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Update From CROI 2008 on Approved HIV Drugs

April 2008

The Conference on Retroviruses and Opportunistic Infections is the most important annual science conference in the US covering HIV/AIDS. This year's meeting was held in Boston, MA and included presentations ranging from vaccines to microbicides and experimental HIV drugs to opportunistic infections. This article reviews the research on approved anti-HIV drugs presented at CROI 2008.

SWEET

A poster presentation showed that people switching from Combivir (zidovudine + lamivudine) to Truvada (tenofovir + emtricitibine), experienced increases in limb fat and no changes in HIV levels, kidney function and bone mass. The SWEET study looked at 234 people on stable regimens of Sustiva (efavirenz) + Combivir. Half were randomly assigned to switch from Combivir to Truvada and half stayed on Combivir. Participants were given DEXA scans, which measure bone and fat.

After 48 weeks, people who had switched to Truvada gained an average of 0.2Kg (0.4lbs.) of limb fat, while those who stayed on Combivir had lost a bit less than 0.2Kg (0.4lbs.) on average. The effects were greatest in people who had taken AZT for less than 3 years, and with less limb fat at baseline. There have been concerns with Truvada over kidney function and bone loss. In both cases there were trends toward more problems with Truvada compared to Combivir, but they were not significant.

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These results confirm what has been known for some time. Combivir, which was the first fixed-dose combination pill, has a higher risk of limb fat loss than Truvada. This switch study showed that the loss of fat on Combivir could be somewhat reversed with a switch to Truvada. While there were no significant differences between the groups on measures of bone or kidney health, there were small trends that tend to confirm concerns about Truvada.

HEAT

Another poster presented at CROI found that that Epzicom (abacavir + lamivudine) and Truvada performed equally well when combined with the boosted protease inhibitor, Kaletra (lopinavir + ritonavir). This head-to-head study, called HEAT, is important because there aren't much direct comparison data between Epzicom and Truvada -- the two preferred fixed-dose combination NRTIs by current Federal Guidelines.

HEAT looked at around 700 people who had never taken HIV drugs, who were randomly selected to take either Epzicom or Truvada alongside Kaletra. About half the volunteers were white and 82% were male. The primary outcome was the proportion of people with HIV levels below 50 copies/ml after 48 weeks. Data were also collected on adverse events and changes in CD4 counts.

After 48 weeks, similar percentages (68% for Epzicom vs. 67% for Truvada) of people in both groups had undetectable HIV. People taking Epzicom had slightly larger increases in CD4 counts (201 vs. 179 cells), but not to a clinically significant degree. There were also similar levels of adverse events among the two groups, with more kidney problems among people taking Truvada and more hypersensitivity reactions in people taking Epzicom.

The current Federal Guidelines, released in late January 2008, list both Truvada and Epzicom as preferred options for first line treatment. To date there has been little direct comparison data to help people choose between these two options. The results from HEAT suggest that either fixed-dose combination is likely to work well, at least when paired with once daily Kaletra.

There are a couple of secondary, but important, notes about this study. First, it used once daily Kaletra, rather than the more widely used and better supported twice daily schedule. This might explain the higher levels of resistance to NRTIs than is typically seen in clinical studies. Also, HLA testing -- which fairly accurately predicts the risk of abacavir HSR -- was not used. Other studies, like PREDICT and SHAPE, suggest if it were used, a much lower rate of abacavir HSR would likely have occurred.

Lastly, this study only compared these fixed-dose combinations when paired with Kaletra. While Kaletra is a widely used first line option, there are others -- notably Sustiva (efavirenz) and Reyataz (atazanavir) -- that are common choices for first line therapy. It would be a mistake to apply the results from this study to other drug combinations.

This is an important study nonetheless. The best way to compare drugs is in these kinds of head-to-head studies. The results from HEAT presented here suggest that, along with HLA testing, Epzicom is a reasonable alternative to Truvada, when either is taken with Kaletra.

D:A:D

Another poster presented at CROI found a higher risk of heart attack (myocardial infarction) in people using the HIV drugs Ziagen (abacavir, and fixed-dose combination pills Epzicom and Trizivir) and Videx/Videx EC (didanosine, ddI).

These findings came from an analysis from the Data Collection on Adverse Events of Anti-HIV Drugs, or D:A:D study. D:A:D is a multi-center study that follows several groups of people, mostly in Europe, and examines the unintended side effects of HIV drugs. Earlier research from D:A:D found that HIV drugs on their own increased a person's risk of heart attack by 26%. The study has also reported on a higher risk related to taking HIV drugs from a specific class -- protease inhibitors.

