July 8, 2013

A brighter future in the fight against hepatitis

Nature Medicine | Editorial

Nature Medicine 19, 791 (2013) doi:10.1038/nm.3269

Published online 08 July 2013

Public health and research efforts directed at managing and targeting viral hepatitis have borne fruit in recent decades. However, more work is necessary to meet the goals of preventing transmission and treating infection to eliminate the enormous burden of hepatitis worldwide.

In 2012, the World Health Organization (WHO) established a Global Hepatitis Program with the goal of fully preventing and treating viral hepatitis. This month, the WHO hopes to increase public awareness through the official World Hepatitis Day, on 28 July. In this issue, Nature Medicine features a series of Review and Perspective articles that discuss promising research and clinical efforts and continuing challenges in viral hepatitis.

Hepatitis B virus (HBV) and HCV are primarily responsible for the high global prevalence of hepatitis disease and for the morbidity and mortality associated with chronic infection. A key challenge for the management of hepatitis is its silent progression, as acute hepatic failure rarely occurs. Infection is often asymptomatic, causing liver scarring and damage decades later in up to 30% of people infected with HCV, and the proportion is even higher in those infected with HBV at birth or during early childhood. Inadequate recognition of infection and region-specific variation in prevalence and risk groups hinders diagnosis and precludes timely treatment. The lack of sufficiently widespread antibody screening to identify all exposed individuals and of follow up with RNA testing, a technique not yet available for routine medical use, to distinguish people with active virus, results in incorrect estimates of infection and increased transmission. In the case of hepatitis C, recent human studies showed that less than half of the infected people in the United States knew they carried the virus (Hepatology 55, 1652–1661, 2012), a number that may be higher in areas with limited disease-control tools. Moreover, the harsh side effects of pegylated interferon-α and ribavirin force many infected people to opt out of this standard therapy, contributing to viral persistence in the community and prevalence of chronic disease.

The advent of effective antivirals is changing the therapeutic landscape, and the goal for eradicating hepatitis viruses may not be as distant as it seemed five years ago, high treatment costs notwithstanding. Current antiviral therapies do not cure chronic hepatitis B, which affects about 210 million people worldwide. At the 2013 International Liver Congress, new approaches to eliminate the HBV replication template, which persists inside liver cells, by modulating host processes such as epigenetic mechanisms and hepatocyte regeneration showed promise and may offer the potential of a cure in the future. For HCV, which affects about 150 million individuals worldwide, there have been rapid advances in drugs. Two protease inhibitors approved in 2011 greatly improved responses in patients infected with the predominant genotype 1; however, host genetic variability affecting antiviral efficacy, evolving drug resistance and the lack of coverage to inhibit all existing HCV genotypes are major drawbacks. Also, these new drugs must be given with the standard therapy, which exacerbates side effects. Second-generation antivirals with different viral targets are under development, and combination strategies should improve efficacy and may even eradicate the virus. Although these therapies are promising, resistance may still develop, and monitoring the emergence of resistant variants will be necessary for guiding treatment choices.

An interferon-free therapy for hepatitis C may also soon exist. In April, a triple combination of direct-acting antivirals without interferon showed efficacy in treatment-naive individuals and in nonresponders to standard of care. And in May, four clinical trials tested an inhibitor of viral polymerase, sofosbuvir, in patients infected with HCV (N. Engl. J. Med. 368, 1867–1887, 2013). In combination with ribavirin, sofosbuvir showed increased efficacy against genotypes 2 and 3 compared to both standard of care and placebo, and adding pegylated interferon alpha-2a to the combination achieved broad genotype coverage. Patients with unacceptable side effects to standard therapy or who were unresponsive to previous therapies may therefore benefit from these new approaches. Research on host factors required for the HCV life cycle has also yielded targets that may overcome virus-acquired resistance and circumvent side effects. A recent example is the targeting of microRNA-122, which is liver specific and necessary for viral replication (N. Engl. J. Med. 368, 1685–1694, 2013) Although long-term studies are necessary to address their safety and toxicity in the long run, interferon-free strategies may become the future of hepatitis C therapy.

