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GRACE (Gender, Race And Clinical Experience): Outcomes by Race at Week 48
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Reported by Jules Levin
ICAAC Sept 11-15 2009 San Francisco
From Jules: This important study shows African-Americans face higher barriers to successful care in the USA. The Federal government should have addressed this problem years ago rather than diverting all our resources overseas. Let's be clear this study does not say African-Americans respond less well to HAART due to any intrinsic inability to respond, the study does show that African-Americans, moreseo women than men, suffer from health disparities requiring more support services.
Kimberly Y. Smith1, Fernando Garcia2, Robert Ryan3, Ron Falcon4, Alan Tennenberg4, Joseph Mrus4
1Rush University Medical Center, Chicago, IL; 2Valley AIDS Council, Harlingen, TX; 3Tibotec, Inc., Yardley, PA; 4Tibotec Therapeutics, Bridgewater, NJ
"This analysis of the Week 48 results from GRACE, stratified by race, demonstrates that DRV/r treatment is safe and effective in treatment-experienced patients regardless of race..... black patients had a higher discontinuation rate (mainly due to loss to follow up and 'other' reasons).... Black patients had more advanced disease at baseline which, among other potential reasons, could reflect differences in care and may have led to increased treatment complexity.... Black patients also had lower adherence rates.... We believe higher discontinuation rates among black patients in GRACE may have been due to socioeconomic and other factors unique to North America that were not measured in the trial. These factors may include lower health literacy and higher levels of depression and injection drug use"
"post-hoc multivariate analysis of all 429 patients enrolled in GRACE showed that being of a non-black race was significantly associated with improved response and a lower likelihood of discontinuation for reasons other than VF or AEs" ...... "The rate of confirmed VF was 32.2% (n=85) in black patients, 24.0% (n=23) in Hispanic patients and 21.5% (n=14) in Caucasian patients"
If you look at Table 3 you will see discontinuation from study is associated with lower adherence, not using etravirine in background regimen, previous/current illegal drug use and race.
from Jules: The study finding is not new. I have been saying for many years that this is a problem being neglected in the USA. Support services at public hospitals are sorely lacking and inadequate but effect more the most vulnerable patients groups, African-Americans, and women more then men. Of note in Table 2 African-American women's percent <50 copies/ml was less than for African-American men (46% vs 53.4% but when eliminating outside factors like non-adherence etc, the responses between Black men & women were the same (69.5% & 67.2%) reflecting that the differences in response between Black women are due to women suffering more than men from the socioeconomic and other factors referred to in this discussion. We are diverting too many resources globally and ignoring crucial needs at home in the USA, and this is one of several being ignored. This study found the African-Americans, and African-American women more than African-American men, did not respond as well as Whites & Latinos because of socio-economic barriers. Blacks had lower adherence rates, had higher discontinuation rates, and more advanced disease at the start of the study, and these differences were NOT driven by safety or tolerability as no race-related differences in adverse events or lab abnormalities. In Table 1 Blacks's Lost-To-Follow-up rate was double that of Caucasians (9.1% vs 4.6% and 5.2% for Hispanics), but adverse events rates were similar (6.4% for Blacks, 7.7% for Caucasians, 6.3% for Hispanics); non-compliance rates were higher for Blacks (4.9% for Blacks, 3.1% for Caucasians and 4.2% for Hispanics, and virologic failure rates were similar between these groups (2.7% for Blacks, 3.1% for Caucasians and 1.0% for Hispanics); Blacks also had a lower rate of completing the trial (67.4% for Blacks, 73.8% for Caucasians, and 76% for Hispanics). The study authors suggested lower health literacy and higher levels of depression and injection drug use as factors that likely contribute to the barriers facing African-Americans but clearly that are many underlying factors unique to African-Americans in the USA.
This study highlights very well NOT that Blacks should be necessarily increasingly enrolled in clinical studies but that African-Amnericans, particularly women, need increased services and support program. I spoke with Kim Smith, the study author, at ICAAC and she is in full agreement. Dr Smith suggested that an appropriate study would be to provide an adequate array of services within a study and evaluate responses to HAART, as a pilot study. Enrolling African-Americans in a standard clinical study does not necessarily help these patients. The study found that differences in response to HAART varied by site. So that African-American patients at the usual types of sites such as ACTG sites did not perform well but at newer sites where African-America patients received additional attention African-Americans performed better, and there is one site in Savannah where the study author and Tibotec highlighted Black patients performed better. At the site the investigator went the extra step in delivering medications to patients and providing support to the patients. Tibotec gets much credit for conducting this study since they designed and implemented this study and devoted quite a lot of resources not just in conducting the study but in analyzing the results and in presenting posters at IAS in Capetown and this poster at ICAAC. The Federal government needs to respond to these problem which is not new, but has been ongoing for many years. Resources for HIV/AIDS should be focused on problems here in the USA!
