Although Highly Active Antiretroviral Therapy (HAART) has significantly improved the morbidity and mortality of individuals living with HIV and AIDS, the complexities associated with taking multiple medications several times daily can present significant challenges. This is particularly true of medications that have specific requirements with respect to administration around meals or with respect to the spacing of other concurrent medications. The need to take multiple medications throughout the day can be difficult to coordinate within an individual's daily schedule. Furthermore, HAART regimens have been associated with short-term side effects as well as long-term toxicities. Collectively, the complexities of HAART can have a negative impact on an individual's overall adherence to antiretroviral therapy. In fact, a recently published study suggests that during a median follow-up period of 14.2 months, as many as 44.4% of patients modified their HAART regimen.1 The majority (64.4%) of these patients did so as a result of toxicities and/or adherence-related issues.

In the face of these challenges, HAART is extremely unforgiving, mandating an extraordinarily high level of adherence (>95%) in order to achieve optimal therapeutic outcome.2 Unfortunately, current research suggests that the eradication of HIV is unlikely with currently available medications and so individuals must commit to lifelong therapy.3 As a result, various treatment-simplification strategies, such as once-daily dosing, are being explored as a way to help individuals achieve the maximum benefit from drug therapy.

Of the currently available antiretroviral agents, efavirenz (Sustiva¨), didanosine (Videx¨ EC), and tenofovir DF (Vireadª) are already approved for once-daily dosing. In addition, in February of this year, the Food and Drug Administration (FDA) approved a once-daily dosing regimen of amprenavir (Agenerase¨) 1,200 mg when each dose was combined with the booster effect of ritonavir (Norvir¨) 200 mg.

Many more recently marketed antiretroviral agents are being investigated for potential once-daily dosing, including: lamivudine (Epivir¨), abacavir (Ziagen¨), and nevirapine (Viramune¨). On the investigational front, two once-daily dosing agents are in final stages of development with approval anticipated later this year: a new extended release formulation (XR) of stavudine (Zerit¨), as well as a new protease inhibitor, atazanavir (BMS-232632). Still other investigational agents, further back in the development pipeline, offer the hope of expanding future once-daily antiretroviral selection.

Most recently, data on select once-daily therapy approaches were presented at the 9th Conference on Retroviruses and Opportunistic Infections. Some of the results reported were as follows.

Once-Daily Lopinavir/Ritonavir (Kaletraª)

A pilot study in 38 antiretroviral-na•ve patients was conducted to evaluate a once-daily lopinavir/ritonavir dosing regimen (800 mg/200 mg) as compared with the standard twice-daily dose.4 Although the efficacy and safety results were similar in both groups at 48 weeks of follow-up, the once-daily regimen was associated with lower and more variable lopinavir trough levels. These preliminary data suggest that once-daily lopinavir/ritonavir may be an option for treatment-na•ve individuals. The potential role of this regimen in treatment-experienced patients remains to be determined.

Once-Daily Saquinavir/Ritonavir

A once-daily saquinavir/ritonavir regimen was evaluated in a cohort of 62 patients who had maintained an undetectable viral load for 3 years on a regimen consisting of twice-daily saquinavir soft-gel capsule (1,400 mg bid) in combination with two NRTIs.5 These patients were switched to a once-daily regimen consisting of saquinavir (1,600 mg) plus ritonavir (100 mg) while continuing the same two NRTIs. At 48 weeks of follow up, 91% had maintained a viral load <50 copies/mL. Although the authors state that the once-daily regimen was well tolerated, this was an uncontrolled trial, and so no data are available concerning the relative adverse effect and drop-out rates associated with once-daily vs twice-daily saquinavir/ritonavir regimens. These data suggest a potential role for once-daily saquinavir/ritonavir as a treatment simplification strategy in stable treatment-experienced patients.

The simplification of antiretroviral therapy, including once-daily dosing, has become an important strategy to help individuals living with HIV achieve maximum benefit from drug therapy. Simplified dosing regimens of currently marketed antiretroviral agents as well as new formulations and investigational once-daily agents on the horizon offer hope that entire once-daily antiretroviral regimens will be the way of future HIV care.

Lidia Gajewski-Verbanac, Pharm.D, is a clinical specialist with CVS ProCare Pharmacy in the Clinical Services Division.

References

     1.   Mocroft A, et al. Reasons for modification and discontinuation of antiretrovirals: results from a single treatment centre. AIDS. 2001;15:.

     2.   Paterson DL, et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med. 2000;133:21-30.

     3.   Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Department of Health and Human Services, 2002.

     4.   Eron JJ, Bernstein B, King M, Manning L, Bertz R, Beall G, et al. Once-daily vs twice-daily Kaletra (lopinavir/ritonavir) in antiretroviral-na•ve HIV+ patients: 48-week follow-up. Program and Abstracts of the 9th Conference on Retroviruses and Opportunistic Infections, February 24-28, 2002; Seattle, Washington. [Abstract 409]

     5.   Cardiello P, Srasuebkul P, Hassink E, Mahanontharit A, Samor T, Worarien W, et al. The efficacy, safety, and immunological changes of qd saquinavir-soft gel capsules 1600 mg/ritonavir 100 mg plus dual nucleosides in patients who had an undetectable viral load after 3 years of treatment. Program and Abstracts of the 9th Conference on Retroviruses and Opportunistic Infections, February 24-28, 2002; Seattle, Washington. [Abstract 549]