African-Americans in ACTG 5095 had shorter time to virologic failure and grade 3/4 side effects
Two years before the 45th ICAAC, ACTG 5095 made a vital contribution to antiretroviral management by finding that three nucleoside reverse transcriptase inhibitors-packaged in one pill as Trizivir-did not slow HIV as well as two efavirenz-based regimens in previously untreated people . The ACTG team shut down the Trizivir arm in a wink but continued to track people taking efavirenz plus AZT/3TC (as Combivir) or efavirenz plus Trizivir for a median of 144 weeks.
At that point, almost 3 years after randomisation, Cornell Universitys Roy Gulick and ACTG colleagues could not sift out a single result suggesting a four-drug efavirenz regimen does better than a three-drug efavirenz regimen . That result confirms a host of earlier studies that found no good reason to start antiretroviral therapy with four drugs instead of three [3-6].
The comparison of the two efavirenz regimens involved 765 people who started therapy with an average viral load of 72,444 copies/mL (57% were below 100,000 copies/mL) and an average CD4 count of 240 cells/mm3. Looking at the primary endpoint-two consecutive viral loads above 200 copies/mL after at least 16 weeks of treatment-Gulick counted 99 failures among 382 people (26%) taking triple therapy and 94 out of 383 (25%) taking quadruple therapy, nowhere close to a statistically significant difference (P = 0.73).
Nor did the three-drug and four-drug groups differ in time to virologic response, time to virologic failure in people with a pretreatment load above 100,000 copies/mL, percentage reaching a load below 50 copies/mL (80% to 85% in each group after 144 weeks), CD4-cell gains, treatment discontinuations, or side effect rates.
Multivariate analysis to track down factors affecting virologic failure found two variables that made failure more likely:
- Coinfection with hepatitis C virus (HCV) raised the failure risk 57% (hazard ratio 1.57, 95% confidence interval 1.02 to 2.40, P = 0.04). HCV coinfected patients had shorter time to viral failure, but they were not found to have shorter time to grade 3/4 adverse events & discontinuation from first regimen.
- Being black instead of white raised the risk 67% (hazard ratio 1.67, 95% confidence interval 1.19 to 2.35, P = 0.003)
The first finding confirms that HIV infection can be more difficult to manage in people also battling HCV. But the racial difference is hard to explain. Gulick stressed that blacks did not differ from whites or Hispanics in overall adherence. About 85% in each ethnic group reported never missing a dose in the 4 days before each self-report.
But poor adherence among blacks at a single point 12 weeks after treatment began did correlate with virologic failure when compared with blacks reporting good adherence at that time and with whites or Hispanics reporting good or bad adherence at 12 weeks.
Gulick speculated that genetic differences affecting efavirenz levels could play a part in this higher risk of failure. Genotyping in an earlier ACTG study found that a certain shift in a gene that codes the CYP2B6 efavirenz-metabolizing enzyme turned up more often in blacks (20%) than whites (3%) and correlated with higher efavirenz levels (P < 0.0001) .
Indeed, Gulick found that black people in his study had a significantly shorter time to virological failure and a shorter time to grade 3 or 4 side effects. But ACTG gene analysts will have to look at blood samples from study participants to see if black people had the critical CYP2B6 gene flips more than other groups, and if those flips correlate with higher efavirenz levels and more efavirenz-induced side effects.
Making that triple correlation – higher rate of critical gene shifts, leading to higher drug levels, leading to more side effects – is not easy. In the earlier ACTG trial, for example, black people had a key CYP2B6 gene change more than white people, and they had higher efavirenz levels, but that gene shift did not correlate with more efavirenz toxicity . An ICAAC study from Londons Chelsea and Westminster Hospital and the University of Liverpool also failed to tie higher efavirenz levels in black people to more efavirenz side effects .
Desmond Maitland and colleagues charted efavirenz concentrations in treatment-naive people beginning either 3TC/ddI/efavirenz or tenofovir/ddI/efavirenz in an open-label (non-blinded) trial. Adherence measured by three methods exceeded 99% in both treatment groups. The study ended early when the tenofovir regimen quickly proved virologically inferior, but the London-Liverpool team did measure 4- and 12-week efavirenz levels in 66 people, including 9 women and 13 Africans.
Efavirenz levels proved significantly higher at weeks 4 and 12 in women than in men, and in Africans than in whites. But high efavirenz concentrations did not correlate with neuropsychiatric symptoms assessed at week 12. People with efavirenz readings above 1100 ng/mL at weeks 4 and 12 were more likely to reach a viral load below 50 copies/mL at week 12, a finding confirming a minimum effective concentration of 1000 ng/mL for efavirenz.
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