Prevalence of drug resistance in children recently diagnosed with HIV-1 infection in France (2006–17): impact on susceptibility to first-line strategies

Prevalence of drug resistance in children recently diagnosed with HIV-1 infection in France... Abstract Objectives To describe the prevalence of transmitted drug resistance (TDR) among 84 children newly diagnosed with HIV in France in 2006–17. Methods HIV-1 resistance-associated mutations (RAMs) were characterized using both the 2009 Stanford list of mutations and the 2017 French National Agency for AIDS Research (ANRS) algorithm. A genotypic susceptibility score (GSS) was estimated for each first-line recommended ART combination. Results Patients were mainly infected through mother-to-child transmission (MTCT) (73/84; 86.9%), but only 18 children (24.7% of vertically infected patients) were previously exposed to antiretroviral prophylaxis from MTCT. Non-B variants were identified in 90.5% (76/84) of patients. The frequency of TDR was 8.3% (7/84) using the 2009 Stanford list and 16.7% (14/84) using both the Stanford list and the 2017 ANRS algorithm. The prevalence of PI-, NRTI-, efavirenz/nevirapine-, etravirine/rilpivirine- and doravirine-associated RAMs was 0%, 3.6%, 6.0%, 11.9% and 2.4%, respectively. Single-, dual- and triple-class resistance was present in 15.5%, 1.2% and 0% of cases, respectively. Additionally, 3/60 (5%) strains had integrase inhibitor (INI)-related RAMs (an isolated E157Q mutation, which could mostly affect the susceptibility to raltegravir/elvitegravir rather than that to dolutegravir). Among the 18 children exposed to MTCT prophylaxis, RAMs were identified in only 1 case (5.6%). The proportion of fully active combinations (GSS = 3) was ≥97.6%, ≥94.1%, ≥92.9% and ≥89.3% for PI-, INI-, efavirenz/nevirapine- and rilpivirine-based regimens, respectively. Conclusions The proportion of NRTI- and NNRTI-related TDR in children is lower in France than in low- and middle-income countries. However, we suggest favouring PI- or dolutegravir- over NNRTI-based combinations to treat newly diagnosed HIV-infected children, even in the absence of previous exposure to antiretroviral prophylaxis of MTCT. Introduction Although currently recommended universal maternal and infant antiretroviral prophylaxis has dramatically reduced the risk and number of infant HIV infections, ∼160 000 new paediatric infections occur each year, mainly in low- and middle-income countries (LMICs) (http://www.who.int/hiv/data). In these countries, the transmission of resistant viruses to infants has become more common.1 In high-income countries, where the rate of HIV mother-to-child transmission (MTCT) is less than 1%, new cases of HIV infection continue to be diagnosed in children whose mothers were not tested for HIV or who seroconverted during pregnancy, and in immigrant children arriving from highly HIV-prevalent areas.2 Monitoring of transmitted drug resistance (TDR) in children is required to optimize treatment success and preserve future therapeutic options. However, recent data about TDR prevalence in children newly diagnosed with HIV in high-income countries still remain limited.3–5 Moreover, few data have been published about the prevalence of resistance to second-generation NNRTIs and integrase inhibitors (INIs), which can now be used in the paediatric population. The present work aimed to evaluate the prevalence of TDR in children newly diagnosed with HIV-1 in France between 2006 and 2017 and referred to Necker Hospital (Paris). Patients and methods Ethics This research was conducted in accordance with the Declaration of Helsinki and national and institutional standards. Parents/guardians provided informed consent for the anonymous use of their children’s clinical and biological data for biomedical research at the time of data collection. Study population The study population comprised 84 children and adolescents newly diagnosed with HIV-1 in France between 2006 and 2017 and referred to Necker hospital. Genotypic resistance analysis Genotypic resistance tests were performed on plasma samples collected before initiation of combined ART (cART). Reverse transcriptase, protease and integrase genes were amplified and sequenced. In INI-naive patients with virological suppression who had not previously undergone integrase gene sequencing, resistance to INIs was evaluated by sequencing the integrase gene from PBMC-associated HIV-1 DNA. Genotypic resistance tests were performed using either commercial assays [TrueGene HIV-1 genotyping kit (Siemens Healthcare, Eragny, France), Viroseq sequencing-based HIV-1 genotyping kit (Abbott, Rungis, France)] or using the consensus technique of the French National Agency for AIDS Research (ANRS) Resistance study group (www.hivfrenchresistance.org). HIV-1 resistance-associated mutations (RAMs) were defined using both the 2009 Stanford RAM list6 for NRTIs, first-generation NNRTIs and PIs and the 2017 French ANRS algorithm v27 (www.hivfrenchresistance.org) for etravirine, rilpivirine and INIs. The ANRS algorithm includes all the rilpivirine-, etravirine- and INI-related RAMs reported in the 2017 IAS-USA resistance mutations list.7 The studied RAMs were: (i) resistance to PIs: L10/I/F/V/C/R/M, V11I, I15A/V, G16E, K20R/M/I/T/V, L23I, L24I, D30N, V32I, L33F/I/V, M36I/L/V, M46I/L, I47A/V, G48V/M, I50V/L, F53L/Y, I54V/L/M/A/T/S, Q58E, D60E, I62V, L63P, A71I/L/V/T, G73C/S/T/A, T74P, L76V, V77I, V82A/C/F/L/M/T/S, I84V/A/C, I85V, N88D/S, L89I/M/R/T/V and L90M; (ii) resistance to NRTIs: M41L, K65R/E/N, D67N/G/E, T69D/Ins, K70E/R, L74V/I, V75A/M/T/S, F77L, Y115F, F116Y, Q151M, M184V/I, L210W, T215A/C/D/E/G/H/I/L/N/S/V/Y/F and K219Q/E/N/R; (iii) resistance to NNRTIs: V90I, A98G, L100I, K101E/H/I/P/R, K103N/S, V106A/M/I, V108I, E138A/G/K/Q/R/S, V179D/F/I/L/M/T, Y181C/I/V, Y188L/H/C, G190A/S/E, H221Y, P225H, F227C/L/V, M230I/L/V, L234I and P236L; and (iv) resistance to INIs: A49G, T66I/A/K, L74I/M, E92G/Q, T97A, G118R, F121Y, E138A/K/T, G140A/C/S, Y143A/C/G/H/R/S, P145S, S147G, Q148E/G/H/K/R, V151L, S153F/Y, N155H/S/T, E157Q, S230G/R and R263K. Mutations defining doravirine resistance were V106A, V106M, V108I, H221Y, F227L, F227C, F227V, M230I, L234I and P236L.8 For estimating the genotypic susceptibility score (GSS), each drug, except ritonavir, was scored as 1 or 0 in the case of ‘susceptibility’ or ‘intermediate/high resistance’, respectively, according to the ANRS interpretation algorithm. For each of the first-line recommended cART combinations in French guidelines,9 the arithmetic sum of the individual scores for the specific drugs provided the total treatment-related GSS. Phylogenetic analysis The HIV-1 subtype was determined by phylogenetic analysis of reverse transcriptase sequences, as previously described.10 Results Study population Overall, 84 patients were included in our study (Table 1). Children were mainly infected through MTCT (73/84; 86.9%), but only 18 patients (24.7% of vertically infected children) were previously exposed to antiretroviral prophylaxis from MTCT. Around one-third of patients were diagnosed late in their disease: the proportion of those with CDC stage C disease and CD4 cell count <15% was 25.7% in 2006–09, 22.9% in 2010–13 and 42.1% in 2014–17. Table 1. Demographic and biological characteristics of the patients Presence of at least one RAM (n = 16) Absence of RAMs (n = 68) Total (n = 84) Male, n (%) 7 (43.8) 34 (50.0) 41 (48.8) Age at diagnosis (months), median (range) 12.3 (0.3–168.0) 36.0 (0.1–174.0) 26.0 (0.1–174.0) Year of diagnosis, n (%)  2006–09 6 (37.5) 24 (35.3) 30 (35.7)  2010–13 3 (18.8) 32 (47.1) 35 (41.7)  2014–17 7 (43.8) 12 (17.6) 19 (22.6) Transmission group, n (%)  mother-to-child 12 (75.0) 61 (89.7) 73 (86.9)  blood transfusion 2 (12.5) 1 (1.5) 3 (3.6)  sexual exposure 0 (0) 1 (1.5) 1 (1.2)  unknown 2 (12.5) 5 (7.4) 7 (8.3) Previous exposure to in utero or postnatal antiretroviral prophylaxis, n (%) 1 (6.3) 17 (25.0) 18 (21.4)  including only NRTI 1 (6.3) 0 (0) 1 (1.2)  including NRTI + PI 0 (0) 11 (16.2) 11 (13.1)  including NRTI + NNRTI 0 (0) 4 (5.9) 4 (4.8)  including NRTI + NNRTI + PI + INI 0 (0) 2 (2.9) 2 (2.4) Maternal country of birth, n (%)  France 0 (0) 7 (10.3) 7 (8.3)  other European countries 1 (6.3) 0 (0) 1 (1.2)  sub-Saharan African country 13 (81.3) 55 (80.9) 68 (80.9)  other countries 2 (12.5) 6 (8.8) 8 (9.5) Country of birth, n (%)  France 5 (31.3) 33 (48.5) 38 (45.2)  other European countries 1 (6.3) 1 (1.5) 2 (2.4)  sub-Saharan African country 8 (50.0) 30 (44.1) 38 (45.2)  other countries 2 (12.5) 4 (5.9) 6 (7.1) CDC clinical stage at diagnosis, n (%)  N 3 (18.8) 30 (44.1) 33 (39.3)  A 2 (12.5) 6 (8.8) 8 (9.5)  B 4 (25.0) 14 (20.6) 18 (21.4)  C 7 (43.8) 18 (26.5) 25 (29.8) CD4 count at diagnosis (cells/mm3), median (range) 17 (0–49) 24 (0–63) 22 (1–63) Plasma HIV-1 RNA at diagnosis (log10 copies/mL), median (range) 6.1 (3.0–7.4) 5.0 (2.3–7.6) 5.2 (2.3–7.6) Genetic HIV-1 subtype, n (%)  A 2 (12.5) 2 (2.9) 4 (4.8)  B 0 (0) 8 (11.8) 8 (9.5)  C 1 (6.3) 5 (7.4) 6 (7.1)  F 2 (12.5) 3 (4.4) 5 (6.0)  CRF02_AG 8 (50.0) 24 (35.3) 32 (38.1)  CRF06_cpx 1 (6.3) 3 (4.4) 4 (4.8)  other group M non-B variants 2 (12.5) 23 (33.8) 25 (29.8) Prevalence of RAMs, n (%)  PI RAMsa 0 (0) NA 0 (0)  NRTI RAMsa 3 (18.8) NA 3 (3.6)  NNRTI RAMsa 5 (31.3) NA 5 (6.0)  rilpivirine and etravirine RAMsb 10 (62.5) NA 10 (11.9)  doravirine RAMsc 2 (12.5) NA 2 (2.4)  INI RAMsb 3/13 (23.1) NA 3/60 (5.0) Presence of at least one RAM (n = 16) Absence of RAMs (n = 68) Total (n = 84) Male, n (%) 7 (43.8) 34 (50.0) 41 (48.8) Age at diagnosis (months), median (range) 12.3 (0.3–168.0) 36.0 (0.1–174.0) 26.0 (0.1–174.0) Year of diagnosis, n (%)  2006–09 6 (37.5) 24 (35.3) 30 (35.7)  2010–13 3 (18.8) 32 (47.1) 35 (41.7)  2014–17 7 (43.8) 12 (17.6) 19 (22.6) Transmission group, n (%)  mother-to-child 12 (75.0) 61 (89.7) 73 (86.9)  blood transfusion 2 (12.5) 1 (1.5) 3 (3.6)  sexual exposure 0 (0) 1 (1.5) 1 (1.2)  unknown 2 (12.5) 5 (7.4) 7 (8.3) Previous exposure to in utero or postnatal antiretroviral prophylaxis, n (%) 1 (6.3) 17 (25.0) 18 (21.4)  including only NRTI 1 (6.3) 0 (0) 1 (1.2)  including NRTI + PI 0 (0) 11 (16.2) 11 (13.1)  including NRTI + NNRTI 0 (0) 4 (5.9) 4 (4.8)  including NRTI + NNRTI + PI + INI 0 (0) 2 (2.9) 2 (2.4) Maternal country of birth, n (%)  France 0 (0) 7 (10.3) 7 (8.3)  other European countries 1 (6.3) 0 (0) 1 (1.2)  sub-Saharan African country 13 (81.3) 55 (80.9) 68 (80.9)  other countries 2 (12.5) 6 (8.8) 8 (9.5) Country of birth, n (%)  France 5 (31.3) 33 (48.5) 38 (45.2)  other European countries 1 (6.3) 1 (1.5) 2 (2.4)  sub-Saharan African country 8 (50.0) 30 (44.1) 38 (45.2)  other countries 2 (12.5) 4 (5.9) 6 (7.1) CDC clinical stage at diagnosis, n (%)  N 3 (18.8) 30 (44.1) 33 (39.3)  A 2 (12.5) 6 (8.8) 8 (9.5)  B 4 (25.0) 14 (20.6) 18 (21.4)  C 7 (43.8) 18 (26.5) 25 (29.8) CD4 count at diagnosis (cells/mm3), median (range) 17 (0–49) 24 (0–63) 22 (1–63) Plasma HIV-1 RNA at diagnosis (log10 copies/mL), median (range) 6.1 (3.0–7.4) 5.0 (2.3–7.6) 5.2 (2.3–7.6) Genetic HIV-1 subtype, n (%)  A 2 (12.5) 2 (2.9) 4 (4.8)  B 0 (0) 8 (11.8) 8 (9.5)  C 1 (6.3) 5 (7.4) 6 (7.1)  F 2 (12.5) 3 (4.4) 5 (6.0)  CRF02_AG 8 (50.0) 24 (35.3) 32 (38.1)  CRF06_cpx 1 (6.3) 3 (4.4) 4 (4.8)  other group M non-B variants 2 (12.5) 23 (33.8) 25 (29.8) Prevalence of RAMs, n (%)  PI RAMsa 0 (0) NA 0 (0)  NRTI RAMsa 3 (18.8) NA 3 (3.6)  NNRTI RAMsa 5 (31.3) NA 5 (6.0)  rilpivirine and etravirine RAMsb 10 (62.5) NA 10 (11.9)  doravirine RAMsc 2 (12.5) NA 2 (2.4)  INI RAMsb 3/13 (23.1) NA 3/60 (5.0) CRF, circulating recombinant form; NA, not applicable. a As defined in the 2009 Stanford RAM list of mutations for surveillance of TDR.6 b As defined in the 2017 French ANRS algorithm (http://hivfrenchresistance.org). c Mutations defining doravirine resistance were V106A, V106M, V108I, H221Y, F227L, F227C, F227V, M230I, L234I and P236L. Table 1. Demographic and biological characteristics of the patients Presence of at least one RAM (n = 16) Absence of RAMs (n = 68) Total (n = 84) Male, n (%) 7 (43.8) 34 (50.0) 41 (48.8) Age at diagnosis (months), median (range) 12.3 (0.3–168.0) 36.0 (0.1–174.0) 26.0 (0.1–174.0) Year of diagnosis, n (%)  2006–09 6 (37.5) 24 (35.3) 30 (35.7)  2010–13 3 (18.8) 32 (47.1) 35 (41.7)  2014–17 7 (43.8) 12 (17.6) 19 (22.6) Transmission group, n (%)  mother-to-child 12 (75.0) 61 (89.7) 73 (86.9)  blood transfusion 2 (12.5) 1 (1.5) 3 (3.6)  sexual exposure 0 (0) 1 (1.5) 1 (1.2)  unknown 2 (12.5) 5 (7.4) 7 (8.3) Previous exposure to in utero or postnatal antiretroviral prophylaxis, n (%) 1 (6.3) 17 (25.0) 18 (21.4)  including only NRTI 1 (6.3) 0 (0) 1 (1.2)  including NRTI + PI 0 (0) 11 (16.2) 11 (13.1)  including NRTI + NNRTI 0 (0) 4 (5.9) 4 (4.8)  including NRTI + NNRTI + PI + INI 0 (0) 2 (2.9) 2 (2.4) Maternal country of birth, n (%)  France 0 (0) 7 (10.3) 7 (8.3)  other European countries 1 (6.3) 0 (0) 1 (1.2)  sub-Saharan African country 13 (81.3) 55 (80.9) 68 (80.9)  other countries 2 (12.5) 6 (8.8) 8 (9.5) Country of birth, n (%)  France 5 (31.3) 33 (48.5) 38 (45.2)  other European countries 1 (6.3) 1 (1.5) 2 (2.4)  sub-Saharan African country 8 (50.0) 30 (44.1) 38 (45.2)  other countries 2 (12.5) 4 (5.9) 6 (7.1) CDC clinical stage at diagnosis, n (%)  N 3 (18.8) 30 (44.1) 33 (39.3)  A 2 (12.5) 6 (8.8) 8 (9.5)  B 4 (25.0) 14 (20.6) 18 (21.4)  C 7 (43.8) 18 (26.5) 25 (29.8) CD4 count at diagnosis (cells/mm3), median (range) 17 (0–49) 24 (0–63) 22 (1–63) Plasma HIV-1 RNA at diagnosis (log10 copies/mL), median (range) 6.1 (3.0–7.4) 5.0 (2.3–7.6) 5.2 (2.3–7.6) Genetic HIV-1 subtype, n (%)  A 2 (12.5) 2 (2.9) 4 (4.8)  B 0 (0) 8 (11.8) 8 (9.5)  C 1 (6.3) 5 (7.4) 6 (7.1)  F 2 (12.5) 3 (4.4) 5 (6.0)  CRF02_AG 8 (50.0) 24 (35.3) 32 (38.1)  CRF06_cpx 1 (6.3) 3 (4.4) 4 (4.8)  other group M non-B variants 2 (12.5) 23 (33.8) 25 (29.8) Prevalence of RAMs, n (%)  PI RAMsa 0 (0) NA 0 (0)  NRTI RAMsa 3 (18.8) NA 3 (3.6)  NNRTI RAMsa 5 (31.3) NA 5 (6.0)  rilpivirine and etravirine RAMsb 10 (62.5) NA 10 (11.9)  doravirine RAMsc 2 (12.5) NA 2 (2.4)  INI RAMsb 3/13 (23.1) NA 3/60 (5.0) Presence of at least one RAM (n = 16) Absence of RAMs (n = 68) Total (n = 84) Male, n (%) 7 (43.8) 34 (50.0) 41 (48.8) Age at diagnosis (months), median (range) 12.3 (0.3–168.0) 36.0 (0.1–174.0) 26.0 (0.1–174.0) Year of diagnosis, n (%)  2006–09 6 (37.5) 24 (35.3) 30 (35.7)  2010–13 3 (18.8) 32 (47.1) 35 (41.7)  2014–17 7 (43.8) 12 (17.6) 19 (22.6) Transmission group, n (%)  mother-to-child 12 (75.0) 61 (89.7) 73 (86.9)  blood transfusion 2 (12.5) 1 (1.5) 3 (3.6)  sexual exposure 0 (0) 1 (1.5) 1 (1.2)  unknown 2 (12.5) 5 (7.4) 7 (8.3) Previous exposure to in utero or postnatal antiretroviral prophylaxis, n (%) 1 (6.3) 17 (25.0) 18 (21.4)  including only NRTI 1 (6.3) 0 (0) 1 (1.2)  including NRTI + PI 0 (0) 11 (16.2) 11 (13.1)  including NRTI + NNRTI 0 (0) 4 (5.9) 4 (4.8)  including NRTI + NNRTI + PI + INI 0 (0) 2 (2.9) 2 (2.4) Maternal country of birth, n (%)  France 0 (0) 7 (10.3) 7 (8.3)  other European countries 1 (6.3) 0 (0) 1 (1.2)  sub-Saharan African country 13 (81.3) 55 (80.9) 68 (80.9)  other countries 2 (12.5) 6 (8.8) 8 (9.5) Country of birth, n (%)  France 5 (31.3) 33 (48.5) 38 (45.2)  other European countries 1 (6.3) 1 (1.5) 2 (2.4)  sub-Saharan African country 8 (50.0) 30 (44.1) 38 (45.2)  other countries 2 (12.5) 4 (5.9) 6 (7.1) CDC clinical stage at diagnosis, n (%)  N 3 (18.8) 30 (44.1) 33 (39.3)  A 2 (12.5) 6 (8.8) 8 (9.5)  B 4 (25.0) 14 (20.6) 18 (21.4)  C 7 (43.8) 18 (26.5) 25 (29.8) CD4 count at diagnosis (cells/mm3), median (range) 17 (0–49) 24 (0–63) 22 (1–63) Plasma HIV-1 RNA at diagnosis (log10 copies/mL), median (range) 6.1 (3.0–7.4) 5.0 (2.3–7.6) 5.2 (2.3–7.6) Genetic HIV-1 subtype, n (%)  A 2 (12.5) 2 (2.9) 4 (4.8)  B 0 (0) 8 (11.8) 8 (9.5)  C 1 (6.3) 5 (7.4) 6 (7.1)  F 2 (12.5) 3 (4.4) 5 (6.0)  CRF02_AG 8 (50.0) 24 (35.3) 32 (38.1)  CRF06_cpx 1 (6.3) 3 (4.4) 4 (4.8)  other group M non-B variants 2 (12.5) 23 (33.8) 25 (29.8) Prevalence of RAMs, n (%)  PI RAMsa 0 (0) NA 0 (0)  NRTI RAMsa 3 (18.8) NA 3 (3.6)  NNRTI RAMsa 5 (31.3) NA 5 (6.0)  rilpivirine and etravirine RAMsb 10 (62.5) NA 10 (11.9)  doravirine RAMsc 2 (12.5) NA 2 (2.4)  INI RAMsb 3/13 (23.1) NA 3/60 (5.0) CRF, circulating recombinant form; NA, not applicable. a As defined in the 2009 Stanford RAM list of mutations for surveillance of TDR.6 b As defined in the 2017 French ANRS algorithm (http://hivfrenchresistance.org). c Mutations defining doravirine resistance were V106A, V106M, V108I, H221Y, F227L, F227C, F227V, M230I, L234I and P236L. HIV-1 diversity Subtype B strains were isolated in eight patients (9.5%) (Table 1). All but one of the subtype B-infected children were born in France to a mother who originated from France or north-west Africa. The viral diversity was high: 90.5% of strains clustered with non-B subtypes, mainly CRF02_AG (42.1% of non-B subtypes). TDR RAMs in the reverse transcriptase and/or protease genes were identified in 7 strains (8.3%) using the 2009 Stanford list and in 14 strains (16.7%) using both the Stanford list and the 2017 French ANRS algorithm (Table 