Durable Virologic Response Research Articles

PS-052-End of study results from LIMT HDV study: 36% durable virologic response at 24 weeks post-treatment with pegylated interferon lambda monotherapy in patients with chronic hepatitis delta virus infection

PS-052-End of study results from LIMT HDV study: 36% durable virologic response at 24 weeks post-treatment with pegylated interferon lambda monotherapy in patients with chronic hepatitis delta virus infection

Direct-acting antiviral drugs for the treatment of chronic hepatitis C virus infection: Interferon free is now.

Chronic hepatitis C (CHC) is a global, serious, and life-threatening disease. Virologic response at 12 weeks post-treatment (SVR12) signifies a durable virologic response and is currently the primary efficacy endpoint used in registrational trials. This change led to more rapid clinical development and earlier approvals of highly effective and well-tolerated therapies, facilitating access to those in need. Hepatitis C virus (HCV) infection is a therapeutic area where mathematical modeling has proven helpful in understanding the drug mechanism and characterizing viral kinetics to inform therapy decisions. The availability of direct-acting antivirals (DAAs) provides various treatment options for HIV/HCV coinfected patients, but the complexity of predicting and managing drug-drug interactions presents a unique challenge. Real-world experience or noninterventional studies can provide insight regarding the safety and use of therapeutics that may not be readily available from traditional clinical trials. This article provides a brief overview of the development of promising drugs for the treatment of CHC.

Long-Term Efficacy and Safety of Raltegravir, Etravirine, and Darunavir/Ritonavir in Treatment-Experienced Patients

Among 103 patients with multidrug-resistant HIV who initiated raltegravir, etravirine, and darunavir/ritonavir-containing regimen in the ANRS 139 TRIO trial, 100 participated in extended follow-up and continued study treatment until week 96. Among them, 87 (87%) received an optimized background therapy including either nucleoside reverse transcriptase inhibitors or enfuvirtide, they were 78 (78%) at week 96. At week 96, 88% achieved durable virologic response (<50 copies/mL). CD4 response was maintained (median change of +150 cells/mm(3)). No major toxicity was reported. This triple drug combination showed sustained efficacy and thus should be strongly considered for patients with multiclass-resistant virus.

Patient Management and Clinical Decision Making in HBV – Aims of Therapy and What we can Achieve

International treatment guidelines for hepatitis B emphasize alanine aminotransferase (ALT) and serum HBV DNA thresholds, but strict adherence to these markers might lead to missed opportunities in some patients with acquisition in early life. Clinical trials have used improvement in liver histology, rate of hepatitis B e antigen seroconversion and sustained HBV DNA suppression as primary end points. These are potentially short-term end points because HBV infection can not be eradicated and delayed relapses might occur. The closest end point to a clinical cure of disease is the loss of hepatitis B surface antigen (HBsAg). The ability of interferon to stimulate the immune response of the host might explain the higher rate of early HBsAg clearance when compared with nucleoside analogues. Early studies suggest that combination therapy with interferon and long-term treatment with nucleoside analogues might lead to an even higher rate of HBsAg seroconversion. Measuring HBsAg concentration during therapy might provide an early indication that a durable virological response, including HBsAg clearance, is likely to occur. Thus far, this has been best studied using interferon. The relationship of this phenomenon to viral genotype will be discussed. There is a need for more flexible on-treatment criteria for hepatitis B. HBsAg clearance remains the best therapeutic end point, but is not readily achievable with current treatments. Future treatment paradigms should take into account the duration as well as the extent of viraemia, place less reliance on the ALT level to indicate the extent of liver injury and consider the possibility that maintenance therapy can prevent liver disease complications.

O311 Pathogenesis of non-AIDS morbidities in HIV disease and implications for management

As the ability of highly active antiretroviral therapy (HAART) to suppress virus in a durable and safe manner improves, the inability of HAART to fully restore a normal immune system may emerge as the primary limitation of therapy. Among individuals who initiate HAART at a CD4 cell count <200 and who exhibit a potent and durable virologic response, only 50% are able to achieve normal peripheral CD4+ T cell within the first 10 years of therapy. The inability to restore CD4+ T cell numbers is predicted and perhaps caused by persistent T cell activation on therapy, which in turn may be due to residual HIV replication, persistent microbial translocation, poorly controlled coinfections and/or other mechanisms. Although long-term treated patients with suppressed virus are at low risk for AIDS-related complications, they remain at high risk for significant non-AIDS morbidity, particularly premature cardiovascular disease. Many of these non-AIDS complications are known to be associated with and perhaps caused by chronic inflammation. These data suggest that persistent inflammation during HAART will emerge as primary factor limiting the long-term effectiveness of therapy. from Ninth International Congress on Drug Therapy in HIV Infection Glasgow, UK. 9–13 November 2008

Lymphoid tissue viral burden and duration of viral suppression in plasma.

