(In the Fall of 2003, ACRIA Update's "Drugs! Drugs! Drugs!" issue gave an overview of all the FDA-approved HIV drugs. Since that issue, one new HIV drug has been approved. We present it here for those wishing to add it to that issue, which is available online.)

Aptivus is the latest protease inhibitor (PI) to receive FDA approval. For a while, it seemed like dosing problems might derail its development, but the drug's benefits for people with PI-resistant HIV led to a narrowly defined approval in June of 2005.

Background

Aptivus is the first non-peptide-based PI to receive FDA approval. (Darunavir, also known as TMC 114, may be the second, this summer.) Previous agents (U-96988 and U-103017) had failed in the early 1990s, but Pharmacia & Upjohn (P&J) generated considerable buzz in June of 1999 when the company reported exciting in vitro (test tube) results of its new compound PNU-140690. Tests showed that 96 of 107 strains of HIV that were highly resistant to currently available PIs were fully sensitive to this new PI.

The effectiveness of this new PI against resistant HIV stemmed from its molecular structure. Whereas all the approved PIs imitated the peptide target of HIV protease, this new compound worked differently. Its structure allowed the drug to bind uniquely with HIV's protease enzyme, so it was not as affected by prior PI resistance mutations. For the many people who had burned through all the older PIs, this offered hope of an effective new drug in the treatment arsenal.

But in human trials, dosing was a problem. In order to achieve adequate drug levels in the body, early studies required eight pills to be taken three times a day with a big meal. At a time when companies were looking for once-a-day drugs with low pill counts, P&J apparently decided that such dosing would limit the drug's market, and in 2000 Boehringer Ingelheim (BI) acquired the rights to develop the drug, now called tipranavir.

Early Studies

BI began Phase II studies of tipranavir with P&J's hard-fill capsule, but soon reformulated the drug as a soft-gel capsule. This meant essentially going back to square one with the drug, and activists wondered if the right dose of this drug would ever be found.

BI's first study (BI 1182.2) was problematic, since it started with the hard-fill capsules and switched to the soft-gel version mid-study. In the study, 41 people took either 1200 mg or 2400 mg of tipranavir twice a day along with Sustiva and two NRTIs. Surprisingly, more people on the lower dose achieved a viral load below 50 than those on the higher dose (68% v. 41%). The probable explanation was poor adherence due to the hard fill capsules used at first.

So, BI tried once again to find the elusive best dose of tipranavir, this time using the emerging strategy of boosting PI blood levels with low doses of Norvir (ritonavir). Another dosing study (BI 1182.52) looked at three different twice-daily doses, boosted with Norvir. Each participant took tipranavir with an optimized background regimen based on resistance testing and their treatment history. Over 90% of participants had 10 or more PI mutations, and all had used at least two PIs.

After six months, 40% of people taking 500 mg of tipranavir with 200 mg of Norvir twice a day saw a one log (90%) decrease in their viral load. Since those taking a higher dose (750 mg) had almost the same result (45%), BI decided the 500 mg dose was better. Unfortunately, this meant taking 400 mg of Norvir a day (most boosted PIs use 100 or 200 mg of Norvir a day), leading to more of the side effects that drug is famous for -- 31% of people reported diarrhea and nausea. (Aptivus lowers levels of Norvir in the body, or these numbers might have been worse.) At this dose, 7% of people had elevated liver enzymes, 11% elevated bilirubin, and 27% elevated triglycerides.

RESIST

So now we finally had a dose -- the question was: would the drug work? The pivotal trials to provide the answer were the RESIST I & II studies (Randomized Evaluation of Strategic Intervention in Multi-Drug Resistant Patients with Tipranavir). A total of 1,483 people were enrolled in North America, Australia, Europe and Latin America. People who had used an average of 12 anti-HIV drugs and who had resistance to at least two PIs took either tipranavir with Norvir or an approved PI with Norvir, along with other anti-HIV drugs chosen after resistance testing.

Aptivus was approved based on 6 months of data, but we now have results for 11 months: 30.4% of people taking Aptivus achieved viral loads below 400, compared to 13.8% taking another PI. While Aptivus did more than twice as well as other PIs, the low numbers emphasize the need for at least two active agents in a regimen. Twice the number of people who also used Fuzeon (enfuvirtide) -- about 25% of people in the RESIST studies -- achieved a one log (90%) decrease in viral load. (Fuzeon was often the only other drug to which this group was not resistant, and was especially effective in people with viral loads above 100,000, CD4 counts below 75, prior use of more than 13 anti-HIV drugs and more than two resistance mutations.) Nevertheless, anyone who had two or more active drugs in their background regimen did better in these studies than those who didn't. Bottom line: Aptivus works against PI-resistant HIV, but the effect may not last if there are no other active drugs in your regimen.