1). The prevalence of PI-, NRTI-, first-generation NNRTI- and second-generation NNRTI-associated RAMs was 0%, 3.6%, 6.0% and 11.9%, respectively (global prevalence of NNRTI-associated RAMs = 14.3%). Viruses with single-, dual- and triple-class resistance were isolated in 15.5%, 1.2% and 0%, respectively (Table 2). The strain with dual-class resistance was isolated in a child infected through blood transfusion in Angola. Additionally, 3/60 (5.0%) strains, belonging to CRF02_AG, had INI-related RAMs (E157Q mutation in all cases). Table 2. Characteristics of 16 patients infected with HIV strains with TDR mutations Transmission route Country of birth Viral subtype Resistance mutations Drug resistance PI NRTI NNRTI INI PI NRTI NNRTI INI Verticala France CRF02_AG 0 T215I 0 0 0 ZDV, d4T 0 0 Verticalb France URF 0 M41L, T69S 0 0 0 0 0 0 Verticala Libya CRF02_AG 0 0 E138G NA 0 0 RPV, ETRc NA Verticala Comoros C 0 0 G190E, M230I 0 0 0 EFV, NVP, RPV, DOR 0 Verticala France CRF06_cpx 0 0 K103N NA 0 0 EFV, NVP NA Verticala Cameroon CRF02_AG 0 0 V90I, K103N 0 0 0 EFV, NVP NA Verticala CAR CRF09_cpx 0 0 M106I, V179D 0 0 0 RPV,c ETRc 0 Unknown Gabon CRF02_AG 0 0 V90I, E138G 0 0 0 RPV, ETRc 0 Verticala DRC F1 0 0 Y181C 0 0 0 EFV, NVP, RPV, ETR 0 Blood transfusion Pakistan A 0 0 E138A, V179I 0 0 0 ETR,c RPV 0 Verticala France CRF02_AG 0 0 M230I 0 0 0 RPV, DOR 0 Verticala Romania F 0 0 K101R, V179I 0 0 0 ETRc 0 Verticala France CRF02_AG 0 0 0 E157Q 0 0 0 RAL, EVG, DTGc Unknown Ivory Coast CRF02_AG 0 0 0 E157Q 0 0 0 RAL, EVG, DTGc Verticala Ivory Coast CRF02_AG 0 0 E138A E157Q 0 0 RPV, ETRc RAL, EVG, DTGc Blood transfusion Angola A 0 M41L, D67N, K70R, M184V, T215F, K219E A98S, K103N, E138Q 0 0 ZDV, 3TC/FTC, d4T, ABC, TDFc EFV, NVP, RPV, ETRc 0 Transmission route Country of birth Viral subtype Resistance mutations Drug resistance PI NRTI NNRTI INI PI NRTI NNRTI INI Verticala France CRF02_AG 0 T215I 0 0 0 ZDV, d4T 0 0 Verticalb France URF 0 M41L, T69S 0 0 0 0 0 0 Verticala Libya CRF02_AG 0 0 E138G NA 0 0 RPV, ETRc NA Verticala Comoros C 0 0 G190E, M230I 0 0 0 EFV, NVP, RPV, DOR 0 Verticala France CRF06_cpx 0 0 K103N NA 0 0 EFV, NVP NA Verticala Cameroon CRF02_AG 0 0 V90I, K103N 0 0 0 EFV, NVP NA Verticala CAR CRF09_cpx 0 0 M106I, V179D 0 0 0 RPV,c ETRc 0 Unknown Gabon CRF02_AG 0 0 V90I, E138G 0 0 0 RPV, ETRc 0 Verticala DRC F1 0 0 Y181C 0 0 0 EFV, NVP, RPV, ETR 0 Blood transfusion Pakistan A 0 0 E138A, V179I 0 0 0 ETR,c RPV 0 Verticala France CRF02_AG 0 0 M230I 0 0 0 RPV, DOR 0 Verticala Romania F 0 0 K101R, V179I 0 0 0 ETRc 0 Verticala France CRF02_AG 0 0 0 E157Q 0 0 0 RAL, EVG, DTGc Unknown Ivory Coast CRF02_AG 0 0 0 E157Q 0 0 0 RAL, EVG, DTGc Verticala Ivory Coast CRF02_AG 0 0 E138A E157Q 0 0 RPV, ETRc RAL, EVG, DTGc Blood transfusion Angola A 0 M41L, D67N, K70R, M184V, T215F, K219E A98S, K103N, E138Q 0 0 ZDV, 3TC/FTC, d4T, ABC, TDFc EFV, NVP, RPV, ETRc 0 CAR, Central African Republic; DRC, Democratic Republic of the Congo; CRF, circulating recombinant form; URF, unique recombinant form; ZDV, zidovudine; 3TC/FTC, lamivudine/emtricitabine; d4T, stavudine; ABC, abacavir; TDF, tenofovir; EFV, efavirenz; NVP; nevirapine; RPV, rilpivirine; ETR, etravirine; DOR, doravirine; RAL, raltegravir; EVG, elvitegravir; DTG, dolutegravir; NA, not available. Susceptibility was predicted using the 2017 French ANRS algorithm (http://hivfrenchresistance.org). a Absence of exposure to antiretroviral-based prophylaxis of MTCT. b Neonatal exposure to zidovudine-based prophylaxis of MTCT. c Virus classified as having ‘intermediate susceptibility’. Table 2. Characteristics of 16 patients infected with HIV strains with TDR mutations Transmission route Country of birth Viral subtype Resistance mutations Drug resistance PI NRTI NNRTI INI PI NRTI NNRTI INI Verticala France CRF02_AG 0 T215I 0 0 0 ZDV, d4T 0 0 Verticalb France URF 0 M41L, T69S 0 0 0 0 0 0 Verticala Libya CRF02_AG 0 0 E138G NA 0 0 RPV, ETRc NA Verticala Comoros C 0 0 G190E, M230I 0 0 0 EFV, NVP, RPV, DOR 0 Verticala France CRF06_cpx 0 0 K103N NA 0 0 EFV, NVP NA Verticala Cameroon CRF02_AG 0 0 V90I, K103N 0 0 0 EFV, NVP NA Verticala CAR CRF09_cpx 0 0 M106I, V179D 0 0 0 RPV,c ETRc 0 Unknown Gabon CRF02_AG 0 0 V90I, E138G 0 0 0 RPV, ETRc 0 Verticala DRC F1 0 0 Y181C 0 0 0 EFV, NVP, RPV, ETR 0 Blood transfusion Pakistan A 0 0 E138A, V179I 0 0 0 ETR,c RPV 0 Verticala France CRF02_AG 0 0 M230I 0 0 0 RPV, DOR 0 Verticala Romania F 0 0 K101R, V179I 0 0 0 ETRc 0 Verticala France CRF02_AG 0 0 0 E157Q 0 0 0 RAL, EVG, DTGc Unknown Ivory Coast CRF02_AG 0 0 0 E157Q 0 0 0 RAL, EVG, DTGc Verticala Ivory Coast CRF02_AG 0 0 E138A E157Q 0 0 RPV, ETRc RAL, EVG, DTGc Blood transfusion Angola A 0 M41L, D67N, K70R, M184V, T215F, K219E A98S, K103N, E138Q 0 0 ZDV, 3TC/FTC, d4T, ABC, TDFc EFV, NVP, RPV, ETRc 0 Transmission route Country of birth Viral subtype Resistance mutations Drug resistance PI NRTI NNRTI INI PI NRTI NNRTI INI Verticala France CRF02_AG 0 T215I 0 0 0 ZDV, d4T 0 0 Verticalb France URF 0 M41L, T69S 0 0 0 0 0 0 Verticala Libya CRF02_AG 0 0 E138G NA 0 0 RPV, ETRc NA Verticala Comoros C 0 0 G190E, M230I 0 0 0 EFV, NVP, RPV, DOR 0 Verticala France CRF06_cpx 0 0 K103N NA 0 0 EFV, NVP NA Verticala Cameroon CRF02_AG 0 0 V90I, K103N 0 0 0 EFV, NVP NA Verticala CAR CRF09_cpx 0 0 M106I, V179D 0 0 0 RPV,c ETRc 0 Unknown Gabon CRF02_AG 0 0 V90I, E138G 0 0 0 RPV, ETRc 0 Verticala DRC F1 0 0 Y181C 0 0 0 EFV, NVP, RPV, ETR 0 Blood transfusion Pakistan A 0 0 E138A, V179I 0 0 0 ETR,c RPV 0 Verticala France CRF02_AG 0 0 M230I 0 0 0 RPV, DOR 0 Verticala Romania F 0 0 K101R, V179I 0 0 0 ETRc 0 Verticala France CRF02_AG 0 0 0 E157Q 0 0 0 RAL, EVG, DTGc Unknown Ivory Coast CRF02_AG 0 0 0 E157Q 0 0 0 RAL, EVG, DTGc Verticala Ivory Coast CRF02_AG 0 0 E138A E157Q 0 0 RPV, ETRc RAL, EVG, DTGc Blood transfusion Angola A 0 M41L, D67N, K70R, M184V, T215F, K219E A98S, K103N, E138Q 0 0 ZDV, 3TC/FTC, d4T, ABC, TDFc EFV, NVP, RPV, ETRc 0 CAR, Central African Republic; DRC, Democratic Republic of the Congo; CRF, circulating recombinant form; URF, unique recombinant form; ZDV, zidovudine; 3TC/FTC, lamivudine/emtricitabine; d4T, stavudine; ABC, abacavir; TDF, tenofovir; EFV, efavirenz; NVP; nevirapine; RPV, rilpivirine; ETR, etravirine; DOR, doravirine; RAL, raltegravir; EVG, elvitegravir; DTG, dolutegravir; NA, not available. Susceptibility was predicted using the 2017 French ANRS algorithm (http://hivfrenchresistance.org). a Absence of exposure to antiretroviral-based prophylaxis of MTCT. b Neonatal exposure to zidovudine-based prophylaxis of MTCT. c Virus classified as having ‘intermediate susceptibility’. RAMs were identified in 1/18 (5.6%) children exposed to antiretroviral-based MTCT prophylaxis. Overall, the prevalence of TDR related to the most commonly prescribed PIs, NRTIs and INIs was very low: 1.2% to lamivudine/emtricitabine, abacavir and tenofovir; 2.4% to zidovudine; and 5.0% to raltegravir, elvitegravir and dolutegravir. None of them were resistant to lopinavir, atazanavir and darunavir. These results contrast with the prevalence of first- and second-generation NNRTI-related TDR: 6.0%, 9.5% and 10.5% of strains were resistant to efavirenz/nevirapine, etravirine and rilpivirine, respectively. Finally, the prevalence of strains resistant to doravirine and cabotegravir was very low (2.4% and 0%, respectively). Impact of TDR on first-line strategies The proportion of fully active (GSS = 3) regimens was 98.8% for abacavir/lamivudine (or tenofovir/emtricitabine) plus darunavir/ritonavir (or atazanavir/ritonavir or lopinavir/ritonavir), 97.6% for zidovudine/lamivudine plus darunavir/ritonavir (or atazanavir/ritonavir or lopinavir/ritonavir), 95.2% for abacavir/lamivudine (or tenofovir/emtricitabine) plus raltegravir (or elvitegravir/cobicistat or dolutegravir), 94.1% for zidovudine/lamivudine plus raltegravir (or elvitegravir/cobicistat or dolutegravir), 94.1% for abacavir/lamivudine (or tenofovir/emtricitabine) plus efavirenz (or nevirapine), 92.9% for zidovudine/lamivudine plus efavirenz (or nevirapine) and 89.3% for abacavir/lamivudine (or tenofovir/emtricitabine) plus rilpivirine. Impact of TDR on future antiretroviral strategies The proportions of fully active combinations were 96.4% for abacavir/lamivudine (or tenofovir/emtricitabine) plus doravirine and 89.3% for rilpivirine/cabotegravir. Discussion We herein report one of the largest recent studies of TDR in children newly diagnosed with HIV-1 in high-income countries. The prevalence of TDR (8.3%) was similar to the prevalences recently reported in Germany3 and in the USA4 but lower