Drug-drug interactions between COVID-19 therapeutics and antiretroviral treatment: the evidence to date.

INTRODUCTION: With new effective treatments for SARS-CoV-2, patient outcomes have greatly improved. However, new medications bring a risk of drug interactions with other medications. People living with HIV (PLWH) are at particular risk for these interactions due to heightened risk of immunosuppression, polypharmacy, and overlap in affected organs. It is critical to identify drug interactions are a significant barrier to care for PLWH. Establishing a better understanding of the pharmacologic relationships between COVID-19 therapies and antiretrovirals will improve patient-centered care in COVID-19. AREAS COVERED: Potential drug-drug interactions between Human Immunodeficiency Virus (HIV) and COVID-19 treatments are detailed and reviewed here. The mechanisms seen in these interactions include alterations in metabolic enzymes, drug transporters, pharmacoenhancement, and organ toxicities. We also review the limitations and solutions that can be used to combat drug-drug interactions between these two disease states. EXPERT OPINION: While current drug interactions are relatively mild between HIV and COVID-19 therapies, improvements in identifying these beforehand must take place as new therapies are approved. Antiretroviral therapy (ART) is essential in PLWH and must be maintained when treating COVID-19. As advancements in care occur, there is the possibility that newly approved drugs may have additional unknown interactions.

Expanding therapeutic options: lenacapavir + bictegravir as a potential treatment for HIV.

INTRODUCTION: Treatment for people with HIV/AIDS has radically evolved since the introduction of the first antiretrovirals. One newly approved antiretroviral is lenacapavir, which targets the viral capsid. Lenacapavir is currently approved as a therapeutic addition for subjects who are treatment-experienced, and who have developed resistance to multiple antiretrovirals. It is available both as a daily oral tablet and a once every 6-month subcutaneous injection. It is currently undergoing clinical trials in combination with the integrase inhibitor bictegravir as a dual therapy option, both for treatment experienced and treatment naïve individuals. AREAS COVERED: We reviewed published articles, conference proceedings, and clinical trial databases to assess the current status of the research into lenacapavir and bictegravir. While the clinical trials are ongoing, with little published data to date, this combination shows promise for the treatment of both treatment experienced and naïve patients. We review the studies relevant to the pharmacokinetic/pharmacodynamic properties of the drugs. EXPERT OPINION: The new combination with bictegravir will be beneficial for treatment experienced patients, as it represents a dual therapy modality with high barriers of resistance. As a therapy for treatment naïve patients, its use is likely more niche, as other combinations are available.

Senescent macrophages alter fibroblast fibrogenesis in response to SARS-CoV-2 infection.

SARS-CoV-2 has, since its emergence in 2019, become a global pandemic. Disease outcomes are worsened in older patients who are infected. The causes for this is multifactorial, but one potential cause for this disparity is increased rates of cellular senescence in older individuals, particularly in immune cells. Cellular senescence, the accumulation of factors resulting in cell growth arrest and apoptosis resistance, increases as individuals age. In immune cells, senescence is associated with increased inflammation, and alterations in immune response. We utilized a co-culture system consisting of senescent or non-senescent macrophages directly cultured with fibroblasts, and infected with SARS-CoV-2. We assessed the expression of collagen and fibronectin, important molecules in the extracellular matrix, as well as a number of fibrogenic factors. We observed that infection with SARS-CoV-2 induced collagen production in co-cultures with senescent, but not non-senescent macrophages. Fibronectin expression was decreased in both co-culture conditions. While significant results were not observed, concentrations of other fibrogenic molecules were consistent with the collagen results. These data demonstrate that senescence in macrophages alters the production of fibrotic molecules from fibroblasts in a SARS-CoV-2 infection model. As collagen and fibronectin expression are generally directly correlated, this suggests that senescence dysregulates fibrogenesis in response to infection with SARS-CoV-2. There is a need to further investigate the mechanisms for these changes.

An evaluation of long-acting cabotegravir + rilpivirine for the treatment of virologically suppressed adults living with HIV.

