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Evaluating a new strategy for prophylaxis to prevent Pneumocystis carinii pneumonia in HIV-exposed infants in Thailand Kulkanya Chokephaibulkita , Rutt Chuachoowongbc , Tawee Chotpitayasunondhd , Sanay Chearskula , Nirun Vanprapara, Naris Waranawatd , Philip Mockc , Nathan Shafferce and R.J. Simondsce, for the Bangkok Collaborative Perinatal HIV Transmission Study Group Objective: To evaluate a strategy for prophylaxis against Pneumocystis carinii pneumonia (PCP) for infants in Thailand. Methods: HIV-infected women were offered trimethoprim±sulfamethoxazole for PCP prophylaxis for their children at 1±2 months of age. When the children reached 6 months of age, investigators simulated a decision to continue or stop prophylaxis on the basis of clinical criteria, and compared their decisions with results of polymerase chain reaction (PCR) testing for HIV. We calculated the proportions of children who received and completed prophylaxis, and compared the rates of pneumonia and death from pneumonia with rates from an earlier prospective cohort. Results: Of 395 eligible infants, 383 (97%) started prophylaxis. By 6 months of age, 10 (2.6%) were lost to follow-up, three (0.8%) were non-adherent, seven (2%) had stopped because of adverse events, four (1%) had died, and 359 (94%) still received prophylaxis. At 6 months of age, 30 (70%) of 43 HIV-infected children and 16 (5%) of 316 uninfected children met the clinical criteria to continue prophylaxis. The incidence of pneumonia at 1 to 6 months of age was 22% (15/68) in the earlier cohort, and 13% (6/46) in the recent cohort [relative risk (RR) 0.6, 95% con®dence interval (CI) 0.3±1.4; P ˆ 0.22]; mortality rates were 9% and 4%, respectively (RR 0.5; 95% CI 0.1±2.3; P ˆ 0.47). Conclusion: This PCP prophylaxis strategy appeared to be acceptable and safe, may have reduced morbidity and mortality from pneumonia, and should be considered in developing countries where early laboratory diagnosis of perinatal HIV infection is & 2000 Lippincott Williams & Wilkins unavailable.

AIDS 2000, 14:1563±1569 Keywords: HIV, infants, Pneumocystis carinii pneumonia, pneumonia, prophylaxis

From the a Department of Pediatrics, and b Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; c The HIV/AIDS Collaboration, Nonthaburi, Thailand; d Queen Sirikit National Institute of Child Health, Department of Medical Services, Ministry of Public Health, Bangkok, Thailand; and e Division of HIV/AIDS Prevention, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.  Members of the study group listed at the end of the paper. Correspondence and reprint requests to: Kulkanya Chokephaibulkit, MD, Division of Infectious Diseases, Department of Pediatrics, Siriraj Hospital, 2 Prannok Road., Bangkoknoi, Bangkok 10700, Thailand. Tel: ‡66 2 419 7027; fax: ‡66 2 718 4769; e-mail: [email protected] Received: 15 February 2000; accepted: 25 February 2000.

ISSN 0269-9370 & 2000 Lippincott Williams & Wilkins

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Introduction Pneumocystis carinii pneumonia (PCP) is the most common serious opportunistic infection among children infected with HIV in the United States [1]. In Thailand, PCP was the cause of at least one third of the cases of severe pneumonia in HIV-infected children hospitalized at Siriraj Hospital, a large tertiary care hospital in Bangkok [2]. Moreover, presumptively diagnosed PCP was the most common AIDS-de®ning condition reported for Thai children during 1988± 1995 [3]. The US Centers for Disease Control and Prevention recommended in 1995 that trimethoprim±sulfamethoxazole (TMP±SMX) be offered as primary prophylaxis for PCP to all children born to HIV-infected women until HIV infection in the child can be reasonably excluded on the basis of virological tests such as polymerase chain reaction (PCR) [4]. This recommendation followed from observations that the incidence of PCP in infants peaks at age 2±6 months, when the HIV infection status of many children is still unknown, the risk of mortality from PCP is high, and the prognosis after PCP is poor [1,4]. Moreover, unlike in adults and older children, PCP may develop in HIVinfected infants who have relatively high CD4 lymphocyte counts, making such counts unreliable as risk markers [5±7].

prophylaxis at 1±2 months of age, and the presence or absence of HIV-related signs or symptoms is used to determine whether to continue or stop prophylaxis at 6 months of age. In this paper, we evaluate the feasibility of this strategy and estimate its impact on preventing pneumonia in HIV-infected children between 1 and 6 months of age.

