When should antiretroviral therapy be started for HIV-infected infants in resource-limited settings?
2008; Future Medicine; Volume: 2; Issue: 3 Linguagem: Inglês
10.2217/17469600.2.3.201
ISSN1746-9619
AutoresAndrew J. Prendergast, Mark F. Cotton, Diana M. Gibb,
Tópico(s)HIV-related health complications and treatments
ResumoFuture HIV TherapyVol. 2, No. 3 EditorialFree AccessWhen should antiretroviral therapy be started for HIV-infected infants in resource-limited settings?Andrew Prendergast, Mark Cotton & Diana M GibbAndrew Prendergast† Author for correspondenceUniversity of Oxford, Department of Paediatrics, Oxford, UK. , Mark CottonChildren's Infectious Disease Clinical Research Unit (KID-CRU), Faculty of Health Sciences, Stellenbosch University, South Africa and Tygerberg Children's Hospital, South Africa. & Diana M GibbMRC Clinical Trials Unit, London, UK. Published Online:6 May 2008https://doi.org/10.2217/17469600.2.3.201AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Figure 1. Maternal–infant pathway to early diagnosis and treatment.*Additional issues for decision makers include cost-effectiveness, capacity expansion and implementation.ART: Antiretroviral therapy; CTX: Cotrimoxazole; pMTCT: Prevention of mother-to-child HIV transmission; Sd: Single-dose.Globally, 1200 HIV-infected infants are born daily. Disease progression in infancy is rapid, with untreated mortality of over 50% by 2 years of age. A recent randomized controlled trial in South Africa demonstrated a 76% reduction in early mortality in infants randomized to immediate compared with deferred antiretroviral therapy (ART). However, there are substantial barriers to starting early infant ART in resource-limited settings: antenatal HIV testing remains limited; early infant diagnosis is frequently unavailable or unaffordable; and treatment of infants is challenging owing to high viral loads, lack of appropriate ART formulations and the paucity of pharmacokinetic data. Lifelong therapy may be unrealistic, and trials are investigating whether limited, short-term ART in infancy may delay the time when lifelong ART is required. Programmatic barriers to implementation of early diagnosis and treatment need to be overcome so that infants in resource-limited settings can benefit from the clear advantages of ART in early life.Mother-to-child transmission & the burden of HIV in infancyAlthough improvement in prevention of mother-to-child HIV transmission (pMTCT) in resource-rich countries has reduced transmission rates to 1–2% [1], the great majority of women in resource-limited settings do not know their own HIV status and are unable to access preventive care [101]. Even in regions with a reasonably high uptake of pMTCT, because of high antenatal seroprevalence, large numbers of HIV-infected infants continue to be born. For example, in South Africa where the seroprevalence in antenatal attendees in 2005 was 30.2%, with 300,000 HIV-exposed infants born annually, even a transmission rate of 5% translates into 15,000 HIV-infected infants born each year [102]. Globally, therefore, HIV-infected infants continue to be born at an alarming rate, with some 1200 new infections daily in 2007 [103]. HIV testing and treatment of infected children has lagged behind the impressive drive to improve provision of ART for adults [2,3]. For infants, this lag has been even more marked. Diagnosis and treatment are more challenging in infants compared with older children and adults. Below 18 months of age, PCR testing is required because of placental transfer of maternal anti-HIV antibodies [4], and this is both more expensive and more difficult to undertake. Even with early diagnosis, treatment of infants has specific challenges: high viral loads [2,3,5–7], poor predictive value of laboratory or clinical indicators to help decisions concerning timing of ART [8], a smaller repertoire of available drugs [2,104], unpalatable formulations [2], a paucity of pharmacokinetic data in an age group with rapid changes in drug metabolism [2], and reliance on caregivers for adherence. Globally, only 7% of people receiving ART by the end of 2005 were children [105], and these tended to be older children who can be treated more similarly to adults [9].With such a large burden of HIV-infected infants and so many hurdles to overcome, is it worth the huge effort that would be required to ensure that all HIV-infected infants are diagnosed and treated? The pediatric HIV epidemic represents a public health emergency in its own right. In the absence of treatment, more than 50% of infected infants in resource-limited settings will die by the age of 2 years [7,10], and this has led to a reversal in previous achievements in the reduction of under-5 mortality rates in Africa [106]. In several parts of southern Africa, HIV/AIDS is the leading cause of death in this age group [107]. In well-resourced countries, mortality has been significantly reduced in HIV-infected infants since combination ART became available [11,12], and it is critical that this success is replicated in all parts of the world. But when should treatment be started in HIV-infected infants, and should this differ in different parts of the world?Timing of ART for HIV-infected infantsIn well-resourced settings, there has not, until recently, been uniform agreement regarding the optimal time to start ART in perinatally infected infants. US guidelines generally recommended universal infant ART more strongly than European guidelines, which gave clinicians the option to treat all infected infants, but only strongly recommended treatment for those with symptomatic disease or evidence of immunosuppression [13]. This guidance has fluctuated somewhat over time, with evidence based on data from cohort studies and expert opinion. In contrast to older children and adults [14], there are no good viral load