# The Relationship between Cocaine Use and Human Papillomavirus Infections in HIV-Seropositive and HIV-Seronegative Women

Authors: Howard Minkoff; Ye Zhong; Howard  D. Strickler; D. Heather Watts; Joel M. Palefsky; Alexandra M. Levine; Gypsyamber D'Souza; Andrea A. Howard; Michael  Plankey; L. Stewart Massad; Robert Burk
Journal: Infectious Diseases in Obstetrics and Gynecology
 (2008)

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## Abstract

Objective. Animal data suggest that cocaine has an immunosuppressive effect, but no human studies have been conducted to assess the relation of cocaine use with human papillomavirus (HPV) infection, the viral cause of cervical cancer. Since both cocaine use and HPV infection are common among HIV-positive women, we sought to determine whether use of cocaine and/or crack influences the natural history of HPV among women with or at high risk of HIV.
Methods. Women enrolled in the Women's Interagency HIV Study (2278 HIV-seropositive and 826 high-risk seronegative women) were examined every six months for up to 9.5 years with Pap smear, collection of cervicovaginal lavage (CVL) samples, and detailed questionnaires regarding health and behavior, including use of crack and cocaine (crack/cocaine). CVLs were tested for HPV DNA by PCR, with genotyping for over forty HPV types.
Results. In multivariate logistic regression models, censoring women treated for cervical neoplasia, crack/cocaine use within the last six months was associated with prevalent detection of oncogenic HPV DNA (odds ratio [OR] = 1.30
(1.09–1.55)), and with oncogenic HPV-positive squamous intraepithelial lesions (SIL) (OR = 1.70 (1.27–2.27)), following adjustment for age, race, HIV-serostatus, and CD4+ T-cell count, the number of sexual partners in the past six months, and smoking. In multivariate Cox models crack/cocaine use was also associated with a trend that approached significance in regard to incident detection of oncogenic HPV-positive SIL (HR = 1.51, 95% CI 0.99–2.30), and while the rate of oncogenic HPV clearance was not related to cocaine use, the clearance of any SIL was significantly lower in those with versus those without recent crack/cocaine use (HR = 0.57, 95% CI 0.34–0.97).
Conclusions. Cocaine use is associated with an increased risk of detection of both prevalent and incident oncogenic HPV infection, as well as an increased risk of HPV-positive SIL over time.


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## Body

## 1. Introduction

Human papillomavirus (HPV) infections
of women, though common, typically resolve. Persistence of oncogenic HPV is
necessary for the development of cervical precancer and invasive cervical
cancer (ICC). The incident detection and persistence of HPV infections and
related lesions have been shown by us [1–4], and others [5–8], to be elevated
among HIV-seropositive compared to HIV-seronegative women, and to be strongly
associated with biomarkers of immune status such as CD4+ T-cell count and HIV
RNA level in HIV-infected women.Cocaine use is also common among
HIV-infected women [9, 10] and has been linked to perturbations of the immune
system in both animal models and humans [11–13]. In one study of lymphocytes
from individuals with cocaine in their urine, it was found that “Memory"
CD8+ T cell subpopulations (i.e., CD45RO+) were reduced in the cocaine-positive
patients leading the authors to conclude that this might “represent a
disruption of particular immunologic cell networks which could ultimately
influence host resistance to infection" [14]. Other researchers have suggested
that cocaine could inhibit the effector functions of neutrophils and
macrophages, thus interfering with the host’s ability to defend against
infections, as well as suppressing cytokine production, thereby diminishing the
capabilities of additional immune cells important in control of viral infection
[15–17].Any disruption to host defenses
attributable to cocaine, in conjunction with those associated with
HIV-infection per se, could increase the incidence and/or duration of oncogenic
HPV infection. That in turn could contribute to an enhanced risk of cervical
neoplasia to which HIV-infected women are demonstrably prone [18]. Additionally,
if cocaine use was found to modify the course of an infectious disease (such as
HPV), it would provide clinical evidence in support of the assertion of
researchers who, on the basis of results in animal models, have expressed
concerns about a potentially enhanced susceptibility to infections among
cocaine users in general. In this paper, we take advantage of a large,
well-characterized cohort of HIV-infected and at risk women to assess the
association of cocaine use with HPV infection and disease.


