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What's Up? New Combos, New Meds, New Info on Viral Suppression

Fall 2004


Two New Combo Nukes, Both One Pill, Once a Day

Over the past few years we have gotten FDA approval for one QD (once-daily) drug after another: efavirenz, ddI EC, tenofovir, 3TC, atazanavir, abacavir, FTC and fosamprenavir (Abbott Labs has submitted data for QD approval of Kaletra).We have had many QD drugs, but not as many QD regimens. That is changing. Now we have the FDA approval of two nucleoside analogue back bone regimens in one pill, taken once daily. Combine one of these nifty new pills with a QD boosted PI or with efavirenz and you've got a kick-ass first line regimen all taken once-a-day at the same time! So let's look at these two new kids on the block and see what you have to choose from. Keep in mind that these two new options come from two different companies. Many times physicians (and treatment writers) have biases toward one company's drugs or another. Sometimes this is because of ongoing relationships, other times because of access to education. We will attempt to present the data and the arguments for and against each combo pill.

Epzicom

From GlaxoSmithKline we have Epzicom: Abacavir/3TC in one pill once a day. Just so that no one is confused, abacavir is also known as Ziagen and 3TC is also known as lamivudine or Epivir. And abacavir and 3TC are both part of the combo pill Trizivir (along with AZT). So this new combo pill contains two drugs that have been around quite awhile. Abacavir was approved in December, 1998 and 3TC was approved in November, 1995. This is one of the main arguing points for Epzicom over the other new combo pill -- many years of experience with both agents. The main argument against Epzicom is the possibility of abacavir hypersensitivity reaction (HSR), which is explained below. Although there are no studies with the new fixed dose pills, there are a couple of studies that the FDA used to approve Epzicom that looked at ABC/3TC in combination with efavirenz (EFV).

Table 1
CNA30021 48 Week Data
Study ArmsABC/3TC + EFV QDABC/3TC + EFV BID
% VL < 5064%65%
Adverse Events13%11%

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Table 2
CNA30024 48 Week Data
Study ArmsABC/3TC/EFVAZT/3TC/EFV
% VL < 5069%69%
Change in CD4+209+155
% HSR9%<1%

Based on these two studies, and GSK's ability to show that the two drugs were stable in the new co-formulation the FDA granted approval of Epzicom on August 2, 2004.

Abacavir Hypersensitivity Reaction (HSR): The incidence of HSR ranges from 5% to 9%. Recent clinical trials have seen an increase in incidence which is likely due to 2 factors: an increased awareness and diagnosis of HSR; and the fact that the more recent ABC trials were in combination with efavirenz (Sustiva) which can also cause a rash and lead to over-diagnosis of HSR (especially in combo with a common side effect when starting any combo, like nausea or fatigue). These explanations are not meant to lessen the seriousness of HSR, but to put it into context of real-world experience.

If you have ever had a possible hypersensitivity reaction (HSR) to abacavir, Ziagen or Trizivir you MUST NOT TAKE EPZICOM!!!

Hypersensitivity Reaction to abacavir is a multi organ clinical syndrome usually characterized by a sign or symptom in 2 or more of the following groups:

  • fever
  • rash
  • gastrointestinal (including nausea, vomiting, diarrhea, or abdominal pain)
  • constitutional (including generalized malaise, fatigue, or achiness)
  • respiratory (including dyspnea, cough, or pharyngitis).

Most (but not all) HSR happens in the first 6 weeks of therapy. If you are taking an abacavir-containing regimen and experience 2 or more of the symptoms listed above, CALL YOUR HEALTH CARE PROVIDER IMMEDIATELY. Rash alone does not constitute a diagnosis of HSR. Once you stop taking abacavir due to possible HSR YOU CAN NEVER TAKE ABACAVIR AGAIN. It is in restarting abacavir that the HSR can be life-threatening.

Truvada

From Gilead Sciences we have Truvada: Tenofovir/FTC in one pill once a day. Again, to avoid confusion, tenofovir is also known as Viread and FTC is also known as emtracitabine or Emtriva. These are both newer antiretroviral agents. Tenofovir was FDA approved in October, 2001 and FTC was just approved last year, in July 2003. Truvada gained FDA approval on the same day as Epzicom, August 2, 2004. What do we know about these two agents?

Table 3
Study 903, 144 wk (3-year) data, ITT missing = failure analysis
Study ArmsTDF/3TC/EFV (n=299)d4T/3TC/EFV (n=301)
% VL < 5073%69%
Change in Triglycerides+1+134
% Neuropathy3%10%
% Lipodystrophy3%19%

Table 4
Study 934, Planned 24 wk (6 month) Interim ITT missing = failure analysis
Study Arms (n=509, 1:1 ratio)TDF/FTC/EFVAZT/3TC/EFV
VL < 40087%78%
VL < 5073%65%
Mean CD4 Increase+129+111
Total Adverse Events (AEs)9%15%
AEs that lead to discontinuation3%8%

Study 903 in Table 3 above shows that over 3 years, tenofovir/3TC vs. d4T/3TC + efavirenz performed equally well virologically, but that there are striking differences in toxicities and side effects between the two regimens. In Study 934 (Table 4) at only 24 weeks mind you, comparing tenofovir/FTC (the Truvada components) vs. AZT/3TC + efavirenz (the gold standard for quite a few years), the TDF/FTC arm significantly outperformed the AZT/3TC (Combivir) arm in both virologic and adverse events measurements. The take away point in both of these studies is that tenofovir (Viread)-based regimens appear to be equally effective in suppressing HIV, and significantly less toxic than older standard of care regimens.

