Novel Antiretroviral Therapeutic Strategies for HIV
Abstract
:1. Introduction
1.1. Global Epidemiology and Viral Genome of HIV
1.2. Replication Cycle of HIV
1.3. Viral Phases of HIV
2. Antiretrovirals and Therapeutic Targets
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- Nucleotide/Nucleoside Reverse Transcriptase Inhibitors (NRTI);
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- Non-Nucleotide Reverse Transcriptase Inhibitors (NNRTI);
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- Integrase Inhibitors (II);
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- Protease Inhibitors (PI);
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- Fusion Inhibitors (FI);
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- Pharmacokinetic Enhancers (PE);
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- CCR5 Antagonist.
2.1. Nucleotide/Nucleoside Reverse Transcriptase Inhibitors (NRTI)
2.2. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
2.3. Integrase Inhibitors (IIs)
2.4. Protease Inhibitors (PIs)
2.5. Fusion Inhibitors
2.6. Pharmacokinetic Enhancers
2.7. CCR5-Antagonist
3. New Drugs—Overview of Phase III Clinical Trials and Recent Approvals
3.1. Post-Attachment Inhibitors: Ibalizumab
3.2. Long-Acting Injectable Cabotegravir/Rilpivirine Formulation
3.3. Fostemsavir
3.4. Leronlimab (PRO 140)
3.5. UB-421
3.6. Others
4. Novel Therapeutic Strategies
4.1. New Transdermal Drug Delivery Systems
4.1.1. Transdermal Delivery System for Tenofovir Alafenamide
4.1.2. Transdermal Delivery of Enfuvirtide (T20) via Ultrasounds
4.2. Nanosystems for Drug Delivery
5. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Class of Antiretroviral Drugs | Therapeutic Target | Approved Drugs | Advantages | Disadvantages | Ref. |
---|---|---|---|---|---|
Nucleotide/Nucleoside Reverse Transcriptase Inhibitors | Reverse Transcriptase | Abacavir (ABC) Ziagen® | Long intracellular half-life period High oral bioavailability Few interactions No problems with administration | Highly prone to resistance Adverse effects: myelosuppression neuropathy pancreatitis, nausea, vomiting fatigue, anemia, lactic acid accumulation | [16,17,18] |
Tenofovir disoproxil fumarate (TNF) Viread® | |||||
Lamivudine (3TC) Epivir® | |||||
Emtricitabine (FTC) Emtriva® | |||||
Zidovudine (AZT) Retrovir® | |||||
Non- Nucleotide Reverse Transcriptase Inhibitors | Reverse Transcriptase | Efavirenz (EFV) Sustiva® | More selective than NRTIs Cheaper to produce Single-tablet regimens | Very prone to resistance. Rash, nausea, vomiting, fatigue, mood swings, depression, jaundice, conjunctivitis, and respiratory issues | [17,19,20] |
Nevirapine (NVP) Viramune® | |||||
Delavirdine (DLV) Rescriptor® | |||||
Etravirine (ETR) Intelence® | |||||
Rilpivirine (RPV) Edurant® Doravirine (Pifeltro®) | |||||
Integrase Inhibitors | Viral Integrase DNA integration) | Raltegravir (RAL) Isentress® | Very selective drugs, they interact with two components of viral replication | Hypersensitivity reactions, rash, jaundice, dark-colored urine, nausea, vomiting, fatigue, blisters in the mouth and skin, diarrhea, and loss of appetite | [16,17,19] |
Dolutegravir (DTG) Tivicay® Bictegravir Biktarvy® | |||||
Protease Inhibitors | Viral protease protein synthesis | Ritonavir (RTV) Norvir® | Active against HIV-1 and HIV-2 | High prevalence of resistance. Arrhythmia, heartburn, fatigue, jaundice, dizziness, abdominal pain, mouth sores, and urinary tract issues | [17,19,21] |
Nelfinavir (NFV) Viracept® | |||||
Atazanavir (ATZ) Reyataz® | |||||
Darunavir (TMC114) Prezista ® | |||||
Saquinavir (SQV) Invirase® Fortovase® | |||||
CCR5 antagonist | CCR5 co-receptor | Maraviroc Celsentri® | Effective in cases of resistance to conventional therapy regimens | Only effective in R5 viruses Nausea, Diarrhea, Fatigue, headache | [22,23] |
