Stimulant Use and Viral Suppression In the Era of Universal Antiretroviral Therapy

Abstract

Background:

HIV-positive persons who use stimulants such as methamphetamine experience difficulties navigating the HIV care continuum that undermine the benefits of anti-retroviral therapy (ART). However, few studies have examined the association of stimulant use with viral suppression in the era of universal ART.

Setting:

Zuckerberg San Francisco General Hospital

Methods:

HIV-positive persons participating in a clinical cohort study and taking ART completed assessments every 4–6 months. The exposure was the cumulative, time-varying proportion of assessments with any self-reported stimulant use. The time-varying outcome, HIV viral suppression (i.e., < 200 copies/mL), was measured at assessments or extracted from the clinical record.

Results:

In total, 1,635 HIV-positive participants on ART contributed 17,610 person-visits over a median of 2.3 (Interquartile Range [IQR] = 1.0– 5.3) years of follow-up. Participants were middle-aged (Median = 45.0; IQR = 38.0–52.0), predominantly white (57%), sexual minority men (78%), with a median CD4+ T-cell count of 409 (IQR = 225–640) cells/mm³ at enrollment. Significant increases in odds of viral suppression over time were less pronounced among stimulant users compared to non-users, particularly prior to the advent of universal ART. Increasing odds of viral suppression were paralleled by declining stimulant use over time. In the universal ART era, increasing odds of viral suppression were observed at lower levels of stimulant use, but not when participants reported using stimulants at every visit.

Conclusions:

Although ART benefits are still not achieved as rapidly in stimulant users, this disparity is not as large in the era of universal ART.

Introduction

HIV-positive persons who use stimulants (i.e., methamphetamine, powder cocaine, and crack-cocaine) experience difficulties navigating the HIV care continuum that undermine the clinical and public health benefits of anti-retroviral therapy (ART). HIV-positive stimulant users initiate ART at lower T-helper (CD4+) cell counts,^1,2 are less likely to remain engaged in HIV care,³ and are more likely to report difficulties with ART adherence and persistence that contribute to substantially elevated HIV viral load.^4–6 The clinical relevance of these difficulties with HIV disease management is supported by prior research indicating that HIV-positive stimulant users may experience faster HIV disease progression,^1,7,8 including 50% greater odds of progression to AIDS or all-cause mortality among HIV-positive sexual minority men on ART who engage in more frequent stimulant use.⁹

One important gap is that relatively little is known about whether stimulant users continue to experience difficulties with achieving viral suppression in the era of universal ART.^10,11 Prior to universal ART, Fairbairn and colleagues¹² observed that injection methamphetamine use was associated with slower viral suppression. Optimizing rates of viral suppression has meaningful implications for reducing HIV incidence because HIV-positive stimulant users are more likely to report engaging in transmission risk behavior,^13–15 resulting in potentially amplified risk of onward HIV transmission where viral load is > 200 copies/mL.¹⁶ In the era of universal ART, it is unknown whether HIV-positive stimulant users who are engaged in HIV clinical care display slower viral suppression.

During the past decade, scientific advances have transformed the medical management of HIV infection such that current guidelines recommend initiation of ART at any CD4+ T-cell count (i.e., universal ART).¹⁷ Contemporary ART regimens are less burdensome. Patients often take one pill daily with far fewer side effects, and ART medication resistance profiles are generally more forgiving of non-adherence.¹⁸ Consequently, most HIV-positive persons receiving ART can achieve viral suppression and early ART initiation is crucial to prevent AIDS-related as well as serious non-AIDS-related clinical events.^19,20 Although universal ART has contributed to decreases in HIV incidence and greater life expectancy for HIV-positive persons,^21,22 not all patients are deriving comparable benefits and potential points of intervention need to be identified to address the resulting disparities.

Leveraging data from a large clinical cohort of HIV-positive persons in San Francisco, we examined the time-varying association of stimulant use with viral suppression in HIV-positive persons receiving ART from 2000 to 2016. We hypothesized that there would be a negative dose-response association between greater stimulant use and slower viral suppression. We also proposed that the time-varying association of stimulant use and delayed viral suppression would be most pronounced prior to the advent of universal ART in San Francisco (2000–2009).

