Influenza Treatment and Prophylaxis

Influenza Treatment

• Oseltamivir may still provide benefit in reducing respiratory failure and death in pregnant women if started 3-4 days after onset.
• Prophylaxis is 70-90% effective in preventing influenza and is a useful adjunct to vaccines, but the CDC recommends against it due to the risk of resistance.
• Prophylaxis is only recommended for populations at risk of complications and to control institutional outbreaks.

Baloxavir Marboxil (Xofluza)

• Single-dose PO treatment for influenza A and B.
• First-in-class medication with a unique MOA that targets ribonuclease activity affecting transcription of viral RNA.
• Approved in the US in 2018 and potentially has fewer side effects compared to oseltamivir.

Herpesvirus Infections

• Cytomegalovirus (CMV) infections are usually asymptomatic in immunocompetent individuals, but can cause retinitis, esophagitis, and colitis in immunocompromised patients.

Nucleoside Analogues

• Acyclovir (Zovirax) is effective in treating serious herpesvirus infections, including encephalitis and infections in immunocompromised patients.
• Topical acyclovir can be used to treat genital herpes and mild mucocutaneous infections, but is less effective than oral treatment.
• Valacyclovir (Valtrex) is a prodrug that gets rapidly converted to acyclovir and has more complete absorption (55%) compared to acyclovir (22%).
• Famciclovir (Famvir) has the greatest bioavailability (80%) and gets rapidly hydrolyzed to penciclovir after absorption.

Other Drugs

• Foscarney (Foscavir) is used to treat CMV retinitis in AIDS patients and acyclovir-resistant HSV infections and shingles.

Treating Genital Herpes

• Oral treatment with acyclovir, valacyclovir, or famciclovir prevents replication of HSV, reduces pain and symptoms of acute infection, and shortens the time to healing of lesions and reduces viral shedding.
• Does not eliminate the virus, and recurrent episodes are common.

Treating Shingles

• Oral treatment with acyclovir, valacyclovir, or famciclovir shortens the duration of acute illness and pain and lowers the incidence of postherpetic pain.
• Famciclovir and valacyclovir are more effective than acyclovir, and newer drugs have less frequent administration and higher serum levels.
• A vaccine is now available (Zostavac) that reduces the incidence and severity of herpes zoster infections in older adults.

Treating CMV

• Nucleoside analogues are used to prevent and treat CMV disease, including retinitis, esophagitis, and colitis.
• Ganciclovir is 100 times more active against CMV than acyclovir.

HIV Infection

• Combined use of 2 or more drugs from different classes has been shown to markedly reduce viral load and improve survival.
• Multidrug treatment called highly active antiretroviral therapy (HAART) has been developed.

HAART

• Initially, complicated regimens required multiple doses of several drugs every day, but recent emphasis is on developing drug regimens that require only a few doses each day or even a single pill (like atripla).
• Guidelines continue to evolve as new regimens are developed and testing improves.

Pathophysiology of HIV

• HIV enters CD4 cells, and viral RNA is produced, which gets converted to double-stranded DNA via reverse transcriptase.
• Viral DNA enters the host cell nucleus and gets incorporated into the host genome via HIV integrase.
• Eventually, the viral DNA gets transcribed/translated to produce polyproteins that get packed into immature virions.

Drug Classes

• 1. Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
• 2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
• 3. Protease inhibitors (PIs)
• 4. Fusion and entry inhibitors
• 5. Integrase strand transfer inhibitors

Reverse Transcriptase Inhibitors

• NRTIs are converted to active triphosphate metabolites by host cell kinases, which compete with corresponding endogenous nucleoside triphosphate for incorporation into DNA, causing chain termination.

Nucleoside vs Nucleotide

• Tenofovir disoproxil fumarate (TDF) is classified as a nucleotide RTI, which gets hydrolyzed in the body to form tenofovir.

Nucleoside Transcriptase Inhibitors (NRTIs)

• First class of drugs developed for treating HIV+ individuals.
• Included in almost all regimens.
• Serve as antimetabolites for different purine and pyrimidine bases of DNA.
• Often more effective when combined with other NRTIs.

Fusion and Entry Inhibitors

• Enfuvirtide (Fuzeon) is a large peptide that binds to HIV glycoprotein 41 and blocks the fusion process.
• Maraviroc (Selzentry) is a newer drug that inhibits fusion and entry of HIV.
• Active against HIV strains resistant to RTIs and PIs.

Integrase Inhibitors

• Raltegravir (Isentress) is the first integrase strand inhibitor approved to treat HIV.
• Works by preventing DNA strand transfer.
• Potent in vitro activity against wild-type and MDR HIV strains.