Management of Patients Coinfected With HCV and HIV: A Close Look at the Role for Direct-Acting Antivirals

Naggie, Susanna; Sulkowski, Mark S.

doi:10.1053/j.gastro.2012.02.012

Cited by 77 publications

(53 citation statements)

References 71 publications

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“…Fifteen to 30% of HIV-infected patients are also infected with HCV, and coinfected patients have a significantly higher rate of HCV disease progression, resulting in high mortality rates due to liver disease in this population (31). As such, any treatment for the cure of HCV infection would ideally be compatible with antiretroviral medications utilized for treatment of HIV, and in vitro combination studies were performed combining LDV with two common HIV inhibitors of various classes.…”

Section: Resultsmentioning

confidence: 99%

In Vitro Antiviral Activity and Resistance Profile Characterization of the Hepatitis C Virus NS5A Inhibitor Ledipasvir

Cheng

Yang

Doehle

et al. 2016

Antimicrob Agents Chemother

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Ledipasvir (LDV; GS-5885), a component of Harvoni (a fixed-dose combination of LDV with sofosbuvir [SOF]), is approved to treat chronic hepatitis C virus (HCV) infection. Here, we report key preclinical antiviral properties of LDV, including in vitro potency, in vitro resistance profile, and activity in combination with other anti-HCV agents. LDV has picomolar antiviral activity against genotype 1a and genotype 1b replicons with 50% effective concentration (EC 50 ) values of 0.031 nM and 0.004 nM, respectively. LDV is also active against HCV genotypes 4a, 4d, 5a, and 6a with EC 50 values of 0.11 to 1.1 nM. LDV has relatively less in vitro antiviral activity against genotypes 2a, 2b, 3a, and 6e, with EC 50 values of 16 to 530 nM. In vitro resistance selection with LDV identified the single Y93H and Q30E resistance-associated variants (RAVs) in the NS5A gene; these RAVs were also observed in patients after a 3-day monotherapy treatment. In vitro antiviral combination studies indicate that LDV has additive to moderately synergistic antiviral activity when combined with other classes of HCV direct-acting antiviral (DAA) agents, including NS3/4A protease inhibitors and the nucleotide NS5B polymerase inhibitor SOF. Furthermore, LDV is active against known NS3 protease and NS5B polymerase inhibitor RAVs with EC 50 values equivalent to those for the wild type.

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Section: Resultsmentioning

confidence: 99%

In Vitro Antiviral Activity and Resistance Profile Characterization of the Hepatitis C Virus NS5A Inhibitor Ledipasvir

Cheng

Yang

Doehle

et al. 2016

Antimicrob Agents Chemother

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“…oinfection with hepatitis C virus (HCV) is an important cause of morbidity and mortality among persons infected with HIV (1,2). Disease progression is accelerated, and coinfected patients respond poorly to treatment with pegylated alpha interferon and ribavirin (Peg-IFN/RBV) compared to those infected only with HCV (monoinfection).…”

mentioning

confidence: 99%

Hepatitis C Virus (HCV) NS3 Sequence Diversity and Antiviral Resistance-Associated Variant Frequency in HCV/HIV Coinfection

Jabara

Mollan

et al. 2014

Antimicrob Agents Chemother

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HIV coinfection accelerates disease progression in chronic hepatitis C and reduces sustained antiviral responses (SVR) to interferon-based therapy. New direct-acting antivirals (DAAs) promise higher SVR rates, but the selection of preexisting resistanceassociated variants (RAVs) may lead to virologic breakthrough or relapse. Thus, pretreatment frequencies of RAVs are likely determinants of treatment outcome but typically are below levels at which the viral sequence can be accurately resolved. Moreover, it is not known how HIV coinfection influences RAV frequency. We adopted an accurate high-throughput sequencing strategy to compare nucleotide diversity in HCV NS3 protease-coding sequences in 20 monoinfected and 20 coinfected subjects with well-controlled HIV infection. Differences in mean pairwise nucleotide diversity (), Tajima's D statistic, and Shannon entropy index suggested that the genetic diversity of HCV is reduced in coinfection. Among coinfected subjects, diversity correlated positively with increases in CD4 ؉ T cells on antiretroviral therapy, suggesting T cell responses are important determinants of diversity. At a median sequencing depth of 0.084%, preexisting RAVs were readily identified. Q80K, which negatively impacts clinical responses to simeprevir, was encoded by more than 99% of viral RNAs in 17 of the 40 subjects. RAVs other than Q80K were identified in 39 of 40 subjects, mostly at frequencies near 0.1%. RAV frequency did not differ significantly between monoinfected and coinfected subjects. We conclude that HCV genetic diversity is reduced in patients with well-controlled HIV infection, likely reflecting impaired T cell immunity. However, RAV frequency is not increased and should not adversely influence the outcome of DAA therapy.

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“…Finally, drug-drug interactions must be carefully considered, especially in direct-acting antivirals (DAAs such as HCV-protease and polymerase inhibitors) [73][74][75]. To this end, several studies have described drug-drug interactions between boceprevir, telaprevir and antiretrovirals in normal subjects.…”

Section: The Influence Of Cart On the Outcome Ofmentioning

confidence: 99%

Antiretroviral Therapy in HIV/HCV Co-Infection Italian Consensus Workshop

Nasta¹,

Cattelan²,

Maida³

et al. 2013

AID

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About 50% of people living with the HIV infection in Italy are co-infected with HCV. In this group of patients, the primary cause of mortality is liver disease, which accounts for up to 14% of deaths. HIV/HCV co-infection also exposes patients to a higher risk of progression to AIDS, a faster evolution towards cirrhosis, more frequent drug toxicity, and lower tolerance for antiretroviral therapy. Moreover, HCV infection can play a part in increasing immune system depression; neurological, cognitive and renal damage; and bone fragility. Hence an optimal antiretroviral regimen needs to be chosen for co-administration with anti-HCV therapy and timed appropriately to improve the prognosis of co-infected HIV/HCV patients. Unfortunately, however, data on the safety and efficacy of antiretroviral drugs in these patients is scarce, as are studies of pharmacokinetics in patients with advanced liver impairment. Furthermore, restoring adequate immune constitution seems not to slow the progression of liver disease, and the metabolic and hepatic toxicity of some antiretroviral drugs can even contribute to inflammatory and fibrogenic processes. It is therefore essential that HIV/ HCV co-infected patients receive only medications capable of ensuring the best immune recovery but possessing the lowest potential to trigger immune reconstitution syndrome or hepatic and metabolic damage.

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Management of Patients Coinfected With HCV and HIV: A Close Look at the Role for Direct-Acting Antivirals

Cited by 77 publications

References 71 publications

In Vitro Antiviral Activity and Resistance Profile Characterization of the Hepatitis C Virus NS5A Inhibitor Ledipasvir

In Vitro Antiviral Activity and Resistance Profile Characterization of the Hepatitis C Virus NS5A Inhibitor Ledipasvir

Hepatitis C Virus (HCV) NS3 Sequence Diversity and Antiviral Resistance-Associated Variant Frequency in HCV/HIV Coinfection

Antiretroviral Therapy in HIV/HCV Co-Infection Italian Consensus Workshop

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