. Highly active antiretroviral therapy started in infants under 3 months of age: 72-week follow-up for CD4 cell count, viral load and drug resistance outcome. AIDS. 2004;18:237-45. http://amedeo.com/lit.php?id=15075541 2. Bergshoeff A, Burger D, Verweij C, et al. Plasma pharmacokinetics of once- versus twice-daily lamivudine and abacavir: simplification of combination treatment in HIV-1-infected children (PENTA-13). Antivir Ther 2005; 10: 239-46. Abstract: http://amedeo.com/lit.php?id=15865218 3. Brambilla P, Bricalli D, Sala N, et al. Highly active antiretroviral-treated HIV-infected children show fat distribution changes even in absence of lipodystrophy. AIDS 2001; 15:2415-22. http://amedeo.com/lit.php?id=11740192 4. Buseyne F, Blanche S, Schmitt D, et al. Detection of HIV-specific cell-mediated cytotoxicity in the peripheral blood from infected children. J Immunol. 1993;150:3569-81. http://amedeo.com/lit.php?id= 8096852 5. Choe BH, Lee JH, Jang YC, et al. Long-term therapeutic efficacy of lamivudine compared with interferon-alpha in children with chronic hepatitis B: the younger the better. J Pediatr Gastroenterol Nutr 2007;44:92-8. Abstract: http://amedeo.com/lit.php?id=17204960 6. Church JA, Hughes M, Chen J, et al.; Pediatric AIDS Clinical Trials Group P1005 Study Team. Long term tolerability and safety of enfuvirtide for human immunodeficiency virus 1-infected children. Pediatr Infect Dis J. 2004;23:713-8. http://amedeo.com/lit.php?id=15295220 7. Dunn D; HIV Paediatric Prognostic Markers Collaborative Study Group. Short-term risk of disease progression in HIV-1-infected children receiving no antiretroviral therapy or zidovudine monotherapy: a meta-analysis. Lancet 2003;362:1605-11 http://amedeo.com/lit.php?id=14630440 8. Dunn DT, Brandt CD, Krivine A, et al. The sensitivity of HIV-1 DNA polymerase chain reaction in the neonatal period and the relative contributions of intra-uterine and intra-partum transmission. AIDS 1995; 9:F7-11. http://amedeo.com/lit.php?id= 8527070 9. Engelhorn C, Hoffmann F, Kurowski M, et al. Long-term pharmacokinetics of amprenavir in combination with delavirdine in HIV-infected children. AIDS. 2004 ;18:1473-5. http://amedeo.com/lit.php?id=15199327 10. Englund JA, Raskino C, Vavro C, et al.; Pediatric AIDS Clinical Trials Group Protocol 152 Team. Mutations linked to drug resistance, human immunodeficiency virus type 1 biologic phenotype and their association with disease progression in children receiving nucleoside reverse transcriptase inhibitors.Pediatr Infect Dis J. 2004; 23:15-22. http://amedeo.com/lit.php?id=14743040 11. Fraaij PL, Neubert J, Bergshoeff AS, et al. Safety and efficacy of a NRTI-sparing HAART regimen of efavirenz and lopinavir/ritonavir in HIV-1-infected children. Antivir Ther. 2004;9:297-9. http://amedeo.com/lit.php?id=15134193 12. Galli L, de Martino M, Tovo PA, et al. Onset of clinical signs in children with HIV-1 perinatal infection. Italian Register for HIV Infection in Children. AIDS. 1995;9:455-61. http://amedeo.com/lit.php?id=7639970 13. Gibb DM, Duong T, Leclezio VA, et al.; Collaborative HIV Paediatric Study Steering Committee. Immunologic changes during unplanned treatment interruptions of highly active antiretroviral therapy in children with human immunodeficiency virus type 1 infection. Pediatr Infect Dis J. 2004;23:446-50. http://amedeo.com/lit.php?id=15131469 14. Gotch F, Hardy G. The immune system: our best antiretroviral. Curr Opin Infect Dis. 2000;13:13-17. http://amedeo.com/lit.php?id=11964767 15. Grosch-Wörner I, Schäfer A, Obladen M, et al. An effective and safe protocol involving zidovudine and caesarean section to reduce vertical transmission of HIV-1 infection. AIDS 2000; 14:2903-11. http://amedeo.com/lit.php?id=11153672 16. Hazra R, Balis FM, Tullio AN, et al. Single-dose and steady-state pharmacokinetics of tenofovir disoproxil fumarate in human immunodeficiency virus-infected children. Antimicrob Agents Chemother. 