Abstract
Initial Results Reported on Raltegravir Once-Daily Dosing
Initial results are in for Merck's phase 3 study investigating the efficacy and safety of raltegravir (Isentress®, Merck, Whitehouse Station, NJ) once-daily tablets in treatment-naïve adult patients. Although the treatment regimen that included raltegravir once daily enabled more than 80% of patients to achieve viral suppression, it did not demonstrate noninferiority to the treatment regimen that included raltegravir twice daily. Based on the initial results and following the recommendation of an independent Data Monitoring Committee, Merck will end the study. Merck recommends that patients enrolled in the once-daily dosing arm of the study be switched to raltegravir twice daily, the FDA-approved dose.
This phase 3 study evaluated the safety and efficacy of once-daily raltegravir (800 mg once daily) versus the approved twice-daily dose (400 mg twice daily), each given in combination with a once-daily fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate. In this study, 775 patients were randomized and 770 patients received the study drug.
After 48 weeks in the study, 83.2% (n = 318/382) of patients receiving the regimen including raltegravir once daily achieved undetectable viral levels (HIV-RNA < 50 copies per milliliter), compared to 88.9% (n = 343/386) of patients receiving the regimen including raltegravir twice daily. The treatment difference between the 800 mg once daily group and 400 mg twice daily group was −5.7%, with an associated 95% confidence interval (CI) of (−10.7%, −0.83%). The difference did not meet the predefined statistical criteria for noninferiority.
The overall treatment difference observed between the once-daily and twice-daily groups was primarily due to results in patients with high viral load. Among patients with more than 100,000 copies per milliliter of HIV-RNA, 74.3% (n = 113/152) of those in the once-daily group achieved viral suppression compared to 84.2% (n = 128/152) of those in the twice-daily group. The safety and tolerability profiles of the two regimens were similar in the study.
Joint Venture Will Investigate Festinavir
Bristol-Myers Squibb has teamed up with Japanese biotech company Oncolys BioPharma Inc. to investigate festinavir, a once-a-day, orally available nucleoside reverse transcriptase inhibitor (NRTI) in phase 2 development for HIV. Bristol-Myers Squibb will acquire exclusive worldwide rights to manufacture, develop, and commercialize festinavir.
Festinavir is a next-generation, orally available NRTI in phase 2 development for HIV. Early preclinical studies suggest that festinavir could have an improved safety profile over previous generations of NRTIs. Festinavir was licensed to Oncolys in 2006 from Yale University.
Findings Show Why Immune Function Improves Despite Lack of Response to Antiretroviral Therapy
Mayo Clinic researchers have shown why, in a minority of HIV patients, immune function improves despite a lack of response to standard antiretroviral treatment. In these cases, HIV has lost its ability to kill immune cells. The findings show for the first time that not all HIV is equally bad for the immune system. Patients who harbor these viruses do not develop certain complications of the disease because of mutations that render some HIV drugs ineffective but also impair the ability of the virus to cause disease.
HIV has evolved many ways to cause the death of CD4 T cells, most of which involve HIV accelerating the normal cell death. One kind of cell death that is unique to HIV involves the HIV enzyme protease, whose normal job is to cut up viral proteins so they can be used. This same process also cuts a normal cell protein which creates a novel protein called Casp8p41. This protein is only created during HIV infection. Casp8p41, in turn, is responsible for the death of many of the infected cells. Researchers found that cells infected with HIV that also contain the mutations, produced less Casp8p41, and therefore fewer of the infected cells died. According to the researchers, the findings may have implications for patients who are failing their current antiretroviral therapy regimen. If no other effective drugs are available, it may be possible to stay on the medication and take advange of HIV's lowered ability to kill CD4 T cells. One approach may be to monitor Casp8p41 levels instead of viral load. Such measurements of the protein could then guide further therapy decisions. The researchers have already developed a way to measure Casp8p41 in the blood of patients.
The findings were published in PLoS Pathogens 2010;6(11).
