POLICY AND PRACTICE
Remise en question du traitement préventif empirique par le cotrimoxazole chez les nourrissons exposés à l'infection par le VIH
Reconsideración de la profilaxis empírica con trimetoprim y sulfametoxazol en lactantes expuestos a la infección por VIH
Christopher J. GillI, 1; Lora L. SabinI; Joseph ThamII; Davidson H. HamerIII
IAssistant Professor, Department of International Health, Center for International Health and Development, Boston University School of Public Health, Boston, MA, USA (firstname.lastname@example.org)
IIAdjunct Assistant Professor, Department of International Health, Center for International Health and Development, Boston University School of Public Health, Boston, MA, USA
IIIAssociate Professor of Medicine and Nutrition, Tufts University School of Medicine and Freedman School of Nutrition, Boston, MA, USA
Infants with HIV infection are vulnerable to Pneumocystis carinii pneumonia (PCP) during their first year of life. WHO and the Joint United Nations Programme on HIV/AIDS now recommend that all children of HIV-positive mothers receive prophylactic cotrimoxazole against PCP from six weeks of age and continue this therapy until exposure through breast milk ceases and the infant is confirmed to be HIV-negative (rarely before one year of age). Empirical prophylaxis invokes a trade-off between possible benefit to the infant versus the risk of resistance to antibiotics and antimalarials. From a critical analysis of the literature, we offer a conceptual model demonstrating how, under certain circumstances, a policy of mass cotrimoxazole prophylaxis may be counterproductive.
Keywords: Trimethoprim-sulfamethoxazole combination/therapeutic use/adverse effects; Pneumonia, Pneumocystis/drug therapy; HIV infections/ complications; AIDS-related opportunistic infections/drug therapy; Disease transmission, Vertical; Drug resistance, Microbial; Sulfadoxine/ pharmacology; Pyrimethamine/pharmacology; Infant; Risk assessment; Meta-analysis; Models, Theoretical; Africa (source: MeSH, NLM).
Les nourrissons atteints d'infection par le VIH sont sensibles à la pneumocystose (pneumonie à Pneumocystis carinii) jusqu'à l'âge d'un an. L'OMS et le Programme commun des Nations Unies sur le VIH/SIDA recommandent actuellement d'administrer à tous les enfants nés de mère VIH-positive un traitement préventif par le cotrimoxazole contre la pneumocystose dès l'âge de six semaines et jusqu'à arrêt de l'exposition via le lait maternel et confirmation de la séronégativité de l'enfant vis-à-vis du VIH (rarement avant l'âge d'un an). Le traitement préventif empirique représente un compromis entre les avantages potentiels pour le nourrisson et le risque de résistance aux antibiotiques et aux antipaludiques. D'après une analyse critique des observations publiées, nous présentons un modèle théorique montrant comment, dans certaines circonstances, une politique de traitement préventif de masse par le cotrimoxazole peut être contre-productive.
Mots clés: Triméthoprime-sulfaméthoxazole, Association/usage thérapeutique/effets indésirables; Pneumocystose/chimiothérapie; HIV, Infection/ complications; Infections opportunistes liées SIDA/chimiothérapie; Transmission verticale maladie; Résistance microbienne aux médicaments; Sulfadoxine/pharmacologie; Pyriméthamine/pharmacologie; Nourrisson; Evaluation risque; Méta-analyse; Modèle théorique; Afrique (source: MeSH, INSERM).
Los lactantes infectados por el VIH son vulnerables a la neumonía por Pneumocystis carinii (NPC) durante el primer año de vida. En la actualidad, la OMS y el Programa Conjunto de las Naciones Unidas sobre el VIH/SIDA recomiendan que todos los niños cuyas madres son VIH-positivas reciban profilaxis con trimetoprim y sulfametoxazol contra la NPC desde las seis semanas de vida, y que sigan con este tratamiento hasta que cese la exposición a través de la leche materna y se confirme que el niño es VIH-negativo (raramente antes del año de vida). La profilaxis empírica se fundamenta en un equilibrio entre el posible beneficio para el lactante y el riesgo de resistencia a los antibióticos y los antimaláricos. Basándonos en un análisis crítico de la literatura médica, proponemos un modelo conceptual que demuestra que, en determinadas circunstancias, una política de profilaxis masiva con trimetoprim y sulfametoxazol puede ser contraproducente.
