HIV-1 Integrase Strand Transfer Inhibitors and Neurodevelopment
Abstract
:1. Introduction
2. Fetal Neurodevelopment
3. Antiretroviral Drugs (ARVs)
4. ARVs during Pregnancy
5. INSTI PK Profiles during Pregnancy
5.1. Raltegravir (RAL)
5.2. Elvitegravir (EVG)
5.3. Dolutegravir (DTG)
5.4. Bictegravir (BIC)
5.5. Cabotegravir (CAB)
6. INSTI Adverse Events
6.1. Neuropsychiatric Adverse Events
6.2. Weight Gain
6.3. Diabetes Mellitus
7. Known Side Effects of INSTIs during Development
7.1. Neural Tube Defects (NTDs)
7.2. Postnatal Neurodevelopmental Deficits
8. Potential Mechanisms Affecting Neurodevelopment
8.1. Maternal Mental Health
8.2. Maternal Weight Gain
8.3. Folate Levels
8.4. Neurotoxicity
8.5. Bilirubin Neurotoxicity
8.6. Inhibition of Matrix Metalloproteinase (MMPs) Activity
9. Long-Acting ARV Formulations and Neuroprotection
10. Conclusions and Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Class | Drug name | Acronyms | US FDA Approval Year | Recommendations for Pregnant Women Who Are ART Naïve | Recommendations for Continuation of ART in Women Who Become Pregnant | Recommendations for Women Planning to Become Pregnant |
---|---|---|---|---|---|---|
Tenofovir Alafenamide | TAF | 2016 | Preferred | Continue | Preferred | |
Nucleoside Reverse Transcriptase Inhibitors (NRTIs) | Emtricitabine Tenofovir disoproxil fumarate Abacavir Lamivudine | FTC TDF ABC 3TC | 2003 2001 1998 1995 | Preferred Preferred Preferred Preferred | Continue Continue Continue Continue | Preferred Preferred Preferred Preferred |
Zidovudine | ZDV | 1987 | Alternative | Continue | Alternative | |
Long-acting rilpivirine | LA-RPV | 2021 | Not recommended | Insufficient data | Insufficient data | |
Doravirine | DOR | 2018 | Insufficient data | Insufficient data | Insufficient data | |
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) | Rilpivirine Etravirine Efavirenz | RPV ETR EFV | 2011 2008 1998 | Alternative Not recommended Alternative | Continue Continue Continue | Alternative Not recommended, except in special circumstances Alternative |
Nevirapine | NVP | 1996 | Not recommended | Continue | Not recommended, except in special circumstances | |
Darunavir | DRV | 2006 | Preferred | Continue | Preferred | |
Tipranavir | TPV | 2005 | Do not use | Switch | Do not use | |
Fosamprenavir | FPV | 2003 | Do not use | Switch | Do not use | |
Protease Inhibitors (PIs) | Atazanavir | ATV | 2003 | Preferred | Continue | Preferred |
Lopinavir | LPV | 2000 | Not recommended, except in special circumstances | Continue | Not recommended, except in special circumstances | |
Saquinavir | SQV | 1995 | Do not use | Switch | Do not use | |
Fusion Inhibitor | Enfuviritide | T-20 | 2003 | Not recommended | Continue | Not recommended, except in special circumstances |
CCR5 Antagonist | Maraviroc | MVC | 2007 | Not recommended | Continue | Not recommended, except in special circumstances |
