Validation of a portable hand-held lactate analyzer for determination of blood lactate in patients on antiretroviral therapy in Uganda.
To the Editor: In a recent issue of AIDS, Dr. Walmsley et al analyzed HIV RNA responses to treatment in the tipranavir/ ritonavir and lopinavir/ritonavir (LPV/r) arms of the RESIST trials by baseline LPV/r mutation score. In the RESIST trials, lower HIV RNA suppression rates in the LPV/r arm as compared with the tipranavir/ritonavir arm were observed when more than 3 LPV mutations were present at baseline. We reanalyzed data from TITAN to investigate the relationship between a more generic genotypic assessment [number of baseline International AIDS Society-USA primary protease inhibitor (PI) mutations] and response using the endpoint of HIV RNA suppression below 50 copies per milliliter at week 48. The overall results of the TITAN trial have been presented previously. In summary, TITAN was an open-label phase III randomized noninferiority trial comparing darunavir/ritonavir (DRV/r) 600/100 mg twice daily versus LPV/r 400/100 mg twice daily in 595 treatmentexperienced, LPV-naive patients with baseline HIV RNA levels above 1000 copies per milliliter. Patients also received 2–3 optimized reverse transcriptase inhibitors selected on the basis of treatment history and screening resistance tests. In TITAN, the median baseline CD4 count and HIV RNA level were 232 cells per microliter and 4.31 log10 copies per milliliter, respectively; 69% of the patients had previously used at least 1 PI, 82% were susceptible to at least 4 PIs, and 90% had #10-fold phenotypic resistance to LPV at baseline (full susceptibility). Baseline levels of genotypic and phenotypic resistance to DRV, LPV, and nucleoside reverse transcriptase inhibitors were well balanced between the arms. After 48 weeks, the percentage of patients with HIV RNA <50 copies per milliliter was 71% in the DRV/r arm versus 60% in the LPV/r arm (P < 0.01) in the intent to treat–time to loss of virological response analysis. There was a considerable range of PI susceptibility observed at baseline, which allowed analysis of the efficacy in the 2 arms by baseline resistance. In the analysis correlating HIV RNA suppression rates with baseline resistance, we censored data for patients who discontinued randomized treatment for nonvirologic reasons. The equivalent analysis by intent to treat–time to loss of virological response showed similar results. The efficacy in the DRV/r and LPV/r arms was correlated with the baseline number of IAS-USA primary PI mutations, using the 2007 list: D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, I54L/M, L76V, V82A/F/L/S/T, I84V, N88S, and L90M. This list, which consists of 21 mutations occurring at 13 amino acid positions, shows substantial overlap with lists of mutations used to estimate resistance to either LPVor DRV. Resistance to DRV depends on accumulation of 11 mutations at 10 positions: V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, and L89V. In patients failing DRV in the POWER studies, these mutations appeared in a background of multiple PI resistance– associated mutations. Seven of the 10 DRV mutation positions are also in the list of IAS-USA primary PI mutation positions. Of the 17 mutation positions in the current IAS-USA list associated with LPV resistance, 10 are also IASUSA primary PI mutation positions. In addition, 7 mutation positions are common to both LPV and DRV. The percentage of patients with full HIV RNA suppression at week 48 is presented by the baseline number of IASUSA primary PI mutations for the overall TITAN population in Table 1. In a sensitivity analyses, this correlation was investigated for patients with a phenotypic LPV fold change in 50% effective concentration (EC50) #10 at baseline (Antivirogram; Virco, Belgium). The percentage of patients with HIV RNA <50 copies per milliliter was similar in the DRV/r and LPV/r arms for the subgroup of patients with no IAS-USA primary PI mutations at baseline. Whereas comparable efficacy results were seen across analyzed patient subgroups receiving DRV/r, there was an increasingly large difference between the arms with increasing numbers of IAS-USA primary PI mutations at baseline. There was a linear fall in the efficacy in the LPV/r arm with increasing numbers of IASUSA primary PI mutations, which was not the case in the DRV/r arm. This trend was also seen for patients with full phenotypic susceptibility to LPV, as defined by a fold change in EC50 #10 (Table 1). In HIV clinical trial design, a difference in rates of full HIV RNA suppression