Ziagen (abacavir sulfate, ABC), approved by the FDA in December 1998, was the first new NRTI to become available in the era of Highly Active AntiRetroviral Therapy (HAART). As such, it had to compete for a special place in combination therapy. Initial studies of Ziagen had shown it to be as powerful as a protease inhibitor at lowering viral load when taken alone, so the drug's manufacturer, GlaxoSmithKline, positioned (and priced) it as an alternative to a protease inhibitor or non-nucleoside as part of a three-drug combination. Two serious obstacles have kept that strategy from working as well as the company might have hoped: the dangerous allergic reaction that Ziagen can cause, and the failure of triple-nucleoside regimens to work as well as predicted.

Background

Before Ziagen's approval, many studies compared various two-drug combinations to two- or three-drug combinations that contained Ziagen. In most cases, Ziagen-containing regimens were better at lowering viral loads and raising CD4 counts than regimens without the drug. To understand how Ziagen might best be used today, we need to look at clinical trials that compare three-drug combinations, at least one of which includes Ziagen. Two such trials -- CNA3005 and CNA3014 -- compared Ziagen to the protease inhibitor Crixivan (indinavir), both taken with Combivir (Retrovir [AZT] plus Epivir [3TC]). The trial participants had never taken antiretrovirals before.

CNA3005 was double-blind and placebo-controlled for dosing and number of pills, meaning that neither the 562 participants nor the investigators knew which combination individual participants were taking. These precautions tried to ensure that adherence issues wouldn't cloud the results since Crixivan is dosed every eight hours without food and requires drinking a lot of water while Ziagen is dosed every twelve hours with no food restrictions. By the end of 48 weeks, there was no significant difference in the percentage of people taking Ziagen with viral loads below 50 copies (40%) and those taking Crixivan (46%). But when the researchers looked at those trial participants whose viral loads were above 100,000 before starting treatment, they found that the Ziagen regimen was significantly less likely than the Crixivan regimen to bring viral loads down to below 50 copies (31% compared to 45%). These results suggest that the combination of Ziagen, Retrovir, and Epivir (and perhaps any triple-NRTI combination) is not for someone with a high viral load, particularly if it's above 100,000.

CNA3014 compared the same two regimens, but this trial was open-label, meaning that the 342 participants knew what they were taking. After 48 weeks, the two groups had similar results in terms of reducing viral load to below 50 copies regardless of whether the participants' viral loads were above or below 100,000 before starting treatment. In fact, the Ziagen group tended to do better than the Crixivan group in almost all respects. This may have been because adherence was much better in the Ziagen group -- 78% of the people taking the Ziagen/Combivir regimen reported being completely adherent compared to only 48% of those taking the much more complicated Crixivan/Combivir regimen. Although difficult to measure, the difference between the results of this trial and those of CNA3005 could be attributed to the discrepancies in adherence.

Unfortunately, early results from a large clinical trial called ACTG 5095 confirmed the results of CNA3005. In March 2003, the Data and Safety Monitoring Board (DSMB) for ACTG 5095 stopped the Ziagen/Retrovir/Epivir arm of the study when participants on that regimen experienced pre-defined virologic failure earlier and more often than participants on the two study regimens that didn't include Ziagen. ACTG 5095 involved 1,147 participants and was designed to compare Ziagen/Retrovir/Epivir (taken as Trizivir) to the non-nucleoside, Sustiva (efavirenz), taken with Retrovir and Epivir to a regimen of all four drugs. This study, too, was for people who had never taken antiretrovirals before. It was double-blind and placebo-controlled for dosing and number of pills.

When the DSMB reviewed the results at 32 weeks, they found that 21% of the participants in the Trizivir arm had experienced virologic failure compared to 11% of the participants on the two Sustiva-containing regimens combined, a highly significant difference. This difference was seen in people who began treatment with viral loads above and below 100,000. Virologic failure was defined as having a viral load greater than 200 at least four months after starting treatment. The Trizivir arm of the trial was stopped and participants in that group were offered other treatment. The closing of this arm of the study doesn't necessarily mean that the combination of Ziagen/Retrovir/Epivir (or Trizivir) doesn't have an important role in HIV treatment, but its role might be more limited than initially thought.

