HIV-1 Infection in Injection Drug Users

Infect Dis Clin N Am 16 (2002) 745–770

HIV-1 infection in injection drug users
Jonathan Allen Cohn, MD, MS
Division of Infectious Diseases, Department of Medicine,
Wayne State University School of Medicine, 4201 St. Antoine,
Suite 7D, Detroit, MI 48201, USA

Human Immunodeficiency Virus–1, the cause of a sexually transmitted
pandemic, is a blood-borne pathogen that gains a foothold and disseminates
through new populations through the shared apparatus of injection drug
users. Initially not recognized as a route of AIDS transmission, shared injection materials promoted the spread of HIV throughout the Eastern Seaboard of the United States and beyond, through parts of Asia, and
through Central and Eastern Europe. Heterosexual transmission of HIV
in the United States and other developed nations is fueled, in part, by spread
from injection drug users (often men) to their sexual partners (often
women). Heterosexual transmission, currently the fastest-rising mode of
transmission in the United States, is closely linked to the stable rates of
ongoing transmission through shared injection apparatus. Thus, efforts
to reduce transmission of HIV worldwide require effective approaches to
reducing drug injection or at least to changing that component of injection
behaviors that promotes HIV-1 transmission.
Drug use further complicates the HIV epidemic by its effect on the clinical
manifestations of disease and on the treatment of HIV, its sequelae, and
comorbidities. There has been longstanding concern that the route of infection or immunologic effects of drug injection might affect the overall prognosis of HIV infection among injection drug users. It seemed reasonable to
expect that the pattern of opportunistic disease associated with HIV–
induced immunosuppression among injection drug users would differ from
that seen in persons with sexually acquired HIV. Injection drug users are
prone to a host of usual (rather than opportunistic) pathogens, such as
hepatitis viruses, that could significantly influence clinical outcomes. Finally,

Supported in part by the Great Lakes to Tennessee Valley AIDS Education and Training
Center, Health Resources and Services Administration, US Department of Health and Human
Services.
E-mail address: [email protected]
0891-5520/02/$ - see front matter
2002, Elsevier Science (USA). All rights reserved.
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the behaviors associated with drug addiction and injection, as well as psychiatric comorbidity among injection drug users, could be expected to exert
a major influence on efforts to treat HIV-1 and associated clinical manifestations. This article reviews the findings about these issues from laboratory, epidemiologic, and clinical research and the implications of these
findings for HIV prevention and care among injection drug users. Data
published or presented during the era of highly active antiretroviral therapy (HAART) are emphasized, updating a review of this topic published
in 1994 [1].

Epidemiology of human immunodeficiency virus–1 in injection drug users
United States epidemiology
Through December 2000, the US Centers for Disease Control and Prevention (CDC) reported that 25% of the 765,559 adults and adolescents
reported with AIDS in the United States used injected drugs [2]. Another
6% were men who had sex with men and who also injected drugs. The
impact of drug use in minority communities during the 20 years of the
HIV epidemic has been particularly severe. Injection drug use has accounted
for more AIDS cases among black adults and adolescents (36%), Hispanics
(42%), and American Indians and Alaskan natives (15%) than among whites
(12%) or Asians and Pacific Islanders (6%). Transmission among same-sex
partners is the major route of transmission for men but is nearly nonexistent
for women. Therefore, drug injection has been a much more common mode
of transmission among female adults and adolescents reported with AIDS
(41%) than among males in the same age groups (22%). Incident AIDS cases
attributed to drug injection annually decreased slightly in the United States
between 1997 (29.92%) and 1999 (28.55%).
Among the 36 states and territories confidentially reporting HIV cases
excluding AIDS, injected drug use as a risk for HIV without AIDS is less
frequent. A cumulative 135,877 adults and adolescents had confidential HIV
reports through December 2000; of these 15% used injected drugs and 4%
were men who had sex with men and used injected drugs. The lower rates
of drug injection among HIV cases may reflect characteristics of the epidemic
in those states with confidential HIV reporting or may reflect differences
in patterns of risk-taking behaviors among persons undergoing voluntary
confidential testing before the onset of AIDS.
Nationwide, HIV incidence rates among injection drug users are thought
to be stable, contributing 25% of the approximately 40,000 new HIV infections estimated to occur annually in the United States [3]. Compiling data
from 10 studies conducted in New York City between 1992 and 1997, Des
Jarlais, Marmor, Friedmann, et al observed a weighted average incidence
of 0.7 per 100 person-years at risk. This finding suggests that previously high

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rates of HIV acquisition among injection drug users in New York City may
be declining [4].
Worldwide epidemiology
Injection drug use is reported to occur in 121 nations among an estimated
5 million persons [5]. Through 1996, injected drug use contributed to HIV
transmission in approximately 80 countries.
Most of the 250,000 adults in Eastern Europe and Central Asia who
became infected during the year 2001 acquired their infection from shared
injection apparatus [6]. In the Ukraine, where the 1% HIV prevalence rate
is the highest in the region, three fourths of infections result from injection
drug use. In South and East Asia, with the most populous nations, HIV is
generally not widespread, but injection drug use is contributing to evolving
epidemics [6]. For example, seven Chinese provinces were experiencing
serious local HIV epidemics in 2001, with prevalence higher than 70% among
injection drug users in a number of areas. In Indonesia, HIV prevalence
among injection drug users was 15% when first measured in 1999 and 2000
but in 2001 had increased to 25% in Borgor and to 53% in Bali. Indeed, HIV
infection rates among injection drug users exceed 50% in Myanmar, Nepal,
Thailand, and Manipur in India. The threat of explosive growth is substantial, given that most injection drug users are sexually active young men with
multiple partners, and that very large populations are at risk.
Although sub-Saharan Africa suffers from the most extensive HIV/AIDS
epidemic in the world, injection drug use contributes little to transmission in
this region. In contrast, although HIV/AIDS rates are low in North Africa
and the Middle East, drug injection contributes significantly to HIV transmission in these areas [6].
In Latin America and the Caribbean, HIV is largely sexually transmitted. Injection drug use is, however, a major route of transmission in Argentina, Chile, Uruguay, and Brazil [6]. In Brazil, however, prevention and harmreduction programs in several large metropolitan areas have been associated
with a substantial decline in HIV prevalence among injection drug users.
Finally, among the high-income nations other than the United States,
injection drug use is the major route of transmission in selected countries.
Mortality from AIDS has exceeded overdose-related mortality among
Italian injection drug users in Northeastern Italy since 1991 [7]. In Portugal,
more than half the 3733 new HIV infections reported in 2000 were caused
by injection drug use, whereas just under one third occurred through heterosexual transmission [6].
Thus, in the mature epidemic of Western Europe and the emerging epidemic of Eastern Europe, the majority of HIV–infected persons are injection
drug users. In the United States 25% of HIV incidence occurs among injection
drug users, whereas in sub-Saharan Africa injection drug users are barely
visible within the large heterosexual epidemic.

