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ZeritAIDS Community Research Initiative of America (ACRIA)Fall 2003/Winter 2004http://www.aegis.org/pubs/cria/2003/CR030923.html-------------------------------------------------Zerit, Zerit XR (d4T, stavudine) - Zerit became the fourth drugavailable for the treatment of HIV when it was approved by theFDA in June 1994. The drug's initial approval was only for peoplewith advanced HIV disease who no longer responded to or whocouldn't tolerate the three drugs available at the time -Retrovir (AZT), Hivid (ddC) and Videx (ddI). Although the drugcan cause serious side effects, it continues to be used in avariety of regimens. The original version was dosed every twelvehours, but once-a-day Zerit XR was approved in December 2002.Once Zerit XR is actually available in pharmacies, the drug willbe able to be used as a part of complete once-daily regimens.Background: The compound that would later be called Zerit wasdiscovered in 1966 by a researcher working under a grant from theNational Cancer Institute, part of the National Institutes ofHealth (NIH). In 1986, researchers at Yale University, alsoworking under a grant from the NIH, discovered that the drug hadactivity against HIV in the test tube (in vitro) and filed for apatent. In early 1988, Yale licensed the marketing rights toBristol-Myers Squibb (BMS). Within a few months, the first trialof Zerit began, conducted jointly by BMS and the NIH. Five yearslater, Zerit was approved by the FDA. Many people felt that Zeritwas a more promising drug than Videx and were angry that BMS hadput Zerit on the back burner as the company moved forward withits development of Videx.Zerit was granted accelerated approval based on early, partialresults from an ongoing BMS study called AI455-019 (019 forsimplicity's sake) and some data from the drug's parallel trackprogram (similar to expanded access programs used today). 019 wasa double-blind study that began enrolling in May 1992. The 822participants had been on Retrovir for at least six months (manyfor much longer) and had never taken Hivid or Videx. They eithercontinued taking Retrovir alone or switched to Zerit. The FDAlooked at data on 359 people who had been in 019 for at leastfour months. Most of the people who had stayed on Retrovir had aCD4 count drop within two weeks of starting the study, whilethose who switched to Zerit had CD4 cell increases through fivemonths, after which CD4 counts began to decrease. CD4 counts wereavailable for some participants who had been in the study forover a year and a half - those on Zerit had an average decreaseof 18 CD4 cells compared to an average decrease of 70 in those onRetrovir. In addition, the people on Zerit showed some weightgain compared to those on Retrovir who showed weight loss.Final results of 019 were reported at a conference in mid-1995and published in 1997. They confirmed that the preliminaryresults indicating Zerit's ability to raise CD4 counts translatedto clinical benefit. After a little over two years of treatment,people on Zerit did better than those on Retrovir in almost everyway measured, including higher CD4 counts, fewer new or recurrentopportunistic infections, less deaths, and better quality oflife. In the end, not surprisingly, the trial showed that it wasbetter to switch to Zerit monotherapy than to continue Retrovirmonotherapy.Moving on to combination regimens containing Zerit, the six-monthFrench ALBI (ANRS 070) trial conducted in 1999 compared thecombinations of Zerit plus Videx to Retrovir plus Epivir to astrategy that alternated the two combinations in 151 people whohad never taken antiretrovirals before. The Zerit plus Videxcombination was far superior in raising CD4 counts and loweringviral loads compared to the other two arms of the trial. As aresult, Zerit plus Videx was widely prescribed for a while as thedual-nucleoside backbone to many three-drug combinations. Otherresearch has found less positive results for this particularnucleoside pair.ACTG 384, for example, was a complex trial that began enrollingparticipants in 1998. The trial studied either Zerit plus Videxor Retrovir plus Epivir in combination with the proteaseinhibitor Viracept (nelfinavir), the non-nucleoside Sustiva(efavirenz), or both as starting regimens in 960 people who hadnever been on antiretrovirals. Overall, Sustiva/Retrovir/Epivirwas the most beneficial triple-drug combination studied in thetrial, and people taking Sustiva/ Retrovir/Epivir had a bettertreatment response and fewer side effects than those takingSustiva/Zerit/Videx.START I and START II were sister trials that compared threedifferent pairs of nucleoside analogs, each in combination withthe protease inhibitor Crixivan (indinavir). The nucleoside pairswere Zerit plus Videx, Zerit plus Epivir, and Retrovir plusEpivir. Most of the 409 participants in the START trials hadnever been on anti-HIV treatment (some had been on treatment forless than four weeks), and none of the participants had evertaken a protease inhibitor or Epivir. After three years offollow-up, there were no significant differences between how wellthe three regimens worked. The three groups had similar resultsin terms of CD4 cell increases and the percentage of participantswith viral loads below 500 copies.Since ACTG 384 and the START trials began to enroll, it hasbecome clear that combining Zerit with Videx should be avoidedbecause of overlapping toxicities - peripheral neuropathy(tingling, pain, and numbness in the feet and