But the holy grail for eradicating and decreasing the burden of any infectious disease is a prophylactic vaccine. Prevention of infection with the effective HBV vaccines and with improved medical and lifestyle practices has reached impressive levels in developed countries, and continuing efforts to improve testing and implement mass vaccination programs in low-income countries should achieve similar results in these regions. A working vaccine for HCV, however, still remains elusive, in part because of the lack of experimental systems to study the virus and the lack of animal models to test vaccine candidates. Moreover, because this virus has developed mechanisms of persistence and has an enormous genetic diversity, vaccines will need to induce both neutralizing antibodies and T cell–mediated responses to achieve broad, lasting cross-protection. Unraveling how the host immune response clears the virus during the course of natural infection and prevents persistence will help us understand what constitutes protective immunity and provide a rationale to develop an effective pan-genotype vaccine.

The goals of preventing infection, slowing disease progression and curing chronic hepatitis will undoubtedly require continuing research and clinical efforts. Pharmaceutical companies should be encouraged to keep investigating future compounds to overcome the existing therapeutic barriers, and public awareness efforts should be intensified to underscore to funding and public health agencies that, although we are closer, we are still far from achieving the goals proposed to tackle these silent elusive killers.


Poor treatment outcomes common among children with HIV/HCV coinfection

Provided by Healio

July 8, 2013

European children with HIV/HCV coinfection often have poor outcomes from HCV therapy, according to results presented at the International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Kuala Lumpur, Malaysia.

In a retrospective case note review, researchers identified 10 patients collected from four of 10 evaluated cohorts containing one or more patients coinfected with hepatitis C and HIV aged younger than 25 years. All patients had perinatal or early childhood HIV acquisition and had received HCV therapy with either pegylated interferon alfa-2a or alfa-2b (n=5 each) with ribavirin for a median duration of 48 weeks.

“Little is known about anti-HCV therapy and its outcomes in HIV/HCV coinfected children,” the researchers wrote. “Our aim was to document use and effectiveness of HCV treatment in HIV/HCV coinfected children and young people in Europe.”

The cohort included six females and four males, with eight cases of HCV genotype 1, one genotype 4 and one with an unknown genotype. The patients (median age at treatment initiation, 17.1 years) had a median HCV infection duration of 13.4 years. Among seven cases with evaluable fibrosis, stage F2 was observed in two cases, F3 in three and F4 in two cases.

One participant experienced early response, defined as undetectable HCV RNA at 12 weeks, and later achieved sustained virological response. No other participants experienced early or sustained response to therapy. No patients discontinued treatment due to adverse events, though investigators noted two cases of decreased neutrophil counts during treatment. One patient, who required retreatment 2 years after the treatment included in this study, died after liver transplantation.

“There is a very limited experience of treating HCV in HIV/HCV coinfected children,” the researchers concluded. “Our results show poor treatment outcomes in these cases, most of whom had advanced fibrosis and [genotype 1].”

For more information:

Turkova A. WEPE484: HCV Treatment in Children and Young Adults with HIV/HCV Coinfection in Europe. Presented at: IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 03, 2013; Kuala Lumpur, Malaysia.


Interferon-based therapy similarly effective with normal, elevated ALT in HCV/HIV coinfected patients

Provided by Healio

July 8, 2013

Treatment with pegylated interferon alfa-2a and ribavirin yielded similar response rates in patients with HIV and HCV coinfection with elevated and persistently normal ALT in a study presented at the International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Kuala Lumpur, Malaysia.

In the prospective, multicenter CONTRA study, researchers administered 180 mcg peginterferon-alfa-2a weekly and 1,000 mg to 1,200 mg ribavirin daily for 48 weeks to 80 patients coinfected with HIV and HCV. The cohort included 42 patients with normal ALT levels as measured five or more times within the prior 2 years (case group) and 38 patients with elevated ALT (controls). The two groups were similar with regard to age, sex, BMI, HCV genotype prevalence and HCV viral load.

Within the ITT population, sustained virologic response occurred at similar rates between the case (38%) and control groups (42%) (P=.7). Complete response also was observed in a similar number of participants between groups at week 4 (32% of cases vs. 33% of controls) and week 12 (49% vs. 60%) (P=.56).