than the prevalences observed in Brazil,11,12 Spain5 and sub-Saharan African countries.1,13 Several factors could explain these differences. First, the rate of MTCT is less than 1% in France, where most of the pregnant women diagnosed with HIV are successfully treated with antiretrovirals.14 Thus, most of the new cases of paediatric HIV infection (78.6% in our study) are diagnosed in children who are unexposed to antiretroviral prophylaxis, i.e. patients whose mothers were not tested for HIV or who seroconverted during pregnancy.2 Second, because >80% of pregnant women diagnosed with HIV and followed up in France receive a PI-based combination,14 the proportion of children exposed to NNRTI during prevention of mother-to-child transmission is low (7.1% in our study). Third, because French guidelines discourage HIV-positive women from breastfeeding, the proportion of newborns exposed to antiretrovirals through breastfeeding is very low. Consequently, the TDR observed in the 11 vertically infected children unexposed to antiretroviral-based prophylaxis of MTCT is probably due to transmission of resistant strains from their antiretroviral-naive mothers and/or to transmission of viruses with polymorphic mutations. The situation is highly different in LMICs, where resistant strains are frequently transmitted during pregnancy or breastfeeding from women experiencing treatment failure (usually NNRTI-containing regimens), or could be selected for by the selection of RAMs in infants who are infected despite neonatal antiretroviral prophylaxis (most commonly nevirapine).1,13 This could explain the lower paediatric TDR prevalence observed in France (not only NNRTI-related but also NRTI-related TDR) than in LMICs. Continuous monitoring of TDR is required given the potential impact on the recommended first-line therapies. Because of the higher prevalence of first- and second-generation NNRTI-related TDR (due in part to polymorphic mutations) compared with PI-related TDR, our results suggest that the preferential choice of PI- over NNRTI-based combinations to treat recently diagnosed children be implemented, as the risk of early failure will be reduced. We also described INI-related TDR, which has been rarely studied in previous paediatric studies, because several INIs are now available for use in infants and children. The E157Q polymorphic mutation in the integrase gene has been considered to be conferring resistance to raltegravir, elvitegravir and once-daily dolutegravir (and intermediate resistance to twice-daily dolutegravir), according to the 2017 ANRS algorithm. However, recent data suggest that the susceptibility to dolutegravir could be less affected by this substitution than the susceptibility to raltegravir and elvitegravir.15 Thus, in newly diagnosed children with an isolated E157Q mutation or without available results of genotypic resistance testing, these data and our results suggest the preferential choice of dolutegravir rather than raltegravir or elvitegravir. Our results support current guidelines to perform genotypic resistance testing in all HIV paediatric new diagnoses, even if cART is not initiated immediately.9 These results could guide the choice of first-line fully active drug combinations but also the discussion of future therapeutic options, including those containing drugs which are not yet available to treat the youngest children. To sum up, we suggest that, even in the absence of previous exposure to antiretroviral MTCT prophylaxis, the preferential choice of PI- or dolutegravir- over NNRTI-based combinations to treat newly diagnosed children be implemented. Continuous monitoring of TDR should continue, given the potential impact on the recommended first-line therapies. Importantly, monitoring of the prevalence of INI-related RAMs will also be key, given the expanding role of these medications in both pregnant women and children. Funding This study was carried out as part of our routine work. Transparency declarations P. F. has received research grants (to his institution) from the French National Agency for AIDS Research (ANRS) and honoraria and travel grants from ViiV Healthcare, Bristol-Myers Squibb, Janssen-Cilag, Gilead Sciences, Pfizer, Astellas and MSD France for participation in advisory boards, educational programmes and international conferences. V. A.-F. has received research grants (to her institution) from the ANRS and the MSD AVENIR Foundation and travel grants from ViiV Healthcare and Janssen-Cilag for participation in educational programmes and conferences. M.-L. C. has received travel grants from ViiV Healthcare, Bristol-Myers Squibb, Janssen-Cilag, Gilead Sciences and MSD France. F. V. and S. B.: none to declare. References 1 Siberry GK , Amzel A , Ramos A et al. Impact of human immunodeficiency virus drug resistance on treatment of human immunodeficiency virus infection in children in low- and middle-income countries . J Infect Dis 2017 ; 216 : S838 – 42 . Google Scholar CrossRef Search ADS PubMed 2 Frange P , Chaix ML , Veber F et al. Missed opportunities for HIV testing in pregnant women and children living in France . Pediatr Infect Dis J 2014 ; 33 : e60. Google Scholar CrossRef Search ADS PubMed 3 Neubert J , Michalsky N , Laws HJ et al. HIV-1 subtype diversity and prevalence of primary drug resistance in a single-center pediatric cohort in Germany . Intervirology 2016 ; 59 : 301. Google Scholar CrossRef Search ADS PubMed 4 Rogo T , DeLong AK , Chan P et al. Antiretroviral treatment failure, drug resistance, and subtype diversity in the only pediatric HIV clinic in Rhode Island . Clin Infect Dis 2015 ; 60 : 1426 – 35 . Google Scholar PubMed 5 Rojas Sanchez P , Dominguez S , Jimenez De Ory S et al. Trends in drug resistance prevalence, HIV-1 variants and clinical status in HIV-1-infected pediatric population in Madrid: 1993 to 2015 analysis . Pediatr Infect Dis J 2018 ; 37 : e48 – 57 . Google Scholar CrossRef Search ADS PubMed 6 Bennett DE , Camacho RJ , Otelea D et al. Drug resistance mutations for surveillance of transmitted HIV-1 drug resistance: 2009 update . PLoS One 2009 ; 4 : e4724. Google Scholar CrossRef Search ADS PubMed 7 Wensing AM , Calvez V , Günthard HF et al. 2011 update of the drug resistance mutations in HIV-1 . Top Antivir Med 2017 ; 24 : 132 – 41 . Google Scholar PubMed 8 Marcelin AG , Santoro MM , Charpentier C et al. Epidemiological study of doravirine associated resistance mutations in HIV-1-infected treatment-naïve patients from two large databases in France and Italy. In: Abstracts of the Fifteenth European Meeting on HIV & Hepatitis. Abstract #08. Rome, Italy, 2017 . 9 Groupe d'experts sous la direction du Professeur Morlat . Prise en charge médicale des personnes infectées par le VIH. Actualisation 2018 . https://cns.sante.fr/category/dossiers/dossier-experts/. 10 Chaix ML , Descamps D , Wirden M et al. Stable frequency of HIV-1 transmitted drug resistance in patients at the time of primary infection over 1996–2006 in France . AIDS 2009 ; 23 : 717 – 24 . Google Scholar PubMed 11 Andrade SD , Sabidó M , Monteiro WM et al. Drug resistance in antiretroviral-naive children newly diagnosed with HIV-1 in Manaus, Amazonas . J Antimicrob Chemother 2017 ; 72 : 1774 – 83 . Google Scholar CrossRef Search ADS PubMed 12 Vaz SN , Giovanetti M , Rego FF et al. Molecular characterization of the human immunodeficiency virus type 1 in women and their vertically infected children . AIDS Res Hum Retroviruses 2015 ; 31 : 1046 – 51 . Google Scholar CrossRef Search ADS PubMed 13 Jordan MR , Penazzato M , Cournil A et al. Human immunodeficiency virus (HIV) drug resistance in African infants and young children newly diagnosed with HIV: a multicountry analysis . Clin Infect Dis 2017 ; 65 : 2018 – 25 . Google Scholar CrossRef Search ADS PubMed 14 Mandelbrot L , Tubiana RL , Chenadec J et al. No perinatal HIV-1 transmission from women with effective antiretroviral therapy starting before conception . Clin Infect Dis 2015 ; 61 : 1717 – 25 . 15 Charpentier C , Descamps D. Resistance to HIV integrase inhibitors: about R263K and E157Q mutations . Viruses 2018 ; 10 : 41. Google Scholar CrossRef Search ADS © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Prevalence of drug resistance in children recently diagnosed with HIV-1 infection in France (2006–17): impact on susceptibility to first-line strategies

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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0305-7453
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1460-2091
D.O.I.