AUTHOR DISCUSSION
GRACE successfully enrolled a population of black, Hispanic and Caucasian patients that was representative of the HIV epidemic across the US. Regardless of race, all patients responded well to DRV/r-based therapy
Overall, black patients had a higher discontinuation rate (mainly due to loss to follow up and 'other' reasons) and a lower response rate (ITT and non-VF censored) than Hispanic or Caucasian patients
- Black patients had more advanced disease at baseline than the other groups, which,
among other potential reasons, could reflect differences in care and may have led to
increased treatment complexity3,5
- Black patients also had lower adherence rates than Hispanics or Caucasians, which may have contributed to their lower response rate and higher VF rate
- Being of a race/ethnicity other than black was found to be a significant predictor of virologic response in the post-hoc analysis of GRACE; the HEAT study, another North-American based trial, also observed this correlation between race and virologic response6
- Race-based differences in discontinuation rates have not previously been observed in large, global DRV/r studies7,8
- We believe higher discontinuation rates among black patients in GRACE may have been due to socioeconomic and other factors unique to North America that were not measured in the trial. These factors may include lower health literacy and higher levels of depression and injection drug use3
- Differences in virologic response did not appear to be driven by differences in response by sex
DRV/r safety and tolerability was similar across races; no clinically relevant race-associated differences in AEs or lab abnormalities were noted, and no specific AEs were identified as driving discontinuations in any race group
- The lower rates of SAEs observed in Hispanic patients compared with black and Caucasian patients may be due to their less severe HIV disease at baseline
- Overall, the incidence of AEs and lab abnormalities was similar to other DRV/r studies in treatment-experienced patients7-9
INTRODUCTION
People of color (black and Hispanic) constitute 25% of the United States (US) population, yet account for nearly 65% of those living with HIV/AIDS in the US1
In 2005, 26% of new HIV/AIDS diagnoses were in women, with women of color constituting over 80% of these cases2
- Despite the disproportionate representation of women and people of color among patients with HIV/AIDS, these populations remain underrepresented in antiretroviral (ARV) clinical trials3
GRACE (Gender, Race And Clinical Experience), a 48-week study, was designed to enroll a high proportion of women and people of color to add to the currently limited pool of clinical data on ARV therapy in diverse patient populations
- The efficacy and safety of darunavir/ritonavir (DRV/r) plus an investigator-selected optimized background regimen (OBR), which could include etravirine (ETR), was assessed
Here we report Week 48 data by race from the GRACE study
Figure 1. Study design
aPatients were allowed to enter the study on treatment interruption of ≥4 weeks; bInvestigator-selected with nucleoside reverse transcriptase inhibitors and NNRTIs
included; ENF, TPV or agents from novel classes were not allowed; PI, protease inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; HAART, highly-active
antiretroviral therapy; DRV/r, darunavir/ritonavir; ETR, etravirine; ENF, enfuvirtide; TPV, tipranavir; bid, twice daily; OBR, optimized background regimen
RESULTS
Patient population and baseline characteristics
Among black patients, 72% were women, compared with 63% and 52% of Hispanic and Caucasian patients, respectively (Table 1)
Black patients had slightly more advanced disease at baseline than Hispanic and Caucasian patients (Table 1)
The mean phenotypic susceptibility score of the OBR was comparable across races; use of ETR in the OBR was similar among black and Caucasian patients, but slightly lower in Hispanic patients (Table 1)
a n=262; b n=95; c n=65; dVircoTYPE HIV-1 resistance analysis; eTwo patients, one Hispanic and one Caucasian, did not have resistance testing at baseline; f Includes ETR, but not DRV; SE, standard error; CDC, Centers for Disease Control and Prevention; DRV, darunavir; PI, protease inhibitor; ETR, etravirine; OBR, optimized background regimen; PSS, phenotypic susceptibility score
Patient disposition
The primary reasons for study discontinuation were lost to follow-up and AEs (Figure 2)
- No specific AEs were identified as driving discontinuations in any race group
Higher discontinuation rates were seen in black patients, mostly due to lost to follow up and 'other' reasons (Figure 2)
