Perinatal acquisition of drug-resistant HIV-1 infection: mechanisms and long-term outcome

Abstract

Background: Primary-HIV-1-infection in newborns that occurs under antiretroviral prophylaxis that is a high risk of drug-resistance acquisition. We examine the frequency and the mechanisms of resistance acquisition at the time of infection in newborns.

Patients and methods: We studied HIV-1-infected infants born between 01 January 1997 and 31 December 2004 and enrolled in the ANRS-EPF cohort. HIV-1-RNA and HIV-1-DNA samples obtained perinatally from the newborn and mother were subjected to population-based and clonal analyses of drug resistance. If positive, serial samples were obtained from the child for resistance testing.

Results: Ninety-two HIV-1-infected infants were born during the study period. Samples were obtained from 32 mother-child pairs and from another 28 newborns. Drug resistance was detected in 12 newborns (20%): drug resistance to nucleoside reverse transcriptase inhibitors was seen in 10 cases, non-nucleoside reverse transcriptase inhibitors in two cases, and protease inhibitors in one case. For 9 children, the detection of the same resistance mutations in mothers' samples (6 among 10 available) and in newborn lymphocytes (6/8) suggests that the newborn was initially infected by a drug-resistant strain. Resistance variants were either transmitted from mother-to-child or selected during subsequent temporal exposure under suboptimal perinatal prophylaxis. Follow-up studies of the infants showed that the resistance pattern remained stable over time, regardless of antiretroviral therapy, suggesting the early cellular archiving of resistant viruses. The absence of resistance in the mother of the other three children (3/10) and neonatal lymphocytes (2/8) suggests that the newborns were infected by a wild-type strain without long-term persistence of resistance when suboptimal prophylaxis was stopped.

Conclusion: This study confirms the importance of early resistance genotyping of HIV-1-infected newborns. In most cases (75%), drug resistance was archived in the cellular reservoir and persisted during infancy, with or without antiretroviral treatment. This finding stresses the need for effective antiretroviral treatment of pregnant women.

Figure 1

Resistance analysis of HIV-1 RNA and DNA from the mother-child pair #9. Time course of HIV-1 RNA and DNA levels in children with resistance mutations as detected by population-based sequencing and clonal analysis (box). Antiretroviral treatment is indicated above. Maternal antiretroviral treatment at delivery, viral RNA load, and the number of wild-type (WT) or resistant clones are indicated. In the phylogenetic tree, maternal viral clones are represented by circles and newborn viral clones by squares. M indicates the time to genotype testing in month. Wild-type quasispecies are represented by open circles and squares, and resistant quasispecies by full circles and squares. HIV-1 RNA results are in blue, and HIV-1 DNA results are in pink. The arrow indicates the maternal viral clone closest to the infant's quasispecies.

Figure 2

Resistance analysis of HIV-1 RNA and DNA from the mother-child pair #11. Time course of HIV-1 RNA and DNA levels in children with resistance mutations as detected by population-based sequencing and clonal analysis (box). Antiretroviral treatment is indicated above. Maternal antiretroviral treatment at delivery, viral RNA load, and the number of wild-type (WT) or resistant clones are indicated. In the phylogenetic tree, maternal viral clones are represented by circles and newborn viral clones by squares. M indicates the time to genotype testing in month. Wild-type quasispecies are represented by open circles and squares, and resistant quasispecies by full circles and squares. HIV-1 RNA results are in blue, and HIV-1 DNA results are in pink. The arrow indicates the maternal viral clone closest to the infant's quasispecies.

Figure 3

Resistance analysis of HIV-1 RNA and DNA from the mother-child pair #12. Time course of HIV-1 RNA and DNA levels in children with resistance mutations as detected by population-based sequencing and clonal analysis (box). Antiretroviral treatment is indicated above. Maternal antiretroviral treatment at delivery, viral RNA load, and the number of wild-type (WT) or resistant clones are indicated. In the phylogenetic tree, maternal viral clones are represented by circles and newborn viral clones by squares. M indicates the time to genotype testing in month. Wild-type quasispecies are represented by open circles and squares, and resistant quasispecies by full circles and squares. HIV-1 RNA results are in blue, and HIV-1 DNA results are in pink. The arrow indicates the maternal viral clone closest to the infant's quasispecies.

Figure 4

Mechanisms of antiretroviral resistance acquisition in HIV-1-infected newborns. Wild-type viruses are shown in green and resistant viruses in red. The length of the yellow-to-red arrow indicates the duration of perinatal prophylaxis and thus the risk of resistance selection.