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Am. J. Trop. Med. Hyg., 74(2), 2006, pp. 239-245
Copyright © 2006 by The American Society of Tropical Medicine and Hygiene

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MORBIDITY AND MORTALITY PROFILE OF HUMAN IMMUNODEFICIENCY VIRUS–INFECTED PATIENTS WITH AND WITHOUT HEPATITIS C CO-INFECTION

ANGEL M. MAYOR*, MARIA A. GOMEZ, DIANA M. FERNANDEZ, EDDY RIOS-OLIVARES, JAMES C. THOMAS, AND ROBERT F. HUNTER
Retrovirus Research Center, and Department of Microbiology, Universidad Central del Caribe, School of Medicine, Bayamón, Puerto Rico; Epidemiology Department, School of Public Health, University of North Carolina, Chapel Hill, North Carolina


ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) co-infection is an important and frequent scenario, predominantly in injecting drug users (IDUs). The present study evaluated morbidity and mortality variation in HIV-infected patients with and without HCV co-infection. Co-infection prevalence was determined in 356 HIV-infected persons. Their clinical manifestations, laboratory findings, risk factors, HIV therapies, and mortality rates were evaluated. The prevalence of HCV was 54% in the overall group and 81% in IDUs, with a predominance of HCV genotype 1. Mortality rates were similar in patients with and without co-infection; however, co-infected patients had significantly higher liver damage as a cause of mortality when compared with those who were not co-infected. The high prevalence of HCV and an emerging mortality from liver diseases showed the significance of this co-infection in the HIV epidemic. Primary and secondary prevention are necessary to reduce the expanding impact of HCV infection in HIV patients.


INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The introduction of highly active antiretroviral therapy (HAART) has increased the life expectancy among subjects infected with the human immunodeficiency virus (HIV). The primary reason for the increased longevity is the decreasing rates of opportunistic infections that often were one direct cause of death. This scenario has introduced a number of issues that are interdisciplinary in nature and will define newer aspects on the HIV epidemic until viral eradication is a possibility. Some of these issues concern the emergence of chronic conditions that are compatible with prolonged survival. Infection with hepatitis C virus (HCV) is one of the chronic infections that are often seen co-infecting HIV patients, particularly in subjects who are injecting drug users (IDUs).1–11

Between 30% and 50% of HIV-infected persons have a concurrent HCV co-infection.1,10,11 The impact of the co-infection appears to be more relevant in certain ethnic groups and particularly among IDUs. In this latter group, the prevalence exceeds 80% with important variations according to the patients’ age and the duration of the risk practice.11–13

Many of the details regarding the interaction between HIV and HCV remain controversial. Certain studies suggest that HCV-related hepatic damage is worsened in patients with HIV infection, and that HCV mutates more readily in HIV patients with low CD4+ lymphocyte counts.14–16 A more controversial point is the impact of HCV infection on the course of HIV infection. Several studies suggest that HCV does not affect the natural history of HIV infection. Some investigators found that co-infection does not influence the rate of progression to either clinical or immunologic endpoints in co-infected HIV patients.17–19 Other studies suggest that the co-infection worsens the immunologic deterioration and thus accelerates the progression to acquired immunodeficiency syndrome (AIDS).20–22 An important variable that is emerging in the literature is the impact that variations in the HCV genotype may have on the progression of HIV infection. The HCV genotypes 1a and 1b have been reported to be associated more often with a rapid progression to AIDS and death than other genotypes.11 This report evaluates differences of HCV-co-infected patients and those not co-infected in a cohort of HIV/AIDS patients followed in Puerto Rico.


MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study population. The study population was composed of 519 HIV-infected patients that entered the Retrovirus Research Center (RRC) cohort in Bayamón, Puerto Rico between February 1998 and August 2000. All persons were invited to participate; 365 accepted and 356 (69%) completed the HCV laboratory tests. Case recruitment and follow-up were conducted at the Ramón Ruiz Arnau University Hospital at Bayamón, Puerto Rico or in HIV ambulatory clinics. Once informed consent was obtained, a baseline questionnaire was completed and appropriate laboratory tests were conducted. Data were gathered by personal interviews and medical record review and abstraction. A questionnaire that included sociodemographic information, HIV risk factors, clinical manifestations, antiretroviral therapy (ART), laboratory findings, and mortality information was used to collect the data. Presumptive and confirmed diagnosis of opportunistic infections such as esophageal candidiasis, Pneumocystis jirovecii pneumonia (PJP), cerebral toxoplasmosis, recurrent bacterial pneumonia, pulmonary tuberculosis, Kaposi’s sarcoma, herpes simplex virus, and wasting syndrome were recorded. A complete explanation of the RRC questionnaires has been reported by Gómez and others.23 Highly active antiretroviral therapy was defined as patients with three or more antiretroviral treatments at study entry. Selected candidates were patients more than 18 years old in whom a HCV qualitative test was conducted. The HCV viral load and HCV genotype were additionally determined in HCV-positive cases. Those cases with detectable HCV viral load composed the co-infected study group. The remaining cases formed the not co-infected group. The death status of the study participants as of December 2003 was used to measure the mortality of the study group.

Laboratory measures. The following laboratory tests were conducted at study entry. Appropriate controls were included for all methods.

CD4+ lymphocyte measurement by flow cytometry. A four-color modular flowcytometry analyzer (FACSCalibur; Becton Dickinson, San Jose, CA) was used to determine CD4+ cell counts. For this assay, peripheral blood samples were collected into EDTA and prepared using a lysed whole blood method. Samples were stained with murine monoclonal antibodies directly conjugated with fluorochromes fluorescein isothiocyanate and phycoerythrin (Simultest reagents; Becton Dickinson) for the quantitation of CD3 (total T cells) and CD3/CD4 lymphocytes.

Quantiation of HIV and HCV virion RNA. The HIV viral load was determined by an RNA reverse transcription–polymerase chain reaction (RT-PCR) (Amplicor HIV monitor version 2; Roche Diagnostic Systems Inc., Indianapolis, IN). This test has a sensitivity of 400–750,000 copies/mL. Those specimens with a viral titer less than 400 were tested with a modified ultrasensitive RT-PCR (Roche Diagnostic Systems Inc.), which has a detection range of 50–75,000 copies/mL. The HCV viral load was determined by an RNA RT-PCR (COBAS Amplicor HCV Monitor; Roche Diagnostic Systems Inc.). This test has a detection limit between 100 and 500,000 IU/mL. Some samples with a viral load less than 100 copies/mL were tested with the TaqMan RNA Real Time PCR (Roche Diagnostic Systems Inc.), which has a detection range of 10–200 x 106 IU/mL.

Genotyping of HCV. The Truegene HCV genotyping sequencing method (Bayer, Norcross, GA) was used with PCR-amplified products to determine the HCV genotype/subtype.

Mortality. Mortality data were obtained from a review of the institutional medical records and from the Puerto Rican AIDS surveillance system. In addition, the mortality registry of the Puerto Rican Health Department was reviewed to confirm the death status of the participants. The reported causes of death were tabulated and organized into several categories. These categories included 1) systems or organ failure (cardiovascular, pulmonary, gastrointestinal, renal, neurologic, and metabolic); 2) AIDS conditions (PJP, cerebral toxplasmosis, and wasting syndrome); and 3) drug overdose or poisoning. A subgroup of liver conditions that included liver failure (chronic and acute) and cirrhosis was included.

Statistical analysis. The SPSS program (SPSS Inc., Chicago, IL) was used to perform univariate, bivariate, and multivariate analyses. Univariate analysis described the frequencies of clinical conditions, immunologic findings, and antiviral drugs regimens used. Quality differences between patients with and without co-infection were analyzed with the chi-square or Fisher’s exact test. Analysis of variance and the Student’s t-test were used to evaluate means differences. The Mann-Whitney test, a non-parametric test, was used to evaluate median differences between groups. Group differences were also evaluated after stratifying by the use of injecting drug use as an HIV risk factor.

