HIV at AASLD
     Reported for NATAP by Douglas T. Dieterich M.D., Clinical Associate Professor of Medicine, NYU School of Medicine, Chief of Gastroenterology and Hepatology, Cabrini Medical Center, New York City.

This year I count 17 abstracts that involve HIV and several others that pertain to people with HIV infection. The usual count at this meeting is 3-4 abstracts, so that amounts to a substantial and probably statistically significant increase. The liver world is beginning to discover HIV. The infectious disease world is also beginning to discover the liver and both fields will benefit from this collaboration. The cross fertilization of scientists is a well known fact and much HIV technology and expertise is moving into the field of hepatitis C and hepatitis B. Indeed, the principles of combination therapy and viral resistance are being applied to the treatment of both liver viruses.

The immunology of hepatitis B and C also is being explored with the same tools that are used in HIV. From the HIV perspective, there is clear acceptance of hepatitis B and C as an opportunistic infection that needs to be taken seriously and studied in an organized, large-scale fashion. As a traveler in both camps, i.e. a card-carrying member of the International AIDS Society both USA and internationally, the Infectious Disease Society of America and the American Association for the Study of Liver Diseases, I am delighted at these developments and even more delighted to tell you about them. 

In alphabetical order, letís start with hepatitis B. There are only three abstracts that concern hepatitis B and HIV, but two are landmark studies, albeit small. The University of Miami has reported on 4 liver transplants performed in HIV+ patients all with hepatitis B. It is early to draw any conclusions this point, but the first two patients are at 13 months and 3 months out and are doing well. All patients were required to have at least 500 CD4 cells and have HIV <400 copies. In addition to those 4, there are reports that four have been done in Pittsburgh, 2 in San Francisco and 1 in New York. These are carefully selected patients in the beginning, almost guaranteed to do well. Living related donor transplants probably have a role in HIV patients as well.

That is an operation that takes the right lobe (usually) of the donor (usually a blood relative) and transplants it into the recipient. This procedure is still new and requires a recipient who is not too ill. It also carries some risk of dying for the donor (<1%). The other abstract that is hopeful is Benhamouís report of adefovir treatment of 30 HIV infected patients who had lamivudine (3TC) resistant hepatitis B. He reported on the 10 mg dose of adefovir which is the hepatitis B dose and his patients had a mean 3 log drop in HBV DNA in 12 weeks.

That is also a short term report, but encouraging nonetheless for people who have resistant HBV. The only small piece of bad news, was a British abstract that noted that during immune reconstitution, 2 patients had seroconversion reactions from Hepatitis B e Antigen to Antibody and that was accompanied by a flare of clinical hepatitis, but a resolution of the hepatitis B. The other 2 patients had a reactivation of hepatitis B when coming off HIV medication.

 As for hepatitis C, there was more information. Two presentations commented on the natural history of hepatitis C. The first was from Paris and dealt with cirrhosis. They looked at about 300 cirrhotics about 50 of whom had HIV for a mean time of 28 months (1 month to 13 years). Overall, the HIV+ patients were more likely to be younger, have a history of IV drug use and to drink more than 5 drinks per day. (That is the French definition of excess alcohol). Mean CD4 was 324 and 28% had CD4's <200 copies. (100% were receiving antiretroviral therapy). The death rate at 3 years was 47% in the HIV+ group and 13% in the HIV negative group, which was significant. The risk factors for early death were HIV, 3.4 times, alcohol 2.3 times and age >40 years at biopsy. This demonstrates even in people with end stage liver disease, that HIV has a serious effect on the outcome of hepatitis C.

(Ed Note from Jules Levin: There are some qualifications to this study. The HIV+ patients had significantly higher alcohol consumption (68 grams per day vs. 38 grams per day). Infected patients had a lower age at HCV infection [24± 8 vs 35± 14, p<0.0001], lower age at HCV cirrhosis [39± 6 vs 54 ± 13, p<0.0001], and a similar proportion of treated patients [61% vs 53%, NS]. The incidence of hepatocellular carcinoma was not more frequent in HIV+ patients. Perhaps most important, death decreased in interferon treated patients [5% vs 7% at 2 years, 10% vs 21% at 5 years, p=0.050]. Absence of interferon treatment was found to be a predictor of death in multivariate analysis. My question is--since HIV-infected patients had lower age at HCV infection by 11 years [24 vs 35] does that explain why their outcome was worse since they had longer duration with HCV infection).

Mark Sulkowski from Johns Hopkins presented his data on the HIV clinic at Hopkins. 45% had HCV and 49% were self- described alcohol abusers. Of the HCV patients 92% were genotype 1. However, 97% of the African Americans were genotype 1 versus 80% of the Caucasians. 48% of the liver biopsies showed at least grade 3 fibrosis, on the Ishak scale, which shows that half of the patients were well on their way to cirrhosis. Risks for cirrhosis in this HIV/HCV cohort were alcohol, 5.2 times, Caucasian race 5.9 times and female sex 6.5 times. Of particular note was that HIV <400 copies was a risk (2.9 times) for cirrhosis. This flies in the face of previous data. However, we also know that controlling HIV does nothing for HCV and this may just be confirming that piece of data. This is a very interesting finding and deserves follow up and confirmation.

