International perspectives, progress, and future challenges of paediatric HIV infection

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International perspectives, progress, and future challenges of paediatric HIV infection Andrew Prendergast, Gareth Tudor-Williams, Prakash Jeena, Sandra Burchett, Philip Goulder Lancet 2007; 370: 68–80 See Editorial page 1 Department of Paediatrics, University of Oxford, Peter Medawar Building for Pathogen Research, Oxford OX1 3SY, UK (A Prendergast MRCPCH, Prof P Goulder DPhil); Department of Paediatrics, Division of Medicine, Imperial College London, London, UK (G Tudor-Williams MRCPCH); Department of Child Life and Health, HIV Pathogenesis Programme, University of KwaZulu-Natal, Durban, South Africa (P Jeena FCP, P Goulder); Division of Infectious Diseases, Children’s Hospital Boston, Harvard Medical School, Boston, MA, USA (S Burchett MD); and Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA (P Goulder) Correspondence to: Prof Philip Goulder [email protected]

Paediatric HIV infection is a growing health challenge worldwide, with an estimated 1500 new infections every day. In developed countries, well established prevention programmes keep mother-to-child transmission rates at less than 2%. However, in developing countries, where transmission rates are 25–40%, interventions are available to only 5–10% of women. Children with untreated natural infection progress rapidly to disease, especially in resource-poor settings where mortality is greater than 50% by 2 years of age. As in adult infection, antiretroviral therapy has the potential to rewrite the natural history of HIV, but is accessible only to a small number of children needing therapy. We focus on the clinical and immunological features of HIV that are specific to paediatric infection, and the formidable challenges ahead to ensure that all children worldwide have access to interventions that have proved successful in developed countries. Paediatric HIV infection is a worldwide public-health challenge in its own right that disproportionately affects children in the poorest parts of the world.1 Although advances in prevention and treatment have had a great effect in Europe and North America,2–5 only 1% of the 2·3 million children infected with HIV live in these regions.1 Over 90% of HIV-infected children live in sub-Saharan Africa, where the pandemic continues to grow, with an estimated 1500 children newly-infected daily.1 More than half these children could die by the age of 2 years,6,7 negating previous advances in the under-5 mortality rate.8 The scale of the epidemic and the rapid progression that is a hallmark of this disease in untreated children, especially in developing countries, emphasises the urgent need for worldwide access to antiretroviral therapy.9 At present, only 23% of HIV-infected people in sub-Saharan Africa who need antiretroviral therapy are receiving it,1 and only 5–7% of those on treatment are children.10 The tragedy of these devastating statistics is that paediatric HIV is a largely preventable pandemic.11 Most children are infected by mother-to-child transmission, which has fallen to less than 2% in developed

Search strategy and selection criteria We considered published material pertinent to the review topic, in addition to relevant publications identified by searching PubMed using the search term “paediatric HIV” or “HIV” in combination with “Africa”, “diagnosis”, “treatment”, “prophylaxis”, “mother-to-child transmission”, “cytotoxic T lymphocyte”, and “antibody”. Reference lists within articles identified by this search strategy were also searched. Review articles and book chapters have been included where appropriate because they provide comprehensive overviews that are beyond the scope of this Seminar. National or international guidelines and reports were also searched. Papers were prioritised by their importance and relevance to the review topic and to meet space constraints. Selected publications were largely from the past 10 years, but landmark older publications were not excluded.

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countries.12 Thus, paediatric HIV infection is now largely prevented and treated in countries where the prevalence is low, but remains largely unprevented and untreated in parts of the world where the prevalence is high. This Seminar focuses on international aspects of paediatric HIV, and contrasts the UK and USA with South Africa.1 An estimated 50 000 HIV-infected children are born every year in South Africa, compared with around 25 per year and 190 per year in the UK and USA, respectively.13,14 Furthermore, the economic capacity of these nations is very different, although the contrast is even more striking in other African countries at the centre of the epidemic (table 1). The disparity between the epidemiology and resources of countries most affected suggests that paediatric HIV infection is a long-term and growing pandemic.

Prevention The most effective way to address the paediatric HIV pandemic is prevention of mother-to-child transmission. However, most infected infants are born to women who are unaware of their status.15 Voluntary counselling and testing is a prerequisite to enable women to access programmes for prevention of mother-to-child transmission.15 Transmission can be reduced substantially in resource-poor settings, as reviewed elsewhere,16–18 but only 5–10% of pregnant women have access to such strategies.1 These programmes, based on WHO recommendations,19 clearly need to be expanded to make interventions available to all women. A major challenge in developing countries is mother-to-child transmission through prolonged breastfeeding.20–22 However, the risk of HIV transmission through breast milk must be balanced against the risk of increased morbidity and mortality from gastroenteritis and malnutrition in the absence of breastfeeding.23,24 Exclusive breastfeeding reduces HIV transmission two-fold to four-fold compared with mixed breastfeeding.25,26 Taken together, present WHO advice27,28 is that choices regarding infant feeding will depend on a mother’s individual circumstances. Mothers should breastfeed exclusively for the first 6 months of life unless formula feeding is acceptable, www.thelancet.com Vol 370 July 7, 2007

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UK

USA

South Africa

Southern African countries*

Total country population

59 000 000

298 000 000

47 000 000

79 000 000 (combined)

GNI per head (US$)

33 940

41 400

3630

740

Infant mortality rate (per 1000 livebirths)

5

7

54

102

Under-5 mortality rate (per 1000 livebirths) 6

8

67

152

Life expectancy (years)

79

78

47

38

Antenatal HIV prevalence

0·18% UK overall 0·55% Inner London

<0·2% USA overall

30·2% overall 40·4% KwaZulu-Natal

5–39% (median 20%)

MTCT rate (without intervention)

15-20%

15-20%

19-36%

25-40%

MTCT rate (with interventions)

<2%

<2%

10-15 %

10-20%

MTCT uptake

~95%

~93%

~25%

~5-10%

Number of births yearly

660 000

4 100 000

1 090 000

3 100 000 (total)

Number of infected infants born per year

~25

~190

~50 000

~150 000 (total)

Main carers for HIV-infected children

90% biological parent(s) 7% extended family 2% adopted 1% in foster care

53% biological parent(s) 33% extended family 9% adopted 6% in foster care

40% biological parent(s) NK 50% extended family 5% adopted 5% in foster care

MTCT=Mother-to-child transmission. ~=approximate. NK=not known. Infant mortality rate and under-5 mortality rate: 2004 data from UNICEF, UN Population Division, and UN Statistics Division. Gross National Income (GNI): 2004 data from World Bank. Country populations, yearly number of births, and life expectancy: 2004 data from UN Population Division. Country populations for southern African countries excluding South Africa are combined; other data for southern African countries expressed as medians for combined data. HIV prevalence data from references 1, 13, 14; see text. Where figures are not available, number of HIV-infected children born every year are estimates calculated from the above data. *Combined data for Lesotho, Swaziland, Mozambique, Zimbabwe, Malawi, Zambia, Botswana, Namibia, and Angola.

For 2004 data from UN Population division see http://www.unicef.org/statistics/ index_countrystats.html

Table 1: Epidemiology of paediatric HIV in UK, USA, South Africa, and other southern African countries excluding South Africa

feasible, affordable, sustainable, and safe. At 6 months, if formula feeding does not still meet these requirements then breastfeeding should continue, with introduction of complementary foods. These issues, including continuing studies that address reduction of mother-to-child transmission through breast milk, are reviewed elsewhere.29–32

Natural history of paediatric HIV infection Most paediatric HIV infections are acquired through mother-to-child transmission,33 although infection via contaminated blood products or tissue, unsafe injection, or incision practices, and sexual abuse also takes place.34–36 In adolescents, horizontal spread through sexual contact and injection drug use are also substantial methods of transmission.33,37 The overall risk of mother-to-child transmission without interventions is 15–30% in Europe and USA38–40 but 25–40% in sub-Saharan Africa,40–43 because of differences in population characteristics, obstetric practice, and method of infant feeding. Overall, in the absence of interventions to prevent transmission, two-thirds of mother-to-child transmission takes place in the peripartum period, which can either occur in utero (around a third of cases), mostly late in the third trimester,44 or intrapartum (around two-thirds of cases). Mother-to-child transmission also arises postpartum during breastfeeding.20,21 In a randomised trial21 of breastfeeding versus formula feeding, undertaken in Kenya, 44% of infections in the breastfeeding group were attributable to breast-milk transmission. This study, and others,45,46 showed that the first few weeks of life are a particularly high-risk period, since colostrum and early milk have a higher viral load than late www.thelancet.com Vol 370 July 7, 2007

milk.47 However, transmission can take place at any time during breastfeeding; a meta-analysis of nine trials showed a cumulative risk that remains constant from 1 month to 18 months of age.20 Historical natural-history studies in the USA and Europe showed that, in the absence of antiretroviral therapy and cotrimoxazole prophylaxis, about 20% of infants vertically infected with HIV were rapid progressors and developed AIDS or died within the first year of life.48,49 These infants were more likely to be born to mothers with advanced disease or to be infected in utero than were children whose disease course was slower.50,51 These rapid progressors present in the first months of life, with failure to thrive, chronic diarrhoea, oral thrush, hepatosplenomegaly, lymphadenopathy, and encephalopathy. A classic presentation around 10–14 weeks of age is severe respiratory disease, caused by Pneumocystis jirovecii (formerly carinii) pneumonia, cytomegalovirus, or both, and even with intensive-care support mortality is high (20–30%).52 Older children present with recurrent infections. Otitis media, sinusitis, lymphadenitis, and skin infections are common, although some children present with more serious infections (pneumonia, meningitis, sepsis). Severe primary or recurrent varicella, measles, or widespread molluscum contagiosum can arise, and many children will have growth faltering and lymphoproliferative manifestations (hepatosplenomegaly, lymphadenopathy, parotitis). Lymphoid interstitial pneumonitis, a disorder characterised by diffuse lymphocytic lung infiltrates, possibly in response to primary infection with EpsteinBarr virus,53 is common after infancy. Clinical presentation ranges from asymptomatic disease to chronic lung disease 69

