Classification of HIV disease in Children – towards pragmatism ?

THE SOUTHERN AFRICAN JOURNAL OF HIV MEDICINE 14 14. Starr SE, Fletcher CV, Spector SA, et al.; PACTG 382 Study Team. Pediatric AIDS Clinical Trials Group. Efavirenz liquid formulation in human immunodeficiency virus-infected children. Pediatr Infect Dis J 2002; 21: 659-663. 15. Saez-Llorens X, Violari A, Deetz CO, et al. Forty-eight-week evaluation of lopinavir/ritonavir, a new protease inhibitor, in human immunodeficiency virusinfected children. Pediatr Infect Dis J 2003; 22: 216-224. 16. Chadwick EG, Rodman J, Palumbo P, et al. PACTG 1030 Study Team. A Prospective evaluation of pharmacologic, virologic, and immunologic parameters for lopinavir/ritonavir for HIV-1 infected infants < 6 months of age (abstract). In: 12th Conference on Retroviruses and Opportunistic Infections, February 2005, Boston, MA. 17. Pau AK, Capparelli EV, Holland D, Fomundam H, Matchaba GU, Moodley NK. Instability of lopinavir/ritonavir capsules at ambient temperature in subSaharan Africa: relevance to WHO antiretrovirals. AIDS 2005; 19: 1233-1234. 18. Krogstad P, Wiznia A, Luzuriaga K, et al. Treatment of human immunodeficiency virus 1-infected infants and children with the protease inhibitor nelfinavir mesylate. Clin Infect Dis 1999; 28: 1109-1118. 19. Schuster T, Linde R, Wintergerst U, et al. Nelfinavir pharmacokinetics in HIVinfected children: a comparison of twice daily and three times daily dosing. AIDS 2000; 14: 1466-1468. 20. Hoody DW, Fletcher CV. Pharmacology considerations for antiretroviral therapy in human immunodeficiency virus (HIV)-infected children. Semin Pediatr Infect Dis 2003; 14: 286-294. 21. Capparelli EV, Mirochnick M, Danker WM, et al. PACTG Study 331 Team. Pharmacokinetics and tolerance of zidovudine in preterm infants. J Pediatr 2003; 142: 47-52. 22. Mirochnick M, Fenton T, Gagnier P, et al. Pharmacokinetics of nevirapine in human immunodeficiency virus type 1-infected pregnant women and their neonates. Pediatric AIDS Clinical Trials Group Protocol 250 Team. J Infect Dis 1998; 178: 368-374. 23. Capparelli E, Blanchard S, Aweeka F, Acosta E. Population pharmacokinetics of nevirapine in infants and children – the impact of body size, age, and concomitant therapies (abstract). In: 6th International Workshop on Clinical Pharmacology of HIV Therapy 2005, Quebec City, CA. 24. Litalien C, Fay A, Compagnucci A, et al. Paediatric European Network for Treatment of AIDS Excecutive Committee. Pharmacokinetics of nelfinavir and its active metabolite, hydroxy-tert-butylamide, in infants perinatally infected with human immunodeficiency virus type 1. Pediatr Infect Dis J 2003; 22: 48-55. 25. Hazra R, Balis FM, Tullio AN, et al. Single-dose and steady-state pharmacokinetics of tenofovir disoproxil fumarate in human immunodeficiency virusinfected children. Antimicrob Agents Chemother 2004; 48: 124-129.

prevalence of Pneumocystis pneumonia (PCP) in young infants with far higher CD4 counts or percentages than would occur in adults.Age is an important determinant for rapid progression in infants.Conditions such as lymphoid interstitial pneumonitis (LIP) are recognised more commonly in children than adults.Differences in disease manifestation between adults and children are shown in Fig. 1 (A and B).In infants, young age and immunological immaturity are probably the most important determinants of disease.

THE CENTERS FOR DISEASE CONTROL AND PREVENTION CLASSIFICATION
The Centers for Disease Control (CDC) classification was first introduced in 1987 and modified in 1994. 1,2It comprised clinical and immunological components, recognising that there could be discordance between the two.Such discordance has been shown in South African children. 3 Clinical categories range from asymptomatic (N) to mild symptoms and signs (A), moderate severity (B) and severe (C) (Table I).Immunological stages range from no CD4+ depletion (stage 1) to moderate depletion (stage 2) and severe depletion (stage 3) (see Table II in the Paediatric ART Guidelines, p. 20).
The classification is well accepted and has shown excellent predictive value, especially in North American and European children.For example, in an analysis for the Pediatric Spectrum of Diseases Project, Barnhart and colleagues could differentiate between the different stages of disease (Table I). 4 In an African setting, although the classification is useful, it is sometimes difficult to fit symptomatic children into the classification system.For example, in a study from Malawi, because of high mortality by 3 years of age only 10% of children were in stage B or C as the majority had already died.For stage B, some conditions have a worse prognosis than others.Galli et al. found that anaemia, candidiasis, diarrhoea, cardiomyopathy, hepatitis and persistent fever had a worse prognosis than other events. 6HIV-associated nephropathy leads to renal failure and death, yet is also in B, while a chronic herpetic ulcer that may respond to acyclovir is in C.
Many conditions seen in Africa are inadequately addressed.Failure to thrive occurs commonly in an African setting and is an independent risk factor for mortality. 3In the CDC classification, wasting must be accompanied by either chronic diarrhoea or fever for at least 30 days to be classified in C.
Tuberculosis is especially common in HIV-infected children.

