Lopinavir/ritonavir pharmacokinetics, efficacy, and safety in HIV and hepatitis B or C coinfected adults without symptoms of hepatic impairment.

OBJECTIVE: Lopinavir/ritonavir plus nucleoside reverse transcriptase inhibitors is one standard antiretroviral therapy regimen, both in patients with HIV alone and coinfected with hepatitis B or C. Our objective was to investigate whether hepatitis coinfection without clinical signs of hepatic impairment is a cofactor altering lopinavir pharmacokinetics and influencing therapy outcome. METHODS: Steady-state 12-hour pharmacokinetic profiles of lopinavir/ritonavir were assessed in patients with (group 1, n = 20) or without (group 2, n = 36) hepatitis coinfection, taking lopinavir/ritonavir 400/100 mg twice a day plus nucleoside reverse transcriptase inhibitors, measured by means of high-performance liquid chromatography-tandem mass spectrometry. Demographic (sex, age, weight), pharmacological (formulation, comedication), clinical, and virological/immunologic parameters (HIV-RNA PCR, CD4(+) cell count) were compared between the groups and included in regression analyses for correlations with lopinavir pharmacokinetic parameters (C(min), C(max), AUC, CL, and t(1/2)) and viral load evolution over 48 weeks on therapy. Patient pairs were matched 1:2 for the parameters sex, age, weight, ethnicity, and drug formulation. RESULTS: None of the hepatitis-related cofactors (aspartate aminotransferase, alanine aminotransferase, γGT, HBe Ag, HBsAg, HCV-RNA PCR, HCV-therapy) had an influence on lopinavir pharmacokinetics in this group of patients. Lopinavir C(min) (P = 0.039) and area under the curve (P = 0.038) and ritonavir C(max) (P = 0.049) were significantly enhanced in hepatitis-coinfected patients, but correlated only with drug formulation (ie, soft gel capsule or Meltrex tablet formulation, multivariate regression analysis, P = 0.001), not hepatitis coinfection. CONCLUSIONS: Despite moderately enhanced lopinavir/ritonavir plasma concentrations, regular therapeutic drug monitoring is not to be considered in hepatitis-coinfected patients without hepatic impairment. Antiviral efficacy is comparable between both groups, a less-pronounced CD4(+) cell increase in hepatitis-coinfected patients is in line with previously published data.

Immune response after two doses of the novel split virion, adjuvanted pandemic H1N1 influenza A vaccine in HIV-1-infected patients.

BACKGROUND: To determine the rate of seroconversion after 2 doses of a novel split virion, inactivated, adjuvanted pandemic H1N1 influenza vaccine (A/California/7/2009) in human immunodeficiency virus type 1 (HIV-1)-infected patients (ClinicalTrials.gov NCT01017172). METHODS: Diagnostic study of adult HIV-1-infected patients scheduled for H1N1 influenza A vaccination. Blood samples where taken before and 21 days after the first dose and 21 days after the second dose of the vaccine. Antibody (AB) titers were determined by hemagglutination inhibition assay. Seroconversion was defined by either an AB titer ≤ 1:10 before and ≥ 1:40 after or ≥ 1:10 before and a ≥ 4-fold increase in AB titer 21 days after vaccination. RESULTS: One hundred thirty-five patients received 2 doses of the H1N1 vaccine and were analyzed. The rate of seroconversion was 68.2% (95% confidence interval, 59.6-75.9) after the first dose and 91.9% (95% confidence interval, 85.9-95.9) after the second dose. Patients who did not seroconvert had a lower mean nadir CD4 cell count (± standard deviation; 81 ± 99 vs 190 ± 148 cells/µL; P = .006), had a longer duration of HIV infection (± standard deviation; 13.1 ± 5.9 vs 8.8 ± 6.8 years; P = .04), and were more likely to have an AB titer ≥ 1:40 before vaccination (4% vs 55%; P < .001) when compared with patients with seroconversion. No other differences were found between the 2 groups, including AIDS status, highly active antiretroviral therapy status, HIV RNA - polymerase chain reaction load <50 copies/mL, CD4 cell count, sex, body mass index, and chronic hepatitis. CONCLUSION: Among HIV-infected patients, the rate of seroconversion after the first dose of an adjuvanted H1N1 influenza A vaccine was 68% and increased to 92% after a second doses.

Low rate of seroconversion after vaccination with a split virion, adjuvanted pandemic H1N1 influenza vaccine in HIV-1-infected patients.

