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Drugs in Development
Very Viread

By Tim Horn

Fall 2001

Like stepping onto the bathroom scale the day after Thanksgiving, viral load assays and drug-resistance tests have an annoying habit of telling the truth when we least want to hear it. Finding out that your virus is resistant to the antiretroviral drugs you are taking, even though you've been doing your best to take them correctly and on time every day, can be a real slap in the face. This is especially true if you've gone through many of the drugs that are currently available. When you factor in cross resistance between these drugs -- including all of the available non-nucleoside reverse transcriptase inhibitors (NNRTIs) and most of the protease inhibitors (PIs) -- that can further limit your options; finding a new combination of drugs can prove to be a real challenge.

Until there's a cure for this dreaded disease, new drugs with unique resistance profiles will always be needed to help patients with limited treatment options stay one step ahead of the game. There are many HIV-positive people out there who are no better off than people living with HIV in the mid-1980s -- with no options to currently choose from, the only possibility is to wait for a modern-day AZT to become available through either a large clinical trial, an expanded access program, or full-fledged approval by the U.S. Food and Drug Administration (FDA). Realistically speaking, adding a new drug that becomes available to "intensify" a last-resort regimen that is no longer working correctly is the only option available to a growing number of HIV-positive people. Thus, whatever becomes available had better be worth the wait.

One of the most eagerly awaited drugs, tenofovir disoproxil fumarate (Viread), was given the green light by the FDA in October and is now available at most pharmacies. While its once-daily dosing schedule and encouraging side effects profile will undoubtedly be alluring to folks who are still picking and choosing their first antiretroviral drug regimen, Viread's crowning glory appears to be its ability to intensify the antiviral effect of regimens that are no longer able to keep viral load undetectable -- good news for patients who don't have much to choose from.

Technically speaking, Viread represents a new class of drugs being studied to treat HIV: nucleotide reverse transcriptase inhibitors. The truth is, nucleotide analogues are very similar to current nucleoside analogues (e.g., Retrovir, Zerit, and Epivir). The only difference is that nucleotide analogues, unlike nucleoside analogues, are chemically preactivated and thus require less processing in the body for them to become active.

So far, so good: Viread only needs to be taken once a day (300mg tablets) and its side effects -- including nausea, vomiting, diarrhea, and flatulence (intestinal gas) -- are usually only temporary. While tenofovir can cause increases in blood levels of creatinine, an enzyme related to kidney function, the drug does not appear to cause the serious kidney problems seen in earlier studies of adefovir (Preveon), Gilead's first nucleotide analogue rejected by the FDA in November 1999.

Because Viread is broken down by the kidneys and not the liver, it's not likely that it will interact with many other antiretroviral medications. The only interaction reported thus far has been an increase in ddI (Videx) blood levels. While nobody has yet figured out what this might mean for people taking Videx and Viread at the same time, it could spell trouble -- increased blood levels of Videx might heighten the risk of developing pancreatitis, a very serious side effect that can damage the pancreas.

It's best to take Viread with food, preferably a meal containing a sizeable percentage of fat. Doing so increases the amount of Viread in the bloodstream, a significant advantage for folks hoping to squeeze as much benefit out of the drug as they possibly can.

As for tenofovir's resistance profile, the drug is active against strains of HIV resistant to AZT (Retrovir), ddI (Videx), ddC (Hivid), 3TC (Epivir), and abacavir (Ziagen). Tenofovir is also active against virus containing the sinister Q151M mutation -- a single mutation that results in high-level resistance to multiple nucleoside analogues.

One of the most important clinical trials of Viread has been GS 902, a phase II study that randomly assigned 189 HIV-positive people to add one of three doses of Viread (75mg, 150mg, or 300mg) or placebo to their current regimen. Depending on your point of view, this was a highly peculiar study design. Most clinical trials offer volunteers a whole new batch of currently approved drugs with the possibility of also getting the experimental compound. But for the volunteers enrolled in this study, coming up with two or three new drugs to combine with Viread was almost impossible -- the majority of patients had been receiving HAART for at least four years prior to entering the study and had already gone through many of the approved options available to them. All of the patients in GS 902 had detectable viral loads (between 400 and 100,000 copies/mL) when they enrolled in the study, meaning that their virus was no longer responding to the "salvage" regimen they were currently taking. In this way, the results of GS 902 would reflect what people with drug-resistant virus might expect in the real world -- would the addition of a single new drug to an already failing regimen offer significant help to patients who didn't have other options to choose from?

Upon entering the study, approximately 94% of the patients had resistance to at least one nucleoside analogue, with more than 71% of the patients resistant to AZT. The average viral load at study entry was between 5,000 and 6,000 copies/mL and the average T-cell count was 375 cells/mm3. After 24 weeks in the study, patients receiving the 300mg daily dose of Viread had reduced their viral load by 75% (0.58 log), compared to almost no change among patients who received placebo. After 48 weeks, viral load had been reduced by almost 80% (0.62 log) in patients originally randomized to receive the 300mg dose of tenofovir. Encouraging results indeed.

While Viread worked well for patients who were resistant to any of the nucleoside analogues prior to entering the study, it's still not clear which mutations are actually caused by this drug. In one recent analysis involving 135 patients who have been taking 300mg daily Viread in combination with their previous regimen for at least 96 weeks, only 21 (15.5%) have seen their viral load increase to levels above and beyond where they were prior to adding the nucleotide analogue. In these 21 patients, new mutations conferring additional resistance to their current PI(s), NNRTI, or nucleoside analogues were found -- which might explain the increase in viral load -- but none developed any tell-tale mutations that have been shown in test tube studies to be associated with resistance to Viread. In other words, Viread may still have been chugging away as the other drugs in the regimen continued to give out. While this certainly suggests that Viread packs some hefty and long-lived antiviral activity, the data are still too mysterious to say this for certain.

Early results from GS 907, a phase III clinical trial that has enrolled 552 people, have also been reported. This study was designed very much like GS 902 and included a number of HIV-positive people who had tried and failed other anti-HIV drugs in the past. After 6 months, 19% of patients who added Viread were able to reduce their viral load to undetectable levels (less than 50 copies/mL), compared to only 1% of patients who added the placebo. Results involving volunteers taking Viread for at least one year will be presented later this year.

Also being conducted in GS 903, a study of Viread in 600 HIV-positive people who have never taken anti-HIV drugs before. Volunteers in this study are receiving efavirenz (Sustiva) plus 3TC (Epivir) plus either Viread or d4T (Zerit). Results from this clinical trial will be released either later this year or within the first few months of 2002.

Back to the CRIA Update Fall 2001 contents page.

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