## 2. Materials and Methods

The Women’s
Interagency HIV Study (WIHS) is a prospective study of the natural history of
HIV infection in women that initially enrolled HIV-seropositive and at risk
seronegative women participants at six clinical sites (Bronx, NY; Brooklyn, NY; Chicago; Los Angeles; San Francisco; Washington, D.C.) between October 1994 and November
1995. A subsequent recruiting cycle
occurred in 2002. The recruitment methods and data collection procedures for
WIHS have previously been described [19]. In brief, participants underwent
visits every six months that included an interviewer-administered
questionnaire, a physical examination, and the collection of specimens,
including cervicovaginal lavage for HPV DNA testing. At each visit participants were asked about drug use (types and
frequency of use).
At baseline, they were asked about lifetime use as well as use in the
last six months. Questions were asked specifically about cocaine and crack, as
well as heroin and alcohol use. Those who acknowledged the use of the drug were
asked about the average frequency of use (e.g., once a month, once a week, once
a day, etc.) over the last six months.There
were a total of 3768 subjects in WIHS. We excluded 16 subjects who had HIV
seroconverted during follow-up, and 253 subjects who did not have a cervix
present at baseline. Thus 3499 women were included.  We censored all the visits after
hysterectomy.  The current analysis includes
women recruited in 1994/1995 and additional women recruited in 2002. The initial
recruits were tested for HPV infection during visit 1 through visit 15, and the
more recent recruits were tested for HPV infection during their baseline visit
(V15 or V16) through visit 19.
Eighty-nine (9.7%) of the 915 HIV-seronegative women and 306 (11.8%) of
the 2584 seropositive women did not have HPV DNA test results available and
were excluded from analysis. Comparisons were made between HPV carriage
patterns (defined below) of women who did or did not acknowledge cocaine use.


### 2.1. Laboratory Methods

The
laboratory technique for HPV assessments have been described in detail
elsewhere [20]. HPV DNA was detected utilizing L1 consensus primer MY09/MY11/HMB01 polymerase chain reaction (PCR) assays [20–22]. Control primer
set PC04/GH20, amplifying a 268 bp cellular beta globin DNA fragment, was
included in each assay to serve as an internal control for amplification.
Following proteinase K digestion, 2–10 μL of each cell digest was used in reactions
containing 10 mM Tris-HCL, 50 mM KCL, 4 mM MgCl2, 200 μM of each
deoxyribonucleotide triphosphate, 2.5 U Taq DNA polymerase, 0.5 μM of each
primer. There were 40 amplification cycles (95°C for 20 seconds, 55°C
for 30 seconds, and 72°C for 30 seconds, with a 5-minute extension
period at 72°C on the last cycle). Amplified material was then
detected using filters individually hybridized with biotinylated type-specific
oligonucleotide probes for multiple HPV types including HPV 6, 11, 16, 18, 26,
31, 32, 33, 35, 39, 40, 45, 51, 52, 53, 54 (AE9), 55, 56, 58, 59, 61, 62, 66,
67, 68, 69, 70, 71 (AE8), 72, 73 (PAP238A), 81 (AE7), 83(PAP291), 82v(AE2), 84 (PAP155), 85 (AE5), and 89 (AE6), as
described in [20, 23]. For these analyses, oncogenic and nononcogenic HPV types
were defined in accordance with recently published data that classified types
utilizing both phylogenetic and epidemiologic criterion. The oncogenic HPVs
were HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 66, and all other
HPV types were considered nononcogenic HPV [24].Pap smears were collected using a
plastic Ayre spatula and an endocervical brush.
Both specimens were smeared onto a single slide and fixed immediately.
Cervical cytology samples from all sites were centrally interpreted at Kyto Meridien
Laboratories (New York , NY) using the 1991 Bethesda System criteria
for cytologic diagnosis [25]. All smears
were read by two cytotechnologists who were blinded to the participants’
status. Ten percent of all negative smears and all abnormal smears were
confirmed by a cytopathologist. Diagnoses were reported as normal or benign,
atypical squamous cells of uncertain significance (ASCUS), low-grade squamous
intraepithelial lesion (LGSIL), moderate- or high-grade squamous
intraepithelial lesion (HGSIL), and cancer.
Glandular abnormalities were not included. Whenever possible the primary
cytologic outcome used was SIL among women with oncogenic HPV. This was chosen
since SIL in the presence of HPV is more clearly a precursor of cancer than are
cases of SIL in which oncogenic HPV is not detected. In cases in which the
number of such outcomes was sparse, we did use SIL among all women as an
outcome.T-cell
subsets were determined by immunofluorescence using flow cytometry in
laboratories participating in the AIDS Clinical Trials Quality Assurance
Program.  Plasma HIV RNA levels were
measured using a nucleic acid sequence-based amplification (NASBA) technique
(Organon Teknika, Durham, NC, USA) with a lower threshold of detection of 4000
copies/ml [26].


