Truvada (Emtricitabine and Tenofovir Disoproxil Fumarate)

Truvada treats and prevents human immunodeficiency virus (HIV), but one of the active ingredients, tenofovir disoproxil fumarate (TDF), has links to major potential side effects like worsening hepatitis B complications and developing drug resistance. Truvada can also cause other severe side effects, like kidney problems and bone loss.

When first introduced in 2004, Truvada represented a major advancement in treating and preventing HIV. Over time, serious safety concerns and side effects have surfaced, leading the U.S. Food and Drug Administration (FDA) to issue black box warnings, the agency’s most serious form of medication alert. In addition, injured patients have filed Truvada lawsuits.

Truvada works by interfering with HIV’s viral reproduction, making it more difficult for the virus to replicate and spread in the body. However, the mechanism TDF uses to slow HIV or prevent infection can lead to severe side effects. In recent years, alternatives to TDF have proved effective at treating and preventing HIV with significantly less risk of damage to bones or organs.

Truvada (TDF) remains an important option for HIV treatment and prevention, but its risks, including serious side effects and FDA black box warnings, cannot be ignored. Newer alternatives may provide safer ways to achieve similar results with fewer health concerns.

TDF is an antiretroviral medication used to treat and prevent HIV and AIDS (acquired immunodeficiency syndrome).

TDF was first sold under the brand name Viread, and is one of the active ingredients in several other branded drugs, including Atripla, Complera and Truvada. These three drugs all combine TDF with another antiviral, emtricitabine (FTC).

Gilead Sciences introduced TDF to the market in 2001, and Truvada — the first drug to combine TDF with another antiretroviral — debuted in 2004. Since 2020, several manufacturers have started selling generic forms of Truvada in the U.S.

According to the National Center for Biotechnology Information, TDF works by interfering with reverse transcriptase, an enzyme that HIV needs to replicate itself and spread through the body. After the body processes TDF, it becomes a sort of “decoy” that HIV incorporates into its DNA. With these decoys in place, the DNA can no longer replicate, which prevents HIV from spreading to other cells or continuing to multiply.

Patients originally took TDF for the treatment of HIV in combination with other antiretrovirals. In 2012, the FDA approved Truvada as a preventive pre-exposure prophylaxis (PrEP) anti-HIV medication for high-risk adults.

Every drug has side effects, and Truvada is no different. Many of the common Truvada side effects are shared with lots of other drugs, including:

These common side effects may seem familiar and relatively mild, as they are similar to those associated with ibuprofen. There are also some more concerning possible side effects to Truvada, but these usually appear with long-term use.

Since people using Truvada for PrEP often take it daily for many years, sometimes decades, the risk of experiencing these effects increases over time.

Kidney Problems

Truvada’s label has warnings for new onset or worsening kidney impairment, including acute renal failure and Fanconi syndrome.

Fanconi syndrome is a rare condition affecting kidney tubules’ function, which impacts the kidney’s ability to reabsorb certain substances. As a result, patients with Fanconi syndrome excrete an overabundance of glucose, bicarbonate, phosphates, uric acid, potassium and certain amino acids through their urine. Too much depletion of these substances can lead to worsening kidney damage and bone problems.

Before patients begin Truvada treatment, health care providers should test kidney function.

Several studies link TDF, one of the active ingredients in Truvada, to kidney problems.

Clinical trial data reassured doctors that TDF would not have the same kidney toxicity as other drugs in its class. Yet, in a 2013 article published in the Journal of the American Society of Nephrology, Dr. Jérôme Tourret and colleagues highlighted the publication of the first case of TDF-induced acute kidney injury in 2001.

“Numerous cases have been published since then, and it is now established that TDF presents a tubular toxicity risk,” the study authors wrote.

According to Truvada’s label, some HIV-infected patients who started high-dose or multiple nonsteroidal anti-inflammatory drugs (NSAIDs) reported acute renal failure. Some patients ended up hospitalized and on renal replacement therapy.

A July 2022 study published in the journal BMC Infectious Diseases looked at the kidney safety of Truvada during pregnancy. Researchers didn’t observe any safety concerns for kidney function for the pregnant person or fetus.

Bone Density Loss

Generally, osteopenia and osteoporosis occur in 40% to 90% of HIV-infected people. People with HIV also have a 60% increased fracture risk compared to uninfected people. Truvada for PrEP or HIV treatment may increase the risk of bone mineral density loss.

According to Truvada’s drug label, cases of osteomalacia, which involves weakened bones due to kidney damage, may manifest as bone pain or pain in the extremities.

Researchers noted signs of increased bone turnover, which is the rate of bone reabsorption in the body. An increased rate of bone turnover can increase the risk of fracture.

There is mixed evidence on how bone loss from TDF compares to the active ingredients in similar drugs. A 2016 study in the journal Current Opinion in HIV and AIDS found 1% to 3% greater bone mineral density loss amongst adults taking TDF medications compared to other HIV drugs.

However, a small 2017 study in the International Journal of Antimicrobial Agents that followed 26 HIV-infected youths for 10 years found that TDF-containing drugs did not impair bone mineral density in young patients.

“Larger studies are needed to confirm these results,” authors Vania Giacomet and colleagues wrote.

Immune Reconstitution Syndrome

Immune reconstitution syndrome, also called immune reconstitution inflammatory syndrome or IRIS, is a collection of disorders that occurs when preexisting infections worsen after starting highly active antiretroviral therapy drugs such as Truvada.

