Zidovudine
| Evidence Level: L1 | Predicted Indications: 6 |
Table of Contents
Zidovudine: From HIV/AIDS Treatment to Prevention of Mother-to-Child HIV Transmission
One-Sentence Summary
Zidovudine (AZT, DrugBank DB00495) was the first antiretroviral drug ever approved, originally used to treat established HIV infection/AIDS in adults. The TxGNN model, together with decades of clinical research, supports its use for prevention of mother-to-child (perinatal) HIV transmission, with 9 clinical trials and 10 publications in this evidence pack directly supporting this direction. This candidate carries the strongest evidence level (L1) among six TxGNN predictions generated for this drug.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | HIV infection / AIDS (established antiretroviral therapy) |
| Predicted New Indication | Congenital HIV infection — prevention of mother-to-child (perinatal) transmission |
| TxGNN Prediction Score | 99.19% |
| Evidence Level | L1 |
| UK Market Status | Not marketed (per current dataset — see UK Market Information) |
| Number of Marketing Authorisations | 0 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Zidovudine is a nucleoside reverse transcriptase inhibitor (NRTI) that directly and competitively inhibits HIV reverse transcriptase, blocking viral replication. This is a well-established, clinically validated mechanism — zidovudine was, historically, the very first antiretroviral agent approved for AIDS. The evidence pack’s own mechanistic rationale further notes that, by inhibiting reverse transcriptase, zidovudine blocks maternal viral replication and crosses the placenta and breast milk, thereby reducing mother-to-child vertical transmission of HIV.
The original indication — treatment of established HIV infection/AIDS in adults — and the predicted new indication — prevention of mother-to-child transmission — share the same core antiviral mechanism applied in a different clinical context. Rather than suppressing replication in an already-infected adult, zidovudine is used prophylactically in HIV-positive pregnant women and their newborns to interrupt transmission during pregnancy, labour, and breastfeeding.
This extension is not speculative: it was formally established by the landmark ACTG 076 trial, which showed that a zidovudine regimen in pregnant women and their infants reduced perinatal HIV transmission by approximately two-thirds, and it went on to become the international standard-of-care prevention strategy (reflected in the 1994 US Public Health Service Task Force recommendations in this pack’s literature evidence). Because reverse-transcriptase inhibition is not tissue- or population-specific, the mechanism validated in adult AIDS treatment is directly applicable across the maternal–fetal interface.
Other TxGNN Predictions Considered
This candidate pack (TW-DB00495-multi) contains six TxGNN-predicted indications for zidovudine. For transparency, all are summarised below; only the indication above was selected as the primary, actionable candidate for this report.
| Rank | Predicted Disease | TxGNN Score | Evidence Level | Recommendation | Note |
|---|---|---|---|---|---|
| 1 | Feline acquired immunodeficiency syndrome | 99.96% | Not yet assessed | — | Veterinary disease model (cats); not a valid human indication despite the highest raw model score |
| 2 | Simian immunodeficiency virus infection | 99.96% | L4 | Hold | Non-human primate model for HIV; supports pre-clinical mechanistic validity only |
| 3 | Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter | 99.96% | L5 | Research Question | Speculative interferonopathy hypothesis (NRTI blocking retrotransposon reverse transcription); no clinical or trial evidence |
| 4 | Obsolete familial combined hyperlipidaemia | 99.62% | L5 | Hold | Deprecated disease term; direction contradicts zidovudine’s known dyslipidaemia/lipodystrophy toxicity — likely knowledge-graph noise |
| 5 | AIDS related complex | 99.19% | L1 | Proceed with Guardrails | Essentially restates zidovudine’s original licensed indication rather than a genuinely new use |
| 6 | Congenital human immunodeficiency virus | 99.19% | L1 | Proceed with Guardrails | Selected as the primary candidate in this report |
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrolment | Key Findings |
|---|---|---|---|---|
| NCT00386230 | Phase 3 | Completed | 1,554 | Short zidovudine regimen non-inferior to longer ACTG-076-like regimen for perinatal HIV prevention in Thailand |
| NCT00000751 | Phase 3 | Completed | 1,600 | HIVIG vs immune globulin combined with intrapartum/neonatal zidovudine for prevention of maternal–fetal HIV transmission |
| NCT00164736 | Phase 3 | Completed | 2,369 | Nutritional supplementation and antiretroviral interventions to prevent HIV transmission during breastfeeding |
| NCT01061151 | Phase 3 | Completed | 3,747 | PROMISE study — optimal antepartum, intrapartum, and postpartum antiretroviral strategies for prevention of mother-to-child transmission |
