Optimizing Treatment Outcomes in HIV-Infected Patients with Substance Abuse Issues

SUPPLEMENT ARTICLE Optimizing Treatment Outcomes in HIV-Infected Patients with Substance Abuse Issues David D. Celentano 1 and Greg Lucas 2 1 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, and 2 Division of Infectious Diseases, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland Drug abuse is associated with poorer virologic and clinical outcomes for patients with human immunodeficiency virus (HIV) infection. Limited evidence, primarily from in vitro and animal studies, shows that some abused drugs (e.g., opioids) may have direct effects on HIV pathology and the immune response to infection, but the clinical effects are not known. Clinical data indicate that the primary effect of drug abuse on HIV disease progression is mediated via factors that may limit access and/or adherence to highly active antiretroviral therapy (HAART). Drug abuse is associated with reduced adherence to HAART, which is strongly correlated with poorer virologic and clinical outcomes. However, the virologic and clinical effects of HAART are generally equivalent among drug abusers and non drug abusers who adhere to therapy. These results underscore the importance of integrating medical and substance abuse interventions for HIV-positive drug abusers, to improve adherence to HAART and optimize outcomes of treatment for HIV infection. Injection drug use (IDU) remains a major risk factor for HIV infection [1]. Additionally, abuse of alcohol and/or illicit noninjection drugs is common among HIV-infected patients who do not inject drugs. Drug abuse is associated with a constellation of medical and psychosocial comorbidities and is widely believed to exacerbate the course of HIV infection. Kapadia et al. [2] suggested 2 possible non mutually exclusive reasons for this relationship: (1) abused drugs directly or indirectly effect viral replication and/or the immune system response to HIV infection, and/or (2) abused drugs adversely effect optimal treatment of HIV infection. This review explores the effects of drug abuse on HIV disease progression, summarizes potential reasons for the impact of drug abuse on treatment outcomes for Presented in part: Conference on Opportunities for Improving HIV Diagnosis, Prevention & Access to Care in the U.S., Washington, D.C., 29 30 November 2006. Reprints or correspondence: Prof. David D. Celentano, Dept. of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St. (E-6547), Baltimore, MD 21205 (dcelenta@jhsph.edu). Clinical Infectious Diseases 2007; 45:S318 23 2007 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2007/4512S4-0020$15.00 DOI: 10.1086/522557 patients with HIV infection, and discusses the importance of integrating substance abuse treatment with medical care for patients with these interrelated conditions. DRUG ABUSE, HIV INFECTION, DISEASE PROGRESSION, AND MORTALITY There is limited evidence, primarily from animal models and in vitro studies, that abused drugs may alter the pathophysiology of HIV infection. For example, opioid exposure has been shown to reduce the ability of human peripheral lymphocytes to repair DNA damage caused by either physical or chemical mutagens that produce single-strand adducts, and it has been suggested that this genetic damage might increase the likelihood of apoptosis and the impact of HIV infection [3]. There is also evidence that opioids have the potential to compromise host responses to viral infections and promote HIV replication in vitro [4] and to increase infection of human blood mononuclear phagocytes [5]. Another group found that methamphetamines enhance the replication of cell-associated feline immunodeficiency virus (FIV) in astrocytes [6]. Although most data from studies involving animal models support the hypothesis that abused drugs have adverse S318 CID 2007:45 (Suppl 4) Celentano and Lucas

effects on viral pathogenesis or host response, not all studies have reached this conclusion. For example, a study using an FIV model found that clinical progression of disease in cats injected with opioids was delayed or moderated [7]. Although these observations have raised the hypothesis that opioids may accelerate the progression of HIV disease via a direct biologic effect, available clinical data have generally not supported this possibility. Results from older epidemiologic studies that examined markers of disease progression and/or reasons for death provide little support for the hypothesis that drug abuse has clinically important direct biologic effects on the course of HIV disease. Rather, these results