Abstract
New Guidelines for Opportunistic Infections in Children
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Specifically, these pediatric guidelines include an emphasis on the importance of effective antiretroviral therapy to improve children's immune function. There is information on diagnosing and managing immune reconstitution inflammatory syndrome, and on the management of antiretroviral therapy in children with opportunistic infections, including potential drug–drug interactions. New guidance is issued on the use of antibiotic drugs to prevent Pneumocystis jirovecii pneumonia in infants. Immunization recommendations for HIV-exposed and HIV-infected children, including hepatitis A, human papillomavirus, meningococcal, and rotavirus vaccines are also updated. A new section outlines treatments for malaria, which may become an opportunistic infection in HIV-infected immigrant children or HIV-infected children who travel to countries with malaria. Finally, there are new recommendations on when to discontinue medication for preventing opportunistic infections.
The complete guidelines are available at
Lipodystrophy Improved with NRTI-Sparing Regimen
Patients who switch to an NRTI-sparing regimen may limit their lipodystropy development as the result of less mitochondrial toxicity. The finding comes from the MULTINEKA Study and researchers at the Universitat Autonoma de Barcelona in Spain.
A total of 77 HIV-infected patients enrolled in the study. All had viral suppression upon entry. A group of 34 patients switched to lopinavir–ritonavir plus nevirapine. The other 33 individuals continued on their existing regimen of lopinavir–ritonavir plus two NRTIs. Changes in mitochondrial parameters and fat redistribution were measured in 20 nevirapine patients and 15 NRTI controls.
The nevirapine group had a progressive increase in mitochondrial DNA content and an improvement in cytochrome c oxidase (COX) activity throughout the 48-week follow-up period compared with the NRTI group. No significant between-group differences in fat distribution were seen at week 48. However, a sustained increase in upper and lower limb fat was observed in the nevirapine group. The NRTI group was noted to have a progressive increase in the trunk-to-extremity fat ratio. There were no virologic failures and no significant changes in CD4+ T cell counts in either arm. The nevirapine group experienced an increase in HDL cholesterol.
The study was published in the September 15th issue of Clin Infect Dis 2009;49:892–900.
Skin Reactions Prompt FDA Warning for Intelence
Severe skin reactions have prompted the FDA to issue a “Dear Healthcare Professional” letter regarding the use of Intelence™ (etravirine) tablets. As a result, Tibotec Therapeutics has added an important safety update to the severe skin reactions “Warnings and Precautions” section (5.1) of the antiretroviral's prescribing information.
Specifically, the existing Warning and Precaution regarding severe skin reactions has been strengthened to reflect that there have been post-marketing reports of fatality due to toxic epidermal necrolysis. In addition, hypersensitivity reactions, sometimes accompanied by hepatic failure, have also been reported. Additionally, guidance has been added that Intelence should be immediately discontinued when signs and symptoms of severe skin or hypersensitivity reactions develop. Given the clinical relevance of these adverse reactions, information regarding severe skin and hypersensitivity reactions has been included in the Intelence Prescribing Information.
Severe, potentially life-threatening, and fatal skin reactions have been reported. These include cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. In Phase 3 clinical trials, Grade 3 and 4 rashes were reported in 1.3% of subjects receiving Intelence compared to 0.2% of placebo subjects. A total of 2% of HIV-1-infected subjects receiving Intelence discontinued from Phase 3 trials due to rash. Rash occurred most commonly during the first 6 weeks of therapy.
Discontinue Intelence immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia). Clinical status including liver transaminases should be monitored and appropriate therapy initiated. Delay in stopping Intelence treatment after the onset of severe rash may result in a life-threatening reaction.
Comparison Data Released on Raltegravir and Efavirenz
New data have been released from the Phase III study called STARTMRK, comparing raltegravir (Isentress®) with efavirenz in maintaining viral load suppression to undetectable levels and at improving CD4 cell counts in previously untreated (treatment-naïve) HIV-1-infected patients through 96 weeks. Patients received either raltegravir or efavirenz in combination therapy. Raltegravir was shown to be as effective as efavirenz in suppressing viral load and increasing immune function.
A total of 563 treatment-naïve adult patients received either 400 mg raltegravir given orally twice daily in combination with tenofovir/emtricitabine or 600 mg efavirenz administered orally once daily in combination with the same agents. The primary endpoints were reductions in HIV-1 viral load to <50 copies/mL and an evaluation of safety and tolerability at week 48. Secondary endpoints included ARV activity as measured by the proportion of patients achieving HIV viral load to <50 copies/mL, <400 copies/mL and change from baseline in CD4 count at week 96, as well as tolerability and safety at week 96. Mean viral loads for patients in the raltegravir group was 103,205 copies/mL (n = 281) and 106,215 copies/mL (n = 282) for the efavirenz group. Mean baseline CD4 cell counts were 218.9 cells/mm3 and 217.4 cells/mm3, respectively.
