Drugs of Abuse and Their Impact on Viral Pathogenesis.

Commonly misused substances such as alcohol, cocaine, heroin, methamphetamine, and opioids suppress immune responses and may impact viral pathogenesis. In recent years, illicit use of opioids has fueled outbreaks of several viral pathogens, including the human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV). This review focuses on the myriad of mechanisms by which drugs of abuse impact viral replication and disease progression. Virus-drug interactions can accelerate viral disease progression and lead to increased risk of virus transmission.

Detection and Genetic Characterization of Hepatitis B and D Viruses: A Multi-Site Cross-Sectional Study of People Who Use Illicit Drugs in the Amazon Region.

Hepatitis B (HBV) and delta (HDV) viruses are endemic in the Amazon region, but vaccine coverage against HBV is still limited. People who use illicit drugs (PWUDs) represent a high-risk group due to common risk behavior and socioeconomic factors that facilitate the acquisition and transmission of pathogens. The present study assessed the presence of HBV and HBV-HDV co-infection, identified viral sub-genotypes, and verified the occurrence of mutations in coding regions for HBsAg and part of the polymerase in HBV-infected PWUDs in municipalities of the Brazilian states of Amapá and Pará, in the Amazon region. In total, 1074 PWUDs provided blood samples and personal data in 30 municipalities of the Brazilian Amazon. HBV and HDV were detected by enzyme-linked immunosorbent assay and polymerase chain reaction. Viral genotypes were identified by nucleotide sequencing followed by phylogenetic analysis, whereas viral mutations were analyzed by specialized software. High rates of serological (32.2%) and molecular (7.2%) markers for HBV were detected, including cases of occult HBV infection (2.5%). Sub-genotypes A1, A2, D4, and F2a were most frequently found. Escape mutations due to vaccine and antiviral resistance were identified. Among PWUDs with HBV DNA, serological (19.5%) and molecular (11.7%) HDV markers were detected, such as HDV genotypes 1 and 3. These are worrying findings, presenting clear implications for urgent prevention and treatment needs for the carriers of these viruses.

Mini review: Promotion of substance abuse in HIV patients: Biological mediation by HIV-1 Tat protein.

Despite successful viral suppression by combinatorial anti-retroviral therapy, HIV infection continues to negatively impact the quality of life of patients by promoting neuropathy and HIV-Associated Neurocognitive Disorders (HAND), where substance use disorder (SUD) is highly comorbid and known to worsen health outcomes. While substance abuse exacerbates the progression of HIV, emerging evidence also suggests the virus may potentiate the rewarding effect of abused substances. As HIV does not infect neurons, these effects are theorized to be mediated by viral proteins. Key among these proteins are HIV-1 Tat, which can continue to be produced under viral suppression in patients. This review will recap the behavioral evidence for HIV-1 Tat mediation of a potentiation of cocaine, opioid and alcohol reward, and explore the neurochemical dysfunction associated by Tat as potential mechanisms underlying changes in reward. Targeting rampant oxidative stress, inflammation and excitotoxicity associated with HIV and Tat protein exposure may prove useful in combating persistent substance abuse comorbid with HIV in the clinic.

TCA cycle metabolic compromise due to an aberrant S-nitrosoproteome in HIV-associated neurocognitive disorder with methamphetamine use.

In the brain, both HIV-1 and methamphetamine (meth) use result in increases in oxidative and nitrosative stress. This redox stress is thought to contribute to the pathogenesis of HIV-associated neurocognitive disorder (HAND) and further worsening cognitive activity in the setting of drug abuse. One consequence of such redox stress is aberrant protein S-nitrosylation, derived from nitric oxide, which may disrupt normal protein activity. Here, we report an improved, mass spectrometry-based technique to assess S-nitrosylated protein in human postmortem brains using selective enrichment of S-nitrosocysteine residues with an organomercury resin. The data show increasing S-nitrosylation of tricarboxylic acid (TCA) enzymes in the setting of HAND and HAND/meth use compared with HIV+ control brains without CNS pathology. The consequence is systematic inhibition of multiple TCA cycle enzymes, resulting in energy collapse that can contribute to the neuronal and synaptic damage observed in HAND and meth use.

Plasma C-reactive protein is lower among marijuana using HIV-negative individuals but not among persons living with HIV.

