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Drugs! Drugs! Drugs!
An Overview of the Approved Anti-HIV Medications

Zerit, Zerit XR (d4T, Stavudine)

Fall 2003/Winter 2004

Zerit became the fourth drug available for the treatment of HIV when it was approved by the FDA in June 1994. The drug's initial approval was only for people with advanced HIV disease who no longer responded to or who couldn't tolerate the three drugs available at the time -- Retrovir (AZT), Hivid (ddC) and Videx (ddI). Although the drug can cause serious side effects, it continues to be used in a variety of regimens. The original version was dosed every twelve hours, but once-a-day Zerit XR was approved in December 2002. Once Zerit XR is actually available in pharmacies, the drug will be able to be used as a part of complete once-daily regimens.


The compound that would later be called Zerit was discovered in 1966 by a researcher working under a grant from the National Cancer Institute, part of the National Institutes of Health (NIH). In 1986, researchers at Yale University, also working under a grant from the NIH, discovered that the drug had activity against HIV in the test tube (in vitro) and filed for a patent. In early 1988, Yale licensed the marketing rights to Bristol-Myers Squibb (BMS). Within a few months, the first trial of Zerit began, conducted jointly by BMS and the NIH. Five years later, Zerit was approved by the FDA. Many people felt that Zerit was a more promising drug than Videx and were angry that BMS had put Zerit on the back burner as the company moved forward with its development of Videx.

Zerit was granted accelerated approval based on early, partial results from an ongoing BMS study called AI455-019 (019 for simplicity's sake) and some data from the drug's parallel track program (similar to expanded access programs used today). 019 was a double-blind study that began enrolling in May 1992. The 822 participants had been on Retrovir for at least six months (many for much longer) and had never taken Hivid or Videx. They either continued taking Retrovir alone or switched to Zerit. The FDA looked at data on 359 people who had been in 019 for at least four months. Most of the people who had stayed on Retrovir had a CD4 count drop within two weeks of starting the study, while those who switched to Zerit had CD4 cell increases through five months, after which CD4 counts began to decrease. CD4 counts were available for some participants who had been in the study for over a year and a half -- those on Zerit had an average decrease of 18 CD4 cells compared to an average decrease of 70 in those on Retrovir. In addition, the people on Zerit showed some weight gain compared to those on Retrovir who showed weight loss.

Final results of 019 were reported at a conference in mid-1995 and published in 1997. They confirmed that the preliminary results indicating Zerit's ability to raise CD4 counts translated to clinical benefit. After a little over two years of treatment, people on Zerit did better than those on Retrovir in almost every way measured, including higher CD4 counts, fewer new or recurrent opportunistic infections, less deaths, and better quality of life. In the end, not surprisingly, the trial showed that it was better to switch to Zerit monotherapy than to continue Retrovir monotherapy.

Moving on to combination regimens containing Zerit, the six-month French ALBI (ANRS 070) trial conducted in 1999 compared the combinations of Zerit plus Videx to Retrovir plus Epivir to a strategy that alternated the two combinations in 151 people who had never taken antiretrovirals before. The Zerit plus Videx combination was far superior in raising CD4 counts and lowering viral loads compared to the other two arms of the trial. As a result, Zerit plus Videx was widely prescribed for a while as the dual-nucleoside backbone to many three-drug combinations. Other research has found less positive results for this particular nucleoside pair.

ACTG 384, for example, was a complex trial that began enrolling participants in 1998. The trial studied either Zerit plus Videx or Retrovir plus Epivir in combination with the protease inhibitor Viracept (nelfinavir), the non-nucleoside Sustiva (efavirenz), or both as starting regimens in 960 people who had never been on antiretrovirals. Overall, Sustiva/Retrovir/Epivir was the most beneficial triple-drug combination studied in the trial, and people taking Sustiva/Retrovir/Epivir had a better treatment response and fewer side effects than those taking Sustiva/Zerit/Videx.

