Studies in Virology Every Pharmacist Should Know
Over the years, a number of landmark clinical studies in virology have been published, shaping how we treat the disease today.
Viruses are small infectious organisms that replicate inside living cells. Although many viruses cause no harm or disease when introduced to a host, others can lead to severe disability or even death.
Viruses are responsible for a number of diseases seen in humans including influenza, HIV, hepatitis, chickenpox, mumps, and herpes. Due to the advent of vaccines, a dozen deadly viral diseases can be cured; in other circumstances, medications can manage symptoms and the course of disease.
Over the years, a number of landmark clinical studies in the field of virology have been published, shaping how we treat many infectious diseases today. In a related article, we looked at 5 of those that helped shape HIV treatment. Here are 5 more studies that every pharmacist should know:
1. ANRS IPERGAY (2015)1
This study sought to build off results from the previous IPrEx trial but instead look at an intermittent, sexual activity-dependent, pre-exposure prophylaxis with TDF-FTC among high-risk men who have sex with men. The hypothesis was that the drawbacks of daily use, including cost and side effects, would negatively impact adherence, and therefore an as-needed intermittent regimen may have a place in therapy.
The study randomly assigned 400 men who engaged in unprotected anal sex with men to either TDF-FTC or to placebo. All study sites were in France or Canada. Study participants were instructed to take 2 tablets 2-24 hours before a sexual encounter, then daily for an additional 2 days. Participants in the study took a median of 15 pills per month.
After a median follow-up of 9.3 months, there was found to be a relative reduction of 86% in the risk of HIV-1 infection with the as-needed TDF-FTC regimen (2 cases in the TDF-FTC group and 14 in the placebo group). Therapy was well-tolerated. No increases in high-risk sexual behavior were observed among the participants during the study period as compared with baseline.
A 3-day PrEP regimen, designed to be taken orally before and after sex, is effective in reducing the transmission of HIV.
2. ION series2-4
ION was a series of 3 separate studies that assessed the impact of ledipasvir/sofosbuvir (Harvoni, Gilead) for the treatment of chronic hepatitis C. Historically, treatment for hepatitis C revolved around interferon-based regimens that had low response rates and poor tolerability due to its adverse event profile.
The ION studies enrolled a combined 1952 adults from 211 sites with chronic hepatitis C. ION-I assessed the response of Harvoni for 12 or 24 weeks in untreated adults with or without cirrhosis. ION-II looked at responses in treatment-experienced adults, with or without cirrhosis, after a 12 or 24 week course of Harvoni. In ION-III, treatment duration was shortened from 12 weeks to 8 weeks in treatment-naïve individuals to determine if the shorter course was non-inferior to 12 weeks. All studies also assessed the response of Harvoni alone, compared to combination use with ribavirin.
All three studies showed a significantly high SVR12 rates in treatment-naïve and treatment-experienced individuals, ranging from 93-99%. An 8-week duration was found to be non-inferior to a 12 week duration, although a post-hoc analysis revealed much lower relapse rates in patients receiving 8 weeks of Harvoni with baseline HCV RNA levels below 6 million IU/mL.
On October 10, 2014, the FDA approved the use of Harvoni as the first single tablet regimen for the treatment of HCV genotype 1 infection. Due to results from additional studies, Harvoni’s indication was later expanded for used in genotypes 4, 5, and 6.
Harvoni is highly effective for the treatment of HCV genotype 1.
Shortly after Harvoni’s approval, another hepatitis C medication called Viekira Pak was approved into the market. A combination of ombitasvir, paritaprevir and ritonavir tablets co-packaged with dasabuvir, Viekira Pak was approved for genotype 1. The approval was based on the pivotal SAPPHIRE-I and II studies.
SAPPHIRE-I enrolled 631 patients with non-cirrhotic hepatitis C genotype 1 who had not previously been treated to receive a 12 week regimen of either Viekira Pak plus ribavirin or placebo. SAPPHIRE-II enrolled 394 patients with non-cirrhotic hepatitis C genotype 1 who had previously been treated with peginterferon-ribavarin and had relapsed, partially responded, or not responded. They were randomly assigned to receive either Viekira Pak plus ribavirin or placebo for a 12-week double-blind period, which was followed by an open-label treatment period of up to 24 week.