That being said, there is a tenofovir safety caveat. People with renal insufficiency (kidney function/disease issues) -- which is measured by a things like creatinine clearance, and other significant kidney dysfunction -- need to use caution when considering including tenofovir in their antiretroviral regimen. If your creatinine clearance rate is less than 50ml/minute, or you have other kidney problems, tenofovir must be dose-reduced. The dose reduction strategy is to take 300 mg tenofovir 3 times per week. Data on this issue was presented at ICAAC 2004 through the Recover Study. In this study 5 out of 1,193 individuals developed acute renal failure after starting tenofovir. This equaled 0.4% of participants. Four out of five of these folks recovered after stopping TDF. One individual with diabetes and baseline renal insufficiency died 2 days later.


How Fast Is That Viral Load Dropping? It Appears to Matter!

In a Medscape (www.medscape.com) journal review John Bartlett, MD of Johns Hopkins highlighted the results of a new study by Smith, Stasewski, Sabin, et al. The study showed that treatment naïve participants whose viral load dropped below 1,000 by week 4 of the study, had a greater chance of having a VL <50 at 24 weeks. In other words, if your viral load drops quickly to a very low level in the 1st month of therapy, your chance of suppressing your virus on that combo, over the long run, is much greater. What's really interesting is that it didn't seem to matter how high the participants' viral loads were to begin with. If individuals' viral loads did not drop quickly, they had a harder time maintaining viral suppression to 24 weeks.

These types of results have been seen in other trials over the years, yet we still see a degree of "patience" when it comes to how fast new treatments work. Many times we hear, "well, don't worry that your viral load isn't undetectable yet, it can take up to six months." This study and others show that it had better be low level viremia ( <1,000) that you're looking to see come down even further. The usefulness of these studies is in how they change clinical practice. Maybe there's something wrong with the combo. Maybe you're missing doses. Maybe there was underlying resistance ...

The Study was published in the Journal of Acquired Immune Deficiency Syndromes, 2004;37:1155-1159.


Good News for Long-Term Survivors Needing New Drugs! Boosted Tipranavir Looks Good for Highly Drug-Resistant Virus

Boehringer Ingelheim has applied for FDA and European approval of their new protease inhibitor tipranavir. When boosted with ritonavir, it performed nearly twice as well as the comparator arm, in a study with highly drug resistant individuals. 620 participants were randomized to either 500 mg tipranavir with 200 mg ritonavir or to the comparator arm that could include T-20 and could be lopinavir, saquinavir/r, amprenavir/r, or indinavir/r.

"A study like this gives us practical information regarding the way to use a new HIV agent," said Denver's own Steven Johnson, MD, director of the Infectious Disease Group Practice at the University of Colorado Health Sciences Center. "It may be a niche drug for highly exposed patients, but it does provide some evidence that this drug may be effective where other protease inhibitors are not." (Medscape, 2004)

In an ongoing attempt to rectify the absurdity of a 400% increase in their drug's price, an Abbott Labs community representative recently informed us at Resolute! that Abbott has agreed to provide the ritonavir necessary for tipranavir patients free of charge, regardless of income or insurance coverage. We do not have an official written announcement from the company on this matter.

RESIST 1 Study at 24 wks ITT analysis
Study ArmTiranavir/rComparator Arms
(other boosted PIs)
Virologic response
(> 1 log drop)
41.5%22.3%
VL <40035%16.5%
VL <5025.1%10%


Sculptra (Formerly Known as New-Fill) Wins FDA Approval for HIV-Related Facial Wasting

For many PWAs, facial wasting has become a barrier to maintaining self-esteem, medical privacy and sometimes employment. Trying to reverse advanced facial lipoatrophy through changing drug therapy seems at best to be a decades-long task. So the approval of a product that is safe and available in the US has been long awaited. Unfortunately, FDA approval does not mean insurance coverage. So availability does not equal access. Right up front -- Sculptra treatment will run you between $5,000 and $10,000! There is hope of a patient assistance program in the future.

Sculptra is a "bio-compatible" injectable poly-L-lactic acid that has been used in various medical applications for years. It has been used in cosmetic procedures in Europe for the past 20 years. The product causes the skin to thicken and fill-out. How well it works varies from individual to individual. The training and expertise of the health care professionals doing the procedure is of utmost importance. There are very few trained physicians performing the procedure in the US. You will, most likely, have to travel. For a really thorough discussion of Sculptra, with personal stories and insightful and accurate information, see the latest issue of Positively Aware. If you can't find a hard copy, go to www.tpan.org.


Back to the Resolute! Fall 2004 contents page.




  
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This article was provided by PWA Coalition Colorado. It is a part of the publication Resolute!.
 

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