Post-attachment inhibitors | CD4+ cells | Ibalizumab Trogarzo® | Pharmacokinetics allows for a weekly administration Does not cause CD4 depletion No evidence of resistance | Immune reconstitution inflammatory syndrome | [17,24] |
Pharmacokinetic Enhancers | CYP3A subfamily | Cobicistat Tybost® | More selective than ritonavir Less drug-drug interactions | Might cause raises in serum creatinine Side effects in the gastrointestinal tract | [17,25,26] |
Fusion Inhibitors | gp41 subunit | Enfuvirtide Fuzeon® | Decreases viral load in a c-ART regimen Increases CD4 cell counts Low toxicity High specificity | Short half-life Low threshold for drug resistance Can cause reaction in its injection-site, nausea, and fatigue High cost Inconvenient route of administration | [18,27,28,29,30] |
Approved Drugs | Active Substances | References |
---|---|---|
Genvoya® Biktarvy® | 150 mg elvitegravir/150 mg cobicistat/200 mg emtricitabine/10 mg tenofovir 50 mg bictegravir/200 mg emtricitabine/25 mg tenofovir alafenamide | [38,39] |
Atripla® | 600 mg efavirenz/200 mg emtricitabine/245 mg tenofovir-DF | [40] |
Rezolsta® | 800 mg darunavir/150 mg cobicistat | [40] |
Triumeq® | 50 mg dolutegravir/600 mg abacavir/300 mg lamivudine | [41] |
Evotaz® | 300 mg atazanavir/150 mg cobicistat | [42] |
Descovy® | 200 mg emtricitabine/10 mg tenofovir alafenamide 200 mg emtricitabine/25 mg tenofovir alafenamide | [43] |
Nanocarriers + ARV | Main Outcomes | References |
---|---|---|
Liposomes + Stavudine | Liposomes were revealed to be a promising alternative for stavudine delivery as these carriers can be easily absorbed by macrophages. | [95] |
Dendrimer + Zidovudine | The formulation reduced the AZT hemolytic effect and prolonged the drug release, decreasing the occurrence of side effects. | [97] |
Carbosilane Dendrimers+Zidovudine Carbosilane Dendrimers + Efavirenz Carbosilane Dendrimers + Tenofovir | An enlarged antiviral activity of all three drugs was observed when formulated with dendrimers. | [98] |
Nanodiamond Particles + Efavirenz | A suitable and slower release profile through a blood–brain barrier model was obtained impairing viral replication for a longer period. | [101] |
PGLA nanoparticles + Efavirenz PGLA nanoparticles + Saquinavir | An enlarged antiviral activity of all three drugs was obtained with PGLA nanoparticles. | [102] |
PGLA nanoparticles + Efavirenz + Raltegravir [thermosensitive gel] | A lower EC90 and a constant release of these loaded drugs were obtained being a promising option for pre-exposure HIV prophylaxis. | [103] |
CAP nanoparticles + Efavirenz (thermosensitive gel) | High encapsulation efficacy and lower cytotoxicity in HeLa cells were observed besides enhanced prophylactic activity in TMZ-bl cells treated with EFV-CAP nanoparticles. | [105] |
CAP nanoparticles + Dolutegravir (thermosensitive gel) | pH (4.2 and 7.4) influenced both the drug release and the cytotoxicity of this formulation. | [104] |
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Cunha, R.F.; Simões, S.; Carvalheiro, M.; Pereira, J.M.A.; Costa, Q.; Ascenso, A. Novel Antiretroviral Therapeutic Strategies for HIV. Molecules 2021, 26, 5305. https://doi.org/10.3390/molecules26175305
Cunha RF, Simões S, Carvalheiro M, Pereira JMA, Costa Q, Ascenso A. Novel Antiretroviral Therapeutic Strategies for HIV. Molecules. 2021; 26(17):5305. https://doi.org/10.3390/molecules26175305
Chicago/Turabian StyleCunha, Rita F., Sandra Simões, Manuela Carvalheiro, José M. Azevedo Pereira, Quirina Costa, and Andreia Ascenso. 2021. "Novel Antiretroviral Therapeutic Strategies for HIV" Molecules 26, no. 17: 5305. https://doi.org/10.3390/molecules26175305