or CD4 thresholds that predict disease progression accurately during infancy, and even infants with high CD4 counts or percentages can experience rapid clinical deterioration [8].Although there are no randomized trials from resource-rich countries, several small, observational studies have suggested benefit from early ART [15–17]. For example, in the French Perinatal Cohort, none of the 40 infants treated before 6 months of age developed encephalopathy or opportunistic infections, compared with six out of 43 infants treated after 6 months of age [17]. Similarly, among infants in the Pediatric Spectrum of Disease project in northern California, USA, there was less progression to AIDS in those treated in the first 2–3 months of age compared with those treated later in infancy [15,16]. Recently, many of these data have been combined in a meta-analysis of 210 infants from 11 European countries; this analysis demonstrated an 80% reduction in clinical progression to AIDS or death among infants treated before, compared with after, a pre-determined age of 3 months [18].The Children with HIV Early Antiretroviral Therapy (CHER) trial: the case for & against early ARTThe first randomized evidence about timing of ART initiation in infancy from a trial carried out in a resource-limited country has undoubtedly clarified the issue of when to start treatment, particularly for well-resourced settings where HIV-DNA PCR for early infant diagnosis is widely available. The Children with HIV Early Antiretroviral Therapy (CHER) trial, undertaken in South Africa, was not specifically designed to answer the question of 'when to start' ART, but rather, whether early limited ART would reduce disease progression and delay the time when lifelong ART had to be commenced. However, the data released following a Data and Safety Monitoring Board review in June 2007 present compelling evidence about the need to start therapy early in all HIV-infected infants (from any part of the world) [19]. A total of 377 asymptomatic infants born to HIV-infected women (nearly all of whom received pMTCT with nevirapine or nevirapine plus zidovudine short course) and diagnosed at 6–12 weeks of age with a baseline CD4 percentage of 25% or more, were randomized to immediate, limited ART (n = 252) or deferred ART (until immunological or clinical progression; n = 125). After a median follow-up of only 32 weeks there was a highly statistically significant 76% reduction in early mortality in the immediate compared with the deferred group. Of note, infants initiated ART at a median of 7 weeks of age, but by this time 20% of those screened already had a CD4 percentage below 25% and were ineligible for this study. Despite intensive clinical follow-up and CD4 monitoring, the deaths in this trial tended to be sudden, and not classically AIDS-defining, with bacterial infections and gastroenteritis particularly common, even amongst untreated children with high CD4 percentages.This mounting evidence has led to a recent change in US and upcoming European guidelines, which will now emphatically endorse starting ART in all infants at HIV diagnosis [108]. This move is also in line with a growing consensus amongst clinicians treating HIV-infected adults and older children that earlier treatment may be beneficial. In the Strategies for Management of Antiretroviral Therapy (SMART) trial, a subgroup of adults with CD4 counts over 350 cells/mm3, who were randomized to start ART, had a fivefold reduction in AIDS and serious non-AIDS events compared with those randomized to defer ART until standard treatment thresholds had been reached [20]. Already, both US and European adult treatment guidelines have been updated to recommend starting ART at CD4 counts of less than 350 cells/mm3 (previously this was for consideration only, and not mandated until CD4 counts <200 cells/mm3).To date, the results of the CHER trial are very short-term (considering children will take ART for life). Therefore, it is important to examine arguments both for and against early initiation of ART in HIV-infected infants (Box 1). A central concern in initiating ART early in life is the potential for poor virological response and resultant development of drug resistance, thus compromising future ART options at an early age [21–24]. Although a suboptimal virological response is seen in a substantial proportion of infants, European data show that treatment results in infants are improving over time [25], and long-term virological response out to early childhood may be better in those starting ART in the first few months of life compared with later in infancy [23]. Even in those with poor virological control, immunological and clinical responses tend to be good because of the capacity for thymic regeneration in infancy [24,26]. ART started soon after birth also raises concerns about long-term drug toxicity and the financial implications of such a strategy.However, deferring therapy for infants in resource-limited settings has additional complications beyond the clear increase in mortality. Follow-up is challenging in many settings and CD4 counts may not be available or the cost of repeated measurements may outweigh the costs of treatment [27]. Even if CD4 monitoring is available, disease progression is rapid, especially in infants infected despite perinatal prophylaxis. In a study from Durban, South Africa, 85% of infants reached WHO criteria to start ART within 6 months of life [6], and in the CHER study, 60% of infants in the deferred arm had already commenced ART after a median follow-up of 32 weeks [19]. There are frequently delays in starting ART even when treatment criteria are reached owing to caregiver training, social problems or treatment of co-infections, and clinical deterioration may occur whilst waiting to start therapy. Delaying therapy may also increase the risk of