HIV/HCV coinfection: amid swirling controversy the profile of a killer emerges

by Michael Marco, Treatment Action Group, New York.

While many people with HIV/AIDS are living longer, more productive lives because of HAART, many who are coinfected with hepatitis C virus (HCV) are winding up in the hospital with end-stage liver disease (ESLD).

As an activist who eschews HCV media hype (i.e., New York Magazine’s outrageous 2000 cover story, “HCV, the Silent Killer!”) and alarmist coinfection data from misleading, outdated and small retrospective case studies, I am here to say that we have a big problem on our hands. ESLD (characterized as conditions, including encephalopathy, ascites, jaundice, gastrointestinal bleeding, hepatorenal syndrome or peritonitis) in HIV-infected patients coinfected with HCV appears to be a leading cause of hospital admissions and death according to a number of US and European data presentations at the 8th Annual Conference on Retroviruses and Opportunistic Infections (8th CROI). Conflicting data from the 8th CROI (and recent journal articles) have also reinvigorated the old debate about whether HCV infection independently leads to advanced HIV disease and death in HIV-infected patients.

ESLD as the Leading Cause of Death in HIV Clinical Cohorts

Epidemiology studies from various HIV cohorts in the US report coinfection in 25-75% of patients.1-3 The higher incidence rates are often found in major metropolitan inner-city clinics that treat patients with a history of intravenous drug use (IVDU). Many HIV clinics in southern Europe have a coinfection rate exceeding 50%. Many coinfected patients, who are living longer due to HAART and are entering their late 40s and 50s, have started to experience symptomatic HCV disease and worse, progression to ESLD. For about 20% of coinfected patients-especially those with a nadir CD4 cell count under 200 cells/mm3-progression to ESLD may be only matter of time.

Martin-Carbonero and colleagues4 from Instituto de Salud Carlos III in Madrid documented a steep rise in the number of hospital admissions and deaths caused by HCV and HBV-related ESLD between 1995 and 2000. Of the 843 HIV-positive patients seen at the institution over these five years, 46% had a viral hepatitis; about 30% with HCV. Hospitalization due to ESLD rose from 5.2% in 1996 to 8.4% in 2000. In fact, 43% of all deaths among HIV-positive individuals were caused by ESLD.

HCV ESLD also emerged as the leading cause of death in the French HIV Aquitaine Cohort. Bonnet and colleagues5 reported that there were 105 death recorded between 1998-1999 in the 2,200 patient cohort. HCV ESLD was responsible for 29% of these deaths. In northern Italy, Di Perri and colleagues6 from the University of Torino and University of Verona found that HCV ESLD was the leading cause of death in their HIV-positive patients during 1998 and 1999. While patients in the cohort have been followed since 1987, Di Perri notes, “ESLD associated with chronic HCV infection, which had only a minor impact on mortality until 1997, became the leading cause of death in the last two years of study.”

This surge in deaths due to ESLD in coinfected individuals is not confined to southern Europe. At Cook County Hospital in Chicago where over 50% of the HIV-positive patients have HCV, Ahmed and colleagues7 found ESLD to be responsible for 35% of patient deaths between January 1998 and September 2000. ESLD was the second leading cause of death behind sepsis (38%).

Does HCV Negatively Impact on HIV Disease Progression and Survival?

A number of studies presented at the 8th CROI attempted to answer a controversial question about HIV-HCV coinfection: Does HCV have a negative impact on HIV disease progression and survival? The best data came from the well-established European HIV cohorts and the Johns Hopkins group.

Studies concluding, “Yes.”

At the 8th CROI, Klein and colleagues8 from Montreal’s McGill University presented results from a chart review of 182 HIV-positive patients that suggested HCV coinfection was associated with faster progression to death and increased hospitalisation. Seventy-eight HIV/HCV coinfected patients were compared with 104 HIV-monoinfected patients. All were seen at the McGill clinic between January 1996 and June 1999. While both groups had similar baseline demographic characteristics (~38 years old; 70% male; ~310 CD4 cells/mm3; and an HIV RNA of ~10,000 copies/ml), 23% of the coinfected patients were on HAART compared to 35% of the HIV-monoinfected patients (p<0.05). The rate of opportunistic infection (OI) was 9.77 vs. 7.91 per 100 patient years (/100 p-y); deaths: 6.67 vs. 2.27/100 p-y; and hospitalisations: 15.03 vs. 6.79/100 p-y in coinfected and monoinfected patients, respectively.

Coinfection was associated with a faster progression to death (p= 0.04). The relative risk of death was 11.7 (p= 0.05) and of hospitalisation was 2.5 (p = 0.03) after adjustment for baseline and follow-up measures of CD4 cell count, HIV viral load, duration of HIV infection, and use of HAART. Even though HAART use was controlled for, the authors speculated that the differences in HIV clinical progression “may be explained in part by the lower use of HAART.” The data here are important, but it is difficult to garner definitive conclusions from such a small, retrospective single-institution case study.

