Project Inform Perspectives 36 - October, 2003

The FDA approved FTC (emtricitabine, Emtriva) in July 2003 for use by adults in combination with other anti-HIV drugs. FTC is a nucleoside analog reverse transcriptase inhibitor (NRTI). Other drugs in this class include 3TC, abacavir, AZT, Combivir, d4T, d4T XR, ddC, ddI, ddI EC and Trizivir.

Who should use it?
FTC is very similar to 3TC. Thus far it has shown relatively few side effects. The advantage of FTC's once daily dosing may appeal to those trying to simplify their regimens.

What does the research show?
Several studies support the approval of FTC. One included 571 people who had never taken anti-HIV drugs. Volunteers received ddI and efavirenz with either FTC or d4T. After 48 weeks (nearly one year), 81% of those receiving FTC sustained undetectable viral loads compared to 68% on d4T. CD4+ cell counts increased about the same between the groups, though slightly higher for FTC recipients. More people on d4T quit the study because of side effects-22% on d4T vs. 15% on FTC.

In another study, 440 people used either FTC (once daily) or 3TC (twice daily) with other anti-HIV drugs. Before study entry, all were on effective, standard therapy including 3TC along with other anti-HIV drugs for at least 12 weeks. People stayed on their regimens but were randomly assigned to either continue on 3TC or switch to FTC. After 48 weeks, outcomes were similar. Side effects were fairly similar between the groups.

In general, results from these two large studies suggest that FTC may be slightly more active and have fewer side effects than d4T. FTC appears to have similar activity and with comparable side effects to 3TC.

How to use it?
FTC is a 200mg pill, taken once daily, with or without food. FTC's once daily dosing makes it attractive to use. Dose changes are likely needed for people with kidney complications, including those on dialysis.

What about side effects?
FTC has relatively few side effects. The most common ones include headache, diarrhea, nausea and rash. Only 1% of volunteers quit the studies due to these side effects. Generally speaking, the levels of side effects were similar with FTC as with other regimens, such as those using d4T or 3TC. A noted exception was skin discoloration of the palms of hands and/or soles of feet among those on FTC. There were no other symptoms related to this discoloration, and researchers aren't sure what is causing this side effect.

In addition to being active against HIV, FTC appears to be active against hepatitis B virus (HBV). People with both HIV and HBV have faced a worsening of HBV-related complications after stopping FTC. For this reason, it's recommended that people living with both use caution when taking FTC, as it has not been tested well in this setting. Moreover, careful monitoring of HBV should follow after stopping FTC.

A relatively rare but serious side effect from using NRTIs is severe chemical imbalances in the body called lactic acidosis. For more information on lactic acidosis, read Project Inform's publication, Mitochondrial Toxicity, as well as new information on ddI and d4T in PI Perspective 35. Also, the use of anti-HIV drugs have been linked to changes in body shape and fat distribution. NRTIs may be particularly associated with loss of fat, such as facial or limb wasting. For more information, read Project Inform's publication, Lipodystrophy.

What about resistance?
Resistance to a drug occurs when the virus changes or modifies itself such that it is no longer crippled in its replication cycle by the effects of a drug. Resistance to FTC may be slow to develop when used with other anti-HIV drugs. However, HIV resistance to FTC has been seen.

Cross-resistance is when resistance to one drug also causes resistance to other drugs. Studies suggest that once HIV has developed resistance to FTC, then 3TC and ddC may be less effective. FTC and 3TC share similar resistance patterns, so virus resistant to 3TC will likely be resistant to FTC as well. Test tube studies suggest that HIV showing certain types of resistance to abacavir, ddI, tenofovir or ddC may also be less susceptible to FTC.

Are there concerns about drug interactions?
It's not expected that FTC will have many drug interactions. Studies have been conducted with a few other anti-HIV drugs and no interactions were observed. Whether or not FTC interacts with other medications (methadone, psychiatric medicines, street drugs, etc.) is not known. There are possible interactions with other drugs that are cleared through the kidneys. People are encouraged to discuss these interactions between ALL of the therapies and substances they are taking with their doctor and/or pharmacist.

Discussion
Some consider FTC to be a “me too” NRTI: just another drug in a growing list with no special benefits. Data suggesting that FTC is superior to d4T may have been important a year or so ago when d4T was among the most used and seemingly favored NRTI among patients and providers. However, the use of d4T has waned because of its implicated role in fat loss and liver complications.

