Neonatal HIV prophylaxis accelerates the clinical progression of MPV-17 mitochondrial neurohepatopathy

Neonatal HIV prophylaxis accelerates the clinical progression of MPV-17 mitochondrial neurohepatopathy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Neonatal HIV prophylaxis accelerates the clinical progression of MPV-17 mitochondrial neurohepatopathy Penelope Rose, Helena Rabie, Ronalda de Lacy, Gillian Riordan, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8855597/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 15 You are reading this latest preprint version Abstract Background MPV17-related mitochondrial DNA depletion syndrome is a rare, lethal, autosomal recessive primary mitochondrial disorder characterised by infantile onset liver disease and neurological features, including hypotonia, developmental delay, failure to thrive and neuropathy. Methods The aim of this study was to describe the presentation and clinical course of infants diagnosed with MPV17 neurohepatopathy, comparing those who were HIV-exposed on antiretroviral therapy, including zidovudine and nevirapine for vertical transmission prevention (VTP), to infants who were not HIV exposed, using data from a multicentre MPV17 natural history study in South Africa. Results Between 2013 and 2024, 25 infants were diagnosed with MPV17 neurohepatopathy, 8 (32%) of whom were HIV-exposed and received ART at birth (7 received zidovudine), none where HIV-infected. Median birth weight was lower at 2.45kg (IQR 2.28–2.71) in infants who were HIV-exposed compared to 2.86kg (IQR 2.54–3.13) in HIV-unexposed infants (p = 0.02). Symptom onset occurred much earlier at a median of 3 days of age (IQR 0–10 days) in HIV exposed infants compared to 60 days (IQR 14–90) in HIV unexposed (p = 0.006). Infants exposed to HIV were more likely to develop liver failure (p = 0.02). Conclusions Perinatal therapy with the nucleoside reverse transcriptase inhibitor zidovudine, a known mitochondrial toxin, may accelerate the clinical presentation and exacerbate the clinical course of MPV17 neurohepatopathy. Our findings suggest that less toxic antiretroviral therapy should be considered for VTP therapy in HIV-exposed infants, particularly in our setting where there is a high carrier frequency of a single pathogenic MPV17 variant. mitochondrial disease MPV17 HIV zidovudine antiretroviral toxicity neurohepatopathy Figures Figure 1 Background MPV17-related mitochondrial DNA depletion syndrome 6 is a rare lethal autosomal recessive primary mitochondrial disorder (PMD) characterised by infantile onset of hepatopathy and encephalopathy, the latter presenting with hypotonia, developmental delay, failure to thrive and neuropathy ( 1 – 3 ). It is caused by pathogenic variants in the human MPV17 gene which encodes a mitochondrial inner membrane channel protein with uncertain function, but thought to be key in mitochondrial DNA maintenance. The age of onset of symptoms varies from infancy to later in childhood ( 3 , 4 ). The rare cases described with juvenile, or even adult onset usually present with a Charcot-Marie-Tooth like sensorimotor axonal neuropathy, with little to no liver involvement ( 5 ). Though infantile MPV17 neurohepatopathy is lethal in all cases, it is unclear why some patients survive for months or years, while others, often with the same genetic background and defects, decompensate and demise within days after birth or early infancy. This is particularly evident in the Navajo population in North America, where this disease was first described ( 5 ). Patients carrying the Navajo-specific MPV17 founder variant, c.149G > A p.(Arg50Gln), can be classed into three different phenotypic groupings based on phenotypic presentation and age of onset: (i) Severe fatal Infantile onset form (typically before 6 months of age) with death in infancy, (ii) Childhood onset form (typically with onset between ages 1 and 5 years), characterised by early onset liver failure and death; and (iii) Classic form, characterised by only moderate liver dysfunction and progressive neuropathy ( 3 ). In South Africa a single MPV17 nonsense-associated splice variant was identified in 38 Black South African infants presenting with mitochondrial neurohepatopathy, attributed to a high carrier frequency of the c.106C > T p.(Gln36Ter) pathogenic MPV17 variant of 1 in 68 Black South African individuals (95% CI: 1/122–1/38 persons), and predicted population disease incidence of 1 in 18 496 (95% CI; 1/59536–1/5776) in the Western Cape province of South Africa ( 6 , 7 ). In contrast to Navajo variant, the more severe South African nonsense variant appears to be exclusively fatal in infancy, although onset still varies between only days after birth (neonatal onset) to more than 5 months after birth. It is well known that certain toxins and pharmaceutical compounds may unmask or exacerbate primary mitochondrial dysfunction. Perhaps the most well described example is the hepatotoxic effects of sodium valproate in patients with POLG -related PMD ( 8 , 9 ). Meldau et al hypothesised that commonly used medicines in South African infants, such as nucleoside reverse transcriptase inhibitors (NRTI) ( 10 , 11 ) known to cause excessive metabolic stress, reactive oxygen species (ROS) production and/or mtDNA depletion, may put affected mitochondria under increased pressure and contribute to earlier disease progression ( 6 ). Identification and characterisation of such modifying factors may lead to a better understanding of the precise disease mechanism and point to improved treatment outcomes and better management strategies. Approximately 280,000 infants are born to South African women living with HIV (WLHIV) annually. These infants are exposed to antiretroviral therapy both antenatally and postnatally to prevent vertical transmission (VTP) of HIV ( 12 ). Although now rarely used as a primary regimen in adults, zidovudine, a thymidine analogue and one of the first nucleoside reverse NRTIs, is still used in HIV exposed infants to prevent infection and remains part of guidelines, particularly if mothers have unsuppressed viral loads at delivery. In this setting zidovudine is effective and deemed safe. However zidovudine is known to have mitochondrial toxicity, primarily through interference with the mitochondrial DNA polymerase gamma ( 13 , 14 ). Lamivudine and emtricitabine are cytidine analogues, but are still key medications in all persons with HIV as part of initial and subsequent regimens, and most pregnant women will receive lamivudine or emtricitabine as part of therapy. Though lamivudine and emtricitabine are not routinely used in infants as vertical transmission prevention (VTP) in South Africa, it is recommended as prevention for infants whose mothers were virally unsuppressed at delivery in some settings. Lamivudine and emtricitabine alone are not thought to elicit significant mitochondrial toxicity but may contribute to toxicity in combination with other NRTIs. Similarly, tenofovir, a modern adenosine nucleotide analogue commonly used in pregnancy in combination with lamivudine or emtricitabine, is thought to have little effect on mitochondrial DNA polymerase with no clear evidence of an effect on infant mitochondrial DNA ( 15 ). Evidence suggests that infants who are perinatally exposed to HIV, but uninfected and received zidovudine at birth are at higher risk of decreased blood mtDNA content, which may be associated with altered mitochondrial fuel utilization ( 16 – 18 ). Clinically relevant mitochondrial dysfunction in infants exposed to NRTI were first reported in 1999 in 8 infants of whom 5 had neurological abnormalities ( 19 ). In that study four children received zidovudine alone and four zidovudine and lamivudine. Nevirapine, a non-NRTI, is used in virtually all children exposed to HIV as part of prevention and, although considered safe and effective, can cause significant hepatotoxicity. Although in vitro studies suggest that nevirapine can induce changes in mitochondrial proteins, there is no clear signal of mitochondrial DNA depletion and the general consensus is that it is not associated with mitochondrial DNA related disease. ( 20 , 21 ) The guidelines for postnatal prevention of HIV include six weeks of nevirapine for all babies, with extension of the prevention for breastfeeding infants with mothers who are not virally suppressed. Zidovudine is given for six weeks to infants with mothers who are virally unsuppressed at birth, but is commonly initiated at birth whilst the results of maternal viral loads are awaited. We hypothesize that NRTI exposure may exacerbate the mtDNA depletion phenotype and liver damage in MPV17 deficient infants who have been exposed to HIV, leading to earlier presentation and accelerated disease progression. Materials and methods Study aim, design and setting This study aimed to describe the presentation and clinical course of infants diagnosed with MPV17 neurohepatopathy, comparing those who were HIV-exposed and uninfected (HEU) and on antiretroviral therapy including zidovudine and nevirapine for VTP to infants with MPV17 disease who were HIV unexposed and uninfected (HUU), using data from an ongoing multicentre MPV17 natural history study in South Africa. Data was collected on infants diagnosed with MPV17 neurohepatopathy during routine clinical care at Tygerberg Hospital and Red Cross War Memorial Children’s Hospital (RCWMCH), two tertiary academic hospitals in Cape Town, South Africa, both prospectively from September 2022 to December 2024 and retrospectively for infants diagnosed and followed between November 2013 and August 2022. Only patients with a genetic diagnosis of homozygosity for the MPV17 : c.106C > T p.