Cabotegravir | CAB | 2021 | Not recommended | Insufficient data | Insufficient data | |
Long-acting cabotegravir | LA-CAB | 2021 | Not recommended | Insufficient data | Insufficient data | |
Integrase Strand Transfer | Bictegravir | BIC | 2018 | Insufficient data | Insufficient data | Insufficient data |
Inhibitors (INSTIs) | Elvitegravir | EVG | 2014 | Not recommended | Continue with viral monitoring or consider switching | Not recommended |
Dolutegravir | DTG | 2013 | Preferred | Continue | Preferred | |
Raltegravir | RAL | 2007 | Preferred | Continue | Preferred | |
Attachment Inhibitor | Fostemsavir | FTR | 2020 | Insufficient data | Insufficient data | Insufficient data |
Pharmacokinetic Enhancers | Cobicistat | COBI, c | 2014 | Not recommended | Not recommended | Not recommended |
Ritonavir | RTV | 1996 | Depends on Protease Inhibitor | Depends on Protease Inhibitor | Depends on Protease Inhibitor |
Raltegravir | Elvitegravir/Cobicistat | Dolutegravir | Bictegravir | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Route of administration | Oral | Oral | Oral | Oral | ||||||
Dosing | 400 mg twice daily | 150/150 mg once daily | 50 mg once daily | 50 mg once daily | ||||||
Metabolism | Primarily UGT1A1 | Primarily CYP3A4 Minor UGT1A1 | Primarily UGT1A1 Minor CYP3A4 | Equal contribution by CYP3A4 and UGT1A1 | ||||||
Protein Binding | 76–83% | Elvitegravir 98–99% | Approximately 99% | Approximately 99.7% | ||||||
AUC0-12 or 0–24 (µg*h/mL) | [43] ad 2nd trimester: 6.6 (2.1–18.5) 3rd trimester: 5.4 (1.4–35.6) Postpartum: 11.6 (1.6–39.9) | [44] bd 3rd trimester: 5.0 (3.56–7.01) Postpartum: 7.11 (4.91–10.30) | [45] ad 3rd trimester: 3.921 (0.699–14.706) Postpartum: 6.770 (1.506–21.859) | [46] ae 2nd trimester: 15.283 (11.939–19.038) 3rd trimester: 14.004 (9.119–18.798) Postpartum: 21.039 (13.532–32.788) | [47] ace 3rd trimester: 14.1 (39) Postpartum: 21.7 (29) | [48] f 3rd trimester: 14.339 Postpartum: 15.356 | [49] ae 2nd trimester: 47.6 (33.4 – 63.7) 3rd trimester: 49.2 (36.4 –62.0) Postpartum: 65.0 (47.8–88.4) | [50] be 3rd trimester: 35.322 (19.196–67.922) Postpartum: 40.127 (22.795–59.633) | [51] ace 3rd trimester: 40.8 (35) Postpartum: 47.0 (42) | [52] e 3rd trimester: 37.9 Postpartum: 58 |
Cmax (µg/mL) | 2nd trimester: 2.250 (0.365–5.960) 3rd trimester: 1.770 (0.315–7.820) Postpartum: 3.035 (0.312–12.600) | 3rd trimester: 1.43 (0.93–2.22) Postpartum: 1.76 (1.10–2.80) | 3rd trimester: NR Postpartum: NR | 2nd trimester: 1.447 (1.133–1.579) 3rd trimester: 1.432 (0.705–1.570) Postpartum: 1.713 (0.955–2.284) | 3rd trimester: 1.4 (42) Postpartum: 1.8 (26) | 3rd trimester: 1.270 Postpartum: 1.352 | 2nd trimester: 3.62 (2.57–4.63) 3rd trimester: 3.54 (2.66–4.24) Postpartum: 4.85 (3.83–5.97) | 3rd trimester: 2.534 (1.462–3.986) Postpartum: 2.899 (1.397–4.224) | 3rd trimester: 3.15 (31) Postpartum: 3.34 (32) | 3rd trimester: 3.82 Postpartum: 4.7 |