- 'Other' reasons for discontinuation among black patients included investigator's decision to close the site (n=4), patient moved out of state (n=2), patient missed appointments, patient ineligible to continue, patient taken out of trial due to old age, patient discontinued due to no virologic response by Week 12, patient too busy to come to appointments, patient's primary care physician discontinued
study medication and started new regimen, and patient removed from trial due to sponsor's decision
Figure 2. Study disposition
a'Other' classification was selected by the investigator as a reason for discontinuation; bIncludes one patient that became pregnant and one patient that
was ineligible to continue; cIncludes one patient that did not continue with study visits
Efficacy
At Week 48 in the ITT population, similar response rates were observed in Hispanic and Caucasian patients, with lower response rates seen in black patients (Figure 3A); in the non-VF censored population, a similar trend was observed (Figure 3B)
- Differences in response rates were observed between sexes in the black and Hispanic populations in the ITT-TLOVR analysis (Table 2)
- When discontinuations for reasons other than VF were censored, response rates were comparable between women and men within each race/ethnic group (Table 2)
The median change in observed CD4+ count from baseline showed steady improvement over time and was comparable across races (Figure 4A)
The median change from baseline in CD4+ count in the ITT-LOCF analysis was similar in Hispanic and Caucasian patients (Figure 4B)
- The lower median CD4+ change in black patients is most likely due to the higher number of discontinuations in this group
A lower proportion of black and Hispanic patients were ≥95% adherent (63.3% and 66.7%, respectively) compared with Caucasian patients (73.8%)
TLOVR, time-to-loss of virologic response
aOne black patient was assessed for response at Week 48 and subsequently discontinued for reasons other than VF; ITT, intent-to-treat;
TLOVR, time-to-loss of virologic response; VF, virologic failure
Multivariate analysis (all patients; intent-to-treat population)
A post-hoc multivariate analysis of all 429 patients enrolled in GRACE showed that being of a non-black race was significantly associated with improved response and a lower likelihood of discontinuation for reasons other than VF or AEs (Table 3)
aContinuous; OR, odds ratio; CI, confidence interval; GI, gastrointestinal; ETR, etravirine; OBR, optimized background regimen;
NNRTI, non-nucleoside reverse transcriptase inhibitor
Resistance
The rate of confirmed VF was 32.2% (n=85) in black patients, 24.0% (n=23) in Hispanic patients and 21.5% (n=14) in Caucasian patients
- Not all patients that experienced VF discontinued the trial; rates of discontinuations due to VF (Figure 2) were lower than overall rates of VF
Patients with treatment-emergent International AIDS Society-USA major PI resistance-associated mutations (RAMs) or DRV RAMs (Table 4) had substantial resistance at baseline, with 1-6 major PI RAMs present4
aOut of 85 black, 23 Hispanic and 14 Caucasian patients with confirmed virologic failure (HIV-1 RNA >50 copies/mL), 35, 7 and 5, respectively, had genotypes
available at baseline and virologic failure; bGenotype determined only for patients with HIV-1 RNA >1000 copies/mL; IAS, International AIDS Society; PI, protease inhibitor; RAM, resistance-associated mutation; NRTI, nucleoside reverse transcriptase inhibitor; DRV, darunavir; ETR, etravirine
aAll deaths unrelated to DRV/r or etravirine; bExcludes lab abnormalities reported as AEs; AE, adverse event; SAE, severe adverse event; DRV/r, darunavir/ritonavir; AST, aspartate aminotransferase; ALT, alanine transaminase
References
1. Centers for Disease Control and Prevention. HIV/AIDS Surveillance Report, 2007. Vol. 19. Available from: http://www.cdc.gov/hiv/topics/surveillance/resources/reports/. Accessed August 22, 2009
2. Centers for Disease Control and Prevention. HIV/AIDS among women. Available from: http://www.cdc. gov/hiv/topics/women/resources/factsheets/pdf/women.pdf. Accessed August 15, 2009
3. Cargill A and Stone V. Med Clin N Am 2005; 89: 895-912
4. Johnson VA, et al. Top HIV Med 2008; 16(5): 138-145
5. Turner BJ, et al. Arch Intern Med 2000; 160: 2614-2622
6. Smith KY, et al. Poster presented at the 5th International AIDS Society conference on HIV pathogenesis, treatment and prevention. July 19-22, 2009, Cape Town, South Africa. Poster MOPEB033
7. Madruga JV, et al. Lancet 2007; 370(9581): 49-58
8. Katlama C, et al. AIDS 2007; 21: 395-402
9. Molina JM, et al. J Acquir Immune Defic Syndr 2007; 46(1): 24-31
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