Reduced exposure to darunavir and cobicistat in HIV-1-infected pregnant women receiving a darunavir/cobicistat-based regimen.

OBJECTIVES: The aim of the study was to evaluate darunavir and cobicistat pharmacokinetics in pregnant women with HIV-1 infection. METHODS: This phase 3b, open-label study enrolled HIV-1-infected pregnant women (18-26 weeks of gestation) receiving combination antiretroviral therapy with once-daily darunavir/cobicistat 800/150 mg. The plasma pharmacokinetics of darunavir (total and unbound) and cobicistat were assessed over 24 h during the second and third trimesters (24-28 and 34-38 weeks of gestation, respectively) and 6-12 weeks postpartum. Pharmacokinetic parameters [area under the plasma concentration-time curve over 24 h (AUC24 h ), maximum plasma concentration (Cmax ) and minimum plasma concentration (Cmin )] were derived using noncompartmental analysis and compared using linear mixed effects modelling (pregnancy versus postpartum). Antiviral activity and safety were evaluated. RESULTS: Seven women were enrolled in the study; six completed it. Total darunavir exposure was lower during pregnancy than postpartum (AUC24 h , 50-56% lower; Cmax , 37-49% lower; Cmin , 89-92% lower); unbound darunavir exposure was also reduced (AUC24 h , 40-45% lower; Cmax , 32-41% lower; Cmin , 88-92% lower). Cobicistat exposure was also lower during pregnancy than postpartum (AUC24 h , 49-63% lower; Cmax , 27-50% lower; Cmin , 83% lower). At study completion, five of six (83%) women were virologically suppressed (HIV-1 RNA < 50 copies/mL). There was one virological failure (the patient was nonadherent; no emerging genotypic resistance was observed and susceptibility to antiretrovirals was maintained). No mother-to-child transmission was detected among six infants born to the six women who completed the study. Overall, darunavir/cobicistat was well tolerated in women and infants. CONCLUSIONS: In view of markedly reduced darunavir and cobicistat exposures during pregnancy, this combination is not recommended in HIV-1-infected pregnant women.

Switching to coformulated rilpivirine (RPV), emtricitabine (FTC) and tenofovir alafenamide from either RPV, FTC and tenofovir disoproxil fumarate (TDF) or efavirenz, FTC and TDF: 96-week results from two randomized clinical trials.

OBJECTIVES: The single-tablet regimen rilpivirine, emtricitabine and tenofovir alafenamide (RPV/FTC/TAF) for treatment of HIV-1-infected adults was approved based on bioequivalence. We assessed the clinical efficacy, safety and tolerability of switching to RPV/FTC/TAF from either RPV/FTC/tenofovir disoproxil fumarate (TDF) or efavirenz (EFV)/FTC/TDF. METHODS: We conducted two distinct randomized, double-blind, active-controlled, noninferiority trials in participants taking RPV/FTC/TDF (Study 1216) and EFV/FTC/TDF (Study 1160). Each study randomized virologically suppressed (HIV-1 RNA < 50 copies/mL) adults (1:1) to switch to RPV/FTC/TAF or continue their current regimen for 96 weeks. We evaluated efficacy as the proportion with HIV-1 RNA < 50 copies/mL using the Food and Drug Administration snapshot algorithm and prespecified bone and renal endpoints at week 96. RESULTS: We randomized and treated 630 participants in Study 1216 (RPV/FTC/TAF, n = 316; RPV/FTC/TDF, n = 314) and 875 in Study 1160 (RPV/FTC/TAF, n = 438; EFV/FTC/TDF, n = 437). In both studies, the efficacy of switching to RPV/FTC/TAF was noninferior to that of continuing baseline therapy at week 96, with respective percentages of patients with HIV RNA < 50 copies/mL being 89.2% versus 88.5% in Study 1216 [difference 0.7%; 95% confidence interval (CI) -4.3 to +5.8%] and 85.2% versus 85.1% in Study 1160 (difference 0%; 95% CI -4.8 to +4.8%). No participant on RPV/FTC/TAF developed treatment-emergent resistance versus two on EFV/FTC/TDF and one on RPV/FTC/TDF. Compared with continuing baseline therapy, significant improvements in bone mineral density and renal tubular markers were observed in the RPV/FTC/TAF groups (P < 0.001). CONCLUSIONS: Switching to RPV/FTC/TAF from RPV/FTC/TDF or EFV/FTC/TDF was safe and effective and improved bone mineral density and renal biomarkers up to 96 weeks with no cases of treatment-emergent resistance.

Pharmacokinetics of once-daily darunavir/ritonavir in HIV-1-infected pregnant women.

