POSITIVELY AWARE November/December 2012
Stribild gets FDA approval as new single-tablet regimen
Stribild (formerly known as the Quad), a complete once-daily single-tablet regimen (STR), was approved by the FDA in August. Stribild joins Atripla and Complera as a complete HIV regimen in one pill, each taken once daily.
The FDA based approval on studies in which Stribild showed non-inferiority at 48 weeks to two standard of care regimens on the market, Atripla or Norvir-boosted Reyataz with Truvada.
Stribild was approved for people taking HIV medications for the first time, although some doctors may inevitably prescribe it for patients switching to a new antiviral therapy.
The Department of Health and Human Services (DHHS) acted right away to update its HIV treatment guidelines, adding Stribild as an alternative regimen, with a B1 rating indicating a “moderate” recommendation based on randomized controlled studies (the gold standard of research). In contrast, Isentress/Truvada (Stribild’s most direct competition based on main drug class) has an A1 recommendation—“strong” based on randomized controlled studies.
Stribild consists of four drugs: the experimental integrase inhibitor elvitegravir, emtricitabine, tenofovir, and cobicistat. Cobicistat has no anti-HIV property; it is used to boost blood levels of elvitegravir. The only other integrase inhibitor on the market is Isentress. Emtricitabine and tenofovir are available as the antiviral Truvada, which is now also approved as PrEP, or pre-exposure prophylaxis for HIV prevention.
DHHS noted, “Limitations include a significant potential for drug-drug interactions, the availability of only 48 weeks of safety data, usage limited to individuals with pre-treatment creatine clearance levels above 70 mL [a kidney laboratory measure], a possible increased risk of proximal renal tubulopathy [a kidney complication], limited data in patients with advanced HIV disease and in women, and the need for the drug to be taken with food.”
Gilead Sciences, maker of Stribild and Complera, as well as two of the three drugs in Atripla, established an access program for Stribild for people without insurance and a co-pay assistance for patients with private insurance. Gilead’s U.S. Advancing Access program can be reached at 1-800-226-2056.
In addition, the company reached a pricing agreement with the ADAP Crisis Task Force, creating a lower price for state AIDS Drug Assistance Programs (ADAPs). Nevertheless, the task force acknowledged the disappointment and controversy within the larger HIV community about Stibild’s $28,500 annual price tag. According to a task force press release, setting the price of Stribild higher than Atripla, despite being less than several protease inhibitor-based regimens, may affect costs outside of ADAP.
Gonorrhea treatment guidelines updated
A team of researchers from Johns Hopkins University School of Medicine reported that the way the body metabolizes the HIV medication efavirenz may contribute to cognitive (brain function-related) impairment. Efavirenz is sold under the brand name Sustiva, and is also found in Atripla. The researchers looked at drug levels of efavirenz and its metabolites (substances created when the drug is broken down by the liver). The metabolite 8-hydroxyefavirenz was “10 times more toxic to brain cells than the drug itself,” the team reported, “and, even in low concentrations, causes damage to the dendritic spines of neurons.” Neurons are cells of the nervous system. The dendritic spine, continued the press release, “is the information processing point of a neuron, where synapses—the structures that allow communication among brain cells—are located.” Efavirenz, one of the most effective and widely prescribed of the HIV drugs (primarily as Atripla) is known for its cognitive side effects, such as vivid and sometimes colorful dreams. Its ability to penetrate cerebral-spinal fluid and enter the brain is considered a good thing, but of course, the potential for harm is important to understand. The findings were reported in September and published online in the Journal of Pharmacology and Experimental Therapeutics.
Sustiva, Atripla tied to neurologic toxicity
The Centers for Disease Control and Prevention (CDC) published updated guidelines for the treatment of gonorrhea in its August 10 Morbidity and Mortality Weekly Report. The presence of the sexually transmitted infection can increase the risk of acquiring HIV.
The CDC previously recommended only oral antibiotic treatment as the first line of defense for gonorrhea. The agency now instead recommends that infections be treated with the injectable antibiotic ceftriaxone in combination with one of two oral antibiotics, either doxycycline or azithromycin. In addition, the cephalosporin oral antibiotics, such as cefixime (brand name Suprax), are no longer recommended for treatment.