10.1093/jac/dky203
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Abstract

Abstract Objectives To describe the prevalence of transmitted drug resistance (TDR) among 84 children newly diagnosed with HIV in France in 2006–17. Methods HIV-1 resistance-associated mutations (RAMs) were characterized using both the 2009 Stanford list of mutations and the 2017 French National Agency for AIDS Research (ANRS) algorithm. A genotypic susceptibility score (GSS) was estimated for each first-line recommended ART combination. Results Patients were mainly infected through mother-to-child transmission (MTCT) (73/84; 86.9%), but only 18 children (24.7% of vertically infected patients) were previously exposed to antiretroviral prophylaxis from MTCT. Non-B variants were identified in 90.5% (76/84) of patients. The frequency of TDR was 8.3% (7/84) using the 2009 Stanford list and 16.7% (14/84) using both the Stanford list and the 2017 ANRS algorithm. The prevalence of PI-, NRTI-, efavirenz/nevirapine-, etravirine/rilpivirine- and doravirine-associated RAMs was 0%, 3.6%, 6.0%, 11.9% and 2.4%, respectively. Single-, dual- and triple-class resistance was present in 15.5%, 1.2% and 0% of cases, respectively. Additionally, 3/60 (5%) strains had integrase inhibitor (INI)-related RAMs (an isolated E157Q mutation, which could mostly affect the susceptibility to raltegravir/elvitegravir rather than that to dolutegravir). Among the 18 children exposed to MTCT prophylaxis, RAMs were identified in only 1 case (5.6%). The proportion of fully active combinations (GSS = 3) was ≥97.6%, ≥94.1%, ≥92.9% and ≥89.3% for PI-, INI-, efavirenz/nevirapine- and rilpivirine-based regimens, respectively. Conclusions The proportion of NRTI- and NNRTI-related TDR in children is lower in France than in low- and middle-income countries. However, we suggest favouring PI- or dolutegravir- over NNRTI-based combinations to treat newly diagnosed HIV-infected children, even in the absence of previous exposure to antiretroviral prophylaxis of MTCT. Introduction Although currently recommended universal maternal and infant antiretroviral prophylaxis has dramatically reduced the risk and number of infant HIV infections, ∼160 000 new paediatric infections occur each year, mainly in low- and middle-income countries (LMICs) (http://www.who.int/hiv/data). In these countries, the transmission of resistant viruses to infants has become more common.1 In high-income countries, where the rate of HIV mother-to-child transmission (MTCT) is less than 1%, new cases of HIV infection continue to be diagnosed in children whose mothers were not tested for HIV or who seroconverted during pregnancy, and in immigrant children arriving from highly HIV-prevalent areas.2 Monitoring of transmitted drug resistance (TDR) in children is required to optimize treatment success and preserve future therapeutic options. However, recent data about TDR prevalence in children newly diagnosed with HIV in high-income countries still remain limited.3–5 Moreover, few data have been published about the prevalence of resistance to second-generation NNRTIs and integrase inhibitors (INIs), which can now be used in the paediatric population. The present work aimed to evaluate the prevalence of TDR in children newly diagnosed with HIV-1 in France between 2006 and 2017 and referred to Necker Hospital (Paris). Patients and methods Ethics This research was conducted in accordance with the Declaration of Helsinki and national and institutional standards. Parents/guardians provided informed consent for the anonymous use of their children’s clinical and biological data for biomedical research at the time of data collection. Study population The study population comprised 84 children and adolescents newly diagnosed with HIV-1 in France between 2006 and 2017 and referred to Necker hospital. Genotypic resistance analysis Genotypic resistance tests were performed on plasma samples collected before initiation of combined ART (cART). Reverse transcriptase, protease and integrase genes were amplified and sequenced. In INI-naive patients with virological suppression who had not previously undergone integrase gene sequencing, resistance to INIs was evaluated by sequencing the integrase gene from PBMC-associated HIV-1 DNA. Genotypic resistance tests were performed using either commercial assays [TrueGene HIV-1 genotyping kit (Siemens Healthcare, Eragny, France), Viroseq sequencing-based HIV-1 genotyping kit (Abbott, Rungis, France)] or using the consensus technique of the French National Agency for AIDS Research (ANRS) Resistance study group (www.hivfrenchresistance.org). HIV-1 resistance-associated mutations (RAMs) were defined using both the 2009 Stanford RAM list6 for NRTIs, first-generation NNRTIs and PIs and the 2017 French ANRS algorithm v27 (www.hivfrenchresistance.org) for etravirine, rilpivirine and INIs. The ANRS algorithm includes all the rilpivirine-, etravirine- and INI-related RAMs reported in the 2017 IAS-USA resistance mutations list.7 The studied RAMs were: (i) resistance to PIs: L10/I/F/V/C/R/M, V11I, I15A/V, G16E, K20R/M/I/T/V, L23I, L24I, D30N, V32I, L33F/I/V, M36I/L/V, M46I/L, I47A/V, G48V/M, I50V/L, F53L/Y, I54V/L/M/A/T/S, Q58E, D60E, I62V, L63P, A71I/L/V/T, G73C/S/T/A, T74P, L76V, V77I, V82A/C/F/L/M/T/S, I84V/A/C, I85V, N88D/S, L89I/M/R/T/V and L90M; (ii) resistance to NRTIs: M41L, K65R/E/N, D67N/G/E, T69D/Ins, K70E/R, L74V/I, V75A/M/T/S, F77L, Y115F, F116Y, Q151M, M184V/I, L210W, T215A/C/D/E/G/H/I/L/N/S/V/Y/F and K219Q/E/N/R; (iii) resistance to NNRTIs: V90I, A98G, L100I, K101E/H/I/P/R, K103N/S, V106A/M/I, V108I, E138A/G/K/Q/R/S, V179D/F/I/L/M/T, Y181C/I/V, Y188L/H/C, G190A/S/E, H221Y, P225H, F227C/L/V, M230I/L/V, L234I and P236L; and (iv) resistance to INIs: A49G, T66I/A/K, L74I/M, E92G/Q, T97A, G118R, F121Y, E138A/K/T, G140A/C/S, Y143A/C/G/H/R/S, P145S, S147G, Q148E/G/H/K/R, V151L, S153F/Y, N155H/S/T, E157Q, S230G/R and R263K. Mutations defining doravirine resistance were V106A, V106M, V108I, H221Y, F227L, F227C, F227V, M230I, L234I and P236L.8 For estimating the genotypic susceptibility score (GSS), each drug, except ritonavir, was scored as 1 or 0 in the case of ‘susceptibility’ or ‘intermediate/high resistance’, respectively, according to the ANRS interpretation algorithm. For each of the first-line recommended cART combinations in French guidelines,9 the arithmetic sum of the individual scores for the specific drugs provided the total treatment-related GSS. Phylogenetic analysis The HIV-1 subtype was determined by phylogenetic analysis of reverse transcriptase sequences, as previously described.10 Results Study population Overall, 84 patients were included in our study (Table 1). Children were mainly infected through MTCT (73/84; 86.9%), but only 18 patients (24.7% of vertically infected children) were previously exposed to antiretroviral prophylaxis from MTCT. Around one-third of patients were diagnosed late in their disease: the proportion of those with CDC stage C disease and CD4 cell count <15% was 25.7% in 2006–09, 22.9% in 2010–13 and 42.1% in 2014–17. Table 1. Demographic and biological characteristics of the patients Presence of at least one RAM (n = 16) Absence of RAMs (n = 68) Total (n = 84) Male, n (%) 7 (43.8) 34 (50.0) 41 (48.8) Age at diagnosis (months), median (range) 12.3 (0.3–168.0) 36.0 (0.1–174.0) 26.0 (0.1–174.0) Year of diagnosis, n (%)  2006–09 6 (37.5) 24 (35.3) 30 (35.7)  2010–13 3 (18.8) 32 (47.1) 35 (41.7)  2014–17 7 (43.8) 12 (17.6) 19 (22.6) Transmission group, n (%)  mother-to-child 12 (75.0) 61 (89.7) 73 (86.9)  blood transfusion 2 (12.5) 1 (1.5) 3 (3.6)  sexual exposure 0 (0) 1 (1.5) 1 (1.2)  unknown 2 (12.5) 5 (7.4) 7 (8.3) Previous exposure to in utero or postnatal antiretroviral prophylaxis, n (%) 1 (6.3) 17 (25.0) 18 (21.4)  including only NRTI 1 (6.3) 0 (0) 1 (1.2)  including NRTI + PI 0 (0) 11 (16.2) 11 (13.1)  including NRTI + NNRTI 0 (0) 4 (5.9) 4 (4.8)  including NRTI + NNRTI + PI + INI 0 (0) 2 (2.9) 2 (2.4) Maternal country of birth, n (%)  France 0 (0) 7 (10.3) 7 (8.3)  other European countries 1 (6.3) 0 (0) 1 (1.2)  sub-Saharan African country 13 (81.3) 55 (80.9) 68 (80.9)  other countries 2 (12.5) 6 (8.8) 8 (9.5) Country of birth, n (%)  France 5 (31.3) 33 (48.5) 38 (45.2)  other European countries 1 (6.3) 1 (1.5) 2 (2.4)  sub-Saharan African country 8 (50.0) 30 (44.1) 38 (45.2)  other countries 2 (12.5) 4 (5.9) 6 (7.1) CDC clinical stage at diagnosis, n (%)  N 3 (18.8) 30 (44.1) 33 (39.3)  A 2 (12.5) 6 (8.8) 8 (9.5)  B 4 (25.0) 14 (20.6) 18 (21.4)  C 7 (43.8) 18 (26.5) 25 (29.8) CD4 count at diagnosis (cells/mm3), median (range) 17 (0–49) 24 (0–63) 22 (1–63) Plasma HIV-1 RNA at diagnosis (log10 copies/mL), median (range) 6.1 (3.0–7.4) 5.0 (2.3–7.6) 5.2 (2.3–7.6) Genetic HIV-1 subtype, n (%)  A 2 (12.5) 2 (2.9) 4 (4.8)  B 0 (0) 8 (11.8) 8 (9.5)  C 1 (6.3) 5 (7.4) 6 (7.1)  F 2 (12.5) 3 (4.4) 5 (6.0)  CRF02_AG 8 (50.0) 24 (35.3) 32 (38.1)  CRF06_cpx 1 (6.3) 3 (4.4) 4 (4.8)  other group M non-B variants 2 (12.5) 23 (33.8) 25 (29.8) Prevalence of RAMs, n (%)  PI RAMsa 0 (0) NA 0 (0)  NRTI RAMsa 3 (18.8) NA 3 (3.6)  NNRTI RAMsa 5 (31.3) NA 5 (6.0)  rilpivirine and etravirine RAMsb 10 (62.5) NA 10 (11.9)  doravirine RAMsc 2 (12.5) NA 2 (2.4)  INI RAMsb 3/13 (23.1) NA 3/60 (5.0) Presence of at least one RAM (n = 16) Absence of RAMs (n = 68) Total (n = 84) Male, n (%) 7 (43.8) 34 (50.0) 41 (48.8) Age at diagnosis (months), median (range) 12.3 (0.3–168.0) 36.0 (0.1–174.0) 26.0 (0.1–174.0) Year of diagnosis, n (%)  2006–09 6 (37.5) 24 (35.3) 30 (35.7)  2010–13 3 (18.8) 32 (47.1) 35 (41.7)  2014–17 7 (43.8) 12 (17.6) 19 (22.6) Transmission group, n (%)  mother-to-child 12 (75.0) 61 (89.7) 73 (86.9)  blood transfusion 2 (12.5) 1 (1.5) 3 (3.6)  sexual exposure 0 (0) 1 (1.5) 1 (1.2)  unknown 2 (12.5) 5 (7.4) 7 (8.3) Previous exposure to in utero or postnatal antiretroviral prophylaxis, n (%) 1 (6.3) 17 (25.0) 18 (21.4)  including only NRTI 1 (6.3) 0 (0) 1 (1.2)  including NRTI + PI 0 (0) 11 (16.2) 11 (13.1)  including NRTI + NNRTI 0 (0) 4 (5.9) 4 (4.8)  including NRTI + NNRTI + PI + INI 0 (0) 2 (2.9) 2 (2.4) Maternal country of birth, n (%)  France 0 (0) 7 (10.3) 7 (8.3)  other European countries 1 (6.3) 0 (0) 1 (1.2)  sub-Saharan African country 13 (81.3) 55 (80.9) 68 (80.9)  other countries 2 (12.5) 6 (8.8) 8 (9.5) Country of birth, n (%)  France 5 (31.3) 33 (48.5) 38 (45.2)  other European countries 1 (6.3) 1 (1.5) 2 (2.4)  sub-Saharan African country 8 (50.0) 30 (44.1) 38 (45.2)  other countries 2 (12.5) 4 (5.9) 6 (7.1) CDC clinical stage at diagnosis, n (%)  N 3 (18.8) 30 (44.1) 33 (39.3)  A 2 (12.5) 6 (8.8) 8 (9.5)  B 4 (25.0) 14 (20.6) 18 (21.4)  C 7 (43.8) 18 (26.5) 25 (29.8) CD4 count at diagnosis (cells/mm3), median (range) 17 (0–49) 24 (0–63) 22 (1–63) Plasma HIV-1 RNA at diagnosis (log10 copies/mL), median (range) 6.1 (3.0–7.4) 5.0 (2.3–7.6) 5.2 (2.3–7.6) Genetic HIV-1 subtype, n (%)  A 2 (12.5) 2 (2.9) 4 (4.8)  B 0 (0) 8 (11.8) 8 (9.5)  C 1 (6.3) 5 (7.4) 6 (7.1)  F 2 (12.5) 3 (4.4) 5 (6.0)  CRF02_AG 8 (50.0) 24 (35.3) 32 (38.1)  CRF06_cpx 1 (6.3) 3 (4.4) 4 (4.8)  other group M non-B variants 2 (12.5) 23 (33.8) 25 (29.8) Prevalence of RAMs, n (%)  PI RAMsa 0 (0) NA 0 (0)  NRTI RAMsa 3 (18.8) NA 3 (3.6)  NNRTI RAMsa 5 (31.3) NA 5 (6.0)  rilpivirine and etravirine RAMsb 10 (62.5) NA 10 (11.9)  doravirine RAMsc 2 (12.5) NA 2 (2.4)  INI RAMsb 3/13 (23.1) NA 3/60 (5.0) CRF, circulating recombinant form; NA, not applicable. a As defined in the 2009 Stanford RAM list of mutations for surveillance of TDR.6 b As defined in the 2017 French ANRS algorithm (http://hivfrenchresistance.org). c Mutations defining doravirine resistance were V106A, V106M, V108I, H221Y, F227L, F227C, F227V, M230I, L234I and P236L. Table 1. Demographic and biological characteristics of the patients Presence of at least one RAM (n = 16) Absence of RAMs (n = 68) Total (n = 84) Male, n (%) 7 (43.8) 34 (50.0) 41 (48.8) Age at diagnosis (months), median (range) 12.3 (0.3–168.0) 36.0 (0.1–174.0) 26.0 (0.1–174.0) Year of diagnosis, n (%)  2006–09 6 (37.5) 24 (35.3) 30 (35.7)  2010–13 3 (18.8) 32 (47.1) 35 (41.7)  2014–17 7 (43.8) 12 (17.6) 19 (22.6) Transmission group, n (%)  mother-to-child 12 (75.0) 61 (89.7) 73 (86.9)  blood transfusion 2 (12.5) 1 (1.5) 3 (3.6)  sexual exposure 0 (0) 1 (1.5) 1 (1.2)  unknown 2 (12.5) 5 (7.4) 7 (8.3) Previous exposure to in utero or postnatal antiretroviral prophylaxis, n (%) 1 (6.3) 17 (25.0) 18 (21.4)  including only NRTI 1 (6.3) 0 (0) 1 (1.2)  including NRTI + PI 0 (0) 11 (16.2) 11 (13.1)  including NRTI + NNRTI 0 (0) 4 (5.9) 4 (4.8)  including NRTI + NNRTI + PI + INI 0 (0) 2 (2.9) 2 (2.4) Maternal country of birth, n (%)  France 0 (0) 7 (10.3) 7 (8.3)  other European countries 1 (6.3) 0 (0) 1 (1.2)  sub-Saharan African country 13 (81.3) 55 (80.9) 68 (80.9)  other countries 2 (12.5) 6 (8.8) 8 (9.5) Country of birth, n (%)  France 5 (31.3) 33 (48.5) 38 (45.2)  other European countries 1 (6.3) 1 (1.5) 2 (2.4)  sub-Saharan African country 8 (50.0) 30 (44.1) 38 (45.2)  other countries 2 (12.5) 4 (5.9) 6 (7.1) CDC clinical stage at diagnosis, n (%)  N 3 (18.8) 30 (44.1) 33 (39.3)  A 2 (12.5) 6 (8.8) 8 (9.5)  B 4 (25.0) 14 (20.6) 18 (21.4)  C 7 (43.8) 18 (26.5) 25 (29.8) CD4 count at diagnosis (cells/mm3), median (range) 17 (0–49) 24 (0–63) 22 (1–63) Plasma HIV-1 RNA at diagnosis (log10 copies/mL), median (range) 6.1 (3.0–7.4) 5.0 (2.3–7.6) 5.2 (2.3–7.6) Genetic HIV-1 subtype, n (%)  A 2 (12.5) 2 (2.9) 4 (4.8)  B 0 (0) 8 (11.8) 8 (9.5)  C 1 (6.3) 5 (7.4) 6 (7.1)  F 2 (12.5) 3 (4.4) 5 (6.0)  CRF02_AG 8 (50.0) 24 (35.3) 32 (38.1)  CRF06_cpx 1 (6.3) 3 (4.4) 4 (4.8)  other group M non-B variants 2 (12.5) 23 (33.8) 25 (29.8) Prevalence of RAMs, n (%)  PI RAMsa 0 (0) NA 0 (0)  NRTI RAMsa 3 (18.8) NA 3 (3.6)  NNRTI RAMsa 5 (31.3) NA 5 (6.0)  rilpivirine and etravirine RAMsb 10 (62.5) NA 10 (11.9)  doravirine RAMsc 2 (12.5) NA 2 (2.4)  INI RAMsb 3/13 (23.1) NA 3/60 (5.0) Presence of at least one RAM (n = 16) Absence of RAMs (n = 68) Total (n = 84) Male, n (%) 7 (43.8) 34 (50.0) 41 (48.8) Age at diagnosis (months), median (range) 12.3 (0.3–168.0) 36.0 (0.1–174.0) 26.0 (0.1–174.0) Year of diagnosis, n (%)  2006–09 6 (37.5) 24 (35.3) 30 (35.7)  2010–13 3 (18.8) 32 (47.1) 35 (41.7)  2014–17 7 (43.8) 12 (17.6) 19 (22.6) Transmission group, n (%)  mother-to-child 12 (75.0) 61 (89.7) 73 (86.9)  blood transfusion 2 (12.5) 1 (1.5) 3 (3.6)  sexual exposure 0 (0) 1 (1.5) 1 (1.2)  unknown 2 (12.5) 5 (7.4) 7 (8.3) Previous exposure to in utero or postnatal antiretroviral prophylaxis, n (%) 1 (6.3) 17 (25.0) 18 (21.4)  including only NRTI 1 (6.3) 0 (0) 1 (1.2)  including NRTI + PI 0 (0) 11 (16.2) 11 (13.1)  including NRTI + NNRTI 0 (0) 4 (5.9) 4 (4.8)  including NRTI + NNRTI + PI + INI 0 (0) 2 (2.9) 2 (2.4) Maternal country of birth, n (%)  France 0 (0) 7 (10.3) 7 (8.3)  other European countries 1 (6.3) 0 (0) 1 (1.2)  sub-Saharan African country 13 (81.3) 55 (80.9) 68 (80.9)  other countries 2 (12.5) 6 (8.8) 8 (9.5) Country of birth, n (%)  France 5 (31.3) 33 (48.5) 38 (45.2)  other European countries 1 (6.3) 1 (1.5) 2 (2.4)  sub-Saharan African country 8 (50.0) 30 (44.1) 38 (45.2)  other countries 2 (12.5) 4 (5.9) 6 (7.1) CDC clinical stage at diagnosis, n (%)  N 3 (18.8) 30 (44.1) 33 (39.3)  A 2 (12.5) 6 (8.8) 8 (9.5)  B 4 (25.0) 14 (20.6) 18 (21.4)  C 7 (43.8) 18 (26.5) 25 (29.8) CD4 count at diagnosis (cells/mm3), median (range) 17 (0–49) 24 (0–63) 22 (1–63) Plasma HIV-1 RNA at diagnosis (log10 copies/mL), median (range) 6.1 (3.0–7.4) 5.0 (2.3–7.6) 5.2 (2.3–7.6) Genetic HIV-1 subtype, n (%)  A 2 (12.5) 2 (2.9) 4 (4.8)  B 0 (0) 8 (11.8) 8 (9.5)  C 1 (6.3) 5 (7.4) 6 (7.1)  F 2 (12.5) 3 (4.4) 5 (6.0)  CRF02_AG 8 (50.0) 24 (35.3) 32 (38.1)  CRF06_cpx 1 (6.3) 3 (4.4) 4 (4.8)  other group M non-B variants 2 (12.5) 23 (33.8) 25 (29.8) Prevalence of RAMs, n (%)  PI RAMsa 0 (0) NA 0 (0)  NRTI RAMsa 3 (18.8) NA 3 (3.6)  NNRTI RAMsa 5 (31.3) NA 5 (6.0)  rilpivirine and etravirine RAMsb 10 (62.5) NA 10 (11.9)  doravirine RAMsc 2 (12.5) NA 2 (2.4)  INI RAMsb 3/13 (23.1) NA 3/60 (5.0) CRF, circulating recombinant form; NA, not applicable. a As defined in the 2009 Stanford RAM list of mutations for surveillance of TDR.6 b As defined in the 2017 French ANRS algorithm (http://hivfrenchresistance.org). c Mutations defining doravirine resistance were V106A, V106M, V108I, H221Y, F227L, F227C, F227V, M230I, L234I and P236L. HIV-1 diversity Subtype B strains were isolated in eight patients (9.5%) (Table 1). All but one of the subtype B-infected children were born in France to a mother who originated from France or north-west Africa. The viral diversity was high: 90.5% of strains clustered with non-B subtypes, mainly CRF02_AG (42.1% of non-B subtypes). TDR RAMs in the reverse transcriptase and/or protease genes were identified in 7 strains (8.3%) using the 2009 Stanford list and in 14 strains (16.7%) using both the Stanford list and the 2017 French ANRS