INTRODUCTION: HIV is a global disease that has seen significant improvements in care over the past decades. Despite improvements, treatments for maintaining suppression are complex for patients and include two to three oral medications. The approval of intramuscular cabotegravir (CAB) and rilpivirine (RPV) offers a new therapeutic modality with the opportunity of a longer dosing frequency. The data from recent trials including FLAIR and ATLAS have shown non-inferiority in treatment based on the current standard of care. This approval has the potential to simplify patient medication regimens, while maintaining virologic suppression in HIV-1 patients. AREAS COVERED: Cabotegravir + rilpivirine's recent approval for the treatment of HIV and its significant impact it may have on people living with HIV. EXPERT OPINION: Cabotegravir + rilpivirine is a long-acting injectable that can be used for patients who want to reduce the frequency antiretroviral administration. CAB+RPV allows for virologic suppression with monthly or less often administration, but comes with a significant price point, although injection site reactions may limit utility for many patients.

The Importance of Tissue Sanctuaries and Cellular Reservoirs of HIV-1.

PURPOSE OF REVIEW: There have been significant developments in the treatment of people living with HIV-1/AIDS with current antiretroviral therapies; however, these developments have not been able to achieve a functional or sterilizing cure for HIV-1. While there are multiple barriers, one such barrier is the existence of pharmacological sanctuaries and viral reservoirs where the concentration of antiretrovirals is suboptimal, which includes the gut-associated lymphoid tissue, central nervous system, lymph nodes, and myeloid cells. This review will focus on illustrating the significance of these sanctuaries, specific barriers to optimal antiretroviral concentrations in each of these sites, and potential strategies to overcome these barriers. RECENT FINDINGS: Research and studies have shown that a uniform antiretroviral distribution is not achieved with current therapies. This may allow low-level replication associated with low antiretroviral concentrations in these sanctuaries/reservoirs. Many methods are being investigated to increase antiretroviral concentrations in these sites, such as blocking transporting enzymes functions, modulating transporter expression and nanoformulations of current antiretrovirals. While these methods have been shown to increase antiretroviral concentrations in the sanctuaries/reservoirs, no functional or sterilizing cure has been achieved due to these approaches. SUMMARY: New methods of increasing antiretroviral concentrations at the specific sites of HIV-1 replication has the potential to target cellular reservoirs. In order to optimize antiretroviral distribution into viral sanctuaries/reservoirs, additional research is needed.

An evaluation of ledipasvir + sofosbuvir for the treatment of chronic hepatitis C infection.

Introduction: Hepatitis C (HCV) is viral disease with a global impact. Over the last 10 years, the treatment of this disease has evolved. Treatment guidelines have evolved to adopt new medications for HCV. These drugs have shown efficacy over 90% throughout the class as well as a better safety profile than the previous recommended pharmacotherapy. Dual-therapy DAAs emerged with FDA approval of Ledipasvir/Sofosbuvir (LDV/SOF) in 2014.Areas Covered: LDV/SOF is a dual-therapy option for chronic HCV patients (>6 months of infection) in select genotypes. This article reviews the studies relevant to the pharmacokinetic/pharmacodynamic properties of these drugs as well as its trials leading to approval.Expert opinion: LDV/SOF is included in the AASLD/IDSA guidelines for the treatment of HCV genotypes 1a and 1b with or without cirrhosis and genotype 4 without cirrhosis with an evidence and recommendation rating of IA. Genotype 4 with cirrhosis and genotypes 5 and 6 carry a Class IIa level B recommendation. The combination is not FDA approved for genotypes 2 and 3. Single-pill regimens, like LDV/SOF, are important to maintain the quality of life of children and other special populations infected with HCV by shortening treatment regimens, avoiding complex pill regimens, and eliminating injection therapies.

Extracellular Vesicles in Viral Replication and Pathogenesis and Their Potential Role in Therapeutic Intervention.