Palabras clave: Combinación trimetoprim-sulfametoxazol/uso terapéutico/efectos adversos; Neumonía por Pneumocystis carinii/quimioterapia; Infecciones por VIH/complicaciones; Infecciones oportunistas relacionadas con el SIDA/quimioterapia; Transmisión vertical de enfermedad; Resistencia microbiana a las drogas; Sulfadoxina/farmacología; Pirimetamina/farmacología; Lactante; Medición de riesgo; Meta-análisis; Modelos teóricos; África (fuente: DeCS, BIREME).
In 2000, WHO and the Joint United Nations Programme on HIV/AIDS (UNAIDS) issued a provisional recommendation: all African infants born to mothers infected with human immunodeficiency virus (HIV) should receive empirical cotrimoxazole (trimethoprim-sulfamethoxazole) prophylaxis against Pneumocystis carinii (now called Pneumocystis jirovecia) pneumonia (PCP) from six weeks of age (1). This proposal was made for the following reasons: the high number of deaths from PCP in infants with HIV infection; cotrimoxazole's efficacy for preventing PCP in adults; and the difficulty in determining HIV infection in exposed infants in poor countries. Nevertheless, cotrimoxazole prophylaxis based solely on HIV exposure, without confirmation of HIV infection status within the first month of life, is not the way this drug is usually used in developed countries and may have unforeseen consequences.
In developed countries, cotrimoxazole prophylaxis for infants exposed to HIV is also recommended from six weeks of age but usually discontinued once HIV infection has been excluded using a direct viral detection assay - ideally within the first few months of life. Direct viral assays are expensive, however, forcing poorer nations to rely on antibody-based HIV tests. Antibody assays are useful for diagnosing HIV in adults or older children but less reliable for neonates or infants. Persistence of maternal HIV antibodies gives high numbers of false positives until at least 12 months of age (2). Moreover, in countries where safe, culturally acceptable, feasible, affordable and sustainable alternatives to breastfeeding are lacking, up to 40% of infant HIV infections occur via breastfeeding (3). Because breastfeeding is nearly universal in developing countries, even tests that directly test for the presence of HIV rather than serologic responses would not resolve this dilemma unless applied after the child has been weaned. In this context, a negative viral assay would not alter the indication of cotrimoxazole until the child is no longer at risk of acquiring HIV through breast milk. Hence, infants exposed to HIV would continue prophylaxis until both weaned and shown to be antibody negative - conditions rarely satisfied before one year of age.
Between 600 000 and 800 000 infants with HIV infection are born each year, 90% of them in sub-Saharan Africa (4). This however represents only 13-30% of infants with peripartum HIV exposure (3). Consequently, at least 2 million infants annually would need prophylaxis under WHO/UNAIDS guidelines. Even though cotrimoxazole is inexpensive on a per-dose basis, providing so many children with a year's supply poses formidable financial and logistical challenges for Africa's poorest nations. Even assuming these challenges could be overcome, it remains unproven whether the potential benefits would exceed the potential risks of mass prophylaxis.
To explore these issues, we critically analyse the natural history of HIV and PCP in African infants, the evidence for cotrimoxazole's benefit in this group, and the known and theoretical risks of prophylaxis. From this analysis, we offer a theoretical model contrasting the risks and benefits of prophylaxis as an aid to framing future public policy responses to the problem of PCP in infants with HIV infection, and for defining future research priorities.
Natural history of HIV and PCP in young children
HIV infection proceeds more rapidly to AIDS in infants than adults. AIDS-related deaths peak during the first six months of life, followed by a more gradual progression to AIDS in the survivors (5). Natural history studies from Europe and the USA before the era of highly active antiretroviral therapy (HAART) are illustrative. Twenty six per cent of infected children developed clinical AIDS before reaching 12 months and 17% died (6); median survival was 38 months (7). Mortality rates in African infants are even higher. In Rwanda, mortality was 45% and 62% by age 2 years and 5 years, respectively (8). Of Malawian infants surviving their first year, 30% died by age 2 years and another 45% died by age 3 years (9). Overall, 90% of HIV-infected African children die before age 5 years (10).
In the pre-HAART era, HIV-infected infants in developed countries frequently died from PCP, particularly during their first six months of life (11) - a trend central to current prophylaxis guidelines. In African infants, the proportion of mortality caused by PCP versus other infectious diseases is unknown but probably small compared with the estimated annual 6 million deaths from malaria, diarrhoeal disease, and bacterial pneumonia (12). Autopsies and studies of African children infected with HIV and hospitalized for severe pneumonia demonstrate the importance of PCP (Table 1) but fail to indicate the proportion of all HIV-infected African infants who succumb to PCP compared with other causes. Natural history studies would provide these data but to date none of the prospective African trials have included PCP incidence data. In the absence of these data, we are forced to extrapolate the incidence data using pre-HAART studies from the USA, where first-year PCP incidence has been reported to range between 12.8% and 25% (7, 13). Based on these data, a plausible estimate of the annual incidence of infant PCP in Africa is between 76 000 (0.128 x 600 000) and 200 000 (0.25 x 800 000) cases.
