| |
Coinfection Studies Find Increased Mortality & Morbidity
|
| |
| |
Reported by Jules Levin
Three studies of HCV/HIV coinfected individuals are published this month in JID, CID, and JAIDS. The VA study finds HCV increases risk for death (all cause mortality) by 30-80% in HIV+ individuals who received HAART. Of note, the study reports this risk persisted for patients with well controlled viral replication. A study from Gazzard et al in London from Chelsea & Westminster Hospital also follows patients post-HAART and finds increased likelihood of developing a CD4+ cell count of <200 cells/mm3 or their first AIDS-defining illness, compared with HIV-1-infected individuals. Rockstruh et al reported a study of patients being followed in the EuroSida patient cohort and reported: no increased incidence of new AIDS-defining illnesses or any deaths was found in the HCV-seropositive patients after adjustment for either baseline factors.....but...HCV+ patients had a significantly increased incidence of any death in the multivariable models, the result of a >10-fold higher incidence of liver disease-related deaths in the HCV-seropositive patients..."
You can read further analysis and study details below. I sent out the full study text for all three studies, but there appears to be quite a bit of discussion about these studies so I put together this more condensed analysis of the 3 studies. There have been conflicting results from the many studies examining the clinical outcomes of coinfected patients. Most studies find that HCV accelerates HIV or that coinfected patients are at greater risk for death and getting sick. Several recent studies from last year suggest HAART may slow HCV disease progression. I think these particular studies do not capture the risk associated with HCV-positivity in HIV. It is very difficult to conduct a study that can capture and reflect the potential risks associated with coinfection. Pre-HAART many studies uniformly found HIV accelerates HCV several fold faster than HCV monoinfection. Since then several studies suggest HAART may slow HCV disease. One thing these studies cannot capture is that a significant proportion of patients do not respond well to HAART and may suffer with hepatotoxocity, which we still have not characterized adequately. The patient population is so heterogenous that it is very difficult to conduct a study that characterizes a general outcome of disease progression for all coinfected patients. Until we have adequate access to good care and treatment, good support programs, and new and easier to take and more effective therapies, we will continue to see increasingly that End Stage Liver Disease is the leading cause of death in HIV. Links to reports of the 3 studies are at bottom of this report.
VA STUDY:
"....The outcome measure was all-cause mortality.....Our analysis showed that HCV infection increases the risk of death in HIV patients who received HAART, controlling for numerous demographic and clinical factors, including exposure to HAART and response to HAART. Depending on the factors for which we controlled, we found that the risk of death among HAART-treated HIV patients was between 30% and 80% higher for those also infected with HCV......In addition, among those with well-controlled HIV viral replication, the increased risk of death persisted for HCV-seropositive patients, suggesting that HCV does not exert its negative effect in HAART-treated patients through ineffective HIV suppression.....
We found that HCV was associated with a decreased immunologic (CD4 cell recovery) but similar virologic response to HAART.
....other predictors of increased mortality were older age, higher baseline HIV viral load, an AIDS-OI before HAART, and NRTI treatment before HAART (likely a proxy for longer standing HIV infection and less optimal early antiretroviral use).
The study period largely preceded the availability of pegylated interferon, and only a small percentage of the HCV-infected patients in our study cohort received any treatment of HCV. Preliminary evidence from other studies indicates that the currently recommended regimen of pegylated interferon and ribavirin has a lower success rate in coinfected patients than in those infected with HCV alone. In the future, new medications, such as HCV RNA polymerase, helicase, and serine protease inhibitors, may increase the effectiveness and tolerability of HCV treatment in coinfected patients. (ED NOTE: it will be at least several years before new HCV drugs begin to become available, & for the foreseeable future peginterferon will be a required part of combination therapy). In the meantime, we note that many of our patients carry a diagnosis of alcohol abuse, hard drug use, or psychiatric illnesses in addition to HIV and HCV. Alcohol abuse certainly accelerates the clinical course of HCV, and other drug use and psychiatric illnesses contribute directly and indirectly to poor outcomes in HIV and HCV infection. Greater emphasis on treatment of these frequent comorbidities may be warranted, especially while awaiting improvements in pharmacologic HCV treatment.