START I and START II were sister trials that compared three different pairs of nucleoside analogs, each in combination with the protease inhibitor Crixivan (indinavir). The nucleoside pairs were Zerit plus Videx, Zerit plus Epivir, and Retrovir plus Epivir. Most of the 409 participants in the START trials had never been on anti-HIV treatment (some had been on treatment for less than four weeks), and none of the participants had ever taken a protease inhibitor or Epivir. After three years of follow-up, there were no significant differences between how well the three regimens worked. The three groups had similar results in terms of CD4 cell increases and the percentage of participants with viral loads below 500 copies.

Since ACTG 384 and the START trials began to enroll, it has become clear that combining Zerit with Videx should be avoided because of overlapping toxicities -- peripheral neuropathy (tingling, pain, and numbness in the feet and hands) and pancreatitis (inflammation of the pancreas). It has also become increasingly clear in recent years that Zerit is specifically associated with lipoatrophy (fat loss in the arms, legs, face, and butt) and increased lipid levels (cholesterol and triglycerides).

A sub-study of about a third of the ACTG 384 participants used DEXA scans to measure changes in body fat in people on Zerit plus Videx compared to those on Retrovir plus Epivir. DEXA (Dual Energy X-ray Absorptiometry) scans measure body composition in terms of fat and fat-free mass in the arms, legs, trunk, and whole body. The sub-study (ACTG 5005s) found that, on average, the Zerit/Videx regimen caused a greater loss of fat in the arms and legs than the Retrovir/Epivir regimen. People taking Zerit plus Videx had lost significantly more limb fat than people taking Retrovir plus Epivir after 48, 64, and 80 weeks on treatment. In fact, by week 80 (more than a year and a half on treatment), people on Zerit plus Videx had about 15% less limb fat than when they joined the study, compared to a 7% loss in people taking Retrovir plus Epivir.

Similarly, results of a sub-study of CPCRA 058 (also called the FIRST study) were presented in July 2003. CPCRA 058 is a large trial comparing various combinations in people who are just starting anti-HIV treatment. Most participants used Zerit plus Videx or Epivir plus Ziagen (abacavir) as their dual nucleoside backbone. Using bioelectric impedance analysis (BIA) and physical measurements, the sub-study of 182 trial participants showed that people taking Zerit plus Videx as the backbone of their three-drug regimen were significantly more likely than those taking Epivir plus Ziagen to experience fat loss after almost three years on treatment.

These sub-studies aren't able to tell us whether Videx also contributed to the loss of body fat since it was paired with Zerit in both trials, but numerous other studies have shown that Zerit is particularly associated with the loss of body fat.

The TARHEEL study (ESS40010) was designed to see if people with lipoatrophy who were doing well on regimens that included Zerit might benefit by switching from Zerit to either Retrovir or Ziagen. The 118 trial participants had been on Zerit for at least six months, most of them (82%) for more than two years. 75% switched to Ziagen and 25% to Retrovir. After 48 weeks, people had average fat increases of 25% in their arms, 15% in their legs, and 23% in their trunks compared to when they entered the study. The increases were more significant in people who switched to Ziagen than in those who switched to Retrovir. This small study shows that switching from Zerit to another nucleoside analog helps some people regain some of the fat they lost while on the drug -- without sacrificing anti-HIV activity.

Gilead Sciences' study 903 compared their nucleotide analog, Viread (tenofovir), to Zerit in 600 people who had never been on antiretrovirals before. Trial participants took the non-nucleoside Sustiva, Epivir, and either Viread or Zerit. After almost two years on treatment, both groups did equally well in terms of CD4 counts and viral loads. But there were statistically significant differences in triglycerides, total cholesterol, LDL (bad) cholesterol, and HDL (good) cholesterol between the groups, and the differences were all in Viread's favor. People on Viread also had significantly more limb fat than those on Zerit.