Methods

Study of the Consequences of the Protease inhibitor Era (SCOPE) is a prospective, clinical cohort that began following HIV-positive persons on ART in the fall of 2000. Most participants (n = 1,049; 64%) were enrolled between 2000 and 2009, prior to the advent of universal ART in San Francisco.²³ All SCOPE participants complete informed consent at enrollment, and cohort procedures are approved by the institutional review board at the University of California, San Francisco. SCOPE assessments occur every four to six months and participants receive $25 at each assessment for their time and travel expenses. In the present study, we included participants receiving ART who had at least one SCOPE assessment. Where participants started ART prior to SCOPE enrollment (i.e., late entries), we included data from all SCOPE assessments that were completed. Where participants started ART after enrolling in SCOPE, only data from those assessments completed after ART initiation were included. All follow-up assessments conducted through December of 2016 were included in the present study regardless of whether participants reported that they remained on ART.

Exposure.

At each SCOPE assessment, participants completed a self-administered questionnaire assessing substance use in the past four to six months. Participants who reported using any methamphetamine, powder cocaine, crack-cocaine, or cocaine injection in the past four to six months were categorized as using stimulants. Consistent with prior research,⁹ we calculated the exposure, “cumulative, time-varying proportion of assessments with any self-reported stimulant use,” by summing the cumulative number of assessments where any stimulant use was reported and dividing by the cumulative number of assessments completed. We chose this measure because it provides meaningful information regarding chronic patterns of stimulant use and greater variability in the exposure variable when compared to a time-varying, binary measure of any recent stimulant use.

Main outcome.

HIV viral suppression (i.e., < 200 copies/mL) was the time-varying outcome. When HIV viral load was not measured at a given SCOPE assessment, it was extracted from the medical record at Zuckerberg San Francisco General Hospital. We extracted the HIV viral load from the medical record if it was collected within three months of a SCOPE assessment. The mean number of days between assessment of self-reported stimulant use and HIV viral load was 33 (SD = 24).

Analyses.

Multilevel modeling with random intercepts, random slopes for time and stimulant use, and unstructured covariance among the random effects were used to account for non-independence of HIV viral load measurements within individual participants over time. Multilevel models were fitted by maximum likelihood estimation. Time since cohort entry was modeled for those who were on ART at enrollment and time following ART initiation was modeled for those who initiated ART after enrollment. Time during which participants discontinued ART was included in the analyses. The intraclass correlation (ICC) was 0.73 for the unconditional model. Model selection was performed using likelihood ratio tests to arrive at the most parsimonious and efficient final model. Viral suppression was modeled against the fixed effects of years in the study, cumulative stimulant use, and their interaction. To understand more fully the interaction, we conducted stratified analyses of the time-varying association of stimulant use with viral suppression prior to the advent of universal ART (i.e., 2000–2009) and then in universal ART era (i.e., 2010–2016). To further interpret the interaction, the final model was used to generate the predicted probabilities in viral suppression over time at different levels of cumulative stimulant use, which were then plotted.

Similarly, we examined the average trajectory of cumulative stimulant use over time using multilevel modeling with random intercepts and slopes. Because there was only a main effect of time, we did not include an interaction term in the final model. We also examined whether there was consistency in changes over time for the cumulative use of each stimulant that was assessed.

The amount of missing data for the fixed effect predictors was less than 1%. Thus, the primary analysis was conducted using listwise deletion of observations with missing predictor data; observations with incomplete outcome data were included in the analysis under the missing at random (MAR) assumption via the maximum likelihood estimation algorithm. All analyses reported below were performed using Stata 13 (College Station, TX).