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in children with fairly well preserved immune function, often in association with other lymphoproliferative manifestations. The disorder is easily misdiagnosed radiologically as pulmonary tuberculosis. The natural history of paediatric HIV in developed countries has changed since the introduction of antiretroviral therapy. Zidovudine monotherapy improved clinical outcome, especially in children with encephalopathy,54 and antiretroviral therapy with two or three drugs reduced progression to AIDS or death.2,3,5 In the UK, progression to AIDS has decreased by 50% and mortality by 80%,4 since highly-active antiretroviral therapy (HAART) became available in 1997, and children are now surviving into adolescence and adulthood. Without treatment, HIV-infected children in developing countries have a mortality rate of 45–59% by 2 years of age,6,7,55 compared with 10–20% in Europe and USA.48,49 Factors that contribute to this difference include a higher rate of other infections, malnutrition, and micronutrient deficiencies in developing countries than in developed countries. HIV-infected children have a ten-fold increased childhood mortality risk compared with HIV-uninfected children.56 Furthermore, children are affected by HIV, even if they are not infected; mortality in children under 5 years of age is three times greater in those born to HIV-infected mothers than in those born to HIV-uninfected mothers.57 Children often become carers for their sick parents, and over 15 million children are already orphaned as a result of the HIV pandemic.58 Irrespective of HIV status, there is a seven-fold higher mortality rate for children whose mothers have died than for those whose mothers are alive.8 Orphaned children are frequently cared for by grandparents, other family members, or each other. Caregivers often struggle financially to provide for this extended family.59 Orphans who do not have caregivers can be exposed to poverty, homelessness, and child exploitation.60 In resource-poor settings, paediatric HIV presents early with infections, and the disease has an especially high case-fatality rate in infants.61 Pneumocystis jirovecii pneumonia is common in African children,62,63 despite earlier reports.64,65 HIV-infected children with pneumonia and other invasive bacterial diseases present in a similar way to HIV-uninfected children, but convalescence is slower and treatment failure higher in children with HIV than in those who are uninfected.66 Children with HIV infection are more at risk of malnutrition because of anorexia, oral infection, malabsorption, diarrhoea, increased metabolic requirements, and cytokinemediated wasting.66 Diarrhoea is the most common cause of death in infancy, either because of rotavirus (the most common pathogen), HIV enteropathy, or other opportunistic infections.66 Persistent diarrhoea in HIV-infected children has an 11-fold increased risk of death compared with persistent diarrhoea in HIVuninfected children.67 70

Coinfection with other organisms is more common in developing countries than in developed countries. In South Africa, 30–50% of HIV-infected children are coinfected with tuberculosis.68,69 HIV increases the risk of this disease up to 20-fold,70 and this risk is strongly associated with the degree of immunosuppression.71 Furthermore, infection is more severe; primary progressive and disseminated disease is more common, relapse more likely, and overall mortality higher in children with HIV than in HIVuninfected children.71–73 In one African series, tuberculosis was the third most common cause of death in HIV-infected children with severe pneumonia.74 Tuberculosis is difficult to diagnose in children, even in the absence of HIV, because sputum can be difficult to collect and mycobacteria are often not found.75 Diagnosis is even more difficult in HIV-infected children. Signs and symptoms of both diseases overlap, chest radiograph findings are less specific for children with HIV than for those uninfected, and the tuberculin skin test is often negative because of anergy.75,76 Treatment therefore is often presumptive and based on known contact history and empiric response to treatment. Although the principles of treatment are the same as in HIV-uninfected children, a longer regimen may be required for those infected, and therapy is complicated by overlapping toxic effects and drug interactions.76 HIV-infected children living in malarial areas have more frequent episodes of malaria, higher levels of parasitaemia, and more severe malarial anaemia than do non-HIV infected children.77,78 The median viral load of HIV-infected children with malaria is up to seven-fold higher,79 and there is evidence that malaria increases the risk of mother-tochild transmission of HIV because of its predilection for the placenta.80 Helminth infections are also common in African populations and could be associated with higher viral load as a result of chronic immune activation caused by the parasite burden.81

Immune control The immune system can contain HIV, at least temporarily, and, in some instances, long term. CD8+ cytotoxic T lymphocytes (CTL)82–84 play a central part in this HIVspecific immune response (figure).82,84–87 The most direct evidence comes from studies in the simian-immunodeficiency-virus-macaque model, in which anti-CD8 monoclonal antibody infusions showed that CD8+ T cells mediate the decline in acute viraemia in adult infection, and contribute to maintenance of the viral setpoint in chronic infection.88–90 Furthermore, in long-term nonprogressors, loss of immune control could be precipitated by the selection of viral escape mutations that enable virusinfected cells to evade recognition by CTL.91–93 In paediatric infection, during the first year of life, when viral loads remain high at 1×10⁵–1×10⁶ copies per mL, HIVspecific CTL activity is generally hard to detect.94 The substantial fall in viraemia in acute adult infection is, correspondingly, not seen (figure). Although viral loads do drop gradually over the first years of life,85,95 whether this www.thelancet.com Vol 370 July 7, 2007

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Adult

Children

107

107

106

106

Viral load

Viral load (copies per mL)

trend is mediated by the gradual emergence of HIV-specific CTL is not firmly established. Long-term control of HIV is less common in paediatric than in adult infection, but reports suggest that HLA alleles such as B*2705 and B*5701 can operate as effectively in paediatric infection as they do in adult infection.92,96 HLA class I molecules present fragments of internally-processed HIV proteins on the surface of infected cells for recognition by CTL. Loss of long-term control after late escape in the B*2705-restricted p24 Gag epitope is seen in both children and adults.92 In the case of B*5701, viral mutation within the dominant p24 Gag epitope targeted in acute infection allows HIV to escape CTL recognition, but only at a substantial cost to viral fitness,97,98 thereby helping with subsequent immune control of HIV by the remaining immune responses. Thus, CTL can have an effective role in suppression of HIV in paediatric infection. The role of other parts of the immune response in control of HIV infection is uncertain. Neutralising antibodies can be generated early in the course of infection99–101 and, unlike CTL, have the potential to provide sterilising immunity.102 However, successful evasion of the neutralising antibody response by mutation within the env gene takes place readily100 and, in contrast to CTL escape, has not been associated with subsequent immune control or a substantial fitness cost to the virus. Several specific challenges face HIV-infected children in generation of an effective immune response (panel 1). First, paediatric transmission happens before the immune system is fully developed. In some infants, the virus can destroy much of the immune system before HIV-specific immune responses can be mounted.103 Second, infected children carry maternally-inherited HLA genes associated with poor control of HIV, since the risk of mother-to-child transmission is strongly related to maternal viral load.104 High viral load is associated with HLA class I alleles, such as HLA-B*1801 and B*5802.105 HIV-infected children are therefore more likely to express these alleles associated with high viraemia than are uninfected children.105 Third, the virus transmitted from a mother with a high viral load is well-adapted to maternally-inherited HLA class I molecules. Thus, even if the child has an advantageous allele such as B*2705, this advantage is lost since the maternally-transmitted virus typically carries escape mutations within the key B*2705-p24 Gag epitope.106,107 The transmitted virus could also be adapted to paternally inherited HLA genes, since the mother often becomes infected by transmission from the child’s father.108 Finally, use of prophylaxis, such as single-dose nevirapine, to prevent mother-to-child transmission means that, when paediatric transmission does take place, the mother typically has a high viral load or transmission has occurred in utero,86 either of which is associated with rapid progression in the child.50,51 An additional factor is the passive transfer of nonneutralising, maternally derived antibodies, which could have a negative effect on the ability of the infant to generate HIV-specific immune responses.94

CTL 105

104

105

Viral load

104

103

103

102

102

CTL

Transmission

6 months

Transmission

6 months

Figure: Changes in viral load over time and magnitude of virus-specific cytotoxic T lymphocyte (CTL) activity in untreated adult and paediatric HIV infection Data drawn from references 82, 84–87. Median viral setpoint in adult B and C clade infection 30 000 HIV RNA copies per mL plasma. Mean viral load in first 6 months of US B clade-infected cohort85 was 6–8x10⁵ copies per mL and median in South African C clade-infected cohort86 1·7x10⁶ copies per mL.

The paediatric immune system does, however, have some immunological advantages. First, there seems to be greater flexibility in paediatric HIV-specific CTL activity than in adults, such that, as the virus develops escape mutations, novel variant-specific CTL responses can be generated.95 By contrast, variant-specific CTL are not typically reported in adult infection.96,109 Second, HIV-specific T-helper activity, a prerequisite to functional CTL activity, usually decreases after introduction of HAART in chronic adult infection.110 Panel 1: Advantages and disadvantages of paediatric versus adult infection with respect to immune control of HIV Disadvantages • Infection takes place before immune system fully developed; destruction of developing immune system by HIV • High frequency of HLA genes associated with poor control of HIV • Transmitted virus adapted to maternal (and paternal) HLA alleles and therefore pre-adapted to child’s HLA • Prevention of mother-to-child transmission interventions (eg, single-dose nevirapine) increase proportion of infected infants progressing rapidly to disease (though transmission rates reduced) • Passive maternally derived, non-neutralising anti-HIV antibody present (could inhibit development of HIV-specific immune responses) Advantages • Active thymus—capacity to generate new variant-specific cytotoxic T lymphocyte activity responses after viral escape • Active thymus—potential to generate HIV-specific T helper responses after initiation of highly-active antiretroviral therapy in chronic infection

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However, suppression of viraemia by this treatment, initiated in chronic paediatric infection, is associated with the generation of HIV-specific T-helper responses.87 The presence of an active thymus in children therefore suggests opportunities for immunotherapeutic interventions that might not be available in adult infection.

