Five of the 13 infected children who were asymptomatic at 6 months of age continued to receive prophylaxis on the basis of PCR test results (three children) or restarted prophylaxis before 9 months of age because symptoms had developed (two children). Pneumonia did not develop in any of the 13 children before 12 months of age, although two of the eight who did not continue prophylaxis died, one of Enterobacter cloacae sepsis and one of diarrhoea with shock. All 16 uninfected children with symptoms suggestive of HIV infection stopped prophylaxis after the PCR results were known. There were no problems with TMP–SMX prophylaxis among the 35 HIV-infected children who continued to receive it between 6 and 12 months of age.
Pneumonia developed at between 1 and 6 months of age in six (13%) of the 46 HIV-infected children who received prophylaxis; two of these children died (one at 6 months of age of suspected pneumonia, at a local hospital). The causes of these pneumonias were not determined.
Among the 68 HIV-infected children in the 1992–1994 cohort, the incidence of pneumonia between ages 1 and 6 months was 15 out of 68 (22.1%) , compared with six out of 46 (13.0%) in the recent cohort [relative risk (RR) 0.59, 95% confidence interval (CI) 0.25–1.41, P = 0.22]. The mortality rate from pneumonia between the ages of 1 and 6 months in the previous cohort was six out of 68 (8.8%), compared with two out of 46 (4.3%) in the recent cohort (RR 0.49, 95% CI 0.10–2.34, P = 0.47).
PCP is an important opportunistic infection in HIV-infected children, especially young infants, and is a common cause of death. In Europe and the United States, PCP develops in 12–25% of HIV-infected children during their first year of life [1,5,11], and the reported median survival of children after an episode of PCP is only 19 months or less [1,12]. Because P. carinii seems to be a ubiquitous organism to which all children are exposed, prophylaxis is the most effective way to prevent PCP among those at risk of disease . The use of PCP prophylaxis prolongs time to category C for HIV-infected children , decreases the risk of the early death of infants , and prolongs the survival of HIV-infected adults . In young infants, however, PCP may develop despite relatively normal CD4 T lymphocyte counts and the absence of symptoms [1,5–7,16], thereby reducing the effectiveness of using clinical or immunological risk markers to guide prophylaxis, a strategy that is effective for older children and adults. This finding led to the 1995 recommendation in the United States to prescribe prophylaxis for all HIV-infected infants in the first year of life . In addition, because PCP may occur before a child's HIV infection status has been determined, these guidelines recommend prophylaxis for all HIV-exposed children until infection can be excluded, even though fewer than 20% of children who receive prophylaxis are HIV infected and are thus at potential risk of PCP.
In Thailand, despite the fact that approximately three times as many children are born to HIV-infected women each year (approximately 15 000) as in the United States (approximately 6000), this approach to primary PCP prophylaxis has not been generally adopted. This is partly because of the unavailability of diagnostic tests to guide decisions about stopping prophylaxis for infants who are not at risk of PCP because they are not HIV infected. The usual practice in hospitals in Thailand is to wait for symptoms of HIV infection to appear before starting prophylaxis. As a result, prophylaxis is not started for many young HIV-infected infants at risk of PCP. To improve PCP prevention in this population, we evaluated a strategy of universal PCP prophylaxis for all HIV-exposed infants during the age of highest risk – 2–6 months of age. Instead of using laboratory tests for HIV infection to guide the decision to stop or continue prophylaxis, we used the presence or absence of HIV-associated clinical findings when the child reached 6 months of age, a strategy that could be useful for Thailand and other developing countries.
On the basis of our evaluation, this strategy seemed acceptable, safe, and helpful in making decisions about prophylaxis. All 383 mothers who were offered prophylaxis agreed, and only 3% adhered poorly to clinic visits or medication. Only 2% of children had to stop prophylaxis because of adverse events, all of which were mild and reversible. In addition, although our ability to determine the efficacy of this strategy was limited and our findings were not statistically significant, the data seem promising. Compared with the incidence in a historical control group, the incidence of pneumonia before 6 months of age was lower by nine cases per 100 HIV-infected children, and mortality as a result of pneumonia was lower by four deaths per 100 HIV-infected children. If this finding represents an actual reduction of pneumonia, it corroborates the findings in one of our hospitals that the incidence of severe pneumonia among HIV-infected children declined after a universal PCP prophylaxis strategy was instituted .
