 |
|
|
| |
HIV/HCV Coinfection: Impact of Antiretrovirals-and peg-IFN Without Antiretrovirals-on HIV Load
|
| |
| |
Written for NATAP: A report from the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Dec 2005.
Mark Mascolini
Tipranavir/ritonavir did a better job of controlling HIV in hepatitis virus-coinfected people than some other boosted protease inhibitors (PIs)-but at the cost of more liver toxicity. Among hepatitis C virus (HCV)-coinfected taking pegylated interferon and ribavirin without antiretrovirals, CD4 and CD8 counts dropped and so did HIV loads. Often absolute counts drop but CD4% does not & absolute counts return to levels they were before peg-IFN after they stop peg-IFN. Another research group charted a higher risk of liver toxicity in antiretroviral-treated with HCV genotype 3.
Tipranavir/ritonavir in people with HCV or HBV
Ritonavir-boosted tipranavir controlled HIV better than some other salvage PI regimens through 24 weeks in HCV- and hepatitis B virus (HBV)-coinfected people in the phase 2 RESIST trials [1]. But tipranavir-treated people with or without hepatitis coinfection had higher rates of liver enzyme elevations than did people infected only with HIV.
The RESIST studies enrolled adults who had tried nucleosides, nonnucleosides, and PIs for at least 3 months. Everyone had taken at least two PIs, including a failing PI regimen being taken at enrollment. All study participants had at least one resistance mutation at protease position 30, 46, 50, 82, 84, or 90. But no one had more than two mutations at position 33, 82, 84, or 90. People coinfected with a hepatitis virus had alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels less than 2.5 times the upper limit of normal when they signed up for the study.
Jürgen Rockstroh from the University of Bonn and an international cast of colleagues randomized 582 people to take tipranavir/ritonavir (500/200 mg twice daily) and 577 to take ritonavir-boosted lopinavir, amprenavir, saquinavir, or indinavir selected on the basis of genotyping for resistant virus. Everyone also took other antiretrovirals, sometimes including the fusion inhibitor enfuvirtide.
Prevalence of hepatitis B surface antigen measured 23% in the tipranavir arm and 29% in the control PI arm. Prevalence of HCV stood at 34% in the tipranavir group and 53% in the control group. Baseline viral loads were similar in the two treatment arms and in people with or without a hepatitis virus (with median values ranging from about 52,500 to 67,600 HIV RNA copies/mL).
After 24 weeks of treatment, coinfected people randomized to tipranavir/ritonavir had better virologic responses than those in the control arms, regardless of coinfection with HBV or HCV (Table).
Response at 24 weeks to tipranavir/ritonavir versus other boosted PIs
Rockstroh did not report whether treatment with enfuvirtide or anti-HCV therapy influenced these response differences.
Rates of new liver enzyme elevations proved consistently higher with tipranavir/ritonavir than with other boosted PIs, again regardless of coinfection with HBV or HCV (Table). Among coinfected people, about twice as many treated with tipranavir had grade 3 or 4 ALT or AST jumps.
New grade 3 or 4 ALT or AST elevations at 24 weeks with tipranavir versus other PIs
Higher risk of antiretroviral-linked liver toxicity with HCV-3
People coinfected with HIV and hepatitis C virus genotype 3 (HCV-3) had twice the risk of serious liver enzyme elevations as people coinfected with other HCV genotypes, according to results from an Italian cohort study [2]. Male gender and coinfection with hepatitis B nearly tripled the risk.
With colleagues in Pavia, Florence, and Turin, the University of Brescia's Carlo Torti tracked 132 people coinfected with HCV-3 and 360 with other HCV genotypes for 3 years after they started a potent antiretroviral regimen to see how many would have alanine or aspartate aminotransferase (ALT or AST) jumps at least 5 times the upper limit of normal. In both HCV groups only 17% had never taken antiretrovirals before. In the HCV-3 group 48% started a protease inhibitor regimen and 39% started a nonnucleoside. Those rates were almost identical in the non-HCV-3 group-47% and 39%. The other study participants started triple-nucleoside regimens.
Upon enrolling in the cohort, people with HCV-3 had a significantly higher median ALT than did people with other HCV genotypes, 87 versus 76 IU/L (P = 0.010). The HCV-3 group also had significantly higher baseline ASTs, 71 versus 61 IU/L (P = 0.012). Those differences held steady through 3 years of follow-up: In both intention-to-treat and on-treatment analyses, the HCV-3 group maintained significantly higher ALT and AST levels (P < 0.001 for both).
