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Background and aims Over the past decades, people who inject drugs (PWID) have been impacted by the development of combination antiretroviral therapy (cART) to combat HIV/AIDS, the prescription opioid crisis, and increased use of lethal synthetic opioids. We measured how these dynamics have impacted mortality among PWID in an urban U.S. city. Design Prospective cohort study using data from the AIDS Linked to the Intravenous Experience (ALIVE) SETTING: Baltimore, Maryland, USA from 1988-2018. Participants 5,506 adult PWIDs (median age at baseline 37 years). Measurements Mortality was identified by linkage to National Death Index-Plus (NDI-Plus) and categorized into HIV/infectious disease (HIV/ID) deaths, overdose and violence-related (drug-related) deaths, and chronic-disease deaths. Person-time at risk accrued from baseline, and ended at the earliest of death or study period. All-cause and cause-specific mortality were calculated annually. Fine and Gray method was used to estimate the sub-distribution hazards of cause-specific deaths accounting for competing risks. Findings Among 5,506 participants with 84,011 person-years of follow-up, 43.9% were deceased by 2018. Among all deaths, 30.5% were HIV/ID-deaths, 24.4% drug-related deaths, and 33.3% chronic-disease deaths. Age-standardized all-cause mortality increased from 23 to 45 per 1000-person-years from 1988-1996, declined from 1996 through 2012, then trended upward through 2018. HIV/ID-deaths peaked in 1996 coincident with the availability of cART, then continuously declined. Chronic-disease deaths increased continuously as the cohort aged. Drug-related deaths declined until 2011, but increased over 4-fold by 2018. HIV/HCV infection and active injecting were independently associated with HIV/ID and drug-related deaths. Female and Black participants had higher risk of dying from HIV/ID deaths and a lower risk of dying from drug-related deaths than male and non-Black participants. Conclusions Deaths in Baltimore, Maryland, USA attributable to HIV/ID appear to have declined following the widespread use of combination antiretroviral therapy. Increases in the rates of drug-related deaths in Baltimore were observed prior to and continue in conjunction with national mortality rates associated with the opiate crisis.

Hepatocellular carcinoma (HCC) incidence is high in The Gambia, and hepatitis B virus (HBV) infection is the main cause. People coinfected with HBV and hepatitis D virus (HDV) have an even greater risk of HCC and cirrhosis. Using a new HDV quantitative microarray antibody capture (Q-MAC) assay, we evaluated the association between HDV infection and HCC or cirrhosis among participants in The Gambia Liver Cancer Study. In this case-control study, cases had HCC (n = 312) or cirrhosis (n = 119). Controls (n = 470) had no clinical evidence of liver disease and normal serum alpha-foetoprotein. Participants were previously tested for hepatitis B surface antigen (HBsAg); we tested HBsAg+ specimens by HDV Q-MAC, western blot and RNA assays. We evaluated separate cut-offs of the Q-MAC assay for predicting anti-HDV and RNA positivity. Q-MAC correctly identified 29/29 subjects who were western blot-positive (sensitivity = 100%, specificity = 99.4%) and 16/17 who were RNA-positive (sensitivity = 94.1%, specificity = 100%). Compared to controls, cases more often had HBV monoinfection (HBsAg+/HDV RNA-; 54.1% vs 17.0%; odds ratio [OR] = 6.28; P < 0.001) or HBV-HDV coinfection (HBsAg+/HDV RNA+; 3.9% vs 0%; P < 0.001). Risk estimates (for HCC or cirrhosis) based on HDV antibody status and adjusted for covariates (demographics, alcohol, smoking, body mass index, anti-HCV and aflatoxin B1 exposure) yielded consistent results for both HBV monoinfection (adjusted OR = 8.29; 95% confidence interval = 5.74-11.98) and HBV-HDV coinfection (adjusted OR = 30.66; 95% confidence interval = 6.97-134.95). In this Gambian population, HDV Q-MAC had high sensitivity and specificity for both anti-HDV and HDV RNA. HDV infection contributed to the high risk of HCC in The Gambia.

