Nicolene Le Roux, Department of Paediatrics & Neonatology, New Somerset Hospital, Cape Town
James Nuttall, Department of Paediatrics & Child Health, University of Cape Town & Red Cross War Memorial Children’s Hospital, Cape Town
A 24-year-old woman presented to a Cape Town hospital-based antenatal clinic in May 2021 during her 2nd pregnancy at 24 weeks gestational age (GA). Her prior obstetric history reflected that she had booked her pregnancy at a local primary healthcare facility in January 2021, and there was 1 prior pregnancy complicated by a 2nd trimester miscarriage in November 2018.
She was known to be HIV-infected since early childhood and presumed to have vertically-acquired HIV infection from her own mother who allegedly died during her infancy of HIV-related illness. She was started on an unknown antiretroviral therapy (ART) regimen in 1998 at a hospital in Bulawayo, Zimbabwe as a child and continued to intermittently access ART for the next 20 years. Self-reported adherence to ART during childhood and adolescence was sub-optimal with multiple periods of treatment interruption due to frequent change of caregivers.
Her last known ART regimen consisted of abacavir (ABC) + lamivudine (3TC) + ritonavir-boosted atazanavir (ATV/r). The patient relocated to South Africa during 2018 where she presented to a local primary healthcare facility and was continued on this ART regimen. Unfortunately no medication history or laboratory records prior to 2018 were available.
She previously reported significant
adherence difficulties indicating that she was taking her medication less than
60% of the time that she related to her not having disclosed her HIV status to
her life-partner. Since June 2021, she self-reported 100% adherence to ART despite
still not having disclosed her HIV status to her life-partner. Her HIV-1 RNA
copies/mL results and other relevant results are shown in Table 1.
ABC, abacavir; 3TC, lamivudine; ATV/r, atazanavir/ritonavir
The persistently unsuppressed HIV viral load in this patient may have been due to poor adherence to her ART regimen, resistance to one or more of the ARV drugs in her treatment regimen, or, most likely, a combination of both factors. Undiagnosed opportunistic infections may also contribute to an unsuppressed HIV viral load but there was no evidence of this in this patient.
She had genotypic HIV-1 drug resistance testing performed on
16/7/2021 during her 3rd trimester of pregnancy which revealed extensive
drug resistance mutations in both the reverse transcriptase and protease genes.
The results are summarised in Table 2.
Following availability of the HIV resistance test results at 37 weeks gestation of pregnancy, the patient was immediately changed to an ART regimen consisting of ritonavir-boosted darunavir (DRV/r) + tenofovir/lamivudine/dolutegravir (TLD) according to the Western Cape third line ART committee algorithm.
In light of the extensive ARV drug resistance in the mother, there was some uncertainty as to what would be the most appropriate infant ARV prophylaxis regimen to administer to the infant after delivery. In consultation, the decision was taken to provide a modified high-risk transmission regimen comprising zidovudine (AZT), 3TC and raltegravir (RAL). We successfully applied to the South African Health Products Regulatory Authority (SAHPRA) and obtained Section 21 approval for the use of RAL granules for oral suspension (not registered in SA) and attempted to obtain donation of this formulation from the manufacturer on a compassionate access basis, however the timelines between HIV drug resistance report and delivery did not allow for successful importation of the formulation in time. Hence, we elected to use the 25 mg chewable RAL tablets dispersed in water and calculate dosing by extrapolating dosing guidelines for RAL granules for oral suspension recommended for infants <4 weeks of age.
Elective caesarean section delivery in the setting of high HIV-1 RNA was offered to the patient and declined as she was not prepared to explain the reasoning to her undisclosed partner.
The mother presented at 39 weeks + 5 days gestation in active labour and reported 100% adherence to her new ART regimen in the interim. The patient consented to emergency caesarean section following poor progress in active labour.
A well female infant was delivered and had HIV-1 polymerase chain reaction (PCR) testing performed shortly after birth. The mother was counselled on feeding options and risks and elected to formula feed the infant to avoid the potential risk of postpartum transmission of multi-drug resistant HIV if she were to breastfeed. The formula milk feeds were provided via the dietetics nutritional therapeutic programme. The infant was initiated on the day of delivery on AZT, 3TC and RAL as prophylaxis against intrapartum HIV transmission.
A day after the birth, the results of the HIV-1 RNA test done on the mother (63 copies/mL, 1.8 log) and the HIV-1 PCR test done on the infant at the time of the birth (negative) became available.
Dosing of RAL was incrementally increased according to weight and age for the first 4 weeks of life. The infant was exclusively formula-fed from birth and remained well during this period with no detectable side-effects of medication or stigmata of HIV infection occurring.
The infant ARV prophylaxis regimen was stopped at 4 weeks age, followed by a 6 week treatment-free window. The 10 week HIV-PCR was negative and the infant remains well. Ongoing monitoring will occur with further HIV testing according to the SA prevention of mother to child transmission (PMTCT) guidelines.
