Antivirals for HIV Yasir Waheed, PhD. Some HIV Facts HIV – the Human Immunodeficiency Virus is the retrovirus that causes AIDS HIV belongs to the retrovirus.

Antivirals for HIV

Yasir Waheed, PhD

Some HIV Facts

• HIV – the Human Immunodeficiency Virus is the retrovirus that causes AIDS

• HIV belongs to the retrovirus subfamily lentivirus.

• HIV attaches to cells with CD4 receptors (T4 cells and macrophages).

HIV Life Cycle1

• Step 1: Attachment of virus at the CD4 receptor and chemokine co-receptors CXCR4 or CCR5

• Step 2: viral fusion and uncoating• Steps 3-5: Reverse transcriptase makes a

single DNA copy of the viral RNA and then makes another to form a double stranded viral DNA

• Step 6: migration to nucleus• Steps 7-8: Integration of the viral DNA into

cellular DNA by the enzyme integrase• Steps 9-11: Transcription and RNA processing• Steps 12-13: Protein synthesis• Step 14: protease cleaves polypeptides into

functional HIV proteins and the virion assembles

• Step 15: virion budding• Step 16: Virion maturation

Anti- HIV Drug Targets2

Three types of drugs are currently in clinical use:

1. nucleoside and nucleotide reverse transcriptase (RT) inhibitors

2. non-nucleoside reverse transcriptase inhibitors

3. protease inhibitors (PIs)

Nucleoside and Nucleotide Analogs

• Nucleoside analogs (NRTI) act as chain terminators or inhibitors at the substrate binding site of RT

• NRTI’s must be phosphorylated (three steps) to their 5’-triphosphate form to become active inhibitors.

• Nucleotide analogs (NtRTI) already contain a phosphate group and only go through 2 steps to become active.

• The 5’-triphosphate of the NRTI’s compete with the 2’-deoxynucleoside’s 5’-triphosphate for binding to reverse transcriptase leading to viral DNA chain termination3.

Nucleoside Analogs

• There are currently 7 FDA-approved NRTI’s and one nucleotide analog.

• The first anti-HIV drug approved was the NRTI known as AZT or Zidovudine (1987).

• AZT was discovered as a treatment of AIDS during a screening process for the identification of effective AIDS treatments.

• Antiviral selectivity due to higher affinity for HIV RT than human DNA polymerases.

Non-Nucleoside Analogs

• Non-nucleoside analog reverse transcriptase inhibitors (NNRTI’s) inhibit viral DNA replication by binding at the allosteric non-bonding site of RT, causing a conformational change of the active site.

• NNRTI’s do not require bioactivation by kinases. • Three NNRTI’s are currently approved for clinical use

in combination therapy: nevirapine, delavirdine, and efavirenz.

Non-Nucleoside Analogs

Delavirdine

BenzoxazinoneNevirapine

Protease Inhibitors• During the reproduction cycle of HIV a specific

protease is needed to process the polyproteins into mature HIV components.

• If protease is missing non-infectious HIV is produced.

• HIV protease inhibitors are specific to HIV protease because it differs significantly from human protease.

• The 6 PI’s currently approved for clinical use were all designed by using structure-based drug design methods.

HIV Protease

• The crystal structure of HIV protease was first obtained at Merck Laboratories.

• HIV protease is a 99 amino acid aspartyl protease that functions as a homodimer with one active site.

• The active sites of protease are hydrophobic.

Protease Inhibitors

• ABT-378 or lopinavir was approved in 2000 for use in combination with ritonavir (a PI) (Kaletra)

• Ritonavir strongly inhibits the metabolism of ABT-378.

Some Alternative Therapies • Virus adsorption inhibitors – interfere with

virus binding to cell surface by shielding the positively charged sites on the gp-120 glycoprotein– Polyanionic compounds

• Viral coreceptor antagonists – compete for binding at the CXCR4 (X4) and CCR5 (R5) coreceptors– bicyclams and ligands

Virus Adsorption Inhibitors• Cosalane was originally

developed as an anti-cancer agent by researchers at Purdue University and the U.S. National Cancer Institute.