Glaxo's focus on making Ziagen work as a part of the combination pill, Trizivir, has resulted in less attention to the study of Ziagen for other purposes. But Ziagen works well with many other anti-HIV medications and can be used effectively in a number of situations.

One possibility is to add Ziagen to a regimen that's working relatively well to get a better antiviral response -- a strategy called intensification. The CNA3002 study included 185 people who had been on treatment for at least three months and as long as three years. They had viral loads between 400 and 50,000 and an average CD4 count of 410. Most of the participants were on two-drug combinations before joining the trial. Everyone continued on their current regimens and added either Ziagen or a placebo. After 48 weeks, 25% of the participants on Ziagen had viral loads less than 400 copies compared to 6% of those on placebo. Looking just at the people who took Ziagen, 41% of those who started the trial with viral loads below 5,000 had viral loads less than 400 copies at the end of 48 weeks compared to 9% of those who started the trial with viral loads above 5,000.

There's also evidence that switching from a protease inhibitor (PI) to Ziagen may help reduce high lipid levels (triglycerides and cholesterol) caused by many PIs while still keeping virus levels low. CNA30017, a trial of 211 people on PI regimens, compared those who stayed on their regimens to those who switched their PI for Ziagen. At the beginning of the trial, everyone had viral loads below 50. After 48 weeks, more people who stayed on their PI experienced treatment failure than those who switched to Ziagen (23% vs. 12%, a statistically significant difference). Treatment failure was defined as having two consecutive viral loads above 400 or leaving the study for any reason, including side effects. The people who switched to Ziagen also experienced statistically significant decreases in triglycerides and cholesterol levels and improvements in lipoatrophy (fat loss) and central fat accumulation. Overall, in this trial, the switch to Ziagen provided some benefit without sacrificing the virologic success achieved by starting treatment with a protease inhibitor.

Ziagen may also be useful as a replacement for Zerit (d4T) in the regimens of people who are experiencing lipoatrophy, an increasingly recognized side effect of Zerit. A number of small studies have shown that replacing Zerit with Ziagen may slow down the rate of fat loss -- or even reverse it -- while maintaining low or undetectable viral loads.

Side Effects

The side effects of Ziagen are usually relatively mild and can include nausea, vomiting, fatigue, headache, fever, rash, diarrhea, and loss of appetite.

Hypersensitivity Reaction

The most serious side effect of Ziagen is a life-threatening hypersensitivity reaction (a severe allergic reaction) that occurs in about 5% of people who take the drug (the numbers vary a lot from study to study, ranging from 1.5% to 10%). Symptoms usually appear within the first two to six weeks on the drug, although the reaction can occur even after you've been on Ziagen for a while. A series of symptoms generally builds up, often getting worse as more doses are taken. Symptoms include a skin rash or two or more other symptoms such as fever, nausea, vomiting, diarrhea, abdominal pain, severe tiredness, or aching muscles or joints. Respiratory symptoms (cough, shortness of breath, and/or sore throat) sometimes occur, but are almost always accompanied by nausea, vomiting, and/or diarrhea. If you suspect that you may be experiencing Ziagen hypersensitivity, call your doctor immediately. If it's determined that you're experiencing a hypersensitivity reaction, you'll need to stop the drug and must not start it again. If you restart the drug, the allergic reaction can reoccur within hours, be much more severe than the first time, and may be extremely dangerous, even fatal.

Some people may experience a hypersensitivity reaction without recognizing it, either because they stopped the drug for some other reason before symptoms of the reaction occurred or were diagnosed or because the initial symptoms were diagnosed as something else such as an acute respiratory disease (even the flu). For these reasons, if you took Ziagen once for even a short time and suffered no noticeable hypersensitivity reaction, be aware if you decide to start the drug again -- it could be the same as restarting the drug after experiencing a hypersensitivity reaction.