The use of marijuana is highly prevalent among young men who have sex with men (YMSM). Past work has also shown that inflammation is elevated among YMSM, independent of HIV status. Here, we aim to examine the relationship between marijuana use and inflammation among this high-risk cohort, relative to use of other substances. Data were collected among YMSM aged 16-29 in Chicago. Multiplex cytokine and inflammatory biomarker assays were run on plasma from all persons living with HIV (PLWH) (n = 195) and a subset of HIV-negative participants (n = 489). Bivariate analyses and multivariable models assessed relationships between various substances and inflammatory biomarkers. Models were stratified by HIV status and adjusted for demographic characteristics. Most participants reported use of marijuana in the past 30 days (416, 60.8%). Mean blood C-reactive protein (CRP) levels were above the upper limit of normal (3.0 mg/L), indicative of increased risk for cardiovascular disease (mean CRP was 3.9 mg/L; SD = 8.5). In adjusted, stratified analyses, CRP was significantly lower among participants reporting frequent marijuana use (≥ 6 times per month), relative to those reporting never using marijuana, (ß = - 0.38; 95% CI: - 0.73, - 0.03). However, this was entirely accounted for by an association among the HIV-negative participants and there was no significant association between marijuana use and blood CRP level among the PLWH. In summary, YMSM had markedly elevated marijuana use and blood CRP levels. Frequent marijuana use was associated with lower inflammation among only those not diagnosed with HIV. Further research is needed to explicate why there are differences between HIV-negative participants and PLWH and to leverage this information to characterize biological mechanisms by which marijuana decreases inflammation.

Comparative impact of methamphetamine and other drug use on viral suppression among sexual minority men on antiretroviral therapy.

BACKGROUND: Substance use decreases the likelihood of achieving undetectable HIV viremia; however, the comparative effects by drug have not been fully described. In this study, we compare the effects of methamphetamine use versus other drugs on viremia in sexual minority men on antiretroviral therapy (ART). METHODS: HIV-positive participants currently on ART (N = 230) were selected from an ongoing cohort of diverse young sexual minority men (mSTUDY) enrolled from August 2014 to May 2018. Substance use and sociodemographic factors associated with viremia outcomes were assessed using ordinal regression analysis with generalized estimating equations. Viremia outcomes were grouped as undetectable (<20 copies/mL), low level suppressed (21-200 copies/mL), or not suppressed (>200 copies/mL). RESULTS: The prevalence of drug use across 825 study visits was 73 %, with methamphetamine use most prevalent (50 %). After adjusting for unstable housing and ART adherence, methamphetamine use, either alone (adjusted OR = 1.87; 95 % CI 1.03-3.40) or with other drugs (adjusted OR = 1.82; 95 % CI 1.12-2.95), was associated with higher odds of increasing viremia compared to no drug use. Other drug use excluding methamphetamine did not show a similar association (adjusted OR = 1.29; 95 % CI 0.80-2.09). Among our study population, nearly half the instances of viremia could be reduced if methamphetamine was discontinued (attributable fraction = 46 %; 95 % CI 3-71 %). CONCLUSIONS: Methamphetamine use, either alone or in combination with other drugs, is associated with failure of viral suppression among sexual minority men on ART independent of adherence and sociodemographic factors. This accounts for nearly half of the observed instances of unsuppressed viremia in this study.

Collateral damage: Impact of SARS-CoV-2 pandemic in people living with HIV.

People living with HIV (PLWH) may be at higher risk for adverse outcomes indirectly associated with the severe acute respiratory syndrome coronavirus (SARS-CoV-2). When comparing responses to questionnaires administered when social distancing and quarantine guidelines were first implemented, we found that PLWH were more likely to have restricted access to medical care, increased financial stress, increased symptoms of anxiety and depression, and increased substance use compared to demographically-similar people without HIV.

Tryptophan degradation is associated with risk-taking propensity in methamphetamine users with treated HIV infection.

