Antivirals, Antifungals, and Antiparasitics

TL;DR. Antivirals are hard to make because viruses use your own cells' machinery, so there is little to target that is not also yours. The successes are spectacular: HIV went from a death sentence to a manageable condition with normal life expectancy, and hepatitis C went from incurable to cured in 8 to 12 weeks with over 95 percent success. Antifungals are similarly constrained because fungi are eukaryotes like us. Most antivirals work best started very early, which is why the window for flu and shingles treatment is measured in days.

1. Why antivirals are hard

A bacterium is a self-contained organism with its own cell wall, ribosomes, and metabolism. There is plenty to attack that you do not have.

A virus is not. It is genetic material in a protein coat that hijacks your cells' machinery to replicate. Most of the machinery it uses is yours, so drugs that block it tend to block you too.

The targets that do exist are the few steps a virus performs itself:

The elegance of aciclovir is worth spelling out because it is the model for selective toxicity in antivirals. Aciclovir is a prodrug that must be phosphorylated to be active. The first phosphorylation is performed by a viral enzyme (thymidine kinase) that only infected cells have. So the drug is activated almost exclusively inside infected cells, and it is then incorporated into viral DNA where it terminates the chain. This is why aciclovir is remarkably non-toxic despite being a DNA chain terminator. Gertrude Elion, who led the work, won a Nobel Prize.

2. The antivirals worth knowing

Herpes family (cold sores, genital herpes, shingles, chickenpox)

Aciclovir, valaciclovir, famciclovir. Valaciclovir is a prodrug of aciclovir with much better oral absorption, so it is dosed less often.

• Cold sores: topical aciclovir cream is marginally effective at best; oral treatment works better. Either way, start at the first tingle, before the blister appears.
• Shingles: oral antivirals within 72 hours of rash onset reduce severity, duration, and the risk of post-herpetic neuralgia, a persistent and sometimes debilitating nerve pain. The 72-hour window is the single most important fact here, and people routinely miss it by waiting.
• Genital herpes: episodic treatment for outbreaks, or suppressive daily treatment for frequent recurrences, which also substantially reduces transmission to partners.
• Chickenpox: usually not treated in healthy children; treated in adults, pregnancy, and the immunosuppressed.

These drugs suppress, they do not cure. Herpes viruses remain latent in nerve ganglia for life.

The shingles vaccine (Shingrix) is over 90 percent effective and, unlike treatment, prevents the problem (Chapter 74).

Influenza

Oseltamivir (Tamiflu) and zanamivir block neuraminidase, the enzyme influenza uses to release new virus from infected cells.

The honest evidence: started within 48 hours, they shorten symptoms by roughly 16 to 24 hours in otherwise healthy adults. Whether they reduce hospitalisation and complications is genuinely contested: the 2014 Cochrane review, produced after a long campaign to obtain the full unpublished trial data from the manufacturer, concluded the evidence for reducing complications was weak. That episode became a landmark case for clinical trial data transparency and prompted policy changes. Subsequent observational data in hospitalised and high-risk patients are more favourable.

Current practice: they are recommended for high-risk groups (older people, pregnancy, chronic disease, immunosuppression) and for hospitalised patients, and their value in otherwise healthy adults is modest.

Baloxavir is a newer single-dose agent with a different mechanism; resistance emerges readily.

COVID-19

Nirmatrelvir/ritonavir (Paxlovid) is a protease inhibitor combined with ritonavir, which is included purely to inhibit CYP3A4 and thereby keep nirmatrelvir levels high. That pharmacokinetic trick is also the source of its major problem: ritonavir causes a very large number of drug interactions, including with statins, some anticoagulants, some antiarrhythmics, and several psychiatric drugs. Every prescription requires an interaction check.

It must be started within 5 days of symptom onset and shows clear benefit in high-risk, unvaccinated, or immunocompromised patients. Benefit in vaccinated, low-risk people is much less clear.

Remdesivir is intravenous, used in hospital. Molnupiravir has weaker efficacy data.

HIV

The clearest success story in antiviral medicine. Combination antiretroviral therapy using three drugs from at least two classes suppresses viral replication to undetectable levels.

The consequences are transformative:

• Life expectancy approaching normal for people diagnosed early and treated consistently.
• Undetectable = Untransmittable (U=U): a person with a sustained undetectable viral load cannot transmit HIV sexually. This is established by large studies (PARTNER, PARTNER2, Opposites Attract) with zero linked transmissions across many thousands of acts, and it is endorsed by the CDC, WHO, and UNAIDS. It remains poorly known outside the affected community and it changes everything about how HIV should be understood.
• PrEP (pre-exposure prophylaxis, typically tenofovir/emtricitabine, or long-acting injectable cabotegravir) reduces sexual acquisition of HIV by around 99 percent when taken as directed.
• PEP (post-exposure prophylaxis) started within 72 hours of an exposure reduces the chance of infection.

Modern regimens are frequently a single daily tablet, and long-acting injectables given every one or two months are now available.

Hepatitis

Hepatitis C is the most dramatic recent change in medicine. Until around 2013, treatment was interferon plus ribavirin: a year of injections, severe side effects, and a cure rate around 50 percent. Direct-acting antivirals (sofosbuvir, glecaprevir, velpatasvir and relatives) now cure over 95 percent of cases in 8 to 12 weeks of oral tablets with minimal side effects.

This is a genuine cure, eliminating a virus that causes cirrhosis and liver cancer. The obstacle is price and access rather than science, and generic production has brought costs down dramatically in low- and middle-income countries. The WHO has an elimination target for 2030.

Hepatitis B is suppressed rather than cured by tenofovir or entecavir, usually lifelong. The vaccine prevents it, and universal infant vaccination has dramatically reduced both infection and liver cancer in countries that adopted it.