(Gln36Ter) pathogenic variant were included in this study, and no exclusion criteria were applied. Clinical variables Clinical, demographic, and family history data were captured into a RedCap database as part of an ongoing multicentre MPV17 natural history study. Data captured and analysed included antenatal exposures to HIV or other maternal illnesses or infections; antenatal exposures to medications, including antiretrovirals, other medications and substances; a detailed family history, including a previous history of infants diagnosed with MPV17 deficiency or presenting with liver disease, neuropathies, myopathies, unexplained deaths or illness; age of first symptom onset; postnatal exposure to medications, including antiretrovirals used for treatment or prevention of mother to child transmission of HIV; results of laboratory investigations, including lactate and liver enzymes; and details of clinical course and death. Ethical approval was obtained from the University of Cape Town Health Research Ethics Committee (071/2022) and Stellenbosch University Health Research Ethics Committee (N22/06/059_RECIP_UCT_071/2022). Statistical methods Results were expressed as medians and interquartile ranges (IQR) for continuous variables, and frequencies and percentages for categorical variables. Comparisons of categorical variables used either the Chi-square or Fisher’s exact test as appropriate. All analyses were two-tailed, p < 0.05 was considered statistically significant and used STATA version 12 (StataCorp LP, College Station, Texas, USA). Results Antenatal characteristics and exposures Between 2013 and 2024, 25 infants were diagnosed with MPV17 neurohepatopathy at Tygerberg Hospital and RCWMCH in Cape Town, South Africa. Of these, 5 were prospectively enrolled into the SA MPV17 natural history study, while data from the remaining 20 cases were captured retrospectively from hospital folders (Table 1). Antenatal exposure to HIV was reported in 8 infants (32%) while 17 (68%) were unexposed. All the HEU infants were exposed to antiretrovirals antenatally, but regimens differed. (Table 1) None of the infants’ mothers were diagnosed with tuberculosis, hepatitis B or C, group B Streptococcus or other infections antenatally. One of the HIV-negative mothers developed hypertension during pregnancy. Postnatal exposures and presenting symptoms Seven HEU infants received both zidovudine and nevirapine from birth and one infant received only nevirapine from birth as part of routine VTP postnatally. One infant also received lamivudine in addition to zidovudine and nevirapine as VTP because their mother was virologically unsuppressed at the time of delivery. All HEU infants were confirmed to be HIV-negative by routine HIV polymerase chain reaction (PCR) testing. Although there was no difference in sex, gestational age at delivery, mode of delivery or family history of previously affected siblings, HEU infants had a lower median birth weight (p=0.02). Symptom onset occurred much earlier (p=0.006) at a median of 3 days of age in HEU infants compared to 60 days in HUU (Figure 1). All HEU infants presented during the first month of life, whereas HUU infants presented during the first six months of life. Presenting symptoms included poor feeding, weakness, failure to gain weight, hypoglycaemia and jaundice (Table 1). All infants had a persistently elevated lactate and deranged liver enzymes with variable coagulopathy. HEU infants were more likely to develop liver failure. Table 1. Patient characteristics HIV exposed N=8 HIV unexposed N=17 All N=25 P-value Age at symptom onset in weeks, median (IQR) 0.4 (0.1 – 1.4) 8.5 (2 – 13) 4 (0.4 – 13) 0.006 Sex, female 7 (88%) 9 (53%) 16 0.2 Family history of MPV17 0 1 1 1.0 Family history of sibling death in infancy 1 (13%) 2 (13%) 3 1.0 Gestational age, median (IQR) 38 (38 – 39) 38 (38 – 39) 39 (38 – 40) 0.3 Birthweight in kg, median (IQR) Low birth weight (<2.5kg) 2.45 (2.28 – 2.71) 4 (50%) 2.86 (2.54 – 3.13) 2 (12%) 2.78 (2.45 – 2.95) 6 (24%) 0.02 0.05 Delivery mode Vaginal delivery Caesarean section 3 (38%) 5 (63%) 11 (67%) 5 (31%) 14 (58%) 10 (42%) 0.2 Antenatal antiretroviral therapy Tenofovir Lamivudine/Emtricitabine Dolutegravir Efavirenz Nevirapine 8 (100%) 8 (100%) 2 (25%) 5 (63%) 1 (14%) - Infant antiretroviral therapy Nevirapine Nevirapine with Zidovudine Nevirapine with Zidovudine and Lamivudine 1 (13%) 6 (75%) 1 (13%) - Presenting features Weakness Jaundice Vomiting Hyperlactataemia Hepatomegaly 5 (63%) 4 (50%) 2 (25%) 8 (100%) 3 (38%) 6 (35%) 11 (65%) 1 (6%) 17 (100%) 11 (65%) 11 (44%) 15 (60%) 3 (12%) 25 (100%) 14 (56%) 0.4 0.7 0.2 1.0 0.4 Later features Weakness Jaundice Poor feeding Metabolic acidosis Failure to thrive Acute liver failure Hypoglycaemia Hepatomegaly 6 (75%) 6 (75%) 1 (13%) 3 (38%) 5 (63%) 5 (63%) 6 (75%) 7 (88%) 16 (94%) 13 (76%) 12 (71%) 2 (12%) 13 (76%) 2 (12%) 14 (82%) 16 (94%) 22 (88%) 19 (76%) 13 (52%) 5 (20%) 18 (72%) 7 (28%) 20 (80%) 23 (92%) 0.2 1.0 0.01 0.3 0.6 0.02 1.0 1.0 Age at death in days, median (IQR) (n=15) 59 (36-225) n=6 206 (161-287) n=9 195 (45-247) n=15 0.2 All infants were exposed to antibiotics at least once as part of empiric treatment of suspected sepsis, 5 in the early postnatal period (ampicillin and gentamycin) and the other 20 at the time of each hospital admission (ceftriaxone, cefotaxime or meropenem). There were also two HUU infants who received traditional medicines of unknown composition. Clinical course and death The duration of antiretroviral exposure to both mothers and infants was not well documented in all cases. In all cases in which MPV17 neurohepatopathy was clinically suspected at presentation to the tertiary centre, zidovudine and nevirapine therapy were immediately interrupted. In some cases there was a delay in referral, with a subsequent delay in interruption of antiretroviral therapy. The median age at death was 59 days in HEU infants, compared to 206 days in HUU. The date of death was only available in 15 patients, as the majority of children were referred for palliative care after diagnosis and not actively followed up at the tertiary hospital at which they were diagnosed. Discussion This is the first description of a cohort of infants all with an identical pathogenic variant in the MPV17 gene (homozygous for c.106C > T p.(Gln36Ter)) in a high HIV prevalence setting. In this cohort of infants diagnosed with MPV17 neurohepatopathy, HEU infants with MPV17 all were exposed to antenatal NRTI and all except one had postnatal zidovudine. These infants had a lower birth weight, presented at a much younger age (during the first month of life), were more likely to develop acute liver failure and, though not significant statistically, appeared to die sooner. Although MPV17 neurohepatopathy is a uniformly lethal condition, we found that HEU infants perinatally exposed to antiretroviral therapy, in most cases zidovudine and nevirapine, had an accelerated clinical course. Zidovudine is known to be a mitochondrial toxin and we postulate that zidovudine had an impact on the phenotypic expression of this rare genetic condition. Many NRTIs, particularly older formulations including zidovudine, cause mitochondrial toxicity due to inhibition of the mitochondrial polymerase γ (pol γ) enzyme ( 13 , 14 , 22 ). Clinical manifestations range from minor to life-threatening conditions ( 14 ). It has previously been demonstrated that HEU infants who received zidovudine postnatally have reduced blood mitochondrial DNA content compared to HUU infants, with the lowest levels recorded at six weeks of life ( 23 ). The mitochondrial dysfunction associated with zidovudine was first linked to symptomatic abnormality in 8 French children. These authors found that the incidence was 30 times higher than that of the general population ( 17 , 19 ). In our cohort, HEU infants presented very early during the first month of life, which is much younger than the French cohort. MPV17 neurohepatopathy is a uniformly lethal condition in South Africa and although it is likely that zidovudine therapy accelerated the clinical course, it is unlikely that the ultimate