Extracellular vesicles (EVs) have shown their potential as a carrier of molecular information, and they have been involved in physiological functions and diseases caused by viral infections. Virus-infected cells secrete various lipid-bound vesicles, including endosome pathway-derived exosomes and microvesicles/microparticles that are released from the plasma membrane. They are released via a direct outward budding and fission of plasma membrane blebs into the extracellular space to either facilitate virus propagation or regulate the immune responses. Moreover, EVs generated by virus-infected cells can incorporate virulence factors including viral protein and viral genetic material, and thus can resemble noninfectious viruses. Interactions of EVs with recipient cells have been shown to activate signaling pathways that may contribute to a sustained cellular response towards viral infections. EVs, by utilizing a complex set of cargos, can play a regulatory role in viral infection, both by facilitating and suppressing the infection. EV-based antiviral and antiretroviral drug delivery approaches provide an opportunity for targeted drug delivery. In this review, we summarize the literature on EVs, their associated involvement in transmission in viral infections, and potential therapeutic implications.

Are heart-lung transplant recipients protected from developing bronchiolitis obliterans syndrome?

BACKGROUND: Heart-lung transplant recipients, when compared with heart transplant recipients, are relatively spared from allograft coronary artery disease. This study was undertaken to investigate whether heart-lung transplant recipients are also spared from experiencing bronchiolitis obliterans syndrome (BOS) when compared with double-lung transplant recipients. In addition, the risk factors for developing BOS after lung transplantation were analyzed. METHODS: Heart-lung and bilateral sequential double-lung transplant recipients were reviewed retrospectively from 1990 to 2000 using the Stanford Transplant Database. The heart-lung transplant group consisted of 77 heart-lung transplant recipients and the double-lung transplant group consisted of 51 double-lung transplant recipients. The rates of BOS, survival, acute rejection, and cytomegalovirus infection at 1, 3, and 5 years were measured. RESULTS: There were no significant differences in patient demographics between the two groups. Rates of survival and acute rejection were similar in the two transplant groups. The incidence of cytomegalovirus infection was significantly higher in heart-lung transplant recipients. Freedom from BOS was similar in the two transplant groups. Risk factors for the development of BOS in the heart-lung and double-lung transplant recipients included male donor, younger recipient age, a diagnosis other than cystic fibrosis, nonuse of cardiopulmonary bypass, and the use of OKT3 induction therapy. CONCLUSIONS: Heart-lung transplant recipients exhibit BOS at a rate similar to double-lung transplant recipients. The immunoprotective effect the lung allograft presumably provides the heart is not reciprocated by the heart in preventing the development of BOS.

Lung transplantation: a decade of experience.

BACKGROUND: Over the past 3 decades, the field of lung transplantation has been refined. However, many barriers exist that limit long-term success. The purpose of this study was to review a single institution's long-term experience with single and double lung transplantation and to assess the effect of different immunosuppressive therapies on outcomes. METHODS: Lung transplant recipients, both single and double, were reviewed, retrospectively. Patients were divided into five groups: group I, all lung transplants (n = 127); group II, single lung transplants (n = 73); group III, double lung transplants (n = 54); group IV, OKT3 induction therapy recipients (n = 27); and group V, RATG induction therapy recipients (n = 100). Rates of survival, rejection, bronchiolitis obliterans syndrome (BOS) and infection were analyzed at 1, 3, and 5 years. RESULTS: There were no significant differences in survival, acute rejection rate, freedom from BOS, nor infection between single and double lung transplant recipients. Induction therapy with RATG (group V) was associated with significantly improved survival and freedom from acute rejection, BOS, and infection when compared to OKT3 induction therapy (group IV). CONCLUSIONS: An earlier impression that RATG is superior to OKT3 induction therapy has borne true in terms of overall survival and incidence of BOS, acute rejection and infection rates. Lung transplantation, using RATG induction therapy, remains an important modality for end-stage pulmonary disease.

Determinants of health utility in lung and heart-lung transplant recipients.

