8th Annual Retrovirus Conference
Original contributions to this section were written by Nancy Shulman, MD, Harvey S. Bartnof, MD, and Jules Levin. A more expanded version of this section is available at this website.
Co-Infection State-of-the-Art Lecture
Kenneth Sherman, MD of the University of Cincinnati in Ohio delivered a summary HIV/HCV co-infection lecture. The lecture including audio and slide viewing is available through the conference website at www.retroconference.org. Highlights include:
There are many unknowns in the area of HIV/HCV co-infection; new research is needed and anticipated in the next several years.
An estimated of 20-30% of HIV positive patients are co-infected with HCV in developed countries (editorial comments: other studies have estimated 40%, but this will vary by transmission risk behavior. Injection drug use has been associated with a 60-90% HCV-infection rate, and hemophilia (genetic blood clotting protein deficiency) has been associated with a 90%+ rate of co-infection).
In most studies, HIV infection increases the rate of liver fibrosis (scarring) and progression to end-stage liver disease and death in patients with HCV infection, if there is no response to HAART or it is not used. (editorial comments: HAART-treated coinfected persons with low HIV viral load and high CD4s can have cirrhosis and progress to End Stage Liver Disease)
The impact of HCV on the natural history of HIV disease is more controversial, with some studies showing an enhanced progression rate and others showing no effect (see new studies below).
People with HIV/HCV co-infection are more susceptible to hepatotoxicity (liver toxicity) associated with HAART
Information is sparse on treatment of HCV in HIV/HCV co-infected populations, usually with small patient numbers in uncontrolled studies.
Based on information to date, Dr. Sherman recommends that co-infected patients be treated with HAART before HCV treatment to enhance the immune status (editorial comments: under certain circumstances it may be appropriate to treat HCV first or both diseases at the same time).
The next standard of care for treatment for chronic hepatitis C in HIV/HCV co-infected patients will be "pegylated" interferon alfa (Peg-Intron, Pegasys; long-acting, once weekly dosing) plus ribavirin.
Better, less toxic drugs are needed.
Dr. Sherman recommends that all HIV positive patients be tested for HCV.
Transplantation in HIV Positive Patients
Two posters presented information on 9 liver transplants and 5 kidney transplants from UCSF (University of California at San Francisco) and Kings College in London, UK. The UK group performed 7 liver transplants, 4 for HCV-related liver complications and 3 for liver disease due to HBV (hepatitis B virus). The lead author was Dr. A. E. Boyd. The UCSF group transplanted 2 livers in one patient (the 2nd liver was transplanted after the first one failed) and 5 kidneys (one in the liver patient). The lead author was Michele Roland, MD. Among the group of 5 HCV liver transplant patients, all had their HCV disease recur rapidly in the new liver and they died between 3 and 25 months after transplant surgery. In contrast, all 3 who were transplanted for HBV disease are alive 6 to 36 months after transplant. One person attempted suicide, but other than that all patients are well and remain on anti-HIV medication with stable CD4 counts and undetectable HIV viral loads. These are reports from only two of the sites that are doing transplantation in HIV positive patients as a part of experimental research. The take-home message from these reports with only few patients is that liver and kidney transplantation is possible in HIV patients, but we need better anti-HCV therapies to contain their virus after transplant. Liver transplantation among patients with HIV/HBV co-infection may be associated with a higher long-term success rate; however, those patients were treated for HBV after transplant. At the University of Pittsburgh, 4 liver transplants have been performed in HIV/HCV co-infected patients. The most recent update was as of the Summer 2000, and 3 were doing well with the longest follow-up being 30 months.
NNRTI Drugs Safe in HIV/HCV and HIV/HBV Co-infected Patients?
NNRTI (non-nucleoside reverse transcriptase inhibitor) drugs to treat HIV are potent, and the two most commonly used ones have convenient dosing. One of the drugs, nevirapine (NVP, Viramune), has been associated with a 10-20% rate of any hepatotoxicity (liver toxicity).
