A Study of HIV Provider Attitudes Toward HLA-B*5701 Testing in the United States

Abstract

Screening for HLA-B*5701 reduces the risk of developing an abacavir hypersensitivity reaction (ABC HSR) and is recommended in all patients before initiating highly active antiretroviral therapy (HAART) with abacavir. Between September 2007 and March 2008 we conducted a study of the attitudes and practice patterns of HIV providers in the United States to identify barriers to HLA-B*5701 testing in clinical practice. Study participants who completed an educational program could receive HLA-B*5701 test kits for use in their clinical practice. Surveys were administered before and after the educational program. A total of 477 HIV providers registered to participate in the survey, and 134 providers tested a total of 874 HIV-infected subjects, of which 6% (49/874) were HLA-B*5701 positive. Of 433 providers who completed the preeducation survey, 97% indicated that the test provided clinical value and 77% anticipated barriers to testing, with cost/reimbursement the most frequently cited. Among 202 providers who completed the posteducation survey, perceptions of the test's value remained largely unchanged while the proportion of providers who anticipated or encountered barriers to testing decreased. Of providers who used HLA-B*5701 test kits, 86% (115/134) found it “very easy” or “easy” to obtain test results, 95% (127/134) found it “very easy” or “easy” to interpret results, and 89% (119/134) indicated that they planned to continue HLA-B*5701 testing after the study. The results of this study suggest that HLA-B*5701 testing is easy to use in clinical practice and is a valuable tool to help reduce the risk of developing ABC HSR.

Introduction

A bacavir (ABC) is an effective nucleoside reverse-transcriptase inhibitor that has been well-studied for the treatment of HIV. The primary treatment-limiting adverse effect of ABC is an immunologically mediated hypersensitivity reaction (HSR) affecting 5% to 8% of patients.^1,2 Symptoms of an HSR to ABC include combinations of fever, rash, constitutional symptoms, gastrointestinal tract symptoms, and respiratory symptoms that become more severe with continued dosing.³ Immediate and permanent discontinuation of ABC is mandated, typically resulting in a rapid resolution of symptoms. Subsequent rechallenge with ABC is contraindicated, since it can result in a more severe, rapid, and potentially life-threatening reaction.³

The genetic basis for ABC HSR was suggested by early reports of familial association and a lower incidence of ABC HSR in black patients.^4,5 Subsequent research has shown a strong association between the major histocompatibility complex class I allele HLA-B*5701 and ABC HSR.^6

–9 The presence of the HLA-B*5701 allele confers a high risk for developing ABC HSR. The frequency of this allele varies by race, with black populations showing lower carriage rates of the HLA-B*5701 allele and a lower incidence of ABC HSR than white populations.^6

–9

Several studies have demonstrated the utility of HLA-B*5701 screening. PREDICT-1 was a prospective, randomized, clinical trial designed to investigate the utility of HLA-B*5701 screening in reducing the incidence of ABC HSR in a predominantly white HIV-infected population in Europe and Australia. The study used a double-blinded design in which subjects' HLA-B*5701 status was unknown to both the investigator and the subject. The results of this study demonstrated a significant reduction in the incidence of clinically-suspected ABC HSR after prospective HLA-B*5701 screening and exclusion of patients from treatment with abacavir who were positive for the allele compared with subjects not prospectively screened (3.4% versus 7.8%, p < 0.001).¹⁰

A retrospective case-control study to evaluate the sensitivity and specificity of the HLA-B*5701 allele as a marker for ABC HSR in black and white populations in the United States with a previous diagnosis of ABC HSR (SHAPE), demonstrated that among 42 white and 5 black patients with immunologically confirmed ABC HSR (via an abacavir skin patch test), 100% carried the HLA-B*5701 allele.¹¹ Therefore, the authors recommended prospective HLA-B*5701 screening in all patients considering ABC therapy regardless of racial or ethnic background.