Author(s): Bourgi, Kassem; Jenkins, Cathy A; Rebeiro, Peter F; Palella, Frank; Moore, Richard D; Altoff, Keri N; Gill, John; Rabkin, Charles S; Gange, Stephen J; Horberg, Michael A; Margolick, Joseph; Li, Jun; Wong, Cherise; Willig, Amanda; Lima, Viviane D; Crane, Heidi; Thorne, Jennifer; Silverberg, Michael; Kirk, Gregory; Mathews, William C; Sterling, Timothy R; Lake, Jordan; Koethe, John R; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) | Abstract: IntroductionWeight gain following antiretroviral therapy (ART) initiation is common, potentially predisposing some persons with HIV (PWH) to cardio-metabolic disease. We assessed relationships between ART drug class and weight change among treatment-naive PWH initiating ART in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD).MethodsAdult, treatment-naive PWH in NA-ACCORD initiating integrase strand transfer inhibitor (INSTI), protease inhibitor (PI) or non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based ART on/after 1 January 2007 were followed through 31 December 2016. Multivariate linear mixed effects models estimated weight up to five years after ART initiation, adjusting for age, sex, race, cohort site, HIV acquisition mode, treatment year, and baseline weight, plasma HIV-1 RNA level and CD4+ cell count. Due to shorter follow-up for PWH receiving newer INSTI drugs, weights for specific INSTIs were estimated at two years. Secondary analyses using logistic regression and all covariates from primary analyses assessed factors associated with g10% weight gain at two and five years.ResultsAmong 22,972 participants, 87% were male, and 41% were white. 49% started NNRTI-, 31% started PI- and 20% started INSTI-based regimens (1624 raltegravir (RAL), 2085 elvitegravir (EVG) and 929 dolutegravir (DTG)). PWH starting INSTI-based regimens had mean estimated five-year weight change of +5.9kg, compared to +3.7kg for NNRTI and +5.5kg for PI. Among PWH starting INSTI drugs, mean estimated two-year weight change was +7.2kg for DTG, +5.8kg for RAL and +4.1kg for EVG. Women, persons with lower baseline CD4+ cell counts, and those initiating INSTI-based regimens had higher odds of g10% body weight increase at two years (adjusted odds ration=n1.37, 95% confidence interval: 1.20 to 1.56 vs. NNRTI).ConclusionsPWH initiating INSTI-based regimens gained, on average, more weight compared to NNRTI-based regimens. This phenomenon may reflect heterogeneous effects of ART agents on body weight regulation that require further exploration.

Aims There is limited longitudinal research examining incarceration and subsequent changes in drug use among people who inject drugs (PWID) in the United States. The objective of the current study was to characterize the frequency of incarceration and estimate the association between incarceration and subsequent injection drug use among current and former PWIDs in one US city. Design ALIVE (AIDS Linked to the Intravenous Experience) is a prospective cohort study of current and former PWIDs, with semi-annual follow-up occurring since 1988. Setting Baltimore, Maryland, USA. Participants A total of 3245 participants with 48 738 study visits were included. Participants enrolled from 1988 to 2012 with a median of 13 follow-up visits per participant (Interquartile range = 7–25). Measurements Incarcerations were defined as any self-reported jail or prison stays in the previous 6 months that were ≥7 days or longer. The primary outcome was defined as any self-reported injection drug use in the previous 6 months. Findings At baseline, 29% were female, 90% African American and 33% HIV-positive. Fifty-seven per cent of participants experienced at least one incarceration episode. After adjusting for confounders, there was a positive association between incarceration and subsequent injection drug use [adjusted odds ratio (AOR) = 1.48, 95% confidence interval (CI) = 1.37–1.59]; however, stratified analysis showed that the effect was restricted to those who were not injecting at the time of incarceration (AOR = 2.11, 95% CI = 1.88–2.37). Conclusions In the United States, incarceration of people who had previously stopped injecting drugs appears to be associated with an increased risk of subsequent injecting.

Aims To understand the environmental and contextual influences of illicit cocaine and heroin use and craving using mobile health (mHealth) methods. Design Interactive mHealth methods of ecological momentary assessment (EMA) were utilized in the Exposure Assessment in Current Time (EXACT) study to assess drug use and craving among urban drug users in real time. Participants were provided with mobile devices and asked to self-report every time they either craved (without using) or used heroin or cocaine for 30 days from November 2008 through May 2013. Setting Baltimore, MD, USA. Participants A total of 109 participants from the AIDS Linked to the IntraVenous Experience (ALIVE) study. Measurements For each drug use or craving event, participants answered questions concerning their drug use, current mood and their social, physical and activity environments. Odds ratios (OR) of drug use versus craving were obtained from logistic regression models with generalized estimating equations of all reported events. Findings Participants were a median of 48.5 years old, 90% African American, 52% male and 59% HIV-infected. Participants were significantly more likely to report use rather than craving drugs if they were with someone who was using drugs [adjusted odds ratio (aOR) = 1.45, 95% confidence interval (CI) = 1.13, 1.86), in an abandoned space (aOR = 6.65, 95% CI = 1.78, 24.84) or walking/wandering (aOR = 1.68, 95% CI = 1.11, 2.54). Craving drugs was associated with being with a child (aOR = 0.26, 95% CI = 0.12, 0.59), eating (aOR = 0.54, 95% CI = 0.34, 0.85) or being at the doctor's office (aOR = 0.31, 95% CI = 0.12, 0.80). Conclusions There are distinct drug using and craving environments among urban drug users, which may provide a framework for developing real-time context-sensitive interventions.