Mark Sulkowski, MD reviewed the large HIV patient database at Johns Hopkins University where 45% of 1,7454 patients are co-infected with HCV. Between 1998 and mid-2000, 203 patients were prescribed NVP-based HAART, while 96 were prescribed an EFV- (efavirenz, Sustiva, NNRTI drug) based HAART. The results showed that 17% of patients taking NVP developed grade 3 (severe) or 4 (life-threatening) liver toxicity, compared to 8% those taking EFV. When analyzing the rate by total patient-months of exposure, the rates for the two regimens were essentially the same: 1.3 cases per 100 patient-months for NVP versus 1.2 cases per 100 patient-months for EFV. Previously, studies have shown the NVP liver toxicity may be more likely to occur within the first few months after starting the drug. So, analysis by total patient-months of exposure may not capture toxicity. When analyzed by the presence or absence of chronic hepatitis B or C, patients with chronic viral hepatitis were at no greater risk for severe liver toxicity than those without hepatitis co-infection. The only independent predictor of hepatotoxicity in a "multivariate" statistical model was a CD4 cell increase greater than 50 cells per microliter. This also might have been a marker for higher adherence. Interestingly, there was a significantly greater increase in the AST among nevirapine patients when compared to efavirenz patients, while the increase in ALT was not significantly different when comparing the two drugs. Liver biopsy sampling was not performed. Alcohol consumption as a co-factor was not reported. Dr. Sulkowski concluded that NNRTI drug combination HAART should not be withheld in HIV patients who are co-infected with chronic hepatitis B or C. Note that the study was not prospective, randomized or blinded.
In another presentation, John Bartlett, MD of Duke University in Durham, North Carolina reported on the rates of liver toxicity associated with NNRTI drugs in HIV patients (Study FTC-302). Note that less than 1% had hepatitis virus co-infection. In this trial, 468 South African patients (59% women and 87% Black) were randomized to receive d4T (stavudine, Zerit, NRTI drug) with FTC (emtricitabine, experimental NRTI drug) or 3TC (lamivudine, Epivir, NRTI drug), plus either NVP (if viral load no greater than 100,000 copies) or EFV (if viral load greater than 100,000 copies per milliliter). NVP was taken by 385 patients, while 83 received EFV. All patients on treatment had taken at least 24 weeks therapy. The toxicity results showed that 9.4% of patients taking NVP and none of the patients taking EFV had grade 4 increases in liver tests (liver enzymes, alkaline phosphatase, and bilirubin). 17% taking NVP had grade 3/4 elevated liver enzymes. These elevations occurred within the first 4 weeks of therapy for 89%. At baseline, one patient had a positive test for hepatitis B surface antigen without liver inflammation, while two others had past infection with HCV. The rate of grade 4 increases was comparable between FTC (9%) and 3TC treatment arms (12%). However, the toxicity rate in women was twice (12%) that of men (6%), a significant difference. In a "multivariate" statistical analysis, female gender was the only identified risk factor for severe toxicity. There were 2 deaths due to liver toxicity, leading to early termination of the study. One of the women who died had chronic hepatitis B, while the other did not; neither had acute hepatitis A or C. These findings underscore the need for monitoring liver enzymes every 2 weeks for NVP therapy, particularly during the first 8-12 weeks.
Note that some researchers are perplexed by the higher rate of liver toxicity in women versus men in this study. In a USA study by Judith Aberg, MD from Washington University, high rash rates in women were seen, but they were not accompanied by liver toxicity. Several speculative explanations have been offered for this discrepancy: (1) in the USA study, NVP was stopped after the rash was seen; (2) in the South Africa study, it is possible that some patients liver enzymes were not as closely monitored; (3) there may be differences in diet and genetics between women in the USA versus South Africa; and (4) rash may not be easily detectable among Blacks.
