Coinfection with hepatitis C virus (HCV) in patients with HIV-1 infection is one of the major comorbidities and associates with worsened mortality.1–6 Although HCV infection is especially common among injection drug users because of transparental infection,7 noninjection illicit drug use and traumatic sexual behavior in the absence of injection drug use are reported in the United States and Europe to enhance noninjection drug-related transmission of HCV.8–14
In Japan, because of the low prevalence of injection drug use in the general population (lifetime prevalence of illicit drug use as a whole in 2009 was only 2.9%), coinfection with HCV in patients with HIV-1 infection is rare.15–18 Recently, however, at our clinic, the AIDS Clinical Center, Tokyo, there has been a surge in the rate of acute HCV infection among men who have sex with men (MSM) with HIV-1 infection who deny using injection drugs. The AIDS Clinical Center is one of the largest referral centers for HIV care in Japan with patients mostly comprising MSM.19
This study was designed to determine the incidence and risk factors of incident HCV infection in MSM with HIV-1 infection at a resource-rich setting in Asia, with a special focus on noninjection illicit drug use.
The study population was HIV-1-infected MSM, aged older than 17 years, who visited our clinic for the first time from January 2005 to December 2010, and with negative HCV antibody (HCVAb) at baseline and at least 1 subsequent HCVAb test result. The following exclusion criteria were applied: (1) patients who visited the clinic for a second opinion, (2) patients referred to other facilities on their first or second visit. The study patients were followed up until December 31, 2012.
At our clinic, HCVAb, CD4 cell count, HIV-1 viral load, hepatitis B surface antigen (HBsAg), and Treponema pallidum latex agglutination (TPHA) test are routinely conducted on the first visit. Patients positive for HCVAb subsequently undergo another HCV-RNA measurement. Patients visit our clinic at least every 3 months for monitoring CD4 cell count, HIV-1 viral load, and liver function tests, because the prescription period under the Japanese health care system is limited to 3 months. Repeat HCVAb tests were performed at the discretion of the treating physician. Laboratory data and baseline demographics on the first visit were collected from the medical records.
Social demographics including sexuality and history and type of illicit drug used (injection or noninjection) were collected through a structured interview conducted on the first visit.20 Because the interview could underestimate the prevalence of illicit drug use, we also searched the medical records for information on illicit drug use and related variables covering the period from the first visit to December 2012.
At our clinic, written informed consent is obtained from each patient to store serum samples drawn at the first visit and subsequent visits at the discretion of the treating physician.21 Either latest HCVAb test result conducted in clinical practice or from the latest stored serum sample was used to determine the status of HCV infection, whichever the follow-up time was longer. This study was approved by the Human Research Ethics Committee of the hospital.
The incidence of HCV was calculated by dividing the number of HCVAb seroconversion by person-time at risk. Person-time represented the time from the first visit to the first positive HCVAb in patients diagnosed with incident HCV infection and the time from the first visit to the last negative HCVAb result in patients without incident infection. Poisson regression was used to compare the incidence of HCV seroconversion among 4 observation periods.
The uni- and multivariate Cox proportional hazards model was used to estimate the impact of illicit drug use as a whole over nonusers on the incidence of HCV infection as a primary exposure.
In multivariate analysis, age was added to the univariate analysis for illicit drug use over nonuse to form model 2. In model 3, injection drug use and insurance status were added because of their significant association with incident HCV infection in univariate analysis. Methamphetamine use and incarceration because of drugs were not added because of their multicollinearity with injection drug use (most injection drug users in Japan use methamphetamine injection).18 Baseline CD4 count, HBsAg, and TPHA were added to the model because previous studies showed that low CD4 count and these infections are risk factors.6,22
Statistical significance was defined at 2-sided P values of <0.05. We used the hazard ratios (HRs) and 95% confidence intervals (95% CIs) to estimate the impact of each variable on the incidence of HCV infection. All statistical analyses were performed with the Statistical Package for Social Sciences version 20.0 (SPSS, Chicago, IL).