Making a clinical decision for children at 6 months of age seems to be an effective tool for continuing prophylaxis for infected children, while excluding low-risk infants from the prolonged use of TMP–SMX. Basing the decision on the presence or absence of one of several clinical findings would have resulted in continuing prophylaxis for most (70%) of the infected children after 6 months of age. Using only the presence of splenomegaly would have resulted in accurate decisions about prophylaxis for 94% of children overall.
Our evaluation had several limitations. We did not examine the effect of this strategy on the development of drug resistance in bacteria or other organisms that cause infections in the population. We also did not examine its cost-effectiveness or effect on the quality of life. We did not have a contemporaneous, randomized control group with which to compare the incidence of pneumonia and death; factors other than PCP prophylaxis may have contributed to the apparent decline in these rates. Moreover, our sample size did not have the statistical power to differentiate effectiveness from chance variation. Finally, the correlation of clinical symptoms with HIV infection status we observed may differ in other populations, and we did not evaluate the ability of providers other than paediatricians to diagnose findings such as splenomegaly.
Nonetheless, the favourable findings may have implications for the care of HIV-exposed children in Thailand and other countries where diagnostic testing and treatment resources are limited. In particular, as more developing countries follow Thailand's lead in implementing perinatal HIV prevention programmes that include routine voluntary HIV counselling and testing during pregnancy [17,18], increasing numbers of HIV-exposed children will be identified and will require care from birth. PCP prophylaxis has become integral to the care of HIV-exposed children in the United States and other countries with substantial healthcare resources. Whether providing PCP prophylaxis for all HIV-exposed children will be adopted in countries with more limited resources will require weighing the probable reduction in morbidity and mortality against the cost (approximately US$3 per treatment to 6 months of age), other potential negative outcomes, such as the development of drug resistance, and the potential decline in the perinatal HIV transmission rate resulting from the introduction of effective interventions. In addition, this approach needs to be evaluated in other settings, especially where other causes of splenomegaly (e.g. thalassaemia, malaria) and other findings may be prevalent and where care is provided by less experienced healthcare workers.
The authors gratefully acknowledge the dedicated field work of the project study nurses and social workers: K. Neeyapun, B. Jetsawang (team leaders); S. Bhengsri, S. Henchaichon, S. Jalanchavanapate, K. Klumthanom, R. Krajangthong, C. Prasert, W. Sanyanusin, W. Suwannapha, S. Sorapipatana, S. Suwanmaitre, W. Triphanitchkul, and C. Yuvasevee. The authors would also like to thank Tim Mastro, Eve Lackritz, Martha Rogers, and Marie Morgan for critical review of the manuscript.
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Other members of the Bangkok Collaborative Perinatal HIV Transmission Study Group
Faculty of Medicine, Siriraj Hospital, Department of Obstetrics and Gynaecology: S. Neungton, P. Chaisilwattana, A. Roongpisuthipong, A. Chalermchokcharoenkit, K. Sirimai, P. Phopong, C. Bhadrakom, P. Chaiyakul, P. Rattananikhom, R. Prechanont
Faculty of Medicine, Siriraj Hospital, Department of Pediatrics: M. Tuchinda, S. Pichitchaichan, W. Boonyavit
Faculty of Medicine, Siriraj Hospital, Department of Microbiology: C. Wasi
Rajavithi Hospital, Department of Obstetrics and Gynaecology: P. Chinayon, W. Siriwasin, S. Asavapiriyanont, B. In-neam, S. Supatosa, C. Kannasot, S. Sangkasuwan, S. Leampojara, P. Pramukhakul
Rajavithi Hospital, Laboratory: S. Singhanati, G. Kaewchaiyo
Rajavithi Hospital, Department of Nursing: J. Sawakwan, N. Montasewee
Queen Sirikit National Institute for Child Health: S. Horpaopan, V. Sangtaweesin, P. Na Chiengmai, R. Kulvisuthpravit, B. Phasukdee, P. Sojirat
The HIV/AIDS Collaboration: T.D. Mastro, K. Limpakarnjanarat, W. Supapol, A. Bennetts, N. Chantharojwong, T. Naiwatanakul, J. Laosakkitiboran, P. Yuentrakul, C. Manopaiboon