outcome would have been different as all infants ultimately die in early life. However, early presentation and demise allows for less time to counsel and support the family, who in some cases have more than one affected infant. The HEU infants in our cohort were more likely to develop acute liver failure than HUU infants, but also less likely to develop poor feeding most likely due to short survival. Although there was no statistically significant difference in age of death, HEU infants tended to die sooner and it is possible that this is the reason that they were less likely to develop poor feeding than HUU infants, who tended to survive longer. Dolutegravir is now part of standard first-line and second-line antiretroviral therapy regimens in adults and children over one month of age, but until recently it was not recommended for neonates under the age of 28 days, due to a lack of dosing and safety information. A recent pharmacokinetic study has provided evidence to support dosing guidance from birth to four weeks of life ( 24 ). Dolutegravir alone and with abacavir and lamivudine is now included in WHO VTP regimens. This regimen may be safer for infants, including those with underlying mitochondrial disorders. Primary mitochondrial disease is a very large group of disorders, with widely heterogenous genetic and clinical features, which has largely made studies like this one very challenging. A strength of this study is the identical pathogenic genetic cause in all patients. Limitations include that the data was collected retrospectively in the majority of cases, resulting in incompleteness of data including date of death. It is also possible that antenatal antiretroviral exposure and maternal HIV viral load might have had an impact on the clinical presentation and course. This is the first study to highlight the impact of NRTIs such as zidovudine on disease progression and outcomes in patients with MPV17-related neurohepatopathy. These findings may have wider implications for HIV exposed and/or HIV positive patients with primary mitochondrial disorders in general, especially those caused by defects in genes involved in mtDNA maintenance. Although this is a significant number of cases of a rare disease, numbers are small and a larger cohort may have shown greater statistical differences between the groups. A further limitation is that the age of death was not known in all cases. Conclusion Perinatal therapy with the NRTI zidovudine, a known mitochondrial toxin, may accelerate the clinical presentation and exacerbate the clinical course of MPV17 neurohepatopathy. Our findings suggest that where possible less toxic antiretroviral therapy should be introduced for VTP therapy in HEU infants, particularly in settings where there is a high prevalence of a common pathogenic MPV17 variant. These findings may further have significant implications for other primary mitochondrial disorders, especially those affecting mtDNA content and ROS, and further studies should look at the effects of toxins and medication on the clinical expression of these disorders both in infantile disease, as well as in older children and adults. Abbreviations HEU HIV-exposed HUU HIV-unexposed IQR Interquartile range NRTI Nucleoside reverse transcriptase inhibitor PCR Polymerase chain reaction RCWMCH Red Cross War Memorial Children’s Hospital VTP Vertical transmission prevention WLHIV Women living with HIV Declarations Ethics approval and consent to participate Ethical approval was obtained from the University of Cape Town Health Research Ethics Committee (071/2022) and Stellenbosch University Health Research Ethics Committee (N22/06/059_RECIP_UCT_071/2022). Informed consent was obtained from the parent or legal guardian of all children enrolled prospectively in this study. A waiver of consent was obtained from both ethics committees to collect retrospective data on children diagnosed prior to commencement of the prospective study. This study adhered to ethical principles as outlined in the Declaration of Helsinki. Consent for publication Not applicable Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding This research was self-funded. Authors’ contributions PCR, SM and HR designed the research study. PCR, RDL and GR recruited participants to the study and captured data for the study. PCR analysed the data and prepared the original draft manuscript. PCR, HR, RDL, GR, GVDW, MVN, RVT, TM and SM discussed, revised and contributed to the final version of the manuscript. All authors have read and approved the final manuscript. References Wong LJC, Brunetti-Pierri N, Zhang Q, Yazigi N, Bove KE, Dahms BB, et al. Mutations in the MPV17 gene are responsible for rapidly progressive liver failure in infancy. Hepatology. 2007 Oct;46(4):1218–27. Uusimaa J, Evans J, Smith C, Butterworth A, Craig K, Ashley N, et al. Clinical, biochemical, cellular and molecular characterization of mitochondrial DNA depletion syndrome due to novel mutations in the MPV17 gene. European Journal of Human Genetics. 2014 Feb;22(2):184–91. Karadimas CL, Vu TH, Holve SA, Chronopoulou P, Quinzii C, Johnsen SD, et al. Navajo Neurohepatopathy Is Caused by a Mutation in the MPV17 Gene [Internet]. Vol. 79, The American Journal of Human Genetics. 2006. Available from: www.ajhg.org El-Hattab AW, Wang J, Dai H, Almannai M, Staufner C, Alfadhel M, et al. MPV17-related mitochondrial DNA maintenance defect: New cases and review of clinical, biochemical, and molecular aspects. Hum Mutat. 2018 Apr 1;39(4):461–70. Baumann M, Schreiber H, Schlotter-Weigel B, Löscher WN, Stucka R, Karall D, et al. MPV17 mutations in juvenile- and adult-onset axonal sensorimotor polyneuropathy. Clin Genet. 2019 Jan 1;95(1):182–6. Meldau S, De Lacy RJ, Riordan GTM, Goddard EA, Pillay K, Fieggen KJ, et al. Identification of a single MPV17 nonsense-associated altered splice variant in 24 South African infants with mitochondrial neurohepatopathy. Clin Genet. 2018 May 1;93(5):1093–6. Meldau S, Owen EP, Khan K, Riordan GT. Mitochondrial molecular genetic results in a South African cohort: Divergent mitochondrial and nuclear DNA findings. J Clin Pathol. 2022 Jan 1;75(1):34–8. Stewart JD, Horvath R, Baruffini E, Ferrero I, Bulst S, Watkins PB, et al. Polymerase γGene POLG determines the risk of sodium valproate-induced liver toxicity. Hepatology. 2010 Nov;52(5):1791–6. Ratnaike TE, Elkhateeb N, Lochmüller A, Gilmartin C, Schon K, Horváth R, et al. Evidence for sodium valproate toxicity in mitochondrial diseases: A systematic analysis. Vol. 6, BMJ Neurology Open. BMJ Publishing Group; 2024. Walker UA, Bäuerle J, Laguno M, Murillas J, Mauss S, Schmutz G, et al. Depletion of Mitochondrial DNA in Liver under Antiretroviral Therapy with Didanosine, Stavudine, or Zalcitabine. Hepatology. 2004 Feb;39(2):311–7. Smith RL, Tan JME, Jonker MJ, Jongejan A, Buissink T, Veldhuijzen S, et al. Beyond the polymerase-γ theory: Production of ROS as a mode of NRTI-induced mitochondrial toxicity. PLoS One. 2017 Nov 1;12(11). Kufa-Chakezha T, Shangase N, Lombard C, Manda S, Puren A. The 2022 Antenatal HIV Sentinel Survey [Internet]. 2022 [cited 2025 Nov 6]. Available from: https://www.nicd.ac.za/wp-content/uploads/2024/01/Antenatal-survey-2022-report_National_Provincial_12Jul2023_Clean_01.pdf Kohler JJ, Lewis W. A brief overview of mechanisms of mitochondrial toxicity from NRTIs. Environ Mol Mutagen. 2007 Apr 19;48(3–4):166–72. Koczor CA, Lewis W. Nucleoside reverse transcriptase inhibitor toxicity and mitochondrial DNA. Expert Opin Drug Metab Toxicol. 2010 Dec 7;6(12):1493–504. Birkus G, Hitchcock MJM, Cihlar T. Assessment of mitochondrial toxicity in human cells treated with tenofovir: Comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother. 2002;46(3):716–23. Jao J, Powis KM, Kirmse B, Yu C, Epie F, Nshom E, et al. Lower mitochondrial DNA and altered mitochondrial fuel metabolism in HIV-exposed uninfected infants in Cameroon. AIDS. 2017 Nov 28;31(18):2475–81. Barret B, Tardieu M, Rustin P, Lacroix C, Chabrol B, Desguerre I, et al. Persistent mitochondrial dysfunction in HIV-1-exposed but uninfected infants: clinical screening in a large prospective cohort. Van der Watt G, Eley B, Henderson H. Whole blood mitochondrial DNA depletion in South African HIV infected children. J Pediatr Biochem. 2010 Oct;01(03):225–32. Blanche S, Tardieu M, Rustin P, Slama A, Barret B, Firtion G, et al. Persistent mitochondrial dysfunction and perinatal exposure to a viral nucleoside analogues. The Lancet. 1999 Sep 25;354:1084–9. Paemanee A, Sornjai W, Kittisenachai S, Sirinonthanawech N, Roytrakul S, Wongtrakul J, et al. Nevirapine induced mitochondrial dysfunction in HepG2 cells. Sci Rep. 2017 Dec 1;7(1). Negredo E, Miró Ó, Rodríguez-Santiago B, Garrabou G, Estany C, Masabeu A, et al. Improvement of mitochondrial toxicity in patients receiving a nucleoside reverse-transcriptase inhibitor - sparing strategy: Results from the multicenter study with nevirapine and kaletra (MULTTNEKA). Clinical Infectious Diseases. 