The immunology of HIV and HCV was explored in an abstract from Bruce Walkerís lab at Harvard. Interestingly enough, virtually all of the patients were able to mount an effective immune response to HIV, but most were not able to mount a broad and strong response to HCV. This implies that HCV is an even more wily adversary than HIV and expert at avoiding the immune systemís response to its presence. This theme was echoed in numerous abstracts in HIV negative patients that demonstrated that the size and breadth of the cell-mediated immune response in HCV patients is the key to both beating the acute infection and eradicating the chronic infection.

From the Bronx VA, a report of the prevalence of HIV in HCV positive patients revealed that 21% were positive for HIV in contrast to a European report that in 1998 57% of HCV patients were HIV infected. Also from the VA system, although Manhattan this time, Ed Bini reported on the Quality of Life of HCV patients compared to HIV patients. The HCV patients have a significantly reduced quality of life when compared to HIV patients. Coinfected patients are not worse and actually fall in between HCV and HIV mono-infected patients. The reasons for this are not at all clear. In a small study of 25 HIV/HCV coinfected patients from Jacksonville, the only new finding was that of increased lymphoid follicles on liver biopsy.

That may warrant further investigation, especially when combined with the data from Texas on ballooning of hepatocytes associated with protease inhibitor use. That was an interesting finding and also unexplained. There may be something else going on in the liver of coinfected patients that we are not understanding yet.

From Barcelona, a small treatment trial of coinfected hemophiliacs showed a sustained virological response rate of 32% with combination interferon TIW and ribavirin. Side effects were standard and HIV RNA nor CD4 counts did not significantly change on therapy. They did see a significant amount of anemia from the ribavirin (about a 2 gram drop) which our group would treat with epoietin alfa, although they did not indicate if they did. With the data from McHutchison, in HIV negative patients that the sustained virologic response was significantly lower (24% vs. 42%) in people who took less than 10.6 mg/kg per day of ribavirin, (basically 800 mg for a 165 pound man), it becomes even more important to keep ribavirin doses at or above 800 mg.

A randomized trial of epoietin alfa versus standard of care (dose reduction) in HCV patients treated with ribavirin showed a dramatically higher hemoglobin (by 3 grams) in the treated group. Maybe even more important was that they were able to take more ribavirin 986 mg per day versus 682 mg in the dose reduction group. By implication, this should impact the sustained virologic response. An identical study is just beginning in HIV+ patients to study epoietin alfa.

A study from Pavia looked at daily interferon monotherapy and showed us a high drop out rate and poor response. This will be eclipsed with peg interferon in the near future.  The evidence is building that combination treatment with interferon and ribavirin is both safe and effective in HIV patients, the only issue being anemia, which is treatable. However these are mostly single center small 15-30 patient studies, but there are about 10 of them now. The larger scale trials are underway and we should have data from them in a year or so.

(Note from Jules Levin: Overall, it is not clear to me that coinfected persons will respond as well to HCV therapy as individuals infected with HCV alone. As Dr Dieterich says the studies so far in coinfected persons are small. I think the response rates to HCV therapy for people with HIV will vary between individuals based on their situations. Some individuals will respond as well as those with HCV alone. In some people HCV may have progressed more quickly because HIV can cause HCV to progress more quickly and they may not respond as well to HCV therapy, particularly if their CD4 nadir is low. African Americans have a poor virologic response rate to combination HCV therapy. Most African Americans are genotype 1 (in one study 96% were genotype 1. One small French study suggests that HCV progression slowed or stopped in individuals on HAART. But a number of treaters I've spoken with aren't convinced of these results. As Dr Dieterich says, larger ongoing studies ought to be revealing).

Finally, a good study of NNRTI toxicity was presented by our group with Ron Palmon who is a second year medical resident at NYU/Bellevue doing most of the presenting. He looked at the liver toxicity of delavirdine, nevirapine and efavirenz in our cohort of largely urban gay white males, using a computerized database. He found that there were no significant differences in the incidence of liver toxicity with the possible exception of delavirdine, which elevated bilirubin more than the other two

Overall the conclusion was that this class of HIV drugs was relatively safe for the liver. On the opposite side of the ocean, in Glasgow, Triangle pharmaceutical was presenting FTC 302 which looked at FTC versus 3TC plus D4T and either nevirapine for viral loads <100,000 or efavirenz for viral loads > 100,000. This was a largely black largely female population in South Africa. Severe liver toxicity was seen in 0/83 patients on efavirenz, but in 58/385 (15%) of the patients on nevirapine, 2 of whom died of liver failure. This agrees with the INCAS, VIRGO and ATLANTIC trials, which had liver toxicity for nevirapine of 15%, 16% and 17% respectively. Why there is such great disparity between trials is not at all clear. There is clustering of liver toxicity in the 1-2% range in some trials and in the 15% range in others. The mechanism of NNRTI liver toxicity is not well understood and may be related to the allergic reaction to nevirapine, which seems to be more common in women.

Another liver toxicity related abstract came from Ireland. Bohan and colleagues showed that HCV seems to cause a deletion of a mitochondrial gene and that it is associated with more fatty liver and fibrosis than when it does not happen. This is particularly pertinent to mitochondrial toxicity of nucleoside analogues in HIV patients because HCV may begin to injure mitochondria and make coinfected patients more susceptible to mitochondrial toxicity. A 1999 article using electron microscopy also showed mitochondrial injury in 92% of HCV patients, setting them up for nucleoside analogue hepatotoxicity.