A historical cohort study in southern Iran investigated the effect of lopinavir-ritonavir treatment, with or without azithromycin and/or hydroxychloroquine, on QT interval prolongation in 500 confirmed COVID-19 patients. The outcomes showed a notable increase in the mean corrected QT interval post-treatment, specifically from 415.75±46.848 ms to 437.91±50.455 ms. QTc prolongation was observed only in patients receiving lopinavir-ritonavir monotherapy who also presented with cardiovascular conditions, angina pectoris, or hypomagnesemia, whereas those receiving concomitant therapy with azithromycin or hydroxychloroquine did not exhibit this effect. Other than one-third of patients with comorbidities or additional QT-prolonging drugs, aside from hypertension and obesity, had clinically the same potential of QT prolongation, and only 10.6% of patients had the problem. The work stresses the significance of careful monitoring of cardiac health, especially for those patients who have electrolyte imbalances and cardiovascular diseases as underlying diseases when they use lopinavir-ritonavir with other QT-prolonging medications.

Despite considerable progress in preventing mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV), eliminating paediatric HIV has not been achieved. Extended postnatal prophylaxis (ePNP), defined as prophylaxis administered to an HIV-exposed child after PMTCT perinatal prophylaxis ends, has been evaluated and is now proposed as an improved approach towards elimination. This approach should be urgently incorporated into international PMTCT recommendations. The antiretroviral drugs most commonly studied as ePNP, either alone or in combination, are lamivudine, nevirapine, lopinavir/ritonavir and zidovudine. In this study, we examined the efficacy, safety, pharmacology, genetic barrier to resistance and practicality of various ePNP regimens. Regimens combining multiple antiretroviral drugs are no more effective than single-drug regimens in terms of protective efficacy but they are associated with increased toxicity. On the basis of these criteria, we recommend lamivudine as the preferred ePNP drug or nevirapine as an alternative. Guided by maternal HIV viral load, ePNP may be particularly indicated, as it could ensure that the prophylaxis provides the greatest benefit/risk to children at highest risk. Long-acting injectable antiretroviral drugs and broadly neutralising antibodies (bNAbs) have yet to be fully evaluated in neonates, infants and children; however, they may offer new alternatives in the future.

Long-term impact of antiretroviral therapy (ART) on bone health in children living with HIV (CLWH) remains uncertain. We aimed to determine associations of change in bone mineral density (BMD) among CLWH in Uganda in a 2-year prospective sub-study in the CHAPAS-4 randomized trial (ISRCTN22964075). CLWH aged 3-15 years switched to second-line ART including tenofovir alafenamide fumarate-emtricitabine (TAF/FTC) or standard-of-care (SOC) (abacavir (ABC) or zidovudine (ZDV) with dolutegravir (DTG), atazanavir/ritonavir (ATV/r), darunavir/ritonavir (DRV/r) or lopinavir/ritonavir (LPV/r). BMD was assessed by dual-energy X-ray absorptiometry (DXA) at baseline, weeks 48 and 96 and bone turnover markers measured at baseline, week 24, 48, and 96. Robust regression analysis determined associations of BMD and bone turnover markers through week 96. Of 196 participants,167 contributed BMD measurements. Median (IQR) age was 9.9(7.0,12.3) years, 47% male, median (IQR) CD4 T-cell count 797(537,1140) cells/µl and mean (SD) viral load (log10 copies/ml) 4.3(0.8). Change in Procollagen type I N-terminal propeptide (PINP), C-terminal telopeptide of type I collagen (CTX) and height-adjusted (HA) BMD were similar between TAF/FTC and SOC. Greater declines in total-body-less-head (TBLH) BMD were associated with higher baseline TBLH (HA) BMD (Coef. -0.30,95% CI: -0.46, -0.15], p < 0.001) and first-line nevirapine (NVP) exposure (-0.25,95% CI: -0.43, -0.06, p = 0.009). Smaller TBLH HA BMD declines were associated with higher baseline fat-mass (0.06, 95% CI:0.01, 0.11, p = 0.021), higher lumbar spine (LS) HA BMD (0.17, 95% CI:0.03, 0.31, p = 0.015), DRV/r (0.46, p < 0.001,95% CI:0.21,0.71), DTG (0.26, p = 0.041,95% CI:0.01,0.51) or ATV/r (0.28, p = 0.026, 95% CI: 0.03, 0.52) use compared with LPV/r. Smaller declines in TBLH BMD were associated with higher baseline fat mass, higher LS HA BMD, and use of DRV/r, DTG, or ATV/r compared with LPV/r. These findings emphasize the importance of ART selection and body composition in supporting bone health among CLWH.