In 2002, with the momentum shifting toward simpler, more convenient dosing, BMS received FDA approval for Zerit XR, extended release capsules that are taken once a day. Zerit's original formulation had to be taken every twelve hours. Data from clinical trials show the two versions to be equivalent in terms of effectiveness and side effects. Unfortunately, Zerit XR has not reached pharmacy shelves yet. According to BMS, the complex process required to manufacture Zerit XR has delayed the release of the once-a-day formulation. Hopefully, it will be available soon.

Side Effects

The most common side effect of Zerit is peripheral neuropathy, which occurs in 15-20% of people on the drug and ranges in severity from mild to severe. If neuropathy occurs and Zerit isn't stopped, it can become irreversible, resulting in permanent nerve damage. Although peripheral neuropathy usually goes away if Zerit is stopped early enough, the symptoms often get worse for a couple of weeks before they get better. Factors that contribute to the likelihood of experiencing peripheral neuropathy while on Zerit include advanced HIV disease, higher doses of Zerit, pre-existing neuropathy, and other drugs that have peripheral neuropathy as a possible side effect such as Videx, Hivid, amphotericin B, Foscavir (foscarnet), dapsone or vincristine.

Less serious possible side effects of Zerit include nausea, vomiting, chills, fever, diarrhea, headache, rash, and elevated liver enzymes. If you experience any of these side effects, they usually go away after the first few weeks on the drug.

A rare but potentially dangerous side effect of Zerit is pancreatitis, which is more likely to occur if Zerit is taken with Videx. Symptoms of pancreatitis can include nausea, vomiting, diarrhea, blood in the urine, and sharp pain in the back or upper stomach. If you experience these symptoms while on Zerit, contact your healthcare provider immediately.

Various aspects of lipodystrophy are at least partly caused by the nucleoside analogs, but many studies have specifically linked lipoatrophy (fat loss) and, to a lesser degree, increased lipid levels to the use of Zerit (see above).

Lactic acidosis is another possible side effect of all of the nucleoside analogs, but Zerit seems to increase the risk. Some pregnant women on regimens that included both Zerit and Videx have had fatal cases of lactic acidosis. The combination of these two drugs should be avoided during pregnancy.

Drug Interactions

Zerit has relatively few drug interactions. The main drugs to avoid are those that may contribute to Zerit's side effects, such as those listed above that also have peripheral neuropathy as a possible side effect. Drugs that may increase the risk of pancreatitis, such as Cytovene (oral ganciclovir), rifampin, and Mycobutin (rifabutin), should also be avoided, especially if you're taking Videx with Zerit. Taking ribavirin for the treatment of hepatitis C while on Zerit may increase the risk of lactic acidosis and lipoatrophy. Test tube (in vitro) studies indicate that ribavirin and Doxil (doxorubicin), used to treat some cancers including Kaposi's sarcoma, may lower levels of Zerit in the body, reducing the drug's anti-HIV effect. Zerit shouldn't be used with Retrovir because the two drugs work against each other in the body, resulting in less anti-HIV activity.

When to Consider It

The question of when it's best to use Zerit while developing a strategy for sequencing antiretrovirals has often been somewhat controversial. As described in the section on Retrovir, the backbone of an HIV regimen is usually a pair of NRTIs, combined with a third or fourth drug -- most often an NNRTI or PI. Either Retrovir or Zerit are often part of a first-line combination (though not both), and researchers have tried to figure out which of the two is better to use first (see Retrovir: When to Consider It).

The current Department of Health and Human Services (DHHS) treatment guidelines recommend Retrovir/Epivir as the dual nucleoside combination "of choice" based on its effectiveness, safety, few interactions with other drugs, the probability of developing resistance mutations, and dosing convenience. Yet the DHHS guidelines recommend Zerit as part of many regimens for people who have never taken antiretrovirals before. The language in the guidelines is vague and confusing about the use of Zerit, frustrating community activists and healthcare providers -- the drug is strongly recommended in some prominent sections, while its potential dangers are only occasionally mentioned or almost hidden in secondary sections. The bottom line is that Retrovir/Epivir really is the preferred dual nucleoside combination.