The published literature provides conflicting results on the impact of HCV infection on mortality among coinfected patients.7-10,24-26 These studies differ in method; differences include the outcome measured (mortality alone vs. mortality combined with an AIDS-OI), inclusion of a measure of HAART and the type of measure, and the time origin.....Among the 4 studies reporting a material number of outcome events for each HCV status group, a likely explanation for some of the conflicting findings involves the extent of HAART use, and thus the prevention of otherwise dominant HIV-related mortality...
"Effects of Hepatitis C Virus Coinfection on Survival in Veterans With HIV Treated With Highly Active Antiretroviral Therapy"
JAIDS 15 August 2005
Backus, Lisa I MD, PhD*; et al, Veterans Health Administration, Palo Alto, CA; and HIV and Hepatitis C Program Office, Veterans Health Administration, Palo Alto, CA.
.....During the study period (mean follow-up of 3.5 years, range: 0.1-6.2 years), 2087 patients died. There were proportionally more deaths among HCV-seropositive patients than among HCV-seronegative patients (22.2% vs. 13.9%; P < 0.0001). The unadjusted death rates were 6.4 deaths per 100 person-years for HCV-seropositive patients and 4.0 deaths per 100 person-years for HCV-seronegative patients (P < 0.0001).....
.....the study cohort consisted of HIV-infected veterans on HAART receiving care at US Department of Veterans Affairs facilities. Inclusion was based on first HAART prescription between January 1997 and February 2003....
.....Of 12,216 patients in the study cohort, 38% were HCV-seropositive. During an observation time averaging 3.5 years, 2087 patients died. The adjusted hazard ratio for HCV-seropositive patients was 1.56 (P < 0.0001) without a HAART exposure measure and 1.38 (P < 0.0001) with the measure. We obtained similar results in analyses also controlling for HAART response. Conclusions: HCV seropositivity was independently associated with increased risk of death in a large cohort of HAART-treated HIV-infected veterans. Given the success of HAART in extending the lives of HIV patients, HCV has become an important predictor of their mortality.
Characteristics of the 12,216 study patients distributed by HCV serostatus are shown in Table 1. A total of 4668 (38.2%) were HCV-seropositive. With such a large sample size, the 2 groups differed statistically for nearly all baseline characteristics investigated. Notably, HCV-seropositive patients were slightly older; more likely to be black or Hispanic; and more likely to have diagnoses of psychiatric illness, alcohol abuse, and hard drug use. Although the distributions of baseline CD4 counts differed, HCV-seropositive patients had a median baseline CD4 count comparable to that of HCV-seronegative patients. HCV-seropositive and -seronegative patients were equally likely to have a prior AIDS-OI. The HCV-seropositive group had a lower median baseline HIV viral load than the HCV-seronegative group. On average, HCV-seropositive patients were in VA care longer before their first VA-prescribed HAART (7.0 vs. 4.5 years; P < 0.0001) and were more likely to have been prescribed NRTIs before HAART. On average, HCV-seropositive patients were exposed to HAART for fewer months than HCV-seronegative patients (21.3 vs. 24.9; P < 0.0001). Overall, 167 patients received HCV treatment.
HCV-seropositive and -seronegative patients had a similar virologic response to HAART; however, the former had a diminished immunologic response. Among 11,546 patients with 1 or more follow-up HIV viral load tests, there was no difference in the percentage of HCV-seropositive and -seronegative patients with at least 1 undetectable HIV viral load (81.1% vs. 82.0%; P = 0.2). Of the 10,800 patients with at least 2 follow-up HIV viral load tests, there was no clinical difference in the percentage of patients with well-controlled viral replication (36.9% vs. 38.6%; P = 0.07). Of the 11,584 patients with at least 1 follow-up CD4 cell measurement, HCV-seropositive patients had a lower maximum CD4 cell count than HCV-seronegative patients (median of 447 [interquartile range (IQR): 260-690] vs. 496 [IQR: 290-747] cells/mL; P < 0.0001). This CD4 maximum reflected a net gain of 199 cells/mL for the HCV-seropositive patients compared with 239 cells/μL for the HCV-seronegative patients. Among the 9062 patients with a 6-month HIV viral load and CD4 cell count, HCV-seropositive patients had similar 6-month HIV viral loads (median of <500 [IQR: <500-5974] vs. <500 [IQR <500-5502] copies/mL; P = 0.23) but lower 6-month CD4 counts (median of 307 [IQR: 169-407] versus 336 [IQR: 177-514] cells/mL; P < 0.0001).
