Viread (tenofovir disoproxil fumarate, TDF) was approved by the FDA in October 2001 and is still the only nucleotide analog available. Nucleotide analogs work like nucleoside analogs (Retrovir [AZT], Videx [ddI], Zerit [d4T], etc.) but need one less chemical step to interfere with HIV replication. Once inside a cell, they work just like nucleosides and can have the same side effects.

Background

Viread is Gilead Sciences' second attempt to enter the HIV market. Their first nucleotide, adefovir, was denied FDA approval in 1999 due to its kidney toxicity. A lower dose of adefovir was later approved for hepatitis B and is marketed under the brand name Hepsera. Viread was in a much earlier stage of development at the time, but Gilead decided to drop adefovir for HIV and concentrate instead on Viread.

It was a smart move. Viread has not shown the same level of kidney problems as adefovir, although they can still occur. And it has been shown to be more effective, lowering viral load significantly (1.2 logs, or 94%) in people who have never taken anti-HIV drugs.

The major study of Viread in people who have not taken anti-HIV drugs was Study 903, a trial of 600 people taking the non-nucleoside Sustiva (efavirenz) and Epivir (3TC), along with either Viread or Zerit. Since Sustiva plus Epivir plus Zerit was a popular combination when the study opened in March 2000, this was an important comparison. Viread did well, showing similar efficacy to Zerit but causing smaller increases in cholesterol and triglycerides. After 96 weeks, LDL (bad) cholesterol increased 20 mg in the Zerit group compared to an 11 mg increase in the Viread group, a significant difference. Triglycerides increased 103 mg with Zerit but only 5 mg with Viread. And so far, Viread seems to do better in terms of body fat redistribution -- doctors reported lipodystrophy in 12% of people on Zerit, but in only 1% of people on Viread.

The most closely watched trial, and the one that led to Viread's FDA approval, was Study 907. In this trial, 550 people who were already taking anti-HIV drugs but who had viral loads between 400 and 10,000 added either Viread or a placebo to their current regimen for six months. After six months, over 40% of people taking Viread had viral loads below 400, compared to only 11% of those taking placebo. Of course, since people stayed on their original drugs, some of which their virus was probably resistant to, they may have been on virtual monotherapy with Viread. It's best to change two or three of your drugs when switching, and, in that situation, Viread could be a potent part of a new regimen.

Since its introduction two years ago, Viread has become a popular drug due to its convenience and potency -- New York State's AIDS Drug Assistance Program reports that its use more than doubled in the last year. But Gilead has received two warning letters from the FDA regarding the company's promotion of its drug. The first, in March 2002, said that Gilead representatives had "made false or misleading representations by describing Viread as 'extremely safe,' 'no toxicities' ... and characterizing it as a 'miracle drug.'" Gilead promised to correct these practices, but the FDA had to send another letter in July 2003 saying that Gilead representatives had once again wrongly said that "because Viread is a nucleotide, not a nucleoside, it is 'more potent,' has 'fewer side effects,' and is 'safer.'" Since the FDA feels these statements have not been proven, they are asking Gilead to retrain its sales force.

In addition, new data have questioned whether Viread should be used as the backbone of a HAART regimen. Two recent studies reported poor results when using Viread with two other NRTIs. In July 2003, a study comparing the combination of Viread, Epivir, and Ziagen (abacavir) to the combination of Sustiva, Epivir, and Ziagen found that close to 50% of people taking Viread either didn't have a significant drop in viral load or saw it rise compared to only 5% of those taking Sustiva. The Viread arm of the trial was stopped. And in October 2003, another study was stopped early due to poor results in people taking Viread, Epivir, and Videx. We don't know whether these results are due to some interaction inside the cell between Viread and the other drugs, or whether triple-NRTI combinations just aren't strong enough in general. Until the reasons for these results are understood, it may be best to avoid using Viread as part of a regimen containing only two other NRTIs.

Side Effects

Viread's most common side effects are gastrointestinal (nausea, diarrhea, vomiting, gas) and dizziness.

