Durban World AIDS Conference
July 9-14, Durban, South Africa

REPORT 36

CD4s & HCV: in HCV/HIV coinfection, HCV treatment should be considered very early

Limited research and knowledge about HCV/HIV coinfection suggests that a coinfected person may be better off starting HCV therapy when CD4s are high--above 500 or at 800. Keep reading. The study reviewed below reported at Durban by Hernan Valdez from Case Western in Cleveland and raises an interesting question. In his study, people with HCV/HIV did not respond to HCV antigen but people with HCV alone did respond. Although responses to HCV antigens improved in HIV-infected persons who were receiving antiretroviral therapy, the responses did not reach the levels seen among HIV-negative HCV+ patients. So HAART may help improve response to HCV, but still the response is less than for those with HCV alone. This study suggests as other studies have suggested that having higher CD4 s may improve response to HCV, as it may help immune system control HCV better. Further, I think it may be the CD4 "repertoire" that is more important than than absolute CD4 count. HIV viral load improvements should lead to CD4 increase. The key CD4 parameter most important for response to IFN/RBV therapy may be CD4 nadir prior to antiretroviral therapy for HIV. I would suggest that as in HIV if a person has lost the CD4 "repertoire" response to a particular antigen (in this case to HCV), maybe that will affect how the coinfected person responds to HCV either before or after HAART. If they've lost the CD4 repertoire for HCV they just may not be able to respond well to HCV and they may not respond well to IFN+RBV therapy.. In Valdez's study, levels of HCV viral load were noted to correlate with the weakness of lymphoproliferative responses to HCV antigens. Thus, one may expect improved control of HCV with immune restoration. So, it may be very important to identify and treat HCV in HIV before CD4s decline.

In a related study detailed below, A group out of Italy led by M. Pouti examined a group of 204 patients.  All of who had HCV infection.  84 of those had co-infection with HIV.  This group looked at the relationship between liver fibrosis in those with HIV vs. those without HIV.  This work has been done before by other groups, the consensus seems to be that HCV has a more rapid progression in the HIV co-infected.  Once again this was confirmed in this study.  In addition however this group analyzed the HIV positive subjects to see if low cd4ís in the HIV/HCV co-infected translated in more advanced liver fibrosis.  And in deed their main finding was that more advanced liver fibrosis, defined by the presence of stage 3 or 4 fibrosis was associated with immune suppression defined as <500 cells/ml and was independent of gender, age, duration of infection (HCV), and ETOH use. 

Abstract # TuPeB3175  Commentary: The cut-offs for what was termed immune suppression are rather high in this study (<500 cd4ís).  Still the results strongly suggest that starting HIV antiviral therapy early in those co-infected with HIV and HCV may be slow the progression to liver fibrosis and cirrhosis.

The information related in this article when taken in consideration with additional knowledge and research suggest that for the HCV/HIV coinfected patient starting HCV therapy when CD4s are high could make a significant difference in the outcome of HCV therapy. Starting HCV therapy when a person has 500 or even 800-900 CD4s may be beneficial because the person may not have lost their HCV-specific CD4 response or the proliferative lymphocyte response to HCV. There is limited research supporting this notion and certainly no or little clinical research supporting this but oftentimes clinical treatment precedes research. Starting HCV treatment when CD4s are depleted, at 250 for example, may be too late to allow for a good virologic response to HCV and a response to HCV therapy. By this time the patient may have less capacity to mount a response to HCV or HCV therapy. The patient may have lost their HCV proliferative lymphocyte or CD4 response capacity. So, when is the best time to treat--when CD4s are 800 or 250? I don't think we know at this point. And, when does the patient lose the lymphocyte proliferative response (LPR) to HCV? In HIV, that question remains unanswered with regards to LPR to specific pathogens or infections like PCP or CMV. In HIV there appears general agreement that the LPR or HIV-specific CD4 response is lost rather quickly after HIV infection. The same may be the case regarding HCV. If that is the case, it may be important to consider HCV therapy as soon as possible after learning one is HIV-positive when CD4s are high.

