Time to initiating highly active antiretroviral therapy among HIV-infected injection drug users

David D. Celentanoa; Noya Galaia,c; Ajay K. Sethia; Nina G. Shaha; Steffanie A. Strathdeea; David Vlahova,b,d; Joel E. Gallantb

From the aDepartment of Epidemiology, School of Hygiene and Public Health and bDepartment of Medicine, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, USA, the cDepartment of Epidemiology, Ben-Gurion University of the Negev, Beer-Sheva, Israel and the dCenter for Urban Epidemiologic Studies, New York Academy of Medicine, New York, New York, USA.

AIDS 2001;15:1707-1715

This article reports how IVDUs do not appear to be getting proper HIV treatment: they are not receiving HAART in an equal fashion as non-IVDUs. This study, completed in 1999, found that among IVDUs eligible for HAART 32% of participants remained treatment-naïve over the 3.5 year follow-up after reaching 500 cd4s and thus were eligible for HAART at that time. At this time-point, 59% had a history of receiving HAART, which represents an encouraging increase when compared with the 14% from a previous analysis of the same group. Over one-third reported non-HAART use only and only 6% reported exclusive use of HAART. Most of them were previously on zidovudine monotherapy or dual combination therapy, and as many as 34% remained on this suboptimal therapy, which is an unacceptable number of patients, taking into account that this modality of treatment is unable to suppress viral replication, and can lead to drug resistance and the limitation of future options.

IVDUs who used drugs consistently were much more likely to have HAART started at a much later time. Patients with intermittent drug use were more likely to start HAART sooner but initiation of therapy was still deferred. And persons who were abstinent were much more likely to received HAART sooner.

A number of reasons for these barriers to proper care for IVDUs. Read below for a more detailed account:


Objective: Studies have shown that HIV-infected injection drug users (IDUs) are less likely to receive antiretroviral therapy than non-drug users. We assess factors associated with initiating highly active antiretroviral therapy (HAART) in HIV-infected IDUs.

Methods: A cohort study of IDUs carried out between 1 January 1996 and 30 June 1999 at a community-based study clinic affiliated to the Johns Hopkins University, Baltimore, Maryland. The participants were a total of 528 HIV-infected IDUs eligible for HAART based on CD4+ cell count. The main outcome measure was the time from treatment eligibility to first self-reported HAART use, as defined by the International AIDS Society­USA panel (IAS­USA) guidelines.

Results: By 30 June 1999, 58.5% of participants had initiated HAART, most of whom switched from mono- or dual-combination therapy to a HAART regimen. Nearly one-third of treatment-eligible IDUs never received antiretroviral therapy. Cox proportional hazards regression showed that initiating HAART was independently associated with not injecting drugs, methadone treatment among men, having health insurance and a regular source of care, lower CD4+ cell count and a history of antiretroviral therapy.

Conclusions: Self-reported initiation of HAART is steadily increasing among IDUs who are eligible for treatment; however, a large proportion continues to use non-HAART regimens and many remain treatment-naive. Although both groups appear to have lower health care access and utilization, IDUs without a history of antiretroviral therapy use would have more treatment options available to them once they become engaged in HIV care.

Previously reported studies going back a few years reported less use of antiretroviral therapy for HIV by IV drug users:

In 1996, protease inhibitors (PIs) became available to treat individuals with human immunodeficiency virus (HIV) infection, and were demonstrated to reduce plasma HIV-RNA to below detectable levels [1­3]. Use of highly active antiretroviral therapy (HAART) was quickly adopted in several populations. In the Multicenter AIDS Cohort Study of homosexual and bisexual men, HAART use at the population level rose from 3% in 1996 to 65% in mid-1998 [4]. In a random sample of HIV-infected individuals in the HIV Cost and Services Utilization Study (HCSUS), 85% of participants eligible for therapy (CD4+ cell count less than 500 ? 106 cells/l) reported receiving a PI or non-nucleoside reverse transcriptase inhibitor (NNRTI) treatment by 31 January 1998 [5]. In this national study, inadequate HIV care was more common among Blacks and Latinos, the uninsured and Medicaid-insured, women and risk groups other than men who had sex with men, even after adjusting for CD4+ cell counts. These data indicate that use of HAART may be less common in those with poor access to health care.