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Mechanisms of human immunodeficiency virus transmission
Sharing injection apparatus
During shared drug injection, there are several opportunities for exposure
to the blood of other persons [5]. Investigations in New Haven, Connecticut,
found that viable, replication-competent HIV-1 can be cultured from residual blood in syringes left at room temperature for 4 weeks [8]. Larger volumes of residual blood and higher titer of virus in the contaminating
sample are associated with a higher frequency of positive cultures. Blood
also can contaminate the spoons or other containers used to heat and dissolve drugs (cookers), the cotton or other material used to filter the drug solution, or the rinse water that may be used between injections. In health care
settings, the risk of infection following a percutaneous exposure such as a
needle stick from an HIV–infected source patient is 0.3%. Among users of
injected drugs, activities that increase the volume of blood exposure or the
number of persons to whose blood a user is exposed increase the risk of HIV
acquisition. ‘‘Booting’’ is the practice, following intravenous injection of a
drug, of withdrawing blood into the syringe to ‘‘rinse’’ the syringe of any
remaining drug, and injecting again. Mixing the current user’s blood with
that of previous users increases the exposure to blood-borne pathogens.
Needle sharing in groups (as in shooting galleries) and more frequent injection (as among cocaine injectors) increase risk. Thirty-nine percent of needles and syringes obtained in a shooting gallery in Miami, Florida, had
detectable HIV-1 RNA at levels between 400 and 268,000 copies/mL, and
94% contained antibodies to HIV-1 [9]. Most injection drug users are repeatedly exposed to a risk substantially greater than that of a health care worker
following a single percutaneous exposure. Nelson and colleagues found that
diabetic users of injection drugs (who had safe and legal access to injection
apparatus) were less likely to share injection apparatus or attend shooting
galleries and had a lower HIV prevalence than nondiabetic drug injectors
(9.8% versus 24.3%, P ¼ 0.03) [10].
Sexual risk
Sexual exposures provide a measurable increase in risk of HIV acquisition among active injection drug users. Among male active injection drug
users in Baltimore, Maryland, HIV incidence doubled for men who also had
sex with men and used cocaine [11]. Among female active injection drug
users in the same cohort, HIV incidence doubled for women with a history
of a recent sexually transmitted infection. Similarly, among active injection
drug users in San Francisco, California, between 1986 and 1998, male injection drug users who had sex with men were 8.8 (95% confidence interval
[CI], 3.7–20.5) times more likely to seroconvert than were heterosexual male
injection drug users [12]. Sexual risk interacts with drug use, especially for
drug-using women who exchange sex for drugs or money. Trading sex for

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money increased the risk of seroconversion 5.1-fold (95% CI, 1.9–13.7)
among female injection drug users in San Francisco [12].
Prevention of human immunodeficiency virus transmission
Preventing the initiation of drug injection is an important long-term
approach but is beyond the scope of this article. Formal drug treatment to stop
injection behavior is a critical intervention, but many injection drug users are
not willing to participate in treatment or are not successful. Also, there are far
fewer treatment slots in the United States than there are injection drug users.
One can attempt to reduce the risk of acquisition among uninfected injection
drug users by changing injection-related and sexual risk behaviors. In addition, one can try to reduce the transmission from infected injection drug users
by increasing the proportion who have been diagnosed with HIV and working
with them to reduce transmission behaviors. This strategy is part of the recently proposed SAFE (Serostatus Approach to Fighting the Epidemic) initiative, by which the CDC hopes to reduce HIV incidence in the United States
by 50%, from 40,000 new infections annually to 20,000, in the next 5 years [13].
Going to the source
Knowledge of positive serostatus and entry into medical care have been
associated with spontaneous reductions in transmission behaviors, in studies
performed in various cities in the United States and worldwide [14–16].
Injection drug users typically use the health care system episodically; therefore HIV testing strategies must take advantage of such episodes. Nine years
ago, the CDC recommended that, in general hospitals with at least 1 HIV–
related diagnosis among every 1000 discharges, voluntary HIV testing
should be offered routinely to inpatients between the ages of 15 and 54 years,
regardless of self-reported risk behaviors [17,18]. More recently, a study in
an inner-city emergency room demonstrated that 84% of injection drug
users accepted testing, and 62% returned for their results; of these persons,
16% were seropositive [19]. Sequential use of paired rapid slide tests for HIV
antibody, each using a different antigen, provides the same sensitivity and
specificity as a screening ELISA and confirmatory Western blot assay, in
a few minutes [20]. Therefore, if several rapid slide tests become licensed
in the United States, the use of paired rapid tests could provide results during an emergency room visit, eliminating the need for a posttest visit to
obtain results. In addition, operational research is underway to evaluate the
use of peers or case managers to increase the success of referrals to medical
care among persons with newly diagnosed HIV infection.
Reducing human immunodeficiency virus transmission and acquisition
Gibson, McCusker, and Chesney reviewed 19 published studies on
behavioral interventions to reduce HIV risk among injection drug users