Methods The evaluation was conducted prospectively at two referral hospitals in Bangkok: Queen Sirikit National Institute for Child Health and Siriraj Hospital, where an estimated one third of HIV-infected children in Bangkok receive care. All infants born to HIV-infected mothers enrolled in a phase III randomized trial of short-course antenatal zidovudine to reduce mother± infant HIV transmission from May 1996 to December 1997 were included in this evaluation [8]. For the trial, infants were seen at 1, 2, 4, 6, 9, 12, and 18 months of age for immunizations and routine child care. HIV± PCR testing was done at birth and at 2 and 6 months of age. HIV-infected women were counselled to avoid breastfeeding and were provided infant formula.

This recommendation has not been adopted widely in Thailand or other developing countries for several reasons. There is concern that the risk of adverse events may outweigh the bene®ts, resistance to TMP±SMX could become widespread and diminish its effectiveness in treating common childhood infections, and the cost of universal prophylaxis may be too great. Moreover, the risk : bene®t ratio will increase as more children born to HIV-infected women escape HIV infection (and the risk of PCP) because of the increasing use of zidovudine to prevent mother±infant HIV transmission [8]. In addition, because PCR and other tests to diagnose perinatal HIV infection in infancy are not generally available, determining that a child is not infected with HIV requires waiting until the second year of life, when HIV antibody testing is reliable. The time necessary to exclude HIV infection may thus be several times longer than in settings in which PCR testing is available, thereby increasing the costs and the risks of using TMP±SMX for uninfected children who are not at risk of PCP.

All women were offered TMP±SMX (150 mg of TMP/M 2 /day in two divided doses three times a week) for their infants at the 1 or 2 month visit, depending on the hospital and the timing of the child's visit, after counselling (Fig. 1). Adherence to prophylaxis (based on self-report and record of medication re®lls), adverse reactions, HIV-related signs and symptoms, illnesses, and hospitalizations were recorded at each visit as part of routine care. To simulate general practice at these hospitals and in Thailand, in which PCR and other early diagnostic tests are usually not available, PCR results for the infants remained masked until the 6 month visit. At the 6 month visit, each child was evaluated by a physician investigator on clinical criteria and the investigator simulated a decision to continue or stop prophylaxis (Fig. 1). After this decision was recorded, the PCR results were unmasked and the decision could be changed on the basis of these results or the later development of HIV-associated symptoms. If a child had symptoms of HIV infection before 6 months of age and there was a need to know the child's HIV status for clinical management, the investigator would unmask the PCR result after categorizing the child as being symptomatic.

The experience at Siriraj Hospital, similar to that in centres in other countries, is that children whose ®rst symptom of HIV infection is PCP are generally younger than 6 months of age [2]. We therefore proposed a strategy for primary PCP prophylaxis, by which all children born to HIV-infected mothers start receiving

HIV antibody and CD4 T lymphocyte count tests were performed when the children were 12 months old. The decision to continue prophylaxis after this age was based on HIV status, clinical status, and CD4 T lymphocyte count. In general, PCP prophylaxis was continued for children classi®ed as immunological category 3 or

Pneumocystis carinii pneumonia prophylaxis for infants in Thailand Chokephaibulkit et al. All babies born to HIV-infected mothers

At 4–8 weeks Start PCP prophylaxis with TMP–SMX

At 2 and 4 months Monitor tolerance and adherence

Stop prophylaxis if intolerant At 6 months Decide whether to continue prophylaxis based on clinical criteria

