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Once-daily antiretroviral HIV treatments


Javier Ena
HIV Unit
Marina Baixa Hospital

Adherence is a key factor in achieving success with antiretroviral therapy. Adherence to greater than 90% of the prescribed dose is required to achieve maximum suppression and avoid emergence of resistance.(1,2) Antiretroviral drug adherence is a complex issue in which one of the determinants is related to the number of pills, the complexity of the regimen and the regimen interference with daily living activities. In one poll study, the optimal regimen selected by patients was a once-daily one with four or less pills. Opinions were based on the better fit of once-a-day regimens in daily lives and to the likeliness of remembering all antiretroviral doses.(3) The recently released US Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents promoted the need for simplification by stating that “to the extent possible, highly active antiretroviral therapy should be simplified by reducing the number of pills and the frequency of therapy…”(4)

Known facts
There are currently five antiretroviral agents approved for once-a-day use: amprenavir/ritonavir (AMP/r), didanosine (ddI), efavirenz (EFV), lamivudine (3TC) and tenofovir (TDF). At least four additional antiretroviral agents are under evaluation for once-a-day use: atazanavir (ATV), emtricitabine (FTC), stavudine extended-release (d4T-XR) and nevirapine (NVP). Several ritonavir-boosted protease inhibitor combinations are also under evaluation for once-a-day use: indinavir/ritonavir (IDV/r), lopinavir/ritonavir (LPV/r), saquinavir/ritonavir (SQV/r) and atazanavir/ritonavir (ATV/r).

Once-a-day administration of nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) are based on half-lives achieved both in plasma and intracellularly.(5) After uptake by host cells, nucleoside or nucleotide analogues are phosphorylated into active drugs. The phosphorylated active drug has high affinity for the HIV-1 reverse transcriptase and competes with the natural enzyme substrates. Didanosine (400mg), emtricitabine (200mg) and tenofovir (300mg) provide enough levels to “forgive” a missed dose. Lamivudine (300mg) achieves borderline concentrations to “forgive” a missed dose. Zidovudine, zalcitabine, stavudine-immediate release and abacavir are not suitable for once-a-day dosage. Non-NRTIs do not require intracellular phosphorylation to exert their blocking action on the HIV reverse transcriptase. Efavirenz (600mg) and nevirapine (400mg) have long half-lives in plasma and provide enough concentrations to “forgive” a missed dose. However, nevirapine administered once daily was associated with greater rate of liver toxicity compared with the standard twice-a-day dose (13.2% vs 7.8%, respectively).(6)

Protease inhibitors do not need intracellular processing to be activated. Protease inhibitors block the production of polyproteins in the late stages of the viral replicative cycle. Regarding once-a-day administered protease inhibitors, co-administration of ritonavir with the protease inhibitor of interest results in serum levels of the protease inhibitor that significantly exceed the IC(50) for at least 24 hours (ie, 24-hour C(min) exceeds the IC(50)). Nevertheless, boosted protease inhibitors administered once a day showed important interpatient variability, especially in saquinavir/ ritonavir (1,200/100mg or 1,600/100mg),(7–9) indinavir/ritonavir (1,000/100mg or 1,200/200mg)(10,11) and lopinavir/ritonavir (800/200mg) combinations.(12) Because of the low interpatient variability, the preferred combinations would be amprenavir/ritonavir (1,200/200mg), approved by the FDA, or atazanavir/ritonavir (300/100mg), which is currently being tested.

Antiretroviral regimens used in once-a-day dosing have been described in the literature.(13–19) Most studies are clinical trials with no reference group to assess their efficacy compared with standard therapy. Only the combinations of didanosine (400mg), lamivudine (300mg) and efavirenz (600mg)(14) and of didanosine (400mg), emtricitabine (200mg) and efavirenz (600mg)(16) have been tested by means of randomised controlled trials in naive patients. These two regimens showed virological efficacy at least similar to that of standard-of-care treatments. The most often reported side-effects were methadone withdrawal symptoms and central nervous system-related symptoms, both attributable to efavirenz. The combination tenofovir (300mg), lamivudine (150mg bid) and efavirenz (600mg) has been compared with stavudine (40mg bid), lamivudine (150mg bid) and efavirenz (600mg) in a randomised clinical trial, showing similar virological efficacy.(15) Although lamivudine was administered twice daily with tenofovir and efavirenz, it is anticipated that once-a-day lamivudine will have similar efficacy. Regimens that include tenofovir, didanosine and efavirenz require didanosine dose reduction, due to the interaction with tenofovir.(20) Once-a-day combinations are being more often used as simplification therapy after virological control of the disease has been achieved with protease inhibitor-based regimens.