algorithm (Table 1). The prevalence of PI-, NRTI-, first-generation NNRTI- and second-generation NNRTI-associated RAMs was 0%, 3.6%, 6.0% and 11.9%, respectively (global prevalence of NNRTI-associated RAMs = 14.3%). Viruses with single-, dual- and triple-class resistance were isolated in 15.5%, 1.2% and 0%, respectively (Table 2). The strain with dual-class resistance was isolated in a child infected through blood transfusion in Angola. Additionally, 3/60 (5.0%) strains, belonging to CRF02_AG, had INI-related RAMs (E157Q mutation in all cases). Table 2. Characteristics of 16 patients infected with HIV strains with TDR mutations Transmission route Country of birth Viral subtype Resistance mutations Drug resistance PI NRTI NNRTI INI PI NRTI NNRTI INI Verticala France CRF02_AG 0 T215I 0 0 0 ZDV, d4T 0 0 Verticalb France URF 0 M41L, T69S 0 0 0 0 0 0 Verticala Libya CRF02_AG 0 0 E138G NA 0 0 RPV, ETRc NA Verticala Comoros C 0 0 G190E, M230I 0 0 0 EFV, NVP, RPV, DOR 0 Verticala France CRF06_cpx 0 0 K103N NA 0 0 EFV, NVP NA Verticala Cameroon CRF02_AG 0 0 V90I, K103N 0 0 0 EFV, NVP NA Verticala CAR CRF09_cpx 0 0 M106I, V179D 0 0 0 RPV,c ETRc 0 Unknown Gabon CRF02_AG 0 0 V90I, E138G 0 0 0 RPV, ETRc 0 Verticala DRC F1 0 0 Y181C 0 0 0 EFV, NVP, RPV, ETR 0 Blood transfusion Pakistan A 0 0 E138A, V179I 0 0 0 ETR,c RPV 0 Verticala France CRF02_AG 0 0 M230I 0 0 0 RPV, DOR 0 Verticala Romania F 0 0 K101R, V179I 0 0 0 ETRc 0 Verticala France CRF02_AG 0 0 0 E157Q 0 0 0 RAL, EVG, DTGc Unknown Ivory Coast CRF02_AG 0 0 0 E157Q 0 0 0 RAL, EVG, DTGc Verticala Ivory Coast CRF02_AG 0 0 E138A E157Q 0 0 RPV, ETRc RAL, EVG, DTGc Blood transfusion Angola A 0 M41L, D67N, K70R, M184V, T215F, K219E A98S, K103N, E138Q 0 0 ZDV, 3TC/FTC, d4T, ABC, TDFc EFV, NVP, RPV, ETRc 0 Transmission route Country of birth Viral subtype Resistance mutations Drug resistance PI NRTI NNRTI INI PI NRTI NNRTI INI Verticala France CRF02_AG 0 T215I 0 0 0 ZDV, d4T 0 0 Verticalb France URF 0 M41L, T69S 0 0 0 0 0 0 Verticala Libya CRF02_AG 0 0 E138G NA 0 0 RPV, ETRc NA Verticala Comoros C 0 0 G190E, M230I 0 0 0 EFV, NVP, RPV, DOR 0 Verticala France CRF06_cpx 0 0 K103N NA 0 0 EFV, NVP NA Verticala Cameroon CRF02_AG 0 0 V90I, K103N 0 0 0 EFV, NVP NA Verticala CAR CRF09_cpx 0 0 M106I, V179D 0 0 0 RPV,c ETRc 0 Unknown Gabon CRF02_AG 0 0 V90I, E138G 0 0 0 RPV, ETRc 0 Verticala DRC F1 0 0 Y181C 0 0 0 EFV, NVP, RPV, ETR 0 Blood transfusion Pakistan A 0 0 E138A, V179I 0 0 0 ETR,c RPV 0 Verticala France CRF02_AG 0 0 M230I 0 0 0 RPV, DOR 0 Verticala Romania F 0 0 K101R, V179I 0 0 0 ETRc 0 Verticala France CRF02_AG 0 0 0 E157Q 0 0 0 RAL, EVG, DTGc Unknown Ivory Coast CRF02_AG 0 0 0 E157Q 0 0 0 RAL, EVG, DTGc Verticala Ivory Coast CRF02_AG 0 0 E138A E157Q 0 0 RPV, ETRc RAL, EVG, DTGc Blood transfusion Angola A 0 M41L, D67N, K70R, M184V, T215F, K219E A98S, K103N, E138Q 0 0 ZDV, 3TC/FTC, d4T, ABC, TDFc EFV, NVP, RPV, ETRc 0 CAR, Central African Republic; DRC, Democratic Republic of the Congo; CRF, circulating recombinant form; URF, unique recombinant form; ZDV, zidovudine; 3TC/FTC, lamivudine/emtricitabine; d4T, stavudine; ABC, abacavir; TDF, tenofovir; EFV, efavirenz; NVP; nevirapine; RPV, rilpivirine; ETR, etravirine; DOR, doravirine; RAL, raltegravir; EVG, elvitegravir; DTG, dolutegravir; NA, not available. Susceptibility was predicted using the 2017 French ANRS algorithm (http://hivfrenchresistance.org). a Absence of exposure to antiretroviral-based prophylaxis of MTCT. b Neonatal exposure to zidovudine-based prophylaxis of MTCT. c Virus classified as having ‘intermediate susceptibility’. Table 2. Characteristics of 16 patients infected with HIV strains with TDR mutations Transmission route Country of birth Viral subtype Resistance mutations Drug resistance PI NRTI NNRTI INI PI NRTI NNRTI INI Verticala France CRF02_AG 0 T215I 0 0 0 ZDV, d4T 0 0 Verticalb France URF 0 M41L, T69S 0 0 0 0 0 0 Verticala Libya CRF02_AG 0 0 E138G NA 0 0 RPV, ETRc NA Verticala Comoros C 0 0 G190E, M230I 0 0 0 EFV, NVP, RPV, DOR 0 Verticala France CRF06_cpx 0 0 K103N NA 0 0 EFV, NVP NA Verticala Cameroon CRF02_AG 0 0 V90I, K103N 0 0 0 EFV, NVP NA Verticala CAR CRF09_cpx 0 0 M106I, V179D 0 0 0 RPV,c ETRc 0 Unknown Gabon CRF02_AG 0 0 V90I, E138G 0 0 0 RPV, ETRc 0 Verticala DRC F1 0 0 Y181C 0 0 0 EFV, NVP, RPV, ETR 0 Blood transfusion Pakistan A 0 0 E138A, V179I 0 0 0 ETR,c RPV 0 Verticala France CRF02_AG 0 0 M230I 0 0 0 RPV, DOR 0 Verticala Romania F 0 0 K101R, V179I 0 0 0 ETRc 0 Verticala France CRF02_AG 0 0 0 E157Q 0 0 0 RAL, EVG, DTGc Unknown Ivory Coast CRF02_AG 0 0 0 E157Q 0 0 0 RAL, EVG, DTGc Verticala Ivory Coast CRF02_AG 0 0 E138A E157Q 0 0 RPV, ETRc RAL, EVG, DTGc Blood transfusion Angola A 0 M41L, D67N, K70R, M184V, T215F, K219E A98S, K103N, E138Q 0 0 ZDV, 3TC/FTC, d4T, ABC, TDFc EFV, NVP, RPV, ETRc 0 Transmission route Country of birth Viral subtype Resistance mutations Drug resistance PI NRTI NNRTI INI PI NRTI NNRTI INI Verticala France CRF02_AG 0 T215I 0 0 0 ZDV, d4T 0 0 Verticalb France URF 0 M41L, T69S 0 0 0 0 0 0 Verticala Libya CRF02_AG 0 0 E138G NA 0 0 RPV, ETRc NA Verticala Comoros C 0 0 G190E, M230I 0 0 0 EFV, NVP, RPV, DOR 0 Verticala France CRF06_cpx 0 0 K103N NA 0 0 EFV, NVP NA Verticala Cameroon CRF02_AG 0 0 V90I, K103N 0 0 0 EFV, NVP NA Verticala CAR CRF09_cpx 0 0 M106I, V179D 0 0 0 RPV,c ETRc 0 Unknown Gabon CRF02_AG 0 0 V90I, E138G 0 0 0 RPV, ETRc 0 Verticala DRC F1 0 0 Y181C 0 0 0 EFV, NVP, RPV, ETR 0 Blood transfusion Pakistan A 0 0 E138A, V179I 0 0 0 ETR,c RPV 0 Verticala France CRF02_AG 0 0 M230I 0 0 0 RPV, DOR 0 Verticala Romania F 0 0 K101R, V179I 0 0 0 ETRc 0 Verticala France CRF02_AG 0 0 0 E157Q 0 0 0 RAL, EVG, DTGc Unknown Ivory Coast CRF02_AG 0 0 0 E157Q 0 0 0 RAL, EVG, DTGc Verticala Ivory Coast CRF02_AG 0 0 E138A E157Q 0 0 RPV, ETRc RAL, EVG, DTGc Blood transfusion Angola A 0 M41L, D67N, K70R, M184V, T215F, K219E A98S, K103N, E138Q 0 0 ZDV, 3TC/FTC, d4T, ABC, TDFc EFV, NVP, RPV, ETRc 0 CAR, Central African Republic; DRC, Democratic Republic of the Congo; CRF, circulating recombinant form; URF, unique recombinant form; ZDV, zidovudine; 3TC/FTC, lamivudine/emtricitabine; d4T, stavudine; ABC, abacavir; TDF, tenofovir; EFV, efavirenz; NVP; nevirapine; RPV, rilpivirine; ETR, etravirine; DOR, doravirine; RAL, raltegravir; EVG, elvitegravir; DTG, dolutegravir; NA, not available. Susceptibility was predicted using the 2017 French ANRS algorithm (http://hivfrenchresistance.org). a Absence of exposure to antiretroviral-based prophylaxis of MTCT. b Neonatal exposure to zidovudine-based prophylaxis of MTCT. c Virus classified as having ‘intermediate susceptibility’. RAMs were identified in 1/18 (5.6%) children exposed to antiretroviral-based MTCT prophylaxis. Overall, the prevalence of TDR related to the most commonly prescribed PIs, NRTIs and INIs was very low: 1.2% to lamivudine/emtricitabine, abacavir and tenofovir; 2.4% to zidovudine; and 5.0% to raltegravir, elvitegravir and dolutegravir. None of them were resistant to lopinavir, atazanavir and darunavir. These results contrast with the prevalence of first- and second-generation NNRTI-related TDR: 6.0%, 9.5% and 10.5% of strains were resistant to efavirenz/nevirapine, etravirine and rilpivirine, respectively. Finally, the prevalence of strains resistant to doravirine and cabotegravir was very low (2.4% and 0%, respectively). Impact of TDR on first-line strategies The proportion of fully active (GSS = 3) regimens was 98.8% for abacavir/lamivudine (or tenofovir/emtricitabine) plus darunavir/ritonavir (or atazanavir/ritonavir or lopinavir/ritonavir), 97.6% for zidovudine/lamivudine plus darunavir/ritonavir (or atazanavir/ritonavir or lopinavir/ritonavir), 95.2% for abacavir/lamivudine (or tenofovir/emtricitabine) plus raltegravir (or elvitegravir/cobicistat or dolutegravir), 94.1% for zidovudine/lamivudine plus raltegravir (or elvitegravir/cobicistat or dolutegravir), 94.1% for abacavir/lamivudine (or tenofovir/emtricitabine) plus efavirenz (or nevirapine), 92.9% for zidovudine/lamivudine plus efavirenz (or nevirapine) and 89.3% for abacavir/lamivudine (or tenofovir/emtricitabine) plus rilpivirine. Impact of TDR on future antiretroviral strategies The proportions of fully active combinations were 96.4% for abacavir/lamivudine (or tenofovir/emtricitabine) plus doravirine and 89.3% for rilpivirine/cabotegravir. Discussion We herein report one of the largest recent studies of TDR in children newly diagnosed with HIV-1 in high-income countries. The