efavirenz--emtricitabine--tenofovir-disoproxil-fumarate-drug-combination and efavirenz

STARTMRK, a phase III noninferiority trial of raltegravir-based versus efavirenz-based therapy in treatment-naive patients, remained blinded until its conclusion at 5 years. We now report the final study results.. Previously untreated patients without baseline resistance to efavirenz, tenofovir, or emtricitabine were eligible for a randomized study of tenofovir/emtricitabine plus either raltegravir or efavirenz. Yearly analyses were planned, with primary and secondary end points stipulated at weeks 48 and 96, respectively. The primary efficacy outcome was the percentage of patients with viral RNA (vRNA) levels <50 copies per milliliter counting noncompleters as failures (NC=F). Changes from baseline CD4 count were computed using an observed-failure approach to missing data. No formal hypotheses were formulated for testing at week 240.. Overall, 71 of 281 raltegravir recipients (25%) and 98 of 282 efavirenz recipients (35%) discontinued the study; discontinuations due to adverse events occurred in 14 (5%) and 28 (10%) patients in the respective groups. In the primary NC=F efficacy analysis at week 240, 198 of 279 (71.0%) raltegravir recipients and 171 of 279 (61.3%) efavirenz recipients had vRNA levels <50 copies per milliliter, yielding a treatment difference {Δ [95% confidence interval (CI)] = 9.5 (1.7 to 17.3)}. Generally comparable between-treatment differences were seen in both the protocol-stipulated sensitivity analyses and the prespecified subgroup analyses. The mean (95% CI) increments in baseline CD4 counts at week 240 were 374 and 312 cells per cubic millimeter in the raltegravir and efavirenz groups, respectively [Δ(95% CI) = 62 (22 to 102)]. Overall, significantly fewer raltegravir than efavirenz recipients experienced neuropsychiatric side effects (39.1% vs 64.2%, P < 0.001) or drug-related clinical adverse events (52.0% vs 80.1%, P < 0.001).. In this exploratory analysis of combination therapy with tenofovir/emtricitabine in treatment-naive patients at week 240, vRNA suppression rates and increases in baseline CD4 counts were significantly higher in raltegravir than efavirenz recipients. Over the entire study, fewer patients experienced neuropsychiatric and drug-related adverse events in the raltegravir group than in the efavirenz group. Based on better virologic and immunologic outcomes after 240 weeks, raltegravir/tenofovir/emtricitabine seemed to have superior efficacy compared with efavirenz/tenofovir/emtricitabine.

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Deoxycytidine; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Male; Organophosphonates; Oxazines; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Outcome

To evaluate the effect of rifampicin-based tuberculosis (TB) treatment on the pharmacokinetics of efavirenz/tenofovir/emtricitabine in a fixed-dose combination tablet, and vice versa, in Tanzanian TB-HIV-coinfected patients.. This was a Phase II open-label multiple dose pharmacokinetic and safety study. This study was conducted in TB-HIV-coinfected Tanzanian patients who started TB treatment (rifampicin/isoniazid/pyrazinamide/ethambutol) at week 1 to week 8 and continued with rifampicin and isoniazid for another 16 weeks. Antiretroviral treatment (ART) of efavirenz/tenofovir/emtricitabine in a fixed-dose combination tablet was started at week 4 after initiation of TB treatment. A 24-h pharmacokinetic sampling curve was recorded at week 8 (with TB treatment) and week 28 (ART alone). For TB drugs, blood samples at 2 and 5 h post-dose were taken at week 3 (TB treatment alone) and week 8 (with ART).. A total of 25 patients (56% male) completed the study; 21 had evaluable pharmacokinetic profiles. The area under the concentration-time curve 0-24 h post-dose of efavirenz, tenofovir and emtricitabine were slightly higher when these drugs were coadministered with TB drugs; geometric mean ratios (90% CI) were 1.08 (0.90, 1.30), 1.13 (0.93, 1.38) and 1.05 (0.85, 1.29), respectively. For TB drugs, equivalence was suggested for peak plasma concentrations when administered with and without efavirenz/tenofovir/emtricitabine. Adverse events were mostly mild and no serious adverse events or drug discontinuations were reported.. Coadministration of efavirenz, tenofovir and emtricitabine with a standard first-line TB treatment regimen did not significantly alter the pharmacokinetic parameters of these drugs and was tolerated well by Tanzanian TB patients who are coinfected with HIV.