2009 Sep 15;49(6):892–900. Kakuda TN. Pharmacology of Nucleoside and Nucleotide Reverse Transcriptase Inhibitor-Induced Mitochondrial Toxicity. Vol. 22. Jao J, Powis KM, Kirmse B, Yu C, Epie F, Nshom E, et al. Lower mitochondrial DNA and altered mitochondrial fuel metabolism in HIV-exposed uninfected infants in Cameroon. AIDS. 2017 Nov 28;31(18):2475–81. Bekker A, Salvadori N, Rabie H, du Toit S, Than-in-at K, Groenewald M, et al. Safety and pharmacokinetics of dolutegravir dispersible tablets and oral films in term neonates exposed to HIV in South Africa (PETITE-DTG study): an open-label, randomised, phase 1/2 trial. Lancet HIV [Internet]. 2025 Nov;12(11):e753–62. Available from: https://linkinghub.elsevier.com/retrieve/pii/S2352301825002395 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 09 Mar, 2026 Reviews received at journal 08 Mar, 2026 Reviewers agreed at journal 08 Mar, 2026 Reviews received at journal 07 Mar, 2026 Reviewers agreed at journal 05 Mar, 2026 Reviewers agreed at journal 05 Mar, 2026 Reviewers agreed at journal 05 Mar, 2026 Reviewers agreed at journal 05 Mar, 2026 Reviewers agreed at journal 05 Mar, 2026 Reviewers agreed at journal 03 Mar, 2026 Reviewers invited by journal 03 Mar, 2026 Editor assigned by journal 26 Feb, 2026 Editor invited by journal 19 Feb, 2026 Submission checks completed at journal 19 Feb, 2026 First submitted to journal 19 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8855597","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":601492717,"identity":"f2e8fb69-7d3d-439d-903d-7a49ae19f8c5","order_by":0,"name":"Penelope Rose","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAkklEQVRIiWNgGAWjYPACGxBhTJKWNNK1HCZBizkD78OHPyrO55szMG82IEqLZQO7sTHPmduWOxvYihOI0mJwgI1NmrHttoHBAR7jA0Rrkfz57xyJWiR4Gw6AtRDnMMtmNmZjnmPJBgaH2YqJ8745exvjwx81dgYGx5s3SxDnMGYYixmfMhQtxCocBaNgFIyCEQwAZGYl0YbcikMAAAAASUVORK5CYII=","orcid":"","institution":"Aalborg University","correspondingAuthor":true,"prefix":"","firstName":"Penelope","middleName":"","lastName":"Rose","suffix":""},{"id":601492718,"identity":"8a7f56c5-fd7d-42dc-85c0-a0fe231adc12","order_by":1,"name":"Helena Rabie","email":"","orcid":"","institution":"Tygerberg Hospital and Stellenbosch University","correspondingAuthor":false,"prefix":"","firstName":"Helena","middleName":"","lastName":"Rabie","suffix":""},{"id":601492719,"identity":"ee146e31-26cb-4f17-8a54-8a99eae6530f","order_by":2,"name":"Ronalda de Lacy","email":"","orcid":"","institution":"University of Cape Town","correspondingAuthor":false,"prefix":"","firstName":"Ronalda","middleName":"","lastName":"de Lacy","suffix":""},{"id":601492720,"identity":"4803107f-c3ff-4a0d-be65-cd50c752ac14","order_by":3,"name":"Gillian Riordan","email":"","orcid":"","institution":"University of Cape Town","correspondingAuthor":false,"prefix":"","firstName":"Gillian","middleName":"","lastName":"Riordan","suffix":""},{"id":601492721,"identity":"fd2756e4-1e3d-47c4-85b0-377ba8749e21","order_by":4,"name":"George van der Watt","email":"","orcid":"","institution":"University of Cape Town","correspondingAuthor":false,"prefix":"","firstName":"George","middleName":"van der","lastName":"Watt","suffix":""},{"id":601492722,"identity":"f0fda276-d0f6-4069-bdbc-d36bfcab6355","order_by":5,"name":"Magriet van Niekerk","email":"","orcid":"","institution":"Tygerberg Hospital and Stellenbosch University","correspondingAuthor":false,"prefix":"","firstName":"Magriet","middleName":"van","lastName":"Niekerk","suffix":""},{"id":601492723,"identity":"d1b00e13-5cda-4e41-bb86-64e2ee47a0ca","order_by":6,"name":"Ronald van Toorn","email":"","orcid":"","institution":"Tygerberg Hospital and Stellenbosch University","correspondingAuthor":false,"prefix":"","firstName":"Ronald","middleName":"van","lastName":"Toorn","suffix":""},{"id":601492724,"identity":"78805b0c-9934-449a-b76b-65c24af23b11","order_by":7,"name":"Tshepang Mokoto","email":"","orcid":"","institution":"Tygerberg Hospital and Stellenbosch University","correspondingAuthor":false,"prefix":"","firstName":"Tshepang","middleName":"","lastName":"Mokoto","suffix":""},{"id":601492728,"identity":"8b909133-3e4a-4529-8ba5-a3086aaf4920","order_by":8,"name":"Surita Meldau","email":"","orcid":"","institution":"University of Cape Town","correspondingAuthor":false,"prefix":"","firstName":"Surita","middleName":"","lastName":"Meldau","suffix":""}],"badges":[],"createdAt":"2026-02-11 21:08:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8855597/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8855597/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104204511,"identity":"c0173d51-03b6-43d1-8e47-60de16fd020a","added_by":"auto","created_at":"2026-03-09 06:37:12","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":49006,"visible":true,"origin":"","legend":"\u003cp\u003eAge at symptoms onset and death for infants exposed to and unexposed to HIV\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8855597/v1/f87100ee0e0a2571ed31ccdf.png"},{"id":104204513,"identity":"7388eba3-46c6-47d7-887b-10aa049fce9a","added_by":"auto","created_at":"2026-03-09 06:37:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":526698,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8855597/v1/a08060e8-ecaa-4741-b903-70a617311326.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Neonatal HIV prophylaxis accelerates the clinical progression of MPV-17 mitochondrial neurohepatopathy","fulltext":[{"header":"Background","content":"\u003cp\u003eMPV17-related mitochondrial DNA depletion syndrome 6 is a rare lethal autosomal recessive primary mitochondrial disorder (PMD) characterised by infantile onset of hepatopathy and encephalopathy, the latter presenting with hypotonia, developmental delay, failure to thrive and neuropathy (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). It is caused by pathogenic variants in the human \u003cem\u003eMPV17\u003c/em\u003e gene which encodes a mitochondrial inner membrane channel protein with uncertain function, but thought to be key in mitochondrial DNA maintenance. The age of onset of symptoms varies from infancy to later in childhood (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). The rare cases described with juvenile, or even adult onset usually present with a Charcot-Marie-Tooth like sensorimotor axonal neuropathy, with little to no liver involvement (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Though infantile MPV17 neurohepatopathy is lethal in all cases, it is unclear why some patients survive for months or years, while others, often with the same genetic background and defects, decompensate and demise within days after birth or early infancy. This is particularly evident in the Navajo population in North America, where this disease was first described (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Patients carrying the Navajo-specific \u003cem\u003eMPV17\u003c/em\u003e founder variant, c.149G\u0026thinsp;\u0026gt;\u0026thinsp;A p.(Arg50Gln), can be classed into three different phenotypic groupings based on phenotypic presentation and age of onset: (i) Severe fatal Infantile onset form (typically before 6 months of age) with death in infancy, (ii) Childhood onset form (typically with onset between ages 1 and 5 years), characterised by early onset liver failure and death; and (iii) Classic form, characterised by only moderate liver dysfunction and progressive neuropathy (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn South Africa a single \u003cem\u003eMPV17\u003c/em\u003e nonsense-associated splice variant was identified in 38 Black South African infants presenting with mitochondrial neurohepatopathy, attributed to a high carrier frequency of the c.106C\u0026thinsp;\u0026gt;\u0026thinsp;T p.(Gln36Ter) pathogenic \u003cem\u003eMPV17\u003c/em\u003e variant of 1 in 68 Black South African individuals (95% CI: 1/122\u0026ndash;1/38 persons), and predicted population disease incidence of 1 in 18 496 (95% CI; 1/59536\u0026ndash;1/5776) in the Western Cape province of South Africa (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). In contrast to Navajo variant, the more severe South African nonsense variant appears to be exclusively fatal in infancy, although onset still varies between only days after birth (neonatal onset) to more than 5 months after birth.\u003c/p\u003e \u003cp\u003eIt is well known that certain toxins and pharmaceutical compounds may unmask or exacerbate primary mitochondrial dysfunction. Perhaps the most well described example is the hepatotoxic effects of sodium valproate in patients with \u003cem\u003ePOLG\u003c/em\u003e-related PMD (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Meldau et al hypothesised that commonly used medicines in South African infants, such as nucleoside reverse transcriptase inhibitors (NRTI) (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) known to cause excessive metabolic stress, reactive oxygen species (ROS) production and/or mtDNA depletion, may put affected mitochondria under increased pressure and contribute to earlier disease progression (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Identification and characterisation of such modifying factors may lead to a better understanding of the precise disease mechanism and point to improved treatment outcomes and better management strategies.