Two recent cross-sectional studies of HAART use among IDUs have been reported. In Baltimore, Maryland, we showed that 14% of treatment-eligible IDUs reported HAART use between July 1996 and June 1997; 49% reported no treatment [6]. Factors associated with reporting no antiretroviral therapy use included active drug use, sub-optimal HIV health care, not receiving drug treatment and recent incarceration. During the same period, in Vancouver, British Columbia, where antiretroviral therapy is offered free to all HIV-infected persons who meet International AIDS Society­USA panel (IAS­USA) guidelines [7], only 40% of eligible IDUs received any antiretroviral therapy, and 27% received HAART [8]. Younger individuals, females, those not currently enrolled in drug treatment, and those with inexperienced physicians were less likely to be receiving HAART. Using our cohort of well-characterized IDUs and factors that were found to be associated with HAART use in our previous cross-sectional study [6],

We identified IDUs who were treatment-eligible between 1 January 1996 and 30 June 1999 and examined factors associated with the time to initiating HAART.

What are the reasons IVDUs get or don¹t get HIV treatment?

Among the socio-demographic factors, older age (P = 0.002) and higher education (P = 0.017) were associated with increased probability of beginning HAART, whereas incarceration (P < 0.001) and consistent injection drug use (P < 0.001) were not associated with HAART initiation. Higher income (P = 0.10) and homelessness (P = 0.020) were associated with commencing HAART, although they were marginally significant. Overall, the probability of initiating HAART did not differ by gender, ethnicity, or employment.

Any injection of drugs was strongly associated with not initiating HAART (P < 0.001). Relative to abstinence, consistent injection drug use was associated with a reduction of over 50% in the probability of beginning HAART (P < 0.001), whereas intermittent use was associated with a 20% reduction in probability, although this was not significant. Overall, enrolment in methadone maintenance was associated with a higher probability of initiating HAART (P < 0.013). However, this effect was limited to male participants only. In our cohort, although women were more likely than men to be enrolled in a methadone maintenance program [odds ratio (OR), 2.76; 95% CI, 2.11­3.61], their participation was not associated with initiating HAART (RH, 0.51; 95% CI, 0.24­1.10).

On average, IDUs with health insurance were over three times more likely to begin HAART (P < 0.001). Not surprisingly, participants reporting having continuity of care were almost four times more likely to initiate HAART (P < 0.001). Similarly, having a regular source of health care (other than ALIVE study visits) was strongly associated with starting HAART (P < 0.001). Among health care utilization measures, participants with less than two ambulatory care visits were, on average, 80% less likely to initiate HAART (P < 0.001). Finally, all clinical variables [AIDS symptoms (P = 0.00), AIDS diagnosis (P < 0.001), and low CD4+ cell count (P < 0.001)] were significantly associated with initiation of HAART in Cox univariate analysis.

Consistent drug use was independently associated with a 58% decrease in probability of initiating HAART after adjusting for other variables (P = 0.001). Men enrolled in methadone maintenance were 80% more likely to commence HAART, whereas no such effect was observed for women (P = 0.052). Health care access, defined as having health insurance and having a regular source of care (at least 90% health care visits are to the same provider), were associated with initiating HAART (RH, 2.05 and 1.74, respectively). In addition, after adjusting for factors in the model, IDUs who reported antiretroviral therapy use prior to 1996 (monotherapy and dual combination therapy) were 2.3 times more likely to initiate HAART during follow-up than those who were treatment-naive (P < 0.001). With respect to clinical health status, each increase in CD4+ cell count of 100 ? 106 cells/l was associated with a 15% decrease in probability of starting HAART after adjusting for other factors (P = 0.011).

Overall, 32% of participants remained treatment-naïve over the 3.5 year follow-up. Over one-third reported non-HAART use only and only 6% reported exclusive use of HAART. Twenty-eight percent reported using both non-HAART and HAART during follow-up, with the majority (138 of 148 or 93%) reporting a switch from a non-HAART to a HAART regimen. Among participants who initiated HAART during follow-up, 159 (89.3%) initiated HAART that contained a PI while 19 (10.7%) started HAART regimens that were PI-sparing.

Although the proportion of individuals receiving non-HAART regimens decreased significantly between 1996 and mid-1999, it remains unacceptably high, at 34%.

These regimens are no longer recommended because they are unable to maximally suppress viral replication and therefore may lead to the development of drug resistance that would limit future treatment options. It has been shown that individuals receiving HAART who have had prior treatment experience are less likely to achieve an undetectable viral load relative to those who were previously treatment-naïve.

Approximately one-third of the cohort remained treatment-naive over the study period, although all were treatment-eligible on the basis of CD4+ cell count. The lack of treatment may reflect patient or provider decisions to delay treatment until it is deemed necessary or when the patient is ready to commence HAART.

