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Rescue Regimen Success Rises 18% Yearly in Italian Cohort
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5th European HIV Drug Resistance Workshop
Cascais, Portugal
March 28, 2007
Mark Mascolini
Rates of reaching a viral load below 50 copies/mL rose 18% yearly in a large, single-center study of rescue regimen success after virologic failure [1]. The steadily climbing success rate did not depend on genotypic sensitivity score (GSS) of the rescue regimen or the actual regimen used. Further work by the same clinicians tracked a steeply declining mutation rate upon treatment failure in more recent years [2].
Simona Di Giambenedetto and colleagues at Rome's Catholic University studied 241 people who switched to a new antiretroviral combination after virologic failure of an ongoing regimen from 1999 through 2005 [1]. Everyone started rescue therapy within 6 months of genotyping after the current regimen's failure (the study baseline) and kept the same new regimen through follow-up. The Catholic University group used the French national resistance table to calculate GSS for each rescue regimen. Principal investigator Andrea De Luca agreed with attendees who argued this GSS has become a crude tool to figure rescue regimen strength because it does not factor in variables like drug potency, barrier to resistance, and tolerability.
The study population was two thirds male, and one quarter acquired HIV through injecting drug use. The group's median age stood at 39 years, their CD4 count at 262, and their viral load 4.11 log copies/mL; 42% had an AIDS diagnosis. They had tried a median of three potent antiretroviral combinations, and 74% had used a suboptimal nucleoside regimen.
After a short median follow-up of 21 weeks, 117 people (49%) had a viral load under 50 copies. That success rate reflected use of a new drug class by 66%, use of a boosted PI by 52%, and use of a nonnucleoside by 26%. Median GSS of the salvage regimen stood at 2 and ranged from 0 to 5. Viral suppression rates climbed from 27% in 1999-2000 to 57% in 2001-2002 and to 59% in 2003-2005 (P < 0.001). Average rescue regimen GSS rose from 1.88 in 1999-2000 to 2.34 in 2001-2002 and 2.28 in 2003-2005 (P = 0.009). Later year proved the only independent predictor of a higher (better) GSS (P = 0.04).
With a statistical analysis adjusting for class of drugs used, HIV risk group, number of potent regimens used, use of suboptimal nucleoside regimens, rescue regimen GSS, use of a new drug class, and prior AIDS, Di Giambenedetto pinpointed two independent predictors of virologic suppression below 50 copies:
- Every later year raised the chance of suppression 18% (hazard ratio [HR] 1.18, 95% confidence interval [CI] 1.05 to 1.34, P = 0.007)
- Every 10-fold higher baseline viral load lowered the chance of suppression 44% (HR 0.56, 95% CI 0.41 to 0.77, P < 0.001)
Every 100-cell higher CD4 count bolstered chances of viral suppression 10%, and using a boosted PI in the salvage regimen improved chances of virologic success 53%. But those two correlations fell just short of statistical significance (P = 0.068 and P = 0.053).
Di Giambenedetto and coworkers proposed that more potent and tolerable newer antiretrovirals probably account for the improved rescue response. Notably, study follow-up ended before some recent powerful salvage drugs became available. But this type of analysis cannot eliminate all possibly confounding variables, such as steadily rising mortality among people who started treatment with one or two nucleosides. A rising death rate in that group would favor chances of suppression in more recent years.
The same Catholic University team charted an ever-dwindling number of nucleoside, nonnucleoside, or PI mutations upon treatment failure from 1999 through 2005 [2]. One possibly important factor in this decline is this clinic's preference for boosted PI regimens in these years versus nonnucleoside regimens. A boosted PI was part of the failing regimen in 3.1% of 1999 regimens and 67.5% of 2005 regimens (P < 0.01), compared with 33.6% of nonnucleoside regimens in 1999 and 20% in 2005 (P = 0.034). Failure of a boosted PI often results in nucleoside resistance but not PI resistance; double-class resistance emerges more readily during failure of a nonnucleoside regimen.
The study population included 494 people in 1999 and 1429 in 2005. Everyone had a successful genotype during those years, a viral load above 1000 copies on two consecutive assays, at least 6 months of treatment experience, and no treatment breaks in the 3 months before genotyping.
The proportion of men in the group fell from 74% in 1999 to 59% in 2005 (P = 0.003), while the proportion of people who acquired HIV sexually rose from 62% to 82% (P = 0.01). The percentage of people starting treatment with one or two nucleosides dropped from 66% to 41% (P < 0.001), and the median number of potent regimens that floundered fell from 5 to 1 (P < 0.001). Compared with 1999, in 2005 the median viral load was lower (3.79 versus 4.28 log, P = 0.0015) and the median CD4 count higher (312 versus 282 cells, P < 0.001).
The prevalence of resistance to any antiretroviral class plunged from around 95% in 1999 to 60% in 2005, a highly significant nosedive (P < 0.001). Declining prevalence of resistance mutations to nucleosides, nonnucleosides, and PIs also dropped significantly over those years (P < 0.001 for all declines).
Four variables independently predicted appearance of at least one mutation at genotyping: earlier calendar year, treatment with one or two nucleosides, male gender, and a higher CD4 count. Later calendar year and female gender independently favored a lower chance of resistance to all three drug classes. The correlations between gender and resistance remain unexplained.
References
1. Di Giambenedetto S, Bracciale L, Colafigli M, et al. Predictors of successful genotype-guided antiretroviral therapy in treatment-experienced individuals over calendar years: a cohort study. 5th European HIV Drug Resistance Workshop. March 28-30, 2007. Cascais, Portugal. Abstract 4.
2. Colafigli M, Di Giambenedetto S, Bracciale L,e t al. Variables associated with the declining prevalence of HIV-1 drug resistance mutations in treatment experienced patients: a clinical cohort study. 5th European HIV Drug Resistance Workshop. March 28-30, 2007. Cascais, Portugal. Abstract 2.
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