Abstract
96-Week MERIT ES Analysis Shows Efficacy of Celsentri/Selzentry
A
MERIT is an ongoing randomized, blinded, non-inferiority trial in treatment-naïve patients with CCR5-tropic HIV-1. The Phase 3 trial compares the safety and efficacy of Celsentri/Selzentry 300 mg twice daily versus efavirenz 600 mg once daily, administered with the fixed-dose combination Combivir.
MERIT ES is an analysis of the data from the MERIT (
At 96 weeks, a similar number of patients taking Celsentri/Selzentry achieved undetectable viral load compared to those taking efavirenz (<50 copies/mL = 58.5% and 62.4%, respectively). Comparable results were seen based on a time to loss of virologic response (TLOVR) analysis (<50 copies/mL =60.5% on Celsentri/Selzentry versus 60.7% on efavirenz). At the end of almost 2 years, a similar number of patients taking Celsentri/Selzentry remained on therapy compared to those taking efavirenz (66.9% and 66.0%, respectively).
For patients from the MERIT ES population with higher viral loads at screening (>100,000 copies/mL), a similar number of patients taking Celsentri/Selzentry maintained undetectable viral load compared to those taking efavirenz (56.0% and 56.7%, respectively, based on TLOVR analysis). At week 96, the increase in CD4 T-cell count was significantly greater with Celsentri/Selzentry than with efavirenz (median change from baseline was +212 cells/mm3 and +171 cells/mm3, respectively, a difference of 41 cells/mm3).
Safety results from the full MERIT population show that, among those patients who remained on therapy (total patient years of exposure of 506 years for Celsentri/Selzentry and 507.9 years for efavirenz), less than half the number of malignancies were observed in patients taking Celsentri/Selzentry compared to those taking efavirenz (1.1% and 2.8%, respectively). There were also fewer cases of tuberculosis with Celsentri/Selzentry compared to efavirenz (0.3% and 2.2%, respectively). The most common adverse events reported by patients taking Celsentri/Selzentry were nausea, headache, fatigue, and dizziness. For patients taking efavirenz, nausea, headache, diarrhea, dizziness, vomiting, and abnormal dreams were the most commonly reported adverse events. Among those patients taking Celsentri/Selzentry in MERIT at 96-weeks, 1.5% had elevated LDL-cholesterol levels that exceeded established thresholds to consider lipid-lowering drug initiation, compared to 9.9% for patients taking efavirenz.
The 96-week results from MERIT ES were presented at the 5th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention in Cape Town, South Africa.
Raltegravir as Effective as Efavirenz in 144-Week Data
The integrase inhibitor raltegravir (Isentress®) was as effective as efavirenz at maintaining viral load suppression to <50 copies/mL) and at improving CD4 counts in treatment-naïve patients through 144 weeks in a Phase II study still underway. Both antiretrovirals were administered in combination with tenofovir and lamivudine.
These 144-week findings are from an ongoing multicenter, dose-ranging, double-blind, randomized trial of previously untreated HIV-infected adult patients. In this study, 198 treatment-naïve, HIV-infected patients received either raltegravir administered orally twice daily in combination with tenofovir and lamivudine or 600 mg efavirenz dosed orally once daily in combination with the same agents. During the first 48 weeks of the study, patients were randomized to one of four dose regimens (100, 200, 400 and 600 mg twice daily). After 48 weeks, all groups getting raltegravir received 400 mg dosed twice daily. The primary endpoints were reductions in HIV RNA to <400 copies/mL and the evaluation of safety at 144 weeks.
After 144 weeks of therapy, 78% of the 160 patients on the regimen containing raltegravir maintained HIV viral load suppression to <50 copies/mL. Results were comparable for patients taking the efavirenz-based regimen, with 76% of the 38 patients maintaining suppression to <50 copies/mL. Eighty percent of patients receiving the regimen containing raltegravir maintained suppression in viral load to <400copies/mL compared to 76% of patients taking the regimen containing efavirenz. Patients on both treatment regimens experienced increases in CD4 cell counts. At 144 weeks of treatment, the mean increase in CD4 cell counts from baseline was 252 cells/mm3 for patients receiving the regimen containing raltegravir and 233 cells/mm3 for patients receiving the regimen containing efavirenz.
At 144 weeks, cumulative rates of drug-related clinical adverse experiences were less frequent in the regimen containing raltegravir versus the regimen containing efavirenz (54% versus 76%, respectively). Raltegravir had less effect on total or LDL cholesterol, or triglycerides.