Few studies have examined neuroimmune pathways that could contribute to impulsivity in people living with HIV who use substances. Eighty-four methamphetamine-using, sexual minority men with an undetectable HIV viral load were administered the Balloon Analogue Risk Task (BART), a behavioral measure of risk-taking propensity. We examined the associations between kynurenine/tryptophan ratio and phenylalanine/tyrosine ratio with BART scores using multiple linear regression. A higher kynurenine/tryptophan ratio was independently associated with greater BART scores (beta = 0.25; 95% CI = 0.05-1.23; p = 0.034). The phenylalanine/tyrosine ratio was not significantly associated with BART scores. Findings support the need for further research to elucidate the neuroimmune mechanisms linking tryptophan degradation with impulsivity to catalyze the development novel pharmacologic treatments for people living with HIV who use methamphetamine.

Extracranial ectasia and embolic infarcts in HIV: two case reports and a clinical decision-making algorithm.

HIV is known to increase the risk of both ischemic and hemorrhagic strokes. There are many postulated mechanisms for this elevated risk including an HIV-induced vasculopathy and/or coagulopathy, opportunistic infections, and cardioembolic etiologies, among others. Regarding vasculopathy, prior reports have described the various changes to the arterial vasculature that can occur in the setting of HIV, yet the appropriate workup and management of this condition remains poorly defined. Here we describe two cases of patients with HIV presenting with large vessel intracranial occlusions in the setting of ectatic extracranial vasculature accompanied by intraluminal thrombus formation. One patient underwent thrombectomy, while the other improved after receiving IV-tPA. Inferring on these cases and the existing literature, a standardized workup and treatment algorithm is proposed, emphasizing the key management decisions that should be considered on a case-by-case basis.

The COVID-19 pandemic and its impact on substance use: Implications for prevention and treatment.

The COVID-19 pandemic has brought major challenges to healthcare systems and public health policies globally, as it requires novel treatment and prevention strategies to adapt for the impact of the pandemic. Individuals with substance user disorders (SUD) are at risk population for contamination due to multiple factors-attributable to their clinical, psychological and psychosocial conditions. Moreover, social and economic changes caused by the pandemic, along with the traditional difficulties regarding treatment access and adherence-will certainly worsen during this period, therefore aggravate their condition. In addition, this population are potential vectors of transmission. In that sense, specific strategies for prevention and treatment must be discussed. health care professionals dealing with SUD must be aware of the risks and challenges they will meet during and after the COVID-19 outbreak. Addiction care must be reinforced, instead of postponed, in order to avoid complications of both SUD and COVID-19 and to prevent the transmission of coronavirus.

Sex-on-premise venues, associated risk behaviors, and attitudes toward venue-based HIV testing among men who have sex with men in Lima, Perú.

BACKGROUND: In Perú, HIV disproportionately affects men who have sex with men (MSM). Despite widespread access to treatment, the high rate of new HIV infections has remained unchanged over the last decade. Low knowledge of HIV status associated with late diagnosis is a key factor underlying the high HIV incidence observed in this setting, creating conditions for efficient onward transmission. Improving access to HIV testing and prevention services for those at highest risk is an important public health priority. Sex-on-premise venues (SOPVs) - saunas, sex clubs, pornographic movie theaters, hourly hotels, and bars/discos with areas where sex is permitted - may be opportune sites for outreach; however, further research on SOPVs and the populations who frequent them is needed to inform such efforts. METHODS: We conducted a cross-sectional online survey of adult MSM in Lima, Perú to evaluate patterns of SOPV attendance, associated sexual risk behaviors, and attitudes toward SOPV-based interventions. Participants were recruited through outreach to social media networks affiliated with local LGBTQ-aligned community groups. Our primary analytic objective was to estimate the association of HIV-related sexual risk behaviors and SOPV attendance. Additionally, we performed exploratory analyses to describe risk behavior stratified by SOPV category and to examine the relationship between SOPV attendance and the use of online platforms to meet sex partners. RESULTS: Overall, 389 MSM completed the survey from November 2018 through May 2019, of whom 68% reported attending an SOPV in the last 3 months. SOPV attendance was associated with multiple sexual risk behaviors, including transactional sex, group sex, substance use around the time of sex, and higher number of partners. Over two thirds of SOPV attendees indicated they would accept HIV testing if offered at SOPVs. CONCLUSIONS: SOPV attendance was common among MSM in Lima who participated in our survey, and SOPV attendees reported significantly greater engagement in sexual risk behaviors related to HIV transmission. Attitudes toward hypothetical SOPV-based interventions were generally favorable. These findings suggest that outreach at SOPVs may be an effective mechanism for reaching a particularly high-risk sub-population of MSM in Perú to deliver targeted HIV testing and prevention interventions.

