Nationally, hepatitis C virus (HCV) outstrips HIV by about 10 to 1 in sheer numbers of inmates infected. Even so, controversy and confusion surround the management of HCV in correctional settings, while HIV testing and treatment is now relatively routine. This controversy stems from debate about the "best time" to treat HCV, and whether HCV treatment should begin to be included in the correctional health care budget or whether the cost should be borne by the public health sector.
While the debate about HCV treatment in corrections continues, significant advances in the treatment of HCV have occurred, and a number of correctional systems are taking advantage of this opportunity to intervene. Will improved care and accelerated implementation of the new therapies lead to diminished health care costs in years to come? Only time will tell. Meanwhile, education, testing, and prevention must be paramount. As has been observed for HIV, programs that test and educate inmates about HCV may lead to a reduction in the transmission of HCV after inmates are released into the community.
It has been estimated that 1-2% of the general population (2.9 to 5.8 million people) in the United States has been exposed to HCV,1
with 75% to 85% developing chronic HCV infection. The behavior that puts people most at risk for exposure to HCV is intravenous drug use (IDU). Other risks include use of shared injection equipment including cotton filters and "cookers,"2
unprotected sex with an HCV-infected partner (3%-13% lifetime risk), and receipt of blood products prior to 1988. Prevalence rates in certain high-risk groups are as high as 90% (Figure 1
). Since so many of the behaviors that put people at risk for developing HCV infection also put them at risk for incarceration (i.e., IDU), it should not be surprising that HCV is common in the correctional setting.
Figure 1: HCV Prevalence in High Risk Populations
Inmates at Risk
The most comprehensive analysis of HCV in the correctional system was compiled by Ted Hammet of Abt Associates in the context of a report for the NIJ and the NCCHC's report to Congress.5
In this report, the researchers estimated that approximately 30% of the total US population living with chronic HCV was released from prisons and jails in the US in 1996 (1.0 to 1.25 million people). The overall prevalence of HCV infection among inmates is estimated to be about 17% nationally, almost 10 times higher than the estimated 1.8% prevalence in the general US population.6
In certain sub-populations of inmates (i.e., those who are HIV-positive or who have abnormal liver function tests) the HCV prevalence can be even higher. Furthermore, the HCV/HIV co-infection rate is about a third higher in incarcerated women than incarcerated men, which reflects womens' participation in HCV and HIV risk behaviors.4
HEPP News recently performed a survey to assess the current practices regarding HCV management in state correctional facilities.7 Based on preliminary data from this study, the prevalence of HCV in inmate populations ranges between 9% and 39% by state (Figure 2).
Figure 2: Percentage of HCV-Positive Inmates by State, 2002
HCV prevalence as estimated by experts working with state correctional systems. These data were collected by HEPP staff who contacted correctional medical decision-makers in 30 states. (Jang, Nerenberg, De Groot, Unpublished data from telephone survey conducted Oct 2001-Feb 2002.)
Approximately 50% of persons with chronic HCV are unaware of their infection.5
Only about 2/3 of chronically infected individuals develop symptoms of infection, and these symptoms are often non-specific malaise and fatigue.8
The CDC states that "[t]esting persons in settings with potentially high proportions of injecting-drug users (e.g., correctional institutions, HIV counseling and testing sites, or drug and STD treatment programs) might be particularly efficient for identifying HCV-positive persons."9
Cost associated with HCV screening can be reduced by focusing on certain sub-populations that have particularly high prevalence of HCV infection (see HEPP News April 2001 p2).10 There are a variety of tests available for diagnosing HCV. Enzyme immunoassay (EIA) is the most cost-effective screening test; recombinant immunoblot assay (RIA) helps confirm positive EIA results, while polymerase chain reaction (PCR) is the "gold standard" for confirming active HCV infection with viral replication. In rare cases, the HCV antibody tests can give false negatives. Repeat antibody or viral load testing may be necessary when there is a significant suspicion of HCV infection in HIV infected patients, as low CD4 T-cell counts have also been associated with false negative HCV antibody and PCR tests.8, 11, 12
Testing for hepatitis infection informs the patient and physician about the potential for and possible existence of liver damage, and it should serve as an important prompt for a discussion about risky behaviors (particularly if the patient is not yet HCV infected), of factors associated with more rapid progression of HCV disease (such as alcohol abuse) and about the potential for transmission to others.13
Who Should Get Treated?