This study examined whether another class of HIV drugs, called NRTIs, also affected the risk of heart attacks. Of the five drugs studied, D:A:D found a significant increase in the risk of heart attacks in people using Ziagen (90%) or Videx (49%), but not Retrovir (zidovudine, AZT), Epivir (lamivudine, 3TC) or Zerit (stavudine, d4T).

Interestingly, the study found that the higher risk was only present when people took the drugs -- that is, the risk was largely reversed when people stopped taking them. This contrasts to the protease inhibitors, where the damage grows over time and is not quickly reversed.

The absolute risk of heart disease (meaning the likelihood a person is to be diagnosed with heart disease) was strongly associated with known risk factors for heart disease. The effects of Ziagen and Videx were present in people regardless of their absolute risk of heart disease, but they were most pronounced in people at the highest underlying risk of heart disease.

There is no known mechanism that explains this NRTI finding. Protease inhibitors are known to increase cholesterol and the risk of diabetes -- both risk factors for heart disease. However, no such affect was seen with these two NRTIs. The fact that the risk disappeared when people stopped the drugs strongly suggests a direct causal relationship between these two NRTIs and the risk of heart disease. More research is needed to understand the mechanism.

It's important to emphasize that the overall rate of heart attacks seen in this study were small. This report does not mean that people on Ziagen or Videx should necessarily stop taking their drugs or switch to others. If you take either drug and you have heart disease or are at high risk for it -- due to family history, smoking or other known risk factors -- discuss these findings with your doctor.

Viramune Once a Day

A poster presented at CROI found that Viramune (nevirapine) given once a day was as safe as when given twice a day for people on stable twice-a-day regimens with Viramune. This study looked at just over 300 people in Spain who had been on twice-a-day Viramune regimens for at least 8 weeks (12 weeks for women with CD4 counts above 250), undetectable levels of HIV, and no signs of liver trouble. Half were randomly assigned to switch to once-a-day Viramune, and half stayed on twice-a-day regimens.

Overall there were low levels of liver problems in the study. More cases of liver problems occurred among people taking Viramune once a day, but the difference was mostly due to people with viral hepatitis. There were no significant differences between the groups in terms of maintaining undetectable HIV.

Viramune is the second most widely used NNRTI, lagging well behind Sustiva (efavirenz). The biggest concern with Viramune is the risk of catastrophic liver toxicity, especially in women and people with higher CD4 counts. Viramune is approved for twice-a-day use, but has been widely used once a day because of its ability to stay in the body for a long time. This study suggests that people who are already taking Viramune successfully -- meaning they have undetectable HIV and no signs of liver problems -- can take it either once or twice a day.

CASTLE

Results from a large head-to-head study of the Norvir (ritonavir) boosted protease inhibitors -- Reyataz (atazanavir) vs. Kaletra (lopinavir) -- were presented at CROI. For people taking HIV drugs for the first time, the CASTLE study found that Reyataz once a day was comparable to Kaletra twice a day, when each is taken with Truvada.

CASTLE enrolled almost 900 people who were randomly assigned to take either 300mg Reyataz + 100mg Norvir once a day or 400mg Kaletra + 100mg Norvir twice a day. Both groups also took one tablet of Truvada (300mg tenofovir + 200mg emtricitabine) once a day. Researchers compared these regimens in terms of lower HIV levels, higher CD4 counts, and various measures of fat metabolism.

After 48 weeks, similar numbers of people in both groups had HIV levels below 50 copies (78% for Reyataz vs. 76% for Kaletra). People on Kaletra had slightly larger gains in CD4 counts (219 vs. 203), though it's not clinically significant. The most significant difference between the regimens was in side effects. More people on Reyataz had higher levels of bilirubin (a protein produced by the liver) and jaundice. People on Kaletra had higher average levels of cholesterol and triglycerides.

This study confirms the growing body of evidence that most, though not all, boosted protease inhibitor regimens perform about the same in lowering HIV levels and raising CD4 counts. The most important differences are found in side effects, drug interactions and convenience. While Kaletra enjoyed a period alone at the top of the hill, the field is now quite crowded, which is a good thing for people with HIV who now have more choices for boosted protease inhibitor regimens than ever before.

Kaletra Once a Day

A poster at CROI found that once-a-day Kaletra is similar to twice-a-day Kaletra, using the new tablet formulation. This contrasts to earlier research that showed higher rates of treatment failure with once-a-day Kaletra, using the older capsule formulation.

The study, titled MO5-730, began as a four-arm study of 664 people randomly assigned to take either formulation (capsule or tablet) of Kaletra, once or twice a day. Everyone in the study also took Truvada. After 8 weeks everyone taking the older capsule formulation was switched to the newer tablet.