Study conducted in HAART era by Gazzard et al at Chelsea & Westminster Hospital in London found....
"....that individuals with HIV-1-HCV coinfection have an increased likelihood of developing a CD4+ cell count of <200 cells/mm3 or their first AIDS-defining illness, compared with HIV-1-infected individuals..."
"Hepatitis C Virus Infection in HIV Type 1-Infected Individuals Does Not Accelerate a Decrease in the CD4+ Cell Count but Does Increase the Likelihood of AIDS-Defining Events"
Justin Stebbing, Laura Waters, Sundhiya Mandalia, Mark Bower, Mark Nelson, and Brian Gazzard
Department of HIV Medicine, Chelsea and Westminster Hospital, London, United Kingdom
Clinical Infectious Diseases Sept 15 2005;41:000
....In other cohorts, the interval between the time of HIV-1 infection diagnosis and the onset of AIDS has been shown to be similar between HIV-1-infected patients and patients with HIV-1-HCV coinfection, supporting the lack of a direct effect of HCV infection on HIV-1 immune progression, as measured by CD4+ cell count. Different outcomes observed may simply be due to differences in the demographic characteristics of the study populations. Further effects of HCV infection on HIV-1 disease progression require additional clarification in large epidemiologic studies..... our data may be explained by an effect of HCV on CD8+ cytotoxic T cells or dendritic cells.
This study focuses on a cohort of individuals who have been followed up since commencement of the HAART era, which we defined as beginning on 1 January 1996, when HAART became routinely available at our institution (and at others). Because our cohort has very low rate of hepatitis B virus infection, the prevalence of this infection was not measured. CD4+ cell subset analysis was performed. We identified individuals who presented during the HAART era and then excluded those who had a baseline CD4+ cell count of <200 cells/mm3. The end points in our small cohort study (considered to be events in this study) were development of a CD4+ cell count of <200 cells/mm3 or onset of an AIDS-defining opportunistic illness, as clinically defined by the Centers for Disease Control and Prevention classification (including Pneumocystis jiroveci [formerly P. carinii] pneumonia, cytomegalovirus infection, candidiasis, Kaposi sarcoma, any lymphoma, toxoplasmosis, and AIDS-associated diarrheas).
Statistical analyses were performed using SAS, version 8.0 (SAS Institute), using parametric tests. The MIXED procedure in SAS was used to calculate the difference in averages (DAVG), which represent the time-weighted difference between the CD4+ cell count at baseline and the CD4+ cell count at each time point. A univariate and multivariable Cox proportional hazards regression method was used to estimate the likelihood of developing a CD4+ cell count of <200 cells/mm3 or developing the first AIDS-defining illness since entry into the cohort of HIV-1-infected patients during the HAART era. Time to event was defined as the time to development of a CD4+ cell count of <200 cells/mm3 or onset of the patient's first AIDS-defining illness. Data were censored at the time of the last clinic visit, and the final multivariate model was tested for its distributional assumptions using Cox-Snell residual plots, adjusting for sex and for age at study entry, stratified by baseline CD4+ cell count for possible confounding or residual effects. Variables that were found to be statistically significant (P < .15) in the univariate model were selected to build a multivariable model. All P values were determined by means of 2-tailed tests.
The prevalence of HIV-1-HCV coinfection in our study cohort was 5.8% (85 of 1467 patients).
