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

Epivir (3TC, Lamivudine)

Fall 2003/Winter 2004

Epivir (3TC, lamivudine) is a powerful drug with minimal side effects, an easy dosing schedule, and few drug interactions. It may be one of the most useful nucleoside analogs available, particularly if it's used strategically. By the time it received accelerated approval from the FDA in November 1995, close to 30,000 people had already received Epivir through the largest expanded access program ever. To qualify for the expanded access program, you had to have a CD4 count less than 300 and have already failed or be unable to tolerate the four approved anti-HIV therapies. The large number of people who were eligible for the program is a reminder of how very few treatment options were available at the time -- and how desperately new treatments were needed.


Background

In the early '90s, clinical trials were designed to study what happened when people took a two-drug combination compared to taking one drug alone -- usually Retrovir (AZT). When the results of these studies, particularly ACTG 175 and the Delta study (described in the discussion of Hivid), were released in late 1995, the message was clear -- combination therapy was dramatically more effective at slowing HIV disease progression and prolonging survival than taking only one drug (monotherapy).

Although there have been many trials to determine the safety and effectiveness of Epivir, perhaps the most influential was the large, international CAESAR study, named for the regions in which it was conducted -- Canada, Australia, Europe, and South Africa. In July 1996, this trial was stopped early when a planned interim analysis showed that adding Epivir to other antiretroviral treatments cut HIV disease progression and death in half. The study had enrolled 1,892 people with CD4 counts between 25 and 250. Upon entry, almost all of the participants were taking Retrovir alone, Retrovir plus Videx (ddI), or Retrovir plus Hivid (ddC). Some had never taken any antiretrovirals before. The participants were then randomly assigned to add placebo, Epivir, or Epivir plus loviride (an experimental non-nucleoside reverse transcriptase inhibitor that was never approved) to their current treatment.

After about a year of follow-up, the rate of disease progression to a new AIDS-defining condition or death was 17% in the group that added placebo to their treatment, 9% in the group that added only Epivir, and 8% in the group that added Epivir plus loviride. In other words, adding Epivir (with or without loviride) showed a 54% reduction in the risk of disease progression or death compared to people who remained on their current treatment alone (those who were given placebo). Changes in CD4 cell counts and viral load levels in a small group of study participants were consistent with the clinical results. When the trial was stopped in mid-'96, all participants were offered Epivir with or without loviride. The CAESAR study also found that adding Epivir to the other medications caused no additional side effects. While highlighting the positive impact of Epivir on slowing disease progression, these results also provided further evidence of the effectiveness of combination therapy.

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Many later studies of protease inhibitors, NNRTIs, and triple-nucleoside regimens have included Epivir as part of their comparative combinations and shown it to be an effective component of many different regimens.


Side Effects

The most common side effects of Epivir include headache, fatigue, nausea, and vomiting. Rare side effects include trouble sleeping, nasal congestion, cough, and, for a very few people, mild hair loss. Peripheral neuropathy (tingling, pain and numbness in the feet and hands) has been associated with Epivir, but is nowhere near as common or severe as that seen with Videx, Hivid, or Zerit (d4T). Pancreatitis (inflammation of the pancreas) is a rare but possible side effect of Epivir, particularly in children.


Drug Interactions

Epivir has fewer problematic drug interactions than just about any other approved antiretroviral. It shouldn't be taken with Hivid because the two drugs interfere with each other. Blood levels of Epivir may increase when taken with TMP/SMX (Bactrim, Septra), which is used to prevent PCP (pneumocystis pneumonia). These increased levels usually don't require changing the dose of either drug.


When to Consider It

As you develop a treatment plan, figuring out when and how to use Epivir is important. It can be useful for people just starting treatment as well as for those who have had experience with a lot of antiretrovirals.

If Epivir were taken alone, complete resistance to the drug would develop very quickly, usually within a few weeks. It only takes one mutation (change) in HIV's reverse transcriptase enzyme to make HIV completely resistant to Epivir. It's important to consider this rapid development of resistance when putting together a regimen. If adherence is likely to be a problem, it might not be a great idea to include Epivir in your combination since you're likely to become resistant to the drug very quickly if you miss doses.