infants acquiring tuberculosis, complicating treatment in terms of choice and timing of ART and potential for drug toxicity [104]. Furthermore, immune reconstitution inflammatory syndrome is more common in these children, especially if starting ART at low CD4 counts, as may occur with a deferred treatment strategy [28]. The potential long-term effects of HIV during infancy include encephalopathy leading to developmental delay and growth failure [17,29]. These complications may well be decreased or completed avoided if ART is started before clinical and immunological disease progression occurs [17]. All these arguments strengthen the case to start treatment early in asymptomatic infants.Feasibility of early diagnosis & ART in resource-limited settingsIs early treatment of large numbers of infants achievable in resource-limited settings? Use of ART in infants is challenging because many drugs remain unavailable for young children or pharmacokinetic data are not available to inform dosing decisions [2,3]. Clinicians may be forced to use adult fixed-dose combinations, limiting flexibility and, where suitable pediatric formulations are available, doses need to be adjusted frequently in line with weight gain. Many pediatric formulations are unpalatable, require large volumes of syrup and are impractical to store. There are few reports specifically addressing the outcome of infants starting ART in resource-limited settings. Most studies to date have reported treatment results from older children, although one study has reported excellent adherence and early virological suppression among infants randomized to either immediate or deferred four-drug ART [30]. There is some evidence to suggest that four-drug regimens in infancy may be more efficacious at reducing high viral loads [23], but it will be important to assess long-term outcomes and resistance data from such a strategy. It remains unclear at the present time what is the optimal starting regimen for infants. A problem in many resource-limited settings is that exposure to single-dose (sd) nevirapine in pMTCT programs leads to non-nucleoside reverse transcriptase inhibitors (NNRTI) resistance mutations. One study from Botswana, in the setting of sd-nevirapine, reported suboptimal virological responses in infants starting an NNRTI-containing regimen a median of 8.5 months after birth [31]; however, a recent report of Ugandan children starting nevirapine-based ART at an older age (range: 0.6–12.4 years) showed similar virological suppression in those exposed and unexposed to sd-nevirapine at birth [32]. More data from resource-limited countries are urgently required to address this issue, since a recommendation to start early ART must be accompanied by a recommendation of what ART to start.Despite compelling arguments for a policy to start ART early in all perinatally infected infants in resource-limited countries, there are clearly major challenges to its implementation (Figure 1). Such a strategy would only work as part of an integrated pMTCT and infant care program. Mothers must be able to access antenatal HIV testing and pMTCT interventions, and early HIV PCR testing for their infants. Currently, PCR testing remains unaffordable or unavailable in many settings, and large numbers of HIV-exposed infants would require screening to pick up all infected cases. Ensuring that diagnosis was undertaken early enough to start treatment before infants became symptomatic would be challenging, given the rapid disease progression and frequent loss to follow-up in infancy. Furthermore, a substantial proportion of infants are infected by late postnatal HIV transmission through breastfeeding, and it is not clear logistically how this group would best fit into an early diagnosis and treatment pathway.Preparation for infant ART should be part of a counseling process, starting antenatally but intensifying with a positive PCR result so that treatment can be started soon after the diagnosis is made. There is a high rate of attrition at each stage of pMTCT programs [33,34], but strengthening the 'run-through' pathway of maternal and infant care may enable timely diagnosis and treatment of women and children [35]. Further economic analysis is required to assess the impact such a strategy would have on countries that are already facing a substantial financial burden from the cost of current HIV prevention and treatment programs. The WHO is considering the evidence and will be aiming to reach consensus as to whether guidelines for resource-limited settings should be changed to advocate immediate treatment at diagnosis for HIV-infected infants.Is lifelong ART realistic?ART started soon after birth raises concerns about possible long-term consequences, including toxicity, cost and potential for drug resistance. The concept of lifelong ART may not be realistic, and alternative strategies need to be evaluated. One possibility, being investigated in two randomized trials in South Africa and one in Kenya, is to start immediate, short-term ART in perinatally infected infants, but to stop therapy at 1 or 2 years of age, until criteria for long-term, definitive ART are met. This strategy ensures that infants are treated during the critical period of rapid disease progression, but allows time off therapy beyond infancy. Early results suggest that this approach is feasible, and preliminary results from one trial suggest that infants likely to benefit from a period off therapy may be identified from a CD4 count taken at diagnosis [36]. Further results from these trials are needed, and are awaited with interest, to ascertain the long-term effects of such a novel treatment strategy.Future perspectiveAn obvious solution to the pediatric HIV epidemic would be to reduce MTCT maximally by use of combination ART in women during pregnancy, and to focus diagnostic and