Nanotechnology has emerged as an innovative tool capable of overcoming the limitations of traditional drug delivery systems, by enabling enhanced drug solubility and stability, controlled drug release, and improved drug targeting. Additionally, nanosystems can allow the co-encapsulation of multiple drugs simultaneously, harnessing their synergistic pharmacological effects, leading to increased therapeutic efficacy and safety. The purpose of this review is to critically analyze studies that have developed triple drug-loaded nanosystems, exploring various different nanoplatforms, such as polymeric nanoparticles, lipid nanoparticles, microcapsules, nanoemulsions, nanoemulgels, thermosensitive hydrogels, and nanocomposite hydrogels. Triple drug co-encapsulation has been achieved for non-steroidal anti-inflammatory drugs such as indomethacin, analgesic and antipyretic drugs such as paracetamol, immunosuppressant drugs such as methotrexate, antiretroviral drugs such as efavirenz, lopinavir, ritonavir, and tenofovir, antibacterial drugs such as amoxicillin and clarithromycin, antiulcer drugs such as omeprazole and famotidine, ion channel antagonists such as lomerizine hydrochloride, oxidized adenosine triphosphate, and zonampanel monohydrate, photosensitive molecules such as indocyanine green, genetic material such as MMP-9 siRNA, enzymes such as catalase, and/or plant-derived bioactive compounds such as curcumin, resveratrol, sinomenine, and thymoquinone. These molecules' triple co-encapsulation into nanometric formulations has led to controlled and sustained drug release, extended circulation time, enhanced bioavailability, and reduced systemic toxicity, with an overall improvement in drug targeting and therapeutic outcomes in rheumatoid arthritis, psoriasis and other inflammation-based conditions, HIV and Helicobacter pylori infection, and trauma-induced central nervous system secondary degeneration, ultimately opening a door for improved patient compliance due to simplified dosing regimens.

The management of advanced HIV can be complicated by immune reconstitution inflammatory syndrome (IRIS) and cerebrospinal fluid (CSF) viral escape. We report a novel case of symptomatic CSF escape driven by a rare bictegravir resistance mutation, emerging after a severe unmasking IRIS event. A 61-year-old male patient with advanced HIV (clusters of differentiations 4+ T-cell count 31 cells/μl) initiated antiretroviral therapy with bictegravir/emtricitabine/tenofovir alafenamide. A total of 1 week later, he developed varicella-zoster virus-associated acute retinal necrosis, consistent with IRIS. Despite successful ocular treatment, he later developed progressive neurocognitive decline. Investigations confirmed CSF HIV escape (CSF HIV-RNA 7100 copies/ml; plasma 583 copies/ml). Resistance testing revealed an M184V mutation and, critically, an R263K mutation conferring resistance to integrase strand transfer inhibitors. His regimen was switched to zidovudine/lamivudine/lopinavir/ritonavir, leading to dramatic clinical improvement, undetectable CSF HIV-RNA, and reduced leptomeningeal enhancement on magnetic resonance imaging. To the best of our knowledge, this is the first reported case of symptomatic CSF escape with documented bictegravir resistance in a treatment-naïve, adherent patient. It demonstrates that sanctuary site-specific resistance can develop against key first-line regimens and highlights the need for a revised therapeutic strategy. CSF viral load quantification and resistance genotyping are essential in such scenarios to guide effective, personalized therapy.

