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Once-a-Day Highly Active Antiretroviral Therapy: A Systematic Review
  Summary: We analyzed the available evidence about the efficacy and tolerability of once-a-day highly active antiretroviral therapy (HAART), searching databases, conference proceedings, and journals. Two reviewers independently selected 6 uncontrolled and 2 randomized clinical trials of at least 24 weeks duration and with 80% participant follow-up. Regimens included didanosine (ddI), emtricitabine (FTC), and efavirenz (EFV) (2 studies, 326 patients); ddI, lamivudine (3TC), and EFV (3 studies, 147 patients); ddI, 3TC, EFV, and adefovir dipivoxil (1 study, 11 patients); ddI, nevirapine, and EFV (1 study, 15 patients); and ddI, 3TC, indinavir, and ritonavir (1 study, 10 patients). Virological efficacy ranged between 70% and 91%. Preliminary randomized clinical trials showed that once-a-day regimens (ddI, 3TC, and EFV or ddI, FTC, and EFV) had a virological efficacy at least similar to that of conventional HAART. The overall CD4 cell increase was at least 114 lymphocytes/L. Tolerability was good, with a low discontinuation rate.
Clinical Infectious Diseases 2003;36:1186-1190
Javier Ena and Francisco Pasquau. HIV Unit, Department of Internal Medicine, Marina Baixa Hospital, Villajoyosa, Alicante, Spain
Adherence to HAART is a determinant factor in obtaining the greatest therapeutic efficacy. The major limitations for adherence to HAART are the burden of pills and dosing of the drugs. Patients with hectic lifestyles and those requiring directly observed therapy (DOT) would benefit most from once-daily administration of antiretroviral drugs. No systematic review to date has evaluated the information available about the efficacy of once-daily administration of antiretroviral drugs. Our study is a comprehensive review of the literature, to determine the proportion of patients with an undetectable HIV RNA load, the increase in CD4 lymphocyte cell counts, and the tolerability of HAART administered once daily.
Studies of HIV-infected patients with detectable virus loads were chosen, and intervention was defined as once-a-day administration of at least 3 antiretroviral drugs. A low dose of ritonavir to boost other protease inhibitors was not considered to be an additional drug to the regimen. A favorable outcome was defined as an undetectable virus load at 24 and 48 weeks of follow-up. The study design included published and unpublished clinical trials in any language with at least 80% participant follow up. We searched the MEDLINE (1996January 2002), AIDSLINE (1980December 2000), and EMBASE databases. We also hand-searched abstracts presented at major infectious diseases meetings between 1998 and 2002. After exhaustive scrutiny, 8 studies were left for the present work: 4 published and 4 unpublished.
Intention-to-treat analysis showed that once-a-day regimens had a virological efficacy of 70%91%. One randomized controlled trial showed that a once-a-day combination of ddI, 3TC, and EFV (34 patients) had a greater virological efficacy (HIV-1 RNA load, <50 copies/mL at 32 weeks of follow-up) than twice-a-day zidovudine (ZDV), 3TC, and nelfinavir (34 patients) (79% vs. 50%; P = .02) but similar to that of twice-a-day ZDV, 3TC, and EFV (34 patients) (81% vs. 79%; P, not significant). Another randomized, double-blind controlled trial showed that once-a-day ddI, FTC, and EFV (286 patients) had greater efficacy (HIV-1 RNA load, <50 copies/mL at 24 weeks of follow-up) than the reference group, who received ddI and stavudine immediate release twice daily plus EFV (285 patients) (81% vs. 65%; P < .001).
Discussion by authors
Our study shows that once-a-day regimens using ddI, FTC, and EFV or ddI, 3TC, and EFV had an efficacy at least similar to that of conventional HAART [14, 15]. Nevertheless, the remaining once-a-day HAART studies were clinical trials, with no reference group to assess their relative efficacy, compared with standard therapy. We did not try to make comparisons among different regimens, because there was a lot of variability among populations, follow-up periods, and lower limits of HIV-1 RNA detection. Few studies accurately evaluated once-a-day HAART adherence or its potential use as DOT. CD4 lymphocyte recovery was satisfactory in every once-a-day regimen.
The safety of once-a-day regimens was not consistently reported. Methadone withdrawal was the most common side effect for combinations that included NVP or EFV. This side effect is significant, because methadone maintenance programs are settings in which directly observed once-a-day HAART might be potentially implemented. One study showed that the addition of adefovir dipivoxil to a regimen containing ddI, 3TC, and EFV did not add efficacy but was associated with an excess of nephrotoxicity that required adefovir discontinuation. Overall, the proportion of patients requiring the discontinuation of once-a-day HAART regimens was low.
Our review included as important features a comprehensive literature review and, in some cases, additional information obtained from the authors of unpublished studies. Nevertheless, many once-a-day regimens have inconclusive data because of the lack of a reference group for comparison.
Currently, only 4 drugs have been approved in Europe and the United States for once-a-day dosing: ddI, 3TC, tenofovir, and EFV. Recently, the US Food and Drug Administration approved stavudine extended release as an additional once-a-day antiretroviral drug. Emtricitabine is a nucleoside reverse-transcriptase inhibitor similar to 3TC that is awaiting commercialization. NVP, although it is used in some once-a-day regimens, is still under study for once-a-day administration. Regarding once-a-day combinations with available protease inhibitors, all of them have as a major drawback the elevated burden of pills (between 7 and 10, in addition to reverse-transcriptase inhibitor drugs) and the possible interpatient pharmacokinetic variability when administered once a day. Combinations that have been tested are IDV and RTV (1200 and 100 mg/day), SQV soft-gel capsules and RTV (1600 and 100 mg/day), amprenavir and RTV (1200 and 200 mg/day), and lopinavir and RTV (800 and 200 mg/day).
In summary, simpler treatment regimens have shown to improve adherence and treatment outcomes in other acute and chronic diseases. Preliminary data showed that some once-a-day HAART regimens had an efficacy at least similar to that of conventional HAART. Once-a-day HAART has potential advantages to be used as DOT or as first-line therapy in patients with hectic lifestyles.
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