Differences in mortality rates, causes of death, and disease duration were evaluated and analyzed in the HIV cohort. Time of follow-up was defined as the time between the patient’s enrollment and their death or as of December 2003. The HIV disease duration was defined as the time between the first documented positive HIV test result and the last follow-up or death of the patient. Kaplan-Meier analysis was performed to explore the variation in the survival time.24 The influence of covariate factors was studied by Cox proportional-hazards analysis.25 A P value < 0.05 was considered statistically significant.


RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
General findings. Of the 356 HIV-infected patients in the study, 193 (54.0%) had an HCV viral load greater than 100 copies/mL. Of the 356 HIV-infected patients, 249 (69.9%) were male and the mean ± SD age at enrollment was 37.6 ± 8.8 years. Injecting drug use as the main risk factor for HIV infection was reported in 57.6% of the patients. This risk factor was slightly higher than that reported for the overall RRC cohort (51.7%). At study enrollment, 16 (4.6%) of the patients had a history of PJP, 21 (5.9%) had cerebral toxoplasmosis, 16 (4.5%) had recurrent pneumonia, 5 (1.4%) had pulmonary tuberculosis, 2 (0.6%) had Kaposi’s sarcoma, and 49 (13.8%) had wasting syndrome. The median CD4+ cell count was 150 cells/µL and more than 57% of the patients had a CD4+ cell count less than 200 cells/µL. The median CD8+ cell count was 660 cells/µL with a median CD4:CD8 ratio of 0.24. The median white blood cell count was 5,400 cells/µL with an absolute lymphocyte count median of 1,200 cells/µL. The median HIV viral load was 10.8 x 104 copies/mL. More than 43% of the patients were ART naive at study entry. Conversely, more than 44% of the patients were receiving HAART at study entry. As of December 2003, 168 of the 356 study patients (47.2%) had died. This mortality was slightly lower than that reported for the overall RRC cohort (52.5%).

Group differences. Table 1Go shows the most relevant parameter differences between the 193 HCV co-infected and the 163 not co-infected patients. Both groups had similar mean ± SD age (37.1 ± 7.9 versus 38.2 ± 9.7; P = 0.256). The co-infected group had a higher proportion of men (79.8% versus 58.3%; P < 0.01) and IDUs (85.5% versus 24.5%; P < 0.01). The median time of injecting drug use was similar in both groups (17.8 years in co-infected patients and 18.4 years in not co-infected patients). Men having sex with men were less frequently reported in co-infected patients (8.5% versus 33.3%; P < 0.01).


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TABLE 1
Demographics, risk factors, clinical manisfestations, and laboratory findings in HIV-infected patients group, by HCV co-infection*
 
The prevalence of the AIDS-defining conditions at study enrollment in the co-infected and not co-infected groups were PJP (3.1% versus 6.1%), recurrent pneumonia (3.1% versus 6.1%), wasting syndrome (11.9% versus 16.0%), and esophageal candidiasis (3.6% versus 6.1%). Although these conditions were lower in co-infected group, statistical significance was not reached. A higher median CD4+ cell count (189/µL versus 120/µL) and a lower median HIV viral load (10.5 x 104 copies/mL versus 11.5 x 104 copies/ml) were seen in the co-infected group. The HIV/HCV co-infected individuals had less clinical and immunologic evidence of HIV infection. The use of HAART at enrollment was similar in both groups (42% versus 48%; P = 0.207). However, their compliance and adherence could not be measured. Conversely, the mortality rate was slightly higher in the co-infected group (57.7% versus 51.1%), but this difference did not reach statistical significance.