\u003c/p\u003e \u003cp\u003eApproximately 280,000 infants are born to South African women living with HIV (WLHIV) annually. These infants are exposed to antiretroviral therapy both antenatally and postnatally to prevent vertical transmission (VTP) of HIV (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Although now rarely used as a primary regimen in adults, zidovudine, a thymidine analogue and one of the first nucleoside reverse NRTIs, is still used in HIV exposed infants to prevent infection and remains part of guidelines, particularly if mothers have unsuppressed viral loads at delivery. In this setting zidovudine is effective and deemed safe. However zidovudine is known to have mitochondrial toxicity, primarily through interference with the mitochondrial DNA polymerase gamma (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Lamivudine and emtricitabine are cytidine analogues, but are still key medications in all persons with HIV as part of initial and subsequent regimens, and most pregnant women will receive lamivudine or emtricitabine as part of therapy. Though lamivudine and emtricitabine are not routinely used in infants as vertical transmission prevention (VTP) in South Africa, it is recommended as prevention for infants whose mothers were virally unsuppressed at delivery in some settings. Lamivudine and emtricitabine alone are not thought to elicit significant mitochondrial toxicity but may contribute to toxicity in combination with other NRTIs. Similarly, tenofovir, a modern adenosine \u003cem\u003enucleotide\u003c/em\u003e analogue commonly used in pregnancy in combination with lamivudine or emtricitabine, is thought to have little effect on mitochondrial DNA polymerase with no clear evidence of an effect on infant mitochondrial DNA (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eEvidence suggests that infants who are perinatally exposed to HIV, but uninfected and received zidovudine at birth are at higher risk of decreased blood mtDNA content, which may be associated with altered mitochondrial fuel utilization (\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Clinically relevant mitochondrial dysfunction in infants exposed to NRTI were first reported in 1999 in 8 infants of whom 5 had neurological abnormalities (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). In that study four children received zidovudine alone and four zidovudine and lamivudine.\u003c/p\u003e \u003cp\u003eNevirapine, a non-NRTI, is used in virtually all children exposed to HIV as part of prevention and, although considered safe and effective, can cause significant hepatotoxicity. Although in vitro studies suggest that nevirapine can induce changes in mitochondrial proteins, there is no clear signal of mitochondrial DNA depletion and the general consensus is that it is not associated with mitochondrial DNA related disease. (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e The guidelines for postnatal prevention of HIV include six weeks of nevirapine for all babies, with extension of the prevention for breastfeeding infants with mothers who are not virally suppressed. Zidovudine is given for six weeks to infants with mothers who are virally unsuppressed at birth, but is commonly initiated at birth whilst the results of maternal viral loads are awaited.\u003c/p\u003e \u003cp\u003eWe hypothesize that NRTI exposure may exacerbate the mtDNA depletion phenotype and liver damage in MPV17 deficient infants who have been exposed to HIV, leading to earlier presentation and accelerated disease progression.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy aim, design and setting\u003c/h2\u003e \u003cp\u003eThis study aimed to describe the presentation and clinical course of infants diagnosed with MPV17 neurohepatopathy, comparing those who were HIV-exposed and uninfected (HEU) and on antiretroviral therapy including zidovudine and nevirapine for VTP to infants with MPV17 disease who were HIV unexposed and uninfected (HUU), using data from an ongoing multicentre MPV17 natural history study in South Africa.\u003c/p\u003e \u003cp\u003eData was collected on infants diagnosed with MPV17 neurohepatopathy during routine clinical care at Tygerberg Hospital and Red Cross War Memorial Children\u0026rsquo;s Hospital (RCWMCH), two tertiary academic hospitals in Cape Town, South Africa, both prospectively from September 2022 to December 2024 and retrospectively for infants diagnosed and followed between November 2013 and August 2022. Only patients with a genetic diagnosis of homozygosity for the \u003cem\u003eMPV17\u003c/em\u003e: c.106C\u0026thinsp;\u0026gt;\u0026thinsp;T p.(Gln36Ter) pathogenic variant were included in this study, and no exclusion criteria were applied.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eClinical variables\u003c/h3\u003e\n\u003cp\u003eClinical, demographic, and family history data were captured into a RedCap database as part of an ongoing multicentre MPV17 natural history study. Data captured and analysed included antenatal exposures to HIV or other maternal illnesses or infections; antenatal exposures to medications, including antiretrovirals, other medications and substances; a detailed family history, including a previous history of infants diagnosed with MPV17 deficiency or presenting with liver disease, neuropathies, myopathies, unexplained deaths or illness; age of first symptom onset; postnatal exposure to medications, including antiretrovirals used for treatment or prevention of mother to child transmission of HIV; results of laboratory investigations, including lactate and liver enzymes; and details of clinical course and death.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eEthical approval\u003c/strong\u003e \u003cp\u003e was obtained from the University of Cape Town Health Research Ethics Committee (071/2022) and Stellenbosch University Health Research Ethics Committee (N22/06/059_RECIP_UCT_071/2022).\u003c/p\u003e \u003c/p\u003e\n\u003ch3\u003eStatistical methods\u003c/h3\u003e\n\u003cp\u003eResults were expressed as medians and interquartile ranges (IQR) for continuous variables, and frequencies and percentages for categorical variables. Comparisons of categorical variables used either the Chi-square or Fisher\u0026rsquo;s exact test as appropriate. All analyses were two-tailed, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant and used STATA version 12 (StataCorp LP, College Station, Texas, USA).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cem\u003eAntenatal characteristics and exposures\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eBetween 2013 and 2024, 25 infants were diagnosed with MPV17 neurohepatopathy at Tygerberg \u0026nbsp;Hospital and RCWMCH in Cape Town, South Africa. Of these, 5 were prospectively enrolled into the SA MPV17 natural history study, while data from the remaining 20 cases were captured retrospectively from hospital folders (Table 1). Antenatal exposure to HIV was reported in 8 infants (32%) while 17 (68%) were unexposed. All the HEU infants were exposed to antiretrovirals antenatally, but regimens differed. (Table 1) None of the infants\u0026rsquo; mothers were diagnosed with tuberculosis, hepatitis B or C, group B Streptococcus or other infections antenatally. One of the HIV-negative mothers developed hypertension during pregnancy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePostnatal exposures and presenting symptoms\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eSeven HEU infants received both zidovudine and nevirapine from birth and one infant received only nevirapine from birth as part of routine VTP postnatally. One infant also received lamivudine in addition to zidovudine and nevirapine as VTP because their mother was virologically unsuppressed at the time of delivery. All HEU infants were confirmed to be HIV-negative by routine HIV polymerase chain reaction (PCR) testing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAlthough there was no difference in sex, gestational age at delivery, mode of delivery or family history of previously affected siblings, HEU infants had a lower median birth weight (p=0.02). Symptom onset occurred much earlier (p=0.006) at a median of 3 days of age in HEU infants compared to 60 days in HUU (Figure 1). All HEU infants presented during the first month of life, whereas HUU infants presented during the first six months of life. Presenting symptoms included poor feeding, weakness, failure to gain weight, hypoglycaemia and jaundice (Table 1). All infants had a persistently elevated lactate and deranged liver enzymes with variable coagulopathy. HEU infants were more likely to develop liver failure.