A number of correctional facilities have developed protocols for deciding which patients should consider initiating treatment while incarcerated (HEPP News
, April 2001).I
HHS recommends antiviral treatment for "patients with chronic hepatitis C who are at greatest risk for progression to cirrhosis. These persons include anti-HCV-positive patients with persistently elevated ALT levels, detectable HCV RNA, and a liver biopsy that indicates either portal or bridging fibrosis or at least moderate degrees of inflammation and necrosis."30
Shifting Standards for Treatment of HCV
Pegylated interferon is the latest advance in HCV treatment (FDA approved, 2001). The standard interferon alfa has been conjugated to a molecule of polyethylene glycol (PEG), which has increased the half-life of the interferon. Pegylated interferon can be given as a once-weekly injection in contrast with the three-times weekly injection of standard interferon alfa.
For those HCV-positive inmates who are going to be treated, initial treatment of chronic HCV with ribavirin/pegylated-interferon alfa is rapidly becoming the standard of care due to improved outcomes (see Table 1), when compared to standard (non-pegylated) combination therapy.16 This will be a significant change from years past, when standard (non pegylated) interferon alfa, in combination with ribavirin, was the standard of care.
|Table 1: SVR1 Rate According to Weight-Based Ribavirin Dosing and Type of Interferon|
|Pegylated Interferon2||Standard Interferon3|
|Overall||54% (274/511)||47% (235/505)|
|Ribavirin dose <10.6 mg/kg||50% (160/323)||27% (6/22)|
|Ribavirin dose >10.6 mg/kg||61% (114/188)||47% (229/483)|
|Overall||42% (145/348)||33% (114/343)|
|Ribavirin dose <10.6 mg/kg||38% (87/226)||20% (3/15)|
|Ribavirin dose >10.6 mg/kg||48% (58/122)||34% (111/328)|
|Genotype 2 or 3|
|Overall||82% (121/147)||79% (115/146)|
|Ribavirin dose <10.6 mg/kg||79% (70/89)||50% (3/6)|
|Ribavirin dose >10.6 mg/kg||88% (51/58)||80% (112/140)|
- SVR = sustained virologic response [see "Expected Outcome" below]
- (PEG-Intron, Schering) 1.5 mg/kg/wk for 48 weeks;
- 3 MIU 3x/wk for 48 weeks
From Manns, et al. Lancet 2001; 358: 958-965.16
The standard regimen now consists of daily oral ribavirin (usually five to six pills divided into two doses) and once-weekly pegylated alfa-interferon injections (dosed by weight; see "HCV 101" for dosing and side effects of treatment regimens). Standard interferon and/or monotherapy are currently only used if the patient cannot take pegylated interferon or ribavirin due to toxicities or side-effects (see Box 1 for anti-HCV drugs).
Currently, PEG-Intron (Schering Plough) is not available immediately to all patients who are prescribed treatment. Because demand has exceeded supply, the company has developed the "Access Assurance" program to ensure that all patients who begin PEG-Intron treatment can successfully complete it.18
A second pegylated interferon alfa (Pegasys, Roche), is expected to be approved by the FDA in the second half of 2002. This product will also require once-weekly injections. Roche is expected to release its own ribavirin along with Pegasys.
Length of Treatment
Recommendations related to the duration of combination therapy depend on viral genotype. Genotypes 1a, 1b, 2, and 3 are the most common in the United States; 70% to 80% of patients are infected with genotype 1.8
- HCV genotype 1: A 48-week (12-month) course of therapy.
- HCV genotype 2 or 3: A 24-week (6-month) course of therapy. Interferon monotherapy is no longer the standard of care for initial therapy.
The goal of HCV therapy is to obtain a sustained virologic response (SVR), which implies that HCV RNA remains undetectable for 6 months or more after therapy stops. This correlates with a viral response lasting >
4 years and with a histologic response of regression or arrested progression of fibrosis or inflammation.8
In a randomized trial of patients with chronic HCV infection, 42% of genotype 1 patients and 82% of genotype 2 or 3 patients on the pegylated regimen experienced SVR in a study of combination therapy (Table 1
Additionally, early HCV viral clearance is a predictor of SVR. Patients on pegylated interferon therapy show an increased phase I HCV viral clearance in comparison to patients on standard therapy. This may directly inhibit viral replication and release, resulting in a more rapid complete viral clearance as predicted by viral kinetics.19
Adherence is also a key component to a favorable outcome: patients who receive >80% of their doses have significantly more favorable outcome than patients who do not.14, 15 In addition, other factors, including combination therapy, careful dosing by weight (see "HCV 101"), age <45, female gender, and mild (rather than advanced) chronic inflammation on liver biopsy also contribute to improved treatment outcomes.
