Importance of HLA-B*5701 Screening

TRIUMEQ is for your HLA-B*5701–negative adult patients with HIV-1.

Help reduce the risk of hypersensitivity reaction (HSR) to abacavir (ABC) and personalize patient care.

Importance of HLA-B*5701 screening

  • Serious and sometimes fatal HSRs have been associated with ABC and ABC-containing products
  • The presence of the HLA-B*5701 allele has been associated with a higher risk for HSR
  • HLA-B*5701 screening significantly reduces the risk of an HSR to ABC1
  • HLA-B*5701 screening should not be used as a substitute for clinical judgment or pharmacovigilance, because a negative HLA-B*5701 result does not eliminate the possibility of an ABC HSR2
  • Screening is recommended by DHHS guidelines2
    • DHHS guidelines recommend screening ABC-naïve patients for HLA-B*5701 status before initiating an ABC-based regimen to reduce the risk of an HSR
    • TRIUMEQ is contraindicated in HLA-B*5701–positive patients
  • Test result should be recorded and maintained, so it is only needed once in a patient's lifetime2

Prospective HLA-B*5701 screening is the first step when considering an ABC-containing regimen.

HLA-B*5701–negative patients may develop an HSR to ABC; however, this occurs significantly less frequently than in HLA-B*5701–positive patients.

Overview of HLA-B*5701 screening

  • One-time testHLA-B*5701 screening is a genetic test, so a patient only needs to be tested once when results are documented in their medical record
  • Helps provide prescribing assurance—Screening for the HLA-B*5701 allele helps you determine which patients may be appropriate candidates for an ABC-containing regimen
  • Screening guidelines—DHHS guidelines recommend screening for the  HLA-B*5701 allele before starting any patient on an ABC-containing regimen to decrease the risk of an HSR2
  • Clinically demonstrated—Multiple clinical trials have established the value, utility, and accuracy of screening for the  HLA-B*5701 allele1,3-6

Always be sure to:

  • Screen all patients for the HLA-B*5701 allele prior to initiating therapy with ABC or reinitiation of ABC therapy in patients who discontinued ABC for reasons other than a suspected HSR, unless patients have a previously documented HLA-B*5701 allele assessment
  • Record HLA-B*5701 status in patients' medical records
  • Maintain clinical vigilance for ABC HSR, regardless of HLA-B*5701 test results, because a negative result does not eliminate the possibility of an HSR2
  • Note that when therapy with TRIUMEQ has been discontinued for reasons other than symptoms of an HSR, and if reinitiation of TRIUMEQ or any other ABC-containing product is under consideration, carefully evaluate the reason for discontinuation of TRIUMEQ to ensure that the patient did not have symptoms of an HSR
  • Permanently discontinue ABC if HSR cannot be ruled out even when other diagnoses are possible, regardless of HLA-B*5701 status

Do not perform HLA-B*5701 testing to:

  • Diagnose an ABC HSR
  • Support a decision to rechallenge with ABC after a suspected HSR
    • Following an HSR to ABC, NEVER restart TRIUMEQ or any other ABC-containing product because more severe symptoms can occur within hours and may include life-threatening hypotension and death

HLA-B*5701 Clinical Studies

PREDICT-1—A trial designed to examine prospective HLA‐B*5701 screening to reduce the risk of HSR to ABC1

PREDICT-1 was a randomized, double-blind, prospective, multicenter, international study conducted between April and September 2006 in 1956 eligible adult patients with HIV-1 infection with a pre-established need for antiretroviral therapy containing ABC but who had unknown HLA-B*5701 status.

PREDICT-1 study design1

Enrollment
ABC-naïve subjects randomized 1:1 (N=1956)

Treatment
Control group (n=976)

  • Subjects initiating ABC-containing regimen (n=913)
  • Began ABC-containing regimen and completed evaluation (n=842)

Prospective screening for HLA‐B*5701 (n=980)

  • HLA‐B*5701–positive (n=55)
  • HLA‐B*5701–negative (n=925)
    • Began ABC-containing regimen and completed evaluation (n=802)

6-week follow-up
HSR monitoring according to recommendations

  • Patients were randomized to undergo prospective HLA-B*5701 screening prior to initiating ABC-containing treatment (screened group, n=980) or retrospective HLA-B*5701 screening (control group, n=976)
  • Enrolled patients were observed for at least 6 weeks
  • The control group was not prospectively screened for the HLA-B*5701 allele
  • In the prospectively screened group, HLA-B*5701–positive patients were excluded

Baseline characteristics of the study population that could be evaluated for clinically diagnosed HSR1

*Race or ethnic group was self-reported. One patient in the prospective screening group did not provide this information. Other includes all racial categories for which there was less than 1% of patients in either study group, including patients reporting.