Of the 356 study cases, 205 were IDUs and 81% of them were seropositive for HCV (Table 2Go). Co-infected IDUs had higher prevalence of men (82.4% versus 72.5) and a lower prevalence of PJP (3.6% versus 5.0%), recurrent pneumonia (3.6% versus 10.0%), and wasting syndrome (12.7% versus 27.5%) when compared with not co-infected IDUs. The median CD4+ cell count (180/µL versus 120/µL) and the HIV vial load median (10.7 x 104 copies/mL versus 10.3 x 104 copies/mL) were slightly higher in this co-infected group. Only the wasting syndrome difference reached statistical significance. The use of HAART (35.8% versus 35.0%) and mortality rates (51.5% versus 55.0%) were similar in these IDU groups.


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TABLE 2
Demographics, risk factors, clinical manifestations, and laboratory findings in HIV-infected IDUs and non-IDUs, by HCV co-infection*
 
Conversely, 28 (18.5%) of the 150 non-IDUs were positive for HCV (Table 2Go). These co-infected patients had lower rates of AIDS-defining conditions, higher median CD4+ cell counts (210/µL versus 128/µL; P < 0.05), lower median HIV viral load (8.3 x 104 copies/mL versus 11.5 x 104 copies/mL), and higher use of HAART (78.6% versus 52.0%; P < 0.05) than the not co-infected, non-IDUs. Mortality was slightly higher in this co-infected group (42.9% versus 39.8%; P > 0.05).

In addition, we found a higher median HCV viral load in co-infected cases who were IDUs when compared with non-IDUs (50 x 104 copies/mL versus 31.6 x 104 copies/mL). However, this difference was not statistically significant.

HCV genotypes. Of the 193 co-infected study cases, 164 were tested for HCV genotype. Genotype 1 was the most prevalent (82.3%), followed by genotype 3 (8.5%), genotype 4 (3.7%), and genotype 2 (3.1%). In four cases (2.4%) the genotype was indeterminate. In those in which the genotype was determined, the most prevalent virus subtypes were 1a (53.1%), 1b (31.3%), and 3a (8.9%). Genotype 1 was more prevalent in the IDUs than in the non-IDUs (88.9% versus 80.0%). Patients with genotype 1 had a higher median HCV viral load (53 x 104 copies/mL versus 40.1 x 104 copies/mL), higher median HIV viral load (12.7 x 104 copies/mL versus 4.9 x 104 copies/mL), and lower median CD4+ cell counts (188 cells/µL versus 200 cells/µL). These differences did not reach statistical significance. We did not detect any other changes in the morbidity or mortality of patients when analyzed according to HCV genotypes.

Mortality. As of December 31, 2003, 168 of the 356 study cases had died. A Cox proportional hazard analysis showed that patients with a CD4+ cell count less than 200/µL or with antecedents of wasting syndrome had a significant increment in the mortality risk (Table 3Go). The antecedents of HAART and PJP prophylaxis at study entry produced a non-significant decrement in the mortality risk. The presence of HCV co-infection or the IDU as a risk factor produced a non-significant increment in the mortality risk. In the analysis of causes of death, several significant differences were seen between HIV/HCV co-infected and not co-infected persons. Of the 168 patients who died, 97 (57.7%) were HCV positive and 71 (42.3%) were HCV negative. As shown in Table 4Go, male sex (83.5% versus 57.7%) and the antecedent of IDU were more prevalent in the co-infected death cases (87.6% versus 31.0%). Men having sex with men was associated with a lower mortality in the co-infected cases (6.2% versus 29.3%). Co-infected patients who died had a longer HIV disease duration (4.1 years versus 3.2 years), slightly higher use of HAART (40.2% versus 36.6%), and a lower prevalence of AIDS (68.0% versus 88.7%) at study entry than not co-infected death cases. Causes of death related to hepatic dysfunction, cirrhosis, or hepatic failure were significantly higher in HCV-infected persons (19.6% versus 1.4%). In general, the presence of gastrointestinal conditions as causes of death were seen more often in the co-infected patients compared with the not co-infected patients (28.9% versus 9.9%). Liver-related dysfunction as a cause of death was more commonly reported in patients infected with HCV genotype 1 compared with other HCV genotypes (19.1% versus 7.7%; P > 0.05). Conversely, co-infected patients had a significantly lower rate of pulmonary conditions, such as pneumonia (38.1% versus 57.7%), reported as the cause of death compared with the not co-infected patients.