Response to Interferon Alfa plus Ribavirin In HIV/HCV Co-infected Patients
Dr. M. Bochet of Hospital Pitie-Salpetriere in Paris, France presented interim results of 56 HIV/HCV co-infected patients (25% women) treated with dual combination therapy for their HCV disease: interferon alfa (Intron A, Roferon) plus ribavirin (Rebetol, combination in US also called Rebetron) for 6-12 months. All patients had been taking stable HAART for their HIV disease for at least 3 months, with reasonably suppressed HIV viral loads. Genotype 1 (the most difficult to treat) was present in 63%. The results showed that the "sustained HCV sustained virologic response (SVR) 6 months after treatment for HCV was stopped was a mere 19.6% in a strict "intent-to-treat" analysis (all enrolled patients considered). Of the patients who remained on therapy ("on-treatment" analysis), approximately 40% achieved a SVR. Early withdrawal occurred among 29%, due to known side effects of anti-HCV therapy, mainly anemia (low red cells), asthenia (weakness), "flu"-like symptoms and/or psychiatric symptoms. CD4 cell counts and HIV RNA levels did not change significantly during the study. Paired liver biopsies performed pre-HCV treatment and 6 months after treatment on 13 patients revealed a trend towards improvement to no change. More detailed information, see this article.
In a separate presentation (abstract 308), the triple combination of didanosine (ddI, Videx), ribavirin and interferon alpha was shown to be highly synergistic (marked anti-HIV activity by combining) in vitro (laboratory). Dr. M. B. Klein of McGill University in Montreal, Quebec suggested that the triple drug combination might have particular benefits for HIV/HCV co-infected patients, but additional ddI exposure may create added toxicity.
Did Not Increase HIV Progression When HAART Was Used
Many studies have shown that HIV can accelerate HCV disease progression in patients who are co-infected. However, studies have not shown definitively whether HCV can effect HIV disease progression. Mark Sulkowski, MD, of Johns Hopkins University reported related findings in I,742 HIV positive patients, 45% of whom had HIV/HCV co-infection. In a "multivariate" (statistical) analysis (that considers multiple factors) HCV co-infection was not significantly associated with a decline of the CD4 count to less than 200 cells per microliter. In the analysis, Sulkowski considered HCV infection, total exposure time on HAART for HIV, percentage of HIV viral load measurements that were greater than 400 copies per milliliter, and CD4 count at baseline. However, HCV co-infection was associated with blunted CD4 count increases with HAART at least during the first two years of treatment. He said that adherence, active IVDU (intravenous drug usage), and HAART-associated liver toxicity might be related to immune recovery in co-infected patients. Dr. Sulkowski also reported that the longer a co-infected patient was taking HAART, the less risk a person had for progression to death ("hazard ratio" 0.33). More detailed information about this report is in this section.
Co-Infection in Hemophiliacs
Eric Daar, MD of the University of California at Los Angeles presented follow-up data about HIV/HCV co-infected hemophiliacs (males with genetic deficiency of normal blood clotting protein) that was originally presented at last years 7th Annual Retrovirus Conference and recently published in the February 15th Journal of Infectious Diseases. Patients were enrolled in the multicenter Hemophilia Growth and Development Study that began between 1989-1990 and followed 207 hemophiliac children ages 7-19 who were co-infected with HIV and HCV and 121 infected with only HCV. They were evaluated annually with T-cell counts and viral load measurements of HCV and HIV. Highlights of Dr. Daars findings are:
During the 7-year follow-up period that was predominantly before the era of HAART, 31% of the co-infected patients progressed to AIDS and 35% to AIDS-related death.
Baseline HCV RNA levels were associated significantly with progression to clinical AIDS and AIDS-related death, even after controlling for HIV-1 RNA levels and CD4 cell counts. For every log or 10-fold increase in HCV RNA level, there was a 1.7 increase in the relative risk ("RR") for progression to AIDS, and a 1.5 increase in the RR for AIDS-related death.