### 2.2. Statistical Analysis

Cocaine
used in the last six months was examined both as a binary outcome (use/no
use), and as an ordinal variable (no use/less than once a month/once a
month—once a week/2–6 times a week/once a day or
more). Consistent with prior studies [4] the prevalence of HPV DNA was defined
as the fraction of women with detectable HPV among those with adequate HPV test
results (as determined by the successful amplification of the human β-globin
gene—see Laboratory Methods). We defined “incident
detection" of HPV as detection of an HPV type that was not found at baseline or
at any other earlier visit in a given woman. The term “incident detection" is
used instead of “incidence" to reflect the fact that it is impossible to
distinguish newly acquired HPV infection and reactivation of previously
acquired latent HPV infection in a population with many years of sexual
activity, regardless of the HIV status of that population. Persistence of HPV
infection was defined as the time to clearance of a specific HPV type, and we
further distinguished in our analysis between the persistence of HPV detected
prevalently at baseline and those first detected incidentally at a subsequent
visit (see below). Clearance itself was defined as either a single negative or
two negative type-specific HPV results at sequential visits. The findings were
similar using either approach for defining clearance, and herein we present the
results of clearance using the former definition.The
baseline characteristics of cocaine users and nonusers in this study were
examined, and the distributions for selected parameters compared using standard
Pearson chi-square tests for categorical data, or by the
Cochran-Mantel-Haenszel tests when examining trends in ordinal data. These
variables were also evaluated as potential confounders in the multivariable
analyses described below.The
association of cocaine use with prevalent HPV DNA detection was measured in multivariate logistic regression models that incorporated
generalized estimating equations (GEE) to adjust the standard errors for
repeated measures (i.e., summarizing data across all HPV types and across study
visits), and assuming an independent correlation structure. In previous papers,
we have shown that the results in this dataset are unaltered by using other possible
correlation structures [4, 27], and, in general, model estimates are robust
with respect to the correlation structure imposed [28].Treatment
of abnormal cervical cytology can introduce a bias into analysis of HPV
infection, since treatment can alter the underlying mucosa; either increasing
infection (e.g., by exposing basal cells which are the cells susceptible to
infection) or decreasing infection (e.g., by removing infected cells or
inducing the replacement of columnar with squamous tissue in the transformation
zone of the cervix). Censoring women at the time of cervical treatment is
commonly employed to address this bias and was used in the analyses reported
herein. Adjusting for therapy is an alternate approach that was also used, but
as the results were in the same direction and of similar magnitude to those
found with censoring they are not presented. Other time-dependent covariates included in our multivariate models were CD4+ T-cell count, recent sexual behavior, smoking status, and age group.
Ethnicity was adjusted as a time-independent variable.Cox
proportional-hazard regression models [29] were used to assess the association of cocaine use and the incident detection of HPV. The event time was defined as
the midpoint calendar date between the last HPV-negative and the first HPV-positive
visit. Since each woman had been tested for multiple HPV types at each visit
time, Wei Lin Weissfeld method was applied to adjust for possible correlations
between multiple incident infections [30]. A similar method was used to measure
the association of cocaine use with time to clearance of HPV, stratified by
whether the HPV type was prevalent at baseline or was first detected during
follow-up (incident detection).
Time-dependent and time-independent covariates, as well as methods for controlling for treatment
of cervical neoplasia, were as described above.Prevalent SIL and its association with cocaine use was assessed using similar
multivariate logistic regression models incorporating GEE, as described above,
to control repeated
observations over time. The associations of cocaine use and incident detection
of SILs were assessed using multivariate Cox models.