Starting Ziagen at the same time as you start another drug that can cause a rash or other similar systemic reaction may make it more difficult to diagnose a hypersensitivity reaction to Ziagen. Examples of such drugs include sulfa-based antibiotics such as Bactrim and Septra, used to prevent and treat PCP (pneumocystis pneumonia), the non-nucleosides Sustiva (efavirenz) or Viramune (nevirapine), and the protease inhibitor Agenerase (amprenavir).

Drug Interactions

There are very few significant drug interactions associated with Ziagen. Alcohol can increase the amount of Ziagen in the blood by as much as 40%, but the increase doesn't require a reduction in your Ziagen dose. You may experience more side effects if you're a heavy drinker and taking Ziagen, so you might want to avoid combining the two. High doses of Ziagen can reduce methadone levels. A very small number of people on methadone maintenance may require an increase in their methadone dose if they're also taking Ziagen at the usual dose.

When to Consider It

As part of a triple-NRTI regimen when you're just starting treatment, Ziagen may not be as useful as originally hoped -- but it can still be useful in many other situations. Recent trials, for example, have shown promising results for people beginning treatment with regimens that included a protease inhibitor or non-nucleoside and the NRTI backbone of Ziagen and Epivir.

The mutations required to make your virus resistant to Ziagen are complex. If you took Retrovir for a long time by itself, later took Epivir, and developed resistance to both, it's unlikely that you'll benefit from Ziagen. Epivir resistance combined with high-level Retrovir resistance (three or more resistance mutations) makes Ziagen ineffective. People who have resistance to Epivir but not to Retrovir may still benefit from Ziagen, though. If you develop a particular mutation (K65R) that makes your virus resistant to Ziagen, you probably won't benefit from Viread (tenofovir), Videx (ddI), or Hivid (ddC) because of cross-resistance.

Ziagen is a strong drug with lots of potential. It may be useful as one of the two NRTIs in a starting regimen, particularly with Epivir. It may be useful as an addition to a regimen that's already working well, to intensify the anti-HIV effect and decrease viral loads further. And it may be useful as a replacement for a protease inhibitor, the NRTI Zerit, or even a non-nucleoside, once viral load is under control. Preliminary data suggest that these uses offer some benefit, but more and larger studies are needed to better understand when it's most valuable.

Good to Know

• Ziagen is one of only a few antiretrovirals with the ability to cross the blood-brain barrier. This makes the drug effective against HIV in the brain and central nervous system and may help prevent neurological disease like dementia. It's important to include at least one antiretroviral that crosses the blood-brain barrier in your combination.

• In July 2003, a study comparing the combination of Viread, Epivir, and Ziagen to the combination of Sustiva, Epivir, and Ziagen found that the people receiving Viread responded very poorly compared to those receiving Sustiva. The Viread arm of the trial was stopped. Another study was stopped early in October 2003 due to poor results in people taking Viread, Epivir, and Videx. The reasons for these poor results are unclear, but until they're better understood, it may be best to avoid using Viread as part of a triple-NRTI regimen, including one that contains Ziagen.

• GlaxoSmithKline is developing an Epivir/Ziagen combination tablet to be taken once a day that contains 600 mg of Ziagen and 300 mg of Epivir.

• A once-a-day formulation of Ziagen is now in clinical trials.

Pregnancy

Ziagen is classified as an FDA pregnancy category C drug. No studies of Ziagen have been conducted in pregnant women or children less than a month old. Some animal studies have shown risk to the fetus and others are ongoing. Ziagen shouldn't be used during pregnancy unless the potential benefit outweighs the potential risk to the mother and fetus.

Dose

600 mg a day, taken as one 300-mg tablet twice a day with or without food. Ziagen is also available as a flavored liquid that contains 20 mg/mL and as part of the combination pill, Trizivir. The pediatric dose (ages 3 months to 16 years) is based on weight: 8 mg/kg twice a day up to a maximum of 300 mg twice a day.

FDA Approval: 1998

Manufacturer: GlaxoSmithKline

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