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New strategies such as boosted-protease inhibitor (PI) monotherapy are being investigated. However, a concern remains regarding the efficacy of this strategy in viral sanctuaries such as the male genital tract. More than 80% of untreated HIV-infected men have detectable HIV-RNA in semen and such a strategy could favour local selection of resistant variants, given the poor penetration of most PIs in semen.To evaluate the impact of a first-line lopinavir/ritonavir alone or standard triple combination on HIV-1 shedding in the genital tract.HIV-1-infected men enrolled in the Monark randomized trial were eligible for the present study after 48 weeks of a first-line lopinavir/ritonavir alone or in combination with zidovudine and lamivudine. Single-paired samples of blood and semen were collected at week 48. Blood plasma HIV-RNA and seminal plasma HIV-RNA were measured at week 48. Lopinavir and ritonavir concentrations were measured in blood and in semen at week 48 by high-performance liquid chromatography.Ten patients were included: five of them received lopinavir/ritonavir monotherapy and five received a triple combination. At week 48, all patients had blood plasma HIV-RNA <1.7 log10 copies/mL. Median lopinavir and ritonavir concentrations were within the expected therapeutic target range in blood plasma (4896 and 130.5 ng/mL, respectively), whereas both lopinavir and ritonavir were undetectable in all seminal plasma samples (<30 ng/mL). All 10 patients had undetectable seminal plasma HIV-RNA at week 48 (<2.3 log10 copies/mL).No local viral production was evident in semen, despite the local absence of therapeutic antiretroviral drug concentrations in the five patients receiving lopinavir/ritonavir alone.