Management Identification of HIV-infected children by reliable, affordable techniques is essential to enable early institution of prophylaxis and treatment. The simplest laboratory test, used to diagnose HIV infection in adults, is an antibody test (usually by ELISA). Although this test is suitable for children older than 18 months, up to this time transplacental-maternal antibody persists, and a positive result is therefore diagnostic only of maternal infection. The gold standard for children under 18 months is an HIV-DNA PCR.111 Other assays, such as real-time PCR112 and the ultrasensitive p24 antigen assay,113 could be more affordable but remain largely unavailable in Africa.66 Quantitative RNA PCR viral load assays have been advocated in developing countries as an alternative to DNA PCR testing because of increased accessibility and turnaround time.76,114 However, users should be cautious of interpreting low positive results close to the assay cutoff as evidence of infection since these could be false-positives.115 When sequence differences exist between HIV subtypes there is potential for under-diagnosis by PCR, but this possibility has been kept to a minimum by use of primers binding to conserved regions. Samples for PCR testing can be obtained from infants by heel-prick onto filter paper as dried blood spots and transported to a centralised laboratory,116 although this method remains expensive and result reporting can be slow. There is also evidence that when single-dose nevirapine is used to prevent mother-to-child transmission, use of dried blood spots in the first days of life can underdiagnose infection by RNA PCR.86,117 In many developing countries, where virological diagnostic techniques remain unaffordable, low-cost alternatives are urgently needed. CD4 count has been advocated as a surrogate marker of HIV infection in early life, but the diagnostic performance needs to be assessed in larger cohorts of infants.118 There has also been interest in the use of simple clinical algorithms to diagnose HIV infection. However, algorithms are better at detecting advanced disease than early disease. Overall, their reported sensitivity assessed in various settings is 41–80%, with a specificity of 79–94%.119,120 Diagnosis of HIV-uninfected infants, in the absence of breastfeeding, should rely on two negative PCR tests after the first month of age, together with a loss of maternal antibodies at 18 months of age.121 However, in developing countries, extended exposure to breastfeeding complicates diagnosis of HIV-uninfected infants because of late postnatal transmission.20 WHO’s advice is to undertake (or 72

repeat) virological testing 6 weeks or longer after complete cessation of breastfeeding to ensure infants are not infected.76

Monitoring Until 2006, two classification systems were in use internationally: the Centers for Disease Control (CDC)122 and WHO Classification systems.123 There were limitations with both; CDC often needed advanced diagnostic technology and did not include more common manifestations seen in developing countries. WHO focused on a narrow range of clinical manifestations and did not include measures of immunological status. A revised fourstage WHO classification system aims to replace the previous CDC and WHO systems.124 CD4 count and viral load are surrogate markers of disease progression in children, and in adults.125 The normal absolute CD4 count varies widely with age, so CD4% is preferred in young children.126 However, above the age of 5 years, absolute counts in children carry the same prognostic significance as in adults. For simplicity, WHO has therefore recommended the same thresholds for clinical decisionmaking in children older than 5 years as in adults.76 Both CD4% and viral load are independent predictors of clinical progression, although CD4% is the stronger predictor.127 In developing countries, where cost of laboratory monitoring of HIV disease could exceed the cost of antiretroviral therapy,128 there is a need for inexpensive markers of disease progression and treatment response. Affordable technology based on microchips to measure CD4 counts on finger-prick blood samples shows promise as a simple and rapid point-ofcare test to guide initiation of antiretroviral therapy.129 Changes in haemoglobin,130 total lymphocyte count,131,132 and clinical condition76 have been proposed as ways to monitor response to treatment, although viral load testing remains the optimal method to detect early treatment failure. However, this remains expensive and use of viral load testing may need to be restricted to patients at high risk of virological failure.133

Treatment Cotrimoxazole is an inexpensive, widely available antibiotic that has prophylactic activity against Pneumocystis jirovecii and many common bacteria, and reduces mortality by 43% even in an area of high bacterial resistance.134 Guidelines for use of cotrimoxazole prophylaxis in developing135 and developed countries136,137 are available. Children under 5-years of age exposed to an adult with smear-positive tuberculosis should receive isoniazid prophylaxis after excluding tuberculosis disease.66 HIV-infected children have a greater risk of vaccinepreventable diseases than do those not infected; therefore vaccination, despite being less effective in these children, is important. WHO recommendations have been to give the standard Expanded Programme on Immunisation (EPI) schedule to HIV-infected infants, with the exception www.thelancet.com Vol 370 July 7, 2007

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Panel 2: Challenges in the effective use of highly-active antiretroviral therapy that are specific to paediatric HIV infection • Inadequate pharmacokinetic data • No paediatric formulation available • Doses need adjustment as children grow (to avoid underdosing and drug resistance) • Adherence challenging because of formulations (poor palatability of syrup, large tablets for children) and dietary restrictions • Fewer drug choices (eg, amprenavir, efavirenz not approved for children less than 3 years of age) than for adults • Fewer data for drug toxicity in children (eg, lipodystrophy) than for adults • Presentation of toxic effects might be non-specific in young children • Long-term toxic effects could be greater because of increased duration of therapy started in childhood than in adulthood • Young children reliant upon care-givers, who may be ill themselves, to give drugs • Adherence might be difficult at certain ages (eg, infancy, adolescence) • Children might not be aware of HIV status, compounding difficulties with adherence

of yellow fever and BCG vaccinations in symptomatic HIV infection.138 New WHO guidance on use of BCG in infants takes into account prevalence of tuberculosis, knowledge of maternal and infant HIV status, and signs or symptoms of disease.139 An additional dose of measles vaccine should be given at 6 months of age in developing countries. Many experts recommend conjugate pneumococcal vaccination,136,137 which should be given together with Haemophilus influenzae type b conjugate vaccination when affordable, since the frequency of invasive bacterial infections in HIV-infected children is high. A nine-valent pneumococcal vaccine (including serotypes one and five) given to HIV-infected children in Soweto, South Africa, substantially decreased episodes of pneumonia and invasive bacterial disease.140 Vitamin A supplementation reduces morbidity and mortality in HIV-infected and uninfected children and should be given routinely in developing countries.141 Growth failure is common in HIV-infected infants and associated with early mortality.142 Adequate nutrition with locally-available foods, and prevention of micronutrient deficiencies, is therefore important.66 Additionally, maternal health and nutrition should be encouraged and basic hygiene education addressed. HAART is part of the standard of care for HIV-infected children in developed countries, to improve health, enable optimum development, and prevent emergence of encephalopathy.143 This therapy can suppress viral loads to undetectable levels (<50 copies per mL) and enable CD4 www.thelancet.com Vol 370 July 7, 2007

recovery,144 although long-term suppression of viraemia in children, as in adults, remains difficult.145 Immune restoration in children may be better than in adults because of an active thymus;146 initiation of HAART is associated with a substantial increase in naive thymic emigrants.147 Many children show a discordant response, with sustained clinical and immunological improvement on treatment, despite an absence of complete virological suppression.148 Efficacy should be balanced with practicality in choosing a drug combination,143 but which are the optimum HAART regimens for children is unclear. Standard practice is to use three drugs (or sometimes four drugs in infants): two nucleoside reverse transcriptase inhibitors and either a protease inhibitor or non-nucleoside reverse transcriptase inhibitor.149,150 PENPACT-1,151 an ongoing European and US collaborative trial, is addressing the issue of the best initial paediatric HAART regimen. There are advantages and disadvantages to every class of drug, and choices in children are restricted by additional factors not encountered in adult practice (panel 2). Some drugs (eg, tenofovir and atazanavir) are not available in paediatric formulations. Even drugs that are available as liquids can require very large volumes to be taken (eg, stavudine), be unpalatable (eg, ritonavir), need refrigeration (eg, lopinavir), or have a short shelf-life (eg, didanosine), which leads to practical difficulties in giving drugs to young children. Furthermore, pharmacokinetic data are not available for some drugs, or are extrapolated from adult studies, which results in uncertain dosing regimens. Doses for paediatric antiretroviral therapy are calculated on the basis of either weight or surface area and should be increased as the child grows to avoid underdosing, which happens frequently.152 Clinicians try to choose the simplest and most convenient regimen, taking into account the age of the child, side-effect profile, expected adherence, and coexistent disorders in every child. Starting antiretroviral therapy is never an emergency, and care-givers should be fully informed and in agreement if treatment is to succeed.150 Adherence is especially challenging in children because of difficulties with medication and reliance on adult care-givers who might themselves be ill or have troubled social circumstances. Adherence to treatment predicts virological and clinical response to therapy153 but poor adherence is common,154 and support is often needed from the multidisciplinary team. In younger children, gastrostomy tube insertion can be beneficial.155 Guidelines for when to start treatment in Europe (PENTA),150 the USA (working group on antiretroviral therapy and medical management of HIV-infected children,149 and developing countries (WHO)76 are available. However, the best possible time to initiate therapy remains unclear, especially in infants150 who could develop rapid immunological decline and encephalopathy,156 with no good indicators to predict rapid progressors.127 HAART started before 3 months of age might reduce risk of encephalopathy and lead to 73

