Pitfalls of Antiretroviral Therapy: Current Status and Long-Term CNS Toxicity
Abstract
:1. Introduction
2. HIV Infection within the CNS
2.1. The Blood-Brain Barrier
2.2. A Trojan Horse Mechanism for HIV Infection of the CNS
2.3. Elusive Latent Proviral Reservoirs within the CNS
3. Pitfalls of ART: Focus on the CNS
3.1. ART Does Not Protect against Latent HIV Infections
3.2. ART Has Limited BBB Penetrance
3.3. ART-Induced CNS Toxicity
Cell Type | Impact from ART | References |
---|---|---|
Astrocyte | ↓ Mitochondria function and metabolism ↓ MMPs ↑ Senescence ↑ ER stress | [3,13,77] |
Endothelial Cell | ↓ Viability ↓ Mitochondria function ↓ Autophagosome formation ↓ TJPs ↑ ROS production ↑ ER stress ↑ Inflammatory cytokine production | [3,12,36,75,78,79] |
Microglial Cell | ↓ Lysosomal function ↓ Autophagosomal function ↑ ROS production ↑ Expression of pro-inflammatory cytokines | [10] |
Neuron | ↓ Axonal length ↓ Neurogenesis ↑ Neuronal death ↑ Oxidative stress ↑ ROS accumulation | [4,73,80,81] |
Neural Progenitor Cell | ↓ Cell proliferation ↓ Mitochondrial function ↑ Senescence ↑ ROS production ↑ MMP production | [82,83,84] |
Oligodendrocyte | ↓ Maturation ↑ ROS production ↑ Oxidative stress ↑ Lysosomal stress | [85,86] |
Pericyte | ↓ Coverage | [87] |
4. Novel Strategies in Developing HIV Therapeutics
4.1. CNS Targeting of Latent HIV Provirus
4.2. Obstructing Infection by HIV
5. Concluding Comments
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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ARVd Class | Function | Drug Examples | CPE Score | Side Effects | Adult Dosage Schedule |
---|---|---|---|---|---|
Nucleoside reverse transcriptase inhibitor (NRTI) | Inhibits reverse transcriptase, blocking production of viral DNA | Lamivudine (3TC) | 2 | Nausea, dizziness, lactic acidosis, pancreatitis, IRIS | 300 mg once or 150 mg twice daily |
Zidovudine (ZDV) | 4 | Nausea, dizziness, lactic acidosis, liver problems, myopathy, severe anemia, neutropenia, IRIS, lipoatrophy | 250–300 mg twice daily | ||
Emtricitabine (FTC) | 3 | Nausea, dizziness, lactic acidosis, IRIS, possible HBV flare up | 200 mg daily | ||
Tenofovir (TFV) | 1 | Nausea, dizziness, lactic acidosis, kidney problems including kidney failure | 300 mg daily | ||
Non-nucleoside reverse transcriptase inhibitors (NNRTI) | Binds to and blocks HIV reverse transcriptase, blocking production of viral DNA | Efavirenz (EFV) | 3 | Nausea, dizziness, mental health problems, liver problems, severe rash, nervous system issues, seizures, IRIS, lipodystrophy, hyperlipidemia | 600 mg daily with a NRTI or PI |
Nevirapine (NVP) | 4 | Nausea, dizziness, severe liver problems, skin rash, IRIS, lipodystrophy syndrome | 200 mg twice daily | ||
Fusion inhibitors (FI) | Inhibits viral binding or fusion of HIV to host target cells preventing the entry of HIV | Albuvirtide * (ABT) | ND | Nausea, headache, diarrhea, rashes, hyperlipidemia | ND |
Enfuvirtide (T20) | 1 | Allergic reaction, nausea, headache, pneumonia, neuralgia, IRIS | 90 mg twice daily | ||
Protease inhibitors (PI) | Blocks proteases required for proteolytic cleavage of precursors necessary viral replication | Atazanavir (ATV) | 2 | Nausea, dizziness, heart arrhythmia, severe rash, liver problems, life-threatening drug interaction, chronic kidney disease, kidney stones, gallbladder problems, IRIS, lipodystrophy, increased bleeding in hemophiliacs, diabetes, and hyperglycemia | 300 mg with 100 mg RTV daily |
Darunavir (DRV) | 3 | Nausea, dizziness, liver problems sever skin reactions, diabetes, hyperglycemia, lipodystrophy, IRIS | 600–800 mg with 100 mg RTV daily | ||
Ritonavir (RTV) ⊥ | 1 | Nausea, dizziness, pancreatitis, heart arrhythmia, severe allergic reactions, liver problems, hyperlipidemia, hyperglycemia, IRIS, lipodystrophy, increased bleeding in hemophiliacs, gastrointestinal problems | 600 mg twice daily | ||
Integrase strand transfer inhibitors (INSTI) | Prevents the integration of HIV DNA into host DNA | Dolutegravir (DTG) | ND | Nausea, dizziness, allergic reactions, liver problems, IRIS, sleep problems | 50 mg once or twice daily |
Raltegravir (RAL) | 3 | Nausea, dizziness, severe skin reactions, allergic reactions, liver problems, IRIS | 1200 mg daily or 400–800 mg twice daily | ||
Chemokine coreceptor antagonists | Blocks coreceptors (CCR5/CXCR4) preventing the entry of HIV | Maraviroc (MVC)—CCR5 | 3 | Nausea, dizziness, liver problems, heart problems (including heart attack), skin reactions, allergic reactions, postural hypotension, IRIS, possible increased risk of other infections or cancer | 150 mg, 300 mg, or 600 mg twice daily depending on concomitant medications |
Leronlimab * (PA14) | ND | Diarrhea, headache, swollen lymph nodes, hypertension, local injection site reactions | ND | ||
CD4 attachment inhibitors/post-attachment inhibitors | Binds to host CD4 receptor blocking HIV attachment and entry | Ibalizumab-uiyk (IBA) | ND | Nausea, dizziness, IRIS, diarrhea, rashes | Loading dose of 2000 mg and maintenance doses of 800 mg every two weeks |
UB-421 * (mAb dB4) | ND | Rash, hives, increased eosinophil count, elevated liver enzyme levels | ND |
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Rudd, H.; Toborek, M. Pitfalls of Antiretroviral Therapy: Current Status and Long-Term CNS Toxicity. Biomolecules 2022, 12, 894. https://doi.org/10.3390/biom12070894
Rudd H, Toborek M. Pitfalls of Antiretroviral Therapy: Current Status and Long-Term CNS Toxicity. Biomolecules. 2022; 12(7):894. https://doi.org/10.3390/biom12070894
Chicago/Turabian StyleRudd, Harrison, and Michal Toborek. 2022. "Pitfalls of Antiretroviral Therapy: Current Status and Long-Term CNS Toxicity" Biomolecules 12, no. 7: 894. https://doi.org/10.3390/biom12070894
APA StyleRudd, H., & Toborek, M. (2022). Pitfalls of Antiretroviral Therapy: Current Status and Long-Term CNS Toxicity. Biomolecules, 12(7), 894. https://doi.org/10.3390/biom12070894