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[21]. Although there were methodologic problems with some of the studies,
most studies showed beneficial behavioral changes in both intervention and
control groups. The authors concluded, ‘‘Participating in evaluation
research may itself be a valuable intervention,’’ but ‘‘despite the large behavioral changes … a substantial proportion of subjects receiving interventions
reported unacceptably high levels of risk behaviors.’’ They stated that interventions are required to change the community standards among drug users
regarding injection and sexual behavior. Summarizing 15 years of research
on HIV–related behavioral change among injection drug users, Des Jarlais
and Friedman [22] commented, ‘‘The most important barrier to reducing
HIV transmission among drug injectors is not a lack of knowledge but the
failure to implement effective prevention programs in many parts of the
world.’’ Both formal drug treatment and harm-reduction strategies have
been used with HIV–infected persons to reduce transmission and with
at-risk injection drug users to reduce HIV acquisition.
Methadone maintenance
To the extent that participation in methadone maintenance reduces
shared needle and syringe use, participants experience diminished HIV risk.
Use of injection drugs, especially among persons who use drugs other than
narcotics, does not cease completely for all enrollees, and sexual risk-taking
often persists. For example, Comacho, Bartholomew, Joe, et al compared
HIV risk behaviors among 435 drug users in Fort Worth, Texas, at methadone maintenance entry and 12 months after completing treatment [23].
Injection and sexual risk behaviors were significantly lower overall 1 year
after leaving maintenance. Longer time in treatment was associated with
greater risk reduction, whereas cocaine use was associated with increased
risk-taking behavior. A recent cost-benefit analysis indicated that the cost
of a quality-adjusted life-year gained by increasing methadone maintenance
capacity was $8200 in a community with 40% HIV prevalence among injection drug users and $10,900 in a community with a 5% HIV prevalence
among injection drug users [24]. Almost half the benefit accrued to persons
who were not injection drug users themselves (ie, sexual partners of injection
drug users). Thus, methadone maintenance provides clinical benefits at a
similar or lower cost than many widely accepted medical interventions, and
the benefits extend beyond the injection drug users themselves.
Disinfection of injection apparatus
In the early years of the epidemic, disinfecting injection apparatus (or
‘‘cleaning works’’) with chlorine bleach was identified as a harm-reduction
intervention. Community groups and others distributed kits with bleach and
instructions in shooting galleries and neighborhoods with a high prevalence
of injection drug use. Studies of cohorts of drug injectors, however, have

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failed to reveal a protective effect of self-reported bleach use. Subsequent
detailed analysis of the actual use of bleach by injection drug users in
Baltimore, Miami, and Dayton, Ohio, demonstrated that even after intensive training injection drug users rarely allowed the minimum 30 seconds
of contact time required for chlorine bleach to disinfect injection apparatus
[25–27].
Needle and syringe exchange programs
In needle and syringe exchange programs, injection drug users are provided
with a number of sterile single-use needles and syringes and return the used
sets. Programs operate either from fixed locations or from vehicles that visit
different neighborhoods on a publicized schedule. In many jurisdictions in the
United States, cooperation from the police is required so that injection drug
users can enter the exchange facilities without risking arrest for possession
of injection paraphernalia. Exchange programs generally provide additional
services such as information on further reducing HIV risk, referrals to free
(often anonymous) voluntary HIV testing and counseling, condom distribution, and referrals (and sometimes rapid entry) into formal drug treatment.
Needle and syringe exchange programs are associated with reduced needle
sharing, reduced HIV incidence, and entry into formal drug treatment.
Among street-recruited injection drug users interviewed during a 6-month
period in California, high-risk injection drug users who began using an
exchange program were more likely than nonparticipants to quit sharing
syringes (adjusted odds ratio [AOR], 2.68; 95% CI, 1.35–5.33] [28]. In an analysis of four studies comparing 1217 injection drug users not involved in needle
exchange with 413 involved in a needle exchange program, the adjusted hazard ratio for acquiring HIV infection was 3.35 (95% CI, 1.29–8.65), demonstrating the higher risk for nonexchangers [29]. In a study of 2306 streetand prison-recruited injection drug users, avoidance of previously used needles protected against acquisition of HIV (relative risk [RR], 0.29; 95% CI,
0.11–0.80]; this behavior was associated with participation in needle exchange
programs (AOR, 2.08; 95% CI, 1.15–3.85) [30]. Similarly, reduction in injection frequency was associated with a lower risk of seroconversion (RR, 0.33;
95% CI, 0.14–0.80), and this behavior was strongly associated with participation in drug treatment programs (AOR, 3.54; 95% CI, 2.50–5.00). Studies
in Baltimore demonstrated that entry into drug detoxification was significantly associated with attendance at the needle exchange program, among other
factors [31], and that injection drug users referred from the needle exchange
program to opiate agonist treatment faired as well as others with less severe
drug-use histories who were referred from other sources [32].
Controversy over exchange programs has persisted because of concern
that access to injection apparatus might increase rates of drug injection,
although no data support that assertion. In Montreal and Vancouver,
Canada, however, needle exchange programs have not been associated with

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reduced HIV transmission [5]. In Vancouver, high rates of cocaine use may
have mitigated the usually beneficial effects of needle exchange, but there
was no increased risk associated with attendance at the program [33]. Increased risks were noted among participants in the exchange program in
Montreal [34].
Retail access to needles and syringes
Sterile injection apparatus is available without prescription in many
states in the United States. The sale of sterile needles and syringes to injection drug users may help reduce exposure to blood-borne pathogens.
Among pharmacists surveyed in Baltimore, 87% reported selling injection
materials without prescriptions at their discretion [35]. Most pharmacists
approved of the planned needle exchange program and also supported selling nonprescription needles and syringes in pharmacies. Most pharmacists,
however, require picture identification or proof of diabetes before selling
injection materials, limiting access for injection drug users [36]. Harm-reduction advocates have proposed that physicians prescribe needles and syringes
to injection drug users [37]. In Rhode Island, a pilot study of such prescription through primary care practices enrolled 260 injection drug users unwilling to enter formal drug treatment [38]. The enrollees participated in the
practice and other health care activities and reported using the syringes for
themselves, but information on syringe disposal was not given. The estimated cost for each case of HIV infection averted by prescription or
exchange of sufficient needles and syringes for a hypothetical cohort of
1 million active users during 1 year was estimated as $34,278 [39].