treatment resources on the much smaller number of infants presenting with symptomatic HIV. However, in the current climate, where 90% of antenatal mothers do not have access to even the most basic pMTCT interventions [101], this is not achievable. Program managers and policy implementers must decide where to focus scarce resources. Ideally, both enhanced pMTCT and early infant diagnosis and treatment should go together. However, it may be appropriate to focus on one aspect first, and incorporate the second once capacity has increased. Early infant diagnosis is currently unavailable or unaffordable in many settings, and even if PCR testing was widely available, the economic and programmatic implications of screening all HIV-exposed infants would have to be assessed. More studies are needed to evaluate whether HIV-exposed infants can be 'triaged' early in life on clinical grounds, to enable PCR testing to be targeted at a smaller number of infants. Future studies will better inform us of the choices of initial ART regimens, but appropriate formulations for young children must be made more widely available. Further data are required on the long-term effects of ART started in infancy and whether early, limited ART is a feasible approach to reduce time spent on medication.ConclusionCurrently, infants are neglected in antiretroviral roll-out programs because of challenges in diagnosis, follow-up and treatment [2,3]. The tragedy is that this age group has the most rapid disease progression, and mortality amongst infants awaiting diagnosis and treatment is unacceptably high. Early diagnosis and treatment of HIV-infected infants reduces morbidity and mortality, but barriers to their implementation need to be overcome. Political and financial commitment is required to enable strengthening of the healthcare infrastructure, support and retention of the medical workforce, and expansion of maternal and infant HIV care provision to reduce the appalling impact of the epidemic on children globally.Box 1. Advantages and disadvantages of universal early ART in infants.Advantages• Reduction in mortality• Reduction in morbidity, including encephalopathy and growth failure• 'Watch and wait' policy requires regular monitoring, with no good markers to guide treatment decisions• CD4 counts may be unavailable, prohibitively expensive or have a long turn-around time to get results; they have poor prognostic value in infants• Rapid progression to AIDS in infancy, which occurs despite regular intensive follow-up• Delaying ART increases the risk of tuberculosis, which complicates ART initiation (choice of drugs, toxicity and immune reconstitution inflammatory syndrome)• Integration with prevention of mother-to-child HIV transmission programs would reduce loss to follow-up and enable caregiver training to start antenatallyDisadvantages• May divert resources from other essential components of the HIV program• Mothers may not be ready to commence ART in their infants at such a young age• Implementing early ART requires increasing capacity of healthcare facilities to provide infant diagnosis, preparatory counseling for ART and follow-up support• Risk of poor adherence and drug resistance in asymptomatic infants, limiting future ART options at a young age• Risk of toxicity from long-term ART• Financial implications of large numbers of infants being diagnosed early and starting long-term therapy early in life• Lifelong ART may well not be cost effective or realisticART: Antiretroviral therapy.Executive summaryBurden of HIV infection in infancy• Globally, 1200 HIV-infected infants are born daily due to inadequate coverage of prevention of mother-to-child HIV transmission (pMTCT) programs (<10% of antenatal women).• Infants are neglected in current antiretroviral therapy (ART) programs because of challenges in diagnosis and treatment.• Disease progression is rapid in infants, with a mortality rate of greater than 50% by 2 years of age in Africa.• There are no good viral load or CD4 markers to predict progression in infancy.Timing of ART in infants• Children with HIV Early Antiretroviral Therapy (CHER), a randomized controlled trial in HIV-infected South African infants, showed 76% reduction in early mortality in those randomized to immediate compared with deferred ART.• Deaths in CHER were generally not classically AIDS-defining, and occurred even in infants with high CD4 counts.• US and European guidelines now emphatically endorse starting ART at diagnosis in HIV-infected infants.• There are advantages and disadvantages to starting early ART in infants (Box 1).Feasibility of early diagnosis & ART in resource-limited settings• Treatment of infants is challenging and more outcome data from resource-limited settings are needed.• Early HIV PCR testing of infants needs to be expanded to identify infants requiring ART.• pMTCT and infant-treatment programs should be better integrated to facilitate early initiation of ART in infants.Is lifelong antiretroviral therapy realistic?• Starting immediate, lifelong ART at diagnosis in infants may not be realistic owing to resistance, toxicity and cost.• Several randomized trials are investigating whether limited, early ART (for 1 or 2 years) might delay the time at which long-term, continuous ART is needed.Future perspective• Enhanced pMTCT and early infant diagnosis need to be implemented in resource-limited settings, but capacity needs to be expanded before this is achievable.• A pragmatic and cost-effective approach to early infant diagnosis is required, and future studies should investigate the feasibility of targeted screening.• Further data are required on optimal starting regimens for infants, long-term effects of ART and the feasibility of short-term ART in infancy.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. 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