Complex dosing regimens, costs, side effects, biodistribution limitations, and variable drug pharmacokinetic patterns have affected the long-term efficacy of antiretroviral medicines. To address these problems, a nanoparticle indinavir (NP-IDV) formulation packaged into carrier bone marrow-derived macrophages (BMMs) was developed. Drug distribution and disease outcomes were assessed in immune-competent and human immunodeficiency virus type 1 (HIV-1)-infected humanized immune-deficient mice, respectively. In the former, NP-IDV formulation contained within BMMs was adoptively transferred. After a single administration, single-photon emission computed tomography, histology, and reverse-phase-high-performance liquid chromatography (RP-HPLC) demonstrated robust lung, liver, and spleen BMMs and drug distribution. Tissue and sera IDV levels were greater than or equal to 50 μM for 2 weeks. NP-IDV-BMMs administered to HIV-1-challenged humanized mice revealed reduced numbers of virus-infected cells in plasma, lymph nodes, spleen, liver, and lung, as well as, CD4+ T-cell protection. We conclude that a single dose of NP-IDV, using BMMs as a carrier, is effective and warrants consideration for human testing.

Antiretroviral therapy (ART) shows variable blood-brain barrier penetration. This may affect the development of neurological complications of HIV infection. In attempts to attenuate viral growth for the nervous system, cell-based nanoformulations were developed with the focus on improving drug pharmacokinetics. We reasoned that ART carriage could be facilitated within blood-borne macrophages traveling across the blood-brain barrier. To test this idea, an HIV-1 encephalitis (HIVE) rodent model was used where HIV-1-infected human monocyte-derived macrophages were stereotactically injected into the subcortex of severe combined immunodeficient mice. ART was prepared using indinavir (IDV) nanoparticles (NP, nanoART) loaded into murine bone marrow macrophages (BMM, IDV-NP-BMM) after ex vivo cultivation. IDV-NP-BMM was administered i.v. to mice resulting in continuous IDV release for 14 days. Rhodamine-labeled IDV-NP was readily observed in areas of HIVE and specifically in brain subregions with active astrogliosis, microgliosis, and neuronal loss. IDV-NP-BMM treatment led to robust IDV levels and reduced HIV-1 replication in HIVE brain regions. We conclude that nanoART targeting to diseased brain through macrophage carriage is possible and can be considered in developmental therapeutics for HIV-associated neurological disease.

Objective Infective endocarditis is associated with high morbidity and mortality and optimal timing for surgical intervention is unclear. We performed a systematic review and meta-analysis to compare early surgical intervention with conservative therapy in patients with infective endocarditis. Methods PubMed, Cochrane, EMBASE, CINAHL and Google-scholar databases were searched from January 1960 to April 2015. Randomised controlled trials, retrospective cohorts and prospective observational studies comparing outcomes between early surgery at 20 days or less and conservative management for infective endocarditis were analysed. Results A total of 21 studies were included. OR of all-cause mortality for early surgery was 0.61 (95% CI 0.50 to 0.74, p<0.001) in unmatched groups and 0.41 (95% CI 0.31 to 0.54, p<0.001) in the propensity-matched groups (matched for baseline variables). For patients who had surgical intervention at 7 days or less, OR of all-cause mortality was 0.61 (95% CI 0.39 to 0.96, p=0.034) and in those who had surgical intervention within 8–20 days, the OR of mortality was 0.64 (95% CI 0.48 to 0.86, p=0.003) compared with conservative management. In propensity-matched groups, the OR of mortality in patients with surgical intervention at 7 days or less was 0.30 (95% CI 0.16 to 0.54, p<0.001) and in the subgroup of patients who underwent surgery between 8 and 20 days was 0.51 (95% CI 0.35 to 0.72, p<0.001). There was no significant difference in in-hospital mortality, embolisation, heart failure and recurrence of endocarditis between the overall unmatched cohorts. Conclusion The results of our meta-analysis suggest that early surgical intervention is associated with significantly lower risk of mortality in patients with infective endocarditis.

Background: Human immunodeficiency virus type-1 (HIV-1) infection leads to acquired immunodeficiency syndrome (AIDS), a severe viral infection that has claimed approximately 658,507 lives in the US between the years 2010-2014. Antiretroviral (ARV) therapy has proven to inhibit HIV-1, but unlike other viral illness, not cure the infection. Objective: Among various Food and Drug Administration (FDA)-approved ARVs, nucleoside/ nucleotide reverse transcriptase inhibitors (NRTIs) are most effective in limiting HIV-1 infection. This review focuses on NRTIs mechanism of action and metabolism. Methods: A search of PubMed (1982-2016) was performed to capture relevant articles regarding NRTI pharmacology. Results: The current classical NRTIs pharmacology for HIV-1 prevention and treatment are presented. Finally, various novel strategies are proposed to improve the efficacy of NRTIs, which will increase therapeutic efficiency of present-day HIV-1 prevention/treatment regimen. Conclusion: Use of NRTIs will continue to be critical for successful treatment and prevention of HIV-1.

Combination antiretroviral (AR) therapy continues to be the mainstay for HIV treatment. However, antiretroviral drug nonadherence can lead to the development of resistance and treatment failure. We have designed nanoparticles (NP) that contain three AR drugs and characterized the size, shape, and surface charge. Additionally, we investigated the in vitro release of the AR drugs from the NP using peripheral blood mononuclear cells (PBMCs).