Biologic and clinical differences in human immunodeficiency virus infection
among injection drug users
Pathogenesis and natural history of HIV-1 disease may differ in injection
drug users and in adults and adolescents who acquire the infection sexually.
Possible influences include:
repeated exposure to different viral strains through the parenteral route
differences in the initial steps of pathogenesis when the virus enters
through the bloodstream rather than through mucosa
repeated exposure to a variety of other antigens
immunologic effects of injected and other drugs
immunologic effects of a drug-injecting lifestyle (such as homelessness or
poor nutrition)
direct interactions of HIV-1 with an array of other blood-borne pathogens
differences in rates of latent infection or exposure to specific opportunistic pathogens

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Overall, although some laboratory data suggest that use of opiates could
have immunosuppressive effects and thereby accelerate disease progression
among HIV–infected drug users, epidemiologic evidence among persons
with stable drug use suggests that the survival experience is the same as
among other HIV–infected persons [40].
Characteristics and evolution of newly acquired human immunodeficiency
virus–1
Human immunodeficiency virus–1 isolates from 12 seroconverters among
Baltimore injection drug users selected for either rapid or slow disease progression were evaluated [41]. Six patients who developed AIDS within
5 years were initially infected with syncytium-inducing (SI) variants or
showed a transition from non–SI-inducing (NSI) to SI variants and experienced rapid decline of both CD8þ and CD4þ T cells. Transmitted SI variants were dual tropic, with efficient replication in primary macrophages and
T-cell lines. In contrast, the six patients with slowly progressing disease
carried only NSI variants and maintained stable or increasing CD8þ T-cell
levels. This finding is consistent with prior observations that macrophagetropic viruses are preferentially transmitted and that SI HIV-1 is
associated with rapid disease progression. An earlier study found lower proportions of SI variants in injection drug users than in men who have sex
with men [42].
Investigators in Vancouver analyzed primary drug resistance among 57
injection drug users who seroconverted to HIV-1 between 1996 and 1998
[43]. Sequencing both envelope and polymerase genes provided no evidence
of acquisition of virus with resistance to either reverse transcriptase inhibitors or protease inhibitors.
The effect of injection drug use on mutation rates in the HIV-1 envelope
gene has been examined [44]. Fifteen Brazilian injection drug users were followed for up to 4 years after seroconversion. After adjustment for time since
seroconversion and rate of progression, injection frequency was positively
and highly significantly associated with HIV-1 envelope genetic diversity
(P ¼ 0.003). The mutation rate among those who had injected at least once
per day during the preceding 6 months was estimated to be 62% greater than
the rate in those who had not injected during that time. The implication was
that ongoing use of injected drugs could increase the rate of emergence of
drug resistance by accelerating the rate of mutations.
Cellular and immunologic susceptibility of the host
Prior studies among non-injection drug users demonstrated a protective
effect of selected mutations among chemokine receptors, which function
as coreceptors for HIV-1 cell entry. There was no difference in disease progression among injection drug users in Amsterdam heterozygous for the 32base pair deletion mutation of CCR5 or heterozygous for the 64I mutation

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in CCR2b compared with injection drug users with two normal alleles [45].
The authors suggest that immunologic differences or the route of HIV-1
acquisition may alter the effect of chemokine mutations on natural history
among injection drug users as compared with men who have sex with men.
In contrast, researchers in Spain found among 150 injection drug users that
15% of slow progressors had the CCR5 deletion mutation compared with
4% of rapid progressors (P ¼ 0.0014), the same observation as previously
made among men who have sex with men [46]. Further, no infected injection
drug users were homozygous for the CCR5 delta 32 deletion mutation compared with 1 of 250 control patients. This finding was consistent with the
previously observed protective effect of the homozygous CCR5 mutation
on acquisition of HIV, although this study was quite small.
Prior studies of populations at high risk for sexually acquired HIV infection indicated that some uninfected persons have evidence of humoral or
cellular immune responses to HIV-1 antigens. This possibility suggests, but
does not prove, that these individuals mounted a protective immune response. In Milan, Italy, immune responses among 21 HIV-1 seronegative
injection drug users were studied [47]. Antibody to shared HIV/HLA
epitopes were found in 33% of uninfected injection drug users and in 4%
of 94 low-risk controls. CD4þ lymphocyte responses to HIV envelope were
observed in 76% of seronegative injection drug users and in 3% of low-risk
controls. Thus, there is some evidence that in some injection drug users an
immune response develops after exposure to, but not acquisition of, HIV-1.
Natural history
Acute seroconversion syndrome was symptomatic in 69% of both injection drug users and men having sex with men. The clinical presentation was
indistinguishable except that men having sex with men had more frequent
oral and anal ulcers [48].
Progression of HIV disease among injection drug users follows a time
course similar to that observed in populations with other routes of HIV
acquisition. For example, in a large European study, progression to AIDS
from time of seroconversion among injection drug users and men who have
sex with men varied by age at seroconversion but not by risk-taking behavior
[49]. Median time to AIDS was between 8 and 10 years, and median survival
after an AIDS diagnosis was 1.0 years. Combined data from two large HIVIDU cohorts in Italy (ISS) and Baltimore (ALIVE) also show that age is an
important predictor of progression to AIDS from time of seroconversion
[50]. After adjustment for age, there were no significant differences by country, sex, race, or time of seroconversion. The median time to AIDS was
12 years for 25-year-olds and 8 years for 35-year-olds. Paradoxically, in some
cohorts of injection drug users, total survival is shorter than survival to
AIDS. Death before AIDS may occur in up to 24% because of infectious
disease, overdose, trauma, or other causes [49]. Deaths from natural causes

