Hydroxychloroquine vs Alternatives: Benefits, Risks & Best Uses

Oct, 4 2025

Key Takeaways

• Hydroxychloroquine is an antimalarial and immunomodulatory drug widely used for lupus and rheumatoid arthritis.
• Its main alternatives differ by indication: chloroquine and artemisinin‑based therapies for malaria, methotrexate and belimumab for autoimmune disease, and azithromycin or doxycycline for certain infections.
• When judging efficacy, look at clinical trial data, disease‑specific outcomes, and real‑world prescribing patterns.
• Safety profiles vary: hydroxychloroquine has a lower cardiac risk than chloroquine but can cause retinal toxicity with long‑term use.
• Cost and availability in the UK NHS influence the practical choice for most patients.

What Is Hydroxychloroquine?

Hydroxychloroquine is a synthetic 4‑aminoquinoline that was first approved in the 1950s as a malaria prophylactic. It works by increasing the pH of intracellular vesicles, which interferes with parasite growth and modulates immune cell signaling. In the United Kingdom it is also licensed for systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) because of its ability to dampen auto‑inflammatory pathways.

How Hydroxychloroquine Works and When It’s Used

The drug accumulates in lysosomes and endosomes, raising their pH and preventing the malaria parasite Plasmodium falciparum from digesting hemoglobin. In autoimmune disorders it blocks Toll‑like receptor activation, reducing cytokine release.

Typical adult dosing for SLE is 200-400mg daily, with a half‑life of about 40days, allowing steady‑state concentrations after 2-3months. For malaria prophylaxis the regimen is 400mg once weekly after a loading dose.

Alternatives to Hydroxychloroquine

Choosing an alternative depends on the disease you’re treating. Below are the most common substitutes, each introduced with a brief definition.

Chloroquine is a close chemical cousin of hydroxychloroquine, historically the first‑line malaria drug before resistance spread. It shares the same lysosomal‑pH mechanism but carries a higher risk of cardiotoxicity and visual disturbances.

Artemisinin‑based Combination Therapy (ACT) combines a fast‑acting artemisinin derivative with a partner drug (e.g., lumefantrine) to clear P. falciparum infections. ACTs are the WHO‑recommended first‑line treatment for uncomplicated malaria worldwide.

Methotrexate is a folate antagonist that inhibits dihydrofolate reductase, reducing DNA synthesis in rapidly dividing immune cells. It is the cornerstone disease‑modifying antirheumatic drug (DMARD) for RA and is used off‑label for severe SLE.

Belimumab is a monoclonal antibody that blocks the B‑lymphocyte stimulator (BLyS) protein, decreasing auto‑antibody production. Approved for SLE in patients who remain active despite standard therapy.

Azithromycin is a macrolide antibiotic often paired with hydroxychloroquine in early COVID‑19 studies, though later data showed limited benefit. It remains useful for atypical bacterial pneumonia and some sexually transmitted infections.

Doxycycline is a tetracycline antibiotic that also serves as a malaria chemoprophylactic for travelers to regions with chloroquine‑resistant strains. It works by inhibiting protein synthesis in the parasite.

Side‑by‑Side Comparison

When to Choose Hydroxychloroquine Over Its Alternatives

If you or your clinician are dealing with a chronic autoimmune disease and need a low‑cost oral agent, hydroxychloroquine often wins because it has a favorable safety record for long‑term use and requires only simple blood monitoring for retinal health.

For acute malaria in regions where chloroquine resistance is high, ACTs are the gold standard. Chloroquine might still be useful for P. vivax in areas without resistance, but the cardiac and visual safety signals push most prescribers toward ACTs or hydroxychloroquine prophylaxis when travel is short‑term.

In severe SLE that does not respond to hydroxychloroquine and methotrexate, biologics like belimumab become cost‑effective despite the high price tag because they can dramatically cut flare rates.

Monitoring and Safety Tips

• Eye exams: Baseline retinal screening and annual OCT scans after five years of use (or sooner if high daily doses).
• Cardiac checks: Baseline ECG if you have a history of arrhythmia or are taking other QT‑prolonging drugs.
• Blood work: Liver function and complete blood count every 3‑6months for autoimmune dosing.
• Drug interactions: Avoid concurrent use of strong CYP2D6 inhibitors that can raise hydroxychloroquine levels.

Practical Decision Tree

1. Identify the primary condition (malaria, SLE, RA, other).
2. If malaria:
   • Check local resistance patterns. If P. falciparum resistance is high → choose ACT.
   • If traveling to chloroquine‑sensitive area → chloroquine or hydroxychloroquine prophylaxis.
3. If autoimmune disease:
   • Start with hydroxychloroquine for mild‑to‑moderate SLE/RA.
   • Escalate to methotrexate if disease activity persists.
   • Consider belimumab or other biologics for refractory SLE.
4. Assess patient‑specific factors: kidney function, ophthalmic health, pregnancy status, cost constraints.

Frequently Asked Questions

Next Steps for Readers

1. Talk to your GP or rheumatologist about whether hydroxychloroquine fits your disease profile.

2. If traveling to a malaria‑endemic region, schedule an appointment with a travel clinic to get the most up‑to‑date resistance map.

3. Arrange baseline eye testing if you plan to be on hydroxychloroquine for more than a year.

4. Keep a written list of all medicines you take; share it with any specialist prescribing a new alternative.

Making an informed choice now can keep you well‑treated and avoid costly side‑effects later.