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improved long-term viral suppression to 4 years of age.157 Two trials taking place in South Africa (Children with HIV Early antiRetroviral therapy [CHER] and Paediatric Early HAART STI Study [PEHSS]) will compare outcome of infants randomly assigned to early or deferred HAART. Early treatment of infants could result in development of drug resistance if high viral loads are not completely suppressed.158 When single-dose nevirapine has been used for prevention of mother-to-child transmission, resistance to the drug can be seen in many infants before initiation of antiretroviral therapy.159,160 One study showed an adverse effect of single-dose nevirapine exposure on subsequent treatment response in ten of 15 infants who started an NNRTI-containing regimen.161 However, pending further evidence, WHO guidance suggests that children should still be regarded as eligible for this firstline therapy.76 There is clearly a potential role for the next generation of NNRTIs, such as TMC125, which needs assessment. All antiretroviral drugs have potential side-effects and families should be warned of these before treatment is started. Gastrointestinal disturbance, especially with protease inhibitors, is common and usually self-resolves, although short-term symptomatic treatment might be needed. Rashes are also common and, although some could be mild, others might be early signs of severe reactions (eg, nevirapine or abacavir), and care-givers should be able to contact clinic staff easily for advice. Longer-term toxic effects in children are of concern because children require much longer treatment than do adults. All the metabolic complications reported in adults have been seen in children. Mitochondrial toxicity from nucleoside reverse transcriptase inhibitors presents nonspecifically and, although rare, can be fatal.162 Fat redistribution syndrome, dyslipidaemia, and insulin resistance can develop, especially in children on proteaseinhibitor drugs.163–165 Use of statins in children is rare; clinicians tend to change HAART regimens if there are substantial metabolic disturbances. Provision of antiretroviral therapy in developing countries has started, although there needs to be a huge expansion if the G8 target of universal treatment by 2010 is to be achieved. WHO has advocated a public-health approach to the treatment initiation process, with standardisation and simplification of regimens, and it recommends combinations based on non-nucleoside reverse transcriptase inhibitors as first-line therapy.76 However, increased availability of affordable and appropriately formulated generic drugs for children is urgently needed to enable this implementation to take place. Liquid formulations might not be appropriate in developing counties, where refrigeration and regular access to clinics is difficult. More crushable, dispersible, and granular solid formulations are needed in paediatric doses. Adult fixed-dose combinations (of stavudine, lamivudine, and nevirapine) divided into parts have been used successfully in children and can be a transitional 74

option, but paediatric fixed-dose combinations need to be made available.166–168 Prescription of antiretroviral therapy by weight bands would also simplify treatment for clinic staff starting large numbers of children on therapy.76 Many children in developing countries will also need treatment for tuberculosis. This issue is not always straightforward, because rifampicin interacts with nonnucleoside reverse transcriptase inhibitor and protease inhibitor drugs and can lead to subtherapeutic dosing. WHO’s recommendation for first-line HAART in children coinfected with HIV and tuberculosis is a triple nucleoside reverse transcriptase inhibitor regimen.76 Initiation of tuberculosis therapy is the priority, and the optimum time to start antiretroviral therapy is uncertain. WHO guidance is that children with stage four disease, or stage three disease with severe immunodeficiency, should start HAART after 2–8 weeks of tuberculosis treatment; for less advanced HIV disease, this therapy should be delayed until after tuberculosis treatment, if possible.76 In addition to improvement of adherence and keeping drug interactions to a minimum, this strategy could reduce the risk of immune reconstitution inflammatory syndrome. This syndrome is thought to be due to restoration of immune responses to previously treated opportunistic infections, or to unrecognised occult infections.169 So far, establishment of antiretroviral therapy programmes in developing countries has been fragmented, and often backed by non-governmental organisations.170 However, impressive results have been achieved. Studies from South Africa, Kenya, and Côte d’Ivoire171–175 have shown good immunological and virological responses in children started on a variety of HAART regimens, despite advanced disease. Of the 544 children started on therapy in Côte d’Ivoire since June, 2004, 84% were still being followed-up 1 year later.176 However, models estimate that a large number of children will need to start treatment in developing countries.177 In a cohort of infected infants in Durban, South Africa, 85% fell below the 25% CD4 threshold proposed by WHO guidelines by 6 months of age.86 Health-care infrastructure will need to be substantially expanded, including training new staff and reversing the trend of staff emigrating abroad, to be able to cope with such demands. The Baylor International Pediatric AIDS Initiative (a collaboration between Baylor College of Medicine, Texas, and five southern Africa countries) has established a network of HIV treatment centres, with 9825 children in follow up and 4062 children on HAART by August, 2006.178 Such partnerships with developed countries will help to increase access to sustainable treatment programmes, improve training, and encourage research in developing countries at the centre of the pandemic.179 Since the epidemiology, natural history, and resources differ between countries, the management of paediatric HIV depends on the setting. To emphasise these differences we contrast three hospitals: St Mary’s Hospital, www.thelancet.com Vol 370 July 7, 2007

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London, UK; Children’s Hospital, Boston, USA; and King Edward VIII Hospital, Durban, South Africa, (table 2). Although the infrastructure of these clinics differs, each has developed a family-centred approach, since HIV often affects several household members. Family clinics enable a multidisciplinary team to integrate medical, social, and psychological care for children and their infected parent or parents.180 Disclosure

of a child’s diagnosis can be difficult because of the effect on other family members, uncertainty about the future, and stigmatisation. Parents are often concerned that disclosure could have a negative psychosocial effect on the child.181 Although most children should understand their diagnosis by adolescence, disclosure is a process rather than a single event and should start early with part explanations appropriate to the child’s age. Integration of

King Edward VIII Hospital, Durban, South Africa

St Mary’s Hospital, London, UK

Children’s Hospital, Boston, USA

Number of children in follow-up

350

225

140

Clinic model

Family clinic

Perinatal/paediatric/adolescent clinics

Perinatal/paediatric/adolescent clinics

Clinic team

Paediatric infectious disease specialists, clinical nurse specialist, Physiotherapist, occupational therapist, dietician, social worker

Paediatric infectious disease specialists, clinical nurse specialists, psychologist, physiotherapist, occupational therapist, dietician, pharmacist, social worker

Paediatric infectious disease specialists, neurodevelopmentalist, social worker

Frequency of follow-up (if stable)

3 monthly

3 monthly

2–3 monthly

Prevalence of coinfections Tuberculosis

30–50%

5% disease, 8% latent tuberculosis

1–2%

Hepatitis B, hepatitis C

Rare

Rare (~2–3%)

3–5%

Helminths

Rare

2%

Rare

Prophylaxis

Cotrimoxazole Isoniazid for tuberculosis contacts Fluconazole for recurrent candidosis

Cotrimoxazole MAC/HSV/fungal: if CD4<5% Valaciclovir if recurrent VZV

Cotrimoxazole Azithromycin/fluconazole if CD4<5% Valganciclovir if CMV and CD4<10% Valaciclovir if recurrent VZV

Children on antiretroviral therapy (%)

6·7%

84%

93%

Use of gastrostomies

Nil

~3% children for medication

~5% children for medication

Typical first-line regimen

2 NRTIs+NNRTI (>3 years) eg, stavudine+lamivudine+efavirenz 2 NRTIs+PI (<3 years) eg, stavudine+lamivudine+lopinavir/r

2 NRTIs+NNRTI eg, abacavir+lamivudine+nevirapine or efavirenz. Adolescents may start with 2 NRTIs and PI (lopinavir/ritonavir)

2 NRTIs+NNRTI if adherent eg, zidovudine+lamivudine+nevirapine or efavirenz 2 NRTIs+PI if adherence questionable eg, zidovudine+lamivudine+nelfinavir mesilate

Typical second-line regimen

2 NRTIs (different)+PI eg, didanosine , zidovudine, lopinavir/r (>3 years) 2 NRTIs (different)+NNRTI Eg, didanosine , zidovudine, nevirapine (<3 years)

2 NRTIs (different)+PI eg, didanosine , zidovudine, or tenofovir (depending on age), lopinavir/r

2 NRTIs (different)+PI (different) eg, didanosine, tenofovir, lopinavir/r

% with undetectable viral load (first-line antiretroviral therapy)

Data unavailable

79% <50 copies per mL at 6 months

80% <50 copies per mL at 6 months

% children exposed to >5 drugs

Data unavailable

37%

25% <10 years; 75% >10 years

Median time to switching to 2nd regimen

Data unavailable

7 years

5 years

Role of therapeutic drug monitoring

Research use only

Used to assess adherence or toxicity or in situations where viral load suboptimal

Used to assess adherence or if drug interactions or where viral load suboptimal

Role of resistance tests

Not tested routinely; only research

Genotypic resistance test if viral load not fully suppressed, and before initial antiretroviral therapy

Genotypic resistance if changing therapy (or phenotypic if heavily antiretroviral therapy treated)

Third-line regimen

Complete change in regimen not feasible Restricted drugs available

Newer agents such as enfuvirtide /TMC114/TMC-125

Change NRTI and add newer agents such as enfuvirtide/TMC-114/TMC-125

Treated mortality

5·8–8·6% at 2 years

~1% at 2 years

<1% at 2 years

MAC=mycobacterium avium complex. HSV=herpes simplex virus. VZV=varicella zoster virus. NRTI=nucleoside reverse transcriptase inhibitor. NNRTI=non-nucleoside reverse transcriptase inhibitor. PI=protease inhibitor. CMV=cytomegalovirus. ~=approximate.

