Viral Suppression in Salvage Treatment With Raltegravir
Viral Suppression in Salvage Treatment With Raltegravir
Background: Nucleoside reverse transcriptase inhibitors (NRTIs) are often administered in salvage therapy even if genotypic resistance tests (GRTs) indicate high-level resistance, but little is known about the benefit of these additional NRTIs.
Methods: The effect of <2 compared with 2 NRTIs on viral suppression (HIV-1 RNA < 50 copies/mL) at week 24 was studied in salvage patients receiving raltegravir. Intent-to-treat and per-protocol analyses were performed; last observation carried forward imputation was used to deal with missing information. Logistic regressions were weighted to create a pseudopopulation in which the probability of receiving <2 and 2 NRTIs was unrelated to baseline factors predicting treatment response.
Results: One-hundred thirty patients were included, of whom 58.5% (n = 76) received <2 NRTIs. NRTIs were often replaced by other drug classes. Patients with 2 NRTIs received less additional drug classes compared with patients with <2 NRTIs [median (IQR): 1 (1-2) compared with 2 (1–2), P Wilcoxon < 0.001]. The activity of non-NRTI treatment components was lower in the 2 NRTIs group compared with the <2 NRTIs group [median (IQR) genotypic sensitivity score: 2 (1.5–2.5) compared with 2.5 (2–3), P Wilcoxon < 0.001]. The administration of <2 NRTIs was associated with a worse viral suppression rate at week 24. The odds ratios were 0.34 (95% confidence interval: 0.13 to 0.89, P = 0.027) and 0.19 (95% confidence interval: 0.05 to 0.79, P = 0.023) when performing the last observation carried forward and the per-protocol approach, respectively.
Conclusions: Our findings showed that partially active or inactive NRTIs contribute to treatment response, and thus the use of 2 NRTIs in salvage regimens that include raltegravir seems warranted.
The treatment options for patients infected with highly drug-resistant HIV markedly improved with the introduction of new antiretroviral compounds, such as fusion inhibitors, second-generation nonnucleoside reverse transcriptase inhibitors (NNRTIs), or new boosted protease inhibitors (PIs), CCR5 antagonists, and integrase inhibitors. To date, knowledge about the optimal combination of these compounds in salvage therapy is lacking. Nucleoside reverse transcriptase inhibitors (NRTIs) are often co-administered in salvage therapy, even if genotypic resistance tests (GRTs) indicate high-level resistance. A therapeutic benefit is assumed because of the possible residual activity of these NRTIs and the maintenance of a resistant virus with reduced replicative capacity. On the other hand, costs, drug-drug interactions, tolerability, and toxicity of these additional NRTIs have to be taken into account. NRTIs can cause mitochondrial dysfunction by inhibiting the DNA γ-polymerase resulting in plasma hyperlactataemia and variable clinical syndromes, such as lipoathrophy and peripheral neuropathy.
The clinical benefit of NRTIs with decreased activity due to drug resistance mutations to date has not been properly assessed. The number of antiretroviral compounds has increased, and additional drug classes have become available, making NRTIs potentially expendable in salvage therapy.
Here, we focused on salvage regimens including raltegravir (RAL) because this drug is now frequently used in Switzerland to treat patients with highly resistant viruses. Using data from the highly representative Swiss HIV Cohort Study (SHCS), we report on the genotypic activity and composition of salvage therapies with RAL and the effect of partially active or inactive NRTIs on the viral suppression rate.
Abstract and Introduction
Abstract
Background: Nucleoside reverse transcriptase inhibitors (NRTIs) are often administered in salvage therapy even if genotypic resistance tests (GRTs) indicate high-level resistance, but little is known about the benefit of these additional NRTIs.
Methods: The effect of <2 compared with 2 NRTIs on viral suppression (HIV-1 RNA < 50 copies/mL) at week 24 was studied in salvage patients receiving raltegravir. Intent-to-treat and per-protocol analyses were performed; last observation carried forward imputation was used to deal with missing information. Logistic regressions were weighted to create a pseudopopulation in which the probability of receiving <2 and 2 NRTIs was unrelated to baseline factors predicting treatment response.
Results: One-hundred thirty patients were included, of whom 58.5% (n = 76) received <2 NRTIs. NRTIs were often replaced by other drug classes. Patients with 2 NRTIs received less additional drug classes compared with patients with <2 NRTIs [median (IQR): 1 (1-2) compared with 2 (1–2), P Wilcoxon < 0.001]. The activity of non-NRTI treatment components was lower in the 2 NRTIs group compared with the <2 NRTIs group [median (IQR) genotypic sensitivity score: 2 (1.5–2.5) compared with 2.5 (2–3), P Wilcoxon < 0.001]. The administration of <2 NRTIs was associated with a worse viral suppression rate at week 24. The odds ratios were 0.34 (95% confidence interval: 0.13 to 0.89, P = 0.027) and 0.19 (95% confidence interval: 0.05 to 0.79, P = 0.023) when performing the last observation carried forward and the per-protocol approach, respectively.
Conclusions: Our findings showed that partially active or inactive NRTIs contribute to treatment response, and thus the use of 2 NRTIs in salvage regimens that include raltegravir seems warranted.
Introduction
The treatment options for patients infected with highly drug-resistant HIV markedly improved with the introduction of new antiretroviral compounds, such as fusion inhibitors, second-generation nonnucleoside reverse transcriptase inhibitors (NNRTIs), or new boosted protease inhibitors (PIs), CCR5 antagonists, and integrase inhibitors. To date, knowledge about the optimal combination of these compounds in salvage therapy is lacking. Nucleoside reverse transcriptase inhibitors (NRTIs) are often co-administered in salvage therapy, even if genotypic resistance tests (GRTs) indicate high-level resistance. A therapeutic benefit is assumed because of the possible residual activity of these NRTIs and the maintenance of a resistant virus with reduced replicative capacity. On the other hand, costs, drug-drug interactions, tolerability, and toxicity of these additional NRTIs have to be taken into account. NRTIs can cause mitochondrial dysfunction by inhibiting the DNA γ-polymerase resulting in plasma hyperlactataemia and variable clinical syndromes, such as lipoathrophy and peripheral neuropathy.
The clinical benefit of NRTIs with decreased activity due to drug resistance mutations to date has not been properly assessed. The number of antiretroviral compounds has increased, and additional drug classes have become available, making NRTIs potentially expendable in salvage therapy.
Here, we focused on salvage regimens including raltegravir (RAL) because this drug is now frequently used in Switzerland to treat patients with highly resistant viruses. Using data from the highly representative Swiss HIV Cohort Study (SHCS), we report on the genotypic activity and composition of salvage therapies with RAL and the effect of partially active or inactive NRTIs on the viral suppression rate.