suggest that the increased mortality among drug-abusing patients with HIV infection was primarily due to factors not directly associated with AIDS. Follow-up during 1994 2000 of 2059 women with and 569 women at risk for HIV infection indicated that 468 (18%) died during this interval. Assessment of the causes of death for 428 participants for whom mortality data were available indicated that drug abuse did not increase the risk for death due to AIDS but that it did significantly increase risk for death due to non AIDSrelated factors, including liver failure, drug overdose, non AIDS-associated malignancies, cardiac disease, murder, suicide, and accidents [8]. Other cohort studies conducted during the pre-haart era generally found no differences between the risk of clinical disease progression and the presence of various HIVacquisition risk factors [9, 10]. Further support for the view that increased mortality associated with drug abuse among patients with HIV infection was not due to more-rapid disease progression was provided by results from other studies during the pre-haart era, which showed that the decrease in CD4 cell count was the same in drug abusers and men who had sex with men (MSM) and was not significantly associated with current use of injection drugs, frequency of drug injection, type of drug abused (heroin, cocaine, or both), or withdrawal episodes [11, 12]. Thus, results from the pre-haart era are consistent with the conclusion that, although the overall risk for death among HIV-infected persons may be higher among drug abusers than among non drug abusers, this difference is not significantly associated with an accelerated decrease in immune system function or an increased risk of AIDS-associated mortality. with poorer adherence among persons for whom HAART is available. Access to HAART. Several studies have demonstrated that HIV-infected drug abusers have decreased access to HAART. In a community-based cohort study, 528 HIV-infected persons with a history of IDU who, on the basis of their CD4 cell count, were eligible for HAART were followed for a 3.5-year period that ended in June 1999 [13]. A total of 41.5% of participants had not initiated HAART by the end of the study period. Furthermore, current use of injection drugs (defined as use of injection drugs during the follow-up period) was significantly associated with a failure to initiate HAART. A study performed in France, where all HIV-infected patients have access to AIDSspecific specialized hospital care, also showed that current use of injection drugs significantly decreased the likelihood of being prescribed antiretroviral therapy [14]. Analysis of treatment data for 764 patients with HIV infection who were attending an urban HIV clinic indicated that current users of drugs were significantly less likely non drug abusers and former drug abusers to be using HAART ( P!.001 for both comparisons) (figure 1) [15]. Delay in initiation of HAART has been associated with poorer outcomes in HIV-positive drug abusers. Investigation of a multicenter, hospital-based cohort of 4643 HIV-infected patients in Spain indicated that the probability of initiating HAART was 33% lower and the risk of AIDS-associated death 2.5 times higher among patients who became infected through IDU, compared with patients who became infected through male-male sex [16]. Adherence to HAART. Adherence to therapy is a critically important determinant of clinical and virologic outcomes for IMPACT OF DRUG ABUSE ON HAART ACCESS, ADHERENCE, AND OUTCOME AMONG HIV- INFECTED PATIENTS Although there is little evidence to support the view that drug abuse has clinically important direct effects on HIV disease progression, a number of studies have demonstrated that drug abuse may be associated with decreased access to HAART and Figure 1. Use of HAART by non drug users, former drug abusers, and current drug abusers. *Versus the other groups. Data are from [15]. HIV Treatment in Substance Abusers CID 2007:45 (Suppl 4) S319