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Antitubercular Agents; Benzoxazines; Cyclopropanes; Deoxycytidine; Drug Combinations; Drug Therapy, Combination; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Ethambutol; Female; HIV Infections; Humans; Isoniazid; Male; Organophosphonates; Oxazines; Pyrazinamide; Reverse Transcriptase Inhibitors; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

In British Columbia, antiretrovirals are distributed at no cost to patients via a publicly funded program, using generic formulations if available. A generic efavirenz-emtricitabine-tenofovir DF (EFV-FTC-TDF) combination pill became available in April 2018. The authors compared EFV untimed drug levels in subjects switching from brand to generic EFV-FTC-TDF.. Archived plasma HIV viral load samples were identified for consenting participants who switched from brand to generic EFV-FTC-TDF; 3 preswitch and 2-3 postswitch samples, collected ≥1 month apart were assessed for each subject. "Untimed" EFV concentrations with unknown dosing and collection time were assessed using a validated liquid chromatography-tandem mass spectrometry method. Participants' mean, minimum, and maximum EFV levels were compared using the Wilcoxon signed rank test. Participants with EFV levels in the range associated with lower risks of virologic failure and central nervous system toxicity (1000-4000 ng/mL), preswitch and postswitch, were enumerated.. EFV levels were assessed in 297 preswitch and 249 postswitch samples from 99 participants, having exposure to brand and generic EFV for a median of 103 (Q1-Q3: 87-116) and 10.3 (Q1-Q3: 8.9-11.7) months, respectively. The final brand sample was collected at a median of 98 days preswitch; the first generic sample was collected at a median of 133 days postswitch. No significant differences were observed in participant mean EFV levels before (median 1968 ng/mL; Q1-Q3: 1534-2878 ng/mL) and after (median 1987 ng/mL; Q1-Q3: 1521-2834 ng/mL) switch (P = 0.85). Eighty participants had mean EFV levels within the 1000-4000 ng/mL range on the brand drug, of which 74 remained within this range postswitch.. There were no statistically significant differences between untimed EFV levels in patients switching from the brand to generic EFV combination pill. Given the long elimination half-life of EFV, untimed drug levels may be a convenient way to estimate product bioequivalence.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drugs, Generic; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; HIV Infections; HIV-1; Humans; Treatment Outcome

We describe a patient with acute renal failure and irreversible kidney damage after an overdose with the fixed dose combination of efavirenz/tenofovir disoproxil fumarate/emtricitabine (Atripla). The acute kidney injury was most probably caused by tenofovir. Efavirenz and emtricitabine seemed relatively safe in overdose. The pharmacokinetics in overdose of all 3 drugs and the effect of hemodialysis on the tenofovir clearance were studied by measuring the plasma concentrations and by the use of clinical pharmacokinetic software.

Topics: Acute Kidney Injury; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Emtricitabine; HIV Infections; HIV-1; Humans; Male; Middle Aged; Tenofovir

Topics: Adenine; Adult; Alkynes; Benzoxazines; Cyclopropanes; Deoxycytidine; Drug Combinations; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; HIV Infections; Humans; Male; Organophosphonates; Oxazines; Psychoses, Substance-Induced; Reverse Transcriptase Inhibitors

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Deoxycytidine; Drug Combinations; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; HIV Infections; Humans; Organophosphonates; Oxazines; Plasma

Topics: Adenine; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Antiviral Agents; Benzoxazines; Cyclopropanes; Deoxycytidine; Drug Approval; Drug Combinations; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Emtricitabine; Europe; HIV Infections; Humans; Organophosphonates; Oxazines; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Tenofovir; Viral Load

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Deoxycytidine; Drug Approval; Drug Combinations; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Emtricitabine; European Union; HIV Infections; Humans; Organophosphonates; Oxazines; Reverse Transcriptase Inhibitors; Tenofovir

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Deoxycytidine; Drug Combinations; Drug Interactions; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Emtricitabine; HIV Infections; Humans; Organophosphonates; Oxazines; Tenofovir