Protease Inhibitors Directly Interfere with Glucose Regulation
Researchers at Washington University School of Medicine in St. Louis have discovered why taking protease inhibitors can lead to insulin resistance and the subsequent complications of cardiovascular disease and diabetes. According to their findings, protease inhibitors directly interfere with the way blood sugar levels are controlled in the body. This leads to insulin resistance. First-generation protease inhibitors, including the drug ritonavir, block GLUT4, a protein that transports glucose from the blood into the cells where it is needed, thereby raising glucose levels in the blood.
The researchers made the discovery in mice that lacked the GLUT4 protein. When they gave these mice ritonavir, the drug had no effect on their glucose tolerance. However, when they gave the drug to normal mice, their blood glucose shot up very quickly, showing that the drugs impair glucose tolerance and promote insulin resistance.
These finding will help researchers better understand the role of glucose transporters in health and disease, including the epidemic of type 2 diabetes in HIV negative patients. The results will also help scientists better understand how to develop new diabetes drugs and the role of glucose transport in diseases such as heart failure. Additional research is now focusing on how HIV drugs inhibit GLUT4 at the molecular level. They are also working with a drug developer to create a new HIV drug that the virus does not develop resistance to and does not block GLUT4.
The study was published in the November 19 issue of Journal of Biological Chemistry 2010;285:36395–3600.
Delayed HIV Treatment Has Costly Economic Consequences
HIV-infected patients whose treatment is delayed not only become sicker than those treated earlier, but also require tens of thousands of dollars more in care over the first several years of their treatment. The finding comes from a study conducted by researchers at the Johns Hopkins University School of Medicine in Baltimore. For their study, researchers reviewed medical records of 8348 patients at nine HIV clinics across the United States between 2000 and 2007. They found that more than 43% of patients were considered late entrants into the health care system. They presented at a clinic with extremely weakened immune systems, characterized by having CD4 counts below 200.
The average difference in cumulative treatment expenditures between early and late presenters ranged from $27,275 to $61,615 higher over the course of the first 7–8 years of treatment. Costs are higher for the late presenters because they tend to be sicker than early presenters, particularly the first year of treatment. According to the researchers, the cost gap does not shrink over time. Late presenters are also hospitalized more often, need to be put on costly antiretroviral therapy and antibiotics, and often must be treated for other diseases that have been exacerbated by a weakened immune system.
The study was published in Medical Care 2010;48:1071–1079.
Recent FDA Approvals and Changes
New Intelence® dosage approved
A new 200 mg Intelence® (etravirine) tablet has been approved by the FDA. Intelence was originally approved in 2008 in only a 100 mg tablet formulation. The dosage Dosage and Administration section was changed to state: 200 mg (one 200 mg or two 100 mg tablets) taken twice daily following a meal. Intelence® is a nonnucleoside reverse transcriptase inhibitor (NNRTI) made by Tibotec Therapeutics (Yardley, PA).
Labeling changed for Zerit
The FDA has approved new labeling for Zerit® (Bristol-Myers, Princeton, NJ) capsules and oral solution. Revisions were made to the Dosage and Administration, Warnings and Precautions, Adverse Reaction sections in both package inserts. Other important changes include conversion of the package insert to physicians labeling rule (PLR) format), and conversion of the patient package insert to Medication Guide. Minor changes to the package inserts were made for consistency.
Under Dosage and Administration, Dosage Adjustment (Section 2.3) was modified to remove statements for dose reductions for peripheral neuropathy because dose reductions for peripheral neuropathy have not been established, and importantly dose reduction is less relevant in the current setting of HIV infection and multiple available HIV treatment options.