To assess virological response in lymphoid tissue and its impact on the durability of response in plasma in HIV-1-infected persons who achieved sustained suppression of plasma viraemia with different antiretroviral regimens. Consecutive patients on first-line antiretroviral therapy were included if they had a plasma HIV-1 RNA viraemia < 20 copies/ml within the last 6 months and tonsillar tissue accessible for biopsy. First-line therapy contained two nucleoside analogues: alone (2NRTI group, n = 3); plus a HIV-1 protease inhibitor (PI group, n = 11) or plus nevirapine (NVP group; n = 16). Patients were followed until virus was detectable in plasma, they changed therapy or were lost to follow-up. Tonsillar HIV-1 RNA could be detected (> 100 copies/mg) in 10 patients: one in the PI group (9%), six (38%) in the NVP group and in all three patients in the 2NRTI group. Primary resistance mutations could be detected in only 2 of these 10 patients. After a median of 9 months after the biopsies, viral suppression in plasma had failed in 6 of these 10 patients whereas failure had only occurred in 1 out of 20 with initially undetectable viral load in lymphoid tissue (P = 0.01; log rank test). In patients with sustained viral suppression in plasma, triple therapy including a HIV-1 protease inhibitor was more potent than triple therapy containing nevirapine or dual therapy with nucleoside analogues to reduce viral burden in lymphoid tissue. A worse response in lymphoid tissue could not be explained by local selection of resistance and was associated with a less durable virological response in plasma.

Combined alpha interferon and ribavirin for the treatment of hepatitis C in patients with hereditary bleeding disorders.

Patients with hereditary bleeding disorders who received non-virally inactivated plasma-derived clotting factor concentrates before the mid-1980s invariably became infected with hepatitis C virus (HCV). Therapy with interferon alpha (IFN-alpha) alone has been disappointing in this group. We conducted an open-label study, using a combination of IFN-alpha2b (3 million units three times per week) and ribavirin 1-1.2 g/d in 28 patients with hereditary bleeding disorders. Twenty-one of the 28 patients had liver biopsy-confirmed chronic hepatitis (median histological activity index 5; range 1-10) and all patients were HCV RNA positive by PCR. Virological response rate to therapy at 3 months was 82% (23 out of 28). Three HIV co-infected patients showed an early virological response with loss of HCV RNA, but two subsequently relapsed after 3 and 6 months of therapy. Four patients stopped treatment early (one at 4, one at 7 and two at 9 months) because of treatment-related side effects, although three of these have maintained a virological response. Seventeen patients completed the 48-week course. Twenty of the 28 (71%) treated have had a durable virological response with a median follow-up of 16 months (range 1-24). Combination therapy represents a significant advance in the treatment of hepatitis C in patients with hereditary bleeding disorders.

Genotypic changes in human immunodeficiency virus type 1 associated with loss of suppression of plasma viral RNA levels in subjects treated with ritonavir (Norvir) monotherapy.

Ten subjects received 600 to 1,200 mg of the human immunodeficiency virus type 1 (HIV-1) protease inhibitor ritonavir per day. Following 2 weeks of therapy, plasma HIV RNA levels decreased by a mean of 1. 57 (range, 0.89 to 1.96) log units. With continued therapy, HIV RNA levels began to rise in eight subjects. The initial rise in plasma RNA levels was temporally associated with the development and quantitative increase in the V82 resistance mutation. Doubling times of the V82A mutant virus were estimated to be 2.4 to 4.8 days. An L63P/A mutation was commonly present at baseline even in subjects with a durable virologic response. The concomitant acquisition of an L63P/A mutation with the V82A/F mutation at the time when plasma RNA levels rebounded suggests a role for the L63P/A mutation in improving the fitness of the V82A/F mutation. Subsequent additional genotypic changes at codons 54 and 84 were often associated with further increases in plasma RNA levels. Ongoing viral replication in the presence of drugs resulted in the appearance of additional genotypic changes, including the L90M saquinavir resistance mutation, and decreased phenotypic susceptibility. The relative fitness of the protease V82A ritonavir resistance mutation and reverse transcriptase T215Y/F zidovudine resistance mutation following drug withdrawal were estimated to be 96 to 98% that of the wild type. Durability of the virologic response was associated with plasma RNA levels at the nadir. A virologic response beyond 60 days was not observed unless plasma HIV RNA levels were suppressed below 2,000 copies/ml, consistent with estimates from V82A doubling times for selection of a single resistance mutation to dominate the replicating population.