Hepatitis C and cigarette smoking behavior: Themes from focus groups.

INTRODUCTION: People with chronic hepatitis C virus (HCV; PWHC) use cigarettes at a much higher prevalence than other individuals, and smoking can exacerbate the harms specifically related to HCV (e.g., hepatocellular carcinoma). Little is known about factors related to cigarette use among PWHC. This study examined focus group data to explore beliefs and behaviors related to cigarette use among PWHC. METHODS: Qualitative data from two focus groups of PWHC reporting current cigarette smoking (n=15, 60% male) were collected using a semi-structured interview guide. Participants were asked about reasons for smoking, barriers to quitting smoking, and the relationship of HCV to smoking. Focus groups were transcribed verbatim and coded in NVivo 12. Four coders examined themes that arose in the focus groups. Common themes are described and supported with quotes. RESULTS: Reasons for smoking included addiction to cigarettes, stress, substituting cigarettes for other drugs, and social norms, while reasons for quitting included health and being free from the use of all drugs. Barriers to quitting included concerns about coping with stress, weight gain, and having a lack of support for and education about quitting. Many participants believed there was a link between smoking and HCV and discussed smoking in relation to the stress of an HCV diagnosis. CONCLUSIONS: Participants identified both HCV-related and non-HCV-related aspects of cigarette smoking and cessation-related behaviors that could be targeted in cessation treatment. More research is needed to identify the best treatment approaches that reduce the significant medical consequences of cigarette use among PWHC. IMPLICATIONS: People with chronic hepatitis C virus (HCV; PWHC) smoke cigarettes at a high prevalence, yet little is known about their smoking behaviors. Moreover, there are no cessation treatments targeting PWHC. This is the first study to collect focus group data from PWHC who smoke in order to identify reasons for cigarette use (HCV-related and non-HCV-related), and motivators and barriers to quitting cigarettes. PWHC report using cigarettes to cope with the stress of an HCV diagnosis and to celebrate HCV cure. These findings suggest there are specific times during the HCV care continuum where providers can aid with cessation efforts.

Impact of reduced restrictions on buprenorphine prescribing during COVID-19 among patients in a community-based treatment program.

Background: Medications such as buprenorphine are considered the gold standard for the treatment of opioid use disorders. This study aimed to determine whether less restrictive buprenorphine prescribing practices during the COVID-19 pandemic impacted retention in and adherence to buprenorphine among patients accessing treatment from 2018-2020 at a community-based syringe services program. Methods: In this retrospective cohort study, we compared retention in treatment before and during the COVID-19 pandemic. Then, with relaxed restrictions acting as the intervention in a natural experiment, we conducted a sub-analysis of "continuity participants" who accessed treatment services both before and during the COVID-19 period. Records of 418 historical control patients treated with buprenorphine before COVID-19 were compared to 88 patients enrolled during COVID-19 (n=43 remote telemedicine and n=45 remote provider with patient on-site). Cox proportional hazards regressions were used to assess risk factors for treatment discontinuation. The sub-analysis used proportion of days covered (PDC) differences before and during COVID-19 (n=164) for a paired analysis in a nonparametric bootstrap test. Results: The risk of discontinuation was 71% lower in those accessing remote telemedicine during COVID-19 (HR=0.29; CI: 0.18, 0.47) and 51% lower in those accessing their remote provider onsite during COVID-19 (HR=0.49; CI:0.31, 0.77), compared to the historical control group. The average PDC did not significantly differ before and during COVID-19 (difference=2.4%; CI:-0.6%, 5.3%). Conclusions: The risk of discontinuing treatment was lower in both COVID-19 treatment groups compared to historical controls. Less restrictive buprenorphine prescribing guidelines during COVID-19 led to improved retention in care over 6-months.

Nonadherence to Ledipasvir/Sofosbuvir Did Not Predict Sustained Virologic Response in a Randomized Controlled Trial of Human Immunodeficiency Virus/Hepatitis C Virus Coinfected Persons Who Use Drugs.