Blood-based inflammation biomarkers of neurocognitive impairment in people living with HIV.

Inflammation in people living with HIV (PLWH) correlates with severity of HIV-associated neurocognitive disorders. The objective of this study is to identify blood-based markers of neurocognitive function in a demographic balanced cohort of PLWH. Seven neurocognitive domains were evaluated in 121 seropositive Black/African American, Non-Hispanic White, and White Hispanic men and women using computerized assessments. Associations among standardized neurocognitive function and HIV-related parameters, relevant sociodemographic variables, and inflammation-associated cytokines measured in plasma and cellular supernatants were examined using multivariate and univariate regression models. Outlier and covariate analyses were used to identify and normalize for education level, CD4 T cell count, viral load, CNS and drug abuse comorbidities, which could influence biomarker and neurocognitive function associations. Plasma levels of chemokine (C-C motif) ligand (CCL) 8 significantly associated with memory, complex attention, cognitive flexibility, psychomotor speed, executive function, and processing speed. Plasma tissue inhibitor of metalloproteinases 1 associated with the aforementioned domains except memory and processing speed. In addition, plasma interleukin-23 significantly associated with processing speed and executive function. Analysis of peripheral blood cell culture supernatants revealed no significant markers for neurocognitive function. In this cohort, CD4 T cell count and education level also significantly associated with neurocognitive function. All identified inflammatory biomarkers demonstrated a negative correlation to neurocognitive function. These cytokines have known connections to HIV pathophysiology and are potential biomarkers for neurocognitive function in PLWH with promising clinical applications.

Spatiotemporal clusters of HIV/AIDS infections caused by drug use and heterosexual contact in Ruili city, China 1989-2016.

BACKGROUND: Ruili is a border city in southwest China along the heroin trafficking route. In recent decades, the city has witnessed increased in HIV transmission. The current study aims to explore the spatiotemporal trends in HIV prevalence identify and map the spatial variation and clustering of factors associated with HIV transmission through drug use and heterosexual contact transmissions at the village level from 1989 through 2016. METHODS: Geographic information system-based spatiotemporal analyses, including global and local spatial autocorrelation analyses and space-time scanning statistics, were applied to detect the location and extent of HIV/AIDS high-risk areas. RESULTS: Drug use and heterosexual contact were identified as the major transmission routes causing infection in Ruili. Results of global spatial analysis showed significant clustering throughout the city caused by transmission via drug use in the early phase of the epidemic and transmission via heterosexual contact in the late phase of the epidemic during the study period. Hotspots of transmission from drug use were randomly distributed throughout the city. However, the hotspots of transmission by heterosexual contact were located in the central area only around the Jiegao China-Myanmar land port. Space-time scanning showed that transmission from drug use clustered in the southwest area between 1989 and 1990, while transmission by heterosexual contact clustered in the central area between 2004 and 2014. CONCLUSIONS: Heterosexual contact has become the dominant mode of transmission. Interventions should focus on highly clustered area where is around the Jiegao land port.

Hepatitis C virus infection status and associated factors among a multi-site sample of people who used illicit drugs in the Amazon region.

BACKGROUND: Elevated rates of Hepatitis C Virus (HCV) infection have been reported in epidemiological studies with people who used illicit drugs (PWUIDs) in different Brazilian regions. In Brazil's Amazon region, studies have already identified the common use of illicit drugs among adolescents and the high prevalence of HCV infections among PWUIDs. However, all studies done with PWUIDs were conducted with small samples and within limited geographic coverage. This study determined the prevalence and risk factors for HCV infection in PWUIDs in the Amazon region, northern Brazil, as well as estimating the prevalence and factors associated with the HCV spontaneous clearance (HSC). METHODS: This cross-sectional study accessed 1666 PWUIDs from multiple municipalities of the Amazon region. Socio-demographic, economic, drug use and health-related information were collected through interviews. Blood samples collected were tested for the presence of anti-HCV antibodies and RNA-HCV. HCV genotypes were identified by real-time polymerase chain reaction (PCR). Logistic regressions were run to identify factors independently associated with HCV infection status and HSC. RESULTS: In total, 577 (34.6%) featured HCV antibodies, of which 384 (23.1%) had active HCV infection and 193 (11.6%) indicated HSC. Genotypes 1 (80.2%) and 3 (18.8%) were detected. HCV infection status was associated with the length of illicit drug use history, factors related to parenteral and sexual transmission, and factors of socio-economic marginalization leading to potential risk activities for HCV. HSC was associated with the ethnic (including indigenous) background of participants. CONCLUSIONS: High levels of HCV infection were detected in PWUIDs. Genotype 1 was predominant. Intense use of illicit drugs, unprotected sexual intercourse, high number of sexual partners and social marginalization were associated with all HCV infection. HSC was associated with origin (Amazonian-born) and non-white (e.g., Black or Indigenous) of PWUIDs. These findings emphasize the need for improve HCV prevention and control services and care for PWUIDs in the Brazilian Amazon region.