This condition can occur in about 10% to 40% of HIV patients with low CD4+ T-cell counts. A CD4+ T-cell is a white blood cell that helps the immune system. A T-cell count of less than 50/μL and a high amount of HIV in the blood are the most common risk factors for IRIS, according to an article published in The Medical Journal of Australia.

Patients with IRIS may develop symptoms anywhere from one week to a few months after starting therapy.

During the initial phase of TDF-based drug therapy, patients may experience infections that require treatment, such as pneumonia, tuberculosis and bacterial or viral infections.

In addition, autoimmune disorders such as Graves’ disease, Guillain-Barré syndrome and polymyositis have occurred in patients.

Lactic Acidosis

Though rare, some patients who used Truvada alone or in combination with other antiretrovirals have experienced lactic acidosis, a buildup of acid in the blood. Some people also developed an enlarged liver or an accumulation of fat in the liver. Some of these were fatal.

In one case reported in the National Journal of Medical Research, a 50-year-old man with HIV started taking tenofovir, lamivudine and efavirenz. After three days on this combination, he experienced nausea, vomiting, upper abdominal pain and breathlessness.

Doctors diagnosed him with lactic acidosis and hepatitis induced by tenofovir. He improved after he stopped taking tenofovir.

It can also affect people with hepatitis B. In a case published in the journal Medicine, a 59-year-old man with hepatitis B developed lactic acidosis after 10 days on TDF. Despite stopping TDF and starting hemodialysis, the patient died.

Black box warnings are the most serious medication warnings the FDA issues. These warnings alert people to significant risks and require doctors to review these risks before prescribing.

The FDA’s Truvada black box warnings address worsening of existing hepatitis B and developing drug-resistant HIV in patients using Truvada for PrEP.

Patients with hepatitis B can experience worsening symptoms or even a reactivation of the hepatitis B virus in their bodies. Additionally, patients who stop taking Truvada may also experience worsening hepatitis B symptoms.

If a patient begins using Truvada for PrEP but has already contracted HIV, their HIV can become resistant to Truvada, making treatment more difficult.

In addition to the black box warnings, Truvada has links to several other potentially serious side effects. Many of these are directly connected to TDF, one of the active ingredients in Truvada and several other medications used to treat or prevent HIV.

Newer drugs like Descovy pair emtricitabine with an alternative to TDF called tenofovir alafenamide, or TAF. TAF works similarly to TDF in blocking HIV replication but does so more selectively, reducing stress on the kidneys and bones. Doctors often recommend Descovy for patients at higher risk of bone or kidney issues.

The U.S. government has accused Gilead Sciences, the maker of Truvada and Descovy, of failing to obtain the appropriate licenses for its drugs and withholding royalties owed to the government.

Manufacturers have not recalled Truvada or other drugs containing TDF in the United States.

Since its introduction in 2004, regulators have closely monitored Truvada, and certain long-term side effects have emerged, including:

Despite these concerns, Truvada has not faced a full FDA recall, and Gilead has not recalled any batches of Truvada due to safety issues.

These side effects have also led to Truvada lawsuits seeking damages from Gilead Sciences.

Since the introduction of newer formulations like TAF, the use of TDF-containing drugs has declined.

Truvada is an effective treatment and preventive for HIV because TDF delivers tenofovir to cells and thereby prevents HIV from replicating. The dangers associated with TDF-containing medications come primarily from the high amounts of tenofovir that TDF introduces to the body.

TDF introduces tenofovir to the bloodstream, where large amounts of tenofovir are circulated throughout the body and absorbed by cells. On the other hand, TAF delivers tenofovir directly to cells, resulting in much lower levels of tenofovir in the bloodstream.

If you or a loved one has undergone cancer treatment, you may know the difference between chemotherapy, which affects the whole body, and targeted radiation. Similarly, TDF acts like chemotherapy, affecting the body more broadly, while TAF works more like targeted treatment.

Most side effects of Truvada and other TDF-containing drugs are linked to the amount of tenofovir in the body. Reducing tenofovir levels by up to 90% can significantly minimize or eliminate many of these serious side effects.

According to the journal InfezMed, studies show that patients treated with TAF experience significantly fewer serious side effects compared to TDF, including lower risks to the kidneys and bones.

TAF has a much smaller impact on kidney function, with a lower risk of new or worsening kidney impairment. It also causes significantly less bone mineral density loss than TDF, particularly in the hip and spine.

Although TDF remains an effective option for HIV treatment and prevention, many patients are transitioning to TAF-based alternatives. Those with preexisting kidney problems or concerns about bone health are prime candidates for moving from TDF to TAF treatments.

Older patients may also benefit from TAF treatment, as aging comes with a higher risk of kidney problems and bone loss.

Long-term users of TDF-based treatments may also benefit from a shift to TAF, since the side effects of TDF treatment tend to get worse over extended use.

Truvada and other TDF-containing drugs remain widely used, and the availability of a generic Truvada means TDF-based treatments will likely continue in cases where cost is a key factor.

If you are taking Truvada or another TDF-containing medication, it is important to understand potential side effects and take steps to protect your health. Never stop taking your medication without consulting your doctor, as this is especially important for Truvada. For patients with hepatitis B, stopping Truvada can cause the reactivation or severe worsening of symptoms, which can be life-threatening.

Patients on Truvada should regularly monitor kidney and liver function, as well as bone density. Staying in close consultation with your doctor helps manage side effects and act promptly if any issues arise.