Finally, combinations of three nucleoside (nucleotide) reverse transcriptase inhibitors have shown poor efficacy. Therefore, the combinations of tenofovir, lamivudine and didanosine and of tenofovir, lamivudine and abacavir have been classified as nonrecommended regimens in the updated guidelines for treatment of HIV infection.

Suggested practice
Since any patient can theoretically benefit from a simplified medication schedule, once-a-day regimens may benefit all patients. Specifically, patients who forget to take their medication in absence of daily routines may benefit from once-a-day regimens. Patients who will likely benefit the most from once-a-day antiretroviral regimens are those requiring directly observed therapy and those attending methadone clinics or correctional facilities.(21)

When selecting once-a-day antiretroviral regimens, those containing protease inhibitors should be avoided, due to the elevated burden of pills (between nine and 12), as should those containing three NRTIs, due to poor efficacy. The regimens with low burden of pills (three pills/day) that have consistently proved their efficacy in randomised clinical trials are: didanosine (400mg), lamivudine (300mg) and efavirenz (600mg) or didanosine (400mg), emtricitabine (200mg) and efavirenz (60mg). Due to the fact that food decreases the bioavailability of didanosine by 55%, once-a-day regimens that include didanosine require administration on an empty stomach. Finally, for patients attending methadone clinics, a 50% increase in methadone dose should be anticipated, due to the methadone withdrawal symptoms induced by efavirenz or nevirapine.(22)

Controversial issues
Comparative trials demonstrating whether once-a-day dosing translates into improved outcomes have yet to be completed. Once-a-day administration of NRTIs would require careful scrutiny for toxicities. Intracellular drug activation by phosphorylation provides antiviral activity, but also a greater drug accumulation. Long-term toxicity caused by mitochondrial DNA inhibition can be manifested as peripheral neuropathy or lipoatrophy.(23) Once-a-day administration of boosted protease inhibitors has shown important interpatient variability. Therefore, it has been suggested that clinicians choosing once-a-day protease inhibitors regimens should consider the degree of underlying viral resistance (ie, by using phenotypic data) and protease inhibitor drug exposure at 24 hours (ie, drug-level monitoring).(24) The amprenavir/ritonavir (1,200/200mg) combination seems to provide sustained high through levels at 48 hours, with small interpatient variability.

Finally, the consequences of nonadherence in once-a-day regimens may not be the same as in twice-a-day regimens. Forgiveness of one dose in once-a-day regimens with drugs, such as lamivudine, that have through levels (serum and intracellular) slightly above the inhibitory concentration of the virus may promote earlier emergence of resistance. On the other hand, emtricitabine, efavirenz, tenofovir, didanosine and nevirapine have half-lives long enough to “forgive” a missed dose.


  1. Arch Intern Med 1998;158:1953.
  2. Clin Infect Dis 2003;37:1112-8.
  3. XIV International AIDS Conference 2002. Abstract MOPeB3290.
  4. Accessed 19 December 2003.
  5. Accessed 19 December 2003.
  6. 10th Conference on Retroviruses and opportunistic Infections 2003. Abstract 176.
  7. J Acquir Immune Defic Syndr 2002;29:464-70.
  8. J Acquir Immune Defic Syndr 2003;32:375-9.
  9. Antimicrob Agents Chemother 2000;44:2672-8.
  10. J Acquir Immune Defic Syndr 2001;26:218-24.
  11. J Acquir Immune Defic Syndr 2000;25:229-35.
  12. 9th Conference on Retroviruses and opportunistic Infections 2002. Abstract 126.
  13. Antivir Ther 2001;6:249-53.
  14. Antivir Ther 2003;8:339-46.
  15. 10th Conference on Retroviruses and Opportunistic Infections 2003. Abstract 564b.
  16. 2nd IAS Conference on HIV Pathogenesis and Treatment 2003. Abstract 38.
  17. HIV Med 2000;1:162-3.
  18. J Acquir Immune Defic Syndr 2003;32:240-1.
  19. J Acquir Immune Defic Syndr 2001;27:260-5.
  20. 10th Conference on Retroviruses and Opportunistic Infections 2003. Abstract 533.
  21. 8th Conference on Retroviruses and Opportunistic Infections 2001. Abstract 528.
  22. Mt Sinai J Med 2000;67:429-36.
  23. Lancet 1999;364:1112-5.
  24. AIDS Read 2002;12:90-6.

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