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TABLE 3
Mortality in 356 HIV-infected patients, by Cox proportional hazard regression analysis*
 

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TABLE 4
HIV death differences, by HCV co-infection*
 

DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The implementation of HAART along with an increase in the presence of chronic conditions of the HIV survivors are producing important changes in the natural history of HIV/AIDS. These changes deserve evaluation. Co-infection with HIV and HCV is emerging as an important and frequent finding in patients seeking therapy for one or the other viral entity. The fact that both viruses share a similar route of transmission and mechanisms of epidemic spread appears to be the most important reason for the growing nature of the co-infection.20–22 The highest prevalence of co-infection is occurring in patients with a current or previous history of injecting drug use. The HIV cohort of the Bayamón RRC is characterized by a high prevalence of IDUs; as such the expanding nature of this co-infection becomes an important issue for our health care delivery system. Our data showed a co-infection prevalence of 54% for the entire group and 82.5% in the IDUs. These findings are consistent with other published information that reported a high prevalence of co-infection associated with the risk scenario and risk practices of IDUs.11–13 MacDonald and others reported an HCV prevalence over 50% among this high-risk group,11 and Sulkowski and Thomas reported a co-infection prevalence of 44.6% among 1,955 cases of the John Hopkins HIV cohort.26

Similar to the overall RRC cohort, we found a high mortality rate in the study group, although no significant mortality differences between co-infected and not co-infected patients were detected. The similarities in their clinical, immunologic, and therapeutic profiles at enrollment could explain this finding. However, comparable findings were previously reported by Sulkowski and Thomas.26 These investigators did not find evidence that HCV co-infection significantly alters the risk of dying or developing AIDS in their HIV study group.

Klein and others argued that the prevalence of IDU increases the morbidity and mortality of HCV infection and prevents an improved health care outcome for these patients.27 In our study, we did not find a significant morbidity or mortality variation between individuals co-infected with HCV and HIV with and without this risk behavior. Conversely to the study of Klein and others27 in which active drug use was unknown, 77% of our IDUs were actively using drugs. Nevertheless, the common presence of injecting drug use with its social, clinical, and psychological dimensions adds an element of therapeutic complexity that needs to be included in the management of these patients with risky life styles and behaviors. In addition, the low HAART adherence and the fear of an increasing rate of HIV viral variants may allow a worse outcome in this population.27

Although our mortality rates were not significantly different between groups, HCV co-infection introduced significant variation in the causes of death among the study groups. Co-infection with HCV produced chronic liver damage in HIV patients and more than 15% developed severe liver damage or cirrhosis.28–34 Additionally, co-infection with HIV and HCV has been associated with more rapid liver failure progression.26 The present study found that 10% of the co-infected patients developed severe hepatic conditions that likely led to their deaths. This specific hepatic-related mortality was higher than that reported in previous studies.2,26 For example, Darby and others reported a death rate of 6.5% related to liver damage in their co-infected hemophilic patients.2 This high prevalence of hepatic damage in our group suggests that some of these patients had been co-infected for long time prior to study enrollment. Furthermore, there were no routine HCV screening tests for our patients prior to the present study.