Table 2: Clinic infrastructure and treatment differences in UK, USA, and South Africa

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HIV services in a family clinic also eases transition of adolescents from paediatric to adult services, enabling young people to become more included in treatment decisions. Adolescents might also need supportive, nonjudgmental, and confidential counselling about sexual health, drug use, and pregnancy. In summary, there have been dramatic advances in the management of HIV disease in developed countries, such that most children now survive into adulthood. Nevertheless, the paediatric HIV pandemic continues to grow and major challenges need to be met to reverse this trend. Every year 380 000 children die from a mostlypreventable and treatable disease.1 Universal access to HIV testing and prevention of mother-to-child transmission programmes would be the most effective intervention to reduce the number of infected children. Early testing of exposed infants to diagnose HIV infection before progression to AIDS or death would enable implementation of prophylaxis and treatment, which must be made universally available to those who need it. The health needs of HIV-infected children should be pushed higher up the political agenda, and a commitment made to increase the availability of affordable, appropriately formulated drugs. Without increased public health and political commitment, interventions that have proved very successful in developed countries will remain inaccessible to almost all children affected by HIV worldwide. Conflict of interest statement We declare that we have no conflict of interest. Acknowledgments Funding support is acknowledged from the Medical Research Council (AP), Wellcome Trust and NIH (PG). We thank the children and families under our care and the dedicated teams of health professionals with whom we work. References 1 UNAIDS/World Health Organisation. AIDS Epidemic Update, December, 2006. http://www.unaids.org/en/HIV_data/epi2006/ (accessed Jan 16, 2007). 2 Five year follow up of vertically HIV infected children in a randomised double blind controlled trial of immediate versus deferred zidovudine: the PENTA 1 trial. Arch Dis Child 2001; 84: 230–36. 3 De Martino M, Tovo PA, Balducci M, et al. Reduction in mortality with availability of antiretroviral therapy for children with perinatal HIV-1 infection. Italian Register for HIV Infection in children and the Italian national AIDS registry. JAMA 2000; 284: 190–97. 4 Gibb DM, Duong T, Tookey PA, et al. Decline in mortality, AIDS, and hospital admissions in perinatally HIV-1 infected children in the United Kingdom and Ireland. BMJ 2003; 327: 1019. 5 Gortmaker SL, Hughes M, Cervia J, et al. Effect of combination therapy including protease inhibitors on mortality among children and adolescents infected with HIV-1. N Engl J Med 2001; 345: 1522–28. 6 Dabis F, Elenga N, Meda N, et al. 18-Month mortality and perinatal exposure to zidovudine in West Africa. AIDS 2001; 15: 771–79. 7 Obimbo EM, Mbori-Ngacha DA, Ochieng JO, et al. Predictors of early mortality in a cohort of human immunodeficiency virus type 1infected African children. Pediatr Infect Dis J 2004; 23: 536–43. 8 World Health Organization. The world health report: make every mother and child count. WHO, Geneva 2005. http://www.who.int/ whr/2005/en/ (accessed Dec 4, 2006). 9 World Health Organization/UNAIDS. Treating 3 million by 2005. Making it happen: the WHO strategy. 2003. http://www.who.int/ 3by5/publications/documents/en/Treating3millionby2005.pdf (accessed Dec 4, 2006)

76

10

11 12

13

14

15

16

17 18

19

20

21

22

23

24

25

26

27

28

Boerma JT, Stanecki KA, Newell ML, et al. Monitoring the scale-up of antiretroviral therapy programmes: methods to estimate coverage. Bull World Health Organ 2006; 84: 145–50. Dabis F. Children and HIV in Africa: what is next? Lancet 2003; 362: 1597–98. European Collaborative Study. Mother-to-child transmission of HIV infection in the era of highly active antiretroviral therapy. Clin Infect Dis 2005; 40: 458–65. Health Protection Agency Centre for Infections, and Health Protection Scotland. Unpublished quarterly surveillance tables number 70, 06/1, table 13b. http://www.hpa.org.uk/infections/ topics_az/hiv_and_sti/hiv/epidemiology/files/2006_Q1_Mar_HIV_ Quarterlies.pdf (accessed Dec 4, 2006). Centers for Disease Control and Prevention. Achievements in Public Health: Reduction in Perinatal Transmission of HIV Infection— United States, 1985–2005. MMWR Morb Mortal Wkly Rep 2006; 55: 592–97. De Cock KM, Mbori-Ngacha D, Marum E. Shadow on the continent: public health and HIV/AIDS in Africa in the 21st century. Lancet 2002; 360: 67–72. Nightingale S, Dabis F. Evidence behind the WHO guidelines: hospital care for children: what antiretroviral agents and regimens are effective in the prevention of mother-to-child transmission of HIV? J Trop Pediatr 2006; 52: 235–38. McIntyre J. Strategies to prevent mother-to-child transmission of HIV. Curr Opin Infect Dis 2006; 19: 33–38. Newell ML. Current issues in the prevention of mother-to-child transmission of HIV-1 infection. Trans R Soc Trop Med Hyg 2006; 100: 1–5. World Health Organization. Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants in resource-limited settings: towards universal access. A public health approach. WHO, Geneva 2006. http://www.who.int/hiv/pub/mtct/ pmtct/en/ (accessed Dec 4, 2006). Coutsoudis A, Dabis F, Fawzi W, et al. Late postnatal transmission of HIV-1 in breast-fed children: an individual patient data metaanalysis. J Infect Dis 2004; 189: 2154–66. Nduati R, John G, Mbori-Ngacha D, et al. Effect of breastfeeding and formula feeding on transmission of HIV-1: a randomized clinical trial. JAMA 2000; 283: 1167–74. Taha TE, Hoover DR, Kumwenda NI, et al. Late postnatal transmission of HIV-1 and associated factors. J Infect Dis 2007; 196: 10–14. Creek T, Arvelo W, Kim A, et al. Role of infant feeding and HIV in a severe outbreak of diarrhoea and malnutrition among young children, Botswana, 2006. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, 2007 (abstract number 770). Onyango C, Mmiro F, Bagenda D, et al. Early breastfeeding cessation among HIV-exposed negative infants and risk of serious gastroenteritis: findings from a perinatal prevention trial in Kampala, Uganda. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, 2007 (abstract number 775). Iliff PJ, Piwoz EG, Tavengwa NV, et al, for ZVITAMBO Study Group. Early exclusive breastfeeding reduces the risk of postnatal HIV-1 transmission and increases HIV-free survival. AIDS 2005; 19: 699–708. Coovadia HM, Rollins NC, Bland RM, et al. Mother-to-child transmission of HIV-1 infection during exclusive breastfeeding in the first 6 months of life: an intervention cohort study. Lancet 2007; 369: 1107–16. World Health Organization. Consensus statement. WHO HIV and infant feeding technical consultation held on behalf of the interagency task team (IATT) on prevention of HIV infections in pregnant women, mothers and their infants. Geneva, Oct 25–27, 2006. http://www.who.int/child-adolescenthealth/New_ Publications/NUTRITION/consensus_statement.pdf (accessed June 11, 2007). World Health Organization. New data on the prevention of motherto-child transmission of HIV and their policy implications: conclusions, and implications. WHO Technical Consultation on behalf of the UNFPA/UNICEF/WHO/UNAIDS Inter-Agency Task Team on Mother-to-Child Transmission of HIV. Geneva, October 11–13, 2000. Report No. WHO/RHR/01.28. 2001. http://www.who. int/child-adolescent-health/New_Publications/CHILD_HEALTH/ MTCT_Consultation.htm (accessed Jan 16, 2007).

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30

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32 33 34

35

36

37

38

39 40

41

42

43

44

45

46

47

48

49

50

Luzuriaga K, Newell ML, Dabis F, Excler JL, Sullivan JL. Vaccines to prevent transmission of HIV-1 via breastmilk: scientific and logistic priorities. Lancet 2006; 368: 511–21. Hartmann SU, Berlin CM, Howett MK. Alternative modified infant-feeding practices to prevent postnatal transmission of human immunodeficiency virus type 1 through breast milk: past, present, and future. J Hum Lact 2006; 22: 75–88. Wilfert CM, Fowler MG. Balancing maternal and infant benefits and the consequences of breast-feeding in the developing world during the era of HIV infection. J Infect Dis 2007; 195: 165–67. John-Stewart GC. Breast-feeding and HIV-1 transmission—how risky for how long? J Infect Dis 2007; 196: 1–3. UNAIDS. Report on the global AIDS epidemic. 2004. http://www. unaids.org/bangkok2004/report_pdf.html (accessed Dec 4, 2006). Lackritz EM. Prevention of HIV transmission by blood transfusion in the developing world: achievements and continuing challenges. AIDS 1998; 12 (suppl A): S81–86. Lindegren ML, Hanson IC, Hammett TA, Beil J, Fleming PL, Ward JW. Sexual abuse of children: intersection with the HIV epidemic. Pediatrics 1998; 102: E46. Schmid GP, Buve A, Mugyenyi P, et al. Transmission of HIV-1 infection in sub-Saharan Africa and effect of elimination of unsafe injections. Lancet 2004; 363: 482–88. Centers for Disease Control and Prevention. Cases of HIV infection and AIDS in the United States, 2004. HIV/AIDS surveillance report, volume 16. http://www.cdc.gov/hiv/topics/ surveillance/resources/reports/2004report/default.htm (accessed Dec 4, 2006). Italian Multicentre Study. Epidemiology, clinical features, and prognostic factors of paediatric HIV infection. Lancet 1988; 332: 1043–46. European Collaborative Study. Risk factors for mother-to-child transmission of HIV-1. Lancet 1992; 339: 1007–12. Nesheim SR, Lindsay M, Sawyer MK, et al. A prospective population-based study of HIV perinatal transmission. AIDS 1994; 8: 1293–98. Adjorlolo-Johnson G, De Cock KM, Ekpini E, et al. Prospective comparison of mother-to-child transmission of HIV-1 and HIV-2 in Abidjan, Ivory Coast. JAMA 1994; 272: 462–66. Datta P, Embree JE, Kreiss JK, et al. Mother-to-child transmission of human immunodeficiency virus type 1: report from the Nairobi Study. J Infect Dis 1994; 170: 1134–40. Temmerman M, Nyong’o AO, Bwayo J, Fransen K, Coppens M, Piot P. Risk factors for mother-to-child transmission of human immunodeficiency virus-1 infection. Am J Obstet Gynecol 1995; 172 (2 Pt 1): 700–05. Chouquet C, Richardson S, Burgard M, et al. Timing of human immunodeficiency virus type 1 (HIV-1) transmission from mother to child: bayesian estimation using a mixture. Stat Med 1999; 18: 815–33. Moodley D, Moodley J, Coovadia H, et al. A multicenter randomized controlled trial of nevirapine versus a combination of zidovudine and lamivudine to reduce intrapartum and early postpartum mother-to-child transmission of human immunodeficiency virus type 1. J Infect Dis 2003; 187: 725–35. Nolan ML, Greenberg AE, Fowler MG. A review of clinical trials to prevent mother-to-child HIV-1 transmission in Africa and inform rational intervention strategies. AIDS 2002; 16: 1991–99. John GC, Nduati RW, Mbori-Ngacha DA, et al. Correlates of mother-to-child human immunodeficiency virus type 1 (HIV-1) transmission: association with maternal plasma HIV-1 RNA load, genital HIV-1 DNA shedding, and breast infections. J Infect Dis 2001; 183: 206–12. European Collaborative Study. Natural history of vertically acquired human immunodeficiency virus-1 infection. Pediatrics 1994; 94 (6 Pt 1): 815–19. Blanche S, Tardieu M, Duliege A, et al. Longitudinal study of 94 symptomatic infants with perinatally acquired human immunodeficiency virus infection. Evidence for a bimodal expression of clinical and biological symptoms. Am J Dis Child 1990; 144: 1210–15. Ioannidis JP, Tatsioni A, Abrams EJ, et al. Maternal viral load and rate of disease progression among vertically HIV-1-infected children: an international meta-analysis. AIDS 2004; 18: 99–108.