Seventy-one percent of cases and 84% of controls experienced adverse events. Treatment discontinuation was required in 10% and 5% of patients, respectively, and one incident of opportunistic infection was observed in the control group. Treatment modification was required in 41% of cases and 45% of controls.

“The treatment with peginterferon-alfa-2a and ribavirin in coinfected patients with persistently normal ALT levels has a similar efficacy to the one observed in patients with elevated ALT serum,” the researchers concluded. “Regarding toxicity, no significant differences were detected between both groups. The same treatment criteria should be used in both types of coinfected patients.”

For more information:

von Wichmann MA. WEPE486: PegIFN-alfa-2a and Ribavirin in HIV-HCV Coinfected Patients with Persistently Normal Aminotransferase Levels: Final Results of the CONTRA Study. Presented at: IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 03, 2013; Kuala Lumpur, Malaysia.


Early Therapy May Lead to HIV Remission

Published: Jul 7, 2013

By Michael Smith, North American Correspondent, MedPage Today

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania

Action Points

  • Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
  • These preliminary results from a randomized trial demonstrated that early HIV therapy in patients with symptoms of primary infection or CD4 counts < 500/mm3 led to marked reduction in viral DNA.
  • Be aware that the primary purpose of the trial -- to evaluate the feasibility of stopping therapy in select patients -- has yet to be reported.

KUALA LUMPUR -- Preliminary data from a French randomized trial suggest that early HIV treatment might be a step toward so-called post-treatment control, a researcher said here.

Post-treatment control is what investigators are calling the ability to stop HIV therapy -- after some time on treatment -- without having the virus resume replication within the body.

Some 14 patients -- known as the Visconti cohort and all treated within weeks of their infection -- have been shown to have such control, some for several years, according to Antoine Cheret, MD, of Sorbonne-Paris-Cite University in Paris.

At the 7th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention here, Cheret presented early data from the first randomized trial aimed at duplicating the Visconti cohort.

The Optiprim study has enrolled 90 patients with early HIV infection and randomly assigned them to 24 months of a standard triple-drug regimen -- boosted darunavir (Prezista) plus tenofovir/emtricitabine (Truvada) -- or the same regimen plus raltegravir (Isentress) and maraviroc (Selzentry).

The primary endpoint of the study is what happens to the levels of HIV DNA -- regarded as the indicator of the reservoir if HIV needed to resume replication -- after the treatment period.

But at that time, Cheret reported, investigators plan to stop treatment for 6 months to see if either regimen leads to post-treatment control.

The "only problem with the presentation is they didn't have the results," commented Robert Murphy, MD, of Northwestern University Feinberg School of Medicine in Chicago.

Nonetheless, Murphy, who's involved in studies aimed at eradicating HIV reservoirs as a potential step to remission, said the data Cheret presented -- overall information about control of HIV and decline in HIV DNA -- is important.

"This will help in designing future trials," he said, even though it's preliminary.

At baseline, Cheret reported, the 90 patients were within a few weeks of infection, had a median plasma viral load of 5.4 log10 copies of HIV RNAS per milliliter, and a median of 472 CD4-positive T cells per microliter of blood.

They also had a median of 3.65 log10 copies of HIV DNA per million peripheral blood mononuclear cells (PBMCs).

As expected, viral loads declined during treatment with 92% of patients having undetectable levels after a year and CD4 cell counts rose by a median of 235 cells.

And HIV DNA fell by a median of 1.43 log10 copies per million PBMCs, while one in four patients had a drop of at least 2.0 log10 copies, Cheret reported.

While it would have been nice to see the data broken down by treatment group, "these are very important numbers," Murphy commented.

The study had support from Merck, Janssen, ViiV Healthcare, and Gilead.

Cheret made no disclosures.

Murphy reported financial links with Gilead.

Primary source: International AIDS Society
Source reference:
Cheret A, et al "Impact of 12 months HAART on cell-associated HIV-DNA in acute primary HIV-1 infection in the OPTIPRIM-ANRS 147 trial" IAS 2013; Abstract WEAB0101.