Truvada is a fixed-dose tablet containing 300 mg of Viread (tenofovir disoproxil fumarate; TDF) and 200 mg emtricitabine (FTC; Emtriva). Combivir (CBV) is a fixed-dose tablet comprised of 300 mg zidovudine (AZT; Retrovir) and 150 mg lamivudine (3TC; Epivir).

Both these fixed-dose combinations are widely used as "backbone drugs" in treatment regimens for antiretroviral-naïve and for antiretroviral-experienced patients.

Gilead Sciences Study 934 is an ongoing Phase III, multicenter, open-label trial in treatment-naïve patients receiving either once-daily Truvada/Sustiva (efavirenz; EFV) or twice daily Combivir plus once-daily Sustiva.

In a poster display at the 4th IAS Conference in Sydney (July 22-25, 2007), Dr. Jose Aribas of the University Hospital La Paz, Madrid, Spain presented 3-year (144 weeks) data from Study 934, which compares the safety and efficacy of these two regimens in antiretroviral-naïve HIV patients.

Patient Population

Table 1: Participants' Baseline Characteristics

Study 934 Results

• Intent-to-treat (ITT) population totaled 509 patients.
  
  
• The once-daily regimen of FTC+TDF+EFV demonstrated superior outcomes compared to twice daily CBV and once daily EFV through 48 weeks in antiretroviral-naïve patients.
  
  
• Primary endpoint (virologic suppression <50 copies/mL) was at 48 weeks and the study has continued through 144 weeks.
  
  
• Twenty-two patients with baseline non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations and 31 patients who completed week 48 and week 96 of the study with HIV RNA (viral load) less than 400 copies/mL but did not consent to participate after week 96 were excluded from the week 144 efficacy population.
  
  
• At study entry, patients were treatment-naïve, had HIV RNA greater than 10,000 copies/mL and any CD4 cell count.
  
  
• At study initiation, patients received Viread and Emtriva with Sustiva. At week 96, which coincided with the commercial availability of Truvada in the U.S., all patients receiving Viread, Emtriva and Sustiva were switched to receive a simplified regimen of Truvada and Sustiva.
  
  
• After 144 weeks of treatment, 71 percent of Truvada/Sustiva patients compared to 58 percent of Combivir/Sustiva patients achieved and maintained viral load less than 400 copies/mL [using the Time to Loss of Virologic Response algorithm (TLOVR) (n=456, p=0.004)].
  
  
• 64 percent of patients in the Truvada/Sustiva arm compared to 56 percent of patients in the Combivir/Sustiva arm achieved and maintained viral load less than 50 copies/mL using TLOVR (n=458, p=0.08).
  
  
• At 144 weeks, the mean increase from baseline in CD4 cell counts was 312 and 271 cells/microliter in the Truvada/Sustiva and Combivir/Sustiva arms, respectively (p=0.09).
  
  
• Through 144 weeks, no patients in either arm of the study developed the K65R mutation, (associated with reduced susceptibility to tenofovir).
  
  
• Fewer Truvada/Sustiva patients developed the M184V/I mutation (associated with resistance to emtricitabine and to the lamivudine component of Combivir (2 vs. 10 patients; p=0.02).
  
  
• After 144 weeks of treatment, a significantly greater percentage of patients in the Combivir/Sustiva group experienced adverse events that resulted in discontinuation of study medications compared to the Truvada/Sustiva arm (11 vs. 5 percent, respectively; p=0.01).
  
  
• The most common cause of discontinuation in the Combivir/Sustiva arm was anemia/hemoglobin decrease (14 vs. 0 patients in the Truvada/Sustiva arm), and in the Truvada/Sustiva arm was rash (4 patients vs. 1 patient in the Combivir/Sustiva arm).
  
  
• Renal adverse events were uncommon at 144 weeks, consistent with study data at weeks 48 and 96. No patient discontinued study medication due to renal (kidney) events.
  
  
• After 144 weeks of treatment, patients in the Combivir/Sustiva arm experienced greater mean elevations from baseline in fasting total cholesterol levels (36 vs. 24 mg/dL in the  Truvada/Sustiva arm; p=0.005) and greater mean increases from baseline in fasting triglycerides (36 vs. 4 mg/dL in the Truvada/Sustiva arm; p=0.047).
  
  
• Loss of limb fat, a marker for lipodystrophy, was observed among patients receiving Combivir/Sustiva.
  
  
• Among 269 patients with available data, median total limb fat was significantly less in patients receiving Combivir/Sustiva compared to patients receiving Truvada/Sustiva (5.4 vs 7.9 kg; p<0.001) at week 144.
  
  
• Among patients with data available at 48 and 144 weeks, median total limb fat decreased significantly in the Combivir/Sustiva arm (from 6.0 kg to 4.9 kg; n=49, 38) and increased significantly in the Truvada/Sustiva arm (from 7.4 kg to 8.3 kg; n=51, 48).