The results were presented at the 5th International AIDS Society's (IAS) Conference on HIV Pathogenesis, Treatment & Prevention in Cape Town, South Africa.
Second Complete Once-Daily Single Tablet Therapy in Development
Gilead Sciences has entered into an agreement with Tibotec Pharmaceuticals for the development and commercialization of a new once-daily fixed-dose antiretroviral regimen containing Gilead's Truvada® (emtricitabine and tenofovir disoproxil fumarate) and Tibotec's investigational NNRTI TMC278 (rilpivirine hydrochloride, 25 mg) for treatment-naïve patients.
If approved, the new product would become the second complete once-daily single tablet therapy. The first one available, Atripla® (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg), was approved by the FDA in 2006. Both Atripla and the new fixed-dose combination contain a NRTI backbone of Truvada.
Current HIV treatment guidelines issued by the U.S. Department of Health and Human Services list emtricitabine and tenofovir (the components of Truvada) in combination with an NNRTI or a PI as a preferred regimen for patients initiating therapy. Tibotec is currently studying the combination of Truvada and rilpivirine in Phase III clinical trials.
Rilpivirine is an investigational NNRTI being developed by Tibotec Pharmaceuticals. Two Phase III trials for rilpivirine are currently being conducted in the United States, Canada, Africa, Asia, Europe and South America.
Efavirenz More Effective Than Nevirapine in Tuberculosis Patients Taking Rifampin
Patients with HIV and tuberculosis who take rifampin may find that nevirapine is less effective when taken as part of an antiretroviral combination. Instead, efavirenz may be more preferable. The finding comes from research conducted by a team from the Ministry of Public Health in Nonthaburi, Thailand. Problems with nevirapine stem from lower blood concentrations of the antiretroviral in the presence of rifampin.
The Thailand researchers studied 141 patients receiving rifampicin. All were randomized to receive antiretroviral therapy that included efavirenz 600 mg or nevirapine 400 mg per day. Lower blood concentrations of nevirapine were seen compared to concentrations associated with efavirenz. At week 48, 73.2% of patients receiving efavirenz and 71.8% receiving nevirapine achieved HIV-1 RNA levels <50 copies/mL. The efavirenz group had mean CD4 cell counts of 274cells/mm3, while those in the nevirapine group had counts of 252 cells/mm3. Risk factors associated with treatment failure were low blood concentrations and having a body weight of <55 kg.
The complete study was published in the June 15th issue of Clin Infect Dis 2009;48:1752–1759.
HIV Therapy May Be Given Safely in Resource-Limited Settings Without Routine Laboratory Monitoring
Five-year results have been released for the study known as DART (Development of Anti-Retroviral Treatment in Africa), The study evaluated the need for routine laboratory monitoring in adults taking antiretroviral therapy in Africa. An analysis of the results suggests that antiretroviral therapy may be given in resource-limited settings even when routine laboratory monitoring isn't readily available.
The DART trial was an open-label, randomized study comparing clinical and laboratory monitoring to clinical monitoring alone for efficacy and toxicity. In this study, 74% of patients were on a treatment regimen containing tenofovir. At baseline, more than 50% of patients had reduced renal function. The results indicated that tenofovir was well tolerated and that the incidence of renal adverse events was low. DART researchers concluded that renal function test results were similar in both arms of the trial for up to 5 years, suggesting that routine monitoring of tenofovir may not be necessary in resource-limited settings when it is used as part of a first-line HIV treatment regimen.
DART was conducted at sites in Uganda and Zimbabwe. It examined whether HIV treatment, including tenofovir, can effectively and safely be provided in settings where availability of laboratory monitoring is limited. Without treatment, the researchers estimated that approximately 80% to 90% of DART patients would have died within 5 years. After 5 years of receiving combination HIV therapy, 88% of DART participants were alive. This is one of the best survival rates ever observed in an HIV treatment program or study conducted in Africa.
The 5-year trial enrolled 3,316 treatment-naïve adults with advanced HIV disease. All trial participants received HIV treatment. Patients were randomized (1:1) into one of two treatment groups. In the first group, patients' laboratory test results were provided to their physicians to help inform their treatment decisions. In the second group, doctors were not given the laboratory test results and made decisions about patient care based on clinical assessments alone. As a safeguard, results were provided for all patients whose laboratory safety results were seriously abnormal. Seventy-four percent of patients received a combination regimen of tenofovir with lamivudine/zidovudine. Sixteen percent of patients received nevirapine/lamivudine/zidovudine, and 9% of patients received abacavir/lamivudine/zidovudine.