Figure 1. Difference in averages analysis demonstrating the changes in CD4+ cell count since entry into the study cohort for patients coinfected with HIV-1 and hepatitis C virus (HCV) and for patients infected with HIV-1 alone. Data were censored at the last clinic visit. Whiskers,95% CIs.
"...Non-HIV-1-related deaths and liver disease-related deaths were significantly more frequent in the HCV-seropositive patients..." in the EuroSida patient cohort...."With better treatment options for HIV-1 infection and an extended duration of HCV infection, coinfected patients obviously become more prone to liver disease..."
In the analysis of the EuroSida patient group (5,000 patients followed since 1994), Rockstroh et al found...no increased incidence of new AIDS-defining illnesses or any deaths was found in the HCV-seropositive patients after adjustment for either baseline factors.....but...HCV+ patients had a significantly increased incidence of any death in the multivariable models, the result of a >10-fold higher incidence of liver disease-related deaths in the HCV-seropositive patients...
"Influence of Hepatitis C Virus Infection on HIV-1 Disease Progression and Response to Highly Active Antiretroviral Therapy"
Rochstroh refers to recent studies finding HAART slows HCV progression and therefore suggests that because in this analysis more coinfected patients were ART-naive (25% vs 16%), more coinfected took ART (38% vs 30%) instead of HAART (53% for mono- vs 36%) for coinfected, these may be reasons why coinfected were more likely to develop liver disease. He says..."the HCV-seropositive patients were more likely to have received prior monotherapy or double-nucleoside therapy, again reflecting the difficulties of treatment in HIV-1/HCV-coinfected individuals in combination with the comorbidity and problems associated with injection drug use. Possible differences in the time point of HAART initiation as well as in the initial treatment choices may also have affected the different outcomes in the various cohort studies. Moreover, many factors-such as treatment adherence, temporal changes in the way HAART is used, better management of toxicities, and more awareness of liver problems as people live longer-that cannot be measured directly and that, therefore, were either incompletely assessed or not assessed at all in the various cohort studies may also have influenced the outcomes."
The Journal of Infectious Diseases Sept 15 2005;192:000
Jurgen K. Rockstroh,1 et al for the EuroSIDA Study Groupa
1Department of Medicine I, University Hospital Bonn, Bonn, Germany;
".....patients of known HCV serostatus at recruitment into the EuroSIDA cohort (started in 1994). Overall, 3997 (67%) were HCV seronegative, and 1960 (33%) were HCV seropositive. Of the HCV-seropositive patients, 78% had been infected with HIV-1 via injection drug use-and, hence, probably also acquired HCV via this route-and 31% were female (compared with 23% of the HCV-seronegative patients [P < .0001]).....
.....Overall, 917 new AIDS-defining illnesses, 819 any deaths, 109 liver disease-related deaths, and 462 non-HIV-1-related deaths occurred in the patients of known HCV serostatus. The event rates of all of the end points considered were significantly higher in the HCV-seropositive patients than they were in the HCV-seronegative patients......
..... However, the event rates may be confounded by other factors that affect the outcomes assessed. The multivariable models are adjusted for (1) fixed factors known at baseline and (2) updated factors for CD4 cell count, initiation of HAART, and, where AIDS was not part of the end point, diagnosis of a new AIDS-defining illness. It is noteworthy that, although the univariable analysis showed a higher incidence of a new AIDS-defining illness or any death in the HCV-seropositive patients than in the HCV-seronegative patients (IRR, 1.44 [95% confidence interval {CI}, 1.29-1.60]; P < .0001]), no increased incidence of new AIDS-defining illnesses or any deaths was found in the HCV-seropositive patients after adjustment for either baseline factors (IRR, 0.97 [95% CI, 0.81-1.16]; P = .72) or updated factors (IRR, 1.06 [95% CI, 0.89-1.28]; P = .50)....
Fixed-factor multivariable models were adjusted for CD4 cell count, age, prior AIDS diagnosis, HIV-1 treatment at baseline, baseline date, hepatitis B surface antigen status, sex, ethnicity, geographic region, and risk group. In the updated-factors multivariable models, CD4 cell count and initiation of highly active antiretroviral therapy were adjusted for as time dependant and, where AIDS was not part of the end point, the models were further adjusted for diagnosis of a new AIDS-defining illness.....