Table 2. Summary Out comes Week 144 TLOVR < 400 copies/mL

a. p = 0.004

Table 3. Adverse Events Leading to Study Drug Discontinuation through Week 144

a. Occurring in more than 1 patient in either arm; patients may have >1 event

b. p= 0.01 for comparison between arms using Fischer’s Exact test

 The U.S. Food and Drug Administration (FDA) has not yet reviewed the data from this study.

Conclusions

Based on their findings at week 144, the authors of Study 934 concluded the following:

• The Truvada/Sustiva arm was associated with significantly greater virologic suppression to HIV RNA < 400 c/mL

        – Significantly less M184V/I was seen in the FTC/TDF+EFV arm

        – No emergence of K65R mutation was demonstrated

• No patient discontinued due to renal adverse events
  
  
• Truvada/Sustiva was associated with significantly lower elevations in fasting cholesterol and triglycerides

• Limb fat was significantly higher in the Truvada/Sustiva arm than in the arm at weeks 96 and 144

• There was a significant decrease in limb fat in the Combivir/Sustiva arm and a significant increase in the Truvada/Sustiva arm among patients with data at weeks 48 and 144

Hospital Universitario La Paz, Madrid, Spain, Chelsea and Westminster Hospital, London, United Kingdom, Johns Hopkins University School of Medicine, Baltimore, MD, United States, Orlando Immunology Center, Orlando, FL, United States, University of Miami, Miami, FL, United States, Gilead Sciences, Foster City, CA, United States.

Funding for Study 934 is provided by Gilead Sciences, manufacturer of emtricitabine (FTC; Emtriva), and tenofovir disoproxil fumarate (TDF; Viread) and the fixed-dose combination tablet Truvada (emtricitabine/tenofovir). Truvada and Sustiva are also available in the United States as the fixed-dose product Atripla (efavirenz 600 mg + emtricitabine 200 mg + tenofovir disoproxil fumarate 300 mg), through a U.S. joint venture between Bristol-Myers Squibb Company and Gilead Sciences. Atripla was approved in the United States in July 2006.

Important Product Safety Information about Truvada and Atripla

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with other antiretrovirals.

Truvada and Atripla are not approved for the treatment of chronic hepatitis B virus (HBV) infection and their safety and efficacy have not been established in patients co-infected with HBV and HIV. Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued Viread or Emtriva, which are components of Truvada and Atripla.

In some of these patients treated with Emtriva, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are co-infected with HIV and HBV and discontinue Truvada or Atripla. If appropriate, initiation of anti-hepatitis B treatment may be warranted.

Additional Important Information about Truvada

In the United States, Truvada is indicated in combination with other antiretroviral agents, such as non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs), for the treatment of HIV-1 infection in adults.

It is not recommended that Truvada be used as a component of a triple nucleoside regimen.

Truvada should not be coadministered with Atripla, Emtriva, Viread or lamivudine-containing products, including Combivir (lamivudine/zidovudine), Epivir® or Epivir-HBV® (lamivudine), Epzicom (abacavir sulfate/lamivudine) or Trizivir (abacavir sulfate/lamivudine/zidovudine).

In treatment-experienced patients, the use of Truvada should be guided by laboratory testing and treatment history.

Emtricitabine and tenofovir are principally eliminated by the kidneys. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported in association with the use of Viread, a component of Truvada. It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy with Truvada and as clinically appropriate during therapy. Routine monitoring of calculated creatinine clearance and serum phosphorous should be performed in patients at risk for renal impairment.

Dosing interval adjustment and close monitoring of renal function are recommended in all patients with creatinine clearance 30-49 ml/min. Truvada should be avoided with concurrent or recent use of a nephrotoxic agent.

No drug interaction studies have been conducted using Truvada. Coadministration of Truvada and didanosine should be undertaken with caution. Patients should be monitored closely for didanosine-associated adverse events and didanosine should be discontinued if these occur.

Patients on atazanavir (Reyataz) and lopinavir/ritonavir (Kaletra) plus Truvada should be monitored for Truvada-associated adverse events and Truvada should be discontinued if these occur. When co-administered with Truvada, it is recommended that atazanavir be given with ritonavir 100 mg. Atazanavir without ritonavir should not be coadministered with Truvada.

Decreases in bone mineral density (BMD) at the lumbar spine and hip have been seen with the use of Viread. The effect on long-term bone health and future fracture risk is unknown. Cases of Osteomalacia (associated with proximal renal tubulopathy) have been reported in association with the use of Viread.

Changes in body fat have been observed in patients taking anti-HIV medicines. The mechanism and long-term health effect of these conditions are unknown.

Immune Reconstitution Syndrome has been reported in patients treated with combination therapy, including Viread and Emtriva.