www.thelancet.com Vol 370 July 7, 2007

51

52

53

54

55

56

57 58 59

60

61

62

63 64

65

66

67

68

69

70

71

Kuhn L, Steketee RW, Weedon J, et al. Distinct risk factors for intrauterine and intrapartum human immunodeficiency virus transmission and consequences for disease progression in infected children. Perinatal AIDS Collaborative Transmission Study. J Infect Dis 1999; 179: 52–58. Williams AJ, Duong T, McNally LM, et al. Pneumocystis carinii pneumonia and cytomegalovirus infection in children with vertically acquired HIV infection. AIDS 2001; 15: 335–39. Andiman WA, Eastman R, Martin K, et al. Opportunistic lymphoproliferations associated with Epstein-Barr viral DNA in infants and children with AIDS. Lancet 1985; 326: 1390–93. McKinney RE Jr., Maha MA, Connor EM, et al. A multicenter trial of oral zidovudine in children with advanced human immunodeficiency virus disease. The Protocol 043 Study Group. N Engl J Med 1991; 324: 1018–25. Spira R, Lepage P, Msellati P, et al. Natural history of human immunodeficiency virus type 1 infection in children: a five-year prospective study in Rwanda. Mother-to-Child HIV-1 Transmission Study Group. Pediatrics 1999; 104: e56. Newell ML, Coovadia H, Cortina-Borja M, Rollins N, Gaillard P, Dabis F, for the Ghent International AIDS Society (IAS) working group on HIV infection in women and children. Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis. Lancet 2004; 364: 1236–43. Newell ML, Brahmbhatt H, Ghys PD. Child mortality and HIV infection in Africa: a review. AIDS 2004; 18 (suppl 2): S27–34. The Lancet. The devastating effects of HIV/AIDS on children. Lancet 2006; 368: 424. Heymann J, Earle A, Rajaraman D, Miller C, Bogen K. Extended family caring for children orphaned by AIDS: balancing essential work and caregiving in high HIV prevalence nations. AIDS Care 2007; 19: 337–45. UNAIDS/UNICEF/USAID. Children on the Brink 2004: A Joint Report of New Orphan Estimates and a Framework for Action. July 2004. http://www.unicef.org/publications/files/cob_layout6-013.pdf (accessed Dec 4, 2006). Rogerson SR, Gladstone M, Callaghan M, et al. HIV infection among paediatric in-patients in Blantyre, Malawi. Trans R Soc Trop Med Hyg 2004; 98: 544–52. Jeena PM, Coovadia HM, Chrystal V. Pneumocystis carinii and cytomegalovirus infections in severely ill, HIV-infected African infants. Ann Trop Paediatr 1996; 16: 361–68. Lucas SB, Peacock CS, Hounnou A, et al. Disease in children infected with HIV in Abidjan, Cote d’Ivoire. BMJ 1996; 312: 335–38. Abouya YL, Beaumel A, Lucas S, et al. Pneumocystis carinii pneumonia. An uncommon cause of death in African patients with acquired immunodeficiency syndrome. Am Rev Respir Dis 1992; 145: 617–20. Malin AS, Gwanzura LK, Klein S, Robertson VJ, Musvaire P, Mason PR. Pneumocystis carinii pneumonia in Zimbabwe. Lancet 1995; 346: 1258–61. Tindyebwa D KJ, Musoke P, Eley B, et al. Handbook on paediatric AIDS in Africa. Uganda: African network for the care of children affected by AIDS, 2004. Thea DM, St Louis ME, Atido U, et al. A prospective study of diarrhea and HIV-1 infection among 429 Zairian infants. N Engl J Med 1993; 329: 1696–702. Jeena PM, Pillay P, Pillay T, Coovadia HM. Impact of HIV-1 coinfection on presentation and hospital-related mortality in children with culture proven pulmonary tuberculosis in Durban, South Africa. Int J Tuberc Lung Dis 2002; 6: 672–78. Madhi SA, Huebner RE, Doedens L, Aduc T, Wesley D, Cooper PA. HIV-1 co-infection in children hospitalised with tuberculosis in South Africa. Int J Tuberc Lung Dis 2000; 4: 448–54. Madhi SA, Petersen K, Madhi A, Khoosal M, Klugman KP. Increased disease burden and antibiotic resistance of bacteria causing severe community-acquired lower respiratory tract infections in human immunodeficiency virus type 1-infected children. Clin Infect Dis 2000; 31: 170–76. Elenga N, Kouakoussui KA, Bonard D, et al. Diagnosed tuberculosis during the follow-up of a cohort of human immunodeficiency virusinfected children in Abidjan, Cote d’Ivoire: ANRS 1278 study. Pediatr Infect Dis J 2005; 24: 1077–82.

77

Seminar

72

73

74

75

76

77

78

79

80

81

82

83 84

85

86

87

88

89

90

91

92

78

Jeena PM, Mitha T, Bamber S, Wesley A, Coutsoudis A, Coovadia HM. Effects of the human immunodeficiency virus on tuberculosis in children. Tuber Lung Dis 1996; 77: 437–43. Mukadi YD, Wiktor SZ, Coulibaly IM, et al. Impact of HIV infection on the development, clinical presentation and outcome of tuberculosis among children in Abidjan, Cote d‘Ivoire. AIDS 1997; 11: 1151–58. Chintu C, Mudenda V, Lucas S, et al. Lung diseases at necropsy in African children dying from respiratory illnesses: a descriptive necropsy study. Lancet 2002; 360: 985–90. Graham SM, Gie RP, Schaaf HS, Coulter JB, Espinal MA, Beyers N. Childhood tuberculosis: clinical research needs. Int J Tuberc Lung Dis 2004; 8: 648–57. World Health Organization. Antiretroviral therapy of HIV infection in infants and children in resource-limited settings, towards universal access: recommendations for a public health approach. WHO, Geneva, 2006. http://www.who.int/hiv/pub/guidelines/ WHOpaediatric.pdf (accessed Dec 4, 2006). Whitworth J, Morgan D, Quigley M, et al. Effect of HIV-1 and increasing immunosuppression on malaria parasitaemia and clinical episodes in adults in rural Uganda: a cohort study. Lancet 2000; 356: 1051–56. Otieno RO, Ouma C, Ong’echa JM, et al. Increased severe anemia in HIV-1-exposed and HIV-1-positive infants and children during acute malaria. AIDS 2006; 20: 275–80. Hoffman IF, Jere CS, Taylor TE, et al. The effect of Plasmodium falciparum malaria on HIV-1 RNA blood plasma concentration. AIDS 1999; 13: 487–94. Brahmbhatt H, Kigozi G, Wabwire-Mangen F, et al. The effects of placental malaria on mother-to-child HIV transmission in Rakai, Uganda. AIDS 2003; 17: 2539–41. Bentwich Z, Kalinkovich A, Weisman Z. Immune activation is a dominant factor in the pathogenesis of African AIDS. Immunol Today 1995; 16: 187–91. Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB. Virusspecific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol 1994; 68: 6103–10. Goulder PJ, Watkins DI. HIV and SIV CTL escape: implications for vaccine design. Nat Rev Immunol 2004; 4: 630–40. Koup RA, Safrit JT, Cao Y, et al. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol 1994; 68: 4650–55. Abrams EJ, Weedon J, Steketee RW, et al. Association of human immunodeficiency virus (HIV) load early in life with disease progression among HIV-infected infants. New York City Perinatal HIV Transmission Collaborative Study Group. J Infect Dis 1998; 178: 101–08. Mphatswe W, Blanckenberg N, Tudor-Williams G, et al. High frequency of rapid immunological progression in African infants infected in the era of perinatal HIV prophylaxis. AIDS 2007; 21: 1253–61. Rosenberg ES, Altfeld M, Poon SH, et al. Immune control of HIV-1 after early treatment of acute infection. Nature 2000; 407: 523–26. Jin X, Bauer DE, Tuttleton SE, et al. Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virusinfected macaques. J Exp Med 1999; 189: 991–98. Matano T, Shibata R, Siemon C, Connors M, Lane HC, Martin MA. Administration of an anti-CD8 monoclonal antibody interferes with the clearance of chimeric simian/human immunodeficiency virus during primary infections of rhesus macaques. J Virol 1998; 72: 164–69. Schmitz JE, Kuroda MJ, Santra S, et al. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 1999; 283: 857–60. Barouch DH, Kunstman J, Kuroda MJ, et al. Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes. Nature 2002; 415: 335–39. Feeney ME, Tang Y, Roosevelt KA, et al. Immune escape precedes breakthrough human immunodeficiency virus type 1 viremia and broadening of the cytotoxic T-lymphocyte response in an HLAB27-positive long-term-nonprogressing child. J Virol 2004; 78: 8927–30.

