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On-line version ISSN 1678-4782
J. Pediatr. (Rio J.) vol.85 no.2 Porto Alegre Mar./Apr. 2009
Robert W. Shafer
MD. Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, CA, USA
The World Health Organization (WHO) estimates that two million children younger than 15 years are infected with HIV-1.1 Although most HIV-1-infected children are in Sub-Saharan Africa, more than 10,000 of the estimated 730,000 HIV-1-infected persons in Brazil are likely to be children.1,2 The extent of the HIV-1 epidemic in children reflects the risk factors for HIV-1 infection in the adult population and the frequency with which maternal HIV-1 infection is not detected and mother-to-child transmission (MTCT) not prevented. The treatment of HIV-1 in children is more challenging than its treatment in adults and is associated with an increased risk of virological failure.
In this issue of Jornal de Pediatria, Almeida et al.3 report the prevalence of HIV-1 drug resistance in 47 children treated between 2000 and 2004 at one hospital in São Paulo, Brazil. Twenty-four of the children were newly HIV-1 diagnosed and had not received antiretroviral (ARV) therapy or been perinatally exposed to ARVs. Twenty-three of the children were receiving ARV therapy and had detectable HIV-1 levels. The number of successfully treated children (i.e., having undetectable HIV-1 levels) at the same hospital during the study period was not reported.
Among the 24 ARV-naïve children, none had genotypic evidence for significantly reduced ARV susceptibility. One child had a virus with the reverse transcriptase (RT) mutation K219N, a mutation typically selected by nucleoside analog RT inhibitor (NRTI) therapy. By itself, this mutation is unlikely to reduce ARV susceptibility or the success of ARV therapy. Whether this mutation emerged as a result of ARV selection pressure prior to being transmitted to the child or from genetic drift within the child cannot be known for certain. Not all ARV-naïve children, however, have drug susceptible viruses. Indeed transmission of drug-resistant viruses occurs frequently to infants of women receiving incompletely suppressive ARV therapy or unsuccessful MTCT prophylaxis.4-6
The fact that 24 ARV-naïve children were diagnosed at a median age of 21.5 months should be cause for concern. The lack of an earlier diagnosis suggests two missed opportunities. First, had the mothers of these children been diagnosed during pregnancy, it is probable that HIV-1 infection would have been prevented.7,8 Indeed, infections resulting from MTCT in Brazil have decreased from about 2,000 per year between 1999 and 2003 to about 1,100 per year between 2004 and 2005. This success has been attributed to an increased frequency of HIV-1 testing during pregnancy in Brazil which was up to 63% by 2006 and to a modestly successful MTCT prophylaxis program which by 2004 had reduced the risk of MTCT to 7%.2
Second, the failure to diagnose HIV-1 during pregnancy places an HIV-1 infected newborn at high risk of morbidity and mortality during the first year of life a time in which the immune system is immature and the risk of rapid HIV-1 progression is high.9 In the recent South African CHER trial, the risk of death in HIV-1-infected infants younger than 12 months during a median follow-up of 40 weeks was four times lower (16 vs. 4%) than in infants randomized to immediate ARV therapy compared with those randomized to CD4-guided therapy.10
Among the 23 ARV-experienced children, most had begun therapy prior to the availability of highly active ARV treatment (HAART) regimens. Genotypic evidence of HIV-1 resistance to NRTIs, non-nucleoside RT inhibitors (NNRTIs), and protease inhibitors (PIs) was present in 96, 61 and 17%, respectively. The most common drug-resistance mutations were the NRTI resistance mutations at RT positions 41, 67, 184, 215, and 219; the NNRTI-resistance mutations at RT positions 103 and 181; and the PI-resistance mutations at protease positions 46, 54, 82, and 90.