Since everyone in the RESIST studies was taking a Norvir-boosted PI, it's useful to compare side effect rates, since that gives an idea of which side effects were caused by Aptivus and which by Norvir. Stomach pain, vomiting, fatigue, headache and rash were reported about as often in people taking Aptivus or another PI. Diarrhea was reported more often in those on Aptivus (10.9% compared to 9.4%) as was nausea (6.7% compared to 4.6%). But the most significant concerns were with liver function tests, leading to the warning that is included in the drug's label (see Side Effects, below).

Approval for Resistant HIV

In June of 2005, the FDA granted accelerated approval to Aptivus for people who are "highly treatment-experienced or have HIV . . . resistant to multiple protease inhibitors." The FDA advisory panel asked for more info on Aptivus in women, children, people with hepatitis B or C or other liver complications, and in people who have not taken anti-HIV drugs. They also asked for more studies of drug interactions and of metabolic and body shape changes.

Activists were once again disappointed with Aptivus' price: over $13,000 a year wholesale, making it the highest-priced PI on the market (other than full-dose Norvir, which is virtually never used).

Aptivus as a First-Line Drug?

To study Aptivus in people who have never taken anti-HIV drugs, BI launched a study comparing two doses of boosted Aptivus to Kaletra (BI 1182.33). But after 11 months, the study's DSMB (Data Safety Monitoring Board) closed the higher-dose Aptivus arm. Liver enzyme elevations were reported in those taking 500mg of Aptivus with 200 mg of Norvir twice a day (the dose approved for those who are resistant to PIs). The study continues to look at a dose of 500 mg Aptivus with 100 mg Norvir. More reports on this study (BI 1182.33) will follow, but at the present time Aptivus is not recommended as a first-line therapy.

Side Effects

Many of the most common side effects (diarrhea, nausea, vomiting and stomach cramps) reported in Aptivus trials may be due to the amount of Norvir that must be taken. Also, Aptivus contains sulfa, which can cause rashes and sensitivity to sunlight, so people who are allergic to sulfa drugs should use it only with caution. Skin rash has been reported in both men (8-10%) and women (14%), especially in women who are taking birth control pills or estrogen.

Aptivus' label says that the drug "has been associated with severe liver disease, including some deaths." It recommends that liver function tests should be done before starting Aptivus and "frequently" thereafter. It also advises caution when Aptivus is used by people with elevated liver enzymes or chronic liver diseases like hepatitis B or C, and recommends it not be given to patients with moderate to severe liver disease.

People taking Aptivus are urged to check their cholesterol and triglycerides regularly and to be on the lookout for body shape changes. As with other PIs, Aptivus may worsen or cause diabetes, and people with hemophilia may experience increased bleeding.

Interactions

When Aptivus is taken with Norvir the P450 pathway in the liver is inhibited, which may raise the level of other drugs in the body. Many drugs may need to have their dose adjusted, but some drugs should not be taken with Aptivus, including certain anti-arrhythmics, antihistamines, ergot derivatives, rifampin, St. John's wort and others. Be sure your doctor knows every medication you are taking (including drugs you buy without a prescription), before you start Aptivus.

When to Consider It

U.S. treatment guidelines recommend Aptivus only for people with multi-drug HIV resistance. It is not recommended for treatment-naïve patients, due to the lack of clinical trial data.

Good to Know

• Keep Aptivus in a refrigerator until the bottle is opened. After opening, it can be stored at room temperature for up to 60 days.

• Videx should be taken 2 hours before or after Aptivus.

• Aptivus lowers blood levels of methadone, so people on methadone maintenance should ask their doctor if their methadone dose should be raised.

• One study showed that Aptivus lowers levels of etravirine (TMC-125), an experimental NNRTI, so use caution if combining these two drugs.

• Some people who have diarrhea from Aptivus have found that taking Immodium before dosing helps.

Pregnancy

Aptivus is classified by the FDA as a pregnancy category C drug. There have been no studies of Aptivus in pregnant women, so it should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.

Dose

Aptivus comes in 250 mg soft gel capsules. The dose is two capsules twice a day with 200 mg of Norvir (two 100 mg capsules). Aptivus should be taken with food to increase drug levels in the body.

FDA Approval: 2005

Manufacturer: Boehringer Ingelheim

Patient Assistance Program: Phone number 1-800-556-8317