A B
classification.A child with multiple episodes of pulmonary tuberculosis may therefore not be adequately classified.Disseminated Bacillus Calmette-Guérin disease is an emerging problem with an extremely poor prognosis yet is also not addressed. 10ronic lung disease, especially bronchiectasis, is seen commonly in children who have not had access to ART, but is not addressed in the CDC system.LIP is classified in B and is considered to have a relatively good prognosis. 11The differentiation between LIP and bronchiectasis is not easy, and many children with bronchiectasis may be misdiagnosed as having LIP, therefore possibly not receiving ART as they are not considered sick enough.Rectovesical and rectovaginal fistulas are also not addressed but have an extremely poor prognosis. 12

WORLD HEALTH ORGANIZATION CLASSIFICATION
The World Health Organization (WHO) developed a four-stage classification system for adults in 1994. 135][16] A three-stage paediatric classification was introduced in 2002. 17While superficially easy to use, it did not address many conditions seen in HIV-infected infants.In 2004, after a period of deliberation with paediatricians experienced in treating HIVinfected children, a revised four-stage system was introduced (Table II). 18It was felt that a four-stage system would be less confusing for health care workers, especially those also dealing with adults, and in addition would assist the transition of children to adulthood when care might be transferred to an adult clinic.
Stage 1 is asymptomatic.Stage 2 includes mainly minor mucocutaneous disorders.Hepatomegaly, hepatosplenomegaly and splenomegaly were placed in stage 2 rather than stage 1 as their presence has been associated with more rapid progression. 19,20Stages 3 and 4 include conditions seen with progressive disease, stage 4 being more serious and more likely to result in early death.Pulmonary tuberculosis is in stage 3. Despite this, tuberculosis is not an automatic indication for ART; rather, the clinical situation should be evaluated for each child.The WHO recommends ART for both stages 3 and 4. Malnutrition is better addressed, with moderate being a stage 3 and severe a stage 4 event.
Bronchiectasis has been included in stage 3 and rectovesical or rectovaginal fistula in stage 4.
Aspects of the classification system still need to be refined.The separation of minor mucocutaneous disorders into a separate stage may be artificial.Wananukul has found increasing frequency of these disorders with increasing disease severity. 21Areas that need to be addressed include multiple episodes of tuberculosis and whether prognosis worsens with cumulative acquisition of staging criteria.In many parts of Africa, although HIV antibodies can be tested easily in infants below 18 months, virological confirmation is either not possible or takes too long.For these circumstances, the WHO has developed criteria for presumptive stage 4, where ART is indicated (Table III).For the first time this recognises that HIV manifests as a symptom complex rather than just a single staging condition.It also provides justification for starting ART in symptomatic infants without virological confirmation.
A few inconsistencies remain.For example, diarrhoea persisting for > 30 days should be classified in stage 4 regardless of whether a pathogen such as Cryptosporidium parvum is identified.

CONCLUSION
The WHO classification has acknowledged conditions commonly seen in Africa and should help with management of children.A revision has been scheduled for 2006.Clinicians working with children have an opportunity for input in improving the classification.

Fig. 1 .
Fig. 1.Relationship between CD4 cells, disease and time in adults (A) and children (B).
TB is particularly difficult to diagnose in infants and young children.§ Severe malnutrition: Defined as very low weight or visible severe wasting or oedema of both feet -http://www.who.int/child-adolescent-health/publications/CHILD_HEALTH/WHO_ FCH_CAH_00.1.htm 5 [7][8][9]Only disseminated tuberculosis is addressed in the CDC
Malnutrition has been integrated into the classification in a way that is understandable to South African health care workers, with underweight for age allowing classification in stage 3 and marasmus allowing classification in stage 4. Pneumonia occurs commonly and is easily treated with *† Moderate malnutrition: Defined as very low weight for age -http://

TABLE II . REVISED WHO CLINICAL STAGING OF HIV FOR INFANTS AND CHILDREN* antibiotics
. For this reason pneumonia has been separated from other causes of bacterial sepsis and is in stage 3.This is of special relevance to children already on ART, in whom intercurrent pneumonia, responding to antibiotics, occurs commonly.