Results

In total, 1,635 HIV-positive participants on ART contributed 17,610 person-visits over a median of seven SCOPE follow-up assessments (Interquartile Range [IQR] = 3 – 16; Table 1). This is equivalent to a median of 2.3 years of follow-up (IQR = 1.0 – 5.3). Participants were middle-aged (Median = 45.0; IQR = 38.0–52.0), predominantly white (57%), sexual minority men (78%), with a median CD4+ T-cell count of 409 (IQR = 225–640) cells/mm³ at baseline (i.e., cohort enrollment or the assessment following ART uptake). Approximately 65% of participants were virally suppressed at baseline. Most participants were on ART at enrollment (n =1,055; 65%) and approximately one-third (35%) initiated ART during follow-up. Approximately one-fourth (28%) of participants reported any stimulant use in the past year at baseline and 42% of participants reported any stimulant use during follow-up.

Table 1.

Sample characteristics at cohort entry or anti-retroviral therapy (ART) initiation(N = 1,635)

Number of SCOPE visits	Median (IQR)	1,635	7.0 (3.0 – 16.0)
Age	Median (IQR)	1,635	45.0 (38.0 – 52.0)
Current gender		1,635
Female			183 (11.2)
Male			1,421 (86.9)
Gender minority			31 (1.9)
Race/Ethnicity	n (%)	1,635
Black/African American			314 (19.2)
White			932 (57.0)
Hispanic/Latino			172 (10.5)
Asian/Pacific Islander			66 (4.0)
Other Ethnic Minority			151 (9.2)
Sexual minority men	n (%)	1,626	1,261 (77.6)
HIV viral suppression (< 200 copies/mL)*	n (%)	1,331	867 (65.1)
CD4+ T-cell count*	Median (IQR)	1,446	409 (225 – 640)
Any stimulant use (Baseline)	n (%)	1,632	451 (27.6)
Any stimulant use over follow-up	n (%)	1,635	688 (42.1)

^*Note: measured closest to SCOPE entry/ART uptake date from +/− 90-day window.

Fixed effects from the overall model indicated a significant, negative interaction between cumulative stimulant use and years in the cohort predicting viral suppression (unstandardized Beta = −0.32 95% CI = −0.50 – −0.13; p = 0.001). As cumulative stimulant use increased, the strength of the positive association between years in the cohort and viral suppression decreased (see Table 2). Where stimulants were used at half of study visits, years in the cohort was significantly associated with greater odds of viral suppression in the era prior to universal ART (Odds Ratio [OR] = 1.36; 95% CI = 1.21 – 1.53) and in the universal ART era (OR =1.28; 95% = 1.06 – 1.55). At the highest level of stimulant use, years in the cohort were not significantly associated with greater odds of viral suppression in the era prior to universal ART (OR = 1.08; 95% CI = 0.89 – 1.32) or in the universal ART era (OR = 1.25; 95% CI = 0.98 – 1.59). Figure 1 provides a graphical representation of the predicted probabilities of viral suppression over time at different levels of cumulative stimulant use (i.e., 0%, 50%, and 100%).

Table 2.

Unadjusted association of years of cohort follow-up with viral suppression prior to and following the advent of universal anti-retroviral therapy (ART)

	Overall: 2000–2016 (N = 1,635)		Pre-Universal ART: 2000–2009 (n = 913)		Universal ART Era: 2010–2016 (n = 1,312)
	OR (95% CI)	p-value	OR (95% CI)	p-value	OR (95% CI)	p-value
Cumulative Stimulant Use
0%	1.62 (1.44 – 1.83)	< 0.0001	1.71 (1.51 – 1.94)	< 0.0001	1.31 (1.00 – 1.73)	0.05
50%	1.39 (1.25 – 1.54)	< 0.0001	1.36 (1.21 – 1.53)	< 0.0001	1.28 (1.06 – 1.55)	0.01
100%	1.18 (1.01 – 1.39)	0.04	1.08 (0.89 – 1.32)	0.44	1.25 (0.98 – 1.59)	0.08

Cumulative stimulant use = proportion of completed assessments where participants reported any stimulant use

Figure 1.