\u003c/p\u003e\n\u003cp\u003eTable 1. Patient characteristics\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eHIV exposed\u003c/p\u003e\n \u003cp\u003eN=8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eHIV unexposed\u003c/p\u003e\n \u003cp\u003eN=17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eAll\u003c/p\u003e\n \u003cp\u003eN=25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eAge at symptom onset in weeks, median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.4 (0.1 \u0026ndash; 1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e8.5 (2 \u0026ndash; 13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e4 (0.4 \u0026ndash; 13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eSex, female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e7 (88%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e9 (53%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eFamily history of MPV17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eFamily history of sibling death in infancy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e1 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eGestational age, median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e38 (38 \u0026ndash; 39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e38 (38 \u0026ndash; 39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e39 (38 \u0026ndash; 40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eBirthweight in kg, median (IQR)\u003c/p\u003e\n \u003cp\u003eLow birth weight (\u0026lt;2.5kg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e2.45\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(2.28 \u0026ndash; 2.71)\u003c/p\u003e\n \u003cp\u003e4 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2.86\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(2.54 \u0026ndash; 3.13)\u003c/p\u003e\n \u003cp\u003e2 (12%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;2.78\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(2.45 \u0026ndash; 2.95)\u003c/p\u003e\n \u003cp\u003e6 (24%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eDelivery mode\u003c/p\u003e\n \u003cp\u003eVaginal delivery\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eCaesarean section\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3 (38%)\u003c/p\u003e\n \u003cp\u003e5 (63%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11 (67%)\u003c/p\u003e\n \u003cp\u003e5 (31%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e14 (58%)\u003c/p\u003e\n \u003cp\u003e10 (42%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eAntenatal antiretroviral therapy\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eTenofovir\u003c/p\u003e\n \u003cp\u003eLamivudine/Emtricitabine\u003c/p\u003e\n \u003cp\u003eDolutegravir\u003c/p\u003e\n \u003cp\u003eEfavirenz\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNevirapine\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8 (100%)\u003c/p\u003e\n \u003cp\u003e8 (100%)\u003c/p\u003e\n \u003cp\u003e2 (25%)\u003c/p\u003e\n \u003cp\u003e5 (63%)\u003c/p\u003e\n \u003cp\u003e1 (14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eInfant antiretroviral therapy\u003c/p\u003e\n \u003cp\u003eNevirapine\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNevirapine with Zidovudine\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNevirapine with Zidovudine and Lamivudine\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1 (13%)\u003c/p\u003e\n \u003cp\u003e6 (75%)\u003c/p\u003e\n \u003cp\u003e1 (13%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003ePresenting features\u003c/p\u003e\n \u003cp\u003eWeakness\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eJaundice\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003cp\u003eHyperlactataemia\u003c/p\u003e\n \u003cp\u003eHepatomegaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5 (63%)\u003c/p\u003e\n \u003cp\u003e4 (50%)\u003c/p\u003e\n \u003cp\u003e2 (25%)\u003c/p\u003e\n \u003cp\u003e8 (100%)\u003c/p\u003e\n \u003cp\u003e3 (38%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6 (35%)\u003c/p\u003e\n \u003cp\u003e11 (65%)\u003c/p\u003e\n \u003cp\u003e1 (6%)\u003c/p\u003e\n \u003cp\u003e17 (100%)\u003c/p\u003e\n \u003cp\u003e11 (65%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11 (44%)\u003c/p\u003e\n \u003cp\u003e15 (60%)\u003c/p\u003e\n \u003cp\u003e3 (12%)\u003c/p\u003e\n \u003cp\u003e25 (100%)\u003c/p\u003e\n \u003cp\u003e14 (56%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.4\u003c/p\u003e\n \u003cp\u003e0.7\u003c/p\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003cp\u003e0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eLater features\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eWeakness\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eJaundice\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ePoor feeding\u003c/p\u003e\n \u003cp\u003eMetabolic acidosis\u003c/p\u003e\n \u003cp\u003eFailure to thrive\u003c/p\u003e\n \u003cp\u003eAcute liver failure\u003c/p\u003e\n \u003cp\u003eHypoglycaemia\u003c/p\u003e\n \u003cp\u003eHepatomegaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6 (75%)\u003c/p\u003e\n \u003cp\u003e6 (75%)\u003c/p\u003e\n \u003cp\u003e1 (13%)\u003c/p\u003e\n \u003cp\u003e3 (38%)\u003c/p\u003e\n \u003cp\u003e5 (63%)\u003c/p\u003e\n \u003cp\u003e5 (63%)\u003c/p\u003e\n \u003cp\u003e6 (75%)\u003c/p\u003e\n \u003cp\u003e7 (88%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e16 (94%)\u003c/p\u003e\n \u003cp\u003e13 (76%)\u003c/p\u003e\n \u003cp\u003e12 (71%)\u003c/p\u003e\n \u003cp\u003e2 (12%)\u003c/p\u003e\n \u003cp\u003e13 (76%)\u003c/p\u003e\n \u003cp\u003e2 (12%)\u003c/p\u003e\n \u003cp\u003e14 (82%)\u003c/p\u003e\n \u003cp\u003e16 (94%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e22 (88%)\u003c/p\u003e\n \u003cp\u003e19 (76%)\u003c/p\u003e\n \u003cp\u003e13 (52%)\u003c/p\u003e\n \u003cp\u003e5 (20%)\u003c/p\u003e\n \u003cp\u003e18 (72%)\u003c/p\u003e\n \u003cp\u003e7 (28%)\u003c/p\u003e\n \u003cp\u003e20 (80%)\u003c/p\u003e\n \u003cp\u003e23 (92%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003cp\u003e0.6\u003c/p\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eAge at death in days, median (IQR) (n=15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e59 (36-225)\u003c/p\u003e\n \u003cp\u003en=6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e206 (161-287)\u003c/p\u003e\n \u003cp\u003en=9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e195 (45-247)\u003c/p\u003e\n \u003cp\u003en=15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAll infants were exposed to antibiotics at least once as part of empiric treatment of suspected sepsis, 5 in the early postnatal period (ampicillin and gentamycin) and the other 20 at the time of each hospital admission (ceftriaxone, cefotaxime or meropenem). There were also two HUU infants who received traditional medicines of unknown composition.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eClinical course and death\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe duration of antiretroviral exposure to both mothers and infants was not well documented in all cases. In all cases in which MPV17 neurohepatopathy was clinically suspected at presentation to the tertiary centre, zidovudine and nevirapine therapy were immediately interrupted. In some cases there was a delay in referral, with a subsequent delay in interruption of antiretroviral therapy. The median age at death was 59 days in HEU infants, compared to 206 days in HUU. The date of death was only available in 15 patients, as the majority of children were referred for palliative care after diagnosis and not actively followed up at the tertiary hospital at which they were diagnosed.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis is the first description of a cohort of infants all with an identical pathogenic variant in the MPV17 gene (homozygous for c.106C\u0026thinsp;\u0026gt;\u0026thinsp;T p.(Gln36Ter)) in a high HIV prevalence setting. In this cohort of infants diagnosed with MPV17 neurohepatopathy, HEU infants with MPV17 all were exposed to antenatal NRTI and all except one had postnatal zidovudine. These infants had a lower birth weight, presented at a much younger age (during the first month of life), were more likely to develop acute liver failure and, though not significant statistically, appeared to die sooner. Although MPV17 neurohepatopathy is a uniformly lethal condition, we found that HEU infants perinatally exposed to antiretroviral therapy, in most cases zidovudine and nevirapine, had an accelerated clinical course. Zidovudine is known to be a mitochondrial toxin and we postulate that zidovudine had an impact on the phenotypic expression of this rare genetic condition.