patients who have been prescribed HAART, and there is considerable evidence that reduced adherence to therapy contributes to poorer outcomes for patients with HIV infection who are also drug abusers [17 19]. The importance of adherence to HAART for patients with HIV infection has been clearly demonstrated by Hogg et al. [20], who followed 1282 patients for 1 year. Their study indicated that the risk of all-cause mortality was nearly 3-fold higher among patients who were 75% adherent to antiretroviral therapy, compared with patients who were 175% adherent to treatment (figure 2). Drug abuse by patients receiving HAART is strongly correlated with poor adherence to therapy and reduced efficacy of treatment in suppressing viral replication. Arnsten et al. [19] showed that adherence, as defined by the number of cap openings measured by the Medication Event Monitoring System (Aprex), during a 6-month study period was 27% for patients who reported current abuse of cocaine and 68% for patients who reported no cocaine abuse. Viral suppression (defined as an HIV RNA level of!500 copies/ml) was achieved by 13% of cocaine abusers and 46% of nonabusers, and achievement of an undetectable viral load was significantly correlated with adherence to therapy. Similar relationships among drug abuse, adherence to HAART, and viral suppression were reported by Wood et al. [21], who, in a comparison between drug abusers and non drug abusers who were adherent to HAART, found that the probabilities for achieving an HIV RNA load of!500 copies/ml were equivalent in the 2 groups (figure 3). In another study, this group observed the same pattern in an analysis of CD4 cell counts [22]. In this report, CD4 cell counts in drug abusers decreased more rapidly than those in non drug abusers, but no such difference was found when the analysis limited to HAART-adherent subjects. These results support the view that poorer outcomes in HIV-infected drug abusers arise because drug abuse adversely affects HAART adherence, rather than because abused drugs have direct biologic effects on HIV pathogenesis. Results from the Johns Hopkins HIV cohort demonstrated that active abuse of drugs increased the risk of opportunistic infection and death during the HAART era. Study of this cohort showed that, during the HAART era (1996 1999), current abusers of drugs had significantly shorter event-free intervals (defined as the absence of AIDS-defining opportunistic infection or death), compared with non drug abusers. In contrast, before the advent of HAART (1991 1995), there was no significant difference between groups for these outcomes [23]. Moreover, the disparity in clinical outcomes between drug abusers and non drug abusers appears to be widening as treatment for HIV infection has improved [24]. Investigation of this same group of patients indicated further that the rate of opportunistic infection among persons currently abusing drugs was significantly Figure 2. Kaplan-Meier product limit estimates of cumulative progression to death among 847 HIV-positive subjects who had at least 12 months of follow-up and were naive to antiretroviral therapy before initiating treatment between August 1996 and September 1999. Adapted from the following article with permission from Lippincott Williams & Wilkins: Hogg RS, Heath K, Bangsberg D, et al. Intermittent use of triplecombination therapy is predictive of mortality at baseline and after 1 year of follow-up. AIDS 2002; 16(7):1051 8. higher than the rate among non drug abusers and among former abusers of drugs and that the rates of opportunistic infection in the latter 2 groups were not significantly different [25]. Although adherence was not evaluated in this study, previous evaluations of the Johns Hopkins cohort indicated that, similar to findings from other studies, current drug abusers had poorer adherence to HAART than non drug abusers [15]. The results summarized in this section suggest that the major reasons for poorer virologic and clinical outcomes among drug abusers with HIV infection are delayed access to therapy and poor adherence to therapy. This conclusion is supported by the observation that, although outcomes for drug abusers and non drug abusers differed little when therapy was relatively ineffective (i.e., before the advent of HAART), differences have emerged during the HAART era. The advent of HAART greatly increased the importance of adherence to therapy, and poor adherence among drug abusers has resulted in increased risk for AIDS-related events and death in this population. BARRIERS TO OPTIMAL HIV CARE Drug abuse is associated with a variety of barriers that may delay initiation of HAART and negatively impact adherence to this therapy once it is started. HIV-infected drug abusers are likely to be poor and to have unstable housing arrangements, S320 CID 2007:45 (Suppl 4) Celentano and Lucas

