Does HCV Negatively Impact on HIV Disease Progression and Survival?
It is often stated that the rate of progression to cirrhosis for individuals infected with hepatitis C virus (HCV) may be accelerated for persons also infected with HIV who have CD4+ counts less than 200 cells/mm3. A recent paper in the British medical journal, The Lancet, and a number of studies presented at the 8th Annual Retrovirus Conference have reported on attempts to answer a parallel question about HIV-HCV coinfection: Does infection with HCV have a negative impact on HIV disease progression and survival? The best data are from the well-established European HIV cohorts and a group at Johns Hopkins University in Baltimore, Maryland. But results remain contradictory and the question is begging for more research.
Studies Concluding "Yes."
A large, prospective study from Greub and colleagues1 of the Swiss HIV Cohort was recently published in The Lancet. Patients initiating HAART between June 1996 and May 1999 were followed for survival, clinical progression, HIV RNA suppression, CD4 cell recovery, and number of 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, 1,015 (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; 58.9% vs. 52.3% were antiretroviral treatment (ART) naive; and median CD4 cell counts were 172 vs. 222 cells/mm3.
After the initiation of HAART, there was no association between HCV infection and the probability of reaching an HIV RNA of <400 copies/mL. Approximately 87% of all patients suppressed their HIV RNA to <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 one's CD4 count by 50 cells/mm3 was 25.1% for HCV-infected patients compared to 16% for the HCV-uninfected patients.
At the end of follow-up, 7.5% of the HCV-infected patients in the Lancet study developed an OI compared to 4.7% of the HIV-only patients. Death from all causes was also more common in the HCV-infected patients: 8.8% vs. 4%. Interestingly, there were significant differences in the probability of clinical progression to AIDS and death when data were stratified by active injection drug use (IDU) and HCV infection. The estimated probability of clinical progression at 2 years was: 6.6% for HIV-only/no active IDU; 9.7% for HCV-positive/no active IDU; and 15% for HCV-positive/active IDU.
This study is one of the first (and largest) to detect an increase in OI and death due to coinfection with HCV. One explanation for this could be the impaired CD4 cell recovery in HCV-infected patients on HAART. Other factors could involve the quality of healthcare that current and former IDUs are likely to receive. These results need to be confirmed in another study of equal size in a different country. The fact that over 85% of these 3,000 Swiss patients had HIV RNA under 400 copies/mL makes this author suspect that Switzerland does not represent the "real world" when it comes to HIV and its medical management.
At the 8th Annual Retrovirus Conference, Klein and colleagues2 from Montreal's McGill University presented results from a chart review of 182 HIV-positive patients that also suggested HCV coinfection was associated with increased hospitalizations and faster progression to death. Seventy-eight HIV/HCV coinfected patients were compared with 104 patients infected with HIV only. All were seen at the McGill clinic between January 1996 and June 1999. While both groups had similar baseline demographic characteristics, only 23% of the coinfected patients were on HAART compared to 35% of the HIV-only patients. Coinfected patients tended to have poorer outcomes (expressed here as the number of events per 100 patient years): the rate of opportunistic infections (OI) was 9.77 vs. 7.91; deaths, 6.67 vs. 2.27; and hospitalizations, 15.03 vs. 6.79 in coinfected and HIV-only patients, respectively.
The authors speculated that the differences in HIV clinical progression "may be explained in part by the lower use of HAART" and "by increased co-morbid factors associated with injection drug use" among coinfected patients. The data here are interesting, but it is difficult to garner definitive conclusions from such a small, retrospective single-institution case study.
Impairment of CD4 cell recovery in HIV/HCV coinfected patients on HAART was also noted in a Spanish study conducted by Martin and colleagues3 from Vincent Soriano's group. A cross-section "snapshot" of 902 HIV-positive patients (72% coinfected with HCV) who attended an HIV clinic between January 1998 and April 2000 observed significant differences in CD4 count and viral load between HCV-infected and HIV-only patients, respectively: mean CD4 count was 518 vs. 620 cells/mm3 and HIV RNA was approximately 11,000 vs. 6,000 copies/mL. Similar proportions of patients in each category were receiving ART (~92%) and there was no reported difference in drug adherence (83% taking >90% of pills).
In a longitudinal analysis over a two year interval, there were striking immunologic and virologic differences between the two groups. HIV RNA on average declined by only 606 copies/mL in the HCV-infected group compared to 5,788 copies/mL in the HIV-only group. Likewise, CD4 counts on average increased by 53 cells/mm3 (11%) compared to 111 cells/mm3 (22%) in the HCV-infected and HIV-only groups, respectively.
The authors raise 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?
Does HCV Negatively Impact on HIV Disease Progression and Survival? Studies Concluding "No."
Data from the Johns Hopkins 1,742 patient HIV cohort suggest that HCV coinfection does not affect HIV disease progression or survival. Sulkowski and colleagues4 prospectively followed this cohort, 45% of whom were HCV-infected, from January 1996 to June 2000 and observed outcomes of CD4 cell decline to under 200 cells/mm3, development of OI, and death. HCV-infected patients were older, more likely to be black (85% HCV+ vs. 65% HCV-negative) and had past or present IDU (85% HCV-positive vs. 14% HCV-negative), yet no differences were observed in baseline CD4 and HIV RNA.
When HAART use and lack of HIV RNA suppression to <400 copies/mL were controlled for in a multivariate analysis, HCV infection was not significantly associated with CD4 decline or survival (relative hazard = 1.18). Use of HAART and lack of HIV RNA suppression 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 studies2,3,4 reporting 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 -- also failed to document an increased rate of HIV clinical progression or mortality in coinfected patients. Rancinan and colleagues5 performed a retrospective analysis of 995 HIV-positive patients from the French Aquitaine Cohort (58% of whom were coinfected with HCV). No significant increase in risk of AIDS or death was noted in the HCV-infected patients compared to the HIV-only patients. In Macias and colleagues'6 504 patient Seville HIV cohort, deaths due to liver failure have increased since 1997, yet no significant difference in survival was observed between HCV-infected and HIV-only patients.
The debate over whether HCV alters HIV clinical progression adds to the growing list of questions for clinical and basic research into HIV/HCV coinfection. In this fledgling field we desperately need large, prospective, collaborative, natural history studies (as well as treatment trials) in the U.S. and abroad and the financial resources to implement and carry them out with proper follow-up.
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: 1800-5, 2000.
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.
Back to the GMHC Treatment Issues April 2001 contents page.