After 96 weeks of treatment, the raltegravir regimen suppressed HIV RNA levels below 50 copies/mL at a rate comparable to the efavirenz regimen (81% versus 79%, respectively). Mean increases in CD4 cell counts were 240 cells/mm3 for the raltegravir group and 225 cells/mm3 for the efavirenz group. There was less of an impact on lipid levels (including total, LDL, and HDL cholesterol) as well as triglycerides for the raltegravir regimen than the efavirenz regimen. The percent of patients experiencing drug-related side effects was 47% for the raltegravir group and 78% for the efavirenz group.
The data were presented at the 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in San Francisco, CA.
Rules Changed for Investigational Drugs
In August, the FDA published two new rules related to investigational drugs. One new rule, “Expanded Access to Investigational Drugs for Treatment Use,” seeks to clarify the methods available to seriously ill patients who lack satisfactory alternatives to have access to unapproved medicines, while balancing the need to safeguard the individual patient and ensure the continued integrity of the scientific process that brings safe and effective drugs to the market.
The changes are meant to consolidate and clarify the requirements and facilitate making investigational drugs and biologics more widely available to seriously ill patients, including those with HIV/AIDS, who have no other treatment options. The proposed changes also seek to clarify the specific circumstances and the types of costs for which a manufacturer can charge for an investigational drug made available for the purpose of treatment, or in clinical trials.
According to the FDA, it hopes the new rules will increase awareness in the patient and healthcare communities of the range of options available for obtaining investigational drugs for seriously ill patients, encourage companies to make such drugs available, and reduce barriers to obtaining them.
The new expanded access rule defines three categories of patient populations to whom investigational drugs could be made available for the purpose of treatment outside of a clinical trial through expanded access, when there is no satisfactory alternative therapy, and defines requirements and safeguards for each. The first category consists of individual patients. The second category contains groups of patients smaller than are typical for a treatment IND or treatment protocol. The FDA may ask a sponsor to consolidate expanded access under this section when the agency has received a significant number of requests for individual patient expanded access to an investigational drug for the same use. Finally, a third group consists of larger populations where widespread treatment use is appropriate (the Treatment IND). The new rule is meant to clearly reflect the full range of treatment use programs available, and ensure broad and equitable access to investigational drugs for treatment use.
The second, “Charging for Investigational Drugs Under an Investigational New Drug Application,” clarifies the specific circumstances and the types of costs for which a manufacturer can charge a patient for an investigational drug, either as part of a clinical trial, or for treatment use outside the scope of a clinical trial through expanded access. FDA's regulations describing when it is appropriate to charge for an investigational drug did not account for the full range of circumstances in which charging should be permissible, and because they had proven difficult to interpret in practice, resulted in confusion over exactly what costs could be recovered by sponsors making drug products available through expanded access programs.
The change simplifies the cost recovery calculation by making clear that charges for an investigational drug used in a clinical trial may include only direct costs associated with the drug's development, and that charges for investigational drugs for treatment use may also include administrative costs of making the drug available for intermediate patient populations and under large scale treatment INDs. Indirect costs, including costs incurred primarily to produce the drug for commercial sale, cannot be recovered.
FDA News and Approvals
On September 3, the FDA granted tentative approval for a generic fixed-dose combination tablet containing efavirenz, lamivudine, and tenofovir disoproxil fumarate (600 mg/300 mg/300 mg). This new fixed-dose combination is manufactured by Matrix Laboratories Limited of Hyberdad, India.
The FDA granted tentative approval on August 6 for a generic formulation of lamivudine tablets (150 mg and 300 mg). It is manufactured by Strides Arcolab Limited of Bangalore, India.
Another tentative approval was issued on August 12 for a generic fixed dose combination product containing efavirenz/emtricitabine/fenofovir disoproxil fumarate (600 mg/200 mg/300 mg) also manufactured by Matrix Laboratories Limited.
On August 3, the FDA granted tentative approval for a generic formulation of efavirenz capsules, 200 mg, manufactured by Cipla, Limited, of Mumbai, India.
All four approvals make the generic antiretrovirals eligible for purchase outside the United States under the President's Emergency Plan for AIDS Relief (PEPFAR).