BUT
.....In addition, compared with the HCV-seronegative patients, the HCV-seropositive patients had a significantly decreased incidence of AIDS-defining illnesses after adjustment. However, they had a significantly increased incidence of any death in both the fixed-factor and the updated-factor multivariable models (IRR, 1.41 and 1.80; P = .0024 and P < .0001, respectively), the result of a >10-fold higher incidence of liver disease-related deaths in the HCV-seropositive patients in the fixed-factor multivariable model (IRR, 11.71 [95% CI, 6.42-21.34]; P < .0001) and an even higher incidence in the updated-factor multivariable model (IRR, 12.31 [95% CI, 6.77-22.41]; P < .0001).....
....Among IDUs, after adjustment for fixed factors, there was a significantly increased incidence of liver disease-related deaths (IRR, 12.66 [95% CI, 6.76-23.71]; P < .0001) in those coinfected with HIV-1 and HCV. A similar trend, although smaller in size and not significant, was observed among non-IDUs (IRR, 6.16 [95% CI, 0.85-44.50]; P = .072). However, it should be noted that this analysis had limited power, as is indicated by the wide CIs; there were 67 liver disease-related deaths during 8037 PYFU in IDUs and 42 liver disease-related deaths during 24,084 PYFU in non-IDUs (P < .0001).....
......Among 2260 patients of known HCV serostatus initiating HAART, after adjustment, there was no significant difference between HCV-seropositive and -seronegative patients with respect to virologic response and immunologic response.
After adjustment for relevant variables, there was no significantly decreased frequency of immunologic response, whether measured as a >50% increase (RH, 0.94 [95% CI, 0.77-1.16]; P = .58) or as a >50 cells/mL increase (RH, 0.92 [95% CI, 0.77-1.11]; P = .40) in CD4 cell count after initiation of HAART, in the HCV-seropositive patients versus the HCV-seronegative patients. Further analyses that considered the change in CD4 cell count at 6 months after initiation of HAART also revealed no difference in immunologic response between the 2 groups. After adjustment for relevant variables, there was no significantly decreased frequency of virologic response (plasma HIV-1 RNA load of <500 copies/mL) in the HCV-seropositive patients, compared with that in the HCV-seronegative patients (relative hazard [RH], 1.13 [95% CI, 0.84-1.51]; P = .42)....
....other studies have reported no increased risk of the development of a new AIDS-defining illness in HCV/HIV-1-coinfected persons, once adjustments are made for receipt of HAART and failure to suppress HIV-1 replication. The reason for these discrepancies remain unclear but may be related to demographic differences in the populations studied and the inclusion criteria employed. For instance, the Swiss HIV Cohort Study included only patients receiving HAART. At baseline, there were more patients with prior AIDS, lower CD4 cell counts, and higher plasma viremia in the coinfected group than in the HCV-negative group. The Johns Hopkins cohort, on the other hand, included both treated and untreated individuals. Moreover, differences in duration of HCV infection might play a role....
Hepatitis C Virus Infection in HIV Type 1-Infected Individuals Does Not Accelerate a Decrease in the CD4+ Cell Count but Does Increase the Likelihood of AIDS-Defining Events
CID Sept 15, 2005 (Stebbing et al, Chelsea & Westminster Hospital)
Influence of Hepatitis C Virus Infection on HIV-1 Disease Progression and Response to Highly Active Antiretroviral Therapy
non-HIV-1-related deaths and liver disease-related deaths were significantly more frequent in the HCV-seropositive patients
The Journal of Infectious Diseases, Sept 15, 2005;192:000
Rockstruh et al, EuroSida
VA Study: HCV Increases Risk of Death Among HAART-Treated HIV+ Patients by 30-80%
"Effects of Hepatitis C Virus Coinfection on Survival in Veterans With HIV Treated With Highly Active Antiretroviral Therapy"
JAIDS, 15 August 2005
Backus et al, VA
|
|
| |
| |
|
|
|