If any clinical criteria met: CONTINUE PROPHYLAXIS

If no clinical criteria met: STOP PROPHYLAXIS

Resume prophylaxis if criteria met later

Clinical criteria for continuing prophylaxis after 6 months of age - Hepatomegaly - Splenomegaly - Lymphadenopathy .2 sites - Oral thrush (.1 week with treatment, or recurrent) - Chronic or recurrent dermatitis - Recurrent or persistent upper respiratory infection, otitis, sinusitis - Recurrent or chronic diarrhoea - Serious bacterial infection - Haematologic abnormality (Hgb ,8 gm/dl, neutrophils ,100/mm3, platelets ,100 000/mm3)

- Hepatitis - Unexplained intermittant or persistent fever - Delayed development - Growth failure (,25th percentile, protracted) or weight loss .10% of baseline - Neurological deficit - Impaired brain growth (5th percentile head circumference for height) - AIDS-defining condition

Fig. 1. Strategy for universal primary Pneumocystis carinii pneumonia prophylaxis. PCP, Pneumocystis carinii pneumonia; TMP±SMX, trimethoprim±sulfamethoxazole.

clinical category C in the Centers for Disease Control and Prevention classi®cation system [9].

Outcome measurement and statistical analysis We measured rates of acceptance of prophylaxis by mothers and completion of PCP prophylaxis until 6 months of age by children. We determined the number of children who stopped taking TMP±SMX because of poor adherence or neutropenia, thrombocytopenia, anaemia, haemolysis, rash, or other reasons. For this analysis, a child was considered to be infected if at least one specimen tested positive by PCR, and a child was considered uninfected if the specimen at 6 months of age tested negative by PCR. The simulated decision about prophylaxis, based on clinical criteria (Fig. 1), was compared with the child's infection status, based on PCR results. In addition, each clinical criterion was

evaluated for correlation with HIV infection status. The incidences of pneumonia and deaths from pneumonia between 1 and 6 months of age in this population were compared with those in a prospective study in the same hospitals in 1992±1994, when primary PCP prophylaxis was not used [10]. In both studies, pneumonia was usually diagnosed on the basis of clinical examination and chest X-ray. We performed comparative analyses by using chi square and Fisher's exact tests. All P values are two-tailed.

Results All 395 infants born in this cohort were included in the evaluation (Fig. 2). TMP±SMX prophylaxis was of-

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12 excluded (2 HIV-infected) • 4 died before prophylaxis offered (congenital infection, diarrhoea/shock, cardiac anomalies, pneumonia) • 7 lost before prophylaxis offered • 1 not offered prophylaxis

383 started on prophylaxis (53 HIV-infected)

4 died ,6 months old (3 HIV-infected) (1 pneumonia, 1 suspected pneumonia, 1 sepsis, 1 encephalitis)

• 10 lost to follow-up (4 HIV-infected) • 3 non-compliant (0 HIV-infected) • 7 intolerant (3 HIV-infected) (5 rashes, 1 oral ulcer, 1 anaemia)

359 continued prophylaxis to 6 months of age (43 HIV-infected)

313 asymptomatic • 13 HIV-infected • 300 uninfected

46 symptomatic • 30 HIV-infected • 16 uninfected

Fig. 2. Flow chart of children evaluated.

fered for 383 infants. After prophylaxis was begun, 10 (2.6%) children were lost to follow-up before 6 months of age, and three (0.8%) did not take the medication regularly. Seven (1.8%) children, three of whom were HIV infected, stopped prophylaxis before 6 months of age because of adverse events (®ve with mild rashes, one each with oral ulcers, mild anaemia); all improved promptly after prophylaxis was stopped and all were still free of illness at 12 months of age. Of the four (1%) infants who received prophylaxis and died before 6 months of age, three were HIV infected. None had symptoms suggesting a reaction to TMP±SMX.