Ch or trough (µg/mL) | 2nd trimester: 0.0621 (0.0128–0.438) 3rd trimester: 0.064 (0.0114–0.607) Postpartum: 0.0797 (0.0199–1.340) | 3rd trimester: 0.077 (0.043–0.137) Postpartum: 0.120 (0.074–0.193) | 3rd trimester: 0.057 (0.003–0.277) Postpartum: 0.069 (0.005–0.248) | 2nd trimester: 0.025 (0.017–0.067) 3rd trimester: 0.048 (0.014–0.075) Postpartum: 0.377 (0.228.5–0.568) | 3rd trimester: NR Postpartum: NR | 3rd trimester: 0.018 Postpartum: 0.068 | 2nd trimester: 0.73 (0.63–1.34) 3rd trimester: 0.93 (0.68–1.34) Postpartum: 1.28 (0.80–1.95) | 3rd trimester: 0.642 (0.188–0.3088) Postpartum: 0.777 (0.348–0.1210) | 3rd trimester: 0.68 (84) Postpartum: 1.03 (68) | 3rd trimester: 0.63 Postpartum: 1.23 |
Tmax (h) | 2nd trimester: 4.0 (1.0–8.0) 3rd trimester: 2.0 (0–12.0) Postpartum: 2.0 (0–8.0) | 3rd trimester: 1.98 (0–11.3) Postpartum: 2.03 (0–7.97) | 3rd trimester: NR Postpartum: NR | 2nd trimester: 4 (2–4) 3rd trimester: 4 (2–6) Postpartum: 4 (2–6) | 3rd trimester: 4 (2.0–6.0) Postpartum: 5 (3.0–7.8) | 3rd trimester: 2.9 Postpartum: 3.0 | 2nd trimester: 2 (2–4) 3rd trimester: 3 (2–4) Postpartum: 2 (2–4) | 3rd trimester: NR Postpartum: NR | 3rd trimester: 3.0 (1.0–4.5) Postpartum: 3.8 (0.5–8.0) | 3rd trimester: NR Postpartum: NR |
T1/2 (h) | 2nd trimester: 2.9 (1.2–85.6) 3rd trimester: 3.7 (1.1–211.7) Postpartum: 3.6 (1.1–30.5) | 3rd trimester: 2.55 (1.88–3.45) Postpartum: 2.53 (1.91–3.36) | 3rd trimester: NR Postpartum: NR | 2nd trimester: 3.1 (2.6–3.9) 3rd trimester: 3.4 (2.7–4.7) Postpartum: 8.8 (7.0–13.2) | 3rd trimester: 4.3 (37) Postpartum: 7.7 (30) | 3rd trimester: 2.6 Postpartum: 3.7 | 2nd trimester: 11.0 (8.9–13.1) 3rd trimester: 12.2 (10.4–15.0) Postpartum: 13.5 (10.6–18.6) | 3rd trimester: NR Postpartum: NR | 3rd trimester: 10.5 (49) Postpartum: 14.4 (46) | 3rd trimester: NR Postpartum: NR |
Cord blood:maternal blood ratio | 1.5 | 1.21 | NR | 0.91 | 0.75 | 0.64 | 1.25 | 1.21 | 1.29 | 1.49 |
Placental Transfer | High | High | High | High | ||||||
T1/2 (h) in infants post delivery | 26.6 (9.3–184) a [53] | 7.6 (6.3–10.2) a [46] | 32.8 (25.9–35.9) a [49] | NR | ||||||
Dosing recommendations in pregnancy | No change in dose indicated | Insufficient data to make dosing recommendations | No change in dose indicated | Insufficient data to make dosing recommendations |
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Foster, E.G.; Gendelman, H.E.; Bade, A.N. HIV-1 Integrase Strand Transfer Inhibitors and Neurodevelopment. Pharmaceuticals 2022, 15, 1533. https://doi.org/10.3390/ph15121533
Foster EG, Gendelman HE, Bade AN. HIV-1 Integrase Strand Transfer Inhibitors and Neurodevelopment. Pharmaceuticals. 2022; 15(12):1533. https://doi.org/10.3390/ph15121533
Chicago/Turabian StyleFoster, Emma G., Howard E. Gendelman, and Aditya N. Bade. 2022. "HIV-1 Integrase Strand Transfer Inhibitors and Neurodevelopment" Pharmaceuticals 15, no. 12: 1533. https://doi.org/10.3390/ph15121533