By Karin Katz, MD
Faculty Peer Reviewed
Last week, the U.S. Supreme Court unanimously ruled that human genes cannot be patented. The case involved Myriad Genetics, a company that patented the BRCA1 and BRCA2 genes in the late 1990s. Since then, the company has offered the most comprehensive test to detect gene mutations associated with breast and ovarian cancer risk, known as BRACAnalysis, with a price tag of over $3000. While the court ruled that “a naturally occurring segment” of DNA cannot be patented, complementary DNA can be. Political and scientific discussions on sharing genetic information have resumed as a result of this ruling, as well as new discussions on the implications for biotechnology and drug development. Now, let’s turn our attention to the realm of infectious disease where this week’s first journal, The Lancet, devotes their entire issue to HIV.
A randomized controlled trial by Choopanya et al. assessed whether antiretroviral pre-exposure prophylaxis in injection drug users in Thailand can reduce HIV transmission (1). Several previous trials have demonstrated a reduction in the risk of HIV infection with daily use of tenofovir-emtricitabine in certain high-risk populations (2,3). The recent Bangkok Tenofovir Study included 2400 men and women, ages 20-60 years, who were HIV-negative and reported injecting drugs during the previous year. Participants were randomly assigned to receive either daily tenofovir or placebo and were followed for a mean of 4 years. Most were men and the median age of participants was 31 years. The tenofovir and placebo groups reportedly had similar rates of injecting and sharing needles and similar numbers of sexual partners during follow up. Throughout the study, 50 participants became newly infected with HIV, which included 17 participants in the tenofovir group (an incidence of 0.35 per 100 person-years) compared to 33 in the placebo group (0.68 per 100 person-years). This represented a 48.9% relative risk reduction in HIV incidence in the intention-to-treat analysis (95% CI, 9.6–72.2, p=0.01). In earlier trials, prophylaxis with tenofovir-emtricitabine reduced the risk of HIV transmission by 44 to 75 percent in other high-risk populations, including men who have sex with men and sero-discordant heterosexuals (2,3). Taken together, these studies have provided data that led the CDC to publish interim guidelines (official guidelines due later this year) for prescribing pre-exposure prophylaxis in the groups at highest risk of HIV infection.
Another study published in the Lancet investigated a new therapeutic option for second-line antiretroviral therapy after first-line treatment failure for HIV (4). This non-inferiority trial was conducted at 37 sites worldwide in adults infected with HIV-1 with first-line treatment failure (defined as confirmed virological failure after 24 weeks or more). Virological failure was defined by two consecutive (at least 7 days apart) plasma HIV viral loads of more than 500 copies per mL. All patients received ritonavir-boosted lopinavir. Participants were then randomly assigned to receive a WHO-recommended regimen of 2 or 3 nucleoside or nucleotide reverse transcriptase inhibitors (control group), versus raltegravir, an integrase inhibitor. At 48 weeks, 81% of patients in the control group had a plasma viral load less than 200 copies per mL, compared to 83% of patients in the raltegravir group (difference of 1.8%, 95% CI, -4.7-8.3). The investigators concluded that the raltegravir regimen was non-inferior to the standard of care. The raltegravir regimen may offer some advantages for treating patients in whom first-line therapy has failed, compared to the current WHO-recommended regimen, including ease of administration. However, the high cost of raltegravir could limit the accessibility of this regimen to many parts of the world.
For more striking news in the world of infectious disease, the prevalence of HPV was reported to drop by half among vaccine-eligible girls (5). The vaccine was recommended as part of routine vaccination for females in 2006 and expanded to males in 2011. Among females aged 14-19 years, the vaccine-type HPV prevalence (6, 11, 16 or 18) decreased from 11.5% in 2003-2006 to 5.1% in 2007-2010. Of note, in 2007-2010 only 34% of females aged 14-19 years reported at least 1 HPV vaccine dose during that time period. The data was analyzed from the National Health and Nutrition Examination Surveys and included 8000 females aged 14 to 59 years. HPV prevalence was determined by assays of cervicovaginal samples; however, the data did not include Pap smear results. We do not know if the incidence of abnormal Pap results has changed since introduction of the vaccine. We do know that there has been a decrease in the incidence of genital warts among girls in this age group, which suggests early vaccine impact.
