Franck Rousseau

Immunologic Responses Associated with 12 Weeks of Combination Antiretroviral Therapy Consisting of Zidovudine, Lamivudine, and Ritonavir: Results of AIDS Clinical Trials Group Protocol 315

Human immunodeficiency virus (HIV)-1 infection is associated with progressive cell-mediated immune deficiency and abnormal immune activation. Although highly active antiretroviral therapy regimens can increase circulating CD4 T lymphocyte counts and decrease the risk of opportunistic complications, the effects of these treatments on immune reconstitution are not well understood. In 44 persons with moderately advanced HIV-1 infection, after 12 weeks of treatment with zidovudine, lamivudine, and ritonavir, plasma HIV-1 RNA fell a median of 2.3 logs (P < .0001). Circulating numbers of naive and memory CD4 T lymphocytes (P < .001), naive CD8 T lymphocytes (P < .004), and B lymphocytes (P < .001) increased. Improved lymphocyte proliferation to certain antigens and a tendency to improvement in delayed-type hypersensitivity also were seen. Dysregulated immune activation was partially corrected by this regimen; however, the perturbed expression of T cell receptor V regions in the CD4 and CD8 T lymphocyte populations was not significantly affected. Ongoing studies will ascertain if longer durations of virus suppression will permit more complete immune restoration.

Three-Year Efficacy and Safety of Tenofovir Disoproxil Fumarate Treatment for Chronic Hepatitis B

BACKGROUND & AIMS Tenofovir disoproxil fumarate (TDF), a nucleotide analogue and potent inhibitor of hepatitis B virus (HBV) polymerase, showed superior efficacy to adefovir dipivoxil in treatment of chronic hepatitis B through 48 weeks. We evaluated long-term efficacy and safety of TDF monotherapy in patients with chronic hepatitis B who were positive or negative for hepatitis B e antigen (HBeAg(+) or HBeAg(-)). METHODS After 48 weeks of double-blind comparison of TDF to adefovir dipivoxil, patients who underwent liver biopsy were eligible to continue the study on open-label TDF for 7 additional years; data presented were collected up to 3 years (week 144) from 85% of participants. Primary efficacy end points at week 144 included levels of HBV DNA and alanine aminotransferase, development of resistance mutations, and presence of HBeAg or hepatitis B surface antigen (HBsAg). RESULTS At week 144, 87% of HBeAg(-) and 72% of HBeAg(+) patients treated with TDF had levels of HBV DNA <400 copies/mL. Among patients who had previously received adefovir dipivoxil and then received TDF, 88% of the HBeAg(-) and 71% of the HBeAg(+) patients had levels of HBV DNA <400 copies/mL; overall, 81% and 74%, respectively, maintained normalized levels of alanine aminotransferase and 34% had lost HBeAg. Amino acid substitutions in HBV DNA polymerase that are associated with resistance to tenofovir were not detected in any patient. Cumulatively, 8% of HBeAg(+) patients lost HBsAg. TDF maintained a favorable safety profile for up to 3 years. CONCLUSIONS TDF was safe and effective in the long-term management of HBeAg(+) and HBeAg(-) patients with chronic hepatitis B.

Overview of the effectiveness of triple combination therapy in antiretroviral-naive HIV-1 infected adults.

AimTo estimate the effectiveness of triple combination therapy in antiretroviral-naive adults. MethodsA systematic overview of results from clinical trials involving triple combination therapy with dual nucleoside reverse transcriptase inhibitors (NRTI) and: a protease inhibitor (PI triple); a non-nucleoside reverse transcriptase inhibitor (NNRTI triple); or a third NRTI (triple NUC). Data from 23 clinical trials involving 31 independent treatment groups, 19 unique antiretroviral regimens, and 3257 enrolled patients were included in this study. ResultsMedian log10 baseline plasma HIV RNA and CD4 cell count over all trials averaged 4.69 (49 329 copies/ml) and 375 × 106 cells/l, respectively. The overall estimated percentage of patients with plasma HIV RNA ⩽ 400 copies/ml at 24 weeks was 64% [95% confidence interval (CI), 60 to 67%]. The percentages of patients with plasma HIV RNA ⩽ 50 copies/ml at 48 weeks by drug class were: PI triple, 46% (95% CI, 41 to 52%); NNRTI triple, 51% (95% CI, 43 to 59%); triple NUC, 45% (95% CI, 36 to 54%). The CD4 cell count increase over all trials at 24 and 48 weeks averaged +123 × 106 cells/l (95% CI, 111 × 106 to 135 × 106 cells/l) and +160 × 106 cells/l (95% CI, 146 × 106 to 175 × 106 cells/l), respectively and did not differ between drug classes. In multivariable regression analysis, neither baseline plasma HIV RNA level and CD4 cell count nor treatment regimen predicted plasma HIV RNA ⩽ 50 copies/ml at week 48. However, pill count was significantly negatively associated with plasma HIV RNA ⩽ 50 copies/ml at week 48 (P = 0.0085). ConclusionsThe results suggest that three drug regimens containing two NRTI with a PI, a NNRTI, or a third NRTI may provide comparable activity, and practical issues such as daily pill burden should be considered when choosing a treatment regimen.