• Cosalane was developed from a chemical known as ATA (aurintricarboxylic acid), which has long been known to have anti-HIV activity.

• The result was cosalane.• Cosalane binds to the HIV

gp-120 protein.

Viral Coreceptor Antagonists • Bicyclams are a type of viral

coreceptor antagonist.• They are very specific and potent

X4 coreceptor antagonists.• Bicyclams belong to a

class of macrocyclic polyamines consisting of two cyclam units linked by an aliphatic bridge

• Bicyclams with an aromatic linker apparently had higher antiviral activity.

• One such compound is AMD3100.

Combination Therapy

• Combination therapy often called HAART is standard care for people with HIV.

• Monotherapy created virus resistance to the individual drug. Some combination therapies increase the time it takes for the virus to become resistant.

• Combinations of a PI or NNRTI with one or two NRTI’s is often recommended.

• Combination therapy may reduce individual drug toxicity by lowering the dosage of each drug

Drug Toxicity and Side Effects

• All available antiretroviral drugs are toxic.• Side effects of nucleoside analogs are lactic

acidosis and severe hepatomegaly with steatosis (enlarged fatty liver).

• Other side effects of anti-HIV drugs include pancreatitis, myopathy, anemia, peripheral neuropathy, nausea, and diarrhea.

Reducing Drug Toxicity

• The use of combination therapy:– Combining agents with favorable synergistic

properties allows a decrease in dose or dosing frequency

– Ritonavir alone cause gastrointestinal side effects but when used in combination with other PI’s it can be administered at a lower dose.

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10 Million Patients on Antiretroviral Therapy

2013 Global AIDS Response Progress Reporting (WHO/UNICEF/UNAIDS)

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Principles of HIV Drug Resistance

• Not all drug failure is due to resistance • Partial HIV suppression promotes resistance • Resistance may fade but not disappear when

a drug is stopped

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Principles of Resistance (2)

• Some mutations allow certain viruses to resist the effects of one or more antiretroviral drugs.

• Each infected person has a mixture of viruses, some of which are resistant to some medications.

• The drug resistant virus usually grows faster and better than the drug susceptible virus.

• The drug resistant virus replaces the drug susceptible virus in the patient.

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Resistance Testing

• Two types:– Genotyping• Less expensive• Can usually be completed in 1-2 weeks

– Phenotyping• More expensive• Generally takes 2-3 weeks to complete

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Suspect Resistance in the Setting of Treatment Failure

• Due to HIV’s high transcription error rate and high level of replication, mutant HIV variants constantly generated.

• These variants often contain mutations that confer variable levels of resistance to antiretroviral agents.

• Poor adherence or suboptimal regimens can lead to resistance and ‘viral breakthrough’.

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How Does Resistance Develop?

• Results from changes (mutations) in the genetic information in the virus.

• These changes occur whenever HIV is replicating.

• Every possible mutation occurs tens of thousands of times each day.

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Resistance Mutations

• For some drugs (NNRTIs and 3TC), a single mutation causes high-level resistance. – Resistance to these drugs occurs very quickly

• For other drugs (most NRTIs and PIs), many mutations must occur before high-level resistance is observed. – Resistance to these drugs occurs more slowly

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Cross-Resistance

• Resistance to one drug can cause resistance to others of the same class– NNRTI: complete cross-class resistance– NRTI: partial cross-class resistance– PI: partial cross-class resistance• Partly overcome by ritonavir boosting

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Minimize Emergence of Viral Resistance

• Never prescribe ARVs in the absence of adherence counseling and support

• Never prescribe monotherapy or dual therapy• Ensure optimal serum drug concentrations– Avoid drug interactions – Diagnose and manage malabsorption

• If ARV medications are to be discontinued, stop all drugs at the same time– Possible exception: NNRTI-based regimen

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2003 vs. 2005 WHO Guidelines

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