How FTC compares to 3TC is perhaps more important. 3TC has long been regarded as one of the most potent NRTIs when used correctly with other potent drugs. The arrival of Combivir as a single pill, taken twice daily, made three-drug therapy immensely easier. Combivir provided two NRTIs as the backbone for a potent three-drug regimen. Doctors and patients alike sighed in relief at the new formulation that helped ease the pill burden and improve adherence

Ultimately the question is what does FTC add to the anti-HIV arsenal? It appears to be a fairly potent NRTI and similar in many ways to 3TC. Like 3TC, it has relatively few side effects (though slightly more than 3TC). One nice advantage is that FTC is taken just once daily. This benefit may be less critical now that more and more drugs are coming out in once daily formulations, however.

Gilead Sciences, who developed FTC, also makes another anti-HIV drug called tenofovir. It is also taken once daily. It is Gilead's goal to make them into a single pill taken once daily, allowing for a potent combination in one pill. With the new protease inhibitor atazanavir (also dosed once daily) and other advances on the horizon, it may soon be possible to construct potent three-drug regimens that need as few as one or two pills once daily.

FTC thus represents a sort of dawning of a new and important phase of refinement in HIV treatment-that is, drugs that are easier to take with fewer side effects and good potency. In and of itself, it offers very little in the short-term. Its real benefits likely won't be realized until it's co-formulated with tenofovir. The company hopes to launch this new pill in 2005.

Atazanavir (Reyataz)

Who should use it?
Atazanavir is a once-daily therapy approved for use in combination with other anti-HIV drugs in adults, regardless of prior anti-HIV therapy use. It's recommended that people receive a resistance test prior to starting the drug to increase the chance that they will benefit from it. The drug does not appear to cause large increases in cholesterol and triglyceride (lipid) levels associated with other protease inhibitors. For this reason it may be a nice option for people with cholesterol concerns and/or those with risks for heart disease.

When used as part of a second or third line therapy, in order for atazanavir to provide benefit, it may well need to be “boosted” with a small amount of ritonavir. Because ritonavir is known to have an effect on cholesterol, the advantages of atazanavir with regard to this side effect may be decreased.

What does the research show?
Three studies were particularly important in supporting the approval of atazanavir. One compared atazanavir to a commonly used NNRTI drug called efavirenz (Table 1). Another compared atazanavir to the protease inhibitor nelfinavir (Table 2). Both of these studies included people who had never used anti-HIV drugs. The third study compared atazanavir to the protease inhibitor Kaletra and included people who had previously used (and failed) one protease inhibitor-containing regimen. In all studies, CD4+ cell counts at study entry were about 300 (321 in the first, 295 in the second and 318 in the third). In the studies that looked at people who had never used anti-HIV treatment, viral loads were about 60,000 at study entry. In the study of people who had used and failed one protease inhibitor, viral load was close to 10,000 at study entry.

In the first study, 810 volunteers received Combivir (AZT + 3TC, given twice daily) and either atazanavir (400mg once daily) or efavirenz (600mg once daily.) Both groups had comparable decreases in viral load and rises in CD4+ cell counts. Overall, about 65% of those receiving the combinations achieved viral load suppression to below the limit of detection of the tests (400) through 48 weeks (about one year) of therapy. Those receiving atazanavir had a mean (average) CD4+ cell increase of close to 180, while those taking efavirenz averaged increases of about 160. In general these therapies appear to be comparable in potency, though have different side effect concerns.

In the second study, 467 people were given d4T and 3TC twice daily in combination with either atazanavir (once daily) or nelfinavir (1,250mg twice daily). Similar percentages of people achieved viral suppression to below detectable (400) in both groups, but those taking atazanavir did slightly better (67% compared to 59%) though 48 weeks. However, when using a more sensitive viral load test (limit of detection less than 50) slightly more people did “better” in the nelfinavir group (38% compared to 33%). CD4+ cell count increases averaged about 234 among those receiving atazanavir compared to 211 nelfinavir recipients. In other words, these therapies appear generally comparable in potency, though again they have differing side effect concerns.