OBJECTIVES: HIV antiretroviral therapy during pregnancy is recommended to reduce the risk of mother-to-child transmission and for maternal care. Physiological changes during pregnancy can affect pharmacokinetics. The impact of pregnancy was evaluated for once-daily (qd) darunavir/ritonavir. METHODS: HIV-1-infected pregnant women on an antiretroviral regimen that includes darunavir were enrolled in the study and further treated with darunavir/ritonavir 800/100 mg qd. Plasma concentrations were assessed over 24 h during the second and third trimesters and postpartum using a validated high-performance liquid chromatography tandem mass spectrometry assay for total darunavir and ritonavir, and using (14) C-darunavir-fortified plasma for unbound darunavir. Pharmacokinetic parameters were derived using noncompartmental analysis. Safety and antiviral response were assessed at all visits. RESULTS: Data were available for 16 women. The area under the plasma concentration-time curve from 0 to 24 h (AUC24h ) for total darunavir was 34-35% lower during pregnancy vs. postpartum. Unbound darunavir AUC24h was 20-24% lower during pregnancy vs. postpartum. The minimum plasma concentration of total and unbound darunavir was 32-50% and 13-38% lower, respectively, during pregnancy vs. postpartum. The antiviral response (< 50 HIV-1 RNA copies/mL) was 59% at baseline and increased to 87-100% during the trial; the CD4 count increased over time. One serious adverse event (gestational diabetes) was judged as possibly related to study medication. All 16 infants born to women remaining in the study at delivery were HIV-1 negative (two were premature). CONCLUSIONS: Total darunavir exposure decreased during pregnancy, but the decrease was less for unbound (active) darunavir. These changes are not considered clinically relevant. Darunavir/ritonavir 800/100 mg qd may therefore be a treatment option for HIV-1-infected pregnant women.

In vitro antimicrobial activity of crude ethanol extracts and fractions of Terminalia catappa and Vitex doniana.

BACKGROUND: The spread of microorganisms resistant to some antimicrobial agents necessitates the need to search for novel and effective antimicrobial agents. In this study, the antimicrobial activity of Terminalid catappa Linn. (Combretaceae) and Vitex doniana Sweet. (Verbenaceae), two Nigerian medicinal plants used in folk medicines for the management of various ailments related to microbial infections were evaluated. OBJECTIVES: To evaluate the antimicrobial activity of the crude ethanol extracts and fractions of the leaves and stem bark of T. catappa and V. doniana. METHODOLOGY: Four crude ethanol extracts and 16 (n-hexane, ethylacetate, n-butanol and aqueous) fractions of leaves and stem bark of T. catappa and V doniana were evaluated for in vitro antimicrobial activity against fifteen (15) strains of bacteria and fungi. The antimicrobial activity was determined in a 96-well plate using a resazurin based broth microdilution method. Two standard antimicrobial drugs ampicillin and nystatin were included as positive control. RESULTS: The butanoL fraction of stem bark of T. catappa and ethanol crude extract of leaf of V don iana displayed the highest antibacterial activity with similar minimum inhibitory concentration (MIC) value of 93.75 microg/mL against S. aureus and B. subtilis. Furthermore, the ethyl acetate fraction of stem bark of T. catappa showed the highest antifungal activity with MIC of 187.5 microg/mL against A. sydowi. Amp icillin had MIC of 15.6 and 31.3 microg/mL against S. aureus and B. subtili, respectively while nystatin produced MIC of 3.9 microg/mL against A. sydowi. CONCLUSION: Termninalia catappa and Vitex doniana may serve as useful sources of plant derived antimicrobial agents.

Total and unbound darunavir pharmacokinetics in pregnant women infected with HIV-1: results of a study of darunavir/ritonavir 600/100 mg administered twice daily.

OBJECTIVES: Antiretroviral therapy during pregnancy is recommended to reduce the risk of mother-to-child transmission of HIV and for maternal care management. Physiological changes during pregnancy can affect pharmacokinetics, potentially altering pharmacological activity. We therefore evaluated the pharmacokinetics of twice-daily (bid) darunavir in HIV-1-infected pregnant women. METHODS: HIV-1-infected pregnant women receiving an antiretroviral regimen containing darunavir/ritonavir 600/100 mg bid were enrolled in this study. Total and unbound darunavir and total ritonavir plasma concentrations were obtained over 12 h during the second and third trimesters and postpartum. Total darunavir and ritonavir plasma concentrations were determined using a validated high-performance liquid chromatography tandem mass spectrometry assay and unbound darunavir was determined using (14) C-darunavir-fortified plasma. Pharmacokinetic parameters were derived using noncompartmental analysis. RESULTS: Data were available for 14 women. The area under the plasma concentration-time curve from 0 to 12 h (AUC12h) for total darunavir was 17-24% lower during pregnancy than postpartum. The AUC12h for unbound darunavir was minimally reduced during pregnancy vs. postpartum. The minimum plasma concentration (Cmin) of total and unbound darunavir was on average 43-86% and 10-14% higher, respectively, during pregnancy vs. postpartum. The antiviral response (< 50 HIV-1 RNA copies/mL) was 33% at baseline and increased to 73-90% during treatment; the percentage CD4 count increased over time. One serious adverse event was reported (increased transaminase). All 12 infants born to women remaining in the study at delivery were HIV-1-negative; four of these infants were premature. CONCLUSIONS: Total darunavir exposure decreased during pregnancy. No clinically relevant change in unbound (active) darunavir occurred during pregnancy, suggesting that no dose adjustment is required for darunavir/ritonavir 600/100 mg bid in pregnant women.