Liver biopsy is necessary to assess fibrotic damage because neither HCV viral load nor ALT level correlates well with the degree of liver damage.17
There are three main indications for liver biopsy: 1) to rule out unsuspected diagnoses that may influence patient management, 2) to assess the severity of liver damage and 3) to assess response to therapy. However, the need for biopsy is a matter of debate in corrections since biopsies are both expensive and logistically complicated. Some state protocols do not require liver biopsies prior to starting treatment. Some facilities have liver biopsies provided on-site. An alternative for correctional settings is to carefully monitor response to therapy over the initial days and weeks of treatment since patients who respond immediately are believed to be likely to continue to benefit from treatment and those who do not are unlikely to benefit and might have treatment discontinued (see HEPP News
, April 2001).20, 21
HIV/HCV co-infection is extremely common in correctional settings. Since HIV and HCV frequently occur in the same individual and HCV exacerbates the progression of HIV, the United States Public Health Service and the Infectious Disease Society of America issued guidelines stating that HIV infected individuals should be screened for HCV23
and named HCV an "opportunistic infection" in 1999.24
Analyses of the effect of HCV and HIV co-infection on progression of either disease are often confounded by coexisting risk factors (i.e., IDU, EtOH) for progression. However, available data seem to indicate that HIV infection accelerates HCV liver disease causing co-infected patients to have a shortened natural history of HCV infection.25-29 Furthermore, co-infected patients appear to have a 12 to 300 fold higher risk of developing hepatocellular carcinoma than non-carriers.30 Additionally, one study found that co-infected patients died earlier because of their more rapid progression to cirrhosis. In this study, patients died earlier due to liver failure and not due to the development of hepatocellular carcinoma.25
|Box 1: Anti-HCV Drugs|
Ribavirin is a nucleoside analog that functions as an immunomodulator in HCV infection by influencing TNF level. Although the drug becomes incorporated into the HCV RNA, acting as a direct mutagen to the viral RNA, this is not the primary mechanism of action in the treatment of chronic infection.
Interferon alfa is a naturally occurring cytokine that the body normally produces. While it may have a minor direct antiviral effect, it functions primarily to recruit cells to kill the virus by activating resting cells. Pegylation increases the half-life of the drug.
Interferon and ribavirin are contraindicated in pregnancy.8
(See "HCV 101," in this issue for details on side effects.)
|Box 2: A Measure of Prevention|
According to current guidelines, vaccination against HAV is recommended for HCV-infected individuals who have no serologic evidence of immunity. Vaccination against HBV may also be beneficial as fulminant liver failure may occur following co-infection with either virus.6
Brand Name, Manufacturer
VAQTA, Merck & Co.
|2 doses: 0 mo. + booster at 6-12 mo.|
|HBV||Engerix B, GlaxoSmithKline|
Recombivax HBR, Merck & Co.
|3 doses: 0, 1, and 6 mo. OR 0, 1, and 4 mo.|
|HAV/HBV||Twinrix, GlaxoSmithKline (combination vaccine)||3 doses: 0, 1, and 6 mo.22|
Moreover, liver inflammation can be due to ART, and this may be more frequent in those who have underlying chronic hepatitis due to HCV or HBV. It is estimated that the risk of hepatic inflammation by antiretroviral agents is approximately 4-6% in co-infected patients.31, 32 Those agents that have been associated with Grade 3 or 4 transaminase abnormalities include ritonavir44 and nevirapine. In contrast, other data have shown that those persons who were on PI containing regimens had lower fibrosis and necroinflammatory scores than those who were on non-PI containing regimens.32 Many HCV treaters would avoid ritonavir as a PI in PI doses, but agree that the small amount of ritonavir in boosted PI therapies (i.e., ritonavir/saquinavir 100/1,000 mg bid; ritonavir/indinavir 200/800 bid) probably poses a much smaller risk for liver inflammation in co-infected patients. Thus, for those co-infected persons in whom treatment has already been initiated, frequent evaluation including transaminases, total bilirubin, and CBC should be performed to monitor drug tolerance and safety. In those who are treatment naïve and HIV therapy is indicated, care should be used in choosing an initial regimen, avoiding the risk of added potential toxicity associated with certain agents.
