Treatment-Emergent Mutations

In the RESIST trials, multiple PI-resistant HIV isolates from 59 treatment-experienced patients who received APTIVUS/r and experienced virologic rebound developed amino acid substitutions that were associated with resistance to tipranavir. APTIVUS resistance was detected at virologic rebound after an average of 38 weeks of APTIVUS/r treatment with a median 14-fold decrease in tipranavir susceptibility.

• The most common amino acid substitutions that developed with APTIVUS/r in greater than 20% of APTIVUS/r virologic failure isolates were L33V/I/F, V82T, and I84V
• Substitutions that developed in 10% to 20% of APTIVUS/r virologic failure isolates included L10V/I/S, I13V, E35D/G/N, I47V, K55R, V82L, and L89V/M

Cross-Resistance

Cross-resistance selected from wild-type virus

APTIVUS-resistant viruses which emerged in vitro had decreased susceptibility to the PIs amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, and ritonavir but remained sensitive to saquinavir.

• The risk-benefit of APTIVUS/r has not been established in pediatric patients.
• APTIVUS should not be used in children under 2 years of age.

About RESIST:
Analysis reflects pooled data from the RESIST trials. The RESIST trials are 2 randomized, controlled, open-label, multicenter studies in HIV-positive, clinically advanced, triple-class–experienced patients, evaluating the efficacy and safety of APTIVUS® (tipranavir) capsules boosted with 200 mg ritonavir (APTIVUS/r) twice daily in combination with an Optimized Background Regimen (OBR) vs comparator ritonavir-boosted protease inhibitors (CPI/r) twice daily and an OBR. Patients had prior exposure to a median of 6 NRTIs, 1 NNRTI, and 4 PIs. Patients had received at least 2 PI-based antiretroviral regimens for ≥3 consecutive months and were failing a PI-based regimen at the time of study entry. Treatment response was defined as having a confirmed ≥1 log₁₀ copies/mL drop in pVL at 48 weeks.

85% of patients were possibly resistant or resistant to the pre-selected CPI/r.

CPI/r: lopinavir/ritonavir 400/100 mg twice daily, indinavir/ritonavir 800/100 mg twice daily, saquinavir/ritonavir 1000/100 mg twice daily, amprenavir/ritonavir 600/100 mg twice daily. All treatment regimens included at least 2 non-PI ARVs. Approximately 21% of patients used ENF during the study. APTIVUS/r median baseline HIV-1 RNA: 4.8 log₁₀ copies/mL. CPI/r median baseline HIV RNA: 4.8 log₁₀ copies/mL. APTIVUS/r median baseline CD4 cell count:158 cells/mm³. CPI/r median baseline CD4 cell count: 166 cells/mm³.

Indications and Usage
APTIVUS, a protease inhibitor co-administered with ritonavir (APTIVUS/r), is indicated for combination antiretroviral treatment of HIV infected patients who are treatment-experienced and infected with HIV strains resistant to more than one protease inhibitor.
This indication is based on analyses of plasma HIV RNA levels in two controlled studies of APTIVUS/r of 48 weeks duration in treatment-experienced adults and one open-label 48-week study in pediatric patients age 2 to 18 years.  The adult studies were conducted in clinically advanced, 3-class antiretroviral (NRTI, NNRTI, PI) treatment-experienced adults with evidence of HIV replication despite ongoing antiretroviral therapy.

The following points should be considered when initiating therapy with APTIVUS/r:

• The use of APTIVUS/r in treatment-naïve patients is not recommended.
• The use of other active agents with APTIVUS/r is associated with a greater likelihood of treatment response.
• Genotypic or phenotypic testing and/or treatment history should guide the use of APTIVUS/r. The number of baseline primary protease inhibitor mutations affects the virologic response to APTIVUS/r.
• Use caution when prescribing APTIVUS/r to patients with elevated transaminases, hepatitis B or C co-infection or patients with mild hepatic impairment.
• Liver function tests should be performed at initiation of therapy with APTIVUS/r and monitored frequently throughout the duration of treatment.
• The drug-drug interaction potential of APTIVUS/r when co-administered with other drugs must be considered prior to and during APTIVUS/r use.
• Use caution when prescribing APTIVUS/r in patients who may be at risk for increased bleeding or who are receiving medications known to increase the risk of bleeding.
• The risk-benefit of APTIVUS/r has not been established in pediatric patients less than 2 years of age.

There are no study results demonstrating the effect of APTIVUS/r on clinical progression of HIV.

APTIVUS/r does not cure HIV or help prevent passing HIV to others.

Important Safety Information for APTIVUS
APTIVUS/r 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 co-infection, as these patients have an increased risk of hepatotoxicity.
Patients with signs or symptoms of clinical hepatitis should discontinue APTIVUS/r treatment and seek medical evaluation. APTIVUS/r has been associated with reports of both fatal and non-fatal intracranial hemorrhage (ICH).

Adverse Events

• In adults the most frequent adverse reactions (incidence > 4%) were diarrhea, nausea, pyrexia, vomiting, fatigue, headache, and abdominal pain

In pediatric patients (age 2 to 18 years) the most frequent adverse reactions were generally similar to those seen in adults.  However, rash was more frequent in pediatric patients than in adults