The new and more onerous treatment recommendations arise from the fact that people are increasingly being infected with gonorrhea that cannot be treated with oral antibiotics. Cephalosporins are the second oral antibiotic in less than a decade to be taken off the CDC’s list of medications used to treat gonorrhea. Both times, drug-resistant gonorrhea was seen primarily in men who have sex with men (MSM).
Although efficacy of cefixime is still being seen, there is laboratory evidence that it is becoming less effective. The CDC reported concern that “continued use of cefixime may prompt resistance to all cephalosporins. Limiting its use now may help preserve ceftriaxone as a treatment option for a little longer.”
Read the report: www.cdc.gov/mmwr.
Truvada’s efficacy as PrEP reaffirmed
New research from an international team of HIV/AIDS experts led by Gladstone Institute investigator Robert Grant, MD, MPH in San Francisco and Peter Anderson, PharmD, at the University of Colorado, provides the first estimate of the drug concentration levels needed for Truvada to prevent the spread of HIV/AIDS.
The new study, available online in the September 12 Science Translational Medicine, builds on the 2010 iPrEx clinical study in which Dr. Grant and his colleagues found that Truvada could prevent new infections in people likely to come in contact with the virus. But questions about the drug’s real-world effectiveness at preventing HIV transmission remain—particularly concerning the issue of adherence to a regimen of taking a pill every day.
“After the initial iPrEx study, there was concern that the protective effect of Truvada was fragile, and that individuals taking the drug would need to adhere perfectly to a daily regimen for it to work,” said Dr. Grant in a press release. He is also a professor at the University of California, San Francisco (UCSF), with which Gladstone is affiliated. “This new study suggests that Truvada can help block the virus even if the person on a daily regimen doesn’t always adhere perfectly.”
Perfect adherence to drug regimens is notoriously difficult for people to accomplish, so the research team looked for a way to calculate Truvada’s effectiveness while taking into account differing adherence levels.
The team developed a clinical trial in which they gave different amounts of the drug (two, four, or seven doses per week) to a cohort of 24 people without HIV. This resulted in different drug concentrations in blood drawn from each participant, thereby mimicking different levels of adherence. They then used a model to compare the drug concentrations in the blood of these participants to the concentrations of original iPrEx study participants in order to determine how well iPrEx participants adhered to the daily regimen, and how well they were protected against HIV at different levels of adherence.
“Surprisingly, we found that the iPrEx participants didn’t have to adhere perfectly to the drug regimen to reap Truvada’s benefits,” said Dr. Grant. “Even in those patients who didn’t adhere perfectly, their risk of contracting HIV still dropped by more than 90%—offering a high level of protection against the virus.”
This study is the first to establish an objective, quantitative method that estimates drug concentration levels and then correlates those levels with the drug’s effectiveness at preventing transmission. These results could open the door to the exploration of ways to make dosing less costly, more convenient, and more adaptable to people’s habits.
“Our immediate next step, however, is to take the methods we’ve developed and create simple yet powerful tools that can measure drug adherence to help doctors monitor how well Truvada is working in their patients,” said Dr. Anderson. “Yet until these and other efficacy studies of alternative dosing strategies have been completed, the only regimen that should be used in clinical practice is the FDA approved one: one Truvada each day.”
“Patients should still take one pill a day to achieve the best results, and we encourage people to explore multiple methods to prevent HIV—such as regular condom use, early treatment of HIV infection in partners, good communication, and male circumcision,” Dr. Grant said. “We hope that our findings lead to more effective use of prevention tools that finally squash the HIV/AIDS epidemic.”
Interim guidelines issued for PrEP for heterosexuals
Just as they did for men who have sex with men, the CDC has now issued interim guidelines for the use of Truvada for pre-exposure prophylaxis (PrEP) for heterosexuals who wish to prevent HIV infection.
Read the press release: www.cdc.gov/nchhstp/newsroom/2012/PrEP-HeterosexualGuidance-PressRelease.html.
