SUBMITTED 31 JAN 22 1 REVISION REQ. 6 MAR 22; REVISION RECD. 24 APR 22 2 ACCEPTED 17 MAY 22 3 ONLINE-FIRST: MAY 2022 4 DOI: https://doi.org/10.18295/squmj.5.2022.039 5 6 Post-Natal Anti-Retroviral Prophylaxis for Neonates Born to 7 Mothers Living with Resistant Human Immunodeficiency Virus 8 (HIV) Infection 9 *Laila S. Al Yazidi,1,2 Philip N. Britton,1,3,4 Nicole Gilroy,5 Tony Lai,1 10 Alison Kesson1,3,4 11 12 1Infectious Diseases and Microbiology, The Children’s Hospital at Westmead, 13 Sydney, Australia; 2Sultan Qaboos University, College of Medicine, Muscat, Oman; 14 3Discipline of Child and Adolescent Health, The University of Sydney, Sydney, 15 Australia; 4Marie Bashir Institute for Infectious Diseases and Biosecurity, The 16 University of Sydney, Sydney, Australia; 5Centre for Infectious Diseases and 17 Microbiology, Westmead Hospital NSW, Sydney, Australia. 18 Corresponding Author’s email: lailay@squ.edu.om 19 20 Abstract 21 Mother-to-child transmission (MTCT) accounts for the majority of new human 22 immunodeficiency virus (HIV) infections among children worldwide. Post-natal 23 prophylaxis along with other preventive measures have been very successful reducing 24 transmission to babies born to mothers living with HIV infection to < 2%. Single-drug 25 prophylaxis with Zidovudine (ZDV) is the mainstay regimen for infants in low-risk 26 transmission settings. The optimal regimen for newborns of women with anti-27 retroviral (ARV)-resistant HIV is unknown. We present a baby born to a young 28 mother living with highly resistant perinatally-acquired HIV and we discuss the 29 challenges with giving postnatal ARV prophylaxis to her baby given the lack of 30 dosing and safety data for many antiretroviral agents for neonates. The baby received 31 a combination of lamivudine and raltegravir for total of 6 weeks and he was not breast 32 mailto:lailay@squ.edu.om fed. He had negative HIV proviral DNA PCR at 6 weeks and 3 months and a negative 33 HIV serology at 18 months of age. 34 Keywords: HIV, postnatal prophylaxis, neonate, antiretroviral, resistant. 35 36 Introduction 37 Mother-to-child transmission (MTCT) accounts for the majority of new HIV 38 infections among children.1 Successful interventions to prevent MTCT include using 39 a combination of antiretroviral therapy for women before and during pregnancy to 40 ensure adequate viral suppression. In addition, optimal infant postnatal antiviral 41 prophylaxis and avoidance of breast feeding play a major role in MTCT prevention.2 42 These interventions have significantly reduced the rates of MTCT of HIV to < 2% in 43 non-breast feeding infants and to < 5% in breast-feeding infants.1,3 As a consequence, 44 the number of HIV infection in infants have dramatically declined by 40% between 45 2003 and 20144 and it has been estimated that HIV infection was prevented in 46 approximately 22,000 cases in the United States since 1994.3 47 48 HIV drug resistance has been a major challenge for controlling HIV and reducing its 49 associated morbidity and mortality. The WHO HIV drug resistance report 2021 50 showed that > 10 % of adults and around 50% of infants, newly diagnosed with HIV, 51 have a virus resistant to the non-nucleoside reverse-transcriptase inhibitors (NNRTIs). 52 In addition, they found that levels of resistance to NNRTIs ranged between 50-97% in 53 adults failing NNRTI-based first line ART.5 In this case report, we discuss the 54 challenges with giving postnatal ARV prophylaxis to neonates born to mothers with 55 resistant virus given the lack of dosing and safety data for neonates for many 56 antiretroviral agents. 57 58 Case Report 59 A term baby was born at 38 weeks of gestation to a perinatally-HIV infected 24-year-60 old mother with a highly resistant HIV strain. The mother had developed resistance 61 due to adherence issues during her treatment over many years. Her virus showed 62 intermediate to high-level resistance to all commonly used nucleoside reverse 63 transcriptase inhibiters (NRTI) except lamivudine which had low-level resistance, 64 high level resistance to nevirapine, and intermediate resistance to other non- 65 nucleoside reverse transcriptase inhibitors (NNRTI). The only protease inhibitor (PI) 66 that tested susceptible was darunavir. All integrase inhibitors tested were susceptible. 