Inhibitory activities of selected south west Nigerian medicinal plants against mycobacterium tuberculosis.

INTRODUCTION: Tuberculosis (TB), an infectious disease prevalent in the tropics especially in Africa and Asia is one of the highest causes of morbidity and mortality and a global concern. With increasing resistance of the pathogen, to existing antituberculosis drugs and the synergy between TB infection and acquired immune deficiency syndrome (AIDS), the need for development of new drugs to cope with the infection is urgent. OBJECTIVE: Extracts from 16 plants identified and selected from the ethnomedicine of the Ijebus in Southwestern Nigeria as remedies for tuberculosis were evaluated for activity against Mycobacterium tuberculosis, in vitro. METHODOLOGY: Plant extracts were screened against clinical isolate of Mycobacterium tuberculosis using agar plate method on Middlebrook 7H11 medium and observed for 12 weeks. RESULTS: The crude aqueous methanol extracts. showed varying degrees of activity at concentrations of 0.025 - 100 mg/mL. Ocimum grattisimum (leaf) demonstrated the highest activity with minimum inhibitory concentration (MIC) of 0.025 mg/mL. Two standard anti-tuberculosis drugs; rifampicin and isoniazid, included in the assay had MIC values of 0.01 mg/mL and 0.0005 mg/mL, respectively. CONCLUSION: The results of the study confirm the ethnopharmacological uses of some of the plants for TB indicating their potential as sources for the discovery of anti-tuberculosis drugs.

Safety and exposure of once-daily ritonavir-boosted atazanavir in HIV-infected pregnant women.

OBJECTIVE: There are limited antiretroviral options for use in the treatment of HIV infection during pregnancy. The purpose of this study was to assess the safety, efficacy and appropriate dosing regimen for ritonavir (RTV)-boosted atazanavir in HIV-1-infected pregnant women. METHODS: In this nonrandomized, open-label study, HIV-infected pregnant women were dosed with either 300/100 mg (n=20) or 400/100 mg (n=21) atazanavir/RTV once-daily (qd) in combination with zidovudine (300 mg) and lamivudine (150 mg) twice daily in the third trimester. Pharmacokinetic parameters [maximum observed plasma concentration (C(max) ), trough observed plasma concentration 24 hour post dose (C(min) ) and area under concentration-time curve in one dosing interval (AUC(τ) )] were determined and compared with historical values (300/100 mg atazanavir/RTV) for HIV-infected nonpregnant adults (n=23). RESULTS: At or before delivery, all mothers achieved HIV RNA <50 HIV-1 RNA copies/mL and all infants were HIV DNA negative at 6 months of age. The third trimester AUC(τ) for atazanavir/RTV 300/100 mg was 21% lower than historical data, but the C(min) values were comparable. The C(min) value for atazanavir/RTV 400/100 mg was 39% higher than the C(min) for atazanavir/RTV 300/100 mg in historical controls, but the AUC(τ) values were comparable. Twice as many patients in the 400/100 mg group (62%) had an increase in total bilirubin (>2.5 times the upper limit of normal) as in the 300/100 mg group (30%). Atazanavir (ATV) was well tolerated with no unanticipated adverse events. CONCLUSIONS: In this study, use of atazanavir/RTV 300/100 mg qd produced C(min) comparable to historical data in nonpregnant HIV-infected adults. When used in combination with zidovudine/lamivudine, it suppressed HIV RNA in all mothers and prevented mother-to-child transmission of HIV-1 infection. During pregnancy, the pharmacokinetics, safety and efficacy demonstrated that a dose adjustment is not required for ATV.

Cerebral phaeohyphomycosis due to a novel species: report of a case and review of the literature.

Cerebral phaeohyphomycosis is a rare disease caused by dematiaceous (darkly pigmented) fungi. Cladophialophora species are highly neurotropic, and Cladophialophora bantiana (synonym=Xylohypha bantiana or C. trichoides) is the most commonly identified agent. Most reported cases of cerebral phaeohyphomycosis have occurred in immunocompetent patients; however, some case reports and experimental data have suggested that cellular immune deficiency is a risk factor. We report a case of pulmonary and cerebral phaeohyphomycosis in a cardiac transplant patient due to a newly identified species of Cladophialophora. Optimal management includes both antifungal therapy and surgery.

Gram-Positive Pneumonia.

Gram-positive pneumonia is a leading cause of morbidity and mortality throughout the world. Of the gram-positive pathogens that cause pneumonia, Streptococcus pneumoniae and Staphylococcus aureus are the most common. The diagnosis of gram-positive pneumonia remains less than satisfactory, and newer diagnostic techniques such as antibody- and polymerase chain reaction-based antigen detection have yet to prove themselves. Drug resistance among gram-positive organisms is now endemic throughout the world and remains a serious therapeutic problem despite the availability of new antimicrobials. Efforts to control the spread of resistant strains include, in the case of S. aureus, stringent isolation policies and topical treatment to reduce carriage and, for S. pneumoniae, increased use of available vaccines and the develop- ment of more immunogenic vaccines.