Chronic Hepatitis B (HB) is the main risk factor for chronic liver disease (CLD) and hepatocellular carcinoma (HCC) in many low-resource countries, where diagnosis is constrained by lack of clinical, histopathological and biomarker resources. We have used proteomics to detect plasma biomarkers that outperform α-Fetoprotein (AFP), the most widely used biomarker for HCC diagnosis in low-resource contexts. Deep-plasma proteome analysis was performed in HCC patients, patients with CLD and in HB-carrier controls from Thailand (South-East Asia) and The Gambia (West-Africa). Mass spectrometry profiling identified latent-transforming growth factor β binding-protein 2 (LTBP2) and Osteopontin (OPN) as being significantly elevated in HCC versus CLD and controls. These two proteins were further analyzed by ELISA in a total of 684 plasma samples, including 183 HCC, 274 CLD and 227 asymptomatic controls. When combined, LTBP2 and OPN showed an area under the receiver operating curve of 0.85 in distinguishing HCC from CLD in subjects with AFP

Aims To determine the incidence of long-term injection cessation and its association with residential relocation and neighborhood deprivation. Design ALIVE (AIDS Linked to the Intravenous Experience) is a prospective cohort with semi-annual follow-up since 1988. Multi-level discrete time-to-event models were constructed to investigate individual and neighborhood-level predictors of long-term injection cessation. Setting Baltimore, USA. Participants A total of 1697 active injectors from ALIVE with at least eight semi-annual study visits. Measurements Long-term injection cessation was defined as 3 consecutive years without self-reported injection drug use. Findings A total of 706 (42%) injectors achieved long-term cessation (incidence = 7.6 per 100 person-years). After adjusting for individual-level factors, long-term injection cessation was 29% less likely in neighborhoods in the third quartile of deprivation [hazard ratio (HR) = 0.71, 95% CI: 0.53, 0.95) and 43% less likely in the highest quartile of deprivation (HR = 0.57, 95% CI: 0.43, 0.76) compared to the first quartile. Residential relocation was associated with increased likelihood of long-term injection cessation (HR = 1.55, 95% CI: 1.31, 1.82); however, the impact of relocation varied depending on the deprivation in the destination neighborhood. Compared to those who stayed in less deprived neighborhoods, relocation from highly deprived to less deprived neighborhoods had the strongest positive impact on long-term injection cessation (HR = 1.96, 95% CI: 1.50, 2.57), while staying in the most deprived neighborhoods was detrimental (HR = 0.76, 95% CI: 0.63, 0.93). Conclusions Long-term cessation of injection of opiates and cocaine occurred frequently following a median of 9 years of injection and contextual factors appear to be important. Our findings suggest that improvements in the socio-economic environment may improve the effectiveness of cessation programs.

Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, with a high burden in West Africa. Data evaluating aetiological differences in HCC presentation from this region are limited. Aims: The aim of this study was to describe the demographical, clinical and pathological characteristics of HCC by aetiology (hepatitis B or C infection, aflatoxin associated). Methods: One hundred and ninty-three cases of HCC diagnosed between 1997 and 2001 in The Gambia were analysed. Characteristics were compared by aetiology using χ2-tests, student t-test and Wilcoxon's rank sum tests as appropriate. Results: The prevalence of hepatitis B surface antigen, hepatitis C antibody and aflatoxin-associated 249serTP53 mutations among HCC patients was 60, 20 and 38% respectively. The typical HCC patient was a 49-year-old male positive for hepatitis B surface antigen presenting with hepatomegaly (93%), abdominal pain (94%) and weight loss (95%) 8 weeks after symptom onset. Most patients had multifocal lesions with background cirrhosis. The median largest tumour was 10.3 cm and the median α-fetoprotein level was 500 ng/ml. Eighty-four per cent of patients had advanced HCC (patients not meeting the Milan criteria) at presentation. Conclusions: Irrespective of aetiological agent, HCC among West Africans presents at very advanced stages. Few clinical or pathological differences exist by aetiology. More studies are needed to understand the mechanisms of hepatocarcinogenesis among these patients as well as identify high-risk populations in which early detection through screening will be beneficial.