BACKGROUND: Eliminating hepatitis C virus (HCV) will require effective treatment delivery to persons with substance use disorders (SUDs). We evaluated the relationship between ledipasvir/sofosbuvir treatment persistence (receiving 84 tablets), adherence, and sustained virologic response (SVR) in persons with human immunodeficiency virus (HIV)/HCV coinfection. METHODS: Of the 144 participants with HIV/HCV and SUDs, 110 initiated a 12-week treatment course under 1 of 3 conditions (usual care, peer mentors, and cash incentives). We used self-report, pharmacy pill counts, and expected date of refill to examine adherence. Persistent participants were categorized as high adherence (taking ≥90% of doses) or low adherence (taking <90% of doses). RESULTS: Most participants persisted on treatment after initiation (n = 105), with 95% (n = 100) achieving SVR. One third (34%) of participants had moderate/heavy alcohol use by the biomarker phosphatidylethanol ([Peth] ≥50 ng/mL), and 44% had urine toxicology positive for cocaine or heroin at enrollment. The proportion of persons with high adherence was 72% (n = 76), and the proportion of persons with low adherence was 28%. Although low adherence was associated with moderate/heavy alcohol use by PEth (relative risk = 2.77; 95% confidence interval, 1.50-5.12), SVR did not vary according to adherence (P = .702), and most participants (97%) with low adherence achieved SVR. CONCLUSIONS: Treatment persistence led to high SVR rates among persons with HIV/HCV, despite imperfect adherence and SUDs.

Prevalence and Correlates of Syringe Disposal Box Use in a Philadelphia Neighborhood with High Levels of Public Drug Injection.

Background: Philadelphia (Pennsylvania, USA) is facing an unprecedented public health crisis due to fentanyl use. To combat drug-related litter, the Philadelphia Department of Public Health installed 7 public syringe disposal boxes (SDB) in Kensington, the neighborhood most impacted by the opioid crisis and home to a syringe exchange. Methods: We used street- and business-intercepts to recruit residents (N=358) and business owners/staff (N=78) who completed a brief survey with two binary items measuring observing and using SDB. Multivariable logistic regression was used to assess factors independently associated with SDB observance and use. Results: 78% (340/436) observed SDB and 34.1% (116/340) had ever used SDB among those who had seen them. Unstably housed persons had 4.3 times greater odds of observing SDB (Adjusted odds ratio [aOR= 4.29; 95% confidence interval [CI]: 1.56, 11.82) and had 2.5 times greater odds of using SDB (aOR = 2.51; 95% CI: 1.33, 4.74) as did people who use opioids (aOR = 2.61; 95% CI: 1.45, 4.72). Among individuals reporting opioid use who also saw SDB (n=123), those who were unstably housed were more likely to use SDB than those with stable housing (67.8% vs 45.3%, p=.012). Conclusion: These results suggest Kensington residents, especially those who are unstably housed, use SDB once they see them in the neighborhood.

Impact of Co-occurring Drug Use, Hazardous Alcohol Use, and Mental Health Disorders on Drug Use Patterns in People With HIV and Hepatitis C Virus Infection.

Drug use, hazardous alcohol use, and mental health disorders are prevalent among people with HIV and hepatitis C virus (HCV) infection. Co-occurrence of alcohol use and depression negatively impacts substance use patterns. Nevertheless, HCV treatment provides a promising opportunity to identify and address co-occurring drug use, hazardous alcohol use, and mental health disorders.

Perceptions of network based recruitment for hepatitis C testing and treatment among persons who inject drugs: a qualitative exploration.

BACKGROUND: Social network interventions that take advantage of existing individual and group relationships may help overcome the significant patient, provider, and system level barriers that contribute to low hepatitis C Virus (HCV) treatment uptake among people who inject drugs (PWID). METHODS: We conducted semi-structured interviews with 20 HCV antibody positive PWID (15 male, 5 female) in Baltimore, Maryland, USA. We utilized thematic analysis and employed both inductive and deductive coding techniques to assess perceptions of barriers and facilitators of social network interventions for HCV testing, linkage to care, and treatment among PWID. RESULTS: PWID perceived a high prevalence of HCV within their social networks, especially within injection drug use networks. Overwhelmingly, participants reported a willingness to discuss HCV and provide informational, instrumental, and emotional support to their network members. Support included sharing knowledge, such as where and how to access HCV care, as well as sharing lived experiences about HCV treatment that could help peers build trust within networks. Participants who were already linked into HCV care had an increased understanding of using social network interventions to provide peer navigation, by accompanying network members to HCV related appointments. Across interviews, drug use related stigma and feeling undeserving of HCV treatment due to previous negative experiences accessing the health care system emerged as a major barrier to linkage to HCV treatment and cure. Undeservingness was often internalized and projected onto network members. To overcome this, participants supported access to low-barrier HCV treatment in alternative locations such as community-based or mobile clinics and drug treatment centers. CONCLUSION: Social network based interventions have potential to increase HCV treatment uptake among PWID. To be successful, these interventions will need to train peers to share accurate information and personal experiences with HCV testing and treatment and enhance their ability to provide support to network members who face significant stigma related to both HCV and drug use.