Clinical decisions about prophylaxis at 6 months Of the 359 children who continued prophylaxis until their 6 month visit, 313 (87.2%) [13 (4.2%) HIV infected] remained asymptomatic (Table 1). One or more signs or symptoms associated with HIV infection

Table 1. Comparison of decision to continue prophylaxis based on clinical conditions at 6 months of age (see Fig. 1) with the child's HIV infection status. Clinical decision Continue Discontinue

HIV infected (n ˆ 43)

HIV uninfected (n ˆ 316)

30 13

16 300

developed in 46 (12.8%) children [16 (34.8%) not infected]. On the basis of clinical criteria, 30 (70%) of 43 HIV-infected children, but only 16 (5%) of 316 HIV-uninfected children, would have continued prophylaxis after 6 months of age. The positive and negative predictive values of the clinical criteria for predicting the child's infection status were 65 and 96%,

Pneumocystis carinii pneumonia prophylaxis for infants in Thailand Chokephaibulkit et al.

respectively. If individual clinical criteria alone were used to make the decision about prophylaxis at 6 months of age, using the presence of splenomegaly or hepatomegaly would have led to the most `correct' decisions (Table 2).

with two out of 46 (4.3%) in the recent cohort (RR 0.49, 95% CI 0.10±2.34, P ˆ 0.47).

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.

Discussion

Bene®t of prophylaxis strategy 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%) [10], compared with six out of 46 (13.0%) in the recent cohort [relative risk (RR) 0.59, 95% con®dence interval (CI) 0.25±1.41, P ˆ 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

PCP is an important opportunistic infection in HIVinfected 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 ®rst 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 [13]. The use of PCP prophylaxis prolongs time to category C for HIV-infected children [14], decreases the risk of the early death of infants [11], and prolongs the survival of HIV-infected adults [15]. 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 ®nding led to the 1995 recommendation in the United States to prescribe prophylaxis for all HIV-infected infants in the ®rst year of life [4]. 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

Table 2. Presence or absence of clinical conditions used for decision about prophylaxis for Pneumocystis carinii pneumonia among HIV-infected and uninfected children at 6 months of age, and overall number of correct treatments expected with each condition.

Clinical condition Splenomegaly Hepatomegaly Lymphadenopathy Growth failure Delayed development Thrush Serious bacterial infection Chronic diarrhoea Impaired brain growth Recurrent upper respiratory infection Any of the above

HIV infected with condition (n ˆ 43) no. (% sensitivity)

HIV uninfected without condition (n ˆ 316) no. (% speci®city)

Correctly treated (n ˆ 359) no. (%)

Positive predictive value (%)

Negative predictive value (%)

22 (51) 21 (50) 10 (23) 5 (12) 4 (9) 3 (7) 2 (5) 3 (7) 1 (2) 1 (2) 30 (70)

315 (. 99) 309 (98) 314 (99) 315 (. 99) 316 (100) 315 (. 99) 316 (100) 314 (99) 316 (100) 313 (99) 300 (95)

337 (94) 330 (92) 324 (90) 320 (89) 320 (89) 318 (89) 318 (89) 317 (88) 317 (88) 314 (87) 330 (92)

96 75 83 83 100 75 100 60 100 25 65

94 93 90 89 89 89 89 89 88 88 96

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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 HIVinfected 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 ®ndings 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 ef®cacy of this strategy was limited and our ®ndings were not statistically signi®cant, 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 ®nding represents an actual reduction of pneumonia, it corroborates the ®ndings in one of our hospitals that the incidence of severe pneumonia among HIV-infected children declined after a universal PCP prophylaxis strategy was instituted [2]. 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 lowrisk infants from the prolonged use of TMP±SMX. Basing the decision on the presence or absence of one of several clinical ®ndings 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 ®ndings such as splenomegaly. Nonetheless, the favourable ®ndings 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 identi®ed 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 ®ndings may be prevalent and where care is provided by less experienced healthcare workers.

Acknowledgements The authors gratefully acknowledge the dedicated ®eld 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.

Pneumocystis carinii pneumonia prophylaxis for infants in Thailand Chokephaibulkit et al.

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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

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