Data from a prospective, open-label study utilizing HLA-B*5701 screening in a racially diverse, antiretroviral-naïve patient population in the United States and Canada (ARIES) demonstrated that prospective screening and exclusion of patients carrying the HLA-B*5701 allele reduced clinically suspected ABC HSR rates to 0.8%, which was substantially lower than that reported in previous studies that did not utilize HLA-B*5701 screening.¹²

In the ARIES study, clinicians knew the HLA-B*5701 status of patients when ABC was initiated, whereas in PREDICT-1 the clinicians had no prior knowledge of HLA-B*5701 status and this knowledge was likely responsible for the lower incidence of clinically-suspected ABC HSR in ARIES (0.8% versus 3.4%). Other cohort studies utilizing HLA-B*5701 screening with prospective knowledge of HLA-B*5701 status have demonstrated similar and significant reductions in the incidence of ABC HSR.^13

–16

Although reliable HLA-B*5701 testing is available throughout the United States and recommended by treatment guidelines,^17,18 widespread adoption of the test by HIV providers requires both high-level evidence that is generalizable to diverse clinical settings and effective strategies to incorporate testing into routine clinical practice.¹⁹ Even a clinically valuable test may not be routinely used if there are practical barriers to its implementation. Therefore, in order to identify the barriers to using the HLA-B*5701 test in clinical practice, we conducted a survey of the attitudes and practice patterns of HIV providers in the United States toward HLA-B*5701 testing.

Materials and Methods

HIV care providers in the United States were invited to participate in a survey study of attitudes toward HLA-B*5701 testing by registering on a website. On study day 1, participants were asked to complete a preeducation survey. This survey included questions about the HIV providers' clinical experience with the HLA-B*5701 pharmacogenetic test, opinion and knowledge of the test, and clinical practice characteristics. A list of potential barriers to HLA-B*5701 testing was predefined on the surveys, but respondents could note other barriers to testing as well. Upon completion of the preeducation survey the HIV providers were asked to view an Internet-based educational video to review the clinical presentation of the ABC hypersensitivity reaction, the association between the HLA-B*5701 allele and ABC hypersensitivity, and the clinical applicability of HLA-B*5701 testing.

Upon completion of both the preeducation survey and the educational program, HIV providers were given the option of participating in the HLA-B*5701 testing program. The program allowed the HIV providers to receive ten testing kits for HLA-B*5701 to be used during the course of their clinical practice as they deemed appropriate. Test kits included the provider's choice of either buccal swab kits (LabCorp, Research Triangle Park, NC) or blood sampling kits (LabCorp or Quest Laboratory, Van Nuys, CA). Central laboratories (LabCorp or Quest Laboratory) analyzed the samples and provided results of the HLA-B*5701 test to the HIV providers. GlaxoSmithKline did not receive a copy of the results, although anonymous composite results from laboratory databases were transferred to GlaxoSmithKline upon completion of the study in order to determine carriage rates of the HLA-B*5701 allele.

Approximately 60 days after completing the educational program, HIV providers were asked to complete a posteducation survey. The posteducation survey addressed the same knowledge and attitude questions from the preeducation survey. It also asked providers whether or not they had used test kits and included additional questions about the ease of use and interpretability of the HLA-B*5701 test within the testing program for those who had used test kits. Both the preeducation and posteducation surveys were self-administered and Web-enabled.

After the initial e-mail inviting providers to participate, those who did not register received up to three weekly reminders. Providers also received up to three weekly e-mails prompting them to initiate or complete the preeducation survey, educational module, and posttest survey. All surveys were completed between September 2007 and March 2008. Providers were not compensated for study participation, nor did they receive CME credit. All participating providers consented to take part in the study.

Survey results were analyzed using SAS V8.2 (SAS Institute, Cary, NC). Descriptive statistics were reported. For select survey questions, the proportion of respondents was summarized and responses were reported by clinical practice characteristics. Differences between groups in clinical practice characteristics were compared using either the Wilcoxon rank sum test or Fisher's exact test. Because few respondents classified themselves as general practitioners, this category was combined with the “internist” category for purposes of statistical analysis. Summaries of change of subject response between preeducation and posteducation survey were also produced. Differences between preeducation and posteducation survey responses were evaluated using McNemar's exact test for marginal homogeneity. No adjustments were made to significance levels to account for multiple comparisons.

Results

Of the 477 HIV care providers that registered to participate, 433 (91%) returned their preeducation surveys, including 155 with HLA-B*5701 testing experience and 278 without. Twelve of 433 presurvey respondents did not request test kits while 421 requested and received test kits. A total of 202 (42%) providers returned both the preeducation and posteducation surveys. Of the providers who completed both surveys, 134/202 (66%) used study-provided HLA-B*5701 test kits and 68/202 (34%) did not.