In a "stratified" statistical analysis looking at HIV viral loads (above or below the median, i.e., upper or lower half) and HCV viral loads (above or below the median), when controlling for CD4 cell count, those with both HIV and HCV viral loads in the upper halves had the greatest risk of developing AIDS or death. The slowest rates of progression to AIDS or death were in the group with low HIV and low HCV viral loads.
Baseline HIV viral loads were directly related to HCV viral loads, supporting the hypothesis if one is controlled, the other is also likely to be controlled due to a good cellular immune response.
As has been shown in other studies, HCV viral loads were inversely related to CD4 counts, meaning a high HCV viral load is associated with a low CD4 count and that a low HCV viral load is associated with a high CD4 count.
Blood serum ALT (liver enzyme) levels did correlate with HCV viral loads.
HIV/HCV co-infected subjects had higher HCV RNA levels than the HCV mono-infected, as has been observed in other studies.
When considering the findings from this study in hemophiliacs, one should bear in mind that we do not know whether HIV and hepatitis virus co-infections have a different "natural history" in this population. The mode of transmission is different, the viruses may be different in their "virulence" (possibly "attenuated" or weaker due to heat and chemical treatment of clotting factor concentrates), the immune response might be different due to foreign protein exposure from multiple transfusions, and hemophiliacs are generally younger when infected, reflecting a younger and more functional thymus (immune) gland. Dr. Daar finds that HCV accelerates HIV progression, but very few patients in this study had taken HAART, due to the time period of the study before it was available. Yet, Dr. Sulkowski in his study (above) found that HCV does not accelerate HIV disease when patients were on HAART.
for HIV/HBV Co-infected Patients With HBV-Resistant to 3TC
Yves Benhamou, MD of Groupe Hospital Pitie-Salpetriere in Paris presented the interim results of an open-label, pilot study of adefovir treatment (10 mg once daily) in 35 HIV/HBV co-infected patients (3% women) who had 3TC-resistant HBV for a mean of 24 months. The interim results after 36 weeks revealed a mean HBV DNA decrease at week 36 of 3.8 log (6,309-fold reduction) copies per milliliter to 4.84 log (69,183) copies per milliliter. Two patients (6%) achieved an undetectable HBV viral load less than 3 log (1,000) copies per milliliter. Three patients (9%) lost "e" antigen, while two (6%) had "e" antigen conversion (developed antibodies to "e" antigen). The drug was tolerated well without any detriment to the CD4 count or HIV viral load. For more information, see this section.
HBV (hepatitis B virus) co-infection occurs in approximately 10% of HIV-infected patients. 3TC (lamivudine, Epivir-HBV) is the drug of choice for most patients with chronic HBV infection, but after 4 years, resistance has developed in 90% of HIV/HBV co-infected patients and in 67% of HBV mono-infected patients. (Interferon alfa also is FDA-approved to treat chronic hepatitis B.) Adefovir dipivoxil is a nucleotide reverse transcriptase inhibitor (NtRTI) drug that was initially developed to treat HIV.
Rates of Liver-Related Deaths from Hepatitis Virus Co-infection in the HAART
There were several presentations about the increasing rates of liver disease, liver hospitalizations and related deaths among patients with HIV infection, often associated with chronic infection due to HCV or HBV or both. Most, but not all of these reports were from southern Europe, including Spain, Italy and France. In those locations, a significant proportion of HIV patients have co-infection with HCV and/or HBV. Other co-factors for disease progression in some reports include ongoing alcohol usage (accelerating progression) and HAART. Researchers at the US CDC (Centers for Disease Control and Prevention) reported at last years 10th International Symposium on Viral Hepatitis and Liver Disease (April 2000; Atlanta, Georgia), as has been reported at other conferences, that liver disease also has become an increasing cause of death among HIV patients in the US, although not to the same degree as the European reports above.