A 24-year-old pregnant, vertically-infected HIV-positive woman with triple-class ARV drug resistance detected at 37 weeks’ gestation who was switched to a DTG- and DRV/r-based ART regimen 2 ½ weeks prior to delivery. An HIV-1 RNA level done at the time of delivery was 62 copies/mL. She gave birth to a well infant who was formula fed and was empirically initiated on a modified high-risk ARV prophylaxis regimen comprising AZT/3TC/RAL for 4 weeks and in whom the HIV-1 PCR tests done immediately after birth and at 10 weeks of age were both negative. Further HIV-1 PCR testing of the infant is planned at 6 months and 18 months of age or if the child develops any symptoms or signs of HIV infection.
This case illustrates the complexities of PMTCT in the context of a virally-unsuppressed, treatment-experienced pregnant patient. It highlights the role of HIV drug resistance testing and rapid switching to an effective ART regimen even during late pregnancy aiming to achieve viral suppression in the shortest time possible and before the onset of labour and delivery, the period of highest transmission risk.
In the context of exclusive formula feeding, infant ARV prophylaxis is a form of post-exposure prophylaxis and is directed at preventing HIV infection in the infant as a result of exposure to maternal blood and genital tract fluids during labour and delivery. Current PMTCT guidelines categorise the risk of intrapartum transmission (low-risk or high-risk) based on the maternal HIV-1 RNA result at the time of delivery with a cut-off of 1000 copies/mL in the SA guidelines and <50 copies/mL in some other guidelines. Evidence on the risk of intrapartum HIV transmission with maternal HIV-1 RNA at the time of delivery between 50-1000 copies/mL is limited. In this case, once the result of the maternal HIV-1 RNA test done at delivery became available, the infant could potentially have be re-categorised as being at low-risk of intrapartum HIV transmission and the infant ARV prophylaxis regimen modified.
However, in this case, HIV genotype testing on the mother during the third trimester indicated high-level resistance to both nevirapine (NVP) and AZT, the current standard high-risk transmission infant ARV prophylaxis regimen recommended in the SA PMTCT guidelines. This presented a dilemma as to what infant ARV prophylaxis regimen to provide.
ARV medications currently approved by the US Food and Drug Administration for use in term newborns from the time of birth are AZT, 3TC, NVP, RAL, and AZT, 3TC, NVP for premature newborns (<37 weeks GA) although dosing recommendations do not extend below 34 weeks GA for NVP and 32 weeks GA for 3TC. DTG is not currently approved for use <4 weeks of age and LPV/r is not recommended prior to a postmenstrual age of 42 weeks and a postnatal age of at least 14 days due to significant toxicity concerns. For RAL, weight-based dosing recommendations for both granules for oral suspension and chewable tablets (which can be dispersed in water) are based on a dose of approximately 6 mg/kg/dose although chewable tablets are generally only recommended from >4 weeks of age and >3 kg.
In this case, the decision to exclusively formula feed could potentially have been re-considered in discussion with the mother once the maternal HIV-1 RNA result of 63 copies/mL at the time of delivery became available the day after birth. However, the previous history of poor maternal adherence to ART and non-disclosure of her HIV status to her intimate partner would mitigate against supporting a change to breastfeeding due to the potential risk of HIV transmission via breastmilk.In conclusion, despite the complexity and potential risk of transmission of multi-drug resistant HIV to this infant, the outcome so far in this case has been good. This report highlights the emerging urgent need for access to appropriate formulations of ARV drugs for infant ARV prophylaxis as part of PMTCT in the context of drug-resistant HIV infection in pregnant women
1. South African National Department of Health. National Consolidated Guidelines for the Management of HIV in adults, adolescents, children and infants and prevention of mother-to-child transmission [homepage on the Internet]. 2020 [cited 2021 Nov 16]. Available at: https://www.knowledgehub.org.za/system/files/elibdownloads/2020-07/National%20Consolidated%20Guidelines%2030062020%20signed%20PRINT%20v7.pdf. Accessed 13 December 2021
2. Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Available at http://aidsinfo.nih.gov/content-files/lvguidelines/pediatricguidelines.pdf. Accessed 13 December 2021, pages L-161 – L-172.
3. Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach. Geneva: World Health Organization; 2021. Available at: https://www.who.int/publications/i/item/9789240031593. Accessed 13 December 2021
4. Archary M, Zanoni B, Lallemant M, Suwannaprom P, Clarke D, Penazzato M. Acceptability and feasibility of using raltegravir oral granules for suspension for the treatment of neonates in a low resource setting”. Pediatr Infect Dis J. 2020;39(1):57-60. doi: 10.1097/INF.0000000000002539
5. Teppler H et al. Crushing of raltegravir (RAL) chewable tablets for administration in infants and young children. 9th International Workshop on HIV Pediatrics 2017. 21–22 July 2017. Paris. Poster abstract 37. Available at: http://regist2.virology-education.com/Abstractbook/2017/2017_7.pdf. Accessed 13 December 2021