Figure 3. Kaplan-Meier estimates of the probability of maintaining a detectable plasma HIV RNA load (defined as an HIV RNA level of 500 copies/ml) in a cohort of 1422 patients who initiated HAART during the study period (left) and a subpopulation of 816 patients who were adherent to HAART (right), according to history of injection drug use. Adapted from the following article with permission from the Canadian Medical Association: Wood E, Montaner JS, Yip B, et al. Adherence and plasma HIV RNA responses to highly active antiretroviral therapy among HIV-1 infected injection drug users. CMAJ 2003; 169:656 61. concomitant mental health problems and a suboptimal social support network. Many of these factors may be associated with patients insufficient adherence to therapy and with health care professionals increased difficulty in ensuring their patients adhere to therapy [26, 27]. Drug abusers may also have comorbid medical conditions, including nutritional deficiencies, coinfection with hepatitis C virus, systemic bacterial infections, and sexually transmitted infections, that negatively affect adherence to HAART and other therapy. It has also been noted that many drug abusers have had negative experiences with health care professionals and the health care system, which may also adversely impact their adherence to antiretroviral therapy [26]. Many factors may negatively affect adherence to therapy and treatment outcomes for HIV-infected drug abusers, and drug abuse has been cited by heath care professionals as a reason for delaying initiation of HAART for these patients [28]. However, HAART should be offered to all patients meeting criteria for initiation of therapy, and integrated models of care should be implemented to reduce the risk for nonadherence among HIV-infected patients who use drugs [29]. INTEGRATED CARE FOR HIV-INFECTED DRUG ABUSERS Services for the multiple medical and psychosocial problems faced by HIV-infected drug abusers are often provided by a wide range of health care professionals (who may not be aware of each other), frequently in different venues. This fragmentation increases the risk for poor adherence, limited follow-up, treatment cessation, and adverse clinical outcomes [30]. Integrated care for HIV-positive drug abusers should be aimed at bringing multiple treatment modalities, including HIV-specific care and general medical care, substance abuse intervention, case management, and psychosocial intervention, under a single roof. Such programs should be patient centered rather than professional centered and should provide opportunities for collaboration among health care professionals with subspecialties that are otherwise typically separated. Treatment should be delivered by health care professionals who are comfortable with drug abusers. Two general approaches have been taken to achieve integration of therapy: the addition of medical care to substance abuse treatment programs or the addition of substance abuse treatment to medical clinics. Although the effectiveness of these approaches for improving long-term outcomes in HIV-infected drug abusers has not yet been demonstrated in large-scale controlled trials [30], results from several studies have provided preliminary support for this approach to treatment delivery. Interventions for Seropositive Injectors Research and Evaluation (INSPIRE) is a randomized controlled trial of an integrated intervention for HIV-positive drug abusers that is being HIV Treatment in Substance Abusers CID 2007:45 (Suppl 4) S321

performed in 4 US cities. For 1161 HIV-positive injection drug users participating in INSPIRE, the retention rate is 180%, HAART is being used by 49%, and an undetectable HIV load have been achieved by 19% [31]. Baseline results from INSPIRE also underscore that a high level social support, a stable housing situation, and good communication between patients and health care professionals are important for achievement of optimal treatment outcomes by drug abusers receiving HAART. In addition, the study showed that all 3 factors were significantly correlated with achievement of an undetectable viral load [32]. DIRECTLY ADMINISTERED ANTIRETROVIRAL THERAPY (DAART) AND OPIOID SUBSTITUTION AS KEY COMPONENTS OF INTEGRATED THERAPY AIMED AT IMPROVING ADHERENCE TO HAART AMONG DRUG ABUSERS DAART. DAART has gained attention as an approach for improving medication adherence and clinical outcomes in patients with HIV infection. Results from several studies support its effectiveness for improving adherence in HIV-positive drug abusers [33 35]. Lucas et al. [34] provided DAART to 82 HIVinfected injection drug users at 3 urban methadone clinics. Findings for these patients were compared with those for the following 3 groups of patients from the Johns Hopkins HIV cohort: patients with a history of IDU who were receiving methadone at the time of HAART use (the IDU-methadone group), patients with a history of IDU who were not receiving methadone at the time of