Preeducation survey results for all providers

The clinical practice characteristics of the HIV providers are summarized in Table 1. The majority of the 433 presurvey respondents were HIV specialists (61%) and providers had treated a median of 85 HIV patients per month over the past 6 months. Based on provider estimates, the median racial/ethnic composition of the HIV-infected patients seen in practices was 35% white, 34% black, and 15% Hispanic. By provider estimates, the median percentage of patients with public insurance was 60%, while a median of 15% had private insurance. A majority of clinical practices (79%) were located in an urban setting.

Table 1.

HIV Provider and Practice Characteristics

Characteristics	All providers a	Providers who returned both surveys b	Providers who returned only the preeducation survey c	Test-kit users (who completed the postsurvey) d	Non-test kit users (who completed the postsurvey) e
Total number of respondents Respondents, n (%)	433	202	231	134	68
General practitioner/internist	65 (15.0)	16 (7.9)	49 (21.3)	12 (8.9)	4 (5.9)
HIV specialist	262 (60.5)	139 (68.8)	123 (53.2)	87 (64.9)	52 (76.5)
Nurse practitioner	66 (15.2)	29 (14.4)	37 (16.0)	23 (17.2)	6 (8.8)
Other	40 (9.2)	18 (8.9)	22 (9.5)	12 (9.0)	6 (8.8)
HIV patients treated each month (on average) over the past 6 months, n	432	202	231	134	68
Mean ± SD	132.3 ± 140.8	126.6 ± 108.9	137.2 ± 163.9	137.5 ± 115.7	105.1 ± 91.3
Median (range)	85 (47–168)	100 (52–166)	80 (44–170)	104 (55–200)	83 (44–129)
Provider estimates of race/ethnicity, % median, (Q1–Q3)
White (n = 433)	35 (10–50)	39 (15–60)	30 (10–50)	40 (15–60)	30 (18–54)
Black (n = 432)	34 (15–60)	30 (10–55)	36.5 (20–60)	30 (10–60)	32.5 (20–53)
Hispanic (n = 433)	15 (5–30)	11 (5–30)	15 (5–30)	12.5 (5–30)	10 (5–34)
Other (n = 430)	1 (0–5)	1 (0–5)	0 (0–5)	1 (0–5)	2 (0–5)
Type of insurance coverage for HIV patients, median % (Q1–Q3)
Private (including managed care)	15.0 (5–45)	20 (5–45)	15 (5–45)	20 (5–50)	20 (10–40)
Public (Medicaid, Medicare, ADAP)	60.0 (35–85)	60 (35–85)	60 (35–90)	60 (33–85)	60 (40–80)
None	2.0 (0–20)	5 (0–20)	1 (0–15)	3 (0–20)	5 (0–20)
Practice location, n (%)
Rural	24 (5.5)	8 (4.0)	16 (16.9)	5 (3.7)	3 (4.4)
Urban	341 (78.8)	161 (79.7)	180 (77.9)	103 (76.9)	58 (85.3)
Suburban	68 (15.7)	33 (16.3)	35 (15.2)	26 (19.4)	7 (10.3)

There are at most 3 missing values in the provider estimates.

There is at most 1 missing value in the provider estimates.

There are at most 2 missing values in the provider estimates.

There is at most 1 missing value in the provider estimates.

There are no missing values in the provider estimates.

Almost all (97%) providers who completed the preeducation survey indicated that the test provides some clinical value. Seventy-two percent indicated that it increases their confidence in deciding among treatment options, while 70% indicated that it improves the risk/benefit profile (Table 2). Approximately three-quarters (77%) reported encountering or anticipating barriers to testing, with cost reimbursement (63%) and difficulty ordering the test (28%) most frequently cited (Table 2).

Table 2.