Primary endpoints1

  • The rates of clinically diagnosed ABC HSR during the 6-week observation period and an immunologically confirmed ABC HSR via skin-patch testing 6 to 10 weeks after clinical diagnosis

Incidence of ABC HSR (ITT–E)1

Skin-patch testing is used as a research tool and should not be used to aid in the clinical diagnosis of an ABC HSR.

ITT–E=intent-to-treat–exposed.

  • Results showed that clinically suspected HSRs were reduced from 7.8% in the control group vs 3.4% in the prospectively screened group, P<0.001

PREDICT-1 conclusions1

  • In PREDICT-1, prospective HLA-B*5701 screening and avoiding ABC therapy in subjects who are positive for the HLA-B*5701 allele:
    • Significantly reduced the incidence of a clinically suspected ABC HSR
    • Significantly reduced the incidence of an immunologically confirmed ABC HSR
  • HLA-B*5701–negative patients may develop a suspected HSR to ABC; however, this occurs significantly less frequently than in HLA-B*5701–positive patients

ARIES—The first large, multicenter, open-label study to utilize prospective HLA-B*5701 screening3,4

  • ARIES was a randomized, open-label, noninferiority study of 515 ART-naïve, HLA-B*5701-negative adult patients with HIV-1 who received ABC/3TC (600 mg/300 mg) + ATV/r (300 mg/100 mg) once daily for 36 weeks, followed by randomization to receive either ABC/3TC + ATV (400 mg/day) or continue on ABC/3TC + ATV/r to Week 843,7,8
  • Conducted in the United States, ARIES utilized prospective HLA-B*5701 screening at baseline consistent with current guidelines when starting ABC-containing therapy in antiretroviral-naïve patients with HIV-18

ART=antiretroviral therapy; 3TC=lamivudine; ATV=atazanavir; r=ritonavir.

ARIES study design3

Entry criteria

  • ART-naïve patients (N=515)
    • HIV-1 RNA ≥1000 copies/mL
    • No CD4+ T-cell count restrictions
    • HLA‐B*5701 negative

Day 1–Week 36*
Induction Phase

  • ATV/r 300 mg/100 mg once daily
  • ABC/3TC 600 mg/300 mg once daily

Week 36–Week 84
Randomization Phase

  • ATV 400 mg once daily + ABC/3TC 600 mg/300 mg once daily
  • ATV/r 300 mg/100 mg once daily + ABC/3TC 600 mg/300 mg once daily

*At Week 36, patients with HIV-1 RNA <50 copies/mL and without previous virologic failure were randomized to receive either ABC/3TC + ATV or continue on ABC/3TC + ATV/r to Week 84. Randomized patients were stratified by baseline viral load. Patients who completed 84 weeks of treatment had the option to extend randomized treatment to Week 144.

Baseline characteristics and patient dispositions at Week 847

As noted on the case report form.

Primary endpoint3,7

  • Proportion of patients with HIV-1 RNA <50 copies/mL (TLOVR) at Week 84

Incidence of ABC HSR in HLA-B*5701–negative patients at 30 weeks (N=515, ITT–E)3,4

Skin-patch testing is used as a research tool and should not be used to aid in the clinical diagnosis of ABC HSR.

  • 725 patients were initially screened; 41 (5.7%) were HLA-B*5701 positive and excluded from the study4

ARIES HLA-B*5701 screening conclusion3,4

  • Among HLA-B*5701–negative individuals, suspected ABC HSR was reported in less than 1% of subjects through 30 weeks and none had immunologically confirmed ABC HSR by positive skin-patch test
  • HLA-B*5701–negative patients may develop a suspected HSR to ABC; however, this occurs significantly less frequently than in HLA-B*5701–positive patients

TLOVR=time to loss of virologic response; ITT–E=intent-to-treat–exposed.


SHAPE—Retrospective, case-controlled study of HLA‐B*5701 screening6

  • SHAPE was a retrospective case-control study conducted in self-identified black and white populations in the United States to evaluate the sensitivity and specificity of the HLA-B*5701 allele as a marker for abacavir hypersensitivity reactions (ABC HSRs)
  • This study used skin-patch testing as a research tool to supplement clinical diagnosis of ABC HSR. Skin-patch testing should not be used to aid in the clinical diagnosis of ABC HSR

SHAPE study design6

CASES
Eligibility

  • Self-identified black or white patients (N=199) with
    • Clinically-suspected ABC HSR (≥2 major symptoms)
    • HSR within 6 weeks of ABC therapy

Skin-patch testing and results

  • Black patients* (n=69)
    • Positive skin-patch test (n=5)
    • Negative skin-patch test (n=63)
  • White patients* (n=130)
    • Positive skin-patch test (n=42)
    • Negative skin-patch test (n=85)

CONTROL
Eligibility

  • Self-identified black or white patients (N=408) with
    • ABC experience (≥12 weeks)
    • No ABC HSR

Skin-patch testing and results

  • Black patients* (n=206)
    • Positive skin-patch test (n=2)
  • White patients* (n=202)
    • Positive skin-patch test (n=8)

*Valid skin‐patch testing results were not available for 4 patients (3 white and 1 black).