hands) andpancreatitis (inflammation of the pancreas). It has also becomeincreasingly clear in recent years that Zerit is specificallyassociated with lipoatrophy (fat loss in the arms, legs, face,and butt) and increased lipid levels (cholesterol andtriglycerides).A sub-study of about a third of the ACTG 384 participants usedDEXA scans to measure changes in body fat in people on Zerit plusVidex compared to those on Retrovir plus Epivir. DEXA (DualEnergy X-ray Absorptiometry) scans measure body composition interms of fat and fat-free mass in the arms, legs, trunk, andwhole body. The sub-study (ACTG 5005s) found that, on average,the Zerit/Videx regimen caused a greater loss of fat in the armsand legs than the Retrovir/Epivir regimen. People taking Zeritplus Videx had lost significantly more limb fat than peopletaking Retrovir plus Epivir after 48, 64, and 80 weeks ontreatment. In fact, by week 80 (more than a year and a half ontreatment), people on Zerit plus Videx had about 15% less limbfat than when they joined the study, compared to a 7% loss inpeople taking Retrovir plus Epivir.Similarly, results of a sub-study of CPCRA 058 (also called theFIRST study) were presented in July 2003. CPCRA 058 is a largetrial comparing various combinations in people who are juststarting anti-HIV treatment. Most participants used Zerit plusVidex or Epivir plus Ziagen (abacavir) as their dual nucleosidebackbone. Using bioelectric impedance analysis (BIA) and physicalmeasurements, the sub-study of 182 trial participants showed thatpeople taking Zerit plus Videx as the backbone of theirthree-drug regimen were significantly more likely than thosetaking Epivir plus Ziagen to experience fat loss after almostthree years on treatment.These sub-studies aren't able to tell us whether Videx alsocontributed to the loss of body fat since it was paired withZerit in both trials, but numerous other studies have shown thatZerit is particularly associated with the loss of body fat.The TARHEEL study (ESS40010) was designed to see if people withlipoatrophy who were doing well on regimens that included Zeritmight benefit by switching from Zerit to either Retrovir orZiagen. The 118 trial participants had been on Zerit for at leastsix months, most of them (82%) for more than two years. 75%switched to Ziagen and 25% to Retrovir. After 48 weeks, peoplehad average fat increases of 25% in their arms, 15% in theirlegs, and 23% in their trunks compared to when they entered thestudy. The increases were more significant in people who switchedto Ziagen than in those who switched to Retrovir. This smallstudy shows that switching from Zerit to another nucleosideanalog helps some people regain some of the fat they lost whileon 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 onantiretrovirals before. Trial participants took thenon-nucleoside Sustiva, Epivir, and either Viread or Zerit. Afteralmost two years on treatment, both groups did equally well interms of CD4 counts and viral loads. But there were statisticallysignificant 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 Vireadalso had significantly more limb fat than those on Zerit.In 2002, with the momentum shifting toward simpler, moreconvenient dosing, BMS received FDA approval for Zerit XR,extended release capsules that are taken once a day. Zerit'soriginal formulation had to be taken every twelve hours. Datafrom clinical trials show the two versions to be equivalent interms of effectiveness and side effects. Unfortunately, Zerit XRhas not reached pharmacy shelves yet. According to BMS, thecomplex process required to manufacture Zerit XR has delayed therelease of the once-a-day formulation. Hopefully, it will beavailable soon.Side Effects: The most common side effect of Zerit is peripheralneuropathy, which occurs in 15-20% of people on the drug andranges in severity from mild to severe. If neuropathy occurs andZerit isn't stopped, it can become irreversible, resulting inpermanent nerve damage. Although peripheral neuropathy usuallygoes away if Zerit is stopped early enough, the symptoms oftenget worse for a couple of weeks before they get better. Factorsthat contribute to the likelihood of experiencing peripheralneuropathy while on Zerit include advanced HIV disease, higherdoses of Zerit, pre-existing neuropathy, and other drugs thathave peripheral neuropathy as a possible side effect such asVidex, Hivid, amphotericin B, Foscavir (foscarnet), dapsone orvincristine.Less serious possible side effects of Zerit include nausea,vomiting, chills, fever, diarrhea, headache, rash, and elevatedliver enzymes. If you experience any of these side effects, theyusually go away after the first few weeks on the drug.A rare but potentially dangerous side effect of Zerit ispancreatitis, which is more likely to occur if Zerit is takenwith Videx. Symptoms of pancreatitis can include nausea,vomiting, diarrhea, blood in the urine, and sharp pain in theback or upper stomach. If you experience these symptoms while onZerit, contact your healthcare provider immediately.Various aspects of lipodystrophy are at least partly caused bythe nucleoside analogs, but many studies have specifically linkedlipoatrophy (fat loss) and, to a lesser degree, increased lipidlevels to the use of Zerit (see above).Lactic acidosis is another possible side effect of all of thenucleoside analogs, but Zerit seems to increase the risk. Somepregnant women on regimens that included both Zerit and Videxhave had fatal cases of lactic acidosis. The combination of thesetwo 