## 2.1. Laboratory Methods

The
laboratory technique for HPV assessments have been described in detail
elsewhere [20]. HPV DNA was detected utilizing L1 consensus primer MY09/MY11/HMB01 polymerase chain reaction (PCR) assays [20–22]. Control primer
set PC04/GH20, amplifying a 268 bp cellular beta globin DNA fragment, was
included in each assay to serve as an internal control for amplification.
Following proteinase K digestion, 2–10 μL of each cell digest was used in reactions
containing 10 mM Tris-HCL, 50 mM KCL, 4 mM MgCl2, 200 μM of each
deoxyribonucleotide triphosphate, 2.5 U Taq DNA polymerase, 0.5 μM of each
primer. There were 40 amplification cycles (95°C for 20 seconds, 55°C
for 30 seconds, and 72°C for 30 seconds, with a 5-minute extension
period at 72°C on the last cycle). Amplified material was then
detected using filters individually hybridized with biotinylated type-specific
oligonucleotide probes for multiple HPV types including HPV 6, 11, 16, 18, 26,
31, 32, 33, 35, 39, 40, 45, 51, 52, 53, 54 (AE9), 55, 56, 58, 59, 61, 62, 66,
67, 68, 69, 70, 71 (AE8), 72, 73 (PAP238A), 81 (AE7), 83(PAP291), 82v(AE2), 84 (PAP155), 85 (AE5), and 89 (AE6), as
described in [20, 23]. For these analyses, oncogenic and nononcogenic HPV types
were defined in accordance with recently published data that classified types
utilizing both phylogenetic and epidemiologic criterion. The oncogenic HPVs
were HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 66, and all other
HPV types were considered nononcogenic HPV [24].Pap smears were collected using a
plastic Ayre spatula and an endocervical brush.
Both specimens were smeared onto a single slide and fixed immediately.
Cervical cytology samples from all sites were centrally interpreted at Kyto Meridien
Laboratories (New York , NY) using the 1991 Bethesda System criteria
for cytologic diagnosis [25]. All smears
were read by two cytotechnologists who were blinded to the participants’
status. Ten percent of all negative smears and all abnormal smears were
confirmed by a cytopathologist. Diagnoses were reported as normal or benign,
atypical squamous cells of uncertain significance (ASCUS), low-grade squamous
intraepithelial lesion (LGSIL), moderate- or high-grade squamous
intraepithelial lesion (HGSIL), and cancer.
Glandular abnormalities were not included. Whenever possible the primary
cytologic outcome used was SIL among women with oncogenic HPV. This was chosen
since SIL in the presence of HPV is more clearly a precursor of cancer than are
cases of SIL in which oncogenic HPV is not detected. In cases in which the
number of such outcomes was sparse, we did use SIL among all women as an
outcome.T-cell
subsets were determined by immunofluorescence using flow cytometry in
laboratories participating in the AIDS Clinical Trials Quality Assurance
Program.  Plasma HIV RNA levels were
measured using a nucleic acid sequence-based amplification (NASBA) technique
(Organon Teknika, Durham, NC, USA) with a lower threshold of detection of 4000
copies/ml [26].