Network-based recruitment of people who inject drugs for hepatitis C testing and linkage to care.

Although oral direct-acting agent (DAA) therapies have the potential to reduce the burden of hepatitis C virus (HCV) infection, treatment uptake remains low, particularly among people who inject drugs (PWID). This study examined the feasibility of an innovative peer-based recruitment strategy to engage PWID in HCV testing and treatment. We interviewed an initial set of HCV antibody-positive PWID as 'primary indexes' to gather demographic, drug use, health information and drug network characteristics. Primary indexes were then briefly educated on HCV and its treatment and encouraged to recruit their injection drug 'network members' for HCV testing and linkage to care. Eligible network members were enrolled as 'secondary indexes' and completed the same index study procedures. In sum, 17 of 36 primary indexes initiated the recruitment of 64 network members who were HCV antibody positive and eligible to become indexes. In multivariable analysis, successful recruitment of at least one network member was positively associated with prior HCV treatment (OR 2.80; CI [1.01, 7.72]), daily or more injection drug use (OR 2.38; CI [1.04, 5.47]), and a higher number of injection drug network members (OR 1.20; CI [1.01, 1.42]). Among the 69 participants with chronic HCV not previously linked to HCV care at enrolment, 91% (n = 63) completed a linkage to HCV care appointment, 45% (n = 31) scheduled an appointment with an HCV provider, and 20% (n = 14) initiated HCV therapy. These findings suggest a potential benefit for peer-driven, network-based interventions focused on HCV treatment-experienced PWID as a mechanism to increase HCV linkage to care.

Unreported alcohol use was common but did not impact hepatitis C cure in HIV-infected persons who use drugs.

We investigated the prevalence and impact of heavy alcohol use on the hepatitis C virus (HCV) care continuum amongst HIV/HCV co-infected persons who use drugs. In the CHAMPS study, 144 HIV/HCV co-infected persons were randomized to contingent cash incentives, peer mentors and usual care to evaluate the impact on HCV care. Alcohol use was ascertained using the 10-item AUDIT (hazardous: male ≥8, female ≥4) and phosphatidylethanol (PEth) (heavy: ≥50 ng/mL), an alcohol biomarker. Log binomial regression was used to evaluate the association between heavy alcohol use and failure to initiate treatment and to achieve sustained virologic response (SVR). Of the 135 participants with PEth data, median age was 55 years, 59% were male, 92% were Black, 91% reported a history of drug use, and 97% were on antiretroviral therapy. Hazardous drinking was reported on AUDIT by 28% of participants, and 35% had heavy alcohol use by PEth. Of the 47 individuals with a PEth ≥50 ng/mL, 23 (49%) reported no or minimal alcohol use by AUDIT. HCV treatment was initiated in 103 of 135 participants, and SVR was achieved in 92%. PEth ≥50 ng/mL (Relative Risk [RR] 0.72, 95% CI 0.35-1.48) was not significantly associated with failure to initiate HCV treatment or failure to achieve SVR (RR 0.85, 95% CI 0.46-1.57).In conclusion, alcohol use was common and frequently not detected by self-report. However, heavy alcohol use, even when measured objectively, was not associated with failure to initiate HCV treatment or to achieve cure.

A Randomized Controlled Trial of Cash Incentives or Peer Support to Increase HCV Treatment for Persons With HIV Who Use Drugs: The CHAMPS Study.