OBJECTIVE: To determine rates of seroconversion after single vaccination with a novel split virion, inactivated, adjuvanted pandemic H1N1 influenza vaccine (A/California/7/2009) in HIV-1-infected patients (ClinicalTrials.gov Identifier: NCT01017172). DESIGN: Single center diagnostic study. SETTING: Institutional HIV outpatient department of an urban university clinic. PARTICIPANTS: Adult HIV-1-infected individuals. INTERVENTION: Serum samples were taken before and 21 days after vaccination. MAIN OUTCOME MEASURES: Antibody titers determined by hemagglutination inhibition assay. Seroconversion to vaccination was defined by either an antibody titer of 1: 10 or less before and of at least 1: 40 after or at least 1: 10 before and at least four-fold increase in antibody titer 21 days after single vaccination. RESULTS: One hundred and sixty patients (125 men/35 women) were analyzed. Before vaccination, 23 patients (14.4%) had a hemagglutination inhibition assay titer of at least 1: 40. A median of 22 +/- 3 days after vaccination, 110 (69%) patients seroconverted. Seroconverters were younger (45.1 +/- 10.0 vs. 48.8 +/- 11.3 years; P = 0.04), had a higher CD4 cell count (532 +/- 227 vs. 475 +/- 281 cells/microl; P = 0.03) and were more likely to have received a previous H5N1 vaccination in 2009 (25 vs. 8%; P = 0.02) when compared to nonresponders. No other significant differences were found comparing the two groups (prevaccination hemagglutination inhibition assay titer of > or =1: 40, AIDS, HAART, HIV RNA PCR <50 copies/ml or CD4 nadir, CD4 and CD8 percentage, sex, BMI, chronic hepatitis B or C). CONCLUSION: Seroconversion after one dose of a split virion, inactivated, adjuvanted pandemic H1N1 influenza vaccine of HIV-infected patients was 69%. Studies to investigate whether a second dose of the vaccine will increase seroconversion rate are needed.

Pharmacokinetics, safety and efficacy of saquinavir/ ritonavir 1,000/100 mg twice daily as HIV type-1 therapy and transmission prophylaxis in pregnancy.

BACKGROUND: A saquinavir/ritonavir-containing regimen is one option for the prevention of mother-to-child transmission of HIV during pregnancy. We evaluated the pharmacokinetics, efficacy and safety of saquinavir/ritonavir 1,000/100 mg twice daily plus nucleos(t)ide reverse transcriptase inhibitors in 13 women during late pregnancy and compared the results to those of 15 non-pregnant women. METHODS: Protease inhibitor plasma concentration profiles were assessed at 12 h using a standardized therapeutic drug monitoring procedure and measured by LC-MS/MS. Minimum and maximum concentrations (C(min) and C(max)), area under the plasma concentration-time curve (AUC(0-12 h)), and total clearance (CL(total)) were compared between the groups and correlated to demographic, physiological and clinical cofactors. Antiviral and immunological efficacy and safety were investigated. RESULTS: The geometric means (90% confidence interval [CI]) for saquinavir C(min), C(max) and AUC(0-2 h) of pregnant versus non-pregnant women were 572 (437-717) versus 765 (485-1,052, P = 0.064) ng/ml, 2,168 (1,594-2,807) versus 3,344 (2,429-4,350; P = 0.045) ng/ml and 15,512 (11,657-19,943) versus 24,027 (17,454-31,548, P = 0.029) ng x h/ml. The geometric means (90% CI) for ritonavir C(min), C(max) and AUC(0+12 h) were 190 (148-234) versus 310 (240-381, P = 0.011) ng/ml, 781 (580-999) versus 1,552 (1,127-2,007, P = 0.004) ng/ml and 5,576 (4,303-7,006) versus 10,528 (8,131-13,177, P = 0.003) ng x h/ml. Age, weight, saquinavir dose per weight and body mass index differed significantly; saquinavir C(min) and AUC(0-12 h) were correlated with ritonavir C(min) and saquinavir dose per weight. After a mean of 11 weeks treatment, 12 of 13 pregnant women had a viral load < 400 copies/ml, which was similar to the results of non-pregnant women. CONCLUSIONS: Although saquinavir plasma concentrations were significantly lower in pregnant women compared with non-pregnant women, all pregnant women displayed a saquinavir AUC(0-12 h) > 10,000 ng x h/ml, 92.3% had a viral load < 400 copies/ml at birth. Saquinavir was well tolerated by the mothers and all newborn children were HIV type-1 negative at 18 months of age.