Gene Mutation Increases HCV Viral Load
New research presented at the 8th Annual Retrovirus Conference indicates a gene mutation on cells is associated with an increased HCV viral load in patients with HCV mono-infection. And, the rate of having two "doses" ("homozygous") of the "CCR5 delta-32" mutation is much higher in this population than would be expected by chance alone. R. P. Woitas, MD of the University of Bonn in Germany also reported that among 130 HIV/HCV co-infected patients, having one dose of the mutation ("heterozygous") was associated with a somewhat higher mean HCV viral load than among co-infected patients without the mutation ("wild-type"). The conclusions of the study require additional statistical "multivariate" analyses and confirmation in other patient cohorts. The "CCR5D32" mutation gained much interest in the area of HIV/AIDS research when it was reported that being homozygous afforded near 100% protection against HIV infection (transmission). Being heterozygous is associated with a slower rate of HIV disease progression in many studies. CCR5 is a major co-receptor for HIV entry into immune cell "macrophages." In other studies of HCV-mono-infected patients, higher HCV viral loads have been associated with a lower response rate to anti-HCV treatment (abstract 499).
Negative" HCV Antibody Tests In HIV/HCV Co-Infected Patients
There were two reports finding a significant rate of false negative antibody tests for HCV infection in HIV/HCV co-infected patients. Findings were:
If CD4 count is low (less than 150 cells per microliter and usually much lower), HCV antibody test may be negative, but chronic HCV infection might be present, as determined by a positive HCV RNA test.
As CD4 count decreases, antibodies to HCV may no longer be detectable.
As HAART leads to increases in the CD4 count, HCV antibodies may appear or reappear.
The findings are very important, since physicians and HIV patients might incorrectly believe there is no HCV infection present that might need treatment. Untreated HCV infection might lead to liver disease and liver-related death.
One group of authors concluded, "Physicians should consider HCV PCR [viral load testing] in [HIV] patients with low CD4 [counts] to accurately screen for HCV infection."
For specifics and more information about these studies, see this section.
A Vaccine Effective in HIV Patients When CD4 is Greater than 200 Cells
Acute hepatitis A can be lethal for HIV or HCV positive patients. A safe and effective vaccine is available that prevents hepatitis A after exposure. C. Kemper, MD of the California Collaborative Treatment Group has reported that the standard 2 injections of Havrix (hepatitis A vaccine at time zero and 6 months) leads to effective antibody levels in 68% of HIV positive patients ("as treated" analysis, including those who were able to be evaluated 3 months after the second injection, excluding drop-outs), when the CD4 count was greater than 200 cells per microliter. In contrast, only 9% of those with a CD4 count less than 200 cells achieved a similarly effective antibody level. HIV RNA did not change significantly in the vaccine or control arms. Dr. Kemper concluded that, "There probably is little value in providing Havrix to HIV positive patients with CD4 counts [less than or equal] to 200 cells per microliter. The authors also commented, The study did not examine whether it is beneficial to delay vaccination in HIV positive patients with lower CD4 counts until their immune status improves with more potent antiretroviral regimens." Hepatitis A is transmitted by fecal contamination of food or water or when fecal material is transmitted to the mouth during sexual contact. After recovery from hepatitis A, lifelong immunity generally is the rule among HIV negative persons. Another hepatitis A vaccine also is marketed in the US (Vaqta).
HCV Transmitted Sexually Among Gay/Bisexual Men?
HCV (hepatitis C virus) is known to be transmitted by routes similar to those of HIV. However, most studies have shown that sexual transmission of HCV appears to be much less efficient than HIV is. Such studies include long-term monogamous (no sex partners outside the couple) "discordant" (one person HCV positive, partner negative), heterosexual partners (less than 5% transmission rate). Studies of "men who have sex with men" reveal that 10% or less are HCV positive, if there is no history of injection drug use. Now, researchers from Vancouver have concluded that sexual transmission of HCV occurs between gay/bisexual men and is associated with specific sexual practices. Note that factors "associated with" HCV infection does not mean "causes." The lead author was Dr. K.J.P. Craib of the British Columbia Center for Excellence in HIV/AIDS.
