Antiretroviral HIV Medications: Understanding Complex Interactions and Drug Resistance

When HIV first became a global crisis, a diagnosis often meant a death sentence. Today, thanks to antiretroviral therapy (ART), people living with HIV can expect to live nearly as long as anyone else-if they stay on treatment. But staying on treatment isn’t as simple as taking a pill every day. Behind that daily routine lies a complex web of drug interactions, evolving resistance patterns, and long-term side effects that can make or break a person’s health.

How Antiretroviral Drugs Work

Antiretroviral medications don’t cure HIV. Instead, they stop the virus from copying itself. HIV attacks CD4 cells, the immune system’s command center. Without treatment, the virus multiplies, weakens the body, and eventually leads to AIDS. ART blocks HIV at different stages of its life cycle. There are six main classes of these drugs:

• NRTIs (like tenofovir and lamivudine) trick the virus into using broken building blocks, stopping it from making new DNA.
• NNRTIs (like doravirine and efavirenz) bind to the virus’s reverse transcriptase enzyme and jam it.
• PIs (like darunavir) prevent the virus from cutting its proteins into usable pieces.
• INSTIs (like dolutegravir and bictegravir) block the virus from inserting its DNA into human cells.
• Fusion inhibitors and CCR5 antagonists stop HIV from entering cells in the first place.

Modern treatment almost always combines at least three drugs from two or more classes. The most common regimen today? Two NRTIs plus an INSTI. Why? Because INSTIs like dolutegravir and bictegravir have the highest resistance barrier-they need multiple mutations before they stop working. That’s why they’re now the first choice for nearly 78% of new HIV diagnoses in the U.S.

Why Drug Interactions Matter More Than You Think

Many people with HIV also take medications for high blood pressure, cholesterol, depression, or diabetes. That’s where things get risky. Some antiretrovirals interfere with how other drugs are processed by the liver, especially through the CYP3A4 enzyme system.

Boosted PIs-like darunavir with ritonavir or cobicistat-are notorious for this. They can cause dangerous spikes in levels of common drugs like simvastatin (a cholesterol medicine), leading to muscle damage. Midazolam, used for sedation, can become life-threatening when combined with boosted PIs. The Liverpool HIV Interactions Database lists 12 major drug classes that should never be mixed with these regimens.

Even newer drugs aren’t risk-free. Efavirenz, an older NNRTI, causes sleep problems and mood changes in up to 50% of users. That’s why many switch to doravirine, which doesn’t trigger CYP3A4 as much. In one trial, only 12% of people on doravirine needed dose adjustments for other meds-compared to 35% on efavirenz.

And then there’s tenofovir. Two versions exist: TDF (older) and TAF (newer). TAF works at 90% lower doses because it targets immune cells more efficiently. That means less kidney and bone damage. Still, TDF-based regimens cause 40% more bone mineral loss than abacavir-based ones over 144 weeks. That’s why doctors now prefer TAF or abacavir for patients with osteoporosis or kidney issues.

Resistance: When the Virus Outsmarts the Drugs

Resistance isn’t magic. It’s evolution. Every time HIV copies itself, it makes mistakes. Most mistakes kill the virus. But sometimes, a mutation lets it survive despite the drug. That mutated strain multiplies. Soon, the drug doesn’t work anymore.

Some drugs are easier to resist than others. NNRTIs like efavirenz can be defeated by just one mutation-K103N. That’s why they’re falling out of favor. INSTIs like dolutegravir need several mutations at once to lose effectiveness. That’s a much higher bar.

But even the strongest drugs aren’t invincible. The R263K and G118R mutations together can reduce dolutegravir’s power. And now, a new drug called VH-184 is showing promise in early trials. In a 2025 study of 22 people with HIV resistant to dolutegravir and bictegravir, VH-184 cut viral load by 1.8 log10-meaning the amount of virus dropped by 63 times. It’s not approved yet, but it could be the next lifeline for people with multi-drug resistant HIV.