| NCT01511237 | Phase 3 | Completed | 379 | PHPT-5 — perinatal antiretroviral intensification to prevent mother-to-child transmission in Thai women with limited prior HAART |
| NCT00102960 | Phase 3 | Completed | 377 | Comparison of antiretroviral treatment strategies for infants infected with HIV at birth in a resource-poor setting |
| NCT03642704 | Phase 4 | Completed | 56 | Early diagnosis plus preventive antiretroviral treatment from birth for HIV-exposed newborns (Guinea) |
| NCT00197587 | N/A | Completed | 1,200 | Mashi study — prevention of milk-borne HIV-1C transmission in Botswana |
| NCT00001007 | Phase 1 | Completed | 18 | Safety and pharmacokinetics of intravenous and oral zidovudine in infants with perinatal HIV exposure |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 7913986 | 1994 | Guideline | MMWR Recomm Rep | US Public Health Service Task Force recommendations for zidovudine to reduce perinatal HIV transmission, based on ACTG 076 (~two-thirds risk reduction) |
| 33541012 | 2021 | Systematic Review / Meta-analysis | Epidemiol Health | Assessed congenital anomaly risk in infants of HIV-positive mothers exposed to antiretroviral therapy |
| 8879761 | 1996 | Review | Clin Infect Dis | Progress report on prevention of perinatal HIV transmission two years after completion of ACTG 076 |
| 28537936 | 2017 | Cohort | AIDS | Zidovudine use in pregnancy — inconsistent evidence for increased overall, cardiac, and male genital malformations |
| 12197800 | 2002 | Cohort | Arch Pediatr Adolesc Med | Determinants of mother-to-infant HIV-1 transmission before and after introduction of zidovudine prophylaxis |
| 26687320 | 2016 | Registry Cohort | Eur J Obstet Gynecol Reprod Biol | Antiretroviral Pregnancy Registry data on prenatal zidovudine exposure and ventricular septal/congenital heart defect risk |
| 40011239 | 2025 | Case/Non-case Study | Eur J Clin Pharmacol | European congenital anomaly registry analysis of antiretroviral drug exposure in pregnancy |
| 9240849 | 1997 | Cohort | Acta Paediatr Suppl | Timing of perinatal HIV infection and its interaction with the design of preventive/therapeutic interventions |
| 8419601 | 1993 | Clinical Study (Phase 1) | J Pediatr | Safety, tolerability, and pharmacokinetics of zidovudine in infants born to HIV-infected mothers |
| 2126136 | 1990 | Case Report | Pediatr Infect Dis J | Zidovudine treatment of an infant with congenital HIV infection |
UK Market Information
According to the regulatory dataset used for this evaluation, zidovudine is currently recorded as Not marketed in the UK, with no active marketing authorisations identified (0 licences on file). This should be treated as a data gap rather than a confirmed regulatory status — the MHRA product database should be checked directly to confirm current UK licensing (e.g. under brand names such as Retrovir or generic zidovudine products) before this candidate progresses further.
Safety Considerations
Formal UK-specific warnings, contraindications, and drug interaction data were not available in this evidence pack (flagged as a blocking data gap, DG001). Please refer to the SmPC and BNF for authoritative safety information, and report suspected adverse reactions via the Yellow Card Scheme.
For context, the literature gathered for this candidate consistently documents dose-dependent haematological toxicity (anaemia, granulocytopenia/neutropenia) as zidovudine’s principal tolerability issue (e.g. Groopman 1990, PMID 2201071; Hewitt et al. 1993, PMID 8460920), and several studies have examined congenital malformation risk with in-utero exposure (e.g. Rough et al. 2017, PMID 28537936; Vannappagari et al. 2016, PMID 26687320) without establishing a consistent teratogenic signal.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale:
- The L1 evidence base — multiple completed Phase 3 RCTs including the landmark ACTG 076-derived and successor regimens (PHPT-5, PROMISE, Mashi) — firmly supports zidovudine’s efficacy in preventing mother-to-child HIV transmission. However, a blocking data gap (missing MHRA-approved SmPC warnings/contraindications, DG001) and an unresolved discrepancy in current UK marketing-authorisation status prevent full safety sign-off at this stage.
To proceed, the following is needed:
- Obtain and review the current MHRA SmPC for zidovudine (warnings, contraindications, pregnancy/lactation guidance) to close DG001
- Verify actual current UK marketing-authorisation status against the MHRA product register (dataset currently shows 0 licences)
- Populate a formal DrugBank-sourced mechanism-of-action record to close DG002
- Cross-check proposed use against current BHIVA pregnancy guidelines for zidovudine-containing perinatal HIV prevention regimens
- Treat the four lower-tier predictions in this pack (feline/simian immunodeficiency virus models, the ataxic-gait neurodevelopmental disorder hypothesis, and the “obsolete” hyperlipidaemia association) as non-actionable research signals only, not for progression
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.