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(ie, infections) increase as the CD4þ cell count falls, whereas deaths before
AIDS from other causes (ie, trauma or drug overdose) are not linked to
CD4þ cell count or time since seroconversion [51].
Coincident with and just following seroconversion, injection drug users
have a high level of plasma HIV RNA which then decreases (by a mean
of 52%) over the next 18 months. The viral load then rises gradually, by a
mean of 23% annually over subsequent years [52]. Many different measures
of HIV viral load have been found to be predictive of disease progression in
injection drug users: peak plasma HIV RNA levels; ongoing plasma HIV
RNA levels; slope of HIV RNA levels, and quantitative HIV culture of
peripheral blood mononuclear cells [52,53]. Among injection drug users,
as in men who have sex with men, the combination of plasma HIV RNA
levels and CD4þ lymphocyte count provides better prognostic information
than viral load alone [54]. Over a median observation of 6.4 years, the cumulative probability of death from AIDS or infectious disease was 0% for those
with HIV RNA levels lower than 500 copies/mL and CD4þ cell counts
higher than 500/mL, compared with approximately 80% for those with viral
loads higher than 10,000 copies/mL and CD4þ cell counts below 200/mL.
Health care professionals commonly tell their patients that ongoing
injected drug use hastens the progression of HIV-1 disease, as an argument
for cessation of drug use and enrollment in formal treatment. Few data support this assertion, however. For example, among 605 HIV–infected injection drug users, faster CD4þ cell decline was significantly associated with
a higher baseline CD4þ cell count (P\0.01) and duration of drug use
(P\0.01), but rate of change was not associated with injection frequency
or with specific drugs [55]. More frequent sharing of injection apparatus has
been associated with slower CD4þ cell decline [56,57].
Clinical events
Specific disease manifestations among injection drug users differ from
those in other persons with HIV because of their exposure to routine and
opportunistic pathogens and the patterns of noninfectious disease that are
associated with injected drug use.
Data from the Adult and Adolescent Spectrum of Disease describe the
annual incidence of AIDS–related opportunistic infections among 4475
injection drug users and 15,588 men who have sex with men in nine cities
in the United States between 1991 and 1996 [58]. Tuberculosis incidence was
threefold greater among injection drug users than among men who have sex
with men. Cytomegalovirus (CMV) retinitis was more than three times more
frequent, and other CMV disease was more than four times more frequent
among men who have sex with men. Kaposi’s sarcoma was more than six
times more frequent among men who have sex with men than among injection drug users. These differences probably reflect different rates of exposure
of injection drug users and men who have sex with men to Mycobacterium

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tuberculosis, CMV, and human herpes virus-8 (HHV-8), respectively. On the
other hand, chronic herpes simplex virus (HSV) infection was rare and had
exactly the same incidence in both groups (0.7 cases per 100 person-years),
perhaps because effective antiviral treatment prevents the development of
chronic HSV disease (defined as mucocutaneous lesions of at least 1-month
duration) in most patients. Among men who have sex with men, incidence
rates for 11 of 13 conditions (all except recurrent pneumonia and chronic
cryptosporidiosis) fell at a statistically significant rate during the 6 years
of observation. Among injection drug users, incidence rates fell for only 5
of the 13 conditions (Pneumocystis carinii pneumonia, disseminated
mycobacterium avim complex [dMAC], tuberculosis, recurrent pneumonia,
chronic HSV, and chronic cryptosporidiosis). Because these data were
collected from patients in care for HIV disease, the differences should not
result from variation in access to medical care. It may be that lower rates
of acquisition of opportunistic pathogens or better adherence to prophylactic regimens for opportunistic infection are important factors in the decreasing rates of opportunistic diseases seen among men who have sex with men.
Tuberculosis
In the United States and Europe, injection drug users have a high prevalence of coinfection with Mycobacterium tuberculosis and HIV [59,60]. In
the United States, rates of active tuberculosis are threefold higher among
HIV–infected injection drug users than among men who have sex with men
[58]. Current recommendations call for screening all HIV–infected persons
for latent tuberculosis infection, defined in this population as 5 mm of induration produced by 5 units of intradermal purified protein derivative (PPD)
[61]. Persons with a positive reaction should be assessed for clinical and
radiologic signs of active tuberculosis. In the absence of active tuberculosis,
treatment of latent tuberculosis infection is indicated for all HIV–infected
persons, regardless of age or other risk factors. Concern had been raised that
HIV–infected persons from populations with high prevalence of latent M.
tuberculosis, such as injection drug users, might have false-negative tuberculin skin tests caused by cutaneous anergy and therefore should be offered
treatment for presumed latent tuberculosis. A large, randomized trial, in
which 58% of the participants were active or prior injection drug users,
failed to demonstrate an advantage to the use of isoniazid therapy among
anergic HIV–infected persons with risk factors for latent tuberculosis [62].
Therefore anergy testing is not routinely recommended [61].
Active tuberculosis among injection drug users in the United States is
often drug resistant. Recommendations for treatment of active tuberculosis
among HIV–infected persons have been published [63]. Use of directly
observed therapy (DOTS), often with intermittent dosing (two or three
times per week) is strongly recommended, along with other measures to
ensure adherence with the entire course of therapy.