In another 3-year intention-to-treat analysis, rates of new grade 3 or 4 liver enzyme surges measured 25 per 100 person-years among people with HCV-3 and 11 per 100 person-years in people with other genotypes, a highly significant difference (P < 0.001).
A multivariate analysis picked out five factors that independently raised the risk of a new grade 3 or 4 liver enzyme leap (Table).
Predictors of grade 3 or 4 ALT or AST jumps after starting antiretrovirals with HCV coinfection
Variables that did not raise the risk of new liver toxicity in this analysis included type of antiretroviral therapy (PI versus nonnucleoside versus triple nucleosides), length of previous antiretroviral therapy, type of previous antiretroviral therapy, age, HIV risk group, lowest-ever CD4 count, or baseline AST, gamma-glutamyltransferase, alkaline phosphatase, or HIV RNA.
A separate multivariate analysis determined that previous grade 3 liver enzyme elevations upped the risk of a new elevation 2.8 times (95% confidence interval 1.8 to 4.3, P < 0.001).
(ED NOTE from Jules Levin: my guess is the reason for this could be due to fatty liver. Genotype 3 is associated with fatty liver, And fatty liver is associated with elevated liver enzymes).
Loading dose doesn't improve response to peg-IFN/ribavirin
Starting HIV/HCV-coinfected people on a higher dose of pegylated-interferon (peg-IFN) alfa-2a for 4 weeks did not improve 12-week HCV responses in a randomized Spanish trial [3]. A ribavirin dose of 1000 to 1200 mg daily did appear to improve responses compared with earlier studies using lower doses.
Cristina Tural from Barcelona's Germans Trias i Pujol Hospital and coworkers randomized 56 coinfected people to high-dose peg-IFN and 60 to the standard dose. The high dose was 270 micrograms/week for 4 weeks, followed by 180 micrograms/week through week 12. People in the control group took 180 micrograms/week for all 12 weeks. Weight-adjusted doses of ribavirin were 1000 or 1200 mg daily. No one had taken anti-HCV therapy before, and everyone had biopsy-confirmed HCV infection. The trial excluded people with worse than Child-Pugh grade A cirrhosis.
Equivalent proportions in the high-dose group (74%) and the standard-dose group (68%) had hard-to-treat HCV genotype 1 or 4. Median HIV loads measured about 100 copies/mL in the high-dose group and 50 copies/mL in the standard-dose group. Median CD4 counts were well above 500 cells/mm3 in both groups. While 40% starting high-dose peg-IFN were taking a PI and 33% a nonnucleoside, 28% in the control group were taking a PI and 45% a nonnucleoside.
After 12 weeks of therapy both groups had a 68% early virologic response rate. At that point 25% in the high-dose group and 23% in the control group had a negative HCV qualitative test. Dropout rates did not differ between the two groups.
(ED NOTE from Jules Levin: At the Nov 2005 AASLD meeting several ongoing studies using double-dose peg-interferon were updated. Preliminary results from these studies find induction/maintenance therapy of double dose Pegasys (360 micrograms/week) improved viral response rates without significantly increased side effects and toxicities. As well, double dose Peg-Intron showed similar benefits. For hard-to-treat patient populations double-dose peg-interferon is a treatment option worth considering for both interferon-naïve and therapy experienced patients.)
REPEAT Study: non-responders to 12 weeks treatment with standard dose PegIntron plus ribavirin received double-dose Pegasys plus ribavirin
http://www.natap.org/2005/AASLD/aasld_36.htm
Safety of Double-Dose Pegasys (REPEAT Study)
http://www.natap.org/2005/AASLD/aasld_56.htm
Double-dose PegIntron Improves Response for Interferon/ribavirin Nonresponders
http://www.natap.org/2005/AASLD/aasld_57.htm
Nadir CD4% predicts CD4 failure with peg-IFN/ribavirin
Because most studies of pegylated-interferon (peg-IFN) plus ribavirin in HIV/HCV-coinfected people involve patients taking antiretrovirals, little is known about the potential impact of anti-HCV therapy on CD4 counts. Diego Aguilar Marucco and University of Turin colleagues closed that info gap in a study of 30 coinfected people starting peg-IFN plus ribavirin without antiretrovirals [4]. CD4 counts and CD8 counts dropped significantly during treatment for HCV, and the lowest-ever (nadir) CD4 count predicted CD4-defined failure.
Aguilar Marucco and coworkers defined failure as a CD4 count falling below 250 cells/mm3 or a CD4% dropping under 20% by the end of the study. They defined end of study as completion or interruption of anti-HCV therapy, or the start of antiretroviral therapy.