In SAPPHIRE-1, SVR12 rate was 96.2%, with equally high SVR12 responses for genotype 1a and 1b. In SAPPHIRE-2, SVR12 rate was also high at 96.3%, with no significant difference between genotype 1a and 1b. High SVR12 rates were seen for all groups that had previously received peginterferon/ribavirin: 95.3% in previous relapsers, 100% in previous partial responders, and 95.2% in previous null responders. Adverse effects were mild in most patients.
Viekira Pak is highly effective for the treatment of HCV genotype 1.
4. C-TEAM (2016)7
Chronic hepatitis B (CHB) affects nearly 2 million people in the United States. CHB patients are at an increased risk of cirrhosis, hepatocellular carcinoma (HCC), and liver-related death. Oral antiviral therapy may reduce the disease progression of CHB patients. Although entecavir is one of 2 antivirals that are recommended as first-line therapy, there is little high-quality evidence on long-term effects of reduced complications and mortality.
To further investigate the efficacy of long-term entecavir therapy in reduction of the risk of HCC, cirrhotic events, and mortality, investigators conducted a multicenter, retrospective-prospective cohort study in Taiwan. Just over 1300 treatment-naïve patients with CHB-related cirrhosis and receiving long-term entecavir therapy were compared to a historical untreated cohort. All patients had been HBsAG-positive > 6 months and had a baseline HBV-DNA level ≥2000 IU/mL. Patients were followed up every 3 months for the entecavir cohort and every 3-6 months for the untreated cohort.
After a median treatment and follow-up duration of 4 and 6 years respectively, entecavir therapy was associated with a 60% HCC risk reduction. Further analysis showed that entecavir therapy significantly reduced risks of variceal bleeding, spontaneous bacterial peritonitis, and liver-related and all-cause mortality. No significant adverse reactions to entecavir were reported.
Four-year entecavir therapy significantly reduces the risk of HCC, cirrhotic events and mortality in patients with CHB-related cirrhosis.
5. M-Flu (2010)8
In a 2007 report, the World Health Organization stated that an influenza pandemic is the “most feared security threat” facing the world. Due to limited effectiveness of medication treatment, the CDC began exploring potential non-pharmaceutical interventions that can be used to mitigate an influenza pandemic. The M-Flu study was conducted to assess the impact of face masks and hand hygiene on the incidence of influenza-like illness (ILI) symptoms.
Researchers conducted a randomized intervention trial involving 1437 young adults living in university residence halls during the 2006—2007 influenza season. Residence halls were randomly assigned to 1 of 3 groups for 6 weeks: face mask use, face masks with alcohol-based hand hygiene, or control. Subjects were asked to wear face masks as much as possible in their residence hall during the intervention period and encouraged to use outside the halls as well.
Study results showed significant reductions in ILI during weeks 4—6 in the mask and hand hygiene group, compared with the control group, ranging from 35% to 51%. Face mask use alone showed a similar reduction in ILI compared with the control group, but adjusted estimates were not statistically significant.
Face masks and hand hygiene may reduce respiratory illnesses in shared living settings and mitigate the impact of influenza.
- Molina JM, Capitant C, Spire B. et al. On-demand preexposure prophylaxis in men at high risk for HIV-1 infection. New Engl J Med. 2015;373(23):2237-2246.
- Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. New Engl J Med. 2014;370(20):1889—1898.
- Afdhal N, Reddy R, Nelson Dr, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. New Engl J Med. 2014;370(16):1483—1493.
- Kowdley KV, Gordon SC, Reddy R, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. New Engl J Med. 2014;370(20):1879—1888.
- Feld J, Kowdley KV, Coakley E, et al. Treatment of HCV with ABT-450/r—Ombitasvir and Dasabuvir with Ribavirin. New Engl J Med. 2014;370:1594-1603.
- Zeuzem S, Jacobson IM, Baykal T, et al. Retreatment of HCV with ABT-450/r—Ombitasvir and Dasabuvir with Ribavirin. New Engl J Med. 2014; 370:1604-1614.
- Su TH, Hu TH, Chen CY, et al. Four-year entecavir therapy reduces hepatocellular carcinoma, cirrhotic events and mortality in chronic hepatitis B patients. Liver Int. 2016;36(12):1755-1765.
- Aiello AE, Murray GF, Perez V, et al. Mask use, hand hygiene, and seasonal influenza-like illness among young adults: a randomized intervention trial. J Infect Dis. 2010;201(4):491-8.