Methamphetamine use drives decreases in viral suppression for people living with HIV released from a large municipal jail: Results of the LINK LA clinical trial.

BACKGROUND: People living with HIV (PLWH) often experience decreases in HIV viral suppression (VS) after release from jail. The Linking Inmates to Care in LA (LINK LA) peer navigation intervention helped maintain VS 12 months after release from jail compared to standard of care. In this study, we analyzed correlates of substance use and tested whether substance use was an independent correlate of decreased VS in LINK LA participants. METHODS: We analyzed LINK LA data collected at baseline, 3, and 12 months. We defined high-risk drug use as any reported methamphetamine, cocaine, or opioid use in the 30 days prior to a study visit (or jail entry at baseline). We used generalized linear mixed models to test associations of sociodemographic variables with type of substance used, and we tested correlates of VS while controlling for time, the intervention, and their interaction. RESULTS: At baseline (n = 356), 71% of participants reported high-risk drug use: 58%, methamphetamine; 17%, cocaine; 7%, heroin; and 4%, prescription opioids. Non-Hispanic Whites and those younger than 35 were most likely to use methamphetamine; Blacks were most likely to use cocaine; people who inject drugs were most likely to use opioids. Participants who used high-risk drugs had 53% lower adjusted odds than non-users of maintaining VS (AOR 0.47, 95% CI 0.31-0.70, p < 0.001). CONCLUSION: High-risk drug use, dominated by methamphetamine use, independently correlated with decreased VS among recently incarcerated PLWH. Improving HIV care continuum outcomes among populations leaving jail requires attention to efforts to address high-risk drug use.

Gender-based violence and engagement in biomedical HIV prevention, care and treatment: a scoping review.

BACKGROUND: While gender-based violence (GBV) has been shown to increase women's risk of HIV acquisition, the role of GBV in the HIV testing to care continuum is less clear. Clarifying how GBV may act as a barrier to accessing HIV services, treatment and care - such as anti-retroviral treatment (ART) or pre-exposure prophylaxis (PrEP) - will not only provide insights into how to best meet individual women's HIV care needs, but also inform public health oriented HIV epidemic control strategies. METHODS: Through a comprehensive scoping review, we synthesized and analyzed existing evidence regarding the influence of GBV on engagement in PrEP and the HIV care continuum among women living with HIV, including members of key populations (female sex workers, transgender women and women who use drugs). We explored PubMed, Scopus and Web of Science for peer-reviewed studies published in 2003-2017. Of the 279 sources identified, a subset of 51 sources met the criteria and were included in the scoping review. RESULTS: Studies were identified from 17 countries. The majority of studies utilized quantitative cross-sectional designs (n = 33), with the rest using longitudinal (n = 4), qualitative (n = 10) or mixed methods (n = 4) designs. Taken together, findings suggest that GBV impedes women's uptake of HIV testing, care, and treatment, yet this can vary across different geographic and epidemic settings. Substantial gaps in the literature do still exist, including studies on the impact of GBV on engagement in PrEP, and research among key populations. CONCLUSIONS: This scoping review contributes to our knowledge regarding the role GBV plays in women's engagement in PrEP and the HIV care continuum. Findings reveal the need for more longitudinal research to provide insights into the causal pathways linking GBV and HIV care and treatment outcomes. Research is also needed to illuminate the impact of GBV on PrEP use and adherence as well as the impact of GBV on engagement along the HIV care continuum among key populations. It is critical that programs and research keep pace with these findings in order to reduce the global burden of GBV and HIV among women.