Cellular immune response (T helper cells or CD4 T cells and Cytotoxic T lymphocytes or CD8 T cells) is involved in mounting an immune defense against HCV. During the acute phase of HCV infection, specific anti-HCV CD4 and CD8 responses are important determinants of self-limited infection.33 Clearly, HCV infected individuals who also have advanced HIV infection (and low CD4 T-cell counts) may be less able to respond to HCV infection due to their compromised cellular immune response. Therefore, in those with advanced HIV disease, it is important to treat the HIV infection first. Bringing the HIV infection under control may, in some cases, subsequently lower the HCV RNA, slowing progression of HCV-associated pathogenesis. With more CD4 cells, a patient will be more likely to mount a specific response against HCV, which will then result in a more favorable outcome for the patient. In the event that an individual is newly infected with HIV, has a good CD4 count, yet has advanced HCV infection with enough liver damage to be unable to tolerate ART, then the HCV must be treated first.
HIV/HCV Response to Therapy
HCV-infected and HIV/HCV co-infected patients respond to standard interferon plus ribavirin HCV therapy34
provided that the HIV infection of the co-infected patient is under control, meaning that the patient's CD4 count is above 300 at the start of HCV treatment.35
Studies of co-infected patients on the new treatment standard, pegylated interferon plus ribavirin, have shown that after 12 weeks, 35% of co-infected patients are HCV RNA negative and 43% had achieved a minimum of a 2-log reduction in HCV viral load.36
A study by Turriani and colleagues has found that HIV co-infection does contribute to a slower clearance rate of HCV.37
However, the discontinuation rate of co-infected patients has matched discontinuation rates of HCV monoinfected patients (about 14 %),38
indicating that HAART and HCV therapy can be concomitantly administered. Patients who start HAART early in HIV have a better clinical prognosis and decreased liver fibrosis than patients who wait to begin HIV treatment.40
Currently, when exclusionary criteria are not present, treatment of hepatitis C is recommended for patients when CD4 and viral load values reflect good response to antiretroviral treatment. Although some controversy remains in regard to the definition of a good response to HAART, a stable CD4 T-cell count greater than 300 with a stable viral load less than 400 is generally accepted.35, 41 Co-infected patients should also be treated with pegylated interferon plus ribavirin, as this new standard of care results in better outcomes for co-infected as well as HCV monoinfected patients. In a new study this treatment was well tolerated in co-infected patients, and there were no adverse affects on the HIV disease when using pegylated interferon in combination with ribavirin.35
Cost of Treatment
With the cost of treatment ranging between $12,000 to $25,000 per year per patient, the cost of treating HCV can be prohibitive to some correctional systems (see "HCV 101
" for pricing guide). Although the treatment itself is expensive, its cost-effectiveness has been ranked in the same range as stool gualac testing, pneumococcal vaccination, and mammography (see Figure 3
). Unfortunately for correctional budget managers, the cost burden falls on corrections, while the money saved by treating inmates benefits society as a whole. With rare exceptions, transplants (i.e., to replace the diseased liver with a disease-free liver) are not routinely performed on incarcerated individuals.
Figure 3: Relative Value, Cost Effectiveness of HCV Therapy vs. Other Medical Interventions3
Wong JB. Am J Med
i. Eddy D.M. Ann Intern Med 1990;113:373-84; ii. Sisk J.E., Riegelman R.K. Ann Intern Med 1986;104:79-86; iii. Johannesson M. Med Decis Making 1994;14:236-44. iv. Tsveat J., et al. Circulation. 1991;83:1194-1201; v. Eddy D.M. Ann Intern Med 1989; 111:389-99.
|Table 2: Monitoring HCV Treatment|
Table also applies to HCV/HIV patients
- HIV viral load, CD4, CBC, LFTs, Chem panel, HCV load, genotype
- Screen for co-morbid disease
- Depression screen (consider anti-depressant prophylaxis)
- If anemic: erythropoeitin or consider adjusting ribavirin dose
- CBC, LFTs, Chem panel
- Evaluate mood, adverse effects
- HCV VL, HIV VL, CD4
- Evaluate for drug-drug interactions
- Screen for IFN-associated thyroid dysfunction (TSH)
Check HCV VL week 12 and 24
- Week 12: HCV RNA >1 log reduction
- Week 24: HCV RNA undetectable
- If genotype 1, continue TX for 48 weeks. If non-genotype 1, stop therapy after 24 weeks.