Will cotrimoxazole prevent PCP in African children?
The survival benefit of cotrimoxazole is well established for adults with HIV infection living in developed countries but less well known for Africa (14). Only three randomized trials have studied primary prophylaxis with cotrimoxazole in Africa. The first was conducted among a population of adults with HIV infection receiving treatment for TB in Abidjan, Côte d'Ivoire. In this cohort, cotrimoxazole reduced all-cause mortality by 46% and hospitalizations by 43% compared with placebo (15). Cotrimoxazole users had reduced rates of enteritis (1.1% vs 3%, P = 0.04), bacteraemia (0.5% vs 3%, P = 0.01), and mycobacterial disease (3.9% vs 6.4%, P = 0.14) (15). The second study, also from Abidjan, was not limited to HIV patients with TB. Here, fewer patients receiving cotrimoxazole were hospitalized for pneumonia (0.7% vs 7%, P < 0.001), malaria (1% vs 9.6%, P < 0.01), or isosporiasis (0.7% vs 4%, P = 0.02). Prophylaxis had no significant impact on mortality (8.4% vs 9.2%, P = 0.5), but did cause increased rates of unexplained fever (13.6% vs 10%, P < 0.01) (16). While insufficiently powered to detect a mortality difference, the Kaplan-Meier curve provides little optimism that a clinically meaningful benefit was missed. The third study, from Dakar, Senegal, found no impact on either mortality or hospitalization, but was ultimately inconclusive, having been terminated early following the publication of the Abidjan studies (17).
While sought, PCP was not detected in either Abidjan study. This finding reinforces an emerging view that PCP may be a less important opportunistic pathogen for African adults with AIDS, compared with adults in developed nations. One possible explanation is that Africans with HIV succumb to TB or other infectious diseases long before their CD4 counts drop to a level where PCP becomes a realistic threat. If so, cotrimoxazole's main benefit for African adults may lie in preventing common bacterial and parasitic diseases.
The WHO/UNAIDS guidelines - including the recommendation for empiric cotrimoxazole for infants - emerged shortly after the publication of the Abidjan studies. This is remarkable given that neither study provided any information about the optimal use or efficacy of cotrimoxazole in children. While the evidence for PCP's importance in African children with HIV infection is robust (Table 1), evidence for cotrimoxazole's efficacy in this age group is weak. To date, no randomized trials of cotrimoxazole's efficacy have been conducted. Evidence supporting the use of cotrimoxazole in children with HIV infection rests principally on observational studies from the USA (18). Studies from developing countries consist of an ecological study from Thailand that documented a rise in community cotrimoxazole use over a period when PCP hospitalizations in children declined (19), and two retrospective analyses showing a reduced proportion of PCP in African infants with HIV infection and pneumonia among those using prophylaxis before hospitalization (20, 21). A third case-control study, however, found no reduction in PCP rates due to prophylaxis (22). One concern with this study's conclusion arises from the fact that cases were defined as children with HIV infection and confirmed PCP, and therefore may have included many children who had simply failed prophylaxis. It is unclear whether or not these children are representative of all children with HIV infection. Nor is it possible to infer how many children receiving prophylaxis remained well and avoided hospitalization.
Despite these ambiguities, the protective benefit found in studies from the USA establishes a strong moral imperative to provide cotrimoxazole to African infants either known or clinically suspected to have HIV infection - in the absence of data demonstrating its ineffectiveness or harm. Accepting the likelihood that prophylaxis will reduce PCP incidence in African infants with HIV infection does not mean that the benefits of mass prophylaxis will outweigh its risks when applied empirically to a population in which children infected with HIV will be a minority.
What are the risks of cotrimoxazole prophylaxis?
Rash, fever, and anaemia are all common during cotrimoxazole prophylaxis (23), and particularly in people with HIV infection (24). Cotrimoxazole appears better tolerated in children (25). Rare life-threatening side-effects, including severe hepatitis or Stevens-Johnson syndrome, can also occur though their incidence is difficult to predict from small clinical studies.
Antimicrobial resistance is arguably the most important adverse consequence of prophylaxis. Children taking antibiotics for a variety of chronic conditions - sickle-cell anaemia, recurrent urinary tract infections, and chronic otitis media - quickly become colonized with drug-resistant bacteria (26-28). Adults with HIV infection taking prophylactic cotrimoxazole also experience drug resistance (29). The list of pathogens whose epidemiology could be altered by cotrimoxazole exposure includes Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, enteropathogens (Shigella spp., Salmonella spp., Isospora belli), and Neisseria spp.