The Canadian study does confirm the results of a much larger study from Greub and colleagues9 of the Swiss HIV Cohort that was recently published in The Lancet. Patients initiating HAART between June 1996 and May 1999 were prospectively followed for survival, clinical progression, HIV RNA suppression, CD4 cell recovery, and HAART changes according to HCV status. Of the 3,111 HIV patients who were followed for a median of 28 months, 1,157 (37.2%) were coinfected with HCV, 1015 (87.7%) of these with a history of IDU. There were significant differences in baseline HIV characteristics between the HCV-infected and HCV-uninfected patients: 27.7% vs. 23.5% had AIDS (p=0.009); 58.9% vs. 52.3% were antiretroviral treatment (ART) naive (p<0.001); and median CD4 cell counts were 172 vs. 222 cells/mm3 (p<0.001).

After the initiation of HAART, there was no association between HCV infection and the probability of reaching an HIV RNA <400 copies/mL. Approximately 87% of all patients suppressed their HIV RNA <400 copies/mL. There were, however, differences between the two groups with regard to CD4 cell recovery. After one year on HAART, the probability of failing to increase ones CD4 count by 50 cells/mm3 was 25.1% for HCV-infected patients compared to 16% for the HCV-uninfected patients (p<0.05).

At the end of follow-up, 7.5% of the HCV-infected patients developed an OI compared to 4.7% of the HCV-uninfected patients (p= 0.001). All-cause death was also more common in the HCV-infected patients: 8.8% vs. 4% (p<0.001). Interestingly, there were significant differences in the probability of clinical progression to AIDS and death when data were stratified by active IVDU and HCV infection. The estimated probability of clinical progression at 2 years was: 6.6% for HCV-/no active IVDU; 9.7% for HCV+/no active IVDU; and 15% for HCV+/active IVDU (p<0.0001). These results were confirmed in a Cox’s regression model with a hazard ratio (HR) for disease progression of 1.70.

This study is one of the first (and largest) to detect an increase in OIs and death due to coinfection with HCV. One explanation for this could be the impaired CD4 cell recovery in HCV-infected patients on HAART. These results will definitely need to be confirmed in another study of equal size in a different country. The fact that >85% of these 3,000 Swiss patients had an HIV RNA <400 copies/mL, makes this author think that Switzerland is not “real world” when it comes to HIV and its medical management.

Impairment of CD4 cell recovery in HIV/HCV coinfected patients on HAART was also seen in a Spanish study conducted by Martin and colleagues10 from Vincent Soriano’s group. Retrospective data were collected on 902 HIV-positive patients (72% of whom were coinfected with HCV) seen between January 1998 and April 2000 to determine the immunologic and virologic impact of HCV infection on those initiating HAART. There were significant differences in baseline characteristics between the HCV-infected and HCV-uninfected patients: mean CD4 count was 518 vs. 620 cell/3 (p<0.001) and HIV RNA was ~11,000 vs. ~6,000 copies/mL (p<0.001). Similar proportions of patients in each group were on ART (~92%) and there was no difference in drug adherence (83% taking >90% of pills).

After two years, there were striking immunologic and virologic differences between the two groups. HIV RNA on average declined by only 606 copies/mL (5%) in the HCV-infected group compared to 5,788 copies/mL (53%) in the HCV-uninfected group (p<0.001). Likewise, CD4 counts on average increased 53 cells/3 (11%) compared to 111 cells/3 (22%) in the HCV-infected and HCV-uninfected group, respectively (p<0.001).

While this study does not give us actual data on HIV clinical disease progression, it is interesting to note such striking differences in the surrogate markers of HIV disease progression. The authors bring up an interesting point for HIV-treating physicians to ponder: Would treating a coinfected patient’s HCV (regardless of liver fibrosis state) indirectly help combat the underlying HIV disease?

Studies concluding, “No.”

Data from the Johns Hopkins 1,742 patient HIV cohort suggest that HCV does not affect HIV disease progression or survival. Sulkowski and colleagues11 followed this cohort, 45% of whom were HCV-infected, from January 1996 to June 2000 to determine outcomes of CD4 cell decline to under 200 cells/3, development of OIs, and death. HCV-infected patients were older, more likely to be black (85% HCV+ vs. 65% HCV-) and had past or present IVDU (85% HCV+>14% HCV-), yet no differences were observed in baseline CD4 and HIV RNA.

At the end of follow-up, no difference in HIV clinical progression was observed in the HCV coinfected patients. Initially, an increased risk of progression and death (relative hazard [RH] 1.74; 95% CI, 1.03-2.95) was documented in HCV-infected patients with baseline CD4 counts between 50 and 200/3, however, when HAART use and lack of HIV RNA suppression to <400 copies/mL were controlled for in the multivariate analysis, HCV infection was no longer significantly associated with CD4 decline or survival (RH 1.18; 95% CI, 0.57-2.49). Use of HAART (0.30; 95% CI, 0.18-0.50) and lack of HIV RNA suppression (6.79; 95% CI, 2.10-21.9) remained significant in the multivariate analysis.