prevalence of TDR (8.3%) was similar to the prevalences recently reported in Germany3 and in the USA4 but lower than the prevalences observed in Brazil,11,12 Spain5 and sub-Saharan African countries.1,13 Several factors could explain these differences. First, the rate of MTCT is less than 1% in France, where most of the pregnant women diagnosed with HIV are successfully treated with antiretrovirals.14 Thus, most of the new cases of paediatric HIV infection (78.6% in our study) are diagnosed in children who are unexposed to antiretroviral prophylaxis, i.e. patients whose mothers were not tested for HIV or who seroconverted during pregnancy.2 Second, because >80% of pregnant women diagnosed with HIV and followed up in France receive a PI-based combination,14 the proportion of children exposed to NNRTI during prevention of mother-to-child transmission is low (7.1% in our study). Third, because French guidelines discourage HIV-positive women from breastfeeding, the proportion of newborns exposed to antiretrovirals through breastfeeding is very low. Consequently, the TDR observed in the 11 vertically infected children unexposed to antiretroviral-based prophylaxis of MTCT is probably due to transmission of resistant strains from their antiretroviral-naive mothers and/or to transmission of viruses with polymorphic mutations. The situation is highly different in LMICs, where resistant strains are frequently transmitted during pregnancy or breastfeeding from women experiencing treatment failure (usually NNRTI-containing regimens), or could be selected for by the selection of RAMs in infants who are infected despite neonatal antiretroviral prophylaxis (most commonly nevirapine).1,13 This could explain the lower paediatric TDR prevalence observed in France (not only NNRTI-related but also NRTI-related TDR) than in LMICs. Continuous monitoring of TDR is required given the potential impact on the recommended first-line therapies. Because of the higher prevalence of first- and second-generation NNRTI-related TDR (due in part to polymorphic mutations) compared with PI-related TDR, our results suggest that the preferential choice of PI- over NNRTI-based combinations to treat recently diagnosed children be implemented, as the risk of early failure will be reduced. We also described INI-related TDR, which has been rarely studied in previous paediatric studies, because several INIs are now available for use in infants and children. The E157Q polymorphic mutation in the integrase gene has been considered to be conferring resistance to raltegravir, elvitegravir and once-daily dolutegravir (and intermediate resistance to twice-daily dolutegravir), according to the 2017 ANRS algorithm. However, recent data suggest that the susceptibility to dolutegravir could be less affected by this substitution than the susceptibility to raltegravir and elvitegravir.15 Thus, in newly diagnosed children with an isolated E157Q mutation or without available results of genotypic resistance testing, these data and our results suggest the preferential choice of dolutegravir rather than raltegravir or elvitegravir. Our results support current guidelines to perform genotypic resistance testing in all HIV paediatric new diagnoses, even if cART is not initiated immediately.9 These results could guide the choice of first-line fully active drug combinations but also the discussion of future therapeutic options, including those containing drugs which are not yet available to treat the youngest children. To sum up, we suggest that, even in the absence of previous exposure to antiretroviral MTCT prophylaxis, the preferential choice of PI- or dolutegravir- over NNRTI-based combinations to treat newly diagnosed children be implemented. Continuous monitoring of TDR should continue, given the potential impact on the recommended first-line therapies. Importantly, monitoring of the prevalence of INI-related RAMs will also be key, given the expanding role of these medications in both pregnant women and children. Funding This study was carried out as part of our routine work. Transparency declarations P. F. has received research grants (to his institution) from the French National Agency for AIDS Research (ANRS) and honoraria and travel grants from ViiV Healthcare, Bristol-Myers Squibb, Janssen-Cilag, Gilead Sciences, Pfizer, Astellas and MSD France for participation in advisory boards, educational programmes and international conferences. V. A.-F. has received research grants (to her institution) from the ANRS and the MSD AVENIR Foundation and travel grants from ViiV Healthcare and Janssen-Cilag for participation in educational programmes and conferences. M.-L. C. has received travel grants from ViiV Healthcare, Bristol-Myers Squibb, Janssen-Cilag, Gilead Sciences and MSD France. F. V. and S. B.: none to declare. References 1 Siberry GK , Amzel A , Ramos A et al. Impact of human immunodeficiency virus drug resistance on treatment of human immunodeficiency virus infection in children in low- and middle-income countries . J Infect Dis 2017 ; 216 : S838 – 42 . Google Scholar CrossRef Search ADS PubMed 2 Frange P , Chaix ML , Veber F et al. Missed opportunities for HIV testing in pregnant women and children living in France . Pediatr Infect Dis J 2014 ; 33 : e60. Google Scholar CrossRef Search ADS PubMed 3 Neubert J , Michalsky N , Laws HJ et al. HIV-1 subtype diversity and prevalence of primary drug resistance in a single-center pediatric cohort in Germany . Intervirology 2016 ; 59 : 301. Google Scholar CrossRef Search ADS PubMed 4 Rogo T , DeLong AK , Chan P et al. Antiretroviral treatment failure, drug resistance, and subtype diversity in the only pediatric HIV clinic in Rhode Island . Clin Infect Dis 2015 ; 60 : 1426 – 35 . Google Scholar PubMed 5 Rojas Sanchez P , Dominguez S , Jimenez De Ory S et al. Trends in drug resistance prevalence, HIV-1 variants and clinical status in HIV-1-infected pediatric population in Madrid: 1993 to 2015 analysis . Pediatr Infect Dis J 2018 ; 37 : e48 – 57 . Google Scholar CrossRef Search ADS PubMed 6 Bennett DE , Camacho RJ , Otelea D et al. Drug resistance mutations for surveillance of transmitted HIV-1 drug resistance: 2009 update . PLoS One 2009 ; 4 : e4724. Google Scholar CrossRef Search ADS PubMed 7 Wensing AM , Calvez V , Günthard HF et al. 2011 update of the drug resistance mutations in HIV-1 . Top Antivir Med 2017 ; 24 : 132 – 41 . Google Scholar PubMed 8 Marcelin AG , Santoro MM , Charpentier C et al. Epidemiological study of doravirine associated resistance mutations in HIV-1-infected treatment-naïve patients from two large databases in France and Italy. In: Abstracts of the Fifteenth European Meeting on HIV & Hepatitis. Abstract #08. Rome, Italy, 2017 . 9 Groupe d'experts sous la direction du Professeur Morlat . Prise en charge médicale des personnes infectées par le VIH. Actualisation 2018 . https://cns.sante.fr/category/dossiers/dossier-experts/. 10 Chaix ML , Descamps D , Wirden M et al. Stable frequency of HIV-1 transmitted drug resistance in patients at the time of primary infection over 1996–2006 in France . AIDS 2009 ; 23 : 717 – 24 . Google Scholar PubMed 11 Andrade SD , Sabidó M , Monteiro WM et al. Drug resistance in antiretroviral-naive children newly diagnosed with HIV-1 in Manaus, Amazonas . J Antimicrob Chemother 2017 ; 72 : 1774 – 83 . Google Scholar CrossRef Search ADS PubMed 12 Vaz SN , Giovanetti M , Rego FF et al. Molecular characterization of the human immunodeficiency virus type 1 in women and their vertically infected children . AIDS Res Hum Retroviruses 2015 ; 31 : 1046 – 51 . Google Scholar CrossRef Search ADS PubMed 13 Jordan MR , Penazzato M , Cournil A et al. Human immunodeficiency virus (HIV) drug resistance in African infants and young children newly diagnosed with HIV: a multicountry analysis . Clin Infect Dis 2017 ; 65 : 2018 – 25 . Google Scholar CrossRef Search ADS PubMed 14 Mandelbrot L , Tubiana RL , Chenadec J et al. No perinatal HIV-1 transmission from women with effective antiretroviral therapy starting before conception . Clin Infect Dis 2015 ; 61 : 1717 – 25 . 15 Charpentier C , Descamps D. Resistance to HIV integrase inhibitors: about R263K and E157Q mutations . Viruses 2018 ; 10 : 41. Google Scholar CrossRef Search ADS © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Journal of Antimicrobial ChemotherapyOxford University Press

Published: May 29, 2018

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