General Information

Aptivus is an HIV-1 protease inhibitor that inhibits the virus-specific processing of the viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions.

Aptivus is specifically indicated in combination with ritonavir for the treatment of HIV-1 infected patients, adult and pediatrics, who are treatment-experienced and infected with HIV-1 strains resistant to more than one protease inhibitor.

Aptivus is supplied as a capsule (250 mg) or oral solution (100 mg/mL) formulation. Aptivus must be co-administered with ritonavir to exert its therapeutic effect. Failure to correctly co-administer Aptivus with ritonavir will result in plasma levels of tipranavir that will be insufficient to achieve the desired antiviral effect and will alter some drug interactions. The recommended initial dose of the drug is as follows:

Adults
Aptivus 500 mg (two 250 mg capsules or 5 mL oral solution) co-administered with 200 mg of ritonavir, twice daily.

Pediatrics (age 2 to 18 years)
Aptivus 14 mg/kg with 6 mg/kg ritonavir (or 375 mg/m2 co-administered with ritonavir 150 mg/m2) taken twice daily, not to exceed a maximum dose of Aptivus 500 mg co-administered with ritonavir 200 mg twice daily. For children who develop intolerance or toxicity and cannot continue with Aptivus 14 mg/kg with 6 mg/kg ritonavir, physicians may consider decreasing the dose to Aptivus 12 mg/kg with 5 mg/kg ritonavir (or Aptivus 290 mg/m2 co-administered with 115 mg/m2 ritonavir) taken twice daily, provided their virus is not resistant to multiple protease inhibitors.

Mechanism of Action

Tipranavir is an HIV-1 protease inhibitor that inhibits the virus-specific processing of the viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions. Tipranavir demonstrates antiviral activity in cell culture against a broad panel of HIV-1 group M nonclade B isolates (A, C, D, F, G, H, CRF01 AE, CRF02 AG, CRF12 BF). Group O and HIV-2 isolates have reduced susceptibility in cell culture to tipranavir with EC50 values ranging from 0.164 -1 µM and 0.233-0.522 µM, respectively.

Side Effects

Adverse events associated with the use of Aptivus in adults may include, but are not limited to, the following:

• Diarrhea
• Nausea
• Pyrexia
• Vomiting
• Fatigue
• Headache
• Abdominal pain
• Hypertriglyceridemia
• Anemia

Adverse events associated with the use of Aptivus in pediatrics may include, but are not limited to, the following:

• Pyrexia
• Vomiting
• Cough
• Rash
• Nausea
• Diarrhea
• Epistaxis

The Aptivus drug label comes with the following Black Box Warning: Hepatotoxicity: Clinical hepatitis and hepatic decompensation, including some fatalities, have been reported. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C co-infection, as these patients have an increased risk of hepatotoxicity. Intracranial Hemorrhage: Both fatal and non-fatal intracranial hemorrhage have been reported.

Clinical Trial Results

The FDA approval of Aptivus was based on the following results:

Adults
Two randomized, controlled, open-label, multicenter studies, dubbed RECIST 1 and RECIST 2, enrolled 1,483 HIV-1 positive, triple antiretroviral class experienced subjects. The subjects received either Aptivus co-administered with 200 mg of ritonavir plus optimal backgroumd therapy (OBR) or a ritonavir-boosted protease inhibitor (PI) (lopinavir, amprenavir, saquinavir or indinavir) plus OBR. The studies evaluated treatment response at 48 weeks. Through 48 weeks of treatment, the proportion of subjects in the Aptivus/ritonavir arm compared to the comparator PI/ritonavir arm with HIV-1 RNA < 400 copies/mL was 30.3% and 13.6% respectively, and with HIV-1 RNA < 50 copies/mL was 22.7% and 10.2% respectively. Among all randomized and treated subjects, the median change from baseline in HIV-1 RNA at the last measurement up to Week 48 was -0.64 log10 copies/mL in patients receiving APTIVUS/ritonavir versus -0.22 log10 copies/mL in the comparator PI/ritonavir arm. The median change from baseline in CD4+ cell count at the last measurement up to Week 48 was +23 cells/mm3 in patients receiving Aptivus/ritonavir versus +4 cells/mm3 in the comparator PI/ritonavir arm.

Pediatrics
This randomized, open-label, multicenter study enrolled 110 HIV-1 infected, treatment-experienced pediatric patients. The subjects were randomized to receive one of two Aptivus/ritonavir dose regimens: 375 mg/m2/150 mg/m2 dose or 290 mg/m2/115 mg/m2 dose, plus background therapy of at least two non-protease inhibitor antiretroviral drugs, optimized using baseline genotypic resistance testing. All patients initially received Aptivus oral solution. Of the 110 enrolled subjects, 83 (75%) completed the 48 week period. At 48 weeks, 40% of subjects had viral load <400 copies/mL. The proportion of subjects with viral load <400 copies/mL tended to be greater (70%) in the youngest group, who had less baseline viral resistance, compared to the older groups (37% and 31%). A greater proportion of subjects receiving Aptivus/ritonavir 375 mg/m2/150 mg/m2 compared to 290 mg/m2/115 mg/m2 achieved HIV-1 RNA < 400 and < 50 copies/mL. A greater proportion of subjects 6 to18 years of age with multiple baseline protease inhibitor resistance-associated substitutions receiving Aptivus/ritonavir 375 mg/m2/150 mg/m2 achieved HIV-1 RNA <400 copies/mL at 48 weeks compared to those receiving Aptivus/ritonavir 290 mg/m2/115 mg/m2. No clinically significant increase in adverse event rates observed with 375 mg/m2/150 mg/m2 compared to 290 mg/m2/115 mg/m2.