Genetic heterogeneity in HCV is a known hallmark of this infection. Although genotype 1a was the most common in our study, genotype 1b was more commonly reported in the United States.35 This geographic variation could be related to the way patients have acquired HCV infection. Genotype 1b is spread more frequently by blood transfusion while genotype 1a is more frequently related to the risky practice of injecting drug use.29,35 The higher prevalence of genotype 1a in our study is in concordance with the high prevalence of IDUs in this group. Previous studies have reported higher morbidity and mortality in HCV patients attributed to genotype 1 virus.10,11,36,37 In addition, HCV genotype 1 has been related to a lower response to anti-HCV pharmacologic therapy.37,38 Our study found that co-infected patients with HCV genotype 1 had more liver-related deaths than patients co-infected with other genotype. However, the mortality rates were not significantly different between patients co-infected with different HCV genotypes. Conversely, this study could not evaluate the relationship between HCV genotypes and anti-HCV therapy outcome because none of the co-infected patients reported the use of antiviral therapy for HCV. Therapy for infection with HCV in HIV-infected persons has substantial complications because of potential drug interactions and treatment-related toxicities.26,39–46 The high prevalence of IDUs in the co-infected patients introduces additional barriers for HCV therapy. The initiation and evaluation of anti-viral therapy for HCV in co-infected patients remains an important challenge, particularly for centers like ours that provide care to medically indigent patients.

The present study had some limitations that could introduce potential biases. These biases could have affected the results and their interpretation. First, this was a prevalence study, not an incidence study. Thus, the real disease duration is this study could not be estimated. This issue could explain the high mortality found after a short period of follow-up. Conversely, the clinical, immunologic, and therapeutic measures were obtained at the time HCV testing was conducted. No further measures were obtained. Consequently, the effects of the change of these variables through time were not evaluated. Second, the study group was selected by convenience and not randomized. This issue could introduce some selection biases. Third, no liver function tests such as those for aspartate aminotransferase or alanine aminotransferase were conducted. The adherence to and compliance with anti-retroviral therapy were also not measured. Consequently, we could not evaluate the impact of these variables in the study group.

Knowledge about the interaction between HIV and HCV infections has become increasingly crucial to public health.7,22,26 Lack of knowledge in this area generates delay in the opportune diagnosis and treatment of HCV, which could increase the possibility of severe target organ damage such as that detected in our patients. Most of our cases became aware of their co-infection with their participation in our study, probably years after their initial HCV inoculum. The urgent implementation of primary and secondary HCV prevention strategies in an HIV-infected population is essential and necessary to reduce the rate of co-infection and its complications, especially in those persons with high-risk behaviors. Until now, there is no vaccine to prevent infection with the HCV; however risk reduction intervention could reduce virus dissemination and opportune HCV medical treatment could reduce liver damage caused by HCV. Conversely, the high mortality and the low prevalence of HAART and PJP prophylaxis in this group of immunocompromised patients show the present limitations of their HIV management. Most of these people were medically indigent with financial barriers that could directly and indirectly affect their HIV management. Nevertheless, additional efforts are needed to improve HIV management to prevent or reduce future disease complications.

Finally, further studies of HIV/HCV co-infection are needed to explore in more detail the current prevention strategies and the therapeutic management of this condition. Another area that needs extensive research is the potential detrimental effects of repeated re-inoculums, with both viruses, in the context of IDUs.

Received January 19, 2005. Accepted for publication September 28, 2005.

Acknowledgments: We thank the Puerto Rican Demographic register for its help and collaboration.

Financial support: This study was supported by RCMI/NIH grants G12RR03035 and 1U54RR01950701, and by Centers for Disease Control and Prevention Adult Spectrum of Disease grant U62/CCU206209.

* Address correspondence to Angel M. Mayor, Retrovirus Research Center, Universidad Central del Caribe School of Medicine, P.O. Box 60327, Bayamón, PR 00960-6032. E-mail: amayorb{at}hotmail.com Back

Authors’ addresses: Angel M. Mayor, Maria A. Gomez, Diana M. Fernandez, and Robert F. Hunter, Retrovirus Research Center, Universidad Central del Caribe, School of Medicine, P.O. Box 60327, Bayamón, PR 00960-6032, Telephone: 787-787-8710, Fax: 787-787-8733, E-mail: amayorb{at}hotmail.com. Eddy Rios-Olivares, Department of Microbiology, Universidad Central del Caribe, School of Medicine, Bayamón, PR 00960-6032. James C. Thomas, Epidemiology Department, School of Public Health, University of North Carolina, Chapel Hill, NC 27599-7435.


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TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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