Liver Fibrosis progression is related to CD4+ cells depletion in patients with Hhepatitis cand human Iimmunodeficiency virus coinfection.

M Puoti is also the lead author on this study. The purpose of the study is to evaluate the relationship between liver fibrosis observed in Human Immunodeficiency Virus (HIV) seropositive patients  with hepatitis C virus (HCV) coinfection and CD4 lymphocyte depletion.  They evaluated liver biopsies obtained from intravenous  drug users with chronic hepatitis C with or without HIV coinfection.  204 HCV infected patients,  84 with and 124 without HIV coinfection were included. They did a blind evaluation of the stage of fibrosis according to the METAVIR  classification. The relationship between  the stage of liver fibrosis and CD4 levels was analyzed taking  into account the variables known or suspected to influence liver  fibrosis progression by using polytomous logistic regression.

Twenty-four patients (11%) showed many fibrous septa with (5%) or without (6%) cirrhosis (group A), 56 (27%) had few  fibrous septa and 124 (60%) had no fibrous septa. An association was found between CD4 lymphocyte counts lower than 500/mmc and the presence of many fibrous septa (OR 3.2; p = 0.037), independently from the other factors such as HIV infection, duration of disease, sex and alcohol abuse.

Puoti concluded that CD4 cells depletion is independently associated with the severity of liver fibrosis in chronic hepatitis  C. Antiretroviral combination therapy aiming at keeping high  CD4 counts should be regarded as a priority in the care of HIV  and HCV coinfected patients.

Immunological responses to hepatitis C and non-hepatitis C antigens in hepatitis C virus (HCV) infected and human immunodeficiency virus (HIV)-HCV coinfected patients

Hern Valdez of Case Western University in Cleveland, USA reports on this study. Vigorous HCV-specific CD4 responses are associated  with clearance of HCV viremia, but these are absent or of low  magnitude in most patients with chronic HCV infection. HIV-HCV coinfected patients progress faster to cirrhosis and hepatocellular carcinoma than HCV-infected  subjects. Although after treating HIV with HAART HCV progression may change. Valdez examined immune phenotype and function in HCV(+)  subjects to better characterize immune function in HCV infection  in the presence and absence of HIV infection.

Uninfected = Un (9), HCV-infected = HCV(+) (9), HCV-HIV  infected = HIV/HCV (10), HCV-HIV infected on HIV treatment =  HIV/HCV-Tx (9), and untreated HIV-infected, HCV-uninfected =  HIV(+) (10) patients had blood drawn for flow cytometry, lymphocyte  proliferation and ELISPOT assays. Entry criteria: no cirrhosis,  >300 CD4 (HIV), no recent treatment with IFN or Hepatitis B  coinfection.

Patients were well matched for age and gender. HCV infection  tended to cause an increase in the percentage of activated CD8  cells (U = 2%, HCV(+) = 6%, p = 0.1). Proliferative responses to non-HCV antigens were comparable in HCV(+) and U subjects. A  greater proportion of HCV(+) had a stimulation index (SI) >3  to NS3 compared to HIV/HCV and HIV/HCV-Tx (67%, 0%, 11%, p>0.006)  and the log SI to NS3 was significantly higher (p>0.04, p>0.009)  in HCV(+) (median, IQR 0.6,0.5) than in HIV/HCV (0.3,0.5) or  HIV/HCV-Tx (0,0.4). Among HCV-infected patients HCV-VL correlated  directly with ALT (r = 0.52, p>0.01) and inversely with the  number of CD4+ lymphocytes (r = -0.55,p>0.008) and proliferation  to NS3 (r = -0.55,p>0.008).

Valdez concluded that lymphocytes of HCV-infected patients fail to respond  to HCV antigens while responses to other antigens are preserved.  Infection with HIVpotentiates this deficiency. Poor CD4+ T cell  responses to HCV may determine the failure to control HCV propagation.