Retrovir (AZT, azidothymidine, ZDV, zidovudine) has been studied more than any other antiretroviral used for the treatment of HIV. It was the first anti-HIV drug approved by the FDA (March 1987) and has been used in clinical trials of almost every new antiretroviral since that time.
AZT was discovered in 1964 as a possible cancer drug by a researcher working under a grant from the National Cancer Institute, part of the National Institutes of Health (NIH). The drug was never approved as an anti-cancer agent, but once HIV appeared in the early '80s, Burroughs Wellcome (later GlaxoWellcome, now GlaxoSmithKline), which owned the rights to AZT, took another look at it. Test tube (in vitro
) studies showed that it slowed down HIV replication, and clinical trials, including pivotal ones at the NIH, were quickly designed to test its safety and efficacy in humans.
The first thing that many people think of when Retrovir is mentioned is the enormous hope, followed by crushing disappointment, when it was first introduced as "close to a cure" in 1986. In the early trials, people took 1,200-1,500/mg a day -- two to three times the current dose. A phase II study conducted in 1986 (ACTG 002) compared Retrovir to placebo in 282 patients with less than 200 CD4 cells or a history of PCP (pneumocystis pneumonia). At the end of six months, one person taking Retrovir had died compared to 19 taking the placebo. The placebo arm was closed, and everyone in the study was given the opportunity to go on Retrovir. Unfortunately, the death rates evened out the longer people stayed on Retrovir, meaning that the drug helped extend survival a relatively short period of time, not indefinitely.
Later large trials looking at Retrovir in people with higher CD4 counts and no symptoms -- particularly the Concorde study results published in 1993 -- showed that the benefits of Retrovir taken alone (increases in CD4 counts and slower disease progression) diminished within one year of being on the drug. And during the second year of Retrovir treatment, disease progression sped up, even surpassing that of patients who weren't treated at all. At the time, it wasn't possible to understand why this was happening. Viral load tests weren't available yet. If they had been, the trial investigators would have seen that, although Retrovir decreased viral loads as people began the drug, within six months to a year, viral loads would rise again, perhaps to even higher levels than before people started the drug. HIV had developed resistance, and within a year of taking Retrovir alone, people were taking a drug that continued to cause side effects but did little or nothing to slow down HIV.
The side effects were significant -- feeling (and looking) sick, debilitating fatigue
, headache, muscle weakness, discolored nails, and bone marrow toxicity, including life-threatening anemia
(low red blood cells) and neutropenia (low neutrophils, a kind of white blood cell). Some of these side effects caused or contributed to illness and even death. Retrovir was not the lifesaver -- let alone the cure -- that many had hoped. Some people who don't remember or never knew the history of the drug think of AZT as the "poison" that killed rather than cured. For some, the idea of AZT as poison extends to all antiretrovirals and poses a considerable barrier to accessing treatment.
In the early '90s, Retrovir was studied as part of two-drug combinations as other nucleoside reverse transcriptase inhibitors (NRTIs) were developed. These studies showed greater clinical benefit when people took two drugs together as opposed to Retrovir alone. The development of protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the mid-'90s showed that three-drug combinations that included Retrovir dramatically decreased the rates of opportunistic infections and deaths even further. These studies confirmed Retrovir as an effective treatment, but showed that it needs to be combined with other anti-HIV drugs to delay the onset of resistance and to prolong the effects on viral load, CD4 cell counts, and survival.
Because of its track record, we probably know more about how Retrovir works -- its efficacy, safety, and side effects -- than any other antiretroviral currently in use. Yet precisely because it was the first anti-HIV drug approved, it comes with a lot of baggage. The early, roller coaster history of Retrovir in many ways anticipated the ups and downs that have characterized the epidemic -- the battles between industry and people with HIV over pricing and access issues, controversies over data, the hopes raised, dashed, then raised again. Despite the memories and myths that the drug invokes, Retrovir remains a useful treatment option with plenty of data to support its inclusion in a variety of combinations. Retrovir is part of nine (43%) of the 21 regimens that the recently revised Department of Health and Human Services (DHHS) treatment guidelines recommend for people who have never taken antiretrovirals before.
The side effects seen in the early days of Retrovir can still occur at today's lower dose, although less often and to a much lesser degree. The most common short-term side effects include headache, fatigue, nausea, loss of appetite, and vomiting. These are more likely to occur during the first few weeks on the drug, although some people experience them for longer. The gastrointestinal side effects (nausea and vomiting) may be lessened if you have some food in your stomach before taking the drug. Long-term use of Retrovir can lead to anemia and neutropenia, so regular blood work is important to catch these irregularities before serious problems develop.
A rare side effect of long-term Retrovir use is myopathy (inflammation of muscle tissue). The symptoms are painful or tender muscles, usually in the thighs, hips, and butt. If you've been on Retrovir for a year or more and experience these symptoms, myopathy is a possibility. There's some evidence that people who experience Retrovir-associated myopathy already have underlying myopathy caused by HIV disease itself. A physical exam will reveal normal muscle reflexes, so the primary way to diagnose myopathy is by having your blood CPK (creatine phosphokinase) levels checked. If the blood level of this enzyme is elevated, it could mean that too many muscle fibers are breaking down. It's important to note, though, that myopathy may not be the only reason for an elevated CPK. There's no specific treatment for myopathy, but Retrovir-associated myopathy is usually reversible if the drug is stopped early. CPK levels and symptoms often improve within one to three months.