Even if your virus is resistant to Epivir, it's possible to keep the drug as part of your three- or four-drug combination and still maintain a low viral load and high CD4 count. HIV that's resistant to Epivir usually can't reproduce as readily as HIV that doesn't have that particular mutation. Also, HIV that's resistant to Epivir is often more sensitive to other anti-HIV drugs, particularly Retrovir, Zerit, and Viread (tenofovir). It's not unusual to stay on an Epivir-containing regimen even when resistance to Epivir has been documented through resistance testing.

But resistance to Epivir isn't always a blessing. If your HIV is resistant to Epivir, for example, it will also be resistant to Emtriva (emtricitabine), which is called cross-resistance. Epivir resistance can also affect HIV's sensitivity to Videx, Hivid, and Ziagen (abacavir).

As described in the section on Retrovir, the backbone of an HIV regimen is usually a pair of nucleosides, combined with a third or fourth drug -- most often an NNRTI or PI. Recent research tends to favor Retrovir/Epivir over other nucleoside pairs. The current Department of Health and Human Services (DHHS) treatment guidelines recommend Retrovir/Epivir as the dual nucleoside combination "of choice." Epivir also figures as part of the two dual-nucleoside pairs described in the DHHS guidelines as alternatives: Epivir/Zerit or Epivir/Viread.

Epivir's efficacy, minimal side effects, few drug interactions, and relatively easy dosing schedule support its inclusion in many combinations. It has the singular distinction of being a component of all 21 regimens that the DHHS guidelines recommend as possibilities for people who have never taken antiretrovirals before.


Hepatitis B

Epivir is also approved for the treatment of chronic hepatitis B (HBV) infection under the brand names Epivir HBV in the United States and Zeffix in most other countries. Before beginning an HIV regimen that includes Epivir, it's a good idea to be tested for chronic HBV, since your use of the drug could change depending on the results. The usual dose to treat HBV is 100 mg a day, one-third the dose used in HIV. People co-infected with HIV and chronic HBV should take the higher HIV dose -- if they take Epivir at all. Chronic HBV is sometimes treated using a combination of therapies, and combination therapy for chronic HBV is likely to be the norm in the future. Using Epivir as part of your anti-HIV combination could mean single-drug therapy for your HBV and cause your hepatitis B to become resistant to the drug. The result could be fewer treatment options for your HBV in the future. Including Viread, another anti-HIV drug with activity against HBV, in your combination with Epivir is another choice.

If you've been taking Epivir, are co-infected, and plan to stop Epivir, your HBV may flare-up once the Epivir is removed, possibly causing liver damage. Be sure to have your liver enzyme levels checked regularly if you stop taking Epivir and have chronic HBV. Even if your HIV becomes resistant to Epivir, it might be worthwhile to stay on the drug to help keep your HBV in check.


Good to Know

  • 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.

  • If you have any kidney problems, be sure to let your healthcare provider know before taking Epivir. Your dose may need to be lowered.


Pregnancy

Epivir is classified as an FDA pregnancy category C drug. Its safety in human pregnancy hasn't been determined and animal studies haven't shown fetal risk, but the drug shouldn't be used during pregnancy unless the potential benefit outweighs the potential risk to the mother and fetus. According to the Antiretroviral Pregnancy Registry, when Epivir has been used during the first trimester, the prevalence of birth defects was 3.0%, compared to an overall prevalence of 3.1% in the U.S. population. In other words, using Epivir during the first three months of pregnancy -- the time when a fetus is most susceptible to birth defects caused by toxic chemicals and medications -- doesn't seem to have any serious effects.


Dose

300 mg a day, taken as one 300-mg tablet once a day or one 150-mg tablet twice a day with or without food. For adults who weigh less than 110 pounds (50 kg), the dose should be adjusted to 2 mg/kg twice a day. Epivir is also available as a flavored syrup that contains 10 mg/mL and as part of the combination pills Combivir and Trizivir. Someone who weighs 90 pounds (41 kg) would need to take 82 mg of Epivir twice a day, not an easy trick considering the formulations. The pediatric dose (ages 3 months to 16 years) is based on weight: 4 mg/kg twice a day up to a maximum of 150 mg twice a day.

FDA Approval: 1995. Once-a-day dosing approved in 2002.

Manufacturer: GlaxoSmithKline

Patient Assistance Program: 866-728-4368





  
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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.
 

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