The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative proposes integrating multi-cardiac ion channel pharmacology to improve the prediction of drug-induced Torsade de Pointes (TdP) risk. However, several studies under CiPA have demonstrated misalignment between nonclinical and clinical data. One study showed ECG changes induced by chloroquine, lopinavir, and ritonavir suggestive of CaV1.2 and NaV1.5 channel block. However, ion channel data used to design the clinical study showed no such interactions. Another study reported TdP cases in patients treated with vanoxerine, a drug with literature data demonstrating similar block potencies for hERG and CaV1.2 channels suggesting lower TdP risk than selective hERG blockers. Finally, astemizole, risperidone, and clarithromycin-"intermediate TdP risk" CiPA drugs-were reported to have hERG-active metabolites, yet hERG data for metabolites were not integrated when developing in silico human myocyte models for risk prediction. To increase the confidence of using nonclinical data in regulatory decision-making, the sources of these inconsistent nonclinical-clinical findings and data gap for metabolites need to be addressed. Here the effects of chloroquine, lopinavir, ritonavir, and vanoxerine on hERG, CaV1.2, and/or NaV1.5 channels were studied using protocols consistent with ICH S7B Q&A 2.1 best practices. hERG block potencies for astemizole, risperidone, clarithromycin plus their major metabolites were also determined. The results showed improved alignment between ion channel block profiles and drug-induced ECG changes and proarrhythmia, underscoring the importance of using physiologically relevant experimental protocols, accounting for ion channel-active metabolites, and continuing to build the knowledge base of arrhythmogenesis mechanisms. Data may be found at: https://osf.io/7rfua/.

In early 2020, no drug had proven efficacy to treat COVID-19 in-patients. This work aimed to describe COVID-19 treatment for in-patients worldwide until June, 2020. A PubMed search was performed with the terms "retrospective observational study", "hospital", "treatment" and "COVID" to identify English-written studies describing treatments given to adult in-patients before June 30, 2020. The identified reports were analyzed, with data extracted regarding patient characteristics and treatments across continents and countries. Overall, 178 studies involving 181,510 patients in 28 countries were analyzed, including 484 patients from Africa, 36,840 from Asia, 69,088 from Europa and 68,524 from North America. The most prescribed drugs were hydroxychloroquine (64.3%, i.e. 41.9% of all patients), corticosteroids (31.0%, i.e. 21.0%) and lopinavir/ritonavir (30.8%, i.e. 12.0%). Corticosteroids was used worldwide with similar rates in Asia, Europe and North America. Hydroxychloroquine dominated prescriptions in Africa, Europe and North America. Asia exhibited unique features: less frequent hydroxychloroquine use, higher oseltamivir use and exclusive use of umifenovir. In Europe, repurposed drugs prescription was the highest in Spain and Italy. Our study is not an exhaustive review of the literature on COVID-19 treatment of in-patients early in 2020 but is the first one to provide a comprehensive overview of COVID-19 treatment modalities in such a broad range of countries worldwide. Our work reveals high prescription rates but also heterogeneity across continents and countries in the treatment of COVID-19 in-patients worldwide. These findings emphasize the critical role of international collaboration in generating and disseminating reliable information for managing emerging diseases.

Lopinavir appears in breastmilk in low levels and can be found in the serum of some breastfed infants. Although lopinavir has been associated with impaired adrenal gland function when given directly to infants, the effect is dose related.[1] No adverse infant effects have been clearly caused by the small amounts of lopinavir in breastmilk. Achieving and maintaining viral suppression with antiretroviral therapy decreases breastfeeding transmission risk to less than 1%, but not zero. Individuals with HIV who are on antiretroviral therapy with a sustained undetectable viral load and who choose to breastfeed should be supported in this decision. If a viral load is not suppressed, banked pasteurized donor milk or formula is recommended.[2,3] Extended postnatal prophylaxis of breastfed infants with the lopinavir-ritonavir combination should continue until breastfeeding is stopped.[4]