ANTIVIRALS

Question 1

Viruses

Answer 1

Consist of:- Nucleic acid (DNA or RNA), Protein (coat - structural, enzymes-non-structural) +/- Lipid envelope
Obligate intracellular parasites

Question 2

ACUTE (rna viruses)

Answer 2

Influenza, measles, mumps, hepatitis A virus

Question 3

Chronic viruses

Answer 3

(generally DNA viruses): Latent with (or without) recurrences- Herpes simplex, Cytomegalovirus
Persistent- HIV, HTLV, Hepatitis B virus, Hepatitis C virus

Question 4

Virus syndromes

Answer 4

Non-vesicular rashes: measles, rubella, parovirus, adenovrus, HHV6.
Vesicualr rashes: Chickenpox, herpes, enterovirus.
Respiratory infections: Infuenz, Respriratyr syncytial virus, parainfluenza, human metapneumovirus, rhinovirus, coronavirus.
Gastroenteritus: Rotavirus, norovirus, astrovirus, sapovirus, adenovirus.
Neurological disease: Encephalitis/Meningitis, HSV (reactivation), Enteroviruses, Rabies, Japanese encephalitis virus, Nipah Virus
Blood boure: Hepatitis viruses, HBV, HCV, Retroviruses, HIV 1,2, HTLV 1,2

Question 5

When to use antivirals:

Answer 5

Acute infections in general population: Primary HSV and Herpes simplex encephalitis, Chickenpox in adolescents and adults, Shingles in eye, Elderly (shingles, influenza)
Chronic infections: HIV, HBV, HCV
Infections in immunocompromised: Post transplant, Individuals receiving immunosupressive therapies

Question 6

Virus Replication

Answer 6

Virus attachment to cell (via receptor) –> Cell Entry –> Virus Uncoating –> Early proteins produced – viral enzymes –> Replication –> Late transcription/translation – viral structural proteins –> Virus assembly –> Virus release and maturation

Question 7

Virus life cycle

Answer 7

Viruses take over much of host intracellular machinery. All viruses encode unique proteins many of which are vital for virus replication and infectivity. These unique proteins are targets for molecular inhibition (anti-viral activity).

Question 8

INHIBITORS OF REPLICATION: polymerases

Answer 8

DNA –> DNA: eukaryotes, DNA viruses. DNA –> RNA: eukaryotes, DNA viruses
RNA –> RNA: RNA viruses. RNA –> DNA: retrovirus (HIV), hepatitis B virus.

Question 9

Nucleotide Reverse Transcriptase Inhibitors (NRTI) inhibit reverse transcriptase

Answer 9

• AZT (azidothymidine): Developed in 1965 as anti-cancer drug In 1985 found to inhibit HIV replication
• HIV NRTIs: Pyrimidine analogues (Thymidine analogues = Zidovudine) and Cytosine analogues (Lamivudine). Purine analogues (Adenosine and Guanosine)- Abacavir and Tenofovir
• Hep B: also contains reverse transcriptase enzyme so some NRTIs are also active against HBV. If duel infection then use these drugs.
• Herpes virus polymerase inhibitors: Aciclovir (HSV and VZV) and Ganciclovir (CMV, HHV6 (as well as HSV and VZV).
• Hep C virus RNA polymerase nucleotide inhibitor: Sofosbuvir.

Question 10

NON- nucleotide reverse transcriptase inhibitors (NNRTI’s)

Answer 10

• Efavirenez and Nevira

Question 11

Protease inhibitors (PI)

Answer 11

Hep C: Paritaprevir, Grazoprevir
HIV: Atazanavir, Darunavir, Ritonavir (now used to boost levels of other PI’s). Aspartase protease of HIV.
Other HIV drugs:
Entry inhibitor: Enfuviritide (T20, given by IM injection) –fusion inhibitor and Maraviroc - Chemokine receptor antagonsit (Co-receptor CCR-5)
Integrase Inhibitors (retroviruses): Raltegravir, Dolutegravir

Question 12

HAART - Highly Active Antiretroviral Therapy

Answer 12

HAART: 2 NRTIs + NNRTI, 2 NRTIs + boosted PI. Started when CD4 falls. Aim to switch off virus replication. Taken lifelong. Suppression >10yrs achieved. Now problems with toxicity

Question 13

HIV MUTATION- ANTIVIRAL RESISTANCE

Answer 13

HIV genome contains ~9,000 nucleotides. Every genome will contain at least one mutation. A strain will become predominant if it has a selection advantage over fellow progeny. For example M184V mutation results in resistance to Lamivudine. In presence of Lamivudine the rare population of strains with this mutation will soon predominate

Question 14

HIV CURE

Answer 14

HIV suppressed on antivirals. Existing CD4 lymphocytes destroyed by conditioning. Stem cells reconstituted with HLA-matched but delta 32 homozygous allogeneic donor. Antiviral therapy stopped following transplantation. Remained HIV negative (by PCR). HIV antibody titres have declined

Question 15

ACYCLOVIR:

Answer 15

For Rx of Herpes Simplex Virus (HSV) and Varicella Zoster Virus (VZV). Nucleoside analogue (phosphorylated by herpesvirus thymidine kinase)

Question 16

VALCICLOVIR:

Answer 16

It slows the growth and spread of the herpes virus to help the body fight the infection

Question 17

OSELTAMIVIR

Answer 17

Neuraminidase inhibitors

Treats Influenza.

Question 18

Influenza treatment

Answer 18

• oseltamivir and inhibitors of M2 protein.

Situated in viral envelope of influenza A virus. good target for treatment.

Question 19

CMV (cytomegalocirus) treatments

HERPES family

Answer 19

Ganciclovir

Cidofovir

Question 20

Be aware of ribavirin (broad spectrum of damage

Answer 20

TREATS:
RSV: Respiratory Syncytial Virus
HCV: Hep C
HEV: Hep E

Question 21

conclusions

Answer 21

Antivirals work by blocking a stage of viral replication. These act on virally encoded proteins
Virus can rapidly mutate and become resistant to antivirals. For acute infections antivirals only tend to work if given soon after symptoms develop.