Xray of man higlighting liver. Photo: iStockPhoto.com/pixologicstudio.
Photo: iStockPhoto.com / pixologicstudio.

Hepatitis B

Treatment for chronic hepatitis B virus (HBV) infection has not advanced as fast as HIV and hepatitis C therapy in recent years, but approval of new drugs has led to higher response rates.

Nucleoside/nucleotide analogs are the mainstay of hepatitis B treatment. FDA-approved options include Baraclude (entecavir), Epivir (lamivudine or 3TC), Hepsera (adefovir dipivoxil), Tyzeka (telbivudine), and Viread (tenofovir disoproxil fumarate). Emtriva (emtricitabine) is also active against HBV, but has not yet been approved for this purpose. These are all pills taken once daily. Conventional interferon and pegylated interferon alfa-2a (Pegasys) are also approved for treating hepatitis B. The more potent formulation, Pegasys, is injected once weekly.

Not everyone with hepatitis B needs treatment, depending on the extent of liver damage and other factors. A complete cure, meaning HBV clearance and development of protective antibodies, is uncommon. But most people can achieve viral load suppression, which lowers their risk of developing liver cirrhosis and liver cancer. Treatment usually lasts for at least one year, and many people stay on nucleoside/nucleotide analogs for several years to maintain viral suppression.

There are three ways to measure hepatitis B treatment response. Virologic response means suppression of viral replication, ideally reaching undetectable HBV DNA viral load in the blood. Biochemical response is normalization of the liver enzyme alanine aminotransferase, or ALT. Serological response refers to clearance of HBV antigens and development of antibodies (seroconversion).

U.S. and European treatment guidelines recommend Baraclude or Viread monotherapy for first-line hepatitis B treatment for HIV-negative people. These drugs offer the best overall response rates and a high barrier to resistance. There are two types of HBV, hepatitis B "e" antigen (HBeAg) negative and positive, the latter being harder to treat. In clinical trials, virologic response rates for Baraclude and Viread were 90% and 93%, respectively, for HBeAg-negative people, and 67% and 76% for HBeAg-positive people. Both drugs are generally safe and well tolerated, though tenofovir can sometimes cause bone loss and kidney impairment. Combining nucleoside/nucleotide analogs does not significantly improve response for hepatitis B treatment-naïve people, but it may be beneficial for people with drug-resistant HBV.

Lamivudine, which is available in a generic formulation, is the least expensive treatment, but drug resistance is common. Pegylated interferon promotes HBeAg seroconversion, and combining interferon with nucleoside/nucleotide analogs improves effectiveness. But interferon can cause difficult side effects, and combining it with Tyzeka can cause peripheral neuropathy.

Viread, Epivir, and Emtriva are active against both HBV and HIV. Guidelines recommend that people with HIV and HBV co-infection should include dually active drugs in their antiretroviral regimen. HIV/HBV co-infection should be managed by clinicians who have experience treating both diseases, since using these medications incorrectly can lead to drug resistance in one or both viruses.

Hepatitis B can be prevented by a three-dose vaccine. This is now included in routine infant vaccinations and is recommended for many adults, including gay men, pregnant women, and people with HIV or hepatitis C.

Computer-generated image of hepatitis B virus. Photo: iStockPhoto.com.
Computer-generated image of hepatitis B virus. Photo: iStockPhoto.com.

Hepatitis C

Treatment for hepatitis C virus (HCV) infection has advanced dramatically in the past few years as direct-acting antiviral agents, or DAAs, have improved cure rates and shortened treatment duration.

The main measure of hepatitis C treatment success is virologic response, or reduction of HCV RNA. Viral load is typically measured after four weeks on treatment (rapid virologic response, or RVR), after 12 weeks (early virologic response, or EVR), at the end of treatment, and after finishing treatment.