2004;48:124-9. http://amedeo.com/lit.php?id=1469352 17. Lainka E, Oezbek S, Falck M, Ndagijimana J, Niehues T. Marked dyslipidemia in HIV-infected children on protease inhibitor-containing antiretroviral therapy. Pediatrics 2002;110:e56. http://amedeo.com/lit.php?id=12415062 18. Lockman S, Shapiro RL, Smeaton LM, et al. Response to antiretroviral therapy after a single, peripartum dose of nevirapine. N Engl J Med 2007;356:135-47. Abstract: http://amedeo.com/lit.php?id=17215531 19. Luzuriaga K, McManus M, Mofenson L, et al.; PACTG 356 Investigators. A trial of three antiretroviral regimens in HIV-1-infected children. N Engl J Med. 2004;350:2471-80. http://amedeo.com/lit.php?id=15190139 20. McComsey G, Bhumbra N, Ma JF, et al. Pediatric Switch Study. Impact of protease inhibitor substitution with efavirenz in HIV-infected children: results of the First Pediatric Switch Study.Pediatrics 2003;111:e275-81. http://amedeo.com/lit.php?id=12612284 21. McKinney RE Jr, Rodman J, Hu C, et al. Long-term safety and efficacy of a once-daily regimen of emtricitabine, didanosine, and efavirenz in HIV-infected, therapy-naive children and adolescents: Pediatric AIDS Clinical Trials Group Protocol P1021. Pediatrics 2007;120: Abstract: http://amedeo.com/lit.php?id=17646352 22. Mora S, Zamproni I, Beccio S, et al. Longitudinal changes of bone mineral density and metabolism in antiretroviral-treated human immunodeficiency virus-infected children. J Clin Endocrinol Metab. 2004;89:24-8. http://amedeo.com/lit.php?id= 4715822 23. Nachman SA, Stanley K, Yogev R, et al. Nucleoside analogs plus ritonavir in stable antiretroviral therapy-experienced HIV-infected children: a randomized controlled trial. JAMA 2000; 283:492-8. http://amedeo.com/lit.php?id=11579244 24. Nastouli E, Atkins M, Seery P, Hamadache D, Muir D, Lyall H. False-positive HIV antibody results with ultrasensitive serological assays in uninfected infants born to mothers with HIV. AIDS 2007;21:1222-3. http://amedeo.com/lit.php?id=17502739 25. Niehues T, Wintergerst U, Funk M, Notheis G, für die Konsensusgruppe der Pädiatrischen Arbeitsgemeinschaft AIDS (PAAD). Empfehlungen zur antiretroviralen Therapie bei HIV-infizierten Kindern - Vollständig überarbeitetes und aktualisiertes Konsensus-Statement der PAAD und der Deutschen Gesellschaft für Pädiatrische Infektiologie (DGPI) Monatsschr Kinderheilkd 2001; 149:1372-82. 26. Paediatric European Network for Treatment of AIDS (PENTA). Comparison of dual nucleoside-analogue reverse-transcriptase inhibitor regimens with and without nelfinavir in children with HIV-1 who have not previously been treated: the PENTA 5 randomised trial. Lancet 2002; 359:733-40. http://amedeo.com/lit.php?id=11888583 27. Persaud D, Siberry GK, Ahonkhai A, et al. Continued production of drug-sensitive human immunodeficiency virus type 1 in children on combination antiretroviral therapy who have undetectable viral loads. J Virol. 2004;78:968-79. http://amedeo.com/lit.php?id=14694128 28. Prendergast A, Tudor-Williams G, Jeena P, Burchett S, Goulder P. International perspectives, progress, and future challenges of paediatric HIV infection. Lancet 2007;370:68-80. Abstract: http://amedeo.com/lit.php?id=17617274 29. Saez-Llorens X, Nelson RP Jr, Emmanuel P, et al. A randomized, double-blind study of triple nucleoside therapy of abacavir, lamivudine, and zidovudine versus lamivudine and zidovudine in previously treated HIV type 1-infected children. The CNAA3006 Study Team. Pediatrics 2001, 107:E4. http://amedeo.com/lit.php?id=11134468 30. Saez-Llorens X, Violari A, Deetz CO, et al. Forty-eight-week evaluation of lopinavir/ritonavir, a new protease inhibitor, in human immunodeficiency virus-infected children. Pediatr Infect Dis J. 2003 Mar;22(3):216-24. http://amedeo.com/lit.php?id=12634581 31. Van Dyke RB, Lee S, Johnson GM, et al. Pediatric AIDS Clinical Trials Group Adherence Subcommittee Pediatric AIDS Clinical Trials Group 377 Study Team. Reported adherence as a determinant of response to highly active antiretroviral therapy in children who have human immunodeficiency virus infection. Pediatrics. 2002;109:e61. http://amedeo.com/lit.php?id=11927734 32. van Rossum AM, Fraaij PL, de Groot R. Efficacy of highly active antiretroviral therapy in HIV-1 infected children. Lancet Infect Dis 2002; 2:93-102 http://amedeo.com/lit.php?id=11901656 33. Verweel G, Sharland M, Lyall H, et al. Nevirapine use in HIV-1-infected children. AIDS. 2003 Jul 25;17(11):1639-47. http://amedeo.com/lit.php?id=12853746 34. Wang LH, Wiznia AA, Rathore MH, et al. Pharmacokinetics and safety of single oral doses of emtricitabine in human immunodeficiency virus-infected children. Antimicrob Agents Chemother. 2004;48:183-91. http://amedeo.com/lit.php?id=4693538 35. Working Group on Antiretroviral Therapy and Medical Management of HIV Infected Children, National Pediatric and Family Resource Center (NPHRC), Health Resources and Services Administration (HRSA) and National Institutes of Health (NIH). Guidelines for the use of antiretroviral agents in pediatric HIV infection, January 2004, http://www.aidsinfo.nih.gov/guidelines