The third study evaluated once daily atazanavir to twice daily Kaletra in combination with two NRTI drugs (like AZT, 3TC, d4T, etc.). Significantly more people receiving the Kaletra-based regimen achieved viral load reductions to below the limit of detection (75% compared to only 54% of those taking atazanavir) through week 24 (6 months). When using the more sensitive viral load test, with a limit of detection of 50, these results held with 50% of Kaletra users and only 34% of atazanavir users achieving suppression to undetectable levels. Moreover, CD4+ cell count increases were more pronounced among Kaletra recipients (121 compared to 101 receiving atazanavir). While Kaletra was clearly a superior option, those receiving Kaletra also experienced more side effects.

In a recent study presented at the International AIDS Society meeting (July 2003), atazanavir was evaluated as part of a third line regimen in 358 people who had failed two previous anti-HIV regimens and demonstrated resistance to at least one drug in each class (NRTI, NNRTI and PI). Volunteers received tenofovir and an NRTI drug and either Kaletra, once daily combination of atazanavir (300mg) + ritonavir (100mg) or once daily combination of atazanavir (400mg) + saquinavir (1,200mg). At 24 weeks (6 months) the Kaletra and atazanavir + ritonavir groups showed comparable results, with the atazanavir + saquinavir combination falling out as inferior. Those receiving the atazanavir + ritonavir combination were less likely to have increases in lipid levels, less likely to experience diarrhea, but more likely to have increases in bilirubin and associated jaundice. Because atazanavir may boost tenofovir levels, however, it's unclear if these same results would hold true if the atazanavir + ritonavir combination were used in conjunction with any NRTI two-drug backbone for a regimen.

For results of an earlier study comparing atazanavir to nelfinavir, and switching from nelfinavir to atazanavir, see PI Perspective 35.

How to use it?
Atazanavir comes in 100, 150 and 200mg capsules. The daily dose for adults is 400mg, once daily, to be taken with food.

Dose adjustments are required when using the drug in combination with some other anti-HIV drugs including efavirenz, ritonavir and tenofovir. With other drugs there are guidelines for use when they are used at the same time (e.g., ddI and ddI EC in combination with atazanavir). For more information about dosing adjustments and concerns, call Project Inform's hotline.

Other dose adjustments may be required when taking atazanavir in combination with other anti-HIV drugs as well and if people have impaired liver function.

In general, boosting with a small dose of ritonavir is recommended for most people who have developed resistance to other protease inhibitors.

What about side effects?
Perhaps the most attractive feature of this drug, besides the ease of use of once-daily dosing, is that, so far, studies have shown relatively few side effects. This may or may not change as doctors and patients have more and longer-term experience with the drug. One of the most common side effects of atazanavir is increases in a laboratory measure called bilirubin. This occurred in 35% and 47% of study participants in the first two studies noted above. In nearly all cases bilirubin levels returned to normal upon discontinuing the drug. In a few instances physical symptoms were associated with this elevated lab marker, including yellowing of the skin or whites of the eyes (jaundice).

Atazanavir does not appear to have the pronounced impact on lipid levels (cholesterol and triglycerides) seen with most other protease inhibitor therapies. When compared to Kaletra, atazanavir appeared to cause dramatically fewer problems with lipids. Some speculate that this might lead to decreases in concerns about body composition changes (particularly fat accumulation in the truncal area, breast or base of the neck) called lipodystrophy associated with protease inhibitor use. Preliminary reports from a study which looked for body composition changes in people receiving either an efavirenz- or atazanavir-containing regimen with AZT + 3TC showed no symptoms of lipodystrophy through 48 weeks of treatment. While some people receiving efavirenz had increases in lipids, no one receiving atazanavir had increases in lipids. It can't be said that atazanavir use won't be associated with lipodystrophy, certainly longer follow and more study is needed, but this preliminary report is encouraging.

When compared to nelfinavir or efavirenz regimens, atazanavir-containing regimens appeared to have similar or slightly fewer side effects. In general, when compared to efavirenz, slightly more people receiving atazanavir experienced nausea (feeling sick) and yellowing of hands/eyes (jaundice). Some of the biggest concerns with efavirenz include sleep disturbances, mental status changes, including depression. These did not occur as often among those receiving atazanavir. With regard to nelfinavir, where the most common side effect is diarrhea, significantly fewer people experienced diarrhea with atazanavir. Also, when people who had used nelfinavir in the first part of a study were later switched to atazanavir, there were significant drops in their cholesterol levels.