\u003c/p\u003e \u003cp\u003eMany NRTIs, particularly older formulations including zidovudine, cause mitochondrial toxicity due to inhibition of the mitochondrial polymerase γ (pol γ) enzyme (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Clinical manifestations range from minor to life-threatening conditions (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). It has previously been demonstrated that HEU infants who received zidovudine postnatally have reduced blood mitochondrial DNA content compared to HUU infants, with the lowest levels recorded at six weeks of life (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). The mitochondrial dysfunction associated with zidovudine was first linked to symptomatic abnormality in 8 French children. These authors found that the incidence was 30 times higher than that of the general population (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). In our cohort, HEU infants presented very early during the first month of life, which is much younger than the French cohort. MPV17 neurohepatopathy is a uniformly lethal condition in South Africa and although it is likely that zidovudine therapy accelerated the clinical course, it is unlikely that the ultimate outcome would have been different as all infants ultimately die in early life. However, early presentation and demise allows for less time to counsel and support the family, who in some cases have more than one affected infant. The HEU infants in our cohort were more likely to develop acute liver failure than HUU infants, but also less likely to develop poor feeding most likely due to short survival. Although there was no statistically significant difference in age of death, HEU infants tended to die sooner and it is possible that this is the reason that they were less likely to develop poor feeding than HUU infants, who tended to survive longer.\u003c/p\u003e \u003cp\u003eDolutegravir is now part of standard first-line and second-line antiretroviral therapy regimens in adults and children over one month of age, but until recently it was not recommended for neonates under the age of 28 days, due to a lack of dosing and safety information. A recent pharmacokinetic study has provided evidence to support dosing guidance from birth to four weeks of life (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Dolutegravir alone and with abacavir and lamivudine is now included in WHO VTP regimens. This regimen may be safer for infants, including those with underlying mitochondrial disorders.\u003c/p\u003e \u003cp\u003ePrimary mitochondrial disease is a very large group of disorders, with widely heterogenous genetic and clinical features, which has largely made studies like this one very challenging. A strength of this study is the identical pathogenic genetic cause in all patients. Limitations include that the data was collected retrospectively in the majority of cases, resulting in incompleteness of data including date of death. It is also possible that antenatal antiretroviral exposure and maternal HIV viral load might have had an impact on the clinical presentation and course.\u003c/p\u003e \u003cp\u003eThis is the first study to highlight the impact of NRTIs such as zidovudine on disease progression and outcomes in patients with MPV17-related neurohepatopathy. These findings may have wider implications for HIV exposed and/or HIV positive patients with primary mitochondrial disorders in general, especially those caused by defects in genes involved in mtDNA maintenance. Although this is a significant number of cases of a rare disease, numbers are small and a larger cohort may have shown greater statistical differences between the groups. A further limitation is that the age of death was not known in all cases.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003ePerinatal therapy with the NRTI zidovudine, a known mitochondrial toxin, may accelerate the clinical presentation and exacerbate the clinical course of MPV17 neurohepatopathy. Our findings suggest that where possible less toxic antiretroviral therapy should be introduced for VTP therapy in HEU infants, particularly in settings where there is a high prevalence of a common pathogenic \u003cem\u003eMPV17\u003c/em\u003e variant. These findings may further have significant implications for other primary mitochondrial disorders, especially those affecting mtDNA content and ROS, and further studies should look at the effects of toxins and medication on the clinical expression of these disorders both in infantile disease, as well as in older children and adults.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eHEU\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;HIV-exposed\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHUU\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;HIV-unexposed\u003c/p\u003e\n\u003cp\u003eIQR\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Interquartile range\u003c/p\u003e\n\u003cp\u003eNRTI\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Nucleoside reverse transcriptase inhibitor\u003c/p\u003e\n\u003cp\u003ePCR\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Polymerase chain reaction\u003c/p\u003e\n\u003cp\u003eRCWMCH\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Red Cross War Memorial Children\u0026rsquo;s Hospital\u003c/p\u003e\n\u003cp\u003eVTP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Vertical transmission prevention\u003c/p\u003e\n\u003cp\u003eWLHIV \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Women living with HIV\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cu\u003eEthics approval and consent to participate\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval was obtained from the University of Cape Town Health Research Ethics Committee (071/2022) and Stellenbosch University Health Research Ethics Committee (N22/06/059_RECIP_UCT_071/2022). Informed consent was obtained from the parent or legal guardian of all children enrolled prospectively in this study. A waiver of consent was obtained from both ethics committees to collect retrospective data on children diagnosed prior to commencement of the prospective study. This study adhered to ethical principles as outlined in the Declaration of Helsinki.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eConsent for publication\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eAvailability of data and materials\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eCompeting interests\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eFunding\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThis research was self-funded.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eAuthors’ contributions\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003ePCR, SM and HR designed the research study. PCR, RDL and GR recruited participants to the study and captured data for the study. PCR analysed the data and prepared the original draft manuscript. \u0026nbsp;PCR, HR, RDL, GR, GVDW, MVN, RVT, TM and SM discussed, revised and contributed to the final version of the manuscript. All authors have read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003e\u003cbr\u003e\u0026nbsp;\u003c/u\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWong LJC, Brunetti-Pierri N, Zhang Q, Yazigi N, Bove KE, Dahms BB, et al. Mutations in the MPV17 gene are responsible for rapidly progressive liver failure in infancy. Hepatology. 2007 Oct;46(4):1218\u0026ndash;27. \u003c/li\u003e\n\u003cli\u003eUusimaa J, Evans J, Smith C, Butterworth A, Craig K, Ashley N, et al. Clinical, biochemical, cellular and molecular characterization of mitochondrial DNA depletion syndrome due to novel mutations in the MPV17 gene. European Journal of Human Genetics. 2014 Feb;22(2):184\u0026ndash;91. \u003c/li\u003e\n\u003cli\u003eKaradimas CL, Vu TH, Holve SA, Chronopoulou P, Quinzii C, Johnsen SD, et al. Navajo Neurohepatopathy Is Caused by a Mutation in the MPV17 Gene [Internet]. Vol. 79, The American Journal of Human Genetics. 2006. Available from: www.ajhg.org\u003c/li\u003e\n\u003cli\u003eEl-Hattab AW, Wang J, Dai H, Almannai M, Staufner C, Alfadhel M, et al. MPV17-related mitochondrial DNA maintenance defect: New cases and review of clinical, biochemical, and molecular aspects. Hum Mutat. 2018 Apr 1;39(4):461\u0026ndash;70. \u003c/li\u003e\n\u003cli\u003eBaumann M, Schreiber H, Schlotter-Weigel B, L\u0026ouml;scher WN, Stucka R, Karall D, et al. MPV17 mutations in juvenile- and adult-onset axonal sensorimotor polyneuropathy. Clin Genet. 2019 Jan 1;95(1):182\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eMeldau S, De Lacy RJ, Riordan GTM, Goddard EA, Pillay K, Fieggen KJ, et al. Identification of a single MPV17 nonsense-associated altered splice variant in 24 South African infants with mitochondrial neurohepatopathy. Clin Genet. 