## 2.2. Statistical Analysis

Cocaine
used in the last six months was examined both as a binary outcome (use/no
use), and as an ordinal variable (no use/less than once a month/once a
month—once a week/2–6 times a week/once a day or
more). Consistent with prior studies [4] the prevalence of HPV DNA was defined
as the fraction of women with detectable HPV among those with adequate HPV test
results (as determined by the successful amplification of the human β-globin
gene—see Laboratory Methods). We defined “incident
detection" of HPV as detection of an HPV type that was not found at baseline or
at any other earlier visit in a given woman. The term “incident detection" is
used instead of “incidence" to reflect the fact that it is impossible to
distinguish newly acquired HPV infection and reactivation of previously
acquired latent HPV infection in a population with many years of sexual
activity, regardless of the HIV status of that population. Persistence of HPV
infection was defined as the time to clearance of a specific HPV type, and we
further distinguished in our analysis between the persistence of HPV detected
prevalently at baseline and those first detected incidentally at a subsequent
visit (see below). Clearance itself was defined as either a single negative or
two negative type-specific HPV results at sequential visits. The findings were
similar using either approach for defining clearance, and herein we present the
results of clearance using the former definition.The
baseline characteristics of cocaine users and nonusers in this study were
examined, and the distributions for selected parameters compared using standard
Pearson chi-square tests for categorical data, or by the
Cochran-Mantel-Haenszel tests when examining trends in ordinal data. These
variables were also evaluated as potential confounders in the multivariable
analyses described below.The
association of cocaine use with prevalent HPV DNA detection was measured in multivariate logistic regression models that incorporated
generalized estimating equations (GEE) to adjust the standard errors for
repeated measures (i.e., summarizing data across all HPV types and across study
visits), and assuming an independent correlation structure. In previous papers,
we have shown that the results in this dataset are unaltered by using other possible
correlation structures [4, 27], and, in general, model estimates are robust
with respect to the correlation structure imposed [28].Treatment
of abnormal cervical cytology can introduce a bias into analysis of HPV
infection, since treatment can alter the underlying mucosa; either increasing
infection (e.g., by exposing basal cells which are the cells susceptible to
infection) or decreasing infection (e.g., by removing infected cells or
inducing the replacement of columnar with squamous tissue in the transformation
zone of the cervix). Censoring women at the time of cervical treatment is
commonly employed to address this bias and was used in the analyses reported
herein. Adjusting for therapy is an alternate approach that was also used, but
as the results were in the same direction and of similar magnitude to those
found with censoring they are not presented. Other time-dependent covariates included in our multivariate models were CD4+ T-cell count, recent sexual behavior, smoking status, and age group.
Ethnicity was adjusted as a time-independent variable.Cox
proportional-hazard regression models [29] were used to assess the association of cocaine use and the incident detection of HPV. The event time was defined as
the midpoint calendar date between the last HPV-negative and the first HPV-positive
visit. Since each woman had been tested for multiple HPV types at each visit
time, Wei Lin Weissfeld method was applied to adjust for possible correlations
between multiple incident infections [30]. A similar method was used to measure
the association of cocaine use with time to clearance of HPV, stratified by
whether the HPV type was prevalent at baseline or was first detected during
follow-up (incident detection).
Time-dependent and time-independent covariates, as well as methods for controlling for treatment
of cervical neoplasia, were as described above.Prevalent SIL and its association with cocaine use was assessed using similar
multivariate logistic regression models incorporating GEE, as described above,
to control repeated
observations over time. The associations of cocaine use and incident detection
of SILs were assessed using multivariate Cox models.