Viread carries the same toxicity concerns as all of the nucleoside analogs since it acts in the same way they do. The particular warnings that the FDA requires in the drug's label are for lactic acidosis and liver enlargement. But Study 903 showed that people taking Viread had significantly less mitochondrial damage (which can lead to lactic acidosis) than those taking Zerit. This may be why Viread increased cholesterol and triglycerides less than Zerit and also raises hopes that Viread may lead to less lipodystrophy. We won't know this for a while, though.

One of the major concerns when Viread was first being tested was kidney toxicity, since this had been the biggest problem with its cousin, adefovir. The studies of Viread didn't show this to be a significant problem, but now that Viread is more widely used, reports of kidney failure are surfacing, especially among people who have some level of kidney damage before starting the drug. Gilead recently revised the package insert for Viread to add new dosing guidelines that reduce the dose for people with kidney impairment. Anyone taking Viread should closely monitor their kidney function, including creatinine levels, especially if they have more advanced HIV disease.

High doses of Viread caused bone problems in animals, so Study 903 was analyzed to see if this happened in humans. While people using Viread had more bone loss than those taking Zerit, they were still within normal ranges, and bone loss stabilized by the end of the first year on the drug. People who have a history of bone fractures or who are at particular risk for osteopenia should consider bone monitoring and possibly supplement with calcium and vitamin D.

Drug Interactions

Since Viread is eliminated mainly through the kidneys instead of the liver, it does not interact with most HIV drugs. Two exceptions are Videx and Reyataz (atazanavir). Viread can double the amount of Videx in the body, so these two drugs should only be taken together with caution, perhaps by taking only one 250-mg Videx EC capsule a day. On the other hand, Viread decreases the amount of Reyataz in the body by 25-40%. But one study (ANRS 107) found that when Reyataz (300 mg) was taken with Norvir (ritonavir) (100 mg) and Viread, the amount of Reyataz was higher than normal. More studies are planned to verify these data -- in the meantime, anyone taking Reyataz with Viread should boost it with Norvir.

Any drugs that are cleared through the kidneys will compete with Viread and increase blood levels of these drugs, as well as the risk of kidney damage. These include Zovirax (acyclovir), Valtrex (valacyclovir), Cytovene (ganciclovir), Valcyte (valganciclovir), Foscavir (foscarnet), Vistide (cidofovir), amphotericin, and Vancocin (vancomycin). Mix these drugs with caution.

When to Consider It

The recently revised Department of Health and Human Services treatment guidelines put Viread on equal footing with Retrovir and Zerit as part of a "preferred regimen" with Epivir and Sustiva for people who have not taken anti-HIV drugs before. And they note that Viread caused less lipodystrophy and lipid abnormalities than Zerit. If this holds up in real-world use, Viread will be a major competitor with Zerit when it comes to picking a first regimen.

The mutation most linked to Viread resistance is K65R. People whose HIV has this mutation will most likely also be resistant to Videx, Epivir, and Hivid (ddC). But Study 908 showed that even people who are resistant to these and other drugs can get some benefit from Viread -- so Viread may be useful in this situation, especially if you can replace your old drugs with one or two new ones.

Good to Know

• Gilead recently received FDA approval for Emtriva (emtricitabine), an Epivir-like drug that is taken once a day. They are developing a Viread/Emtriva combination pill that they hope to release in 2005. That could be a useful combination and, with its once-daily dosing, would give Combivir some stiff competition. People who take it with Sustiva will take just two pills once a day -- the most convenient regimen to date.

• Viread is also active against chronic hepatitis B (HBV) infection. People should be tested for chronic HBV before starting Viread, since there have been reports of disease flare-ups in people with HBV when they stop the drug.

• A microbicide gel that contains Viread is being studied to prevent vaginal HIV transmission. Studies in monkeys were successful even when the gel was given 24 hours after exposure.

Pregnancy

Viread is classified as an FDA pregnancy category B drug. It has not caused birth defects when studied in animals, but hasn't been studied in pregnant women. It should be used during pregnancy only if clearly needed.

Dose

300 mg a day, taken as one 300-mg tablet once a day, with or without food. Viread is not yet approved for pediatric use.

FDA Approval: 2001

Manufacturer: Gilead Sciences

Patient Assistance Program: 800-445-3235 #6