Hepatocellular carcinoma (HCC) is frequent in areas of high exposure to aflatoxin and high prevalence of HBV infection, such as western Africa and south-east China. A selective mutation in TP53 (AGG-->AGT at codon 249, Arg-->Ser) has been identified as a hotspot in HCCs from such areas, reflecting DNA damage caused by aflatoxin metabolites. Recent studies have shown that circulating free DNA can be retrieved from human plasma, and it is hypothesised that plasma DNA may serve as a source for biomarkers of tumorigenic processes. In our study, we have determined the prevalence of Ser-249 mutation, using a PCR-restriction digestion method, with selective use of short oligonucleotide mass spectrometry analysis (SOMA), in a series of 29 biopsy specimens of HCC from The Gambia in West Africa. Overall, we identified the Ser-249 mutation in 35% (10/29) of the tumours. In parallel, we tested 17 plasma samples from HCC patients with matching tumour tissue. The 249 status concordance between tumour tissues and matched plasma was 88.5%. These results indicate that the Ser-249 mutation is common in HCC in The Gambia (35%), although a higher prevalence has been reported in other regions with high population exposure to aflatoxin (e.g., eastern China: >50%). Moreover, our studies indicate that plasma is a convenient source of liver tumour-derived DNA, thus holding promise for earlier detection and diagnosis of cancer.

Aflatoxins together with chronic hepatitis B virus (HBV) infection contribute to the high incidence of hepatocellular carcinoma in developing countries. An understanding of the mechanism of interaction between these factors would provide a strong rationale for developing effective prevention strategies. In this study in The Gambia we examined the effect of environmental (place of residence and timing of sample collection) and host factors (age, sex, HBV status and interindividual variations in carcinogen metabolising enzymes) in determining blood aflatoxin-albumin adduct levels in 357 individuals of whom 181 were chronic HBV carriers. Samples were analysed for aflatoxin-albumin adducts, HBV status and genotypes of glutathione S-transferase (GST) M1, GSTT1, GSTP1 and epoxide hydrolase (EPXH). Urine samples were analysed for 6beta-hydroxycortisol:cortisol ratio as a marker of cytochrome P450 (CYP) 3A4 activity. Adduct levels were significantly higher in subjects resident in rural [geometric mean adduct level 34.9 pg aflatoxin B1-lysine equivalent (28.5-42.8; 95%CI)/mg albumin] than in periurban areas [22.2 pg (14.9-33.4)/mg] and were approximately twice as high in the dry season [mid-February to March; 83.2 pg (53.3-130.8)/mg] than the wet [July to August; 34.9 pg (28.5-42.8)/mg]. In contrast, HBV status, CYP3A4 phenotype, GSTT1, GSTP1 and EPXH genotypes were not associated with aflatoxin-albumin adduct level. However, mean adduct levels were significantly higher in non-HBV infected subjects with GSTM1 null genotype. The main factors which affect aflatoxin-albumin adduct levels in this population are environmental, notably place of residence and timing of sample collection. This study further emphasises the priority to reduce aflatoxin exposure in these communities by primary prevention measures.

Human papillomavirus (HPV) is widely accepted as the primary etiologic agent in the development of cervical cancer. DNA of a particular HPV type, HPV 16, is found in about half of tumors tested. Inconsistent with this causal relationship, however, population-based studies of HPV DNA prevalence have often failed to find high rates of anogenital HPV infection in countries with high cervical cancer rates. To examine this issue, we used serology to compare HPV 16 exposure in healthy volunteer blood donors in the United States (n = 278) and similar subjects from a country with 3-fold higher cervical cancer rates, Jamaica (n = 257). Jamaican sexually transmitted disease (STD) patients (n = 831) were also studied to examine in detail the relation of HPV 16 antibodies with sexual history. Serology was conducted using an ELISA employing HPV 16 virus-like particles (VLPs). Age-adjusted seroprevalence rates were greatest among male (29%) and female (42%) STD patients, intermediate in male (19%) and female (24%) Jamaican blood donors and lowest among male (3%) and female (12%) U.S. blood donors. The higher seroprevalence in women was significant, and prevalence tended to increase with age. In multivariate logistic regression, controlling for age and gender, Jamaican blood donors were 4.2-fold (95% CI 2.4-7.2) and STD patients 8.1-fold (95% CI 5.0-13.2) more likely to have HPV 16 VLP antibodies than U.S. blood donors. Among STD patients, HPV 16 antibodies were associated with lifetime number of sex partners and years of sexual activity, as well as other factors. Our data suggest that HPV 16 VLP antibodies are strongly associated with sexual behavior. Moreover, exposure to HPV 16 appears to be much greater in Jamaica than in the United States, consistent with the high rate of cervical cancer in Jamaica.