67 A summary of her antiretroviral resistance profile is included in table 1. When she 68 was planning to get pregnant, she was treated with emtricitabine/tenofovir (Truvada), 69 etravirine dolutegravir and darunavir / ritonavir with an undetectable viral load and 70 CD4 count between 200-300/uL through the pregnancy. The baby was born by 71 elective caesarean section at term with Apgar score of 9 and 9 at 1 and 5 minutes 72 respectively. We found it challenging to provide advice on postnatal ARV 73 prophylaxis given the mother’s HIV antiviral resistance and the limited dosing and 74 safety data on many ARV agents for neonates. The baby received lamivudine 2 75 mg/kg/dose twice daily and raltegravir (1.5 mg/kg/dose once daily until 1 week of 76 age, 3 mg/kg/dose twice daily from 1-4 weeks of age and then 6 mg/kg/dose twice 77 daily from 4-6 weeks of age) for a combined total of 6 weeks and he was not breast 78 fed. He had a normal full blood count at 6 weeks of age. Unfortunately, there was no 79 baseline HIV PCR done at the first week of life prior to commencing the antiviral 80 prophylaxis. He had a negative HIV proviral DNA PCR at 6 weeks, 3, 6 and 12 81 months of age and negative HIV serology at 18 months of age. Guardian consent was 82 obtained for publication purposes. 83 84 Discussion 85 The strongest individual predictor of risk of MTCT is the maternal plasma viral load 86 and the viral suppression was found to be the most effective way to minimize the risk 87 of perinatal transmission.2,6 All pregnant and breast feeding women living with HIV 88 infection should be given ARV to optimally suppress viral replication.6,7 Prevention 89 of MTCT has been a real challenge in cases with ARV resistance. Resistant virus can 90 be transmitted to the infant during pregnancy and labour and through breast feeding.8 91 ARV-resistance appears to be more common in women who acquired HIV infection 92 perinatally. Despite that, a recent study from Rio de Janeiro, showed a high 93 prevalence rate of ARV resistant HIV in 17.2% in treatment-naïve patients.6,8 So, this 94 strongly supports the need for resistance testing in pregnant women prior to initiating 95 ARV to optimise strategies to avoid MTCT of resistant HIV strains to the baby.8 96 97 Updated US guidelines recommend that all newborns perinatally exposed to HIV 98 should receive postpartum prophylaxis with selection of the appropriate regimen 99 guided by the level of transmission risk.1,6 For ‘low risk’ groups - mothers who 100 received ART during pregnancy with undetectable viral load at time of delivery - 4 101 weeks of zidovudine (ZDV) prophylaxis can be used.1,6 However, the additional 102 benefit of infant prophylaxis may be negligible in such cases.1 There is no uniform 103 definition for a ‘high-risk’ group, but includes ARV naïve pregnant woman and 104 women who received insufficient ARV therapy during pregnancy resulting in a 105 detectable viral load at the time of delivery.1 A systematic review showed that 106 multidrug regimens have significantly reduced risk of HIV transmission in ‘high-risk’ 107 HIV-exposed infants however, 3 drug regimens were not superior to 2 drugs.1,6 If the 108 neonate has high risk of transmission, the updated US guidelines recommend using 109 presumptive HIV therapeutic regimen with either ZDV, lamivudine (3TC) and 110 treatment doses of nevirapine (NVP) or ZDV, 3TC and RAL from birth for total of 6 111 weeks.6 112 113 The optimal post-natal prophylaxis for newborns of women living with ARV-resistant 114 HIV is unknown.6 ARV drug-resistant virus may have decreased capacity of 115 replication and transmission