Of interest, impairment of CD4 cell recovery on HAART was also noticed in the coinfected patients at Hopkins. With three studies9,10,11 documenting this fact, TAG believes that intensified research on the immunology of HCV coinfection is warranted.

Two other studies presented at the 8th CROI-one French, one Spanish-failed to document increased HIV clinical progression or mortality in coinfected patients. Rancinan and colleagues12 from the French Aquitaine Cohort followed 995 HIV-positive patients (58% of whom were coinfected with HCV) for ~3 years.

No significant increase risk of AIDS or death was noted in the HCV-infected patients compared to the HCV-uninfected patients (hazard ratio [HR] 1.24; 95% CI, 0.77-1.97). In Macias and colleagues’13 504 patient Seville HIV cohort, deaths due to liver failure increased since 1997, yet no significant difference in survival was observed between HCV-infected and HCV-uninfected patients (p= 0.35).

Opening up the debate of whether HCV alters HIV clinical progression adds to the growing list of questions for HIV/HCV coinfection clinical and basic research. In this fledgling field we desperately need large, collaborative, multicentre natural history coinfection studies (as well as treatment trials) in the US and abroad and the financial resources to implement, follow and carry them out properly.

Source: Treatment Action Group

Comment

A higher rate of fibrosis and cirrhosis rate is so far the main threat for HIV/HCV coinfected patients. In addition a recently published series of case reports by V Sorianos’ group (AIDS 2001) it was suggested that HIV coinfection may result in early manifestations of hepatocellular carcinoma.

The interaction of HIV and HCV may be substantially affected by the reluctance of physicians to treat coinfected patients as early and as aggressively as HIV negative monoinfected patients. In addition the PK profile of antiretrovirals may be substantially altered with coinfection.

It should also be noted that HCV infection is definitely not only restricted to the liver and may affect the immune system and CNS. Therefore an array of interactions of both viruses is plausible.

References:

Matthews C, et al. Prevalence of HCV in a HIV cohort at a university Clinic [abstract 211]. Digestive Disease Week, San Diego, 2000.
Sherman KE, et al. Hepatitis C prevalence in HIV-infected patients: a cross-sectional analysis of the US adult clinical trials group [abstract 116]. 10th International Symposium on Viral Hepatitis and Liver Disease, Atlanta, 1999.
Sulkowski MS, Mast EE, Seeff LB, Thomas DL. Hepatitis C virus as an opportunistic disease in persons infected with human immunodeficiency virus. Clin Infect Dis 30:S77-84, 2000.
Martín-Carbonero L, Soriano V, Valencia ME, et al. Impact of chronic viral hepatitis on hospital admission and mortality in HIV-infected patients [abstract 297]. 8th Conference on Retroviruses Opportunistic Infections (8th CROI), Chicago, 2001.
Bonnet F, Morlat P, Chene G, et al. Causes of death among HIV-infected patients in the era of highly active antiretroviral therapy (HAART). Aquitaine Cohort (France), 1998-1999 [abstract 299]. 8th CROI, Chicago, 2001.
Di Perri G, Raiteri R, Bonora S, et al. Liver failure from HCV as the current leading cause of death in HIV-Infected patients in Northern Italy [abstract 573]. 8th CROI, Chicago, 2001.
Ahmad S, Pulvirenti J, Shastri P, et al. Death in HIV-infected in patients in the HAART era: an evaluation of mortality in an inner-city hospital [abstract 300]. 8th CROI, Chicago, 2001.
Klein MB, Lalonde RG, Suissa S. Hepatitis C (HCV) co-infection is associated with increased morbidity and mortality among HIV-infected patients [abstract 596]. 8th CROI, Chicago, 2001.
Greub G, Leergerber B, Battegay M, et al. Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss HIV Cohort Study. Lancet 356: 1800-05, 2000.
Martin J, Lopez M, Arranz R, et al. Impact of hepatitis C in HIV-infected individuals in an urban centre in Madrid, Spain [abstract 572]. 8th CROI, Chicago, 2001.
Sulkowski M, Moore R, Mehta S, Thomas D. Effect of HCV coinfection on HIV disease progression and survival in HIV-infected adults [abstract 34]. 8th CROI, Chicago, 2001.
Rancinan C, Neau D, Saves M, et al. Does hepatitis C virus (HCV) coinfection modify survival in HIV patients on combinations of antiretrovirals? [abstract 570]. 8th CROI, Chicago, 2001.
Macias J, Pineda JA, Melguizo I, et al. Influence of hepatitis C virus (HCV) infection on mortality of patients with HIV disease under highly active antiretroviral therapy (HAART) [abstract 571]. 8th CROI, Chicago, 2001.