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Hepatitis B
Persons with either sexually acquired or injection-acquired HIV may be
coinfected with hepatitis B virus (HBV), but the frequency of coinfection
is higher among injection drug users. Persons infected with HIV become
chronic carriers of hepatitis B more often than persons not infected with
HIV [64]. Infection with HBV probably does not influence the course of
HIV disease [65]. Clinical disease caused by HBV is immunologically mediated [66]. Despite high levels of HBV replication, persons with HBV and
HIV–induced immunosuppression are believed to have rates of clinical hepatitis similar to or lower than those in persons infected only with HBV.
Many persons with a history of injected drug use have both HBV and hepatitis C virus (HCV) infection. A large proportion of patients with chronic
HBV and HCV infection lack serum hepatitis B surface antigen (HBsAg)
but have hepatitis B DNA present in the circulation or liver tissue [67]. In
that circumstance, it is common to detect antibody to hepatitis antigen B
core in the serum but to detect neither HBsAg nor antibody to HBV surface
antigen [68–70]. Some data suggest that the HBV and HCV each partially
suppress the other’s replication [67].
Limited data suggest that patients coinfected with HIV and HBV and
with CD4þ cell counts of at least 250 cells/mm3 experience the same modest
response rates with alpha-interferon monotherapy for 6 months as persons
without HIV infection [71,72]. Certain reverse transcriptase inhibitors have
activity against hepatitis B. Lamivudine (Epivir, Epivir-HB, GlaxoSmithKline, Research Triangle Park, NC) is licensed both for HIV and HBV therapy, although therapy for HBV alone requires a lower daily dose. Hepatitis
B virus DNA was suppressed in about 40% of HBV–infected persons treated
with lamivudine for 1 year. Biochemical and histologic improvement
occurred in more than 50%, but seroconversion (development of antibody
to HBV e antigen) occurred in only 16% [73,74]. Three years of therapy produced seroconversion to anti-HBV e antigen among 40% [75]. Hepatitis B
virus mutations conferring resistance to lamivudine developed in about
20% of patients per year, however [75,76]. Combination therapy with interferon and lamivudine does not provide a statistically significantly improved
response rate [77].
The short-term rates of e-antigen seroconversion among small numbers
of patients coinfected with HIV and HBV who received combination antiretroviral therapy were similar to the rates of seroconversion in HBV
patients receiving lamivudine monotherapy [78,79]. Lamivudine resistance,
however, develops in HIV-HBV coinfected patients receiving 300 mg of
lamivudine per day at the same rate (20% per year) as in HBV-infected
patients receiving only 100 mg per day [80]. There are a small number of
case reports of severe exacerbations of clinical hepatitis in HIV-HBV coinfected patients when lamivudine therapy is discontinued or when HBV
develops lamivudine resistance [81]. There have been reports of hepatitis

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B exacerbations in patients receiving antiretroviral therapy without lamivudine resistance [82].
It is prudent, therefore, to know the HBV status of HIV–infected persons
before initiating antiretroviral therapy to avoid inadvertent development of
HBV resistance. In persons coinfected with HIV-HBV who are not being
treated with combination antiretroviral therapy (because of a high CDþ cell
count or low plasma HIV RNA level), interferon therapy of HBV would be
preferred to lamivudine monotherapy, so as to avoid development of drug
resistance in either HIV or HBV.
Two nucleotide analogues are active against hepatitis B. Although
adefovir dipivoxil is no longer in development as an antiretroviral agent
because of nephrotoxicity, studies are continuing with adefovir at lower doses
for treatment of hepatitis B. Tenofovir disoproxil fumarate (Viread, Gilead
Sciences, Inc., Foster City, CA) was recently licensed for intensification of
combination antiretroviral therapy. Limited data suggest that tenofovir has
useful activity against both lamivudine-susceptible and lamivudine-resistant
hepatitis B in HIV coinfected patients. Concurrent combination therapy of
both HBV and HIV may prove useful in the future and may reduce rates of
drug resistance during treatment.
Hepatitis B and hepatitis D coinfection
Superinfection of HbsAg–positive patients with the RNA delta hepatitis
(hepatitis D virus, HDV) agent is common among injection drug users and
may be more common among persons with AIDS [83]. In one observational
study in Spain, mortality among patients with HDV infection was not
significantly different among persons coinfected with either HCV or HIV
[84]. Neither interferon monotherapy nor lamivudine are successful for treatment of HDV, nor is interferon effective in patients coinfected with HDV
and HIV [85,86].
Hepatitis C
Hepatitis C coinfection is emerging as an extremely important cause of
morbidity and mortality among HIV–infected persons. Human immunodeficiency virus infection, alcohol consumption, male gender, and older age at
acquisition of HCV are associated with a higher probability of development
of cirrhosis and more rapid progression to cirrhosis and death from HCV
disease [87,88]. The risk of end-stage liver disease increases significantly with
each decade of HCV infection and also with each decade of HIV infection
(relative risk [RR], 2.18; 95% CI, 1.36–3.49; P ¼ 0.0013). In a case-control
study, HIV-HCV coinfection was associated with an increased risk of hepatocellular cancer occurring at a younger age, and after a shorter estimated
duration of HCV infection (17.8^2.7 years versus 28.1^10.9 years;
P\0.05), compared with persons infected only with HCV [89].

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759

Data regarding the effect of HCV infection on HIV disease progression are
inconsistent. In the Swiss HIV Cohort Study, the probability of progression
to a new AIDS–defining clinical event or to death was independently associated with HCV seropositivity [hazard ratio (HR), 1.7; 95% CI, 1.26, .30], and
with active intravenous drug use (HR 1.38; 95% CI 1.02–1.88) [90]. Further,
during antiretroviral therapy, HCV seropositivity was associated with a
smaller CD4-cell recovery (HR for a CD4-cell count increase of at least 50
cells/mL ¼ 0.79; 95% CI, 0.72–0.87). Other authors report no difference in
HIV disease progression or in mortality between coinfected patients and
those not infected with HCV [91]. Comparing survival is complicated by competing causes of deaths, including overdose, other infections, complications
of end-stage liver disease, and classic HIV– and AIDS–related conditions.
Increased hepatotoxicity of antiretroviral drugs has been demonstrated
for protease inhibitors, especially ritonavir (Norvir, Abbott Laboratories,
Inc., North Chicago, IL) [92]. Use of efavarinz (Sustiva, Bristol-Meyers
Squibb Company, Princeton, NJ), a nonnucleoside reverse transcriptase
inhibitor (NNRTR), in HIV-HCV coinfected patients is associated with
increases in serum aminotransferase levels [93]. Nevirapine (Virammune,
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT), also a nonnucleoside reverse transcriptase inhibitor, may cause idiosyncratic hepatotoxicity but is not known to have increased hepatotoxicity among persons
coinfected with hepatitis C. Patients infected with HIV and with active HBV
or HCV infection have a twofold risk of developing elevated aminotransferase levels during antiretroviral therapy [94]. Some authorities suggest that
patients infected with HIV and HCV who have good immune function
might first be treated for HCV, in the hopes that sustained responders to
HCV treatment will have less hepatotoxicity from subsequent antiretroviral
therapy. This strategy has not been tested.
The limited data currently available suggest that combination therapy
with interferon and ribaviron in HIV- and HCV-infected patients with only
mild or moderate immunosuppression produces virologic and biochemical
response rates similar to those seen in persons without HIV infection [95–
98]. Studies on the efficacy and toxicity of combined pegylated interferon
and ribavivon among patients coinfected with HIV and HCV are underway.
At the Wayne State University School of Medicine, HCV treatment is usually deferred until the CD4þ lymphocyte count exceeds 300 cells per mm3
because (1) inteferon may be more efficacious, (2) CD4þ cell counts may fall
during interferon therapy (as discussed later), and (3) expected survival with
HIV should be sufficiently long to realize a clinical benefit from reducing the
progression of HCV disease. Because experience with treatment of coinfected persons is limited and the range of underlying liver disorders may
be greater than appreciated, a liver biopsy is usually performed before
initiating HCV treatment in coinfected patients. The CD4þ lymphocyte
count decreases by an average of 100 cells during interferon treatment,
although CD4þ lymphocyte percentages remain stable. This phenomenon is