VL (viral load); CBC (complete blood count); LFTs (liver function tests); Chem (chemistry panel); TSH (thyroid stimulating hormone).
Most experts recommend that HCV treatment be monitored by an infectious disease or GI specialist. Many HIV specialists in correctional settings have become local experts on the management of HCV, due to the high co-infection rate in their patients and because of their familiarity with the management of side effects (neutropenia, anemia) related to HCV therapy. One expert believes that "HIV caregivers who are willing to learn about hepatitis C treatment and stay current should be the ones responsible for the day-to-day care" of co-infected patients.45
Patients must be monitored carefully for adherence, side effects, and response to treatment. See Table 2
for suggestions for monitoring HCV treatment.
New Guidelines for Corrections?
The CDC and HHS have issued guidelines for the management of HIV and for HCV.42, 43
These guidelines do not specifically address the management of the two viral infections in correctional settings. Due to the disproportionate prevalence of viral hepatitis among incarcerated populations, the CDC is planning to issue corrections-specific HCV management guidelines. The guidelines have been in progress since last year, and are expected to be released in late summer or early fall 2002. Although these guidelines will not suggest a specific treatment protocol, they may serve as an important reference for developing correctional standards of care and management protocols for the HCV-infected inmate. The NIH will be revising its treatment guidelines in June (see "Save the Dates" on page 9 of the print version or in the PDF
When thinking about managing the HCV epidemic in corrections, it is important to keep the reality of correctional health care in perspective. If it is not possible to test all incoming inmates for HCV, savvy providers will set up protocols that will help them identify inmates who may be at high risk for HCV infection, and educate those who are not yet infected. And whereas treatment initiatives may have been poorly received in the past, armed with new data on the successful management of HIV and HCV co-infected individuals and new data on improved outcomes due to pegylated interferon plus ribavirin, providers may be able to enroll more inmates in treatment protocols. As the CDC and the NIH compile guidelines and consensus papers this spring, correctional physicians eagerly await further direction in managing HCV and HIV/HCV co-infection among the inmate population.
Nothing to disclose
** Consultant & Speaker's bureau: Abbott, Agouron Pharmaceuticals, BMS, Boehring-Ingelheim, Cubist, Fujisawa, Gilead, GSK, IntraBiotics, Merck, Ortho McNeill, OrthoBiotech, Pfizer, Roche, Schering, Trugene/Visible Genetics
*** Consultant & Speaker's bureau: Abbott, Agouron Pharmaceuticals, Merck, Roche, Boehringer-Ingelheim
- See protocol developed by Lou Tripoli and colleagues for CMS in Hepp News, April 2001, p.6 for example.
- Thorpe L.E., Ouellet L.J., et al. Am J Epidem 2002; 155 (7): 645-653.
- Table and figure courtesy of Michael Wong, M.D.
- Reindollar R.W. Am J Med 1999 Dec 27; 107 (6B): 100S-103S.
- Hammett T.M., Harmon P., and Rhodes W. The Burden of Infectious Diseases Among Inmates and Releasees From Correctional Facilities. Prepared for NCCHC-NIJ "Health of Soon-to-Be-Released Inmates" Project, June 14-15, 1999, Chicago, IL.
- Hepatitis Control Report, Winter 1999-2000; 4(4), 1.
- Brown University student Marcus Jang and HEPP staff Rebecca Nerenberg have contacted correctional medical decision-makers in 30 states, assessing the estimated prevalence of HCV, criteria for testing and treating HCV, the types of testing are available, and the education inmates receive about HCV infection and transmission.
- Satoor S., Raufman J.P. Clin Cornerstone 3 (6): 36-26, 2001.
- MMWR 1998 Oct 16; 47 (RR19).
- Pfister J.R. CDC Consultants' Meeting, Atlanta GA, March 5-7, 2001.
- Bonacini M., Puoti M. Arch Intern Med 2000; 160 3365-3373.