3. Antifungals

The problem: fungi are eukaryotes, like us. Their cells are far more similar to ours than bacteria are, so there are fewer selective targets and antifungals are correspondingly more toxic.

Common uses:

• Thrush (candidiasis): topical clotrimazole or a single oral fluconazole capsule. Recurrent thrush needs investigation, including for diabetes.
• Athlete's foot, ringworm, jock itch: topical terbinafine or an azole cream, applied for the full course and for a week or two after it looks better, because relapse is common.
• Fungal nail infection: this is the one that requires patience. Oral terbinafine for 6 weeks for fingernails and 12 weeks for toenails, with liver function monitoring. Topical treatments have low cure rates. The nail continues to look abnormal for months after cure because it must grow out.
• Seborrhoeic dermatitis and dandruff: ketoconazole shampoo.
• Serious systemic fungal infection: amphotericin B, historically nicknamed "ampho-terrible" for its kidney toxicity and infusion reactions, now largely given in lipid formulations that are better tolerated.

Antifungal resistance is a growing problem, notably Candida auris, which is multi-drug-resistant, persists on surfaces, and causes hospital outbreaks. Azole resistance in Aspergillus has been linked to agricultural azole fungicide use (Chapter 6), which is the same story as antibiotic use in livestock.

Azoles are potent CYP3A4 inhibitors, which makes them a major source of drug interactions: itraconazole and ketoconazole in particular raise levels of statins, some anticoagulants, and many other drugs substantially.

4. Antiparasitics

Ivermectin deserves a note. It is a genuinely important drug: its discovery won the 2015 Nobel Prize, and mass administration programmes have brought river blindness and lymphatic filariasis close to elimination in several regions. It has no established role in treating COVID-19. Large well-conducted randomised trials (TOGETHER, ACTIV-6, PRINCIPLE) found no benefit, and several of the early positive studies were withdrawn or found to contain fabricated data. Veterinary formulations taken by people caused poisonings.

5. Practical guidance

• Start antivirals early. Shingles within 72 hours of the rash; flu within 48 hours; Paxlovid within 5 days; cold sore treatment at the first tingle. Waiting to see how it goes wastes the window.
• Complete antifungal courses, especially topical ones, for the full duration plus a margin. Under-treatment is the main reason athlete's foot and ringworm recur.
• Nail fungus takes months. Judge success by new growth from the base, not by the old nail.
• Treat household contacts for threadworm, scabies, and head lice simultaneously, or you will simply re-infect each other.
• Post-scabies itch is normal for weeks and is not treatment failure.
• Check interactions carefully with azole antifungals and with ritonavir-containing products; both are potent CYP3A4 inhibitors.
• Vaccination beats treatment for influenza, shingles, hepatitis B, and HPV.
• If you are at risk of HIV, PrEP works. If you have had a potential exposure, PEP within 72 hours works. If you are living with HIV and virally suppressed, you cannot transmit it sexually.

6. The bottom line

• Antivirals are hard because viruses use your machinery. The successful ones target the few steps the virus does itself, and aciclovir's activation by a viral enzyme is the classic example of selective toxicity.
• Timing is everything: shingles within 72 hours, flu within 48, Paxlovid within 5 days, cold sores at the first tingle.
• HIV treatment produces near-normal life expectancy, and an undetectable viral load means the virus cannot be transmitted sexually. PrEP prevents acquisition with around 99 percent effectiveness.
• Hepatitis C is now curable in 8 to 12 weeks with over 95 percent success, which is one of the great recent achievements in medicine.
• Antifungals are constrained because fungi are eukaryotes. Nail infections take months, topical courses must be completed, and azoles are potent CYP3A4 inhibitors with many interactions.
• Treat the whole household for threadworm, scabies, and head lice, and expect post-scabies itch to persist for weeks.

Sources and notes

Doses, cautions, and interactions follow the British National Formulary and the electronic Medicines Compendium; US figures follow FDA labelling. Aciclovir's selective activation by viral thymidine kinase follows Elion's Nobel-recognised work. Shingles treatment within 72 hours and post-herpetic neuralgia reduction follow NICE and IDSA guidance. Oseltamivir evidence follows the Cochrane review by Jefferson et al., 2014, obtained after a campaign for full clinical study reports, and subsequent observational analyses in hospitalised patients. Nirmatrelvir/ritonavir efficacy follows EPIC-HR, Hammond et al., NEJM, 2022, and its extensive interaction profile follows the Liverpool COVID-19 Drug Interactions resource. HIV antiretroviral outcomes and life expectancy follow the Antiretroviral Therapy Cohort Collaboration. U=U rests on PARTNER (Rodger et al., JAMA, 2016), PARTNER2 (The Lancet, 2019), and Opposites Attract, and is endorsed by CDC, WHO, and UNAIDS. PrEP efficacy follows PROUD and IPERGAY. Hepatitis C direct-acting antiviral cure rates and the WHO 2030 elimination target follow WHO hepatitis guidance. Antifungal classes and resistance, including Candida auris and azole-resistant Aspergillus linked to agricultural fungicide use, follow CDC and Verweij et al.'s work. Terbinafine nail treatment durations follow BNF. Ivermectin's Nobel-recognised role in river blindness follows the 2015 prize citation; its failure in COVID-19 follows TOGETHER (Reis et al., NEJM, 2022), ACTIV-6, and PRINCIPLE, plus the retraction of several early positive studies.

Open questions. Whether antivirals for influenza reduce hard outcomes in otherwise healthy adults is still disputed. Antifungal resistance is rising faster than the development pipeline, and the agricultural contribution is difficult to quantify.

👉 Next: vaccines.