Adverse events observed with Viread and Emtriva used in combination in Study 934 were generally consistent with those seen in other studies in treatment-experienced or treatment-naïve patients receiving Viread and/or Emtriva. Treatment-emergent adverse events occurring in at least 3 percent of patients receiving Viread and Emtriva in Study 934 included dizziness (8%), diarrhea (7%), nausea (8%), fatigue (7%), sinusitis (4%), upper respiratory tract infections (3%), nasopharyngitis (3%), somnolence (3%), headache (5%), dizziness (8%), depression (4%), insomnia (4%), abnormal dreams (4%) and rash (5%).

Skin discoloration has been reported with higher frequency among Emtriva-treated patients. Skin discoloration, manifested by hyperpigmentation on the palms and/or soles was generally mild and asymptomatic. The mechanism and clinical significance are unknown.

Additional Important Information about Atripla

In the United States, Atripla is indicated for use alone as a complete regimen or in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults. Atripla contains the components Truvada (emtricitabine and tenofovir disoproxil fumarate) and Sustiva (efavirenz), co-formulated as a single tablet. As such, the important safety information appearing in the above Truvada section also applies to Atripla, in addition to the following important product information.

As a fixed-dose regimen of Viread (tenofovir disoproxil fumarate), Emtriva (emtricitabine) and Sustiva (efavirenz), Atripla should not be coadministered with Viread, Emtriva, Truvada (emtricitabine and tenofovir disoproxil fumarate) or Sustiva.

Due to similarities between Emtriva and lamivudine (Epivir), Atripla should not be coadministered with drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine) or Trizivir (abacavir sulfate/lamivudine/zidovudine).

Serious psychiatric adverse experiences, including severe depression (2.4 percent), suicidal ideation (0.7 percent), nonfatal suicide attempts (0.5 percent), aggressive behavior (0.4 percent), paranoid reactions (0.4 percent) and manic reactions (0.2 percent) have been reported in patients treated with efavirenz (Sustiva), a component of Atripla.

In addition to efavirenz, factors identified in a clinical study that were associated with an increase in psychiatric symptoms included a history of injection drug use, psychiatric history and use of psychiatric medication. There have been occasional reports of death by suicide, delusions, and psychosis-like behavior, but it could not be determined if efavirenz was the cause. Patients with serious psychiatric adverse experiences should be evaluated immediately to determine whether the risks of continued therapy outweigh the benefits. Patients should tell their doctor if they have a history of mental illness or are using drugs or alcohol.

Fifty-three percent of patients in clinical studies have reported central nervous system symptoms including dizziness (28.1 percent), insomnia (16.3 percent), impaired concentration (8.3 percent), somnolence (7.0 percent), abnormal dreams (6.2 percent) and hallucinations (1.2 percent) when taking efavirenz compared to 25 percent of patients receiving control regimens.

These symptoms usually begin during the first or second day of therapy and generally resolve after the first two to four weeks of therapy. After four weeks of therapy, the prevalence of central nervous system symptoms of at least moderate severity ranged from 5 to 9 percent in patients treated with regimens containing efavirenz. Nervous system symptoms are not predictive of the less frequent psychiatric symptoms.

Women should not become pregnant or breastfeed while taking Atripla. Serious birth defects have been seen in children of women treated with efavirenz during pregnancy. Women must use a reliable form of barrier contraception, such as a condom, even if they also use other methods of birth control.

Rash is a common side effect that usually goes away without any change in treatment. Rash may be a serious problem in some children.

Patients with liver disease may require the healthcare provider to check liver function or check drug levels in the blood.

Atripla should be used with caution in patients with a history of seizures. Convulsions have been observed in patients receiving efavirenz, generally in the presence of a known medical history of seizures.

Invirase® (saquinavir) should not be used as the only protease inhibitor in combination with Atripla.

The most significant adverse events observed in patients treated with efavirenz are nervous system symptoms, psychiatric symptoms and rash. The most common adverse events (at least 5 percent) observed in clinical studies with Sustiva include fatigue, pain, dizziness, headache, insomnia, impaired concentration, nausea, vomiting, diarrhea, depression, rash, and pruritus.

Links to more information about Atripla, and www.atripla.com

7/31/07

References

J Aribas, A Pozniak, J Gallant, and others. Three-year safety and efficacy of emtricitabine (FTC)/tenofovir DF (TDF) and efavirenz (EFV) compared to fixed dose zidovudine/lamivudine (CBV) and EFV in antiretroviral treatment-naïve patients. 4^th IAS Conference. July 22-25, 2007. Sydney, AU. WePeBo29.

Gilead Sciences. 144-week data from Gilead’s Study 934 Comparing Truvada to Combivir, Both in Combination with Sustiva presented at International AIDS Society Meeting in Sydney. Press Release. July 23, 2007.

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