Moving on to rheumatology, a study in the New England Journal of Medicine investigated therapies for active rheumatoid arthritis after methotrexate failure (6). For patients who still have active disease despite therapy with methotrexate, many clinicians will add a TNF inhibitor (7). However, such biologic agents are extremely costly. The authors compared combined methotrexate with sulfasalazine and hydroxychloroquine (non-biologic DMARDS), to methotrexate with etanercept in patients with active disease. The primary outcome was the Disease Activity Score for 28-joint counts at 48 weeks. This scale includes the number of swollen and tender joints, the ESR, and patient-reported disease activity. All participants were treated with the dose of methotrexate they were on prior to starting the trial. In both groups, if patients did not have a response to the assigned therapy, they were switched to the other treatment group at 24 weeks. The results revealed that triple-therapy was noninferior to etanercept-methotrexate therapy, although there was more rapid clinical improvement in the etanercept-methotrexate group. This study suggests a cost-effective and safe approach to treating patients with active RA, although more studies are needed to compare the impact of these treatments on disease activity in the long term.
Also interesting this week:
1. Chlan et al. Effects of patient-directed music intervention on anxiety and sedative exposure in critically ill patients receiving mechanical ventilatory support: a randomized clinical trial. JAMA. 2013;309(22):2335-44. http://jama.jamanetwork.com/article.aspx?articleid=1687827
This study looked at the potential benefit of music therapy in awake ICU patients using patient-direct music, noise-cancelling headphone use, or standard care. Patient-directed music resulted in less anxiety than usual care, and in less sedation use.
2. Pan et al. Changes in red meat consumption and subsequent risk of type 2 diabetes mellitus: three cohorts of US men and women. JAMA Intern Med. 2013:1-8. Advance online publication. doi: 10.1001/jamainternmed.2013.6633. http://archinte.jamanetwork.com/article.aspx?articleid=1697785
As the summer heats up and we start to crave barbeque food, we sigh as we read the latest article with bad news about red meat. This study found that increasing red meat intake over a four-year period was associated with an elevated risk of T2DM. In addition, reducing red meat consumption by more than 0.50 serving per day from baseline was associated with a 14% lower risk of developing T2DM.
3. WHO: Interim guidance on the use of bedaquiline to treat MDR-TB. http://www.who.int/tb/challenges/mdr/bedaquiline/en/index.html
WHO issued “interim policy guidance” on the inclusion of bedaquiline, a new tuberculosis drug, in the combination therapy of multidrug resistant TB. Bedaquiline is the first FDA-approved TB drug in 40 years.
Dr. Karin Katz is an internal medicine resident at NYU Langone Medical Center
Peer reviewed by Matthew Vorsanger, MD, Associate Editor, Clinical Correlations
Image courtesy of Wikimedia Commons
References:
1. Choopanya, K et al. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomized, double-blind, placebo-controlled phase 3 trial. Lancet. 2013;381(983):2083-90. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2961127-7/fulltext
2. Grant RM et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363(27):2587.
3. Baeten JM et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367(5):399.
4. Boyd, MA et al. Ritonavir-boosted lopinavir plus nucleoside or nucleotide reverse transcriptase inhibitors versus ritonavir-boosted lopinavir plus raltegravir for treatment of HIV-1 infection in adults with virological failure of a standard first-line ART regimen (SECOND-LINE): a randomised, open-label, non-inferiority study. Lancet 2013;381(9883):2091-9. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2961164-2/fulltext
5. Markowitz et al. Reduction in HPV prevalence among young women following HPV vaccine introduction in the United States, National Health and Nutrition Examination Surveys, 2003-2010. J Infect Dis. Advance online publication. doi: 10.1093/infdis/jit192. http://jid.oxfordjournals.org/content/early/2013/06/18/infdis.jit192
6. O’Dell JR, et al. Therapies for active rheumatoid arthritis after methotrexate failure. N Engl J Med. Advance online publication. doi: 10.1056/NEJMoa1303006. http://www.nejm.org/doi/full/10.1056/NEJMoa1303006
7. Update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken) 2012;64:625-639.