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'sside effects, such as those listed above that also haveperipheral neuropathy as a possible side effect. Drugs that mayincrease the risk of pancreatitis, such as Cytovene (oralganciclovir), rifampin, and Mycobutin (rifabutin), should also beavoided, especially if you're taking Videx with Zerit. Takingribavirin for the treatment of hepatitis C while on Zerit mayincrease 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'ssarcoma, may lower levels of Zerit in the body, reducing thedrug's anti-HIV effect. Zerit shouldn't be used with Retrovirbecause 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 Zeritwhile developing a strategy for sequencing antiretrovirals hasoften been somewhat controversial. As described in the section onRetrovir, the backbone of an HIV regimen is usually a pair ofNRTIs, combined with a third or fourth drug - most often an NNRTIor PI. Either Retrovir or Zerit are often part of a first-linecombination (though not both), and researchers have tried tofigure 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 dualnucleoside combination "of choice" based on its effectiveness,safety, few interactions with other drugs, the probability ofdeveloping resistance mutations, and dosing convenience. Yet theDHHS guidelines recommend Zerit as part of many regimens forpeople who have never taken antiretrovirals before. The languagein the guidelines is vague and confusing about the use of Zerit,frustrating community activists and healthcare providers - thedrug is strongly recommended in some prominent sections, whileits potential dangers are only occasionally mentioned or almosthidden in secondary sections. The bottom line is thatRetrovir/Epivir really is the preferred dual nucleosidecombination.When Zerit was first approved, it wasn't believed that resistancewas as much of a problem with this drug as with other NRTIs. Inrecent years, however, researchers have come to recognize thatZerit's resistance profile is very similar to that of Retrovir.HIV that becomes resistant to Zerit will probably be resistant toRetrovir - and vice versa. And as with Retrovir, HIV that hasbecome resistant to Epivir is often more sensitive to Zerit. Someof the mutations (called thymidine analogue mutations) that ariseduring therapy with either Zerit or Retrovir can causecross-resistance to almost all of the available NRTIs. But thisseems 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 tocross the blood-brain barrier. This makes the drug effectiveagainst HIV in the brain and central nervous system and may helpprevent neurological disease like dementia.Because of overlapping toxicities, including peripheralneuropathy, the combinations of Zerit plus Videx and Zerit plusHivid should be avoided if possible.Heavy alcohol use can increase the risk of pancreatitis and liverdamage. If possible, avoid alcohol while taking Zerit.Your Zerit dose may need to be reduced if you have kidneyproblems.Taking Zerit and Viramune (nevirapine) at the same time couldincrease the risk of severe liver toxicity, especially in women.If both drugs are included in a combination, careful and regularmonitoring of liver function is particularly important.The Zerit XR capsules, once they become available, can be openedup 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!Pregnancy: Zerit is classified as an FDA pregnancy category Cdrug. When high doses of Zerit were given to pregnant rats, somedevelopmental problems to the fetus were seen. According to theAntiretroviral Pregnancy Registry, when Zerit has been usedduring the first trimester, the prevalence of birth defects was2.2%, compared to an overall prevalence of 3.1% in the U.S.population. But the FDA and Bristol-Myers Squibb issued a warningthat pregnant women may be at increased risk of fatal lacticacidosis when prescribed a combination that includes Zerit andVidex. These drugs should only be prescribed together forpregnant women if the potential benefit clearly outweighs thepotential risk to the mother and fetus.Dose:Zerit is taken twice a day (every twelve hours), with or withoutfood. Capsules are available in 15, 20, 30, and 40-mg versions.The dosage is based on weight. People who weigh 60 kg (132pounds) 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 mgevery twelve hours). The pediatric dose (ages two weeks andolder) is 1 mg/kg every twelve hours. Children who weigh 30 kg(66 pounds) or more take the recommended adult dosage. Zerit isalso available as a fruit-flavored powder that your pharmacistmixes with purified water, providing 1 mg of drug per mL ofsolution.Zerit XR capsules, once they're available, will be taken once aday, with or without food. The capsules will come in 37.5, 50,75, and 100-mg versions. The dosage is based on weight. Peoplewho weigh 60 kg (132 pounds) or more will take one 100-mg capsuleonce a day; those who weigh less than 132 pounds will take one75-mg capsule once a day. There is no pediatric version of ZeritXR.FDA Approval: Zerit 1994; Zerit XR 2002 (not yet available)Manufacturer: Bristol-Myers SquibbPatient Assistance Program: 20030910CR030923--------------------------------------------------------------------------------Copyright © 2003 - AIDS Community Research Initiative ofAmerica. Reproduction of this article (other than one copy forpersonal reference) must be cleared through the Editor, ACRIAUpdate, 230 West 38th Street, 17th Floor, New York, NY 10018;; Fax .

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