- Bonacini M. AIDS Reader 12 (1): 19-26, 2002.
- See the CDC Serostatus Approach to Fighting the Epidemic, SAFE, March 2001 HEPP News.
- Schiff E.R., Maddrey W.C., et al. Tx Reporter Jan 2001; 7-9.
- Manns M.P., McHutchison J.G., Gordon S, et al. [abstract 552]. Hepatology 2000; 32: 297A.
- Manns M.P., McHutchison J.G., et al. Lancet 2001; 358: 958-65.
- Peters M.G., Louie K., Terrault N. Medscape HIV/AIDS eJournal 8 (1), 2002. www.medscape.com/viewarticle/420681.
- Providers must contact the Access Assurance program (1-888-437-2608) to register their patients for the first-come, first-serve wait list for PEG-Intron supply. In a written statement in January, Schering Plough estimated a 10-12 week wait for new patients beginning therapy, however the manufacturer currently does not believe anyone will have to wait the full 10-12 weeks.
- Sherman K.E., Horn P., Rouster S., et al. Abstract 122, 9th CROI, Feb 24-28, 2002; Seattle, WA.
- Wong J.B. Am J Med 2000 Apr 1; 108(5): 366-373.
- Lake-Bakaar, G. Lancet 2002; 359 (9311): 1064.
- 1999 USPHS/IDSA Guidelines. MMWR 1999, 48: 1-59.
- Di Martino V., Cavallaro L., Ezenffis J., et al. Abstract 1095, 52nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); Nov 9-13, 2001; Dallas, TX.
- Darby S.C., Ewart D.W., et al. Lancet 1997; 350: 1425-1431.
- Benhamou Y., Bochet M. Di, et al. Hepatology 1999; 30: 1054-1058.
- Soto B, Sanchez-Quijano A, et al. J Hepatol 1997; 26: 1-5.
- Puoti M., Bonacini M., et al. J Infect Dis 2001; 183: 134-137.
- National Institutes of Health Consensus Development Conference Panel Statement: Management of Hepatitis C. Hepatology 1997; 26 (Suppl 1): 2S-10S.
- Dieterich D., Fischl M., Rimland D., Sepulveda G. Abstract 663-M, 9th CROI, Feb 24-28, 2002; Seattle, WA.
- Benhamou Y., Di Martino V., et al. Hepatology 2001; 34:283-7.
- Talal A.H., Canchis P.W., Jacobson I.M. Cur Gastr Rep 2002, 4:15-22.
- Bini E., Reid M., Klinzman D., et al. Abstract 653, 52nd AASLD; Nov 9-13, 2001; Dallas, TX.
- Chung R., Andersen J., Alston B., et al. Abstract LB15, 9th CROI, Feb 24-28, 2002; Seattle, WA.
- Khalili M., Hoffman-Terry M., Hassanein T., et al. Abstract 623, 52nd AASLD; Nov 9-13, 2001; Dallas, TX.
- Turriani F.J., Ribeiro R.M., Gilbert T.L., et al. Abstract 121, 9th CROI, Feb 24-28, 2002; Seattle, WA.
- Perez-Olmeda M., Romedo M., Asensi V., et al. Abstract 641, 52nd AASLD; Nov 9-13, 2001; Dallas, TX.
- Sabin C., Dauer B., Phillips A., et al. Abstract 639-M, 9th CROI, Feb 24-28, 2002; Seattle, WA.
- Fuster D., Tural C., Tor J., et al. Abstract 646-M, 9th CROI, Feb 24-28, 2002; Seattle, WA.
- Carpenter C.J., Cooper D.A., Fischl M.A., et al. JAMA 2000, January 19; 283(3): 381-391.
- MMWR 2001 Nov 9; 50 (RR19). www.cdc.gov/mmwr/PDF/RR/RR5019.pdf.
- MMWR 1998 Oct 16; 47 (RR19). www.cdc.gov/mmwr/PDF/RR/RR4719.pdf.
- Puoti M., Bonacini M., et al. J Infect Dis 2001; 183: 134-137.
- Dieterich D.T. The AIDS Reader 2002; 12 (1): 22-23.
- Garfein R.S., Vlahov D., Galai N., Doherty, M.C., Nelson, K.E. Am J Pub Health 1996; 86: 655-61.
- Staples C.T., Rimland D., Dudas D. CID 1999; 29: 150-154.
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