The Safety, Effectiveness and Concentrations of Adjusted Lopinavir/Ritonavir in HIV-Infected Adults on Rifampicin-Based Antitubercular Therapy

Rifampicin co-administration dramatically reduces plasma lopinavir concentrations. Studies in healthy volunteers and HIV-infected patients showed that doubling the dose of lopinavir/ritonavir (LPV/r) or adding additional ritonavir offsets this interaction. However, high rates of hepatotoxicity were observed in healthy volunteers. We evaluated the safety, effectiveness and pre-dose concentrations of adjusted doses of LPV/r in HIV infected adults treated with rifampicin-based tuberculosis treatment.Adult patients on a LPV/r-based antiretroviral regimen and rifampicin-based tuberculosis therapy were enrolled. Doubled doses of LPV/r or an additional 300 mg of ritonavir were used to overcome the inducing effect of rifampicin. Steady-state lopinavir pre-dose concentrations were evaluated every second month.18 patients were enrolled with a total of 79 patient months of observation. 11/18 patients were followed up until tuberculosis treatment completion. During tuberculosis treatment, the median (IQR) pre-dose lopinavir concentration was 6.8 (1.1-9.2) mg/L and 36/47 (77%) were above the recommended trough concentration of 1 mg/L. Treatment was generally well tolerated with no grade 3 or 4 toxicity: 8 patients developed grade 1 or 2 transaminase elevation, 1 patient defaulted additional ritonavir due to nausea and 1 patient developed diarrhea requiring dose reduction. Viral loads after tuberculosis treatment were available for 11 patients and 10 were undetectable.Once established on treatment, adjusted doses of LPV/r co-administered with rifampicin-based tuberculosis treatment were tolerated and LPV pre-dose concentrations were adequate

Antiretroviral Therapy Outcomes in HIV-Infected Children after Adjusting Protease Inhibitor Dosing during Tuberculosis Treatment

Modification of ritonavir-boosted lopinavir (LPV/r)-based antiretroviral therapy is required for HIV-infected children co-treated for tuberculosis (TB). We aimed to determine virologic and toxicity outcomes among TB/HIV co-treated children with the following modifications to their antiretroviral therapy (ART): (1) super-boosted LPV/r, (2) double-dose LPV/r or (3) ritonavir.A medical record review was conducted at two clinical sites in Johannesburg, South Africa. The records of children 6-24 months of age initiating LPV/r-based therapy were reviewed. Children co-treated for TB were categorized based on the modifications made to their ART regimen and were compared to children of the same age at each site not treated for TB. Included are 526 children, 294 (56%) co-treated for TB. All co-treated children had more severe HIV disease, including lower CD4 percents and worse growth indicators, than comparisons. Children in the super-boosted group (n = 156) were as likely to be virally suppressed (<400 copies/ml) at 6 months as comparisons (69.2% vs. 74.8%, p = 0.36). Children in the double-dose (n = 47) and ritonavir groups (n = 91) were significantly less likely to be virally suppressed at 6 months (53.1% and 49.3%) than comparisons (74.8% and 82.1%; p = 0.02 and p<0.0001, respectively). At 12 months only children in the ritonavir group still had lower rates of virological suppression relative to comparisons (63.9% vs 83.3% p<0.05). Grade 1 or greater ALT elevations were more common in the super-boosted (75%) than double-dose (54.6%) or ritonavir (33.9%) groups (p = 0.09 and p<0.0001) but grade 3/4 elevations were observed in 3 (13.6%) of the super-boosted, 7 (15.9%) of the double-dose and 5 (8.9%) of the ritonavir group (p = 0.81 and p = 0.29).Good short-term virologic outcomes were achieved in children co-treated for TB and HIV who received super-boosted LPV/r. Treatment limiting toxicity was rare. Strategies for increased dosing of LPV/r with TB treatment warrant further investigation

Ertapenem for osteoarticular infections in obese patients: a pharmacokinetic study of plasma and bone concentrations

Purpose: Ertapenem is used off-label to treat osteoarticular infections but there are few pharmacokinetic (PK) data to guide optimal dosing strategies in patients who may be obese with multiple co-morbidities including diabetes and peripheral vascular disease. Methods: Participants undergoing lower limb amputation or elective joint arthroplasty received a dose of intravenous ertapenem prior to surgery. Eight plasma samples were collected over 24 h, together with at least one bone sample per patient. Ertapenem concentrations in plasma and bone were measured using liquid-chromatography/mass-spectroscopy and analysed using non-linear mixed effects PK modelling. Results: Plasma and bone concentrations were obtained from 10 participants. The final population PK model showed that a fat free body mass was the most appropriate body size adjustment. Ertapenem diffused rapidly into bone but concentrations throughout the 24 h dosing period were on average 40-fold higher in plasma, corresponding to a bone to plasma ratio of 0.025, and highly variable between individuals. Simulations demonstrated a high probability of target attainment (PTA) for free plasma concentrations when the minimum inhibitory concentrations (MIC) were = 0.25 mg/L. By contrast, at MICs of 0.5 mg/L and = 1 mg/L, the fractions of patients attaining this target was ~ 80% and 40%, respectively. In bone, the PTA was = 45% when the MIC was = 0.25 mg/L. Conclusion: Local bone and free plasma concentrations appear adequate for osteoarticular infections where Enterobacteriaceae are the main causative pathogens, but for Staphylococcus aureus and other bacteria, conventional dosing may lead to inadequate PTA

Management of HIV-associated tuberculosis in resource-limited settings: a state-of-the-art review.

The HIV-associated tuberculosis (TB) epidemic remains a huge challenge to public health in resource-limited settings. Reducing the nearly 0.5 million deaths that result each year has been identified as a key priority. Major progress has been made over the past 10 years in defining appropriate strategies and policy guidelines for early diagnosis and effective case management. Ascertainment of cases has been improved through a twofold strategy of provider-initiated HIV testing and counseling in TB patients and intensified TB case finding among those living with HIV. Outcomes of rifampicin-based TB treatment are greatly enhanced by concurrent co-trimoxazole prophylaxis and antiretroviral therapy (ART). ART reduces mortality across a spectrum of CD4 counts and randomized controlled trials have defined the optimum time to start ART. Good outcomes can be achieved when combining TB treatment with first-line ART, but use with second-line ART remains challenging due to pharmacokinetic drug interactions and cotoxicity. We review the frequency and spectrum of adverse drug reactions and immune reconstitution inflammatory syndrome (IRIS) resulting from combined treatment, and highlight the challenges of managing HIV-associated drug-resistant TB