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attributed to changes in lymphocyte traffic or neutropenia rather than a
selective effect suppressing cell-mediated immunity. Ribaviron potentially
could alter pharmacokinetics of some nucleoside reverse transcriptase inhibitors by decreasing phosphorylation of zidovudine and stavudine and
increasing phosphorylation of didanosine. No untoward events have been attributed to concurrent use of ribaviron and nucleoside reverse transcriptase
inhibitors among HIV– and HCV–coinfected persons, but this possibility
is being examined further in ongoing randomized trials.
Additional infections
The GB virus C, (GB-C) previously known as hepatitis G virus, occurs
among HIV–infected injection drug users as well as those with sexually and
blood product–acquired HIV. The GB-C virus neither replicates in hepatocytes nor causes hepatitis. Recent data suggest that persons coinfected with
HIV and GB-C have slower HIV disease progression and lower mortality
rates [99,100].
Another human retrovirus, HTLV-II, is common among injection drug
users in the United States. Goedert, Fung, Felton, and colleagues [101] investigated cause-specific mortality of injection drug users with and without HIV
and HTLV II over a period of approximately 10 years. Infection with HIV
increased the risk of death from medical causes 3.7-fold (95% CI, 3.3–4.2).
Mortality was slightly reduced (RR, 0.8; 95% CI, 0.7–0.9) among injection
drug users with HTLV-II infection, regardless of concomitant HIV infection.
A cohort study of injection drug users with HIV in Baltimore found no
increase in bacterial infections among those coinfected with HTLV-II
[102]. Thus, HTLV II is not a significant cause of mortality among injection
drug users in the United States, either alone or combined with HIV.
Bacterial pneumonia is more frequent among HIV–infected injection
drug users than among seronegative controls [103]. Additional risk factors
include decreasing CD4þ lymphocyte counts and injection drug use. Cigarette smoking is an added risk factor for those with low CD4þ cell counts.
Neuropsychiatric disorders
Drug abuse and HIV infection are each associated with psychiatric disease. Pre-existing major psychiatric disease such as depression, bipolar disease, and schizophrenia may contribute to development of substance abuse
and to increased risk of HIV acquisition. Substance abuse is also common
among persons with pre-existing personality disorders. Diagnosis of HIV
infection, still an incurable and ultimately fatal disease, is associated with
adjustment disorders and depression. Recent data suggest that depression
may contribute to HIV–associated mortality, independent of its effect on
treatment utilization or medication adherence [104].
Drug abuse and HIV infection are each associated with cognitive disorders. Human immunodeficiency virus infection of brain macrophages and

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761

microglial cells leads, through various mediators, to neuronal damage [105].
This damage is manifest as the symptoms and signs of HIV–associated encephalopathy, AIDS dementia complex, or a less severe syndrome termed
AIDS–associated cognitive deficits. Human immunodeficiency virus–associated encephalopathy occurs in persons with advanced disease but may itself
contribute to mortality.
A number of investigators in the United States and Europe have tried
to distinguish the roles of injection drug use and HIV disease in cognitive
disturbances [106–112]. Consistent findings include more frequent presence
of cognitive abnormalities in injection drug users compared with those who
do not inject drugs and the presence of cognitive deficits in persons with
advanced HIV disease. Studies differ on the presence of cognitive abnormalities in early or asymptomatic HIV disease. Differences in testing methods,
criteria for abnormal results, and study populations may account for the
varied results.
Patients with substance abuse require extra intervention by HIV care
providers.
Supportive counseling is the glue that holds treatment plans together.
Demoralized patients with substance use disorders, personality problems
and major depression are common in our HIV clinic. They arrive with
an apparently endless list of problems that can overwhelm many clinicians.
A careful description of the way in which life gets better over time, a view
of the future, a focus on the strengths of the patient and on ways in
which those strengths can be exploited to improve the quality of life, and
experience with successful outcomes for similar patients are the foundation of successful treatment. Maintenance of therapeutic optimism can
be difficult in the face of these problems, but it is essential to good outcomes [113].

Antiretroviral treatment
Effectiveness of highly active antiretroviral therapy
Treatment of HIV disease has been transformed in the past 6 years with
the advent of HAART. Generally, two nucleoside reverse transcriptase
inhibitors are paired with one or two potent drugs from the nonnucleoside
reverse transcriptase inhibitor or protease inhibitor classes [114]. Current
standards target nearly total viral suppression, that is, reducing quantitative
plasma HIV RNA levels to below 50 or 25 copies/mL (below the limit of
detection of quantification), to achieve maximal immunologic recovery and
the longest duration of activity from the combination. Clinical responses at
their best are extraordinary: mortality has decreased in all countries where
these drugs are readily available to infected persons; previously incurable
opportunistic infections succumb to immune reconstitution; the direct sequelae of viral replication, such as HIV encephalopathy, go into remission.