Long‐term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen–positive chronic hepatitis B

Treatment of 171 patients with hepatitis B e antigen (HBeAg)‐positive chronic hepatitis B (CHB) with adefovir dipivoxil (ADV) 10 mg over 48 weeks resulted in significant histological, virological, serological, and biochemical improvement compared with placebo. The long‐term efficacy and safety of ADV in a subset of these patients was investigated for up to 5 years. Sixty‐five patients given ADV 10 mg in year 1 elected to continue in a long‐term safety and efficacy study (LTSES). At enrollment, the 65 LTSES patients were a median 34 years old, 83% male, 74% Asian, 23% Caucasian, median baseline serum hepatitis B virus (HBV) DNA 8.45 log10 copies/mL, and median baseline alanine aminotransferase (ALT) 2.0 × upper limit of normal. At 5 years on study, the median changes from baseline in serum HBV DNA and ALT for the 41 patients still on ADV were 4.05 log10 copies/mL and −50 U/L, respectively. HBeAg loss and seroconversion were observed in 58% and 48% of patients by end of study, respectively. Fifteen patients had baseline and end of follow‐up liver biopsies; improvements in necroinflammation and fibrosis were seen in 67% and 60% of these patients, respectively. Adefovir resistance mutations A181V or N236T developed in 13 LTSES patients; the first observation was at study week 195. There were no serious adverse events related to ADV. Conclusion: Treatment with ADV beyond 48 weeks was well tolerated and produced long‐term virological, biochemical, serological, and histological improvement. (HEPATOLOGY 2008;48:750–758.)

Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease

Data are limited on the safety and effectiveness of oral antivirals other than lamivudine and adefovir dipivoxil for treatment of chronic hepatitis B (CHB) in patients with decompensated liver disease. This Phase 2, double‐blind study randomized 112 patients with CHB and decompensated liver disease to receive either tenofovir disoproxil fumarate (TDF; n = 45), emtricitabine (FTC)/TDF (fixed‐dose combination; n = 45), or entecavir (ETV; n = 22). The primary endpoint was safety; more specifically, tolerability failure (adverse events resulting in permanent treatment discontinuation) and confirmed serum creatinine increase ≥0.5 mg/dL from baseline or confirmed serum phosphorus <2 mg/dL. Patients with insufficient viral suppression (e.g., confirmed HBV DNA ≥400 copies/mL at week 8 or 24) could begin open‐label FTC/TDF but were considered failures in this interim week 48 analysis for efficacy endpoints. Tolerability failure was infrequent across arms: 6.7% TDF, 4.4% FTC/TDF, and 9.1% ETV (P = 0.622) as were confirmed renal parameters meeting threshold 8.9%, 6.7%, and 4.5% (P = 1.000), respectively. Six patients died (none considered related to study drug) and six received liver transplants (none had HBV recurrence). The adverse event and laboratory profiles were consistent with advanced liver disease and complications, with no unexpected safety signals. At week 48, HBV DNA was <400 copies/mL (69 IU/mL) in 70.5% (TDF), 87.8% (FTC/TDF), and 72.7% (ETV) of patients. Proportions with normal alanine aminotransferase were: 57% (TDF), 76% (FTC/TDF), and 55% (ETV). Hepatitis B e antigen (HBeAg) loss/seroconversion occurred in 21%/21% (TDF), 27%/13% (FTC/TDF), and 0%/0% (ETV). Child‐Turcotte‐Pugh and Modification for End‐stage Liver Disease scores improved in all groups. Conclusion: All treatments were well tolerated in patients with decompensated liver disease due to CHB with improvement in virologic, biochemical, and clinical parameters. (HEPATOLOGY 2011.)

Severe Hepatotoxicity Associated with Nevirapine Use in HIV-Infected Subjects

Human immunodeficiency virus (HIV)-infected South African patients (n=468) received blinded lamivudine or emtricitabine, stavudine, and either nevirapine or efavirenz (based on screening viral load). Baseline characteristics were analyzed in univariate and multivariate regression, to identify risk factors for hepatotoxicity (grade 3 or greater increase in serum aminotransferase levels). The occurrence of early hepatotoxicity was 17% in the nevirapine group and 0% in the efavirenz group and was balanced between the lamivudine and emtricitabine arms. Two subjects died of hepatic failure. Independent risk factors were body-mass index (BMI) <18.5, female sex, serum albumin level <35 g/L, mean corpuscular volume >85 fL, plasma HIV-1 RNA load <20,000 copies/mL, aspartate aminotransferase level <75 IU/L, and lactate dehydrogenase level <164 IU/L. The use of nevirapine in female patients with a low BMI should be discouraged.