BACKGROUND: Despite access to direct-acting antivirals, barriers to a hepatitis C virus (HCV) cure persist, especially among persons living with human immunodeficiency virus (HIV) (PLWH) who use drugs. Interventions such as peer mentors or cash incentives may improve the care continuum. METHODS: The CHAMPS (Chronic HepAtitis C Management to ImProve OutcomeS) study randomized 144 PLWH, recruited from an outpatient clinic, with substance use disorders into three treatment groups: usual care (UC) (n = 36), UC plus cash incentives (n = 54), and UC plus peer mentors (n = 54) to evaluate HCV treatment uptake and cure. All participants received 12-weeks of ledipasvir/sofosbuvir (LDV/SOF). Trained peer mentors had well-controlled HIV and HCV. Cash incentives were contingent on visit attendance (maximum $220). The primary endpoint was HCV treatment initiation; secondary endpoints included sustained virologic response (SVR) and HCV reinfection. RESULTS: The majority of participants were male (61%), Black (93%), and unemployed (85%). Depression and active drug and alcohol use were common. Overall, 110 of 144 (76%) participants initiated LDV/SOF. Although treatment initiation rates were higher in PLWH randomized to peers (83%, 45 of 54) or cash (76%, 41 of 54) compared to UC (67%, 24 of 36), these differences were not statistically significant (P = .11). Most PLWH who initiated treatment achieved SVR (100 of 110, 91%). LDV/SOF was well tolerated; peers and cash had no effect on drug and alcohol use during therapy. One individual from the cash cohort experienced HCV reinfection. CONCLUSION: After removal of system barriers, one-third of PLWH in UC did not initiate HCV treatment. Among those who initiated, SVR rates were high. Research involving PLWH who use drugs should focus on overcoming barriers to treatment initiation. CLINICAL TRIAL INFORMATION: The registration data for the trial are in the ClinicalTrials.gov database, number NCT02402218.

Can Slot-Machine Reward Schedules Induce Gambling Addiction in Rats?

Similar to drugs of abuse, random-ratio reward schedules are highly motivating and, in humans, are thought to foster gambling addiction. Animal gambling models, however, have not yet demonstrated the compulsivity so characteristic of drug addiction. Three criteria have been used to evaluate addiction-like behavior in drug models: (1) response inhibition when reward is not available, (2) persistence under a progressive ratio schedule, in which the response-to-reward ratio is stretched, and (3) persistence in spite of punishment. We tested whether prolonged exposure (6 weeks) to a gambling-like reward schedule would induce addiction-like symptoms in rats. In two studies, separate groups were trained to respond to either random- or fixed-ratio schedules for food reward. We found that rats trained on random-ratio schedules showed higher response rates and dramatically shorter pauses after rewards. Tests of addiction-like behavior, however, were largely negative. Response rates were not different during cued no-reward periods nor when reward was coupled with punishment. We also found no group differences when food was devalued nor in reinstatement of reward-seeking after a 1-week delay. The sole exception to this pattern was that rats in the second experiment showed greater persistence on a progressive ratio test. After experiment two, subjects were also orally administered pramipexole, which caused increased perseveration during progressive ratio testing, especially in the random ratio group. While, it is possible that longer training or more appetitive rewards might have led to addiction-like behavior, our results, on the surface, suggest that random-ratio schedules are motivating but not addictive.

A bioactive probe for glutathione-dependent antioxidant capacity in breast cancer patients: implications in measuring biological effects of arsenic compounds.

INTRODUCTION: Glutathione, a major cellular non-protein thiol (NPSH), serves a central role in repairing damage induced by cancer drugs, pollutants and radiation and in the detoxification of several cancer chemotherapeutic drugs and toxins. Current methods measure glutathione levels only, which require cellular extraction, rather than the glutathione recycling dependent antioxidant activity in intact cells. Here, we present a novel method using a bioactive probe of the oxidative pentose phosphate cycle, termed the OxPhos™ test, to quantify glutathione recycling dependent antioxidant activity in whole blood and intact human and rodent cells without the need for the isolation and cytoplasm extraction of cells. METHODS: OxPhos™ test kit (Rockland Immunochemicals, USA), which uses hydroxyethyldisulfide (HEDS) as a probe for the oxidative pentose phosphate cycle, was used in these studies. The results with OxPhos™ test kit in human blood and intact cells were compared with total thiol and high pressure liquid chromatography/electrochemical detection of HEDS metabolism. RESULTS: The OxPhos™ test measured glutathione-dependent antioxidant activity both in intact human and rodent cells and breast cancer patient's blood with a better correlation coefficient and biological variability than the thiol assay. Additionally, human blood and mammalian cells treated with various arsenicals showed a concentration-dependent decrease in activity. DISCUSSION: The results demonstrate the application of this test for measuring the antioxidant capacity of blood and the effects of environmental pollutants/toxins. It opens up new avenues for an easy and reliable assessment of glutathione-dependent antioxidant capacity in various diseases such as stroke, blood borne diseases, infection, cardiovascular disease and other oxidative stress related diseases and as a prognostic indicator of chemotherapy response and toxicity. The use of this approach in pharmacology/toxicology including screening drugs that improve the glutathione-dependent antioxidant capacity and not just the glutathione level is clinically relevant since mammalian cells require glutathione dependent pathways for antioxidant activity.

