Timothy O'Shea, PharmD, is a Clinical Pharmacist at Horizon Blue Cross Blue Shield of New Jersey. He graduated from MCPHS University - Boston in 2015 and subsequently completed a PGY-1 Managed Care Pharmacy Residency at Horizon. His professional interests include pharmacy legislation and managed care pharmacy. He can be followed on Twitter at @toshea125.
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. Here are 5 of those studies that every pharmacist should know:
1. AZT Trial (1987)1
This multicenter, double-blind, placebo-controlled trial was the first large-scale study to assess the impact of antiviral therapy (ART) in patients with HIV/AIDS.
Two-hundred and eighty-two patients with HIV were enrolled in the study; all but 13 were men. One hundred and sixty of 282 patients had AIDS and the remaining 122 had AIDS-related complex, defined as unexplained weight loss or oral candidiasis plus at least one other finding seen with HIV/AIDS. Patients were randomly assigned to either oral zidovudine every 4 hours or placebo.
The study was intended to last 24 weeks, however the trial was stopped early due to the efficacy seen with therapy. After an average follow-up of 4 months, the zidovudine group had a statistically significant higher rate of survival (99.3% vs. 86.1%) and reduction in opportunistic infections. Shortly following the trial’s publication, zidovudine gained FDA approved for the treatment of HIV.
Zidovudine reduces mortality compared to placebo in patients with HIV/AIDS.
2. SMART Study (2006)2
By the early 2000s, potent ART was well proven to dramatically reduce disease progression and death among patients with HIV; however, therapy is also associated with risks. These include both short-term and long-term adverse events, drug resistance (especially if adherence is poor), and high cost of therapy. As a result, this study sought to understand whether treatment-sparing strategies provide the benefits of ART while minimizing the risk of adverse events and other risks associated with long-term use.
Between January 2002 and January 2006, 5472 participants were randomly assigned to 2 treatment groups. The first, a viral suppression group, was a control strategy to treat HIV in an uninterrupted manner with the goal of maximal and continuous suppression of HIV replication.
The second, an experimental drug conservation strategy, deferred ART until CD4+ decreased to less than 250 cells/mm3
, at which time antiretroviral therapy was to be initiated and continued until the CD4+ count increased to more than 350 cells/mm3
, at which time ART was stopped. The primary end point was new or recurrent opportunistic disease or death from any cause.
After a mean follow-up of 16 months, the episodic ART group had a significantly increased risk of opportunistic disease or death from any cause, as compared with continuous ART. This was largely a consequence of lowered CD4+ cell count and increased viral load during follow-up in patients on ART interruption. Additionally, episodic therapy was not shown to reduce the risk of adverse events that have been associated with ART.
Continuous use of ART is superior to its episodic use as guided by the CD4+ count.
3. NA-ACCORD (2009)3
Although ART had been shown to reduce disease progression and death among patients with HIV, the optimal time to begin therapy was uncertain. At the time, guidelines recommended treatment for asymptomatic patients when CD4+ count <350, which was based on data from accumulating observational studies.
To further investigate this question, researchers conducted a retrospective, multicenter cohort study that evaluated 17,517 ART-naive, HIV-positive patients who received care at 60 centers between 1996-2005. Two parallel analyses were conducted with patients stratified according to their CD4+ count (351 to 500 cells/mm3 or >500 cells/mm3) at the initiation of antiretroviral therapy. The researchers compared all-cause mortality for those started ART when the CD4+ count was above the 2 thresholds of interest (early-therapy group) or when their CD4+ count dropped below that range (delayed-therapy group).
In the first analysis, which involved 8362 patients with a baseline CD4+ count of 351 to 500 cells/mm3, there was a 69% increase in the risk of death among patients in the deferred-therapy, as compared with that in the early-therapy group. In the second analysis, involving 9155 patients with a baseline CD4+ count of more than 500 cells/mm3, there was a 94% increase in the risk of death among patients in the deferred-therapy group.
The study led HIV guidelines to be updated in 2009 to recommend ART initiation in patients with a CD4+ count between 350 and 500 cells/mm3 and as optional in patients with CD4 counts >500 cells/mm3.
In asymptomatic patients with HIV, early initiation of antiretroviral therapy significantly improves survival.
4. INSIGHT START (2015)4
By 2015, newly-diagnosed patients with HIV and a CD4+ count < 500 cells/mm3 were routinely being treated, however there was still some disagreement, and a lack of well-conducted randomized studies, on whether those over 500 cells/mm3
should also be treated. INSIGHT START marked the first large-scale randomized clinical trial to establish whether it is safe and beneficial to initiate antiretroviral therapy in asymptomatic patients who have a CD4+ count that is much higher than 350 cells/mm3
The study randomly assigned 4685 HIV-positive adults who had a CD4+ count of more than 500 cells/mm3 to start ART immediately (immediate-initiation group) or to defer it until the CD4+ count decreased to 350 cells/mm3 or until the development of AIDS (deferred-initiation group). The primary composite end point was any serious AIDS-related event, serious non–AIDS-related event, or death from any cause.
After a mean follow-up of 3 years, an interim analysis revealed the composite endpoint was significantly reduced in the immediate-initiation arm compared to the deferred-initiation arm (1.8% vs 4.1%). More than two thirds of the primary end points (68%) occurred in patients with a CD4+ count over 500 cells/mm3. The immediate-initiation arm was also associated with significantly fewer serious AIDS or non-AIDS-related events.
As a result of this study, guidelines were updated to recommend ART for all HIV-infected individuals, regardless of CD4+ cell count. This serves to reduce the morbidity and mortality associated with HIV infection and also to prevent HIV transmission.
In patients with HIV with CD4+ counts >500 cells/mm3
, early ART initiation is superior to delayed treatment in reducing serious AIDS-related and non-AIDS-related complications.
5. IPrEx (2010)5
Prior to 2010, ART had been demonstrated to be effective in those with HIV and was recommended after occupational or non-occupational exposure to HIV-infected fluids. Due to several small-scale studies there was belief that ART may also decrease the transmission of the virus to uninfected partners.
To further investigate this association, IPrEx was conducted to evaluate the safety and efficacy of once-daily oral emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) combination as compared with placebo for the prevention of HIV acquisition among men and transgender women who have sex with men.
Of 4905 subjects who were screened, 2499 were enrolled in the study from July 2007 through December 2009, at 11 sites in six countries. At each scheduled visit, all subjects also received a comprehensive package of preventative services including HIV testing, risk-reduction counseling, condoms, and management of sexually transmitted infections.
After a median follow-up of 1.2 years, FTC-TDF was shown to be associated with a 44% relative risk reduction in the incidence of developing HIV compared with placebo (36 infections in the FTC–TDF group and 64 in the placebo group). Antiviral therapy was more effective in those with higher adherence to the therapy. The study helped lead to Truvada’s approval to help reduce the risk of getting HIV-1 infection, when used in combination with safer sex practices.
Prophylactic treatment with emtricitabine-tenofovir reduces the risk of sexually-acquired HIV-1 infection in high risk males.
- Fischl MA, Richman DD, Grieco MH, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. N Engl J Med. 1987;317(4):185-191.
- The Strategies for Management of Antiretrovirl Therapy (SMART) Study Group. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006 Nov 30;355(22):2283-96.
- Kitahata MM, Gange SJ, Abraham AG, et al. Effect of Early vs. Deferred Antiretroviral therapy for HIV on Survival. N Engl J Med. 2009; 360(18):1815-1826.
- INSIGHT START Writers. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. N Engl J Med. 2015;373(9):795-807.
- Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363(27):2587-2599.