Bronchiolitis obliterans syndrome (BOS) is associated with poor health-related quality of life (HRQL) following lung and heart-lung transplantation, but few other determinants of HRQL have been described. We performed a cross-sectional study of standard gamble utility, a preference-based measure of HRQL, in 90 stable lung and heart-lung transplant recipients. We used bivariate analyses and multiple linear regression to evaluate associations between utility scores and candidate predictor variables including age, sex, indication for transplant (obstructive, interstitial, suppurative and pulmonary vascular diseases), transplant type (bilateral, single and heart-lung), time since transplant, body mass index, arterial PO(2), creatinine clearance, number of medications, presence of BOS and risk-attitude score. The median utility was 0.88 (inter-quartile range: 0.50-0.99). Multivariable analysis showed that female sex, absence of BOS, better renal function and longer time since transplantation were associated with higher utility scores, and that there were utility differences across diagnostic groups. Although BOS is a major determinant of utility following lung and heart-lung transplantation, other demographic and clinical factors are also associated with significant differences in this measure of HRQL.

Chylothorax after heart/lung transplantation.

Chylothorax is a potentially serious complication of lung and heart-lung transplantation. This article describes the clinical course of chylothorax in 3 heart-lung allograft recipients. We discuss management options, including dietary modifications, octreotide infusion, thoracic duct ligation and embolization, and surgical pleurodesis. In addition, we describe the novel use of aminocaproic acid to reduce lymph flow. We propose a multidisciplinary approach for the management of chylothorax that includes both medical and surgical options.

Gastric pacing for severe gastroparesis in a heart-lung transplant recipient.

Gastroparesis is a serious complication of lung and heart-lung transplantation that can lead to malnutrition, gastroesophageal reflux, aspiration pneumonia and deteriorating lung function. Some patients with severe gastroparesis have symptoms that are refractory to dietary modifications and gastric promotility agents and require surgery. We describe the successful use of gastric pacing for the management of intractable gastroparesis, malnutrition and recurrent aspiration in a heart-lung allograft recipient. Lung transplant recipients with severe gastroparesis may benefit from gastric pacing.

Matrix metalloproteinase inhibition decreases ischemia-reperfusion injury after lung transplantation.

Increased microvascular permeability and extravasation of inflammatory cells are key events of lung ischemia-reperfusion (IR) injury. The purpose of this study was to investigate the role of matrix metalloproteinases (MMP) in IR-induced alveolar capillary membrane disruption after experimental lung transplantation. We used a rat model of lung orthotopic transplantation (n = 86) with a prolonged cold ischemic phase. MMP2 and MMP9 were elevated 4 h after the onset of ischemia and further increased during reperfusion. Compared to sham values, the alveolar-capillary membrane permeability increased by 105% and 82.6% after 4 h of ischemia and 2 h or 24 h of reperfusion, respectively. A 4- and 5-fold increase of the infiltration of ischemic tissue by neutrophils was also observed after 2 h and 24 h of reperfusion. The PO2/FIO2 ratio dropped significantly from 244 to 76.6 after 2 h of reperfusion and from 296.4 to 127.6 after 24 h of reperfusion. A nonselective inhibitor of MMP, administered to the rats and added to the preservation solution, reduced significantly the alveolar-capillary leakage, the transmigration of neutrophils and improved gas exchanges in animals submitted to 4 h of ischemia combined with 2 h or 24 h of reperfusion. We conclude that inhibition of MMP attenuates IR injury after experimental lung transplantation.

Validity of standard gamble utilities as measured by transplant readiness in lung transplant candidates.

PURPOSE: To evaluate the validity of standard gamble (SG) utilities, by comparing utilities with decision-making behavior in a group of lung transplant candidates facing a risky health decision. METHODS: The authors elicited SG utilities for current health from 57 transplant candidates. They assessed the concordance between utility scores and patients' self-reported readiness to be placed on the transplant waiting list ("listed"). Because transplantation represents a real-life gamble with a short-term survival probability of 85%, the authors defined their minimum validity criterion as utility for current health < or = 0.85 in transplant-ready patients. RESULTS: Utilities were significantly higher in patients who were not ready for listing (n = 22, median utility = 0.79, range 0.06-1) than in those who were ready or listed (n = 35, median utility = 0.50, range 0-0.85, P < 0.00005). All transplant-ready patients had utilities < or = 0.85 for current health. CONCLUSIONS: Low SG utilities were associated with transplant readiness in this population of lung transplant candidates. These results provide one line of evidence supporting the validity of SG utilities as a measure of health-related quality of life, using the criterion of decision-making behavior.