Predicted probability of viral suppression as a function of cumulative stimulant use (N = 1,635)

Fixed effects from the model examining changes in cumulative stimulant use over time indicated that for each year in the cohort, there was a resulting 0.8 percent decrease of cumulative stimulant use (unstandardized Beta = −0.80; 95% CI = −1.15, −0.47; p < 0.0001). There was strong consistency in declining cumulative stimulant use over time as a function of the universal ART era and when cumulative use of specific stimulants were examined separately (results not shown).

Discussion

This study is among the first to observe higher odds of viral suppression over time among less frequent stimulant users who were engaged in HIV care. Consistent with prior research,^4–6 there was no significant increase in the odds of viral suppression over time at the highest level of cumulative stimulant use. Among HIV-positive individuals participating in this modern universal ART era clinical cohort, the proportion of stimulant users who are able to achieve viral suppression appears to be rising. Taken together, results presented here provide support for the clinical decision to initiate universal ART with stimulant users and concurrently deliver evidence-based substance use interventions such as cognitive-behavioral therapy and contingency management to reduce stimulant-related harms.^10,11

It is noteworthy that participants reported concurrent decreases in stimulant use over time, which may partially explain increasing odds of viral suppression in less frequent stimulant users. Many people who use stimulants experience chronic, relapsing stimulant use disorders that were indexed in the present study using a measure of cumulative, time-varying stimulant use. Findings highlight the possibility that implementation of evidence-based treatments for stimulant use disorders could yield meaningful benefits for optimizing viral suppression, even without achieving complete abstinence from stimulants.^10,11

Important gaps in the implementation of universal ART continue to hinder progress toward achieving the UNAIDS 90–90-90 targets,^24,25 and comprehensive approaches are needed to boost the effectiveness of universal ART with HIV-positive substance users. Previous randomized controlled trials provide support for the efficacy of contingency management and multi-component behavioral interventions for short-term improvements in ART adherence and viral suppression.^26,27 Novel interventions that integrate pharmacologic and behavioral approaches are needed to optimize sustained viral suppression in HIV-positive substance users.^1,2,27 Although stimulant users achieved viral suppression more slowly, the present study provides further support for the potential clinical and public health benefits of expanding access to universal ART in this population.^21,28

Findings from this study should be interpreted in context of several important limitations. First, faster death rates among more frequent stimulant users could have introduced bias by inflating the rates of viral suppression over time. Future studies should incorporate information on mortality in competing risks analyses. Second, we observed declining stimulant use in a middle-aged cohort and assessment of viral suppression was within a 90-day window period of self-reported stimulant use. Further research is needed in younger cohorts that are followed over longer periods including collection of more nuanced diagnostic information about stimulant use disorder severity as well as biomarkers of recent stimulant use. Third, less than half of participants in this cohort were newly enrolled from 2010–2016. Further research with cohorts enrolled in the universal ART era is needed to examine the time-varying association of stimulant use and viral suppression. Fourth, it is unlikely that findings from a single clinical cohort are generalizable. This cohort was comprised of patients who were receiving HIV care in a well-resourced city where universal ART was implemented in 2010²³ and substance use disorder treatment was more readily accessible than most other cities in the United States.²⁹ Fifth, because these individuals were participating in an ongoing clinical cohort study, they may also have been more actively engaged in HIV medical care than the general population of HIV-positive stimulant users in the community. Sixth, prior research with injection drug users observed that female sex was associated with unsuppressed viral load,³⁰ suggesting the importance of understanding the role of sex as a biological variable among HIV-positive people who use drugs. The majority of participants in the present study were white sexual minority men and only 11% were women. Future community-based cohort studies that are more diverse will provide additional clarity on the extent to which distinct sub-groups of stimulant users display increasing odds of viral suppression in the universal ART era.

Conclusions

Increasing odds of viral suppression over time were paralleled by declining stimulant use. Delayed viral suppression at the highest level of stimulant use underscores the continued need for comprehensive efforts to optimize the benefits of universal ART with HIV-positive stimulant users.