## 3. Results

This analysis included data from 2584 HIV-seropositive and 915
HIV-seronegative women. The median follow-up time among those recruited during
1994-1995 was 10 years and for those recruited during 2002 was 3 years; a total
of 20 849 person years of observation among HIV-seropositive and 6385 among HIV-seronegative women
were included in this analysis. At baseline 16.1% of participants reported use
of crack within the prior 6 months, 11.5% had used cocaine, and 6.9% had used
both. The prevalence of HPV in the cohort was
34.4%. Although we initially analyzed the effects of cocaine use on HPV
infection separately from the effects of crack use, no significant (or
otherwise notable) differences were observed (data not shown). Therefore, we
combined these data, and herein report a comparison of the prevalence,
incidence and time to clearance of HPV among women who used either cocaine or
crack (crack/cocaine use) to that among women who used neither drug.Table1 shows the demographic characteristics of the study population at
baseline. Women acknowledging crack/cocaine use were older, more likely to be
African Americans, less likely to be Hispanic, had more sex partners in the
last six months, and were more likely to report heavy cigarette use. Among
women who reported crack/cocaine during the past 6 months, 18% reported using
less than once per month (< once/mo), 31% reported using between once/month and once/week
(once/mo-once/wk), 25% 2–6 times per week (2–6/wk), and 25% once per day or
more (≥ once/day).Table 1
Selected
baseline characteristics of cocaine users and noncocaine users in last 6 months at baseline in the Women’s Interagency HIV Study*.
CharacteristicN (%)P-valueUsed crack/cocaine1 in last 6 monthsYesNoTotal726 (%)2761 (%)—Age (yr)<.0001**<30116 (16)914 (33)—30–34160 (22)680 (25)—35–39207 (29)607 (22)—40–44171 (24)339 (12)—>=4572 (10)221 (8)—Race<.0001White95 (13)433 (16)—Hispanic121 (17)829 (30)—African American494 (68)1397 (51)—Others16 (2)102 (4)—HIV
status and CD4 T-cell count0.0559**HIV-negative218 (31)694 (26)HIV-positiveCD4>500150 (21)664 (25)—200≤CD4≤500212 (30)859 (32)—CD4<200121 (17)490 (18)—Number of male sex partners in
past 6 months<.0001**0155 (22)772 (28)—1 (married)80 (11)506 (18)—1 (single)223 (31)1049 (38)—297 (14)266 (10)—>2160 (22)159 (6)—Smoking
status<.0001**None60 (8)1106 (40)—Former smoker37 (5)483 (18)—Current smoker <10 pack-years282 (39)706 (26)—Current smoker >=10 pack-years344 (48)456 (17)—Frequency
of crack/cocaine useLess than once per month131 (18)NA—Once per month—once per week224 (31)NA—2–6 times per week185 (25)NA—Once per day or more180 (25)NA—*Limited
to those contributing data to the present analysis. Some data were missing at
baseline for selected patients. Percentages do not always add up to 100% due to
rounding.
**Two-sided Cochran-Mantel-Haenszel test. All other P values were determined with the two-sided Pearson’s chi-square test.Prevalent detection of
oncogenic HPV was significantly more common among women who reported
crack/cocaine use during the prior 6 months (Table2), than women who did not
use either drug (OR = 1.30; [95% CI: 1.09–1.55]), after adjustment for age,
race, HIV serostatus and CD4+ T-cell count, the number of sexual partners
during the prior 6 months, and smoking behavior, all factors that we found to
be associated with cervical HPV detection in prior studies [4, 31]. Nononcogenic HPV was also more prevalent
among crack/cocaine users; OR= 1.18
(1.04–1.34). Oncogenic HPV-positive cervical neoplasia (i.e., squamous
intraepithelial lesions [SIL] at risk of progression [oncogenic HPV+ SIL]) was
also significantly more common among women who reported crack/cocaine use
during the prior 6 months (Table 2; OR = 1.63; 95% CI 1.20–2.21).Table 2
Association of crack and cocaine use with prevalence,
incidence, and clearance of human papillomavirus (HPV) and cervical squamous intraepethelial
lesions (SIL) (adjusted analysis*).
Crack or cocaine use in the past six monthsAny HPVOncogenic HPVNononcogenic HPVSIL with oncogenic HPVPrevalent HPV and SIL: OR (95% CI)No1.01.01.01.0Yes1.22 (1.09–1.37)1.30 (1.09–1.55)1.18 (1.04–1.34)1.70 (1.27–2.27)Incident HPV and SIL: HR (95% CI)No1.01.01.01.0Yes1.20 (1.02–1.42)1.21 (0.97–1.52)1.20 (1.00–1.44)1.51 (0.99–2.30)Clearance of HPV and SIL**: HR (95% CI)No1.01.01.01.0Yes1.02 (0.88–1.17)0.96 (0.80–1.16)1.05 (0.88–1.25)0.57 (0.34–0.97)*Adjusted for CD4 count, number of sexual partners,
smoking, age and race.
**As there were a limited number of SIL infections with
oncogenic HPV for analysis of SIL clearance, results presented for risk of SIL
clearance include all SIL observed with or without oncogenic HPV.Incident detection of
oncogenic HPV was increased among crack/cocaine users, although the
relationship did not reach significance at traditional values (Table2; hazard
ratio [HR] = 1.21, 0.97–1.52). Similar
results were observed for incident detection of nononcogenic HPV and any HPV
(Table 2). Crack/cocaine was also associated with a trend that approached
significance in regard to an elevated risk of incident oncogenic HPV+ SIL (OR 1.51;
95% CI: 0.99–2.30).Clearance of oncogenic HPV infection was not associated with crack/cocaine use during the prior 6 months (Table2). Similarly, no association was found between
cocaine use and clearance of HPV+ SIL, although the data were sparse
given the more limited occurrence of this endpoint (data not shown). Therefore, we assessed associations between cocaine use and any
SIL (with or without oncogenic HPV). We found a significant association between
delayed clearance of SIL and cocaine use, (HR 0.57; 95% CI 0.34–0.97). No statistically significant dose response was seen with any of the
outcomes when frequency of cocaine use was assessed as an ordinal variable
(data not shown).Similar analyses were
performed for alcohol and heroin use. No association was found between either
drugs (whether we considered exposure as a dichotomous or as an ordinal
variable) and any of the outcomes of interest (oncogenic or nononcogenic HPV,
or SIL).