Sustained virologic response (SVR), or continued undetectable HCV viral load 24 weeks after completing treatment, is traditionally considered a cure. The FDA recently said SVR at 12 weeks post-treatment can also be considered a cure. Sustained response can halt liver disease progression and lowers the risk of developing cirrhosis and liver cancer.

Not everyone with hepatitis C needs treatment, but it is recommended for people with at least moderate liver damage, usually determined by a liver biopsy. Treatment during acute infection (the first six months after infection) has a very high success rate, but most people do not realize they are infected this soon. Overall, about 25% of people clear HCV spontaneously without treatment, but the proportion is lower among people with HIV.

The previous standard of care for chronic hepatitis C was pegylated interferon alfa-2a (Pegasys) or alfa-2B (PegIntron) injected once weekly plus a weight-adjusted oral dose of ribavirin. Treatment duration is 48 weeks for people with difficult-to-treat HCV genotypes 1 or 4 and 24 weeks for those with genotypes 2 or 3. The overall SVR rate for HCV mono-infected people is about 75% for genotypes 2 or 3, but less than 50% for genotype 1. For the most difficult-to-treat groups of patients, response rates can be as low as 5%.

Several factors influence how well interferon-based therapy works. In addition to HCV genotype, high pre-treatment HCV viral load, advanced liver fibrosis or cirrhosis, insulin resistance, and HIV co-infection are associated with poorer response. People trying treatment again after previous non-response do not do as well as those being treated for the first time. People of African descent generally do not respond as well as white patients.

In 2009, researchers discovered that the latter two factors are largely attributable to variations in the IL28B gene. People with the favorable "CC" gene pattern respond best to interferon, people with the "TT" pattern have the lowest response rates, and people with the "CT" pattern are in between.

Pegylated interferon causes notorious side effects, including flu-like symptoms (fever, chills, fatigue, muscle aches), depression, and low white blood cell count. Ribavirin can cause anemia due to red blood cell destruction. These side effects may be severe enough that people avoid going on treatment, stop treatment prematurely, or lower their drug doses.

The current standard of care for hepatitis C combines direct acting antivirals with the previous standard of care, pegylated interferon plus ribavirin. DAAs work by targeting different steps of the viral lifecycle. Polymerase inhibitors, which interfere with copying viral genetic material, and protease inhibitors, which block construction of new viral particles, are familiar from HIV treatment. NS5A replication complex inhibitors target an HCV enzyme that works in conjunction with polymerase.

"Overall, about 25% of people clear HCV spontaneously without treatment, but the proportion is lower among people with HIV."

In 2011, the FDA approved the first two DAAs for genotype 1 chronic hepatitis C, the protease inhibitors Incivek (telaprevir, developed by Vertex) and Victrelis (boceprevir, developed by Merck). In pivotal clinical trials, adding one of these drugs to pegylated interferon/ribavirin raised overall treatment response rates significantly, both for HIV-negative and HIV-positive patients.

Both drugs are taken three times daily with pegylated interferon/ribavirin (Incivek for 12 weeks, Victrelis for 28 or 36 weeks), followed by continued treatment with pegylated interferon/ribavirin alone. Treatment-naïve people with good early viral suppression can stop treatment sooner (at 24 or 28 weeks), while others continue treatment through week 48.

In Phase 3 clinical trials of HIV-negative people, Incivek SVR rates were 79% for previously untreated people, 86% for prior relapsers, and 32% for prior null responders (those who previously had little or no decrease in HCV viral load). Victrelis SVR rates were 90% for previously untreated people and 66% for prior relapsers and partial non-responders (null responders were excluded).

So-called difficult-to-treat patient groups do not respond as well to hepatitis C therapy but may have a more urgent need for treatment. People with liver cirrhosis can be successfully treated with triple therapy including Incivek or Victrelis, but they have a higher frequency of side effects; studies of liver transplant recipients are underway. HIV/HCV co-infected people using Incivek or Victrelis can achieve response rates close to those of HCV mono-infected people with similar side effects. However, due to drug-drug interactions, these DAAs should not be combined with certain antiretrovirals.