Opinions of the HLA-B*5701 Test Preeducation and Posteducation Survey

	Surveys returned, n (%)
	Preeducation (all providers)	Preeducation (providers who returned both surveys)	Posteducation (providers who returned both surveys)
Questions	n = 433	n = 202	n = 202
What clinical value or perceived value does HLA-B5701* testing provide to your practice?
Missing	1 (< 1)	—	—
Perceived value	422 (97)	198 (98)	201 (100)
It allows me to consider an increased number of treatment options	257 (59)	120 (59)	117 (58)
It increases my confidence in deciding among treatment options	312 (72)	158 (78)	161 (80)
It enhances my ability to plan for future treatments	221 (51)	113 (56)	112 (55)
It improves the risk/benefit profile to my patients	305 (70)	150 (74)	151 (75)
Other	8 (2)	4 (2)	2 (1)
What barriers to HLA-B5701* testing do your encounter or anticipate in your practice?
Missing	1 (< 1)		—
Barriers anticipateda	335 (77)	157 (78)	142 (70)
Cost/reimbursementa	272 (63)	139 (69)	122 (60)
Difficulty ordering the test	120 (28)	49 (24)	33 (16)
Difficulty interpreting the testa	28 (6)	9 (4)	2 (1)
Results not available quickly enough for me to make treatment decisions	75 (17)	32 (16)	38 (19)
Patient acceptability	17 (4)	7 (3)	4 (2)
Other	10 (2)	4 (2)	4 (2)
I do not encounter or anticipate any significant barriers	88 (20)	44 (22)	60 (30)
Not sure	9 (2)	1 (< 1)	N/A

Significant difference between preeducation and posteducation responses for 202 providers completing both surveys.

Preeducation survey results for providers with and without testing experience

One hundred fifty-five HIV providers had previous experience using the HLA-B*5701 test whereas 278 providers did not (results not shown). Providers with previous HLA-B*5701 testing experience had ordered a median (interquartile range) of 4 (2–8) tests. The distribution of provider types was significantly different for providers who had previously ordered the HLA-B*5701 test compared with those who had not (p = 0.03). The group with prior testing experience included a larger proportion of HIV specialists (65% versus 58%) and a smaller proportion of GPs/internists (9% versus 18%). Providers with prior testing experience had a lower proportion of black patients (median 30% versus 35%, p = 0.04) and higher proportions of white patients (median 40% versus 30%, p < 0.01) and patients covered by private insurance (median 20% versus 15%, p = 0.03).a They also reported seeing more patients per month (median 124 versus 66, p < 0.01) and a longer history of treating HIV patients (median 14 versus 10 years, p = 0.02).

Of those without previous experience, the primary reasons for not ordering the test were “unaware that the test was available” (93/278, 33%), “unsure how to order the test” (65/278, 23%), and “other” reasons (97/278, 35%).

Providers with previous HLA-B*5701 testing experience had more favorable views of testing. A significantly higher proportion of providers with testing experience endorsed each of the four aspects of value (p < 0.01 for each), with the greatest percentage point difference in the proportions indicating that testing enhances the ability to plan for future treatments (68% versus 42%). Conversely, 64% of providers with testing experience reported anticipating/encountering barriers compared with 85% of providers without testing experience (p < 0.01). In both groups, cost/reimbursement and difficulty ordering the test were the barriers most often cited, but they were more commonly reported by providers who had not ordered the test than by providers who had (69% versus 59%, p < 0.01 and 32% versus 19%, p < 0.01, respectively). Difficulty interpreting the test was also more commonly cited as a barrier by providers without prior testing experience (9% versus 2%, p < 0.01).

Preeducation survey results for postsurvey respondents and nonrespondents

Two hundred thirty-one providers completed the preeducation survey but not the posteducation survey. The only substantive difference between these two groups was in the distributions of provider type (p < 0.01). Among providers completing both surveys there was a higher proportion of HIV specialists (69% versus 53%) and a lower proportion of internists/general practitioners (8% versus 21%). These providers also had a small but significantly higher proportion of patients whose race/ethnicity they classified as “other” (1% versus 0%, p = 0.01).

Providers who completed both surveys tended to endorse more aspects of value and a significantly higher proportion indicated that testing increases their confidence in deciding among treatment options (78% versus 67% p < 0.01). The proportions of postsurvey respondents and nonrespondents that experienced/anticipated one or more barriers to testing were almost identical (78% versus 77%). In both groups cost/reimbursement and difficulty ordering the test were the most frequently cited barriers, however, a higher proportion of postsurvey respondents reported cost/reimbursement as a barrier (69% versus 58%, p = 0.02).