In our cohort, a larger percentage (33%) of IDUs are uninsured, and fewer (54%) are covered by Medicaid, underscoring the strong association between health care access and the initiation of effective treatment. Our participants who reported Medicaid insurance were as likely to receive HAART as those who were privately insured. Poor utilization of health care among IDUs can be partially explained by the fact that HIV-infected IDUs seek medical attention later in the course of disease [15­19]. In the present study having a low CD4+ count during the previous 6 months was associated with receiving HAART and recently seeing a physician.

Although we lack data on the characteristics of the HIV care providers utilized by our cohort, less experienced providers may continue to treat patients with non-HAART regimens until the patient demonstrates adherence with their medication and clinic visits and substance abuse is under control. Some providers may believe that if IDUs are less likely to attain undetectable viral loads than non-IDUs because of poorer adherence.

Some providers may believe that if IDUs are less likely to attain undetectable viral loads than non-IDUs because of poorer adherence [20] there could be potential transmission of multi-drug resistant HIV [21,22]. A comparison of exposure groups in the EuroSIDA study revealed that IDUs were indeed less likely to commence HAART, but among those who did, their response to therapy was similar to other risk groups.

Due to the rapid development of new drugs and continually evolving treatment strategies, staying abreast of the most advanced information can be challenging for providers. As a result, patients seen by primary care providers who see few HIV-infected patients may receive sub-optimal care [24,25]. On the other hand, it is possible that less experienced clinicians may follow treatment guidelines too rigidly, prescribing HAART to all patients without first assessing their ability to adhere to therapy.

However, to ensure long-term success of antiretroviral treatment in patients who can wait to initiate HAART, experienced providers recommend delaying therapy, until adherence-related issues are addressed [13,26]. Such issues, which include drug and alcohol use, active mental illness, including depression, and homelessness, require referrals to substance abuse treatment, psychiatrists, and social workers. Other factors that may impact adherence to antiretroviral therapy include poor knowledge about HIV infection and treatment and the lack of belief in the efficacy of antiretroviral therapy, which require continual counseling by providers.

Clinician awareness of patient drug use may lead to more conservative management, not prescribing antiretroviral therapy.

The study period covered in this analysis is from 1 January 1996 to 30 June 1999. Since then, expert opinion regarding the optimum time to start therapy has changed somewhat. Today, many providers feel that CD4+ cell count may be a better indicator of the need for therapy than viral load, and patients could wait longer before starting. Whereas many suggest waiting until CD4+ cell count has dropped to 350 ? 106 cells/l, some will even suggest waiting for a nadir of 200 ? 106 cells/l. The rationale for delayed therapy is based on the following considerations: (1) early therapy may lead to premature drug resistance, due in part to non-adherence; (2) the long-term toxicity of antiretroviral therapy may prevent patients from taking these regimens continuously for decades; (3) most patients who begin therapy with CD4+ cells counts above 200 ? 106 cells/l have excellent virologic and immunologic responses to therapy. Thus, many IDUs in whom therapy was deferred (regardless of the reason) will find themselves in the enviable position of being treatment-naive, whereas all too many of those who were treated according to the guidelines at that time have already run out of treatment options or are experiencing difficult toxicity. However, many IVDUs are not starting therapy until they are sick: very low CD4s, high viral load, and have opportunistic infections.

Integrating antiretroviral therapy regimens and drug abuse treatment may offer one avenue for the effective management of these two related medical problems. Current treatment guidelines call for addressing issues of substance abuse as an integral component of HIV management. Participants who reported being on methadone maintenance may be viewed by their providers as being stable and more likely to be adherent to HAART regimens, although in our analysis, this may not be the case for women. Although the confidence interval around our point estimate includes 1.0 for women who reported methadone use, the relative hazard was substantially lower than 1.0, suggesting that this subgroup of women are actually less likely to initiate HAART. It is believed that methadone treatment may encourage health-seeking behaviors, including antiretroviral therapy utilization, among drug users who had previously not sought care. Given our observation, this may be truer for men than women, perhaps reflecting a woman's reluctance to seek medical care to avoid disclosing their drug use. Alternatively, this may reflect a tendency of providers to be less willing to prescribe HAART to female IDUs. As providers become more experienced in the HIV treatment of drug users, there appears to be increased willingness to prescribe more complex and aggressive therapies for this population. (Often, women may have more barriers to starting therapy: children or a spouse to care for leading to more difficult living circumstances).

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