Resistance isn’t just about treatment failure. It can be passed on. About 16.7% of newly diagnosed people in the U.S. already carry drug-resistant HIV. That’s why every new diagnosis should include a resistance test. The results guide which drugs to start with-and which to avoid.

Long-Acting Injections: A Game-Changer With a Catch

For many, daily pills are a burden. Side effects, stigma, forgetfulness-they all add up. That’s why long-acting injectables like Cabenuva (cabotegravir + rilpivirine) are changing the game. Instead of pills, patients get shots every month. In the ATLAS trial, 94% of users preferred injections over daily pills.

But here’s the catch: if you miss a shot, the drug level drops slowly. For months, you’re exposed to subtherapeutic levels. That’s a perfect setup for resistance. Dr. Sharon Lewin warns that “missed injections can breed resistance just like missed pills.”

Even more advanced options are coming. Lenacapavir, approved in 2022 for multi-drug resistant HIV, is now recommended by WHO for prevention too. It’s given every six months. And ViiV Healthcare is testing a six-month version of VH-184. If it works, it could mean just two shots a year for treatment or prevention.

But these innovations require perfect adherence. One missed injection could mean years of resistance. That’s why they’re not for everyone.

Side Effects That Change Lives

Not all problems come from resistance or interactions. Some come from the drugs themselves.

Abacavir, an NRTI, can cause a severe allergic reaction in people with the HLA-B*5701 gene. Testing for this gene before starting abacavir is now standard. Without it, 90% of those with the gene will develop a dangerous rash, fever, and breathing trouble.

Neuropsychiatric side effects from efavirenz-nightmares, depression, suicidal thoughts-are so common that many patients quit. The Positive Voices 2024 survey found 37% of people switched regimens because of these effects. In contrast, 89% of those on dolutegravir-based regimens like Biktarvy or Dovato reported no side effects that affected their daily lives.

And then there’s cardiovascular risk. People with HIV have a 33% higher chance of heart disease, especially if they’re on boosted PIs. The REPRIEVE trial showed that taking pitavastatin daily cuts major heart events by 36%. Now, many doctors prescribe it alongside ART-not just for cholesterol, but for protection.

What Happens When Treatment Fails

Viral rebound-when the virus starts growing again-is a red flag. It almost always means resistance. The first step? A genotype test. It tells you which mutations are present. Based on that, your doctor picks a new regimen.

For multi-drug resistance, the old approach was stacking drugs: five or six antiretrovirals at once. Now, it’s smarter. Drugs like lenacapavir and VH-184 are designed to work even when other drugs fail. Dr. Cal Cohen reports 92% suppression rates using darunavir plus dolutegravir in tough cases. But Dr. Kimberly Smith argues that future regimens may not need multiple drugs at all.

What’s clear? You can’t guess your way out of resistance. Testing is non-negotiable. The DHHS guidelines require it at diagnosis and after any treatment failure. In the U.S., Medicaid now covers it 100%. But in rural areas, delays are common-21 days on average in community labs. That’s why tools like the NIH’s HIV Drug Interaction Checker and the Johns Hopkins HIV Guide app are so vital. They help clinicians make fast, accurate decisions.

The Future: AI, Prevention, and Equity

The global ART market is worth $38.7 billion and growing. But access isn’t equal. In sub-Saharan Africa, 29% of new HIV cases already involve drug resistance-nearly double the U.S. rate. Many countries lack routine resistance testing. Only 40% have the systems to track it.

Meanwhile, AI is stepping in. Tools like HIV-TRACE can predict how resistance spreads through networks by analyzing genetic sequences. When linked to electronic health records, they help doctors choose the best drugs before resistance even develops.

And prevention is changing too. WHO’s 2025 recommendation of lenacapavir for PrEP means people at risk can now get protection with just two injections a year. That’s huge for those who struggle with daily pills. But it also means resistance must be monitored even in people who aren’t infected yet.

The goal by 2030? 95% viral suppression worldwide. But that won’t happen without solving three things: better access to testing, smarter drug combinations, and global equity in care. Resistance isn’t just a medical problem-it’s a social one.