Not surprisingly, adding another drug to the mix can increase adverse events. The most notable side effect of Incivek is skin rash, while Victrelis can cause anemia. The tradeoff is shorter treatment duration and a better chance of achieving a cure.

HCV Drugs in the Pipeline

Several new HCV protease inhibitors are now in clinical trials including asunaprevir (BMS-650032, developed by Bristol-Myers Squibb), danoprevir (RG7227, Roche/Genentech), faldaprevir (BI 201335, Boehringer Ingelheim), simeprevir (TMC435, Janssen), sovaprevir (ACH-1625, Achillion), vaniprevir (MK-7009, Merck), ABT-450 (Abbott), and GS-9256 (Gilead Sciences).

Experimental polymerase inhibitors include the nucleoside/nucleotide analogs mericitabine (RG7128), sofosbuvir (GS-7977), and VX-135 (Vertex). Non-nucleoside polymerase inhibitors include setrobuvir (ANA598, Roche), tegobuvir (GS-9190), ABT-333, BI 207127, BMS-791325, and VX-222.

NS5A replication complex inhibitors under development include daclatasvir (BMS-790052), ABT-267, and GS-5885. Other therapies under study for hepatitis C include the cyclophilin inhibitor alisporivir and pegylated interferon lambda, a new type of interferon that works as well as pegylated interferon alfa but with fewer side effects.

Several experimental DAAs are taken once daily with treatment durations as short as eight weeks. In general, the new drugs are better tolerated than current standard-of-care treatment. For many of these drugs, the IL28B gene pattern does not matter as much as it does for interferon. However, HCV subtype has emerged as an important factor, with subtype 1b being easier to treat than 1a.

Several DAA candidates have demonstrated good outcomes in combination with pegylated interferon alfa and ribavirin in Phase 2 clinical trials and are now moving into Phase 3 testing.

"Hepatitis C treatment has improved markedly with the advent of direct-acting drugs."

Many people with hepatitis C are waiting for all-oral, interferon-free regimens, several of which (with or without ribavirin) are currently in Phase 2 or Phase 3 clinical trials. Like antiretroviral therapy for HIV, combining medications from different classes improves effectiveness and lowers the risk of drug resistance.

Regimens that combine an HCV protease inhibitor and a NS5A inhibitor appear especially potent. For example, a 12-week regimen of sofosbuvir plus daclatasvir cured 90% to 100% of treatment-naïve people with HCV genotypes 1, 2, or 3. A 12-week triple regimen of sofosbuvir, GS-5885, and ribavirin has so far produced 100% sustained response at four weeks post-treatment in an one study, while another is looking at sofosbuvir/GS-5885 in a co-formulated pill without ribavirin.

Daclatasvir plus asunaprevir for 12 weeks cured about 80% of people with HCV subtype 1b, rising to 100% when ribavirin was added. The first two drugs plus BMS-791325 cured more than 90% of people with both HCV subtypes. Almost all genotype 1b patients -- even null responders -- were cured with a four-drug, oral regimen of ABT-450, ABT-333, ABT-267, and ribavirin taken for only eight weeks, as well as various three-drug combinations taken for 12 weeks. Faldaprevir, BI-207127, and ribavirin for 28 weeks cured 80% of genotype 1b patients, with a cure rate almost as high for those with cirrhosis.

In summary, hepatitis C treatment has improved markedly with the advent of direct-acting drugs. People who do not respond to or cannot tolerate interferon have the most to gain from the new DAAs. Interferon-free combinations are now entering late stages of testing and some experts predict that the first such regimens may be available in two to three years. Some people will likely continue to need pegylated interferon for the foreseeable future, but adding DAAs will shorten treatment and increase the likelihood of a cure.

Liz Highleyman (liz@hivandhepatitis.com) is a San Francisco-based medical journalist specializing in HIV and viral hepatitis, and is editor-in-chief of HIVandHepatitis.com.