NATAP: Methamphetamine May Increase HIV Viral Load

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Increased HIV Viral Loads in Active Methamphetamine Users Are Explained by

Reduced Effectiveness of Antiretroviral Therapy

The Journal of Infectious Diseases 2003;188:1820-1826

J. Ellis,1,2 Meredith E. Childers,1,2 na Cherner,2,3 Deborah

Lazzaretto,2,3 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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