Warnings and Precautions (Section 5.5) for Fat Redistribution was modified in both package inserts. The changes reflect the strong causal relationship of lipodystrophy with stavudine demonstrated in clinical trials. Data from longitudinal clinical trials in both antiretroviral naïve and treatment-experienced patients demonstrate a higher frequency of clinical lipoatrophy in subjects receiving stavudine-containing regimens compared to regimens containing other nucleotides, specifically tenofovir or abacavir (Haubrich 2009; Podzamczer 2007). Additionally, stavudine use was associated with decreases in limb fat compared to increases in limb fat observed with other nucleotides. Other published reports indicate lipoatrophy did not completely resolve following stavudine discontinuation, although modest increase in limb fat was observed after discontinuation (Carr 2002; Martin 2004).
Section 5.5 Fat Redistribution: Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. In randomized controlled trials of treatment-naive patients, clinical lipoatrophy or lipodystrophy developed in a higher proportion of patients treated with stavudine compared to other nucleosides (tenofovir or abacavir). Dual energy x-ray absorptiometry (DEXA) scans demonstrated overall limb fat loss in stavudine-treated patients compared to limb fat gain or no gain in patients treated with other nucleosides (abacavir, tenofovir, or zidovudine). The incidence and severity of lipoatrophy or lipodystrophy are cumulative over time with stavudine-containing regimens. In clinical trials, switching from stavudine to other nucleosides (tenofovir or abacavir) resulted in increases in limb fat with modest to no improvements in clinical lipoatrophy. Patients receiving Zerit® should be monitored for symptoms or signs of lipoatrophy or lipodystrophy and questioned about body changes related to lipoatrophy or lipodystrophy. Given the potential risks of using Zerit® including lipoatrophy and lipodystrophy, a benefit-risk assessment for each patient should be made and an alternative antiretroviral should be considered.
Adverse reactions (Section 6.3) were modified to include neutropenia, lipoatrophy, and lipodystrophy under Postmarketing Events in the package inserts. New Lipodystrophy Drug Approved.
Egrifta™ (tesamorelin) has been approved to treat HIV patients with lipodystrophy. Egrifta™ was approved to induce and maintain a reduction of excess visceral abdominal fat in HIV-infected patients with lipodystrophy. As the first FDA-approved treatment for lipodystrophy, Egrifta™ is a synthetic growth hormone releasing factor (GRF) drug that is administered in a once-daily injection.
Egrifta™ was evaluated in two clinical trials involving 816 HIV-infected adult men and women with lipodystrophy and excess abdominal fat. Of these, 543 patients received Egrifta™ during a 26-week, placebo-controlled period. In both studies, patients treated with Egrifta™ experienced greater reductions in abdominal fat (15–17%) as measured by CT scan, compared with patients receiving another, non-active injectable solution (placebo). Some patients reported improvements in their self image. Whether Egrifta™ decreases the risk of cardiovascular disease or improves compliance with antiretroviral drugs has not been studied.
The most commonly reported side effects in the studies included joint pain (arthralgia), skin redness and rash at the injection site (erythema and pruritis), stomach pain, swelling, and muscle pain (myalgia). Worsening blood sugar control occurred more often in patients treated with Egrifta™ than with placebo. Egrifta™ was developed by Montreal-based Theratechnologies Inc. and marketed in the U.S. by Rockland, Massachusetts-based EMD Serono.
Tentative approvals
The FDA has granted tentative approval for a formulation of abacavir sulfate tablets, 60 mg, made by Matrix Laboratories Limited of Hyberdad, India. The tablet formulation is intended for pediatric use, allowing dosing for patients weighing as little as 5 kg, and is unique in that it can be dispersed in liquid for patients unable to swallow tablets.
Another tentative approval was given for another generic formulation of abacavir sulfate, this time 300 mg tablets. This generic formulation is manufactured by Hetero Drugs Limited, of Hyberdad, India.
FDA's tentative approval means that although a product meets all of the safety, efficacy, and manufacturing quality standards required for marketing in the United States, existing patents and/or proprietary issues currently prevent marketing of the product in the United States. Tentative approval, however, does qualify the product for consideration for purchase under the President's Emergency Plan for AIDS.