## 4. Discussion

In this prospective study of
HIV-infected and HIV-uninfected women, we observed increased risk of oncogenic
and nononcogenic HPV infection in those with crack/cocaine use but not in those
with heroin or alcohol use, consistent with our a priori hypothesis. If correct, the data suggest that the immunologic effects of cocaine, previously reported primarily in animal models, may have relevance to humans.Shen and colleagues, evaluating a
mouse model in which cocaine was injected intraperitoneally found that all
immune parameters, other than lymphocyte transformation of the
splenic or the peripheral blood lymphocytes, were suppressed [11]. Other
investigators have shown that withdrawal from cocaine can also induce
deleterious immune alterations. Using a rat model, Avila demonstrated that
repeated exposure to cocaine followed by withdrawal led to activation of the
neuroendocrine stress response, which alters cellular immunity and possibly
contributes to an increased susceptibility to infection [13]. HPV in humans is felt to be controlled, at least in part, by an intact mucosal immune system [32]. Perhaps most germane to our findings is the work of Lopez [33] and colleagues,
who found that daily cocaine administration induced a significant decrease
in the number of IgA+ cells with a concomitant increase in the number of CD8+
cells per villi in the intestinal lamina propria (ILP). Murine retrovirus
infection alone decreased the number of IgA+ and CD4+ cells in the ILP, and
this decrease was even more marked when murine acquired immune deficiency
syndrome (MAIDS) mice also received cocaine. The authors concluded that,
“cocaine administration could potentiate the dramatic effect that MAIDS
infection has on the mucosal-associated lymphoid tissues" [33].These data suggest
that response to HPV infection might be altered by cocaine. While HIV-infected
women are already at immunologic jeopardy and prone to numerous coinfections,
the relationship between cocaine use and HPV, one of the most common sexually
transmitted infections, has not, to our knowledge, been the focus of prior
research.  While we and others have considered drug use as a covariate in studies of HPV infections, those studies
have often not looked specifically at cocaine or crack, controlled for other
factors, or used drug use as a primary focus of analysis [20]. Our data
appear to confirm the immunomodulatory effects of cocaine, and suggest that
further clinical/laboratory research is indicated to better understand the
associations between cocaine use and the detection, and natural history of HPV
infection as well as the mechanism that underpins the relationship.This
study had several limitations. The finding of increased detection of HPV among
women acknowledging cocaine or crack use could reflect either an immunologic
phenomenon or a behavioral one (i.e., increased sexual activity) despite our
efforts to control
this in our analyses. However, we did not find a similar relationship between
HPV and the use of other drugs that might also be markers of risk taking. Our
failure to detect a consistent biologic gradient in cocaine’s effect (there was
an increasing effect with increasing exposure except at the highest strata when
sample size became small; data not shown) suggests that caution must be exercised in interpretation of results and that further work is warranted to
confirm and potentially extend these findings.An additional limitation to this study
is our inability to provide biologic measures of drug exposure. We note,
however, that the same study personnel performed repeated interviews over the
course of the study and formed a close rapport with the WIHS participants.
Further, we have previously observed a close correlation of acknowledged drug
use and reliable surrogates (e.g., use of injection drugs and hepatitis C
infection, data not shown). More importantly, it is most likely that
misclassification would have been in the direction of understating the frequency
of drug use, which would most likely have biased our results toward the
null. A final concern is that, since we
have previously shown that HAART use can modify the course of HPV disease [34], it is possible that some of the perceived effect of cocaine may have been
mediated by a lower rate of medication adherence among cocaine users. To
investigate this possibility, we repeated the analyses described above, but
limited only to the time frame prior to the availability of HAART. All findings
were in the same direction (data not shown) as reported for the time frame
after HAART became available. Thus, compliance with HAART use would not seem to
be an explanation for our findings.In summary, our data suggest
an association of crack/cocaine use with increased prevalence, incidence, and
delayed time to clearance of oncogenic HPV among HIV-infected women and women
at risk of HIV. These data lend support to animal studies suggesting a link
between cocaine use and predilection to infections and add to the litany of
reasons for making drug treatment a component of the care of HIV-infected
individuals.



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*Source: 587082-2008-04-15.xml*