A bioactive probe of the oxidative pentose phosphate cycle: novel strategy to reverse radioresistance in glucose deprived human colon cancer cells.

The specific effects of glucose deprivation on oxidative pentose phosphate cycle (OPPC) function, thiol homeostasis, protein function and cell survival remain unclear due to lack of a glucose-sensitive chemical probe. Using p53 wild type and mutant human colon cells, we determined the effects of hydroxyethyl disulfide (HEDS) on NADPH, GSH, GSSG, total glutathione, total non-protein and protein thiol levels, the function of the DNA repair protein Ku, and the susceptibility to radiation-induced free radicals under normal glucose or glucose-deprived conditions. HEDS is rapidly detoxified in normal glucose but triggered a p53-independent metabolic stress in glucose depleted state that caused loss of NADPH, protein and non-protein thiol homeostasis and Ku function, and enhanced sensitivity of both p53 wild type and mutant cells to radiation induced oxidative stress. Additionally, high concentration of HEDS alone induced cell death in p53 wild type cells without significant effect on p53 mutant cells. HEDS offers a useful tool to gain insights into how glucose metabolism affects OPPC dependent stress-induced cellular functions and injury, including in tumor cells, where our findings imply a novel therapeutic approach to target glucose deprived tumor. Our work introduces a novel probe to address cancer metabolism and ischemic pathology.

Hydroxyethyl disulfide as an efficient metabolic assay for cell viability in vitro.

Cell viability assays have a variety of well known practical and technical limitations. All the available approaches have disadvantages, such as non-linearity, high background and cumbersome protocols. Several commonly used tetrazolium chemicals rely upon generation of a colored formazan product formed by mitochondrial reduction of these compounds via phenazine methosulfate (PMS). However, sensitivity is inherently limited because their reduction relies on mitochondrial bioreduction and cellular transport of PMS, as well as accessibility to tetrazolium chemicals. In this study, we identify hydroxethyldisulfide (HEDS) as an inexpensive probe that can measure cellular metabolic activity without the need of PMS. In tissue culture medium, HEDS accurately quantitated metabolically active live cells in a linear manner superior to tetrazolium based and other assays. Cell toxicity produced by chemotherapeutics (cisplatin, etoposide), oxidants (hydrogen peroxide, acetaminophen), toxins (phenyl arsine oxide, arsenite) or ionizing radiation was rapidly determined by the HEDS assay. We found that HEDS was superior to other commonly used assays for cell viability determinations in its solubility, membrane permeability, and intracellular conversion to a metabolic reporter that is readily transported into the extracellular medium. Our findings establish the use of HEDS in a simple, rapid and low cost assay to accurately quantify viable cells.

Glucose deprivation increases nuclear DNA repair protein Ku and resistance to radiation induced oxidative stress in human cancer cells.

Recent studies have indicated that nutrient deprivation particularly glucose may play a major role in tumor cell tolerance to a generally oxidative stress environment in solid tumors. Here, we studied the impact of glucose deprivation on the response of human colon (HT29) and prostate (DU145) cancer cells to gamma radiation. A significant decrease in intracellular glucose level was observed in glucose deprived cells as measured by bioreductive assay. The survival of HT29 and DU145 were increased by 30 and 100% respectively when these cells were exposed to gamma radiation in the absence of glucose compared to that in the presence of glucose. In glucose depleted medium, glutathione (GSH), a free radical scavenger, content remained the same, and showed no correlation with the radiation resistance induced by glucose deprivation. Glucose regulated protein78 (GRP78), a stress response survival protein, was not significantly increased in cells deprived of glucose for 4 h compared to those cells in glucose. DNA repair protein Ku, which is known to play a major role in cellular resistance to radiation, was significantly increased in glucose deprived cancer cells that showed enhanced radiation resistance. These results have demonstrated, for the first time, that glucose deprivation mediated stress increased the expression of nuclear Ku and resistance to radiation induced oxidative stress in human cancer cells. The additional resistance caused by glucose deprivation in cancer cells has clinical significance since solid tumors are known to have low level of glucose due to diffusion limited blood supply and higher metabolic activity.