Resistant pathogens spread readily from infants to close contacts (30, 31), thereby extending this consequence of prophylaxis to families and ultimately the community at large. Rising cotrimoxazole resistance rates could impair the effectiveness of the WHO's Integrated Management of Childhood Infections (IMCI) guidelines, which currently recommend cotrimoxazole as first-line therapy for a variety of childhood infections (32).
The genetics of drug resistance adds another layer of complexity. Transmissible genetic elements often incorporate multiple antibiotic-resistance genes. For example, prior cotrimoxazole use has been identified as a risk factor for colonization with penicillin resistant pneumococci (33). Thus, our mental calculus of cotrimoxazole's impact extends beyond cotrimoxazole resistance alone, to include also penicillins, cephalosporins, macrolides, tetracyclines, and chloramphenicol (28, 34, 35).
Widespread cotrimoxazole use could also foster sulfadoxine-pyrimethamine resistance in Plasmodium falciparum, an organism which kills approximately one million children each year - the most attributable to any single childhood pathogen (36). With the loss of chloroquine as a reliable treatment for malaria, sulfadoxine-pyrimethamine has emerged as the first-line antimalarial throughout Africa. Rising resistance rates meant it was abandoned in the Amazon region of Brazil within a decade of introduction (37), and sulfadoxine-pyrimethamine may be a temporary solution to the problem of chloroquine resistance in Africa as well. Inexpensive and non-toxic alternatives are currently lacking, making it essential to maximize sulfadoxine-pyrimethamine's useful life (38).
Cotrimoxazole and sulfadoxine-pyrimethamine are close pharmacologically and share extensive in vitro cross-resistance (39, 40). Indeed, while cotrimoxazole is not typically considered an antimalarial, comparative studies show it to be equally effective as sulfadoxine-pyrimethamine for treating falciparum malaria (41, 42). As yet, there is no convincing evidence that this in vitro cross-tolerance will translate into clinical failures, though interestingly, sulfadoxine-pyrimethamine has been linked with increased rates of cotrimoxazole-resistant pneumococci (43). But this is not reassuring given the absence of prospective studies addressing the question. With the stakes that are involved, it would be irresponsible not to question whether the efficacy of sulfadoxine-pyrimethamine, and potentially other sulfonamide-containing antimalarials, could be reduced by mass cotrimoxazole prophylaxis.
Another concern is whether cotrimoxazole prophylaxis could impede the acquisition of natural malaria immunity by infants. Because of maternal antibodies, infants in areas of high malaria incidence are often born with immunity to malaria (44). As this passive immunity wanes, natural immunity emerges after exposure to infectious mosquitoes. Cotrimoxazole reduces both clinical malaria and asymptomatic parasitaemia and, in so doing, could hypothetically attenuate the normal acquisition of immunity. This creates an ethical dilemma since HIV-exposed infants discontinuing prophylaxis, after a negative HIV test at one year of age, might be more vulnerable to severe malaria than if they had never received prophylaxis.
Do the benefits exceed the risks of empiric prophylaxis?
Table 2 summarizes some of the most important risks and benefits of prophylaxis. Though their magnitudes are unknown, conceptualizing their interactions may still allow us to derive insights into how these risks and benefits compete, and identify areas where additional data could support a formal quantitative analysis.
Fig. 1 presents a basic conceptual model of the relationship between the risks and benefits of mass empiric prophylaxis when applied to a mixed population of HIV-positive and HIV-negative children. For simplicity we consider both risks and benefits to exist on a universal scale, such that 1 risk unit is equivalent in magnitude to 1 benefit unit. Because prophylaxis chiefly aims to prevent PCP, the benefit of empiric prophylaxis increases in proportion to HIV's prevalence in the target population (if prevalence were 100%, benefits would be maximal). Setting aside the less worrisome risk of cotrimoxazole side-effects, there is no compelling reason to expect that the more important risks of prophylaxis (microbial resistance) will be influenced by HIV infection per se. Therefore, the risk line should remain constant regardless of HIV prevalence. At some degree of HIV prevalence, the benefits and risks lines intersect and balance. When HIV prevalence exceeds this point, empiric prophylaxis is warranted; below this prevalence level, mass empiric prophylaxis is unjustified since the risks exceed benefits.