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96

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102

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105

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111

112

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Goulder PJ, Phillips RE, Colbert RA, et al. Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat Med 1997; 3: 212–17. Luzuriaga K, McManus M, Catalina M, et al. Early therapy of vertical human immunodeficiency virus type 1 (HIV-1) infection: control of viral replication and absence of persistent HIV-1specific immune responses. J Virol 2000; 74: 6984–91. Shearer WT, Quinn TC, LaRussa P, et al. Viral load and disease progression in infants infected with human immunodeficiency virus type 1. Women and Infants Transmission Study Group. N Engl J Med 1997; 336: 1337–42. Feeney ME, Tang Y, Pfafferott K, et al. HIV-1 viral escape in infancy followed by emergence of a variant-specific CTL response. J Immunol 2005; 174: 7524–30. Leslie AJ, Pfafferott KJ, Chetty P, et al. HIV evolution: CTL escape mutation and reversion after transmission. Nat Med 2004; 10: 282–89. Martinez-Picado J, Prado JG, Fry EE, et al. Fitness cost of escape mutations in p24 Gag in association with control of human immunodeficiency virus type 1. J Virol 2006; 80: 3617–23. Geffin R, Hutto C, Andrew C, Scott GB. A longitudinal assessment of autologous neutralizing antibodies in children perinatally infected with human immunodeficiency virus type 1. Virology 2003; 310: 207–15. Wei X, Decker JM, Wang S, et al. Antibody neutralization and escape by HIV-1. Nature 2003; 422: 307–12. Wu X, Parast AB, Richardson BA, et al. Neutralization escape variants of human immunodeficiency virus type 1 are transmitted from mother to infant. J Virol 2006; 80: 835–44. Ferrantelli F, Rasmussen RA, Buckley KA, et al. Complete protection of neonatal rhesus macaques against oral exposure to pathogenic simian-human immunodeficiency virus by human anti-HIV monoclonal antibodies. J Infect Dis 2004; 189: 2167–73. Kourtis AP, Ibegbu C, Nahmias AJ, et al. Early progression of disease in HIV-infected infants with thymus dysfunction. N Engl J Med 1996; 335: 1431–36. Sperling RS, Shapiro DE, Coombs RW, et al. Maternal viral load, zidovudine treatment, and the risk of transmission of human immunodeficiency virus type 1 from mother to infant. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1996; 335: 1621–29. Kiepiela P, Leslie AJ, Honeyborne I, et al. Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA. Nature 2004; 432: 769–75. Kuhn L, Abrams EJ, Palumbo P, et al. Maternal versus paternal inheritance of HLA class I alleles among HIV-infected children: consequences for clinical disease progression. AIDS 2004; 18: 1281–89. Goulder PJ, Brander C, Tang Y, et al. Evolution and transmission of stable CTL escape mutations in HIV infection. Nature 2001; 412: 334–38. Pillay T, Zhang HT, Drijfhout JW, et al. Unique acquisition of cytotoxic T-lymphocyte escape mutants in infant human immunodeficiency virus type 1 infection. J Virol 2005; 79: 12100–05. Allen TM, Yu XG, Kalife ET, et al. De novo generation of escape variant-specific CD8+ T-cell responses following cytotoxic T-lymphocyte escape in chronic human immunodeficiency virus type 1 infection. J Virol 2005; 79: 12952–60. Lichterfeld M, Kaufmann DE, Yu XG, et al. Loss of HIV-1-specific CD8+ T cell proliferation after acute HIV-1 infection and restoration by vaccine-induced HIV-1-specific CD4+ T cells. J Exp Med 2004; 200: 701–12. Owens DK, Holodniy M, McDonald TW, Scott J, Sonnad S. A meta-analytic evaluation of the polymerase chain reaction for the diagnosis of HIV infection in infants. JAMA 1996; 275: 1342–48. Rouet F, Ekouevi DK, Chaix ML, et al. Transfer and evaluation of an automated, low-cost real-time reverse transcription-PCR test for diagnosis and monitoring of human immunodeficiency virus type 1 infection in a West African resource-limited setting. J Clin Microbiol 2005; 43: 2709–17. Fiscus SA, Wiener J, Abrams EJ, Bulterys M, Cachaefeiro A, Respess RA. Ultra-sensitive P24 antigen assay for the diagnosis of perinatal HIV-1 infection. J Clin Microbiol 2007; published online May 2. DOI:10.1128/JCM.00813-07.

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114 Rouet F, Montcho C, Rouzioux C, et al. Early diagnosis of paediatric HIV-1 infection among African breast-fed children using a quantitative plasma HIV RNA assay. AIDS 2001; 15: 1849–56. 115 Rich JD, Merriman NA, Mylonakis E, et al. Misdiagnosis of HIV infection by HIV-1 plasma viral load testing: a case series. Ann Intern Med 1999; 130: 37–39. 116 Cassol S, Salas T, Arella M, Neumann P, Schechter MT, O’Shaughnessy M. Use of dried blood spot specimens in the detection of human immunodeficiency virus type 1 by the polymerase chain reaction. J Clin Microbiol 1991; 29: 667–71. 117 Goulder PJ, Blanckenberg N, Dong K. Nevirapine plus zidovudine to prevent mother-to-child transmission of HIV. N Engl J Med 2004; 351: 2013–15; author reply 2013–15. 118 Rouet F, Inwoley A, Ekouevi DK, et al. CD4 percentages and total lymphocyte counts as early surrogate markers for pediatric HIV-1 infection in resource-limited settings. J Trop Pediatr 2006; 52: 346–54. 119 Lepage P, van de Perre P, Dabis F, et al. Evaluation and simplification of the World Health Organization clinical case definition for paediatric AIDS. AIDS 1989; 3: 221–25. 120 Otieno FA, Mbori-Ngacha DA, Wafula EM, Ndinya-Achola JO. Evaluation of a proposed clinical case definition of paediatric acquired immune deficiency syndrome. East Afr Med J 2002; 79: 111–14. 121 Hawkins D, Blott M, Clayden P, et al. Guidelines for the management of HIV infection in pregnant women and the prevention of mother-to-child transmission of HIV. HIV Med 2005; 6 (suppl 2): 107–48. 122 Centers for Disease Control and Prevention. Revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR Morb Mortal Wkly Rep 1994; 43: 1–10. 123 World Health Organization. Scaling up antiretroviral therapy in resource-limited settings. 2003 revision. http://www.who.int/hiv/ pub/prev_care/en/arvrevision2003en.pdf (accessed Dec 4, 2006). 124 World Health Organization. WHO case definitions of HIV surveillance and revised clinical staging and immunological classification of HIV-related disease in adults and children. WHO, Geneva, 2006. http://www.who.int/hiv/pub/guidelines/ WHO%20HIV%20Staging.pdf (accessed Dec 4, 2006). 125 Palumbo PE, Raskino C, Fiscus S, et al. Predictive value of quantitative plasma HIV RNA and CD4+ lymphocyte count in HIV-infected infants and children. JAMA 1998; 279: 756–61. 126 European Collaborative Study. Age-related standards for T lymphocyte subsets based on uninfected children born to human immunodeficiency virus 1-infected women. Pediatr Infect Dis J 1992; 11: 1018–26. 127 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. 128 Rabkin M, El-Sadr W, Katzenstein DA, et al. Antiretroviral treatment in resource-poor settings: clinical research priorities. Lancet 2002; 360: 1503–05. 129 Rodriguez WR, Christodoulides N, Floriano PN, et al. A microchip CD4 counting method for HIV monitoring in resource-poor settings. PLoS Med 2005; 2: e182. 130 Florence E, Dreezen C, Schrooten W, et al. The role of non-viral load surrogate markers in HIV-positive patient monitoring during antiviral treatment. Int J STD AIDS 2004; 15: 538–42. 131 Schreibman T, Friedland G. Use of total lymphocyte count for monitoring response to antiretroviral therapy. Clin Inf Dis 2004; 38: 257–62. 132 Mofenson LM, Harris DR, Moye J, et al, for the NICHD IVIG Clinical Trial Study Group. Alternatives to HIV-1 RNA concentration and CD4 count to predict mortality in HIV-1-infected children in resource-poor settings. Lancet 2003; 362: 1625–27. 133 Colebunders R, Moses KR, Laurence J, et al. A new model to monitor the virological efficacy of antiretroviral treatment in resource-poor countries. Lancet Infect Dis 2006; 6: 53–59. 134 Chintu C, Bhat GJ, Walker AS, et al. Co-trimoxazole as prophylaxis against opportunistic infections in HIV-infected Zambian children (CHAP): a double-blind randomised placebo-controlled trial. Lancet 2004; 364: 1865–71.

