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Increased Human Immunodeficiency Virus Loads in Active Methamphetamine Users Are Explained by Reduced Effectiveness of Antiretroviral Therapy
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The Journal of Infectious Diseases 2003;188:1820-1826
Ronald J. Ellis,1,2 Meredith E. Childers,1,2 Mariana Cherner,2,3 Deborah Lazzaretto,2,3 Scott Letendre,2,4 Igor Grant,2,3 and the HIV Neurobehavioral Research Center Groupa
1Department of Neurosciences, 2HIV Neurobehavioral Research Center, and Departments of 3Psychiatry and 4Medicine, University of California San Diego, San Diego
ABSTRACT/SUMMARY
Abuse of methamphetamine (METH) is a frequent comorbidity among individuals infected with human immunodeficiency virus (HIV) type 1. In cell cultures and animal models, METH accelerates retroviral replication. To determine whether METH increases HIV replication in humans, we evaluated HIV loads in HIV-positive METH users and nonusers.
We studied 3 groups: Tox+, active METH use and positive urine toxicology results; METH+Tox-, previous METH dependence/abuse and negative urine toxicology results; METH-Tox-, no METH dependence/abuse and negative urine toxicology results. Tox+ subjects' plasma virus loads were significantly higher than METH+Tox- and METH-Tox- subjects'; cerebrospinal fluid virus loads showed a similar but nonsignificant trend.
Stratification by use of highly active antiretroviral therapy (HAART) revealed that virus loads were higher only in those Tox+ subjects who reported receiving HAART. In contrast, abstinent former METH abusers (METH+Tox-) receiving HAART effectively suppressed viral replication.
These data suggest that abstinence programs are a key component of effective treatment of HIV in METH-abusing populations.
BACKGROUND
Recreational methamphetamine (METH) use is common in many areas of the United States, and its prevalence continues to increase. METH use and human immunodeficiency virus (HIV) infection frequently coexist, perhaps, in part, because of the association of METH use with behaviors that carry a high risk for infection. Interactions between METH use and HIV infection are of public health concern for 3 principal reasons. First, experimental evidence from cell cultures and animal models suggests that METH exposure can accelerate feline immunodeficiency virus (FIV) replication, potentially hastening progression to AIDS and death. Second, the specific pathogenic mechanisms by which METH influences replication may be amplified in the central nervous system (CNS), raising the possibility of additive or synergistic neurological damage and disability in HIV-infected METH users. Third, factors such as reduced access to medical care and inadequate adherence to the therapy regimen may limit the ability of METH users to benefit from highly active antiretroviral therapy (HAART).
In the present study, we evaluated potential interactions between METH use and HIV infection by measuring HIV loads in current METH users and abstinent former abusers and comparing them to subjects with no history of METH dependence or abuse. To address the possibility that the effects of METH use on virus load are amplified in the CNS, we measured virus load in cerebrospinal fluid (CSF) as well as in blood plasma. To assess the potential influence of METH use on HAART efficacy, we grouped subjects according to current use of HAART and analyzed their self-reported adherence to the therapy regimen.
DISCUSSION by authors
METH stimulates secretion of tumor necrosis factor (TNF) in splenocytes from retrovirus-infected mice. Similarly, cocaine, a recreational stimulant with prominent dopaminergic effects that are similar to those of METH, increases production of TNF- and HIV replication in human peripheral blood mononuclear cells and stimulates viral replication in human peripheral blood leukocytes implanted into severe combined immunodeficient mice. These findings suggest that stimulants such as METH might increase virus loads in humans by dysregulating inflammatory cytokine production. The present study has found that, in fact, plasma virus loads were higher in Tox+ subjects than in METH+Tox- subjects or METH-Tox- subjects. Although this intriguing finding is consistent with the in vitro data, further analyses demonstrated a compelling alternative explanation for the increased virus loads seen in Tox+ subjects.
