Antiretroviral HIV Medications: Understanding Drug Interactions and Resistance

When HIV was first identified, a diagnosis often meant a death sentence. Today, thanks to antiretroviral therapy (ART), people living with HIV can expect a near-normal lifespan-if they stay on treatment. But staying on treatment isn’t as simple as taking a pill every day. Behind the scenes, these medications are locked in a constant battle with the virus, and sometimes, they fight each other too.

How Antiretroviral Drugs Work

Antiretroviral drugs don’t kill HIV. They stop it from copying itself. HIV is a sneaky virus that slips into your immune cells and uses them to make more copies of itself. Antiretrovirals block that process at different stages. There are six main classes of these drugs, each targeting a different step in the virus’s life cycle.

NRTIs like tenofovir and lamivudine act like fake building blocks. When HIV tries to build its genetic code, it grabs these fake pieces instead, and the whole process breaks down. NNRTIs like doravirine and efavirenz stick to the virus’s reverse transcriptase enzyme and lock it in place. INSTIs like dolutegravir and bictegravir stop HIV from inserting its DNA into your cells. PIs block the final step where the virus cuts its proteins into usable pieces. Fusion inhibitors and CCR5 antagonists keep the virus from even entering the cell.

Modern treatment usually combines two NRTIs with one drug from another class-most often an INSTI. Why? Because combining drugs makes it harder for the virus to survive. If one drug fails, the others might still hold it back. That’s why regimens like Biktarvy (bictegravir/tenofovir alafenamide/emtricitabine) or Dovato (dolutegravir/lamivudine) are now first-line choices. They’re effective, simple, and have fewer side effects than older combinations.

Why Drug Interactions Matter

Many people with HIV also take medications for high blood pressure, cholesterol, depression, or diabetes. That’s where things get complicated. Some antiretrovirals mess with the liver enzymes that break down other drugs. This can cause dangerous spikes in drug levels-or make them disappear too fast.

Boosted protease inhibitors, like darunavir with ritonavir, are notorious for this. They can cause statins like simvastatin to build up to toxic levels, leading to muscle damage. Midazolam, a sedative used in hospitals, becomes dangerously strong when taken with boosted PIs-its concentration can jump nearly eightfold. Even common OTC meds like St. John’s wort can drop HIV drug levels so low that the virus starts replicating again.

On the flip side, newer drugs like doravirine (in Delstrigo) are designed to be cleaner. They don’t trigger liver enzymes as much, so fewer interactions occur. Studies show only 12% of people on doravirine needed dose changes for other meds, compared to 35% on efavirenz. That’s a big deal for someone juggling five or six prescriptions.

Even something as simple as antacids can interfere. Tenofovir alafenamide (TAF) needs an empty stomach to absorb properly. If you take it with calcium supplements or acid reducers, your body might not get enough of it. That’s why timing matters-and why doctors now use tools like the Liverpool HIV Drug Interactions Database to check every new prescription.

Resistance: When the Virus Outsmarts the Drugs

HIV mutates fast. Every time it copies itself, there’s a chance for a mistake. Most of those mistakes kill the virus. But sometimes, a mutation lets it survive despite the drug. That’s resistance.

Some drugs are more forgiving than others. INSTIs like dolutegravir and bictegravir have high genetic barriers-they need several mutations before the virus escapes. That’s why they’re preferred. NNRTIs like efavirenz, on the other hand, can be defeated by just one mutation, like K103N. One missed dose, and the virus might already be changing.

Resistance isn’t just about missing pills. It can be transmitted. About 1 in 6 new HIV diagnoses in the U.S. involve a strain already resistant to at least one drug. That’s why everyone gets a genotype test at diagnosis. It tells doctors which drugs will work from day one.

Even with perfect adherence, resistance can creep in. Long-acting injectables like Cabenuva (cabotegravir/rilpivirine) are great for people who struggle with daily pills. But if you miss an injection, drug levels drop slowly over weeks. That’s a perfect window for resistance to develop. Experts warn: if you’re on these injections, missing one dose isn’t like missing a pill-it’s like leaving the door open for the virus to rebuild its defenses.

There’s also the case of PrEP failure. Truvada and Descovy prevent HIV, but if someone gets infected while on PrEP and doesn’t know it, the virus can grow under low drug pressure and become resistant. The M184V mutation-common in people who took lamivudine-is one of the most frequent culprits.

The Rise of Next-Generation Drugs

Science isn’t standing still. New drugs are being developed to tackle resistance head-on. ViiV Healthcare’s VH-184, a third-generation INSTI, showed promise in early trials by suppressing HIV strains that had already resisted dolutegravir and bictegravir. In a 22-person trial, it slashed viral load by 1.8 logs in just weeks.

Lenacapavir (Sunlenca), approved in 2022, works differently-it blocks a step earlier in the virus’s life cycle. It’s now used for people with multi-drug resistant HIV and, as of July 2025, is recommended by WHO for prevention too. Given as a twice-yearly injection, it’s a game-changer for people who can’t stick to daily pills.

But innovation comes with risks. Gilead’s islatravir implant, meant to last a full year, was put on hold in early 2025 after some users saw drops in CD4 counts. Sometimes, the cure is worse than the disease.

Meanwhile, research into CRISPR gene editing is showing that we might one day be able to cut HIV DNA right out of infected cells. In animal studies, this approach reduced viral DNA by 95%. It’s still years away, but it’s proof that we’re thinking beyond pills and injections.

Real-World Challenges

Behind the science are real people. On Reddit’s r/HIV, users talk about insomnia from efavirenz, bone pain from tenofovir disoproxil fumarate (TDF), and the anxiety of switching regimens after resistance. One person described how missing doses because of side effects led to viral rebound-forcing them into a more complex, less tolerable regimen.

Surveys show 22% of people with HIV have had to switch meds because of resistance or side effects. Bone pain from TDF affected 41% of those who switched. Neuropsychiatric issues from efavirenz hit 37%. But those on dolutegravir-based regimens? 89% reported no side effects that disrupted their daily lives.

Access is another hurdle. In rural areas, getting a resistance test can take three weeks. In low-income countries, only 40% have routine resistance monitoring. That means people are getting treatment that might not work-and spreading resistant strains without knowing it.

And cost? Branded Truvada used to cost $2,800 a month. Generic tenofovir now runs $60. But even with generics, people still struggle to afford co-pays, lab tests, and follow-ups. Insurance doesn’t always cover the tools doctors need to make smart choices.

What You Need to Know

If you’re on ART, here’s what matters:

• Never skip doses. Even one missed pill can give the virus a chance to mutate.
• Tell your doctor everything you take. Supplements, OTC meds, recreational drugs-everything. Use the NIH Drug Interaction Checker if you’re unsure.
• Get tested for resistance at diagnosis and after any treatment failure. It’s not optional-it’s standard.
• If you’re on long-acting shots, treat them like a lifeline. Missing one can have long-term consequences.
• Ask about newer options. Dolutegravir, bictegravir, doravirine-these are safer, simpler, and more forgiving than older drugs.

ART has turned HIV from a death sentence into a chronic condition. But it’s not magic. It’s a partnership between science and discipline. The drugs are powerful. The virus is clever. And the stakes? Your health, your future, and the health of others.