Preeducation to posteducation survey changes among providers who completed both surveys

Table 1 displays the characteristics of the 202 providers who completed both surveys. There were no statistically significant differences between preeducation and posteducation survey responses in the perceived value of HLA-B*5701 testing. In contrast, the proportion of providers who anticipated or encountered one or more barriers to testing was reduced from 78% on the preeducation survey to 70% on the post-education survey (p = 0.04). Cost/reimbursement was the most frequently reported barrier at both time points, however, the rate at which it was reported to be a barrier decreased from 69% to 60% (p = 0.03). There was also a small but statistically significant decrease in the proportion of providers who anticipated or encountered difficulty interpreting the test (4% versus 1%, p = 0.02).

Preeducation to posteducation survey changes for providers who did and did not use test kits

There were no significant differences in the characteristics of providers who used test kits during the study compared with those who did not. Of the 134 HIV providers who used HLA-B*5701 test kits during the study, 54 (40%) had previous testing experience. On the preeducation survey, a higher proportion of test kit users indicated that testing improves the risk/benefit profile (79% versus 65%, p = 0.04) and a lower proportion indicated timeliness of results as a barrier (12% versus 24%, p = 0.04).

Test kit users reported using a median (interquartile range) of 4 (2–9) study kits. More providers used blood samples (112/134; 84%) than buccal swabs (29/134; 22%) as the method of sample collection, although some used both. Among providers who used test kits, the proportion that anticipated or encountered difficulty ordering the test decreased from the preeducation to posteducation survey (25% versus 10%, p < 0.01.), while the proportion that identified timeliness of results as a barrier increased (12% versus 20%, p = 0.04). By comparison, among those who did not use test kits, there were no statistically significant changes from preeducation to posteducation survey in any aspect of either perceived value or barriers to testing.

On the posteducation survey, a higher proportion of test kit users than nonusers indicated that testing increases their confidence in deciding among treatment options (84% versus 71%, p = 0.03) and a lower proportion reported difficulty ordering the test (10% versus 28%, p < 0.01). Eighty-six percent (115/134) of test kit users found it “very easy” or “easy” to obtain test results, and 95% (127/134) found it “very easy” or “easy” to interpret the test results. Most providers (119/134, 89%) indicated that they planned to continue HLA-B*5701 testing after the program.

HLA-B5701* carriage rate

In this study, HIV providers screened a total of 874 HIV-positive patients using the HLA-B*5701 test. Of the 874 test results obtained, HLA-B*5701 was present in 49 patients (6%) (Table 3). When summarized by self-reported racial subgroup, the allele was present in 10% (38/375) of white, Caucasian, or European heritage patients, 1% of African Americans, 3% of other races, and 5% of those not identifying their race. When summarized by self-reported ethnicity, the allele was present in 4% of Hispanics, 5% of non-Hispanics, and 9% of those not identifying their ethnicity.

Table 3.

HLA-B*5701 Carriage Rate by Race and Ethnicity

	HLA-B5701 carriage rate* n/N (%)
Total screened Race	49/874 (6)
African American	2/264 (1)
White/Caucasian/European heritage	38/375 (10)
Other	4/140 (3)
Not selected	5/95 (5)
Ethnicity
Hispanic	8/179 (4)
Not Hispanic	27/532 (5)
Not selected	14/163 (9)

Discussion

This survey found that HIV providers who participated in an educational program on HLA-B*5701 testing and subsequently conducted testing in their practices reported that the test was clinically valuable and easy to use, and that results were easy to interpret. Results from the preeducation survey indicated that cost/reimbursement was the most commonly reported barrier to testing, followed by difficulty ordering the test. This was true for the group of 433 providers who completed the preeducation survey, as well as for providers who completed both surveys and for those who used test kits.

Among providers who completed both preeducation and posteducation surveys, perceptions of the clinical value of the test remained largely unchanged. There was a statistically significant decrease in the proportion of providers reporting cost/reimbursement as a barrier and difficulty interpreting the test. The proportion reporting difficulty ordering the test was observed to decrease among this group and was statistically significant in the subgroup of test kit users.

Of 477 providers who registered for the study, 433 returned the preeducation survey and 202 (42%) returned the posteducation survey. Factors that could have influenced response rates included difficulty accessing the website if it was slow and/or experienced server problems and the time required to complete the survey. In addition, reminders to participants were limited to e-mails rather than in-person or telephone follow-ups.