but perinatal transmission of multidrug-resistant virus has 116 been reported.2,6,8 Two studies showed that ARV-resistance does not increase the risk 117 of HIV MTCT compared with sensitive HIV strains.2,8 Guidelines recommend that in 118 such cases consultation with a paediatric HIV specialist before delivery should be 119 done early.6 There is no evidence that customized prophylaxis, based on maternal 120 drug resistance patterns, are more effective than standard neonatal prophylaxis.6 We 121 advocated for tailoring the postnatal prophylaxis to maternal resistance pattern 122 especially if the baby is at ‘high risk’. We customized a regimen for our patient 123 depending on his maternal viral resistance profile. We gave him raltegravir and 124 lamivudine and he tolerated them very well and they were effective. His HIV PCR at 125 6 weeks, 3 and 6 months and 18-months serology were negative. 126 127 ZDV resistance does not affect the indications for use as a prophylaxis.5,9 The 128 rationale for using ZDV is that the wild-type virus appeared to be mainly transmitted 129 to infants born to mothers who have mixed virus populations including low-level 130 ZDV resistance.9 ZDV crosses the placenta readily and it is the best for central 131 nervous system cover compared with other drugs and ZDV is beneficial at eliminating 132 a potential reservoir of HIV in the neonate.6,10 133 134 There is limited data on pharmacodynamics/pharmacokinetic, safety, dosing regimen, 135 and toxicity of ARV in neonates.11 There is no significant difference in adverse 136 reactions between term neonates receiving combination therapy or ZDV alone.12 137 Transient hematologic toxicity is the most common side effect.12 Paediatric 138 formulations for some protease inhibitors like lopinavir/ritonavir (LPV/r) are 139 available however their use in neonates in the first week of life is not preferred due to 140 safety concerns. LPV/r induced-cardiotoxicity in neonates has been reported 141 previously.6,12 Based on post-marketing reports of cardiotoxicity of protease 142 inhibitors, the US Food and Drug Administration (FDA) recommends that LPV/r oral 143 solution not be used in term neonates < 14 days of age.6 Maraviroc (MVC) was recently 144 approved for use in infants ≥2 kg which may provide an additional option for treatment and 145 prophylaxis of newborns born to mothers with multidrug-resistant HIV-1infection. However, 146 the lack of data and risk of drug interactions of MVC may limit its role for routine use in 147 neonates.6 148 149 We decided to be guided by the maternal viral resistance profile for prophylaxis. We 150 used lamivudine and raltegravir for our patient. There is some data on raltegravir 151 dosing and safety in neonates derived from the IMPAACT P1110 study. In this trial 152 there were no adverse effects detected in the 26 term neonates included.13 Our patient 153 did not develop any skin rash or GI symptoms after receiving raltigravir. We note that 154 in December 2017 the FDA approved expanded dosing in neonates for raltegravir.14 155 156 Conclusion 157 In conclusion, we believe that the postnatal prophylaxis regimen for newborns born to 158 mothers with known or suspected drug resistance should be determined with 159 knowledge of the level of transmission risk and maternal HIV resistance profile 160 notwithstanding the limited therapeutic options in this vulnerable group. Such infants 161 at risk of vertical HIV acquisition should also have close monitoring, optimal follow-162 up and prompt initiation of ARV therapy where infection has occurred. Studies 163 assessing the rates of HIV resistance among neonates are highly required. In addition, 164 more studies are urgently required to assess the efficacy and the safety of more anti-165 retroviral options that can be used for post-natal prophylaxis in babies born to mother 166 with HIV resistant virus. 