Simplified application form now available for all PAPs
The Common Patient Assistance Program Application (CPAPA), announced by Health and Human Services (HHS) Secretary Kathleen Sebelius at the International AIDS Conference in July, went into effect on September 12 and is now available at hab.hrsa.gov/patientassistance/index.html.
This single common application allows uninsured individuals living with HIV and/or their providers/caregivers to use one application to apply for multiple patient assistance programs (PAPs).
HHS, working collaboratively with the National Alliance of State and Territorial AIDS Directors (NASTAD) through a cooperative agreement with the Health Resources & Services Administration’s (HRSA) HIV/AIDS Bureau, seven pharmaceutical companies, and key community stakeholders, took the lead in developing the application form. The form collects the necessary information required by all seven companies’ PAPs. Company PAPs that will now accept the common application form include: Abbott Laboratories, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Inc., Johnson & Johnson (Janssen Therapeutics), Merck, and ViiV Healthcare.
Cure-focused research grants announced by amfAR
The Foundation for AIDS Research (amfAR) announced in September the awarding of three new grants to research teams as part of the Foundation’s two-year-old amfAR Research Consortium on HIV Eradication (ARCHE).
One of the grants will go to Dr. Timothy Henrich of Brigham and Women’s Hospital in Boston to determine which elements of the “Berlin patient’s” treatment were critical to his cure—findings that may guide attempts at designing a cure that could be applied more widely.
Another ARCHE grant will go to Dr. Deborah Persaud of Johns Hopkins University and Dr. Katherine Luzuriaga of the University of Massachusetts, who hope to determine if it is possible to cure HIV with antiretroviral therapy (ART) alone in children in whom ART had been started soon after birth and continued for an average of 15 years.
The third grant will fund a study that will continue to investigate using disulfiram—a drug used to treat alcoholism—to flush the virus out of latently HIV-infected cells. The study, conducted by Dr. Steven Deeks of the University of California, San Francisco, and Dr. Julian Elliott of Monash University in Australia, will build on a smaller study that suggested that the drug may reverse HIV latency in some people.
Drug news from ICAAC
Also see pages 19–21. Some abstracts available at www.natap.org.
A new INSTI
The investigational drug S/GSK1265744 is a long-acting injectable with hopes for once-a-month dosing. Shionogi and GlaxoSmithKline reported finding limited cross-resistance between S/GSK1265744 and two similar medications already on the market (the oral drugs Isentress and elvitegravir, which is available in the recently approved Stribild). All three medications are integrase strand transfer inhibitors, or INSTIs. The researchers reported a “potential for a high barrier to [drug] resistance” and that their data suggests “a favorable profile for both HIV treatment and PrEP” (pre-exposure prophylaxis, or prevention).
Switch from Truvada to Epzicom
HIV-positive people taking Norvir-boosted Reyataz with Truvada were able to maintain their viral load suppression out to 24 weeks when switching out the Truvada and replacing it with Epzicom and dropping Norvir. The switch also allowed them to significantly improve their biomarkers for potential kidney and bone toxicity. Truvada is associated with the potential for such toxicity. Also, their HDL (good cholesterol) increased. While the results were positive, 24 weeks is a short period of time. Nearly 300 individuals participated in the study, with nearly 200 switching meds; the study will continue out to 48 weeks.
Son of tenofovir
GS-7340 is a next-generation prodrug of tenofovir (brand name Viread, found in Truvada, Atripla, Complera, and Stribild). These popular formulations containing tenofovir make it one of the most widely prescribed HIV medications in the country. It is metabolized inside human cells to take its active form. The GS-7340 prodrug avoids this step in the absorption of tenofovir. Researchers reported test tube results showing superior antiviral potency with GS-7340 as well as synergy with other HIV medications, with higher intracellular levels for the prodrug.
A new NNRTI?
MK-1439 represents a sort of blast from the past: it’s a non-nucleoside reverse transcriptase inhibitor (NNRTI), or from the second class of HIV medications that were developed. The class includes Intelence, Edurant (found in Complera), Sustiva (found in Atripla), and Viramune-XR. Merck & Co. researchers reported drug resistance data comparing MK-1439 to the NNRTIs on the market, finding the potential for it to work when current drugs don’t.