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Attaining excellent virologic control, however, requires levels of medication
adherence rarely achieved among patients with chronic illnesses. Using a
system of computer chips in medication bottles, Paterson, Swindells, Mohr,
et al found that among persons taking at least 95% of their protease inhibitor, 78% achieved viral loads below 400 copies/mL [115]. Only 49% of
patients taking 80% to 94.9% of their protease inhibitor medication achieved
that level of viral suppression.
Is it possible for drug injectors to obtain the same benefits from HAART
as other HIV–infected patients? Heavy alcohol use, active use of injected
drugs, and depression are consistently linked to low levels of adherence with
antiretroviral therapy [116]. Past use of injected drugs, however, has not
been a significant factor in most studies, nor have race, age, or sex. For
example, in a multicountry European cohort (EuroSIDA), injection drug
users receiving antiretroviral agents had the same rates of virologic suppression and immunologic recovery as persons with other risk behaviors [117].
In a retrospective Canadian study, a history of injection drug use was significantly associated with lower rates of viral suppression in the mid-1990s but
was no longer significant in the late 1990s when new guidelines expanded
eligibility for treatment [118]. Similarly, in the United States, disease-free
survival in a clinic cohort during a period of mono- or dual antiretroviral
therapy (1990–1995) was compared with the period of HAART (1995–
2000) [119]. Disease-free survival increased for all groups during the
HAART period; however, gains in survival were greater for men than for
women, and for persons who did not use injected drugs than for injection
drug users. Among injection drug users, median disease-free survival time
increased by 16% (baseline CD4þ cell count > 200 cells/mm3) and by 34%
(baseline CD4þ cell count \200 cells/mm3), whereas among non–injection
drug users survival time increased by 65% and 135%, respectively. Antiretroviral therapy was used at lower rates by injection drug users than others.
Injection drug users receiving antiviral therapy who had CD4þ counts greater
than 200 cells/mm3 had the same success in suppressing plasma HIV
RNA levels as non–injection drug users; however injection drug users with
CD4þ cell counts below 200 cells/mm3 were less likely to suppress plasma
HIV RNA fully during therapy. Thus, injection drug users who begin therapy before advanced immunosuppression occurs may have virologic success
similar to that of non–drug injectors.
Access and adherence
In European studies of injection drug users, participation in narcotic
agonist therapy (methadone or buprenorphine maintenance) was associated
with improved adherence and better virologic and clinical outcomes
[117,120,121]. Among injection drug users in Baltimore, active drug use was
associated with diminished use of HAART, whereas methadone maintenance was associated with use of HAART among men but not women

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763

[122]. In another Baltimore study, participation in any drug treatment or
case management by HIV–infected patients was associated with greater
ongoing use of health services, regardless of active drug use. Active alcohol
use, on the other hand, was associated with use of emergency rooms as
health care providers [123]. In several other studies, past or current injection
drug users were less likely to start antiretroviral therapy than other persons
similarly eligible according to treatment guidelines current at the time
[117,122].
Is it patient reluctance or provider reluctance that leads to lower rates of
HAART use among injection drug users? Undoubtedly both contribute;
however, data on this issue are not currently available. Current guidelines
for antiretroviral therapy recommend delaying the initiation of therapy for
asymptomatic patients until moderate immunosuppression or high plasma
viral loads occur, to minimize risks of drug resistance and toxicity [114].
Another criterion for initiating therapy is the readiness of the patient to
commit to treatment and to nearly perfect adherence, unless a desperate situation warrants starting HAART (such as in a hospitalized patient, previously untreated, with dementia). Stone has reviewed current approaches
to maximizing adherence [116]. Adherence and outcomes can be improved
if injection drug users enter drug treatment and are treated for psychiatric
comorbidity before beginning HAART. Social situations should be stabilized. Addressing homelessness through social services is important,
although some programs have used intensive outreach to treat homeless persons successfully. Assistance with obtaining a mechanism to pay for medical
visits and medications is a requirement; enrollment in programs using federal
funds through the Ryan White Emergency Care Act will allow access for
persons without private insurance, Medicaid, or Medicare. Providing
patient teaching on the use of medications, individualizing treatment regimens, and developing a personalized schedule for drug administration are
all useful. Working closely with patients to address the many toxicities of
antiretroviral drugs is necessary. For some patients, mechanical supports
such as pill boxes and timers with alarms are useful. For others, daily personal reminders from family, loved ones, or friends are more effective. Close
monitoring of adherence by the prescribing physician is important and
requires a supportive, nonjudgmental approach combined with specific,
detailed questioning to overcome all patients’ tendency to exaggerate adherence. Finally, in some settings, including methadone maintenance, prisons,
and perhaps in communities, directly observed therapy (especially of simplified or once-daily regimens) may be useful.
Summary
Injection drug use is an efficient and ongoing means of HIV transmission
and is the principal mode of transmission in some parts of the world. In the
United States, approximately 10,000 injection drug users are believed to

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acquire HIV each year. The US Public Health Service hopes to decrease all
HIV transmission in the United States by 50% in the next 5 years, by promoting care and prevention services to infected persons.
Subtle differences in the virology and immunopathogenesis of HIV
between injection drug users and other groups at risk are still being investigated. So far such differences have no practical implication. Comparison of
progression rates and survival with HIV across risk groups has been difficult
because of the many competing causes of death unrelated to HIV among
injection drug users, but overall HIV disease progression rates are similar
across risk groups, after adjusting for age. Some AIDS–related opportunistic infections are more common (such as tuberculosis) or less common (such
as Kaposi’s sarcoma) among injection drug users, based on rates of exposure and latent infection. Other comorbidities, including chronic psychiatric
disorders and hepatitis C disease, are more common among injection drug
users than among others with HIV infection.
Highly active antiretroviral treatment seems to be as effective in persons
with a history of injected drug use as in others. Increasing the numbers of
HIV–infected injection drug users who know their diagnosis, increasing
their access to care and prevention services, and increasing their adherence
to a therapeutic regimen are the current challenges in confronting the HIVepidemic among injection drug users. To overcome these obstacles, clinicians must have both technical knowledge and skill in assisting patients
with behavior change.

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