A total of 1182 MSM patients with HIV-1 infection visited the AIDS Clinical Center for the first time during the study inclusion period. Of these, 114 patients were excluded from the analysis (Fig. 1). The remaining 1068 patients had baseline HCVAb results, of whom 22 were positive for HCVAb. Of 1046 HIV-1 infected MSM patients with negative baseline HCVAb, the follow-up HCVAb test was available for 753 (72%) patients, either with clinical data (n = 295) or with stored blood samples (n = 458). The study population comprised the latter group of 753 patients.
Twenty-one patients (2.8%) incidentally seroconverted to HCVAb positive over 2246 person-years (PY) of total observation period, with an incidence of 9.35 per 1000 PY (95% CI: 6.12 to 14.2). The median time from the first visit to HCV seroconversion was 852 days [interquartile range (IQR), 324–1491 days]. The incidence increased over time from 0 per 1000 PY (0 case/270 PY) in 2005–2006, 3.0 per 1000 PY (2/672 PY) in 2007–2008, 7.7 per 1000 PY (6/779 PY) in 2009–2010, to 24.9 per 1000 PY (13/522 PY) in 2011–2012 (P = 0.012). As sensitivity analysis, the same calculations were conducted for the study population excluding injection drug users, and the results were similar; 17 patients became HCVAb positive over 2146 PY for an incidence of 7.92 per 1000 PY, and the incidence increased over time [0/1000 PY (0/258 PY) in 2005–2006, 1.5/1000 PY (1/650 PY) in 2007–2008, 8.0/1000 PY (6/747 PY) in 2009–2010, and 20.2/1000 PY (10/495 PY) in 2011–2012 (P = 0.045)].
The study patients were mostly Japanese men of relatively young age, covered with health insurance (Table 1); 40% of the study patients were illicit drug users based on the interview and medical records. Amyl nitrite, 5-methoxy-diisopropyltryptamine, 3,4-methylenedioxymethamphetamine, cannabis, heroin, cocaine, and opium were named by the patients. Patients with incident HCV infection were significantly more likely to be illicit drug users (P = 0.003). In addition, incident HCV cases were more likely to be injection drug users (P = 0.016), methamphetamine users (P = 0.039), and incarcerated owing to illicit drug use (P = 0.026) (Table 1). In contrast to the high prevalence of illicit drug use (40%), the prevalence of injection drug use was low (5%).
Among the 21 HCV incident cases, only 4 (19%) patients were injection drug users. Of the 21, 18 patients were screened for HCVAb because of high serum alanine aminotransferase levels, including all 17 positive for HCV RNA.
Among illicit drug users (n = 298) and nonusers (n = 455), 15 (5.0%) and 6 (1.3%) patients, respectively, were infected with HCV, with incidence of 16.6 and 4.48 per 1000 PY, respectively. Illicit drug users were significantly more likely to be infected with HCV, compared with nonusers (P = 0.004, Log-rank test). The total observation period was 906 PY (median, 1012 days; IQR, 543–1607 days) for illicit drug users and 1340 PY (median, 963 days; IQR, 538–1542 days) for nonusers.
Univariate analysis showed a significant relationship between illicit drug use and incident HCV infection (HR = 3.662; 95% CI: 1.420 to 9.439; P = 0.007) (see Table S1, Supplemental Digital Content, http://links.lww.com/QAI/A479). Furthermore, injection drug use (HR = 5.387; 95% CI: 1.804 to 16.09; P = 0.003), methamphetamine use (HR = 3.220; 95% CI: 1.083 to 9.573; P = 0.035), incarceration owing to illicit drugs (HR = 4.857; 95% CI: 1.429 to 16.51; P = 0.011), and on social benefits (government financial assistance) (HR = 6.982; 95% CI: 2.308 to 21.12; P = 0.001) were significantly associated with incident HCV infection. Conversely, age, low baseline CD4 count, positive HBsAg, and positive TPHA were not associated with incident HCV infection.
