In resourced settings with access to HAART, perinatally acquired HIV-1 infection has become a chronic disease with increasing numbers of adolescents surviving to adulthood. However, attaining long-term good therapeutic adherence and viral suppression remains a challenge in children, whose overall rate of virologic failure is over two-times higher than in adults, even in high resource countries [1,2]. Suboptimum virologic suppression might lead to the emergence of drug-resistant viruses, the consequences of which are particularly important for children who will need antiretrovirals (ART) for longer period than adults.
Sigaloff et al. have recently described that the M184V mutation was the most frequent nucleoside reverse transcriptase inhibitor (NRTI)-resistance-associated mutation after failure of first-line HAART in children living in resource-poor regions. Restricting the analysis to children treated with a first-line lamivudine (3TC)-based regimen, the frequency of M184V/I mutation was reported in 55.6–100.0% of virologic failure in previous HIV-1 drug resistance studies, as summarized in Table 1[3–17]. Similar frequencies of M184V/I mutation were reported in resource-poor and high-income countries, and whatever the type of ART combination used: three NRTI, two NRTI + one non-NRTI (NNRTI), two NRTI + one protease inhibitor, two NRTI + one protease inhibitor with ritonavir (PI/r). This mutation was often selected a few weeks after the onset of the virologic failure: M184V/I was detected in 36.6–88.9% of virologic failure in the first 6 months after the initiation of the treatment [4,8,10,12]. This rapid selection of M184V/I reflects the low-genetic barrier of 3TC and differs from what is usually observed for the thymidine analog mutations (TAMs), which required prolonged viral replication to be selected in case of zidovudine (ZDV) or stavudine (D4T)-based therapy. These findings will have major consequences on the future therapeutic options in children. Indeed, all the antiviral fixed coformulations, which are now available or currently in development to treat HIV-infected adolescents and adults, include emtricitabine (FTC) or 3TC, and cannot be fully active in case of M184V/I mutation. Limited data in adults with virologic failure have suggested that continuation of 3TC could contribute to decrease the HIV replication despite the presence of 3TC-resistance mutations [18–20]. However, this potential benefit was not seen in the prospective randomized COLATE trial, which found that continuing (versus discontinuing) 3TC in a new treatment combination after failure of a 3TC-containing regimen does not provide additional virologic or immunological benefit in case of M184V/I mutation . Moreover, as strongly recommended in the American, European and French pediatric guidelines, a combination of three fully active drugs should be preferred in case of virologic failure [22–24]. Thus, the only strategy to ensure future access to fully active fixed combined ART during adolescence and adulthood should be a preferred 3TC-sparing first-line HAART in children, as many of them will experience a virologic failure during early infancy.
These findings should influence the choice of first-line NRTI backbone in HIV-1 infected young children. According to the PENTA 5 randomized trial [25,26], the PENTA 2009 guidelines recommend preferring 3TC+abacavir (ABC) as first-line NRTI backbone . On the contrary, the WHO and American guidelines consider as alternative preferred regimens NRTI backbones which all include 3TC or FTC [22,27]. However, the studies comparing the virologic and immunological efficacies of different NRTI combinations are sparse in HIV-infected adults and children [25,26,28], except the recent reports comparing TDF+FTC and 3TC+ABC, whose results could not influence therapeutic strategies in young children because TDF is not licensed in this population. The only pediatric trial comparing several NRTI backbones was the PENTA 5 study, which suggested the virologic superiority of 3TC+ABC over ZDV+ABC and ZDV+3TC. However, the included children received two NRTI with nelfinavir (NFV) or a placebo, and no similar trial has been performed with a currently recommended first-line regimen in children, that is, a HAART including a NNRTI or a PI/r (lopinavir/ritonavir or atazanavir/ritonavir). Thus, we cannot exclude that ZDV+ABC could be at less equally potent than 3TC+ABC in combination with a NNRTI or a PI/r in young children.
Advantages and disadvantages of the three main nucleoside backbones available in young children are summarized in Table 2. All of them are available as palatable liquid formulations. Moreover, coformulated pills are available for ZDV+3TC and 3TC+ABC combinations, but the acceptability of such formulations is usually poor under the age of 6–7 years. For this population, no liquid coformulation has been licensed and the three NRTI backbones harbor similar acceptability.
The three main nucleoside combinations seem to have similar rates of toxicity, although large prospective trials comparing their toxicity profiles in young children remain sparse. In a large retrospective study of 2233 perinatally infected children, Van Dyke et al. concluded that ZDV-based backbones had less toxicity than D4T-based regimens, with a similar toxicity profile of the D4T+3TC, D4T+didanosine (DDI) and DDI+3TC combinations. However, the small number of patients receiving ABC in this PACTG 219C study prevented their inclusion in the safety analysis. In the only prospective pediatric study comparing the safety of the ZDV+3TC, ABC+3TC and ZDV+ABC combinations, no major difference between the three regimens was reported [25,26]. To summarize, although additional prospective studies are needed to fully define the toxicity profile of these backbones when used in combination with a NNRTI or a PI/r, published data suggested similar safety profiles of these regimens in young children, except the risk of hypersensitivity reaction to ABC in case of HLA genotype B*5701, which is rarely found in African-originated patients.
To conclude, further randomized studies are needed to compare ZDV+3TC-based, ZDV+ABC-based and 3TC+ABC-based HAART in ART-naïve HIV-1 infected young children. To date, there is no compelling evidence for the superiority of one of these combinations concerning the virologic response, the immunological efficacy, the formulation and the safety profile. However, because the risk of virologic failure is dramatically high in young children and lead to the frequent and rapid selection of the M184V/I mutation in case of 3TC-based first-line regimen, no fixed antiviral coformulation – all of them containing 3TC or FTC – will be fully active throughout the life of many children after an early episode of virologic failure. Thus, we suggest to include the ZDV+ABC combination in preferred NRTI backbones in this population, as currently recommended in the French guidelines . Such regimen, which avoids an early use of 3TC/FTC, will preserve a wide choice of future therapeutic options in perinatally HIV-1 infected children.
P.F., S.B. and M.L.C. have contributed to the report's conception, have read, reviewed and approved the article.
Conflicts of interest
Conflict of interests and source of funding: P.F. received grants from French National Agency for Research on AIDS and viral hepatitis (ANRS) (to his institution) and from SIDACTION, payment for development of educational presentation from BMS and travel supports from MSD. MLC received travel supports from ViiV Healthcare. S.B. received consulting fee from Boehringer (expertise on Pediatric tipranavir) and payments from Pfizer (French coordination of trial A4001031) and Tibotec (participation to the trial DIONE TMC114C232).
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