The DHHS recommendations are in stark contrast to those of the British HIV Association (BHIVA). Because of the risks of lipoatrophy and increased lipids, the July 2003 BHIVA treatment guidelines strongly recommend against using Zerit as part of a first regimen. Of course, not everyone on Zerit experiences fat loss or increased lipid levels, even after being on it for years. These are just two of many factors to take into account when considering the potential risks and benefits of the drug.

When Zerit was first approved, it wasn't believed that resistance was as much of a problem with this drug as with other NRTIs. In recent years, however, researchers have come to recognize that Zerit's resistance profile is very similar to that of Retrovir. HIV that becomes resistant to Zerit will probably be resistant to Retrovir -- and vice versa. And as with Retrovir, HIV that has become resistant to Epivir is often more sensitive to Zerit. Some of the mutations (called thymidine analogue mutations) that arise during therapy with either Zerit or Retrovir can cause cross-resistance to almost all of the available NRTIs. But this seems to happen rarely, and most HIV that's resistant to Zerit (or Retrovir) is still sensitive to NRTIs like Ziagen and Videx.

Good to Know

  • HIV reproduces in many parts of the body, including the brain. Zerit 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.

  • Because of overlapping toxicities, including peripheral neuropathy, the combinations of Zerit plus Videx and Zerit plus Hivid should be avoided if possible.

  • Heavy alcohol use can increase the risk of pancreatitis and liver damage. If possible, avoid alcohol while taking Zerit.

  • Your Zerit dose may need to be reduced if you have kidney problems.

  • Taking Zerit and Viramune (nevirapine) at the same time could increase the risk of severe liver toxicity, especially in women. If both drugs are included in a combination, careful and regular monitoring of liver function is particularly important.

  • The Zerit XR capsules, once they become available, can be opened up and their contents mixed with some yogurt or applesauce. Swallow the mixture whole -- no chewing or you'll crush the beads. Consume the tasty mixture right away -- don't save it for later!


Zerit is classified as an FDA pregnancy category C drug. When high doses of Zerit were given to pregnant rats, some developmental problems to the fetus were seen. According to the Antiretroviral Pregnancy Registry, when Zerit has been used during the first trimester, the prevalence of birth defects was 2.2%, compared to an overall prevalence of 3.1% in the U.S. population. But the FDA and Bristol-Myers Squibb issued a warning that pregnant women may be at increased risk of fatal lactic acidosis when prescribed a combination that includes Zerit and Videx. These drugs should only be prescribed together for pregnant women if the potential benefit clearly outweighs the potential risk to the mother and fetus.


  • Zerit is taken twice a day (every twelve hours), with or without food. Capsules are available in 15, 20, 30, and 40-mg versions. The dosage is based on weight. People who weigh 60 kg (132 pounds) or more take 80 mg a day (40 mg every twelve hours); those who weigh less than 132 pounds take 60 mg a day (30 mg every twelve hours). The pediatric dose (ages two weeks and older) is 1 mg/kg every twelve hours. Children who weigh 30 kg (66 pounds) or more take the recommended adult dosage. Zerit is also available as a fruit-flavored powder that your pharmacist mixes with purified water, providing 1 mg of drug per mL of solution.

  • Zerit XR capsules, once they're available, will be taken once a day, with or without food. The capsules will come in 37.5, 50, 75, and 100-mg versions. The dosage is based on weight. People who weigh 60 kg (132 pounds) or more will take one 100-mg capsule once a day; those who weigh less than 132 pounds will take one 75-mg capsule once a day. There is no pediatric version of Zerit XR.

FDA Approval: Zerit 1994; Zerit XR 2002 (not yet available)

Manufacturer: Bristol-Myers Squibb

Patient Assistance Program: 877-758-7877

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This article was provided by AIDS Community Research Initiative of America. It is a part of the publication ACRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.