HAART use (the IDU-nonmethadone group), and patients with no history of IDU (the non-idu group). Twelve months after initiating therapy, a viral load of!400 copies/ml was achieved by 56% of patients in the DAART group, compared with 32% in the IDU-methadone group ( P p.009), 33% in the IDU-nonmethadone group ( P p.001), and 44% in the non-idu group ( P p.077). It is important to note that DAART is not invariably more effective than standard care for improving adherence among patients with HIV infection. A comparison of DAART, intensive adherence-based case management, and standard care in a study of 250 randomized patients (only 6% of whom were infected via IDU) indicated no significant differences among treatment arms with respect to the percentage of patients adherent to therapy, the percentage of patients with a viral load of!400 copies/ml, and CD4 cell counts during 6 months of follow-up [36]. Of note, adherence and viral suppression rates were high for the control group in this nonrandom patient sample, making it difficult to ascertain whether the adherence intervention had a beneficial effect. Opioid substitution. Buprenorphine therapy may provide a viable way to bring treatment of substance abuse into the HIV clinic [37]. Buprenorphine is a partial opioid agonist approved in 2002 for outpatient treatment of opioid dependence, and it may represent a significant advancement in substance abuse treatment for patients with HIV disease [38]. A clinical trial involving individuals without HIV infection had shown that buprenorphine is highly effective for the treatment of opioid dependence and that it can be administered with a twiceweekly dosing schedule [39]. A small-scale observational study of 164 HIV-positive drug abusers indicated that treatment with buprenorphine was associated with improved adherence to HAART [40]. CONCLUSIONS Results summarized in this brief review indicate that drug abuse and HIV infection are interacting chronic diseases. There is limited evidence that drug abuse has clinically significant biologic effects on the pathogenesis of HIV infection, but there is stronger support for the view that drug abuse negatively interferes in multiple ways with optimal management of HIV infection. HIV-infected drug abusers start treatment later than non drug abusers, have poorer long-term adherence to HAART, achieve viral suppression less frequently, and experience more rapid disease progression and higher mortality than non drug abusers. Integrated-care models that combine medical therapy with interventions aimed at eliminating substance abuse have the potential to significantly improve outcomes for drug abusers with HIV infection. However, these approaches must be validated by results from large-scale, long-term, controlled clinical trials. Improving outcomes in HIV-infected drug abusers requires vigilance and ongoing counseling to decrease high-risk behaviors and enhance adherence to therapy. Acknowledgments We thank Bob Rhoades for his assistance in preparing this manuscript. The Opportunities for Improving HIV Diagnosis, Prevention & Access to Care in the U.S. conference was sponsored by the American Academy of HIV Medicine, amfar, the Centers for Disease Control and Prevention, the Forum for Collaborative HIV Research, the HIV Medicine Association of the Infectious Diseases Society of America, and the National Institute of Allergy and Infectious Diseases. Funding for the conference was supplied through an unrestricted educational grant from Gilead Sciences, amfar, GlaxoSmithKline, Pfizer, Abbott Virology, OraSure Technologies, Roche Diagnostics, and Trinity Biotech. Supplement sponsorship. This article was published as part of a supplement entitled Opportunities for Improving the Diagnosis of, Prevention of, and Access to Treatment for HIV Infection in the United States, sponsored by the American Academy of HIV Medicine, amfar, the Centers for Disease Control and Prevention, the Forum for Collaborative HIV Research, the HIV Medicine Association of the Infectious Diseases Society of America, and the National Institute of Allergy and Infectious Diseases. Potential conflicts of interest. D.D.C. and G.L.: no conflicts. References 1. Centers for Disease Control and Prevention (CDC). HIV/AIDS surveillance report, 2005. Rev. ed., Vol. 17. Atlanta, GA: US Department of Health and Human Services, CDC, 2007. Available at: http://ww w.cdc.gov/hiv/topics/surveillance/resources/reports/2005report/pdf/2 005SurveillanceReport.pdf. Accessed 7 June 2007. S322 CID 2007:45 (Suppl 4) Celentano and Lucas

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