Of the 24 men and 6 women in the study, 22 had antiretroviral experience. Twenty-six started peg-IFN alfa-2a and 4 started peg-IFN alfa-2b. Median nadir CD4 count measured 328 cells/mm3 (interquartile range [IQR] 215 to 492 cells/mm3) and baseline CD4 count 494 cells/mm3 (IQR 423 to 572 cells/mm3). Median nadir CD4% stood at 23.1% (IQR 15.2% to 33.6%) and baseline CD4% at 27.9% (IQR 22.5 to 38.9%).
Median end-of-study time measured 132 days (IQR 92 to 184 days). Twenty people completed anti-HCV therapy, 8 stopped because of side effects, and 2 started antiretrovirals. CD4 count and CD8 count fell significantly from baseline to end of study, while neither CD4% nor CD8% changed significantly (Table).
CD4 and CD8 changes with peg-IFN/ribavirin without antiretrovirals
Six of 30 people (20%) met the CD4 failure definition in a median of 91 days (IQR 44 to 112 days). All 6 were among the 13 people (46%) who started the study with a CD4% nadir below 20%. None of 17 with a higher baseline CD4% had a CD4 failure (P = 0.003).
Aguilar Marucco and coworkers suggested that "nadir CD4 percentage could be a useful tool in deciding [on] antiretroviral maintenance or suspension during HCV treatment" in coinfected people.
Peg-IFN lowers HIV load in small pilot study
Many clinicians know that interferon exerts an anti-HIV effect, but the magnitude of that activity remains poorly defined. A University of Turin group headed by Lorenzo Veronese found that HIV loads drop more than 10-fold after 12 weeks of pegylated-interferon (peg-IFN) therapy in people not taking antiretrovirals [5].
The study involved 11 men and 4 women starting ribavirin plus a weight-adjusted dose of peg-IFN alfa2a (median 2.53 micrograms/kg, interquartile range [IQR] 2.19 to 3.05 micrograms/kg). Four study participants had antiretroviral experience, but none took antiretrovirals during the 12-week study.
Median HIV load at study entry measured about 38,000 copies/mL, median CD4 count 469 cells/mm3 (IQR 425 to 560 cells/mm3), and nadir CD4 count 431 cells/mm3 (IQR 302 to 542 cells/mm3).
HIV loads dropped sharply through 4 weeks of peg-IFN/ribavirin therapy, especially in people with no antiretroviral experience (Table).
Median HIV RNA change with peg-IFN/ribavirin without antiretrovirals
After 2 weeks of treatment, six variables correlated with a bigger drop in HIV load: higher baseline HIV load (r = -0.565, P = 0.028), higher nadir CD4 count (r = -0.653, P = 0.008), higher CD4% nadir (r = -0.552, P = 0.033), higher baseline CD4% (r = -0.549, P = 0.034), higher baseline CD4/CD8 ratio (r = -0.532, P = 0.041), and higher peg-IFN weight-adjusted dose (r = -0.537, P = 0.039).
But after 4 weeks of therapy, only higher peg-IFN dose correlated with HIV RNA decline (r = -0.658, P = 0.008).
Veronese and colleagues concluded that both immunologic and pharmacologic factors influence HIV RNA dips in people taking peg-IFN/ribavirin without antiretrovirals. They believe peg-IFN deserves more study for its antiretroviral activity in HIV/HCV-coinfected people.
Mark Mascolini writes about HIV infection
References
1. Rockstroh J, Sulkowski M, Neubacher D, et al. 24-Week efficacy of tipranavir boosted with ritonavir in hepatitis B or hepatitis C coinfected patients. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract H-525.
2. Torti C, Puoti M, Lapadula G, et al. The influence of genotype 3 hepatitis C co-infection on liver enzyme elevations in HIV-infected patients after commencement of a new HAART: results from the MASTER-EPOKA cohort. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract H-1484.
3. Sola R, Tural C, Rubio R, et al. Lack of benefit of an induction dose of peginterferon alfa2a on early hepatitis C virus kinetics in HIV/HCV coinfected patients: results from the CORAL-1 pilot, multicenter study. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract H-416b
4. Aguilar Marucco D, Veronese L, Gonzalez de Requena D, et al. Nadir CD4% independently predicts immunological failure in antiretroviral therapy free HIV/HCV coinfected subjects treated with pegylated interferon alfa and ribavirin. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract H-1479.
5. Veronese L, Aguilar Marucco D, Gonzalez de Requena D, et al. Determinants of early anti-HIV effect of pegylated interferon alfa 2a and ribavirin in antiretroviral therapy-free coinfected HIV/HCV patients. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract H-1487.
|
|
| |
| |
|
|
|
|
|