Multivariate analysis identified illicit drug use as a significant risk for incident HCV infection after adjustment for age (adjusted HR = 3.814; 95% CI: 1.447 to 10.05; P = 0.007) and for other variables (adjusted HR = 3.006; 95% CI: 1.092 to 8.275; P = 0.033) (see Table S2, Supplemental Digital Content, http://links.lww.com/QAI/A479). Injection drug users (HR = 4.672; 95% CI: 1.425 to 15.31; P = 0.011) and on social benefits (HR = 7.942; 95% CI: 2.370 to 26.62; P = 0.001) were also risk factors for incident HCV infection in multivariate analysis.
At our large urban HIV clinic in Tokyo, 21 (2.8%) HIV-infected MSM patients were newly infected with HCV during the study period, with an incidence of 9.35 per 1000 PY. The incidence of HCV infection showed statistically significant increase over the observation period, from 0 per 1000 PY in 2005–2006 to 24.9 per 1000 PY in 2011–2012. Most incident HCV cases were noninjection drug users, as 17 (81%) patients were not identified as using injection drugs. The incidence of new HCV infection was >3-folds higher in any illicit drug users than nonusers, with estimated incidence of 16.6 and 4.48 per 1000 PY, respectively, and illicit drug use was identified as a significant risk factor for incident HCV infection in multivariate analysis.
To our knowledge, this is the first study in Japan and is the second in Asia to report the incidence and risk factors for incident HCV infection among HIV-infected MSM.23 The incidence of 9.35 per 1000 PY was similar to that reported in North America and Western Europe (8.7–16.3/1000 PY) and was also very close to that of Taiwan (9.25/1000 PY).23–26 The results of this study demonstrated the emergence of noninjection drug-related HCV infection in HIV-1-infected MSM in resource-rich settings in Asia and support routine rescreening for HCVAb among HIV-infected MSM, in particular among drugs users, both injectors and noninjectors.
The reason for the increasing trend of incident HCV infection in HIV-infected MSM noninjection drug users remains to be elucidated. Both baseline positive HBsAg and TPHA, markers for sexual activity, were not associated with incident HCV in this study. This is probably because these variables were collected at the baseline and do not necessarily reflect the ongoing sexual activity during observation period. However, based on reports from Western Europe and North America, it is reasonable to assume that such change in the incidence is mainly because of increased practice of high-risk sexual behaviors, such as unprotected anal intercourse, group sex, and fisting (often practiced in the context of illicit drug use that can lower the pain threshold, leading to increased bleeding) among MSM with HIV-1 infection in Japan.10 Sharing of drug paraphernalia and possible intranasal/intrarectal transmission can also contribute.27,28 Because of the introduction of effective and tolerable antiretroviral therapy, the life expectancy and quality of life of people with HIV infection has improved substantially, which could associate with increased high-risk behavior in MSM with HIV-1 infection.29,30
Several limitations need to be acknowledged. First, because this study did not count the number of HCVAb tests for each patient during each observation period, it is possible that the increasing trend of incident HCV infection is because of increasing number of HCV testing in recent years. However, most patients with incident HCV infection were tested for HCVAb in clinical practice, because they were suspected to have acute HCV infection based on elevated liver enzymes. Thus, it is highly likely that the increasing trend of HCV infection shown in this study is true for this cohort. Second, we were not able to rescreen for HCVAb for 28% of the patients with negative baseline HCVAb result. Third, the structured interview designed for data collection and chart review do not necessarily prevent underreporting of illicit drug use and injection drug use. However, underreporting to a certain degree is unavoidable with regard to issues such as illicit drugs.31
In conclusion, this study showed that incident HCV is increasing among mostly noninjection drug use MSM with HIV-1 infection at resource-rich setting in Asia. Illicit drug use was identified as an independent risk factor for incident HCV infection. It is important to raise awareness of noninjection drug-related HCV infection and to take appropriate measures to prevent HCV infection in this population.
The authors thank Yukiko Takahashi and Fujie Negishi for their assistance in sample processing, Misao Takano for invaluable comments for the manuscript, and Akiko Nakano for the project coordination. They also thank all other clinical staff at the AIDS Clinical Center, National Center for Global Health and Medicine, for the dedicated clinical practice and patient care.
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