Our goal is to reduce PCP - and increase longevity - in HIV-positive children. Applying our current diagnostic limitations we do not know which HIV-exposed children are born infected or which will become infected during their first year. We will assume that the mother's HIV status will be ascertained during antenatal clinic voluntary counselling and testing (though in reality, this number will be reduced by those women who choose not to learn their HIV status). Currently, our options for preventing PCP in these children are either to use 4 million doses of nevirapine (half to the 2 million HIV-exposed infants and half to their HIV-positive mothers) or 750 million doses of cotrimoxazole to treat these children for one year each (2 million children exposed to HIV x 365 daily doses). Obviously, these are not mutually exclusive, and would probably be combined in the real world. This is logically appealing: nevirapine reduces the risk of HIV infection - and indirectly also PCP - in the majority, while cotrimoxazole protects the unlucky HIV-positive minority directly from PCP.
Careful examination of Fig. 1 reveals why this combined approach could have a paradoxical adverse effect. Let us assume that, in the absence of any intervention, this population's HIV prevalence places us precisely where the lines of risk and benefit intersect. If this population of HIV-exposed children receives nevirapine at birth, HIV prevalence will decline, shifting us to the left on the x axis. Even though nevirapine reduces the number of children at risk of PCP our ignorance of which children still become infected with HIV still compels us to provide cotrimoxazole presumptively to all 2 million. The result: even though cotrimoxazole's efficacy for preventing PCP for an individual HIV-positive infant remains constant, at a population level the effectiveness of mass prophylaxis deteriorates and the strategy becomes unjustifiable because the risks now exceed the benefits.
The purpose of this subjective exercise is not to suggest that this scenario would necessarily be the result of mass prophylaxis. Indeed our current knowledge of the magnitude of the risks involved is simply inadequate to know at what HIV prevalence the risk and benefits lines intersect (or even if these theoretical lines are straight or curved). But this is precisely the point - we don't know where this critical threshold lies, so why is it acceptable to assume that we are safely above it?
Without providing a quantitative measure of these outcomes, our thought experiment still identifies two problems deriving from our ignorance of which children are actually HIV-positive. First, because the same number of cotrimoxazole doses are used to prevent fewer cases of PCP, nevirapine reduces the additional benefit of cotrimoxazole prophylaxis. Second, the prior use of nevirapine increases the ratio of risk to benefit of subsequent cotrimoxazole prophylaxis. Accordingly, we suggest that improving strategies for preventing postnatal HIV transmission and for identifying HIV-infected children earlier (so that cotrimoxazole prophylaxis can be appropriately applied to those who will benefit most) may prove a better investment of limited resources than mass empiric prophylaxis.
Ultimately, the merit of a mass empiric prophylaxis strategy rests on the degree of risk it entails. Mass prophylaxis will inevitably increase rates of drug-resistant bacteria and malaria in cotrimoxazole users - and likely their communities at large - but how quickly, and to what extent? Quantifying the magnitude of this risk is essential and we urge countries that choose to implement WHO's strategy to initiate their programmes in parallel with a systematic means for prospectively monitoring the microbiological effects of mass prophylaxis in their populations. Given their unambiguous contribution to paediatric disease, monitoring the resistance patterns of S. pneumoniae and P. falciparum longitudinally would seem a logical starting point.
In their original declaration, WHO/UNAIDS acknowledged their strategy's potential for risk, but concluded that action was preferable to further debate (1). This sentiment is quite understandable given the magnitude of the humanitarian disaster unfolding before us. However, without a safety net of surveillance, it is critical that we better understand the consequences of this strategy, rather than taking a leap of faith.
We wish to thank the following people for their thoughtful advice during the preparation of this manuscript: Jonathan Simon, Donald Thea, Christine Ayash, and Matthew Fox (Center for International Health and Development); Dr Ira Wilson (Health Institute, Tufts-New England Medical Center); Dr Stephen Graham (Malawi-Liverpool-Wellcome Trust Clinical Research Programme and Department of Pediatrics, University of Malawi); and Dr Shamim Qazi (WHO).
This paper was made possible through generous support provided by the United States Agency for International Development (Applied Research on Child Health (ARCH) grant: HRN-A-00-96-90010-00), and by a CDC/ASPH/ATDSR cooperative agreement grant (Zambia-Boston University Malaria Project: S1954-21/21).
The grants cited provided salary support to conduct applied research in developing nations, but did not otherwise have any input into the content of this manuscript.
Conflicts of interest: none declared.
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Submitted: 26 August 03
Final revised version received: 7 November 03
Accepted: 8 December 03
1 Correspondence should be sent to this author.
a Stringer JR, Beard CB, Miller RF, Wakefield AE. A New Name (Pneumocystis jiroveci) for Pneumocystis from Humans. Emerging Infectious Diseases 2002; 8:891-6.