Although Retrovir has fewer drug interactions than many other antiretrovirals, particularly the protease inhibitors, there are some important ones to be aware of. Retrovir shouldn't be used with Zerit (d4T) because the two drugs work against each other in the body, resulting in less anti-HIV activity. Methadone can increase Retrovir levels so much that some people need to cut their Retrovir dose in half. Other opiates such as morphine, heroin, codeine, and Demerol (meperidine) can have the same effect. If you're on ribavirin as part of combination therapy for hepatitis C, Retrovir shouldn't be part of your HIV regimen. Taking ribavirin and Retrovir together may make each less effective. And since anemia is a possible side effect of each drug, taking both increases the likelihood of developing the condition.
When to Consider It
When someone is thinking about antiviral treatment, the issue of which drugs to use first is an important consideration, since what you start with can affect your future choices. If you develop high-level resistance to Retrovir, you're also likely to be resistant to all of the NRTIs -- Epivir (3TC), Videx (ddI), Zerit, Hivid (ddC), Ziagen (abacavir), and, probably, Emtriva (emtricitabine). Previous use of Retrovir, Zerit, and Videx can make Epivir less effective. Resistance to Retrovir and Epivir may mean resistance to Ziagen. Sounds complicated, and it can be. But it's not necessarily a reason to avoid a combination that includes Retrovir. The trick is to choose your regimen carefully, adhere to it, and, as much as possible, avoid the development of resistance.
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. Over the years, many studies have compared various dual NRTI combinations, and recent research tends to favor Retrovir/Epivir over other combinations. The current 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 compared to other dual nucleoside combinations.
Either Retrovir or Zerit are often part of a first-line combination (though not both). In 2000, researchers looked at the CD4 counts and viral loads of patients who used Retrovir as part of their first regimen compared to those who used Zerit first. People who took Retrovir before Zerit had greater viral load drops, more often reaching undetectable levels, than those who took the medications in the reverse order. There was no difference in CD4 counts between the groups. These results suggest that going from Retrovir to Zerit may work better than the reverse. Our growing understanding of Zerit's long-term side effects makes it a less-than-ideal choice for first-line therapy (see Zerit), so the issue of which of the two to use first may be less important now than it was only a few years ago.
Good to Know
- Retrovir 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.
- If your virus has become resistant to Retrovir, using Epivir with Retrovir can sometimes make HIV that's resistant to Retrovir sensitive to Retrovir again.
- So many people have used Retrovir over such a long period of time that the transmission of Retrovir-resistant virus may make up more than 10% of new HIV infections in the United States.
- Barring any lawsuits (which are likely), generic AZT could be available in 2005, when Glaxo's patent on the drug as a treatment for HIV expires.
Retrovir's ability to reduce transmission of HIV from positive mothers to their children was discovered in 1994 with the release of the results of PACTG 076. This trial, conducted in France and the United States, compared two groups of HIV-positive pregnant women, all with CD4 counts above 200 and none of whom had taken any antiretroviral therapy at the start of their pregnancy. One group of women took Retrovir alone beginning 14 weeks or later in their pregnancies and intravenously during labor. Their babies were given Retrovir for six weeks immediately following their birth. The other group of women and their children were given placebo (no Retrovir). Of the newborns evaluated in the study, 8% in the Retrovir group were HIV-positive compared to 25% in the placebo group. Later trials confirmed Retrovir's ability to reduce mother-to-child transmission. Even with the use of combination therapy in women during pregnancy, the Retrovir protocol continues to be recommended to reduce the risk of transmission.
There was, and continues to be, much concern about possible negative effects of Retrovir when used in this way. Thankfully, no dangerous short-term side effects were observed in either the women or the newborns in PACTG 076 or in subsequent similar studies. The children continue to be monitored for long-term side effects; having been followed for up to six years, researchers have found no differences between those infants who were exposed to the Retrovir regimen and those who received placebo. Early in 2003, researchers published the results of PACTG 288, a follow-up study of women who participated in PACTG 076. Three to six years after the women gave birth, no differences in HIV disease progression, CD4 counts, viral load, opportunistic infections or death were observed in the women who had taken Retrovir during their pregnancies compared to those who took placebo.
Ironically, Retrovir is still classified as an FDA pregnancy category C drug. Despite the short- and long-term data from PACTG 076, the FDA still considers its safety in human pregnancy to be unproven. This is probably because some studies using very high doses in pregnant rodents resulted in fetal tumors. Aside from the encouraging results of PACTG 076 and PACTG 288, the Antiretroviral Pregnancy Registry has found that, when Retrovir has been used during the first trimester, the prevalence of birth defects was 2.8%, compared to an overall prevalence of 3.1% in the U.S. population.
600 mg a day, usually taken as one 300-mg tablet twice a day, with or without food. Also available as 100-mg capsules, as a flavored syrup that contains 50 mg per teaspoonful, and as part of the combination pills, Combivir
. The pediatric dose (ages 6 weeks to 12 years) is 160 mg per meter squared (m2
) of body surface area every 8 hours (480 mg/m2
daily up to a maximum of 200 mg every 8 hours). Children over 12 take the usual adult dosage. Interestingly, although 600 mg is the recommended daily dose for adults and adolescents in the United States, Retrovir is available as 250-mg tablets in many countries, including the United Kingdom, with a recommended dose of 500 mg a day.
FDA Approval: 1987
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