I hate the term "salvage therapy." "Salvage" is raising a nuclear submarine from the icy depths of the Barents Sea. "Salvage" is picking through charred fuselage to look for Concorde flight recorders. "Salvage" is not, however, a term I'm particularly fond of when it comes to defining options for HIV-infected individuals in need of new therapies. We don't need salvaging. We need new drugs.

Yet, options for HIV-infected folks who have tried and failed existing HAART regimens leave a lot to be desired. This is particularly true when it comes to the protease inhibitors (PIs). There are five PIs currently available, all of which are hobbled by similar resistance mutations. HIV-positive folks who fail one of these drugs often have a difficult time keeping their viral load undetectable upon switching to another PI, even when the new drug is combined with new nucleoside analogues or, perhaps, a second protease inhibitor.

New protease inhibitors are desperately needed for patients who have failed one or more of the current PI options. Here's a look at one that was just approved by the Food and Drug Administration (FDA) and another that is furthest along in clinical trials:

Lopinavir (Kaletra; ABT-378/r)

In test tube studies, lopinavir -- which was awarded the brand name Kaletra by Abbott Laboratories -- is approximately 10 times more powerful than its predecessor, ritonavir (Norvir). When used with small amounts of ritonavir -- hence, the little "r" in its name (ABT-378/r) -- lopinavir's blood levels remain high for a long period of time. One Kaletra capsule contains 133 mg of lopinavir and 33 mg of ritonavir. The recommended daily dose is three capsules taken twice a day with food.

In terms of its resistance profile, lopinavir was specifically developed to be active against HIV strains carrying mutations at position V82 of the protease gene. This is a major mutation associated with resistance to ritonavir (Norvir), indinavir (Crixivan), and possibly saquinavir (Fortovase). Thus, lopinavir has at least one foot in the door when dealing with strains of HIV resistant to any of these three drugs. Unfortunately, the activity of lopinavir weakens a bit when going up against viruses containing mutations at positions M46 and I84. The former mutation can result from Crixivan therapy, whereas the latter mutation is caused by all currently approved PIs.

The true test of lopinavir is its activity in clinical trials. Results of three studies have been reported to date: one involving folks who have never taken a PI before, a second that enrolled patients who had failed only one PI in the past, and a third study involving patients who had failed more than one PI before enrolling in the study. Data from the third study were presented at the 13th International AIDS Conference in Durban.

A total of 57 patients were enrolled in the trial. On average, each patient had tried -- and failed -- three protease inhibitors in the past. In looking at some blood samples collected at the start of the trial, it appeared that most patients were already resistant to lopinavir before even starting therapy. However, this turned out not to be the case.

All patients were treated with one of two doses of lopinavir: 400 mg (with 100 mg ritonavir) or 533 mg (with 133 mg ritonavir), both taken twice daily. Lopinavir was combined with efavirenz (Sustiva) and two nucleoside analogues.

After six months of therapy, approximately 80% of patients receiving the lower-dose lopinavir regimen and 96% receiving the higher-dose lopinavir regimen had undetectable viral loads (<400 copies/mL). Good news . . . but wait a minute! All patients who enrolled in this study had never taken an NNRTI before and, thus, would definitely respond well to Sustiva. Yet according to Dr. Joseph Eron of the University of North Carolina at Chapel Hill, who spoke recently with CRIA Update, there's more to this than meets the eye. Most patients in the study were not only resistant to many of the PIs currently available, but were also resistant to most of the nucleoside analogues currently on the market. Without the addition of lopinavir, Sustiva would have been nothing more than monotherapy. And, as we know from previous clinical studies, NNRTI monotherapy results in rapid resistance. So lopinavir worked well for folks with an extensive prior treatment history, regardless of the added benefit of an NNRTI.

Sadly, the side effects of lopinavir are similar to those being seen with other PIs: nausea and headache are chief complaints, along with increased liver enzymes and increased lipid (fat) levels in the blood.

Lopinavir was approved by the FDA in mid-September and is now available.


Like lopinavir, tipranavir has a great deal to offer folks at the end of their PI rope. Tipranavir represents a new class of protease inhibitors believed to have greater flexibility in binding with HIV protease enzymes resistant to current PIs. The compound was originally developed by Pharmacia & Upjohn and was recently sold to Boehringer Ingelheim, the manufacturers of nevirapine (Viramune).

Tipranavir is different from other PIs in a number of ways. All PIs now on pharmacy shelves inhibit the liver enzyme system known as P450. In other words, current PIs slow down the way in which the liver breaks down drugs in the bloodstream, allowing for the PIs to stay in the body for long periods of time. Tipranavir is different. This drug speeds up the liver enzyme system, requiring very high doses of tipranavir three times a day to keep adequate blood levels.

Nobody wants to take a lot of pills multiple times a day, regardless of how "unique" a drug's resistance profile is. To make the drug more user friendly, the people at Boehringer Ingelheim are working on a new formulation -- called a self-emulsifying drug-delivery system (SEDDS) -- to slow down the rate at which tipranavir is metabolized in the body. Like lopinavir, tipranavir will also need to be taken with low doses of ritonavir to block the P450 enzyme system. Using the SEDDS formulation, along with low doses of ritonavir, will permit much lower doses of tipranavir to be taken twice daily.

Unfortunately, not a whole lot of data have been produced by clinical trials involving patients resistant to current PIs. However, some interesting test tube study results have been reported over the past year. Dr. Brendan Larder, a researcher at Virco Laboratories, manufacturer of a phenotypic drug-resistance test, tested tipranavir against 107 different strains of HIV. Most of the strains studied were highly resistant to three or four of the PIs now available. According to Dr. Larder, only 3% of all the strains tested were highly resistant to tipranavir. Most strains -- 90% -- remained sensitive to tipranavir.

Of course, what happens in test tube studies rarely proves the effectiveness within the human body. Unfortunately, studies involving HIV-positive folks with multiple-PI resistance are not expected to begin until mid-2001 and it's unlikely that we'll see an expanded access program or approval until 2002 or 2003.

Both lopinavir and tipranavir are testaments to the hope that exists in the drug-development pipeline. We need these drugs and we need them studied in combination with each other. "Salvage" is not an option. New drugs -- studied together in people who need them most -- are.