Protease inhibitors have been associated with an increased risk of diabetes. In the study which compared atazanavir to efavirenz in combination with AZT + 3TC, noted above, at 48 weeks no one in either group showed evidence of insulin resistance, which is a measure for risk of diabetes. Diabetes may also be less of a concern with atazanavir compared to other protease inhibitor drugs.

As with other protease inhibitors, it's possible that symptoms of hepatitis C or B may worsen upon starting atazanavir. People are encouraged to be tested for hepatitis prior to starting anti-HIV drugs and monitor liver tests carefully after starting anti-HIV therapy.

What about resistance?
HIV resistance to atazanavir is likely to be a concern, and thus the drug should be used in combination with other anti-HIV therapies. Resistance to a drug occurs when the virus changes or modifies itself such that it is no longer crippled in its replication cycle by the effects of a drug. Cross-resistance is when resistance to one drug also causes resistance to other drugs. Studies suggest that cross-resistance to other protease inhibitor drugs, in particular, is likely to be a problem with atazanavir.

Once a person has developed resistance to atazanavir, they are very likely not going to benefit as well from other approved protease inhibitors. It might be possible, however, to use boosted doses of these other therapies to overcome some of this resistance. Some test tube studies suggest that even though resistance may have developed to some other protease inhibitors, atazanavir may still have some anti-HIV effect. The bottom line message, however, is that the story of atazanavir resistance is still an evolving story.

Are there concerns about drug interactions?
Atazanavir is processed through the liver and has many drug interactions. Some of these interactions may be life-threatening, others may merely require dose adjustments of the therapies. For a list of known and suspected drug interactions, call Project Inform's hotline and request the publication, Atazanavir.

Discussion
It remains a bit unclear how atazanavir fits into the arsenal of other approved protease inhibitor drugs. The most attractive features of this drug are its ease of use (it only needs to be taken once daily), and its relatively few side effects. These features may make it of particular interest as part of first line therapy for treating HIV, for those who are experiencing problems with adhering to more complex medication schedules, for those who are experiencing problems with lipid elevations (increases in cholesterol and triglycerides) while using other therapies and for people who may have risks for high cholesterol and heart disease (e.g., family history, smokers, etc.).

When considering atazanavir as part of a regimen if you've never used anti-HIV therapies before, there are a few issues to consider. First, in studies atazanavir appeared to have equal potency when compared to efavirenz-containing regimens. Efavirenz is in a different class of drug, it's an NNRTI, and it is a very popular drug for first line use. The advantages of starting with atazanavir as opposed to efavirenz may be that atazanavir does not have the mental status side effects associated with efavirenz (like sleep disturbances, hallucinations, etc.). Also, when someone develops resistance to efavirenz, nearly complete cross-resistance to all the other currently available NNRTIs is very likely (i.e., the other NNRTIs are likely to not work at all). While there is some evidence that resistance to atazanavir may also lead to cross-resistance to other protease inhibitors, it's less clear if this will present a major obstacle in benefiting from other protease inhibitor-containing regimens in the future. Also, because atazanavir need only be taken once daily, especially for someone starting therapy for the first time this may be very attractive as it may decrease the interference with daily routines while a person adjusts to taking anti-HIV medications.

When it comes to atazanavir use as part of second line therapy, the picture becomes a little more complicated. Resistance testing will be particularly important here to help determine if a person is likely to benefit from the drug. Resistance to other protease inhibitors may decrease the effectiveness of atazanavir. In some cases, particularly where resistance may be a concern, it may be necessary to boost blood levels of atazanavir by using a small dose of another protease inhibitor called ritonavir. In these cases, some of the attractive features of atazanavir are lost to some degree. Because ritonavir is known to increase lipid levels, using the combination of the two drugs will still likely lead to risks for this side effect. With this said, however, it's likely that lipid problems will be less of a concern with this boosting regimen compared to other ritonavir-boosted regimens where the second drug may also have this side effect concern (e.g., ritonavir + indinavir, Kaletra, etc.).

Increasingly, data suggests that atazanavir use in third line or salvage situations will require ritonavir boosting. In this situation the combination of atazanavir and ritonavir may be equally potent to Kaletra (lopinavir + ritonavir) and have fewer lipid-related side effects, less associated diarrhea, but higher risks for increased bilirubin and possibly jaundice.

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