167 168 Author’s Contribution 169 PB, NG and AK conceptualized the idea. AK provided the patient’s data. LSAY 170 drafted the manuscript and TL drafted the medication dosing. PB, NG, TL and AK 171 revised the manuscript. All authors approved the final version of the manuscript. 172 173 References 174 1. Beste S, Essajee S, Siberry G, Hannaford A, Dara J, Sugandhi N, et al. 175 Optimal antiretroviral prophylaxis in infants at high risk of acquiring HIV. Pediatr 176 Infect Dis J. 2018;37(2):169-75. DOI: 10.1097/INF.0000000000001700 177 2. Teixeria M, Nafea S, Yeganeh N, Santos E, Gouvea M, Joao E, et al. High 178 rates of baseline antiretroviral resistance among HIV-infected pregnant women in an 179 HIV referral centre in Rio de Janeiro, Brazil. 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Clarke DF, Acosta EP, Chain A, Cababasay M, Wang J, Teppler H, et al. 209 IMPAACT P1110: Raltegravir pharmacokinetics and safety in hiv-1 exposed 210 neonates: dose-finding study. Poster presented at: Conference on Retroviruses and 211 Opportunistic infections. 2017 Feb 13-16; Washington. 2020. 1;84(1):70-7.doi: 212 10.1097/QAI.0000000000002294. 213 14. FDA Approves Expanded Dosing in Neonates for Raltegravir. Frontier science 214 foundation. https://www.frontierscience.org/news/2017/12/11/fda-approves-215 expanded-dosing-in-neonates-for-raltegravir.html Last accessed July 2018. 216 https://www.frontierscience.org/news/2017/12/11/fda-approves-expanded-dosing-in-neonates-for-raltegravir.html https://www.frontierscience.org/news/2017/12/11/fda-approves-expanded-dosing-in-neonates-for-raltegravir.html Table 1: Mother’s antiretroviral resistance profile 217 Drug Class Drug Primary mutations Secondary mutations Profile Nucleoside RT Inhibitors Zidovudine (ZDV) D67G (2005) K219KN K219N (2012) L210LW M41L T215C D67G (2004) K219N (2005) L210W (2012) V118I (2012) High-level resistance Lamivudine (3TC) M184V (2008) M41L (2012) L210W (2012) M41L L210LW V118I (2012) Potential low-level resistance Stavudine (D4T) D67G (2005) K219KN K219N (2012) L21W L74V (2004) M4IL T210W (2012) T215C D67G (2004) K219N (2005) L210W (2008) M41L (2008) T215Y (2004) V118I (2012) High-level resistance Emtricitabine (FTC) M184V (2008) M41L (2012) L210W (2012) L210LW M4IL V118I (2012) Potential low-level resistance Didanosine (DDI) K219V (2008) K219KN (2012) L74LV L74V (2012) L210LW L210W (2012) M4IL T215C D67G (2005) L210W (2004) K219KN M41L (2004) M184V (2008) T215Y (2004) V118I (2012) High-level resistance Abacavir (ABC) K219N (2008) K219KN (2012) L210LW L210W (2012) L74LV L74V (2012) M4IL T215C D67G (2005) K219KN L210W (2004) M41L (2004) M184V (2008) T215Y (2004) V118I (2012) High-level resistance Tenofovir (TDF) K219KN (2012) L210LW L210W (2012) M4IL T215C (2013) D67G (2005) K219KN L210W (2004) M41L (2004) T215C V118I (2012) High-level resistance Non- nucleoside RT Inhibitors Nevirapine (NVP) H2211HY V108IV Y181C V108I (2012) V108IV (2013) H221HY (2013) High-level resistance Efavirenz (EFV) H221HY V108IV Y181C V108I (2012) V108IV (2013) H221HY (2013) Intermediate resistance Rilpivirine (RPV) H221HY Y181C V108I (2012) H221HY (2013) Intermediate resistance Etravirine (ETR) H221HY Y181C V108I (2012) H221HY (2013) Intermediate resistance Protease Inhibitors Indinavir (IDV) I47V (2008) I47IV (2013) I54V I54LV (2012) L10F L90M M46I N88D (2005) N88DG (2013) V32I (2012) V32IV (2013) D30DN (2012) D30N (2013) A71V (2008) A71AV (2013) L10F (2013) L33I (2013) M36I (2005) N88G (2008) N88DG (2012) Q58E (2013) High-level resistance Saquinavir (SQV) I54V 154LV (2012) L90M M46I (2013) N88D (2005) N88DG (2013) D30DN (2012) D30N (2013) V32IV (2013) I47IV (2013) A71V (2008) A71AV (2013) L10F (2013) L33I (2013) M36I (2005) M46I N88G (2008) N88DG (2012) L10F (2012) Q58E (2013) High-level resistance Tipranavir (TPV) D30N (2013) D30DN (2012) I47V (2013) I47IV (2013) I54V I54LV (2012) L90M (2013) M46I (2013) N88DG (2013) Q58E V32I (2013) V32IV (2013) L90M (2012) A71V (2013) A71AV (2013) L10F (2013) L33I (2013) M36I (2005) M46I N88G (2008) N88DG (2012) Q58E (2013) Intermediate resistance Atanazavir (ATV) I47V (2008) I47IV (2013) I54V I54LV (2012) L90M M46I N88D (2005) N88DG (2013) V32I (2008) V32IV (2013) D30DN (2012) D30N (2013) A71V (2013) A71AV (2013) L10F (2013) L33I (2013) M36I (2005) N88D N88DG (2012) Q58E High-level resistance Darunavir (DRV) D30N (2013) D30DN (2012) I47IV (2013) I54V (2013) I54LV (2012) L90M (2013) M46I (2013) N88DG (2013) V32I (2013) V32IV (2013) A71V (2013) A71AV (2013) L10F L33I (2013) M36I (2005) N88G (2008) N88DG (2012) Q58E (2013) Susceptible Lopinavir (LPV) I47V (2008) I47IV (2013) I54V I54LV (2012) L90M M46I V32I (2008) V32IV (2013) D30DN (2012) D30N (2013) N88DG (2013) A71V (2008) A71AV (2013) L10F L33I (2013) M36I (2005) N88G (2008) N88DG (2012) Q58E (2013) Intermediate resistance Nelfinavir (NFV) D30N D30DN (2012) I47V (2008) I47IV (2013) I54V I54LV (2012) L10F L90M M46I N88D N88DG (2013) V32I (2008) V32IV (2013) A71V (2008) A71AV (2013) L10F (2013) L33I (2013) M36I (2005) N88G (2008) N88DG (2012) Q58E High-level resistance Fosamprenavir (FPV) I54V I54LV (2012) I47V (2008) I47IV (2013) L10F L90M M46I V32I (2008) V32IV (2013) D30DN (2012) D30N (2013) N88DG (2013) A71V (2008) A71AV (2013) L10F (2013) L33I (2013) M36I (2005) N88G (2008) N88DG (2012) Q58E (2013) Intermediate resistance Integrase Inhibitor Dolutegravir (DTG) Susceptible Elvitegravir (EVG) Susceptible Raltegravir (RAL) Susceptible 218 Table 2: Antiretroviral drug dosing for neonates 219 Drug Doses Note 1 Zidovudine (ZDV)  ≥ 35 Weeks’ Gestation at Birth: - 0 - 4 weeks of age: 4mg/kg/dose PO twice daily - Age > 4 weeks: 12 mg/kg/ dose PO twice daily (increase dose in cases of confirmed HIV infection only)  30 - < 35 Weeks’ Gestation at Birth - Age 0 – 2 weeks: 2mg/kg/dose PO twice daily - Age 2 – 6 weeks: 3mg/kg/dose PO twice daily - Age > 6- 8 weeks: 12 mg/kg/dose PO twice daily (increase dose in cases of confirmed HIV infection only)  < 30 weeks’ gestation at birth - Age 0 – 4 weeks: 2mg/kg/dose PO twice daily - Age 4 – 8 weeks: 3mg/kg/dose PO twice daily - Age > 8 – 10 weeks: 12 mg/kg per dose PO twice daily (increase dose in cases of confirmed HIV infection only) If the neonates does not tolerate oral agents, the IV dose should be 75% of the oral dose while maintaining the same dosing interval. 2 Abacavir (ABC)  ≥ 37 Weeks’ Gestation at Birth - Age 0 – 1 month: 2 mg/kg/dose PO twice daily - Age 1 - < 3 months: 4 mg/kg/ dose PO twice daily - ABC has not been approved yet by the FDA for use in neonates <1 month of age. -The current dosing recommendations have been modeled using PK simulation 3 Lamivudine (3TC)  ≥32 Weeks’ Gestation at Birth - Age 0 – 4 weeks: 2 mg/kg/dose PO twice daily - Age > 4 weeks: 4 mg/kg/dose PO twice daily - 4 Nevirapine (NVP)  ≥37 Weeks’ Gestation at Birth - Age 0 – 4 weeks: 6 mg/kg/dose PO twice daily - Age > 4 weeks: 200 mg/m2 BSA/ dose PO twice daily (increase dose in cases of confirmed HIV infection only)  ≥34 to <37 Weeks’ Gestation at Birth - Age 0 – 1 week: 4 mg/kg/dose PO twice daily - Age 1 – 4 weeks: 6 mg/kg/dose PO twice daily - Age > 4 weeks: 200 mg/m2 BSA/ dose PO twice daily (increase dose in cases of confirmed HIV infection only) -  ≥32 to <34 Weeks’ Gestation at Birth - Age 0 – 2 weeks: 2 mg/kg/dose PO twice daily - Age 2 – 4 weeks: 4 mg/kg/dose PO twice daily - Age 4 – 6 weeks: 6 mg/kg/dose PO twice daily. - Age > 4 weeks: 200 mg/m2 BSA/dose PO twice daily (increase dose in cases of confirmed HIV infection only) 5 Raltegravir (RAL)  ≥37 Weeks’ Gestation at Birth and Weighing ≥2 kg - Age 0 – 1 week: 1.5 mg/kg/dose PO daily - Age 1 – 4 weeks: 3 mg/kg/dose PO twice daily - Age 4 – 6 weeks: 6 mg/kg/dose PO twice daily No dosing information is available for preterm infants or infants weighing <2 kg at birth. 6 Maraviroc (MVC)  Infants ≥2 kg : - Age 0 – 6 weeks: 8 mg/kg/ dose PO twice daily -Approved recently for infants ≥2 kg -Presence of limited data about MVC use in infants and the risk of drug interactions will limit its routine use in neonates 220