Immune Reconstitution in the First Year of Potent Antiretroviral Therapy and Its Relationship to Virologic Response

The effects of 1 year of zidovudine, lamivudine, and ritonavir treatment on immune reconstitution were evaluated in 34 human immunodeficiency virus (HIV)-infected individuals. After 48 weeks of therapy, 20 (59%) subjects had <100 copies HIV RNA/mL. CD4+ T cells increased from a median of 192/mm3 at baseline to 362/mm3 at week 48. Lymphocyte proliferative responses to Candida normalized within 12 weeks, but responses to HIV and tetanus remained depressed throughout therapy. Alloantigen responses increased within 12 weeks and then declined to baseline levels. Recovery of delayed-type hypersensitivity responses occurred after 12 weeks for Candida and after 48 weeks for mumps. The magnitude of virologic suppression was correlated with numeric increases in CD4+ T cells, but not with measures of functional immune reconstitution. Plasma virus suppression <100 copies/mL was not significantly correlated with increases in CD4+ T cells or functional immune reconstitution.

A phase II dose‐escalating trial of clevudine in patients with chronic hepatitis B

Current therapies available for the treatment of chronic hepatitis B are limited in their ability to result in a cure. Clevudine is a new pyrimidine analog with potent anti‐hepatitis B virus (HBV) activity in vitro. A multicenter dose‐escalation study evaluated clevudine at 10, 50, 100, and 200 mg once daily for 28 days. Eligible patients had HBV DNA levels of 3 × 106 copies/mL or more, had not undergone nucleoside treatment, and were without human immunodeficiency or hepatitis C virus coinfection. Thirty‐two patients were enrolled (5, 10, 10, and 7 patients in the 10‐, 50‐, 100‐, and 200‐mg dose groups, respectively), 81% were male, 81% Asian, and 88% were hepatitis Be antigen (HBeAg) positive at baseline. Median pretreatment serum HBV DNA levels ranged from 7.3 to 8.8 log10 copies/mL. After 28 days, the median HBV DNA log10 change from baseline was −2.5, −2.7, −3.0, and −2.6 log10. Six months after dosing, median changes from baseline were −1.2, −1.4, −2.7 and −1.7 log10 in the 10‐, 50‐, 100‐, and 200‐mg cohorts, respectively. Six of 27 patients lost HBeAg, and 3 of 27 patients seroconverted to HBe antibody. Clevudine was well tolerated, with no dose‐limiting toxicities. A transient increase in alanine aminotransferase of up to 7.8 times the upper limit of normal (increase ranged from 20 to 186 IU/L) was observed in six patients in the 100‐mg cohort, without signs of liver failure. These increases were associated with improved viral suppression. The pharmacokinetic profile of clevudine was proportional to the dose. In conclusion, these results demonstrate the tolerability and potent activity of clevudine in HBV‐infected patients and support further clinical study. (HEPATOLOGY 2004;40:140–148.)

Pharmacogenetics of Nevirapine-Associated Hepatotoxicity: An Adult AIDS Clinical Trials Group Collaboration

Associations have been reported between an MDR1 variant and responses to nonnucleoside reverse-transcriptase inhibitors. We explored associations between MDR1, CYP2B6, and CYP3A polymorphisms and nevirapine hepatotoxicity. Among participants in a randomized study in South Africa (FTC-302), MDR1 3435C-->T was significantly associated with decreased risk of hepatotoxicity (risk ratio, 0.30; P=.016).

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of GS-9450 in Subjects With Nonalcoholic Steatohepatitis

In nonalcoholic steatohepatitis (NASH), the extent of hepatocyte apoptosis correlates with disease severity. Reducing hepatocyte apoptosis with the selective caspase inhibitor GS‐9450 has a potential for altering the course of the liver disease. In this phase 2, double‐blind study, 124 subjects with biopsy‐proven NASH were randomized to once‐daily placebo or 1, 5, 10, or 40 mg GS‐9450 for 4 weeks. Absolute and percent changes from baseline in ALT levels, AST levels, and caspase‐3–cleaved cytokeratin (CK)‐18 fragments at week 4 were assessed by an analysis of covariance model with adjustment for baseline values. In the 40‐mg group, mean (SD) ALT decreased by 47 (43) U/L from baseline to week 4 (P < 0.0001 versus placebo), and the proportion of subjects with normal ALT increased from 0% to 35% at week 4. In the 40‐mg group, mean AST decreased by 13 U/L from baseline (not significant), and the proportion with normal AST increased from 20% at baseline to 48% at week 4. By week 4, mean CK‐18 fragment levels had decreased to 393 (723) U/L in the GS‐9450 10‐mg group and 125 (212) U/L in the 40‐mg group, but these reductions were not statistically significant. No serious adverse events were reported during treatment, and the percentage of subjects with at least one treatment‐emergent grade 3 or 4 laboratory abnormality ranged from 11.5% to 17% across the GS‐9450 treatment groups versus 35% in the placebo group. Conclusion: GS‐9450 treatment induced significant reductions in ALT levels in NASH patients. Reductions in CK‐18 fragment levels also occurred, although they were not statistically significant. At appropriate therapeutic indices, selective caspase inhibitors may be a promising treatment option in patients with NASH. (Hepatology 2012)