  • A subset of these patients had skin-patch test–defined HSRs and were then tested for the HLA-B*5701 allele
  • All patients, white (n=42) and black (n=5), with skin-patch test–defined HSRs tested positive for HLA-B*5701
  • When considering the impact of these results in clinical practice, the limited number of black patients in this study should be taken into account

Baseline characteristics by study groups and race6

Baseline characteristics by race and results in clinically suspected cases6

Study objectives6

  • Primary objective: Estimate the sensitivity of HLA-B*5701 in white and black patients with immunologically confirmed HSRs
  • Secondary objective: Calculate the sensitivities for determination of clinically suspected HSRs among white and black patients and specificities among white and black control subjects

Sensitivity of HLA-B*5701 screening as a marker for ABC HSR6

  • The sensitivity estimate of HLA-B*5701 as a marker for immunologically confirmed ABC HSRs was 100% for both white and black patients

SHAPE conclusions6

  • The SHAPE study showed that screening for the HLA-B*5701 allele is important for identifying persons, both white and black, at higher risk of developing an ABC HSR, especially to facilitate individualized treatment decisions
  • HLA-B*5701–negative patients may develop a suspected HSR to ABC; however, this occurs significantly less frequently than in HLA-B*5701–positive patients

The Warning Card for TRIUMEQ

Patients should be screened for HLA-B*5701 before starting TRIUMEQ or any ABC-containing product

  • It is important to know the result of a patient's HLA‐B*5701 screening and enter the result in the patient's medical record
  • HLA-B*5701–positive patients should not take TRIUMEQ or any ABC-containing product
  • Patients who test negative for HLA-B*5701 can still develop an HSR

Patients will receive the Warning Card and Medication Guide at the pharmacy each time they pick up their prescription for TRIUMEQ. Instruct the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about TRIUMEQ. The symptoms of ABC HSR are listed on the Warning Card for patient reference. Instruct patients to carry this Warning Card with them at all times.



An important patient conversation

  • Have a conversation with your patients with HIV-1 about their HLA-B*5701 screening test results and the Warning Card, a valuable resource in HIV-1 treatment management
    • It's important that patients understand the information the Warning Card contains and recognize the importance of carrying it with them at all times

The following are important points to cover with appropriate patients with HIV-1 about the HLA-B*5701test and the Warning Card

 

Please see full Prescribing Information, including Boxed Warning and Medication Guide, for TRIUMEQ.

References

  1. Mallal S, Phillips E, Carosi G, et al; PREDICT-1 Study Team. HLA‐B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008;358(6):568-579.
  2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed July 18, 2016.
  3. Squires KE, Young B, DeJesus E, et al; for the ARIES Study Team. Safety and efficacy of a 36-week induction regimen of abacavir/lamivudine and ritonavir-boosted atazanavir in HIV-infected patients. HIV Clin Trials. 2010;11(2):69-79.
  4. Young B, Squires K, Patel P, et al. First large, multicenter, open-label study utilizing HLA‐B*5701 screening for abacavir hypersensitivity in North America. AIDS. 2008;22(13):1673-1675.
  5. Small CB, Wohl D, Margolis DA, et al. Prevalence of HLA‐B*5701 allele in HIV-infected subjects in North America and reductions in risk for development of abacavir associated hypersensitivity reaction. Presented at: 52nd International Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 9-12, 2012; San Francisco, CA. Poster H-895.
  6. Saag M, Balu R, Phillips E, et al. High sensitivity of human leukocyte antigen-B*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients. Clin Infect Dis. 2008;46:1111-1118.
  7. Squires KE, Young B, DeJesus E, et al; for the ARIES Study Team. Similar efficacy and tolerability of atazanavir compared with atazanavir/ritonavir, each with abacavir/lamivudine after initial suppression with abacavir/lamivudine plus ritonavir-boosted atazanavir in HIV-infected patients. AIDS. 2010;24(13):2019-2027.
  8. Data on file. ViiV Healthcare group of companies. Research Triangle Park, NC.
  9. Min S, Song I, Borland J, et al. Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers. Antimicrob Agents Chemother. 2010;54(1):254-258.