A total of 662 gay/bisexual men participated in the Vancouver Lymphadenopathy-AIDS Study. The results showed that the HCV positivity rate was 5.9%. A significantly higher percentage of HIV positive men were HCV positive (9%), when compared to HIV negative men (3%). In a "multivariate" statistical analysis, the following factors were found to be significantly associated with HCV positivity: lifetime injection drug use ("odds ratio" [OR] 25), HIV infection (OR 2.5) and number of male sex partners in the last year (OR 2.2). HCV positive men reported significantly greater number of male sexual partners and a significantly higher rate of using injection and non-injection, illicit recreational drugs.
However, 49% of the 39 HCV positive men "reported never injecting drugs." Among those men, the HCV positive ones were significantly more likely to report "insertive" oral-anal contact ("rimming") and "insertive fisting" (placing a hand into partners rectum). Whether the above sexual practices represent the true cause and mechanism of HCV transmission for non-injecting gay/bisexual men is not known. They might simply represent behaviors associated with the actual mechanism of transmission that might be more likely to occur with increasing numbers of sexual partners. For more information about this study and discussion, see this section.
HIV/HCV Co-Infection: "Autoimmune Diseases" and Other HCV Abnormalities Outside the Liver
Co-infected patients may have more "joint aches"
Infection with HCV has been associated with "autoimmune" abnormalities (when the immune system makes antibodies to normal human proteins and antigens in the body) and other manifestations outside of the liver. At the Conference, R.P. Woitas, MD of the University of Bonn in Germany reported, "HIV co-infection modulates the frequency of HCV-related extrahepatic manifestations differentially." For example, "cardiolipin" antibodies (increases the risk of abnormal clots) were significantly more common (46%) in HIV/HCV co-infected patients than among patients with either mono-infection alone. Whereas, "cryoglobulins" (abnormal "precipitation" or clustering of proteins from blood liquid, i.e., no longer in solution, after exposure to the cold) were present in 21% of both HIV/HCV co-infected and HCV mono-infected, compared to only 5% in HIV mono-infected patients. Interestingly, "arthralgias" (joint aches), symptoms of "vasculitis" (abnormal inflammation of blood vessels) and "Raynauds phenomenon" (abnormal excess constriction of blood vessels in fingers causing bluish color, tingling, pain after exposure to cold) were significantly more common among co-infected patients (76%) and HCV mono-infected patients (56%) than among HIV mono-infected patients (none). These differing rates of autoimmune abnormalities would need to be confirmed in a greater number of patients followed prospectively.
"Lypoatrophy" & Insulin Resistance in HIV/HCV Co-Infected
Dr. M. Duong of Hospital de Dijon in France found in a cross-sectional study that lipoatrophy (loss of fat under the skin) was observed significantly more frequently among 28 HIV/HCV co-infected patients taking HAART (48%) than among 76 HIV-infected patients taking HAART (19.5%) (abstract 654). Also, the HIV/HCV co-infected and 121 HCV mono-infected patients had a significant increase in "insulin resistance" (associated with diabetes or pre-diabetes) when compared with HIV mono-infected patients. All those with HIV were taking HAART.
A retrospective, case-control study of 40 HIV/HCV co-infected (20% women), with 78% taking PI-drug based HAART, revealed a significantly higher rate of developing high blood sugar than among matched HIV positive persons, according to Margaret Hoffmann-Terry, MD of Lehigh Valley Hospital in Allentown, Pennsylvania (abstract 619). Known risk factors for high blood sugar were exclusion criteria. 80% of those developing high blood sugar met the "ADA" definition of diabetes. Previously, HCV mono-infection has been associated with a higher risk of non-insulin dependent diabetes. The mechanisms involved in the new reports are unclear and require further investigation.
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