The high proportion of providers citing cost/reimbursement as a barrier to HLA-B*5701 testing may reflect concerns over the extent of insurance coverage and differences in coverage across the United States. Given that this study offered no compensation for participation but did offer free HLA-B*5701 testing, the cost/reimbursement barrier identified by providers may reflect the fact that this study selectively attracted those providers who were limited in their ability to perform HLA-B*5701 testing due to reimbursement issues. Providers who used study test kits were not more likely to cite cost/reimbursement as a barrier, however.

Among the limitations of the current study is that the sample may not be representative of all HIV providers. Providers invited to participate in the study could elect not to complete one or both surveys and no data were collected on nonresponders. Additionally, the number of providers who used tests but did not complete the posteducation survey is unknown. Another limitation of the current study is that the significance level was not adjusted for multiple comparisons, therefore, some statistically significant differences may be spurious.

The cost-effectiveness of HLA-B*5701 testing prior to ABC use has been evaluated in two recent studies. The first study examined the cost-effectiveness of three strategies for first-line treatment: initiation of ABC- based treatment without HLA-B*5701 testing; initiation of ABC-based treatment with testing; and tenofovir (TDF)- based treatment.²⁰ In the base case, testing for HLA-B-5701 prior to ABC initiation increased discounted lifetime costs by $110 per person and increased quality-adjusted life years by 0.04 relative to the no test strategy. Furthermore, in the base case, initiation of ABC with testing was less costly than TDF treatment. A second study comparing HLA-B*5701 testing and conditional initiation of fixed-dose ABC/lamivudine (3TC) to TDF/emtricitabine (FTC), each with efavirenz, corroborated the conclusion that ABC/3TC treatment with testing reduces lifetime total costs in the base case scenario.²¹ The results of these cost-effectiveness analyses, together with evidence that prospective HLA-B*5701 screening significantly reduces the incidence of clinically suspected ABC HSR, supports reimbursement for HLA-B*5701 testing in the United States. With HIV treatment guidelines recommending HLA-B*5701 testing prior to initiating ABC treatment,^17,18 insurance coverage and reimbursement for testing might be expected to improve, leading to greater use of HLA-B*5701 testing.

Of the 433 participants who returned the preeducation survey, more than 50% had no prior experience with HLA-B*5701 testing either because they were unaware that the test was available or did not know how to order it. These findings suggest that further educational and public health initiatives may be needed in order to make HLA-B*5701 testing more readily available. Of note, however, the preeducation survey was conducted prior to publication of the PREDICT-1 results in the New England Journal of Medicine in February 2008.¹⁰

The carriage frequencies of the HLA-B*5701 allele in Caucasians (10%), African Americans (1%), and Hispanics (4%) reported in this study in HIV-infected patients are consistent with those reported in the five major ethnic groups of the United States.²²

Conclusion

The results of this survey suggest that HLA-B*5701 testing is easy to use in clinical practice and is a valuable tool to help identify appropriate patients for ABC therapy by excluding patients at high risk of developing HSR.

Footnotes

Acknowledgments

This survey was sponsored by GlaxoSmithKline. We thank Terry Paul, Ph.D. for his writing and editorial assistance in the preparation of the manuscript, Hardik Raval and Lynn Dix for analyses of the survey results, and an anonymous reviewer for this journal for thoughtful comments. We thank Covance for setting up the Web-based system and collecting the survey data.

Author Disclosure Statement

All authors are full-time employees of GlaxoSmithKline.

a

There was also a statistically significant difference between these two groups in the estimated proportions of patients whose race/ethnicity was classified as “other,” however, the magnitude of the difference (2 percentage points) is not considered meaningful.

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A Study of HIV Provider Attitudes Toward HLA-B*5701 Testing in the United States

Abstract

Introduction

Materials and Methods

Results

Preeducation survey results for all providers

Preeducation survey results for providers with and without testing experience

Preeducation survey results for postsurvey respondents and nonrespondents

Preeducation to posteducation survey changes among providers who completed both surveys

Preeducation to posteducation survey changes for providers who did and did not use test kits

HLA-B*5701 carriage rate

Discussion

Conclusion

Footnotes

Acknowledgments

Author Disclosure Statement

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References

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