The RT mutations at positions 41, 67, 215, and 219 are called thymidine analog mutations (TAMs) because they are selected primarily by the thymidine analogs AZT and stavudine (d4T). However, the TAMs, particularly the combination of M41L and T215Y with another TAM L210W, also confer cross-resistance to abacavir, didanosine, and tenofovir. The RT mutation M184V confers high-level phenotypic resistance to the cytidine analogs lamivudine (3TC) and emtricitabine (FTC) and low-level cross-resistance to abacavir and didanosine. Despite the high level of phenotypic 3TC and FTC resistance caused by M184V, there is often some benefit in including 3TC or FTC in a salvage therapy regimen because M184V increases susceptibility to AZT, d4T, and tenofovir and causes a modest decrease in HIV-1 replication capacity. The RT mutations K103N and Y181C are the two most commonly occurring NNRTI-resistance mutations. Protease mutations at positions 46, 54, 82, and 90 are among the most commonly occurring PI-resistance mutations. Six different PI-resistance mutations at position 54 (I54V/L/M/T/A/S) and seven different PI-resistance mutations at position 82 (V82A/T/F/S/L/M/C) have been reported. Different mutations at these two positions often have divergent effects on PI susceptibility.11
The extensive drug resistance reported by Almeida et al.3 is typical for HIV-1-infected children and adults who begin therapy with incompletely suppressive non-HAART regimens. Indeed similar results have been reported from other studies of heavily treated children from Brazil, as well as from the United States, France, and the U.K. For example, Machado et al. analyzed RT and protease sequences from 37 children at a different São Paulo hospital and reported that 84, 35, and 14% had viruses with mutations associated with resistance to at least one, two, or three drug classes, respectively.12
Delaugerre et al. analyzed RT and protease sequences from 119 children in Paris between 2001 and 2003 and reported that 82, 32, and 27% had viruses with genotypic evidence of resistance to at least one, two, and three drug classes, respectively, with three-class resistance significantly more common in boys compared with girls.13
Although the risk of virological failure and the extent of ARV resistance are lower among children receiving a first-line HAART therapy, both virological failure and resistance are also frequent problems in these children. Although the immune defense against HIV-1 improves after the first year of life,14 ARV treatment remains challenging because of the availability of fewer drugs, less convenient formulations, unpredictable pharmacokinetics, and greater barriers to adherence. The risk of ARV treatment failure appears to be higher in children than in adults. For example, in a group of 134 children in Abidjan, Cote d'Ivoire, receiving two NRTIs + one NNRTI or nelfinavir between 1998 and 2003, 44% experienced virological failure. Similarly, from 2004 to 2005, virological failure occurred in 26% of 250 children compared with 14% of 526 adults in a university clinic in Kampala, Uganda, treated for 6 months with d4T + 3TC + nevirapine or AZT + 3TC + efavirenz. Virological failure was significantly higher in males than females, children with a CD4% < 5, and in children receiving the combination of d4T + 3TC + nevirapine. Among 212 Cambodian children receiving one of three fixed-dose combinations of two NRTIs plus one NNRTI for 12 months between 2003 and 2005, ongoing viremia was detected in 19%.15 In these studies, virological failure was nearly always accompanied by the emergence of both NRTI and NNRTI resistance.
Subtypes B, C, and F are the most common HIV-1 subtypes in Brazil. Almeida et al. report that 18 of 23 children were infected with subtype B viruses. It is therefore not surprising that the RT and protease mutations they report were typical of those observed in other resistant subtype B viruses from Brazil.16-19 By contrast, certain mutations such as K20T, V82L, N88S, and L89V may be more common in subtype F viruses from Brazil,20,21 while slight variations in the pattern of PI-resistance mutations have been described in subtype C viruses in Brazil.22,23
Brazil's National STD/AIDS Program, which has coordinated the response to the HIV epidemic, offers generic drugs for first-line therapy and patent-protected drugs for second-line therapy.24 In 2006, an estimated 180,000 HIV-1-infected individuals in Brazil were receiving therapy representing about 90% of the patients for whom therapy has been indicated.2,24 Heavily-treated individuals, such as the children described in the study by Almeida et al., will stress the finances of Brazil's treatment program because it is likely that one or more of the most recently approved ARVs such as the PIs darunavir and tipranavir, the NNRTI etravirine, the integrase inhibitor raltegravir, and the cell entry inhibitors enfuvirtide and maraviroc would be needed for the patients with the greatest ARV experience and the highest levels of drug resistance. Judicious use of such newer drugs under close supervision to ensure adherence and increased efforts to prevent MTCT and the emergence of virological failure during initial HAART are needed to maintain the health of HIV-1-infected children and to minimize new infections.
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Correspondence: No conflicts of interest declared concerning
the publication of this article.
Robert W. Shafer
Division of Infectious Diseases, Department of Medicine, Stanford University
Stanford, CA 94301 - USA
Suggested citation: Shafer RW. The challenge of antiretroviral drug resistance in HIV-1-infected children. J Pediatr (Rio J). 2009;85(2):91-93.
No conflicts of interest declared concerning
the publication of this article.