Exclusion criteria for DART enrollment included creatinine levels of more than 360 μmol/l (4.1 mg/dl) and/or urea levels of more than five times the upper limit of normal. Sixty-five percent of patients in the DART trial were female, and the median age of trial participants was 37 (18–73). The median CD4 cell count was 86 cells/mm3.
Among patients whose doctors received regular laboratory test results, the survival rate after 5 years was 90%. Among patients whose doctors relied on clinical assessments alone, the survival rate similarly was 87%. No difference in the occurrence of drug-related side effects was seen between the two groups.
Researchers also examined various measures of drug safety, including the effect of HIV medicines on kidney function. At baseline, 52% of DART trial participants had impaired renal function upon enrollment, defined as having an estimated glomerular filtration rate (eGFR) of <90 ml/min/1.73m2. In addition, researchers evaluated the presence of chronic kidney disease (CKD) using two defining criteria: The first defined CKD as GFR of <60 ml/min/1.73m2 present on at least two occasions for more than 3 months, or a 25% drop in GFR for patients whose GFR was already less than 60 ml/min/1.73m2 at baseline. The second definition characterized CKD as being present among any patient who experienced a 25% drop in GFR from baseline.
After 216 weeks of treatment, a severe decrease in GFR to <30 ml/min/1.73m2 was observed infrequently in DART participants receiving tenofovir. Severe GFR decreases were seen in 3.1% of participants on a tenofovir-based regimen, compared to 2.4% and 1.9% of patients receiving study regimens based on the drugs abacavir and nevirapine, respectively, which was not statistically significant. CKD was slightly more common among patients receiving a tenofovir-based regimen. Depending on the defining criteria used, either 3.4% or 5.9% of patients receiving tenofovir experienced CKD during the study, compared to 2.1% or 3.1% of patients receiving an abacavir-based regimen, and 1.1% or 2.1% of patients receiving a nevirapine-based regimen. Severe decreases in GFR or CKD were infrequent among DART participants regardless of whether laboratory testing was provided and regardless of patients' treatment regimens.
Renal disease contributed to 16 deaths during DART. Most of these cases also involved other HIV-related illnesses. Only two deaths were definitely or probably related to antiretroviral therapy that included tenofovir. Three other deaths involved patients who had severely decreased GFR at baseline, all of whom received tenofovir as part of their treatment regimen.
The results of the study were presented at the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2009) in Cape Town, South Africa.
Recent FDA Approvals
On June 22, the FDA granted tentative approval for lamivudine tablets (150 mg and 300 mg versions), manufactured by Matrix Laboratories Ltd of Hyberdad, India. It originally granted tentative approval for the Matrix Laboratories formulation of lamivudine 150 mg on March 19, 2007. The current tentative approval adds lamivudine tablets 300 mg, and also addresses scoring issues associated with the 150 mg tablet.
On July 8, the FDA granted approval for raltegravir (Isentress) as therapy in treatment-naïve patients. The recommended dose is 400 mg twice daily. It may be taken with or without food. The approval in treatment-naïve patients was based on a 48-week randomized, double-blind, active control trial to evaluate the safety and efficacy of Isentress 400 mg twice daily + emtricitabine + tenofovir versus Sustiva® (efavirenz) 600 mg + emtricitabine + tenofovir. The proportion of patients with HIV RNA <50 copies/mL was 87% for the Isentress group compared to 82% for the Sustiva group. Several major revisions were also made to the package insert.
Later in the summer, on July 15, the FDA granted tentative approval for a fixed-dose combination tablet containing abacavir sulfate, lamivudine, and zidovudine (300 mg/150 mg/300 mg). The generic is manufactured by Matrix Laboratories Limited of Hyberdad, India. It is a version of the FDA-approved Trizivir® Tablets (300 mg/150 mg/300 mg), manufactured by GlaxoSmithKline.
On July 16, the FDA granted tentative approval for stavudine, lamivudine, and nevirapine fixed dose combination tablets (40mg/150mg/200mg and 30mg/150mg/200mg versions) manufactured by Emcure Pharmaceuticals Limited of Pune, India.
The FDA granted tentative approval on July 23 for fixed-dose combination lamivudine/zidovudine scored tablets (30mg/60mg) for pediatric use. This generic is manufactured by Aurobindo Pharma Limited of Hyberdad, India. On the same date, the company also received approval for its zidovudine 60 mg scored tablets for pediatric use. The tablet is an alternate formulation to oral syrup for pediatric use, facilitating distribution and storage in settings where weight can negatively affect shipping/distribution, and high temperatures can shorten product shelf life. It will not be marketed in the United States, where the oral syrup formulation serves pediatric dosing needs.