The poster presented data on efficacy and tolerability after 48 weeks. Overall, people in both arms were equally likely to have HIV levels below 50. There was also no difference seen when dividing the groups into people with pre-treatment HIV levels above or below 100,000 copies. There were also no significant differences seen in rates of side effects, which differs from some studies using the capsule once a day. Similar changes in cholesterol and triglycerides were seen in both groups as well.

Resistance testing was done on 17 people who experienced treatment failure during the study: 10 in the once-a-day group and 7 in the twice-a-day. Nobody had developed primary resistance mutations that have been linked to resistance to Kaletra and Viread. Three people developed the M184V mutation strongly linked to resistance to Emtriva.

Selzentry

Further results from the pivotal studies of the recently approved CCR5 antagonist Selzentry (maraviroc) were presented in an oral presentation and poster at CROI. Project Inform has written extensively on the development of Selzentry, especially in the past two years as the drug moved closer to FDA approval. Results presented here at CROI 2008 confirm earlier research but also leave important questions open about this new drug.

As reported here, the first set of results for the MERIT studies, which compared Selzentry to Sustiva both combined with Truvada in people taking HIV drugs for the first time, were presented last summer at the IAS meeting. Overall, Selzentry didn't quite match up to Sustiva, using pre-defined criteria. Surprisingly, the difference between the drugs was only seen in people in the southern hemisphere.

In an oral presentation at CROI, further analysis was presented of treatment failure in the MERIT trial. In MERIT more people stopped Selzentry due to treatment failure (11.9% vs. 4.2%) than Sustiva. This study sought to explain what caused these treatment failures. Several explanations were presented. In some cases (3.3%) participants' HIV shifted from R5-only to dual/mixed between the time they were screened and started taking Selzentry. Among people who failed on Selzentry who had R5-only HIV when they started taking drug, about one-third had X4-using HIV emerge. This also led them to develop resistance to the NRTI drugs they were taking. Among people who failed while still having R5-only HIV, resistance to Selzentry was detected in only a small number, while most had developed resistance to their NRTIs.

These results raise further questions about using Selzentry in people taking HIV drugs for the first time. One issue is the reliability of the Trofile test -- the only widely used test to determine whether a person's HIV is only R5 or can use X4. A small, but significant group of people had different results in the short time between screening and taking their first dose. This issue is important because it takes three or more weeks to get the results of the Trofile test back.

However, the biggest problem is the higher rates of treatment failure compared to Sustiva, which is widely used in as first line treatment. While it is true that more people stopped taking Sustiva due to intolerance in this study, the treatment failures experienced by people in taking Selzentry often led them to develop resistance to other drugs in their combination, therefore limiting future treatment options.

A poster presentation covered both efficacy and safety after 48 weeks of Selzentry compared to placebo, both combined with optimized background therapy in people with experience taking HIV drugs in the MOTIVATE studies. This poster basically confirmed earlier results. About half the people taking Selzentry had HIV levels below 50 copies after 48 weeks, compared to 22% of people taking a placebo. There was a significant difference in responses between people with pre-treatment HIV levels above vs. below 100,000 copies. For people with high pre-treatment HIV levels, only around 35% had undetectable HIV levels, compared to almost 60% of people with lower pre-treatment levels.

There were no significant differences in rates of side effects between people taking Selzentry or placebo. This is important to emphasize, because there has been a high degree of concern over toxicity with this class of drugs. So far, it hasn't been confirmed in studies of Selzentry.

The best use of Selzentry is still unclear. It has not performed as well as some other recently developed drugs when used in treatment experienced people, but it has shown some significant benefit for a subset these folks. Many think that CCR5 drugs are better used earlier, when a higher proportion of people are likely to have R5-only HIV, but the head-to-head studies against Sustiva have raised almost as many questions as it has answered. Further muddying the waters are the concerns over the accuracy, turnaround time and cost of the Trofile test needed to use Selzentry.

Another study was presented comparing changes in lipids in MERIT. On average people taking Selzentry experienced less increases in blood fats, compared to people taking Sustiva. Sustiva has been associated with changes in lipids for some time, so this finding was not surprising.

Wrap Up

With the pace of new HIV drug development slowing, research on approved HIV drugs becomes more important. While there were few headline grabbing stories on approved HIV drugs at CROI 2008, each piece of research deepens our understanding of these drugs. More head-to-head and strategy studies are needed to better understand when and how best to use HIV drugs. Alongside our efforts to promote research on experimental HIV drugs and an outright cure, Project Inform advocates for more of this kind of research to improve the treatment of HIV/AIDS.



  
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This article was provided by Project Inform. It is a part of the publication Project Inform Perspective. Visit Project Inform's website to find out more about their activities, publications and services.
 
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