Racial Differences in Virological Response and Adverse Effects of Antiretroviral Therapy

Various studies have suggested there may be racial/ethnic differences in the natural history of HIV disease and its treatment, though it is unclear whether such variations are due to biological/genetic factors or socioeconomic factors.

Two recently published studies shed further light on differences by race/ethnicity in response to antiretroviral therapy and experience of treatment-related adverse events.

Adherence and Virologicaal Response

In the first study, reported in the December 15, 200 Journal of Acquired Immune Deficiency Syndromes (JAIDS), researchers with the AIDS Clinical Trials Group (ACTG) A5095 study explored factors underlying the higher rate of virological failure on efavirenz (Sustiva)-containing regimens observed in black compared with white patients.

To this end, the investigators rigorously examined associations over time among race, virological failure, 4 self-reported adherence measures, and quality of life (QOL).

ACTG A5095 was a double-blind, placebo-controlled study of treatment-naive HIV patients randomly assigned to receive 1 of the following regimens:

• AZT (zidovudine; Retrovir) + 3TC (lamivudine; Epivir) + abacavir (Ziagen);

• AZT + 3TC + efavirenz;

• AZT + 3TC + abacavir + efavirenz.

The triple-nucleoside reverse transcriptase inhibitor (NRTI) regimen of AZT/3TC/abacavir was discontinued in 2003 due to inferior virological efficacy. After a median follow-up period of about 3 years, the 2 efavirenz-containing regimens worked similarly, indicating that the addition of the third NRTI did not add extra benefit. Unexpectedly, black participants were 66% more likely to experience virological failure compared with whites.

The present analysis included 299 white, 260 black, and 156 Hispanic/Latino participants with at least 1 adherence evaluation. The authors examined differences in the rates of virological failure (defined as confirmed HIV RNA ≥ 200 copies/mL after 16 or more weeks) among participants in the 2 efavirenz-containing arms according to 4-day adherence (adherent defined as missing 0 doses; non-adherent defined as missing at least 1 dose), alternative self-reported adherence metrics, and QOL based on a 100-point self-report scale.

Results

• At week 12, virological failure was associated with non-adherence during the past 4 days among blacks, but not among whites (data for Hispanic patients was not reported):

• Blacks: virological failure in 53% of non-adherent vs 25% of adherent patients (P < 0.001)

• Whites: failure in 20% of non-adherent vs 20% of adherent patients (P = 0.91).

• After adjusting for baseline variables and treatment, there was a significant interaction between race and week 12 adherence (P = 0.02).

• In time-dependent Cox models using self-reported adherence over time to reflect recent adherence, there was a significantly higher risk of virological failure for non-adherent subjects (hazard ratio [HR] 2.07; P < 0.001).

• Significant race-adherence interactions were also seen with other measures of adherence:

• Missing at least 1 medication dose ever (P = 0.04);

• Missing a dose in the past month (P < 0.01);

• Missing a dose during the past weekend (P = 0.05).

• Lower QOL was also significantly associated with virological failure (P < 0.001).

• Patients with a QOL score < 75 (out of 100) were about twice as likely to experience virological failure as those with a score ≥ 90.

• However, there was no evidence of an interaction between QOL and race (P = 0.39) or adherence (P = 0.51) in predicting virological failure.

“There was a greater effect of non-adherence on virologic failure in blacks given efavirenz-containing regimens than in whites,” the researchers concluded. “Self-reported adherence and QOL are independent predictors of virologic failure.”

Adverse Effects of HAART

The analysis included treatment-naive patients enrolled in a long-term Community Programs for Clinical Research on AIDS (CPCRA) randomized clinical trial of 3 different initial antiretroviral strategies: protease inhibitor (PI)-based HAART, non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART, or a regimen containing PIs plus NNRTIs.

Complete data were available for 1301 participants: 701 black, 225 Hispanic/Latino, and 375 white or other; 263 were women. Several baseline characteristics differed by race/ethnicity and sex, including age, HIV transmission category, HIV viral load, AIDS diagnosis, hepatitis B or C coinfection, body mass index, and baseline hypertension.

Over a median follow-up period of 5 years, participants were compared according to race/ethnicity and sex for 14 categories of Grade 4 (severe) adverse events, discontinuation of initial antiretroviral therapy, and death due to any cause.

Results

• Virological and immunological response (CD4 cell recovery) did not differ based on race/ethnicity or sex.

• Grade 4 events occurred in a total of 409 participants, for an overall rate of 8.9 events per 100 person-years (PY).

• There were a total of 176 deaths, or 3.0 per 100 PY.

• 523 patients discontinued a regimen due to any type of toxicity, for a rate of 13 discontinuations per 100 PY.

• Overall adverse event rates did not differ based on race/ethnicity or sex.

• However, in an adjusted analysis controlling for baseline risk factors, blacks were at greater risk for cardiovascular events (hazard ratio [HR] 2.64) and kidney problems (HR 3.83) compared with whites or Hispanics.

• Black men had a higher rate of psychiatric events (HR 2.45) than men of other racial/ethnic groups or women.

• Women (regardless of race) had a higher risk of anemia (HR 2.34,).

In conclusion, the authors wrote, “Among HIV-infected participants initiating antiretroviral therapy, there were significant risk-adjusted differences for specific adverse events by gender and race, but not in the overall adverse event rates, all-cause mortality, or rates of toxicity-related treatment discontinuations.”

Some of the differences in adverse events seen in this study were not surprising, given that blacks in the general HIV negative population have a higher rate of cardiovascular and kidney disease, and women are more likely to develop anemia due to menstrual blood loss. In a majority of studies, however, psychiatric events more common among women than men.

01/15/08

References

B Schackman, H Ribaudo, A Krambrink, and others. Racial Differences in Virologic Failure Associated With Adherence and Quality of Life on Efavirenz-Containing Regimens for Initial HIV Therapy: Results of ACTG A5095. Journal of Acquired Immune Deficiency Syndromes 46(5): 547-554, December 15, 2007.

E Tedaldi, J Absalon, A Thomas, and others. Ethnicity, Race, and Gender: Differences in Serious Adverse Events Among Participants in an Antiretroviral Initiation Trial: Results of CPCRA 058 (FIRST Study). Journal of Acquired Immune Deficiency Syndromes. December 20, 2007 [Epub ahead of print].

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