More than half of the subjects in this study were receiving HAART. HAART is prescribed to suppress viral replication, and its effects on virus load typically are very significant. Thus, declines of 100-1000-fold from baseline are quite common. We therefore considered it important to assess whether HAART effects modified the influence of METH use on virus load. Indeed, subgroup analyses demonstrated that, compared with subjects in the other groups, Tox+ subjects had increased plasma virus loads only if they were receiving HAART. Untreated Tox+ subjects and those receiving suboptimal therapy had virus loads statistically indistinguishable from those of subjects in the other groups. This is not consistent with a direct biological effect of METH use itself on viral replication. Rather, it suggests that recent METH use and ART interact in their effects on virus load.
Antiretroviral medications suppress viral replication only if drug concentrations are maintained at levels greater than a certain, drug-specific threshold. Inadequate adherence to strict medication administration schedules can allow concentrations to fall below these thresholds, resulting in a rebound of viral replication. Enhanced elimination of antiretrovirals via metabolic pathways due to drug-drug interactions also may lower concentrations below these thresholds. Thus, the increase in virus load that we found among Tox+ subjects receiving HAART may be due to poor adherence or to altered metabolism of antiretroviral medications. Although no consistent reports of altered drug metabolism related to METH use exist, there is substantial literature on impaired adherence to the therapy regimen among stimulant users. Impaired adherence to the therapy regimen, in turn, is believed to contribute to less-effective inhibition of viral replication and to the development of resistance to antiretroviral drugs. We collected self-reports of adherence to the HAART regimen and found these to be similar in Tox+ subjects, compared with subjects in the other groups. However, self-reports of adherence to the therapy regimen are frequently inaccurate.
It is possible that some METH+Tox- subjects falsely reported abstinence from METH during the 30 days before evaluation. If so, virus loads in these subjects would be expected to be similar to those of Tox+ subjects. Including these subjects would therefore introduce a conservative bias, favoring the null hypothesis of no group differences. In fact, we observed a robust and statistically significant difference.
Recreational drug users typically do not limit themselves to 1 substance, but instead use drugs that are available and affordable. This raises the possibility that use of substances other than METH might explain the increased virus loads seen in our subjects. To address this possibility, we replicated our initial analysis after excluding subjects who tested positive for any drugs of abuse other than METH (excluding marijuana). Comparable results were obtained. Although this approach does not eliminate the possibility that these subjects had used other substances recently, it does diminish the possibility that other drugs could account for the observed effects on virus load.
For several reasons, the CNS is a particularly important site for interactions between METH and HIV. METH penetrates the brain and CSF rapidly because of its lipid solubility and is sequestered in the CNS. Virus-infected cells in the CNS may be selectively affected by METH. Thus, Gavrilin et al. showed that METH exposure dramatically enhances FIV replication in infected brain astrocytes expressing the chemokine receptor CXCR4. Both FIV and HIV are able to use this receptor, which is expressed on astrocytes and immune system cells. Additionally, METH may injure the brain microvascular endothelium, potentiating CNS tissue infiltration by HIV-infected monocytes. These observations suggest that the effects of METH on immune dysregulation and stimulation of virus replication are likely to be enhanced in the brain. Indeed, previous research has found that HIV encephalitis is more prevalent among drug users, compared with nonusers. Despite these observations, we found no evidence of increased CSF virus load in METH users. We plan to address the effects of METH use on cytokine and chemokine concentrations in CSF in separate studies.
We have found that HAART, as expected, effectively lowers virus loads in METH+Tox- subjects, but not in Tox+subjects. Understanding HAART efficacy in METH users is important for a number of reasons. First, HIV-infected substance abusers frequently have diminished access to health care, and health care providers may be less motivated to treat them. Comorbid conditions associated with drug use, such as higher rates of mood disorders and hepatitis than among nonusing peers, can present obstacles to effective treatment. Despite concerns that the complexities of HAART therapy make it impractical for persons with a history of drug abuse, our findings demonstrate that former METH users who maintain abstinence can effectively suppress HIV replication with potent ART. These data suggest that providers involved in the clinical care of HIVinfected persons who are METH users will need to make efforts to get their patients into substance abuse treatment programs to assist them in achieving stable abstinence. Once abstinence is achieved, the responses to ART by former METH-dependent persons are similar to those of nonsubstance abusing control subjects.
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