AIDS Community Research Initiative of America (ACRIA) - Fall 2003 / Winter 2004

Hivid (ddC, zalcitabine, dideoxycytidine) is rarely used anymore, but, as with most new drugs, its approval by the FDA in June 1992 was eagerly anticipated. Now, its three-times-a-day dosing, poor showing in clinical trials, multiple drug interactions, and potentially serious side effects combine to make it the least prescribed nucleoside analog.

Background: Hivid was the first drug to receive accelerated approval, meaning that it was approved by the FDA very quickly, supported by limited but promising data. Hivid was also the first antiretroviral to be approved for use only as a component of combination therapy, specifically with Retrovir (AZT). This wasn't due to any particular foresight, but because early data from clinical trials that were ongoing showed that people who started treatment with Hivid plus Retrovir had greater increases in CD4 cells than people who started treatment with Retrovir alone. Retrovir plus Hivid was widely used as a two-drug combination in the early to mid-'90s.

Unfortunately, Hivid was far weaker individually than either of the antiretrovirals approved at the time, Retrovir and Videx (ddI). Many early trials showed Hivid to be less effective both alone and as part of a two-drug combination than the other two drugs. ACTG 114, for example, which involved more than 600 participants, showed that Retrovir was far superior to Hivid in people who had advanced HIV disease and little or no experience with antiretrovirals. The full study results weren't published until 1995, but the outcome was well known before then. The trial was stopped a year earlier than planned, in late 1991, when the study's Data and Safety Monitoring Board found a significantly higher percentage of deaths in the people taking Hivid compared to those taking Retrovir.

ACTG 175, which started in early 1992, enrolled almost 2,500 people, 40% of whom had never taken antiretrovirals before; among those who had, Retrovir alone was the most common treatment. Trial participants took Retrovir alone, Videx alone, Retrovir plus Videx, or Retrovir plus Hivid. After three years, people taking Retrovir alone had the worst results whether or not they had been on therapy before. For people who had never taken antiretrovirals before joining the study, the Retrovir plus Hivid combination did slightly better than Videx alone or Retrovir plus Videx in people who had never taken antiretrovirals before. For those who had taken antivirals before, Videx alone or Retrovir plus Videx produced the best results. The modest benefit seen for Hivid in people who had never been on treatment was crucial to its FDA approval.

Another trial that included Hivid was the Delta study, which also began in 1992. The Delta study was highly influential in our understanding of HIV treatment and how antiretrovirals came to be used in clinical practice. It enrolled over 3,200 participants in Europe and Australia. Some had never taken Retrovir before, while others had taken it alone for at least three months. Participants took Retrovir plus Videx, Retrovir plus Hivid, or Retrovir plus placebo.

After two and a half years, the results for people who had taken Retrovir before joining the trial were not encouraging. Adding Videx to Retrovir improved survival compared to staying on Retrovir alone, but adding Hivid showed no benefit.

The participants who hadn't taken Retrovir before joining the Delta study experienced much more positive results; compared to people who took Retrovir alone, the death rate for those on Retrovir/Videx was reduced by 42% and for those on Retrovir/Hivid it was reduced by 32%. The results of the Delta study strongly suggested the benefit of using more than one drug to treat HIV and helped to establish both Videx and Hivid as useful components of what would come to be called combination therapy.

Early data from these trials, particularly ACTG 175, contributed to Hivid's approval. Unfortunately, once the trials were completed and the final results were available, it was clear that Hivid's role in the treatment of HIV was less promising than people had originally hoped.

Because of the availability of stronger, less toxic nucleoside analogs, Hivid has rarely been used in large trials of triple-drug combinations; therefore, there's little information comparing the effectiveness of Hivid to that of other NRTIs as part of various three-drug combinations.

Side Effects: The most common serious side effect of Hivid is peripheral neuropathy (tingling, pain, and numbness in the feet and hands), which occurs in 10-30% of people who take the drug. If the drug isn't stopped, the neuropathy is often irreversible, resulting in permanent nerve damage. Other side effects of Hivid can include rash, headache, fever, nausea, fatigue, sores in the mouth or esophagus, and rash. Another possible serious side effect is pancreatitis (inflammation of the pancreas). Symptoms of pancreatitis can include nausea, vomiting, diarrhea, and sharp pain in the back or upper abdomen. If you experience these symptoms while on Hivid, contact your healthcare provider immediately. Pancreatitis can be fatal.

Drug Interactions: Antacids that contain magnesium or aluminum (Rolaids, Maalox, Milk of Magnesia and others) decrease levels of Hivid in the blood, so don't take them together. Other drugs, such as amphotericin B (Amphocin, Fungizone and others), foscarnet (Foscavir), probenecid, and Tagamet (cimetidine) can increase levels of Hivid in the blood.

Hivid shouldn't be combined with Videx, Zerit (d4T), Epivir (3TC), or any other drug that has peripheral neuropathy as a possible side effect. Similarly, any drug that lists pancreatitis as a possible side effect should not be used with Hivid.

When To Consider It: It's probably best to avoid Hivid unless your umpteenth combination has failed you and you're trying to put together a rescue regimen. Hivid is no longer included in any regimens recommended by the Department of Health and Human Services treatment guidelines for people who have never taken antiretrovirals before. In fact, one of the only times that the guidelines mention Hivid is to state that it "should rarely if ever be recommended."

You're unlikely to benefit from Hivid if your virus is already resistant to many of the NRTIs, including Videx, Zerit, Epivir and, probably, Retrovir. With the availability of drugs that are less toxic, better studied, and easier to take - compounded by the risk of cross-resistance to other NRTIs - it's hard to know when to consider Hivid, if ever. Even as a component of a rescue regimen, cross-resistance to previously used NRTIs severely limits the benefits of the drug.

Good To Know:

• Your Hivid dose may need to be reduced if you have kidney problems.
  
  
• Rare cases of liver failure have been reported among people with hepatitis B infection who were taking Hivid. Anyone with liver problems should probably avoid Hivid or at least consider it with extreme caution.
  
  
• Avoid alcohol if you're taking Hivid, since alcohol can also cause pancreatitis.
  
  
• A study called HIVBID was designed to compare twice-a-day Hivid to twice-a-day Epivir, each combined with Retrovir and Viracept (nelfinavir). Perhaps not surprisingly, the study was unable to recruit the 100 participants it needed to move forward.

Pregnancy: Hivid is classified as an FDA pregnancy category C drug. No studies of Hivid have been conducted in pregnant women or children less than a month old. Certain cancers have occurred in rodents given very high doses of Hivid, and abnormalities including low birth weight and skeletal defects have been seen in offspring born to rodents given moderate to high doses. Hivid shouldn't be used during pregnancy unless the potential benefit outweighs the potential risk to the mother and fetus.

Dose: 2.25 mg a day, taken as one .75-mg tablet every eight hours, with or without food (although taking it on an empty stomach may improve absorption). Hivid also comes in .375-mg tablets. No liquid formulation is commercially available, although you can get it through a compassionate use program. Hivid is not recommended for pediatric use.

FDA Approval: 1992

Manufacturer: Hoffmann-La Roche

Patient Assistance Program: 800-282-7780

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