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135 World Health Organization. Guidelines on co-trimoxazole prophylaxis for HIV-related infections among children, adolescents and adults in resource-limited settings. Recommendations for a public health approach. WHO, Geneva, 2006. http://www.who.int/ hiv/pub/guidelines/ctxguidelines2006.pdf (accessed Dec 4, 2006). 136 US Public Health Service and Infectious Diseases Society of America Prevention of Opportunistic Infections Working Group. Guidelines for the preventing opportunistic infections among HIVinfected persons—2002 recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. http://aidsinfo.nih.gov/ContentFiles/OIpreventionGL.pdf (accessed Dec 4, 2006). 137 Children’s HIV Association of UK and Ireland. Guidelines for prevention of opportunistic infections (OI’s) in children with HIV. November 2004. http://www.bhiva.org/chiva/index.html (accessed Dec 4, 2006). 138 Moss WJ, Clements CJ, Halsey NA. Immunization of children at risk of infection with human immunodeficiency virus. Bull World Health Organ 2003; 81: 61–70. 139 World Health Organization. Meeting of the Immunization Strategic Advisory Group of Experts, April 2007—conclusions and recommendations. http://www.who.int/immunization/sage/ SAGE_report_April2007.pdf (accessed June 13, 2007). 140 Klugman KP, Madhi SA, Huebner RE, Kohberger R, Mbelle N, Pierce N. A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection. N Engl J Med 2003; 349: 1341–48. 141 Fawzi WW, Mbise RL, Hertzmark E, et al. A randomized trial of vitamin A supplements in relation to mortality among human immunodeficiency virus-infected and uninfected children in Tanzania. Pediatr Infect Dis J 1999; 18: 127–33. 142 Berhane R, Bagenda D, Marum L, et al. Growth failure as a prognostic indicator of mortality in pediatric HIV infection. Pediatrics 1997; 100: E7. 143 Walters S. Practical aspects of antiretroviral treatment in children. In: Pollard AJ, Finn A, eds. Hot topics in infection and immunity in children. New York: Springer, 2006: 221–28. 144 Fraaij PL, Verweel G, van Rossum AM, et al. Sustained viral suppression and immune recovery in HIV type 1-infected children after 4 years of highly active antiretroviral therapy. Clin Infect Dis 2005; 40: 604–08. 145 Resino S, M Bellon J, Gurbindo D, et al. Viral load and CD4+ T lymphocyte response to highly active antiretroviral therapy in human immunodeficiency virus type 1-infected children: an observational study. Clin Infect Dis 2003; 37: 1216–25. 146 Steinmann GG. Changes in the human thymus during aging. Curr Top Pathol 1986; 75: 43–88. 147 De Rossi A, Walker AS, De Forni D, Klein N, Gibb DM. Relationship between changes in thymic emigrants and cellassociated HIV-1 DNA in HIV-1-infected children initiating antiretroviral therapy. Antivir Ther 2005; 10: 63–71. 148 Chiappini E, Galli L, Zazzi M, de Martino M. Immunological recovery despite virological failure is independent of human immunodeficiency virus-type 1 resistant mutants in children receiving highly active antiretroviral therapy. J Med Virol 2003; 70: 506–12. 149 Working group on antiretroviral therapy and medical management of HIV-infected children. Guidelines for the use of antiretroviral agents in pediatric HIV infection. October 26, 2006. http://aidsinfo. nih.gov/ContentFiles/PediatricGuidelines.pdf (accessed Dec 4, 2006). 150 Sharland M, Blanche S, Castelli G, Ramos J, Gibb DM. PENTA guidelines for the use of antiretroviral therapy, 2004. HIV Med 2004; 5 (suppl 2): 61–86. 151 Paediatric European network for the treatment of AIDS. PENPACT1 trial. http://www.ctu.mrc.ac.uk/penta/trials.htm#penpact1 (accessed Jan 16, 2007). 152 Menson EN, Walker AS, Sharland M, et al. Underdosing of antiretrovirals in UK and Irish children with HIV as an example of problems in prescribing medicines to children, 1997–2005: cohort study. BMJ 2006; 332: 1183–87. 153 Van Dyke RB, Lee S, Johnson GM, et al. Reported adherence as a determinant of response to HAART in children who have HIV infection. Pediatrics 2002; 109: e61.

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154 Watson DC, Farley JJ. Efficacy of and adherence to highly active antiretroviral therapy in children infected with human immunodeficiency virus type 1. Pediatr Infect Dis J 1999; 18: 682–89. 155 Shingadia D, Viani RM, Yoger R, et al. Gastrostomy tube insertion for improvement of adherence to highly active antiretroviral therapy in pediatric patients with human immunodeficiency virus. Pediatrics 2000; 105: E80. 156 Mayaux MJ, Burgard M, Teglas JP, et al. Neonatal characteristics in rapidly progressive perinatally acquired HIV-1 disease. The French Pediatric HIV Infection Study Group. JAMA 1996; 275: 606–10. 157 Chiappini E, Galli L, Tovo PA, et al. Virologic, immunologic, and clinical benefits from early combined antiretroviral therapy in infants with perinatal HIV-1 infection. AIDS 2006; 20: 207–15. 158 Aboulker JP, Babiker A, Chaix ML, et al. 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. 159 Eshleman SH, Mracna M, Guay LA, et al. Selection and fading of resistance mutations in women and infants receiving nevirapine to prevent HIV-1 vertical transmission (HIVNET 012). AIDS 2001; 15: 1951–57. 160 Eshleman SH, Nissley D, Claasen C, et al. Sensitive drug resistance assays reveal long-term persistence of HIV-1 variants with the K103N nevirapine-resistance mutation in some women and infants after single-dose NVP: HIVNET-012. Presented at the 12th Conference on Retroviruses and Opportunistic Infections. 2005, San Francisco, USA. (Abstract 800). 161 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. 162 Alimenti A, Burdge DR, Ogilvie GS, Money DM, Forbes JC. Lactic acidemia in human immunodeficiency virus-uninfected infants exposed to perinatal antiretroviral therapy. Pediatr Infect Dis J 2003; 22: 782–89. 163 Brambilla P, Bricalli D, Sala N, et al. Highly active antiretroviraltreated HIV-infected children show fat distribution changes even in absence of lipodystrophy. AIDS 2001; 15: 2415–22. 164 Melvin AJ, Lennon S, Mohan KM, Purnell JQ. Metabolic abnormalities in HIV type 1-infected children treated and not treated with protease inhibitors. AIDS Res Hum Retroviruses 2001; 17: 1117–23. 165 Rhoads MP, Smith CJ, Tudor-Williams G, et al. Effects of highly active antiretroviral therapy on paediatric metabolite levels. HIV Med 2006; 7: 16–24. 166 Barlow-Mosha L, Musoke P, Ajuna P, Luttajumwa M, Walabyeki J, Owor M. Early effectiveness of Triomune in HIV-infected Ugandan children. Presented at the third International AIDS Society Conference on HIV Pathogenesis and Treatment 2005, Rio de Janeiro, Brazil. (Abstract WeOa0/03). 167 Chokephaibulkit K, Plipat N, Cressey T, et al. Pharmacokinetics of nevirapine in HIV-infected children receiving an adult fixed-dose combination of stavudine, lamivudine and nevirapine. AIDS 2005; 19: 1495–99.

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168 Corbett A, Hosseinipour M, Nyirenda J, Kanyama C, Mshali I, Chinyama S. Pharmacokinetics between trade and generic liquid and split tablet formulations of lamivudine, stavudine and nevirapine in HIV-infected Malawian children. Presented at the International Conference on Antimicrobial Agents and Chemotherapy 2005, Washington D.C., USA. (Abstract H-1905). 169 French MA, Price P, Stone SF. Immune restoration disease after antiretroviral therapy. AIDS 2004; 18: 1615–27. 170 O’Brien DP, Sauvageot D, Olson D, et al. Treatment outcomes stratified by baseline immunological status among young children receiving nonnucleoside reverse-transcriptase inhibitor-based antiretroviral therapy in resource-limited settings. Clin Infect Dis 2007; 44: 1245–48. 171 Eley B. Addressing the paediatric HIV epidemic: a perspective from the Western Cape Region of South Africa. Trans R Soc Trop Med Hyg 2006; 100: 19–23. 172 Fassinou P, Elenga N, Rouet F, et al. Highly active antiretroviral therapies among HIV-1-infected children in Abidjan, Cote d’Ivoire. AIDS 2004; 18: 1905–13. 173 Reddi A, Leeper SC, Grobler AC, et al. Preliminary outcomes of a paediatric highly active antiretroviral therapy cohort from KwaZuluNatal, South Africa. BMC Pediatr 2007; 7: 13. 174 Nyandiko WM, Ayaya S, Nabakwe E, et al. Outcomes of HIV-infected orphaned and non-orphaned children on antiretroviral therapy in western Kenya. J Acquir Immune Defic Syndr 2006; 43: 418–25. 175 Rouet F, Fassinou P, Inwoley A, et al. Long-term survival and immuno-virological response of African HIV-1-infected children to highly active antiretroviral therapy regimens. AIDS 2006; 20: 2315–19. 176 Wemin L, et al. Taking care of HIV-exposed and infected children in the Help Expand Antiretroviral Therapy for children and families (HEART) ACONDA/ISPED/EGPAF program: routine indicators of access to HIV care and field effectiveness. Presented at the PEPFAR Annual Meeting 2006, Durban, South Africa. (Abstract 463). 177 Little K, Newell ML, Luo C, Ngongo N, Borja MC, McDermott P. Estimating the number of vertically HIV-infected children eligible for antiretroviral treatment in resource-limited settings. Int J Epidemiol 2007; published online April 17. DOI: 10.1093/ije/dym019. 178 Kline M, Anabwani G, Kekitiinwa A, et al, and Baylor Coll of Med Intl Pediatric AIDS Initiative. Catalyzing the care and treatment of HIVinfected children in Sub-Saharan Africa: early uutcomes from 5 Baylor College of Medicine Centers. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, 2007 (abstract number 79). 179 Kline M. Perspectives on the Pediatric HIV Pandemic: catalyzing access of children to care and treatment. Pediatrics 2006; 117: 1388–93. 180 Gibb DM, Masters J, Shingadia D, et al. A family clinic—optimising care for HIV infected children and their families. Arch Dis Child 1997; 77: 478–82. 181 Oberdorfer P, Puthanakit T, Louthrenoo O, Charnsil C, Sirisanthana V, Sirisanthana T. Disclosure of HIV/AIDS diagnosis to HIV-infected children in Thailand. J Paediatr Child Health 2006; 42: 283–88.

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