2018 May 1;93(5):1093\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eMeldau S, Owen EP, Khan K, Riordan GT. Mitochondrial molecular genetic results in a South African cohort: Divergent mitochondrial and nuclear DNA findings. J Clin Pathol. 2022 Jan 1;75(1):34\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eStewart JD, Horvath R, Baruffini E, Ferrero I, Bulst S, Watkins PB, et al. Polymerase \u0026gamma;Gene POLG determines the risk of sodium valproate-induced liver toxicity. Hepatology. 2010 Nov;52(5):1791\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eRatnaike TE, Elkhateeb N, Lochm\u0026uuml;ller A, Gilmartin C, Schon K, Horv\u0026aacute;th R, et al. Evidence for sodium valproate toxicity in mitochondrial diseases: A systematic analysis. Vol. 6, BMJ Neurology Open. BMJ Publishing Group; 2024. \u003c/li\u003e\n\u003cli\u003eWalker UA, B\u0026auml;uerle J, Laguno M, Murillas J, Mauss S, Schmutz G, et al. Depletion of Mitochondrial DNA in Liver under Antiretroviral Therapy with Didanosine, Stavudine, or Zalcitabine. Hepatology. 2004 Feb;39(2):311\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eSmith RL, Tan JME, Jonker MJ, Jongejan A, Buissink T, Veldhuijzen S, et al. Beyond the polymerase-\u0026gamma; theory: Production of ROS as a mode of NRTI-induced mitochondrial toxicity. PLoS One. 2017 Nov 1;12(11). \u003c/li\u003e\n\u003cli\u003eKufa-Chakezha T, Shangase N, Lombard C, Manda S, Puren A. The 2022 Antenatal HIV Sentinel Survey [Internet]. 2022 [cited 2025 Nov 6]. Available from: https://www.nicd.ac.za/wp-content/uploads/2024/01/Antenatal-survey-2022-report_National_Provincial_12Jul2023_Clean_01.pdf\u003c/li\u003e\n\u003cli\u003eKohler JJ, Lewis W. A brief overview of mechanisms of mitochondrial toxicity from NRTIs. Environ Mol Mutagen. 2007 Apr 19;48(3\u0026ndash;4):166\u0026ndash;72. \u003c/li\u003e\n\u003cli\u003eKoczor CA, Lewis W. Nucleoside reverse transcriptase inhibitor toxicity and mitochondrial DNA. Expert Opin Drug Metab Toxicol. 2010 Dec 7;6(12):1493\u0026ndash;504. \u003c/li\u003e\n\u003cli\u003eBirkus G, Hitchcock MJM, Cihlar T. Assessment of mitochondrial toxicity in human cells treated with tenofovir: Comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother. 2002;46(3):716\u0026ndash;23. \u003c/li\u003e\n\u003cli\u003eJao J, Powis KM, Kirmse B, Yu C, Epie F, Nshom E, et al. Lower mitochondrial DNA and altered mitochondrial fuel metabolism in HIV-exposed uninfected infants in Cameroon. AIDS. 2017 Nov 28;31(18):2475\u0026ndash;81. \u003c/li\u003e\n\u003cli\u003eBarret B, Tardieu M, Rustin P, Lacroix C, Chabrol B, Desguerre I, et al. Persistent mitochondrial dysfunction in HIV-1-exposed but uninfected infants: clinical screening in a large prospective cohort. \u003c/li\u003e\n\u003cli\u003eVan der Watt G, Eley B, Henderson H. Whole blood mitochondrial DNA depletion in South African HIV infected children. J Pediatr Biochem. 2010 Oct;01(03):225\u0026ndash;32. \u003c/li\u003e\n\u003cli\u003eBlanche S, Tardieu M, Rustin P, Slama A, Barret B, Firtion G, et al. Persistent mitochondrial dysfunction and perinatal exposure to a viral nucleoside analogues. The Lancet. 1999 Sep 25;354:1084\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003ePaemanee A, Sornjai W, Kittisenachai S, Sirinonthanawech N, Roytrakul S, Wongtrakul J, et al. Nevirapine induced mitochondrial dysfunction in HepG2 cells. Sci Rep. 2017 Dec 1;7(1). \u003c/li\u003e\n\u003cli\u003eNegredo E, Mir\u0026oacute; \u0026Oacute;, Rodr\u0026iacute;guez-Santiago B, Garrabou G, Estany C, Masabeu A, et al. Improvement of mitochondrial toxicity in patients receiving a nucleoside reverse-transcriptase inhibitor - sparing strategy: Results from the multicenter study with nevirapine and kaletra (MULTTNEKA). Clinical Infectious Diseases. 2009 Sep 15;49(6):892\u0026ndash;900. \u003c/li\u003e\n\u003cli\u003eKakuda TN. Pharmacology of Nucleoside and Nucleotide Reverse Transcriptase Inhibitor-Induced Mitochondrial Toxicity. Vol. 22. \u003c/li\u003e\n\u003cli\u003eJao J, Powis KM, Kirmse B, Yu C, Epie F, Nshom E, et al. Lower mitochondrial DNA and altered mitochondrial fuel metabolism in HIV-exposed uninfected infants in Cameroon. AIDS. 2017 Nov 28;31(18):2475\u0026ndash;81. \u003c/li\u003e\n\u003cli\u003eBekker A, Salvadori N, Rabie H, du Toit S, Than-in-at K, Groenewald M, et al. Safety and pharmacokinetics of dolutegravir dispersible tablets and oral films in term neonates exposed to HIV in South Africa (PETITE-DTG study): an open-label, randomised, phase 1/2 trial. Lancet HIV [Internet]. 2025 Nov;12(11):e753\u0026ndash;62. Available from: https://linkinghub.elsevier.com/retrieve/pii/S2352301825002395\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"mitochondrial disease, MPV17, HIV, zidovudine, antiretroviral, toxicity, neurohepatopathy","lastPublishedDoi":"10.21203/rs.3.rs-8855597/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8855597/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eMPV17-related mitochondrial DNA depletion syndrome is a rare, lethal, autosomal recessive primary mitochondrial disorder characterised by infantile onset liver disease and neurological features, including hypotonia, developmental delay, failure to thrive and neuropathy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe aim of this study was to describe the presentation and clinical course of infants diagnosed with MPV17 neurohepatopathy, comparing those who were HIV-exposed on antiretroviral therapy, including zidovudine and nevirapine for vertical transmission prevention (VTP), to infants who were not HIV exposed, using data from a multicentre MPV17 natural history study in South Africa.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eBetween 2013 and 2024, 25 infants were diagnosed with MPV17 neurohepatopathy, 8 (32%) of whom were HIV-exposed and received ART at birth (7 received zidovudine), none where HIV-infected. Median birth weight was lower at 2.45kg (IQR 2.28\u0026ndash;2.71) in infants who were HIV-exposed compared to 2.86kg (IQR 2.54\u0026ndash;3.13) in HIV-unexposed infants (p\u0026thinsp;=\u0026thinsp;0.02). Symptom onset occurred much earlier at a median of 3 days of age (IQR 0\u0026ndash;10 days) in HIV exposed infants compared to 60 days (IQR 14\u0026ndash;90) in HIV unexposed (p\u0026thinsp;=\u0026thinsp;0.006). Infants exposed to HIV were more likely to develop liver failure (p\u0026thinsp;=\u0026thinsp;0.02).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003ePerinatal therapy with the nucleoside reverse transcriptase inhibitor zidovudine, a known mitochondrial toxin, may accelerate the clinical presentation and exacerbate the clinical course of MPV17 neurohepatopathy. Our findings suggest that less toxic antiretroviral therapy should be considered for VTP therapy in HIV-exposed infants, particularly in our setting where there is a high carrier frequency of a single pathogenic \u003cem\u003eMPV17\u003c/em\u003e variant.\u003c/p\u003e","manuscriptTitle":"Neonatal HIV prophylaxis accelerates the clinical progression of MPV-17 mitochondrial neurohepatopathy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-09 06:37:08","doi":"10.21203/rs.3.rs-8855597/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-09T07:12:33+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-08T10:34:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"160648877192986479054565942184991630261","date":"2026-03-08T09:37:34+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-07T23:59:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"217368808442192567538675749579340488031","date":"2026-03-05T21:28:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"155553531865880771004587348385807304042","date":"2026-03-05T19:20:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"62533570993748628316638481702653266925","date":"2026-03-05T19:07:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"186679823494616761204167071662157465420","date":"2026-03-05T16:50:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"204057607940951650866344569507485791751","date":"2026-03-05T08:50:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"92091468249337980818973379209825153028","date":"2026-03-03T14:37:24+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-03T12:41:07+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-26T05:37:07+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-19T09:06:44+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-19T07:39:26+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2026-02-19T07:34:36+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7a8079bc-b10c-4e93-9528-5e46b2d8ac5b","owner":[],"postedDate":"March 9th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-07T03:09:42+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-09 06:37:08","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8855597","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8855597","identity":"rs-8855597","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}