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A Lame Duck, a Dark Horse and a Goat

Three Experimental HIV Drugs Take Three Different Paths

May/June 2005


Tipranavir (Aptivus) is a protease inhibitor (PI) with activity against HIV that is resistant to most available PIs. Aptivus was approved for sale in the United States on June 22, 2005. The drug is indicated for the treatment of HIV infection in combination with other antiretroviral (ARV) drugs in adults with unsuppressed virus and extensive experience with protease inhibitors or evidence of resistance to multiple PIs. The dose of Aptivus is 500 mg (two 250 mg capsules) taken twice daily. The drug must be co-administered with 200 mg of ritonavir (Norvir) as a pharmacokinetic booster.

Twenty-four week experience in two Phase III trials in highly treatment experienced patients demonstrated that the best antiviral response was obtained when Aptivus was used in combination with at least one other ARV with activity against the patient's virus. In most individuals requiring so-called salvage therapy, this means Aptivus will be combined with Fuzeon to achieve the optimal effect.

The sprawling package insert supplied with Aptivus runs to five feet of tiny-type information about drug-drug interactions and toxicity warnings. But the main warning is placed in a box at the top of the label: "Aptivus co-administered with 200 mg ritonavir has been associated with reports of clinical hepatitis and hepatic decompensation including some fatalities. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C coinfection, as these patients have an increased risk of hepatotoxiticity."

While this warning singles out those with hepatitis, hepatic injury also occurred to individuals in the clinical trials who had no prior evidence of liver problems. The bottom line for this drug is, if you need it, you need it; and it may well save your life. But keep an eye on your liver.

Tipranavir originated in a cardiovascular research lab at Pharmacia Upjohn (PU) that had been looking for renin inhibitors in the 1980s. Renin is an aspartyl protease, like HIV protease, so many workers in that field segued into HIV research projects in the 1990s. Straight out of Kalamazoo, PNU-140690 first appeared in the scientific press in 1996. By 1997 it was dubbed tipranavir and put into a human body. But PU stumbled through their initial clinical development program and when Boehringer Ingelheim (BI) acquired rights to the drug in 2000, they soon realized that much of the basic development work needed to be done over.

Tipranavir would have been right on time in 2001. Resistance was rampant and people were accustomed to hard-to-tolerate PIs. But as BI's development program dragged on, the field passed them by as boosted PIs and simpler regimens made therapy less burdensome. Yet salvage patients were, and still are, being produced everyday and, while not the sexiest market, they represent the most pressing unmet medical need in HIV.

Aptivus might be a lifesaver for those who need it and can stand it, but it's certainly not for everybody. With this drug we now see a clear divergence in HIV therapy. Treating drug resistant HIV -- especially in persons with advanced AIDS -- is a complicated and not always successful business. Like treating cancer, it is a job for a specialist. Meanwhile, treating wild type HIV -- when it has not progressed too far along -- is becoming more like treating high blood pressure or cholesterol, where therapy is guided by the test numbers. Still, if you don't get it right, there is a high probability that you can cross over into the other group.

Not coincidentally, the cost of the salvage drugs are increasingly lining up with the cost of cancer therapies. While a simple Sustiva-based regimen might run $15,000 a year, a salvage regimen that includes tipranavir and Fuzeon could be pushing $50,000 per year. Although the price of Aptivus came in significantly higher than the price for Reyataz, the last PI to be approved, once you add in the cost of the necessary Norvir, Aptivus is cheaper, because the maker of ritonavir, Abbott Laboratories, (in penance for their 400% Norvir price increase) has promised to give away Norvir for free to anyone who needs 400 mg or more per day; those who only need 200 mg have to pay.

Since the benefit of Aptivus likely depends on using it with Fuzeon, one bright spot for salvage patients would be the roll-out of the proposed needle-free Biojector system for administering the injectable drug. Initial reports are encouraging and a study is underway to determine if administration site reactions are significantly decreased.


The non-nucleoside reverse transcriptase inhibitor (NNRTI) capravirine is another drug that followed a long and winding path, passing from Shinogi in Japan to Agouron in La Jolla and finally to Pfizer. First used in patients in the late 1990s, clinical trials were halted in 2001 when animal toxicity studies produced vasculitis in beagle dogs. The drug languished for a year while researchers tried to sort out the problem. Pfizer jump-started the development program in 2003, but at this point the drug had already acquired the aroma of failure. As information dribbled in about rash, the need for boosting, interactions with other drugs, and uncertainties about dose, capravirine increasingly smelled like a goat. When long awaited phase II results finally came in that showed no apparent efficacy benefit in treatment experienced patients, the handwriting was on the wall. Still Pfizer soldiered on for another few months before finally ending the not-so-wonderful life of capravirine in July 2005.


This as yet unnamed protease inhibitor from Tibotec Pharmaceuticals, is chemically similar to amprenavir, but has modifications that allow it to bind much more tightly into its active site -- even in HIV protease that has mutated to evade most conventional PIs. Like tipranavir, TMC114 is active against HIV isolates resistant to other PIs and is very slow to produce its own resistance mutations in the test tube. Unlike tipranavir, however, TMC114, in its initial studies at least, is more tolerable and appears to generate far fewer and less severe liver and blood lipid abnormalities than Aptivus. Although TMC114 still depends upon the curse of ritonavir boosting to get adequate amounts of medicine into the blood (a dose of 600 mg/100 mg twice-a-day is going forward into phase III trials), the drug is not expected to cause the dramatic kinds of drug-drug interactions that many fear will make tipranavir so difficult to use.

In a phase II trial among patients with extensive prior PI exposure, TMC 114/ritonavir at the 600 mg/100 mg dose produced an average viral load drop of -1.85 log and delivered 59% of patients to below 400 copies at 24 weeks, although achieving these results was highly dependent upon the inclusion of Fuzeon in the mix. This again underscores the importance in the salvage setting of taking at least two drugs that are active against multi-drug resistant virus. Rates of adverse events, primarily headache and GI upset, were similar to those in the comparator group and serious increases in triglyceride blood levels were observed in about 6% of subjects in all groups.

The FDA must have been impressed because in mid-June 2005 it gave the green light for Tibotec to file for accelerated approval based upon its phase II trial results. This surprise ruling allows TMC114 to leapfrog to the head of the new drug pipeline and the announcement effectively stole thunder from the Aptivus debut a week later. If all goes well Tibotec will likely submit its data in early 2006 and the drug could be in pharmacies by summer. The company is planning to open an expanded access program in the fourth quarter of 2005. If this drug pans out to be as effective and tolerable as it now appears, Boehringer Ingelheim may wish it had sent tipranavir the way of capravirine as it watches Aptivus sales sink beneath the waves less than a year after hitting the market.

One lesson from all of this is that the bar for acceptable toxicity and efficacy is now set much higher, and drugs that looked promising in 1999 won't cut it in 2006 and beyond. Now, if we could only get rid of ritonavir boosting.

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This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.