Recreational ART use among individuals living with HIV/AIDS in South Africa: Examining longitudinal ART initiation and viral suppression.

BACKGROUND: South Africa has the highest number of people living with HIV (PLWH) and one of the largest antiretroviral therapy (ART) programs globally. High rates of substance use comorbidity exist, including speculation of recreational ART use (i.e., mixing ART with other illicit drugs). Recreational ART use may affect viral load among PLWH due to ART nonadherence and/or viral resistance; however, prior quantitative research has not examined rates of recreational ART use, nor associations with HIV treatment outcomes longitudinally. METHODS: Data were drawn from a prospective, observational cohort study (n = 500) of ART-eligible adults recruited from two HIV voluntary counseling and testing centers in Cape Town, and Johannesburg, South Africa. Multiple logistic regression models assessed recreational ART use as a predictor of ART initiation over six months and viral load suppression over nine months, above and beyond other substance use (binge drinking and illicit drug use). RESULTS: Approximately 5% (n = 24) reported recreational ART use, which was less frequent in Cape Town compared to Johannesburg (AOR = 0.025; 95%CI: 0.003-0.19; p < 0.001). Recreational ART use was not significantly associated with ART initiation or viral suppression. Other substance use, but not recreational ART use, was significantly associated with lower odds of ART initiation (AOR = 0.54; 95%CI: 0.33-0.87; p = .01) and viral suppression (AOR = 0.47; 95%CI: 0.25-0.89; p = .02). CONCLUSIONS: Recreational ART use was infrequent and not uniquely associated with ART initiation or viral suppression. Findings suggest that comorbid use of other substances is ultimately what may make recreational ART use problematic for ongoing engagement in care and viral suppression.

Elevated prevalence of high-risk HPV in healthy oral mucosa of users and nonusers of drugs in Northeastern Brazil.

Variable rates of HPV infection have been reported in healthy oral mucosa worldwide. The main objective of this study was to detect and genotype HPV infection in users and nonusers of drugs with clinically healthy mucosa from the Northeast Brazil. Samples from 105 patients were amplified using the primers MY09/MY11 and GP5+/GP6+, and genotyping was performed by multiplex-PCR for HPV-6/11, 16 and 18. A total of 81.9% samples were positive. Among drug users, 84.5% presented the virus and 20.4% showed multiple infections. Among non-drug users, 78.7% were positive and 13.5% had multiple infections. Limited information is available on oral HPV in Brazilian population, especially for drug users, and our results showed higher HPV infection rates in both users and nonusers of drugs. More studies and researches focused on drug users including factors like sexual behavior, nutrition and cultural habits are necessary to enhance the comprehension of this relationship, and develop preventive strategies.

Associations between drug use patterns and viral load suppression among HIV-positive individuals who use support services in New York City.

BACKGROUND: Drug use (DU) represents a significant barrier to maintaining physical health among people living with HIV (PLWH). Few studies, however, have examined the relationship between DU over time and HIV treatment outcomes. Such studies are needed because an individual's risk of poor health outcomes may vary with their DU behaviors. We examined associations between DU patterns over time and unsuppressed viral load (VL). METHODS: The sample included 7896 PLWH in New York City who completed ≥3 substance use assessments over a 24-month period. DU was defined as crystal methamphetamine, crack/cocaine, heroin, and/or recreational prescription medication use in the last three months. Four behavior patterns were constructed: (1) persistent use (DU reported on each assessment); (2) intermittent use-active (DU reported on the third, but not all previous assessments); (3) intermittent use-inactive (DU reported previously with no DU reported on the third assessment); (4) persistent non-use (no DU reported on any assessment). Unsuppressed VL (>200 copies/mL) was assessed based on the last VL value in the New York City HIV Surveillance Registry in the 12 months following an individual's third DU assessment. RESULTS: Compared with persistent non-users, individuals with intermittent use-inactive (aOR = 1.24, 95% CI = 1.03-1.49), intermittent use-active (aOR = 1.68, 95% CI = 1.36-2.06), and persistent use (aOR = 2.21, 95% CI = 1.69-2.89) were significantly more likely to have unsuppressed VL. CONCLUSIONS: While providers may be more likely to intervene with persistent or active drug users, our findings suggest the importance of addressing the risk of poor HIV treatment outcomes among those with any DU behavior.