Weight gain after lung transplantation.

BACKGROUND: Weight gain is frequently observed after lung transplantation, but the magnitude, predictors and implications of weight gain after lung transplant are unknown. METHODS: This retrospective cohort study included 826 lung transplant recipients randomly selected from 12 international transplant centers. We included adult patients with available weight data at baseline and 1 year post-transplant. We examined demographic and clinical predictors of first year weight gain using a multiple linear regression model (n = 579) with percent weight change as the dependent variable. To study the association between first year weight gain and subsequent survival, we performed a Cox proportional hazards analysis. p < 0.05 was considered statistically significant. RESULTS: The median weight change was 10% (range -32% to 84%). On multi-variate analysis, increasing age and prolonged mechanical ventilation were inversely associated with weight gain; obstructive disease, interstitial disease and increasing ischemic time were positively associated with weight gain. Increasing baseline weight was negatively associated with weight gain in patients with obstructive and interstitial disease. The model accounted for 14% of the variance in weight gain. Patients with weight gain above the median had better subsequent survival (adjusted hazard ratio 0.61, 95% confidence interval 0.41 to 0.90). Infection was a more common cause of death in these patients, whereas malignant deaths were more frequent in patients with below-median weight gain. CONCLUSIONS: Substantial weight gain occurs in the first year after lung transplantation. The predictors of weight gain may be used to target high-risk patients for early intervention. Higher weight gain is associated with better subsequent survival.

PG490-88, a derivative of triptolide, attenuates obliterative airway disease in a mouse heterotopic tracheal allograft model.

The current treatment of obliterative bronchiolitis in lung transplant recipients is sub-optimal. Triptolide is a novel immunosuppressant that has a mechanism of action distinct from currently available immunosuppressants, including induction of T-cell apoptosis, blockade of fibroblast proliferation/maturation and inhibition of transforming growth factor-beta (TGF-beta) mRNA production. We hypothesized that triptolide may be helpful in blocking obliterative airway disease in lung transplant recipients. We investigated the effect of PG490-88, a water-soluble derivative of triptolide, in a mouse heterotopic tracheal allograft model of obliterative airway disease. We show that PG490-88 attenuates airway obliteration in this model and inhibits accumulation of inflammatory cells, and therefore may have preventive or therapeutic benefits for patients with obliterative airway disease (OAD) following lung transplantation.

Oligoclonal CD4(+) T cell expansions in lung transplant recipients with obliterative bronchiolitis.

Obliterative bronchiolitis (OB) is a dreaded and frequent complication of lung transplantation with a poorly understood immunopathogenesis. To further evaluate disease mechanisms, we used T cell antigen receptor (TCR) beta-chain variable region RNase protection assays, after polymerase chain reaction amplification of TCR cDNA, to quantitate circulating CD4(+) and CD8(+) repertoires of transplant recipients with OB or no evidence of rejection (NER). All six recipients with OB had markedly abnormal CD4 expansions (2.5 +/- 0.5 expansions/recipient) attributable to oligoclonal proliferations. Only two of six recipients with NER had a single, much lesser, CD4(+) abnormality each (p < 0.01). Moreover, one of these patients developed OB shortly thereafter, and the other NER abnormality may have predated transplantation. In contrast, CD8(+) expansions were common in both recipient populations. Findings of CD4(+) expansions had 100% sensitivity and 80% specificity for the presence or imminent development of OB. These data suggest proliferations of CD4(+) T cells are important in OB pathogenesis, and these are most likely part of a major histocompatibility complex Class II-dependent process of indirect alloantigen presentation. These CD4(+) clones are likely to have facultative helper functions for the multiple and diverse immune processes that have been implicated in OB. Furthermore, the close association of CD4(+) expansions with OB raises possibilities of development of novel diagnostic and therapeutic approaches.