A combination drug of abacavir‐lamivudine‐zidovudine (Trizivir®) for treating HIV infection and AIDS
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The primary objective of this review will be to evaluate the antiviral efficacy of co‐formulated zidovudine‐lamivudine‐abacavir (Trizivir®) for initial treatment of HIV/AIDS. The secondary objectives will be to evaluate the safety and tolerability of the triple drug combination.
Background
The human immunodeficiency virus (HIV) pandemic poses one of the greatest challenges to global public health. An estimated 39.4 million people are currently living with HIV and approximately 4.9 million new infections and 3.1 million acquired immunodeficiency syndrome (AIDS) related deaths were registered in 2004 alone (UNAIDS 2004). Prevention is commonly advocated to curb the spread of HIV infection, and though preventive methods have considerably slowed down the spread of HIV in most parts of the world, people who are already infected need care and treatment.
The goal of antiretroviral therapy is to achieve prolonged suppression of HIV replication. The ideal antiretroviral drug(s) should be effective in suppressing viral replication; they should be affordable, available in simplified regimens, well tolerated, and have no dietary interactions. The use of monotherapy and dual therapy has often led to mutations and long‐term resistance (Eron 1995; Pialoux 1998; Rutherford 2003), necessitating the development of combination therapy with three drugs taken separately at a time. Current initial regimens, referred to as highly active antiretroviral therapy (HAART), consist of two nucleoside reverse transcriptase inhibitors (NRTIs) combined with either a non‐nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI) (Carpenter 2000; Yeni 2002). In well‐resourced countries (Ledergerber 1999) and, recently, Brazil (Hacker 2004; Teixeira 2004), HAART has contributed substantially towards delaying HIV progression to AIDS and death. However, these combinations are complex and difficult to take (due to high pill burden, stringent intake schedules, and food and fluid restrictions), and may be associated with drug‐drug interactions and numerous side effects including various lipid abnormalities (Mehta 1997; Gifford 2000). This complexity also makes HAART less accessible to patients in the most resource‐constrained regions of the world, such as sub‐Saharan Africa, which are currently hardest hit by the pandemic. Sub‐Saharan Africa is inhabited by approximately 10% of the world's population, but is home to 60% of all people currently living with HIV/AIDS (UNAIDS 2004).
Concern over toxicity, adherence, and drug‐drug interactions has led to the development of simpler antiretroviral regimens, including fixed‐dose combinations of two NRTIs (zidovudine and lamivudine), Combivir®, and three NRTIs, abacavir‐lamivudine‐zidovudine, in single tablets (Trizivir®) (Anon 2000; Saez‐Llorens 2001). Three NRTIs simplify PI‐based therapy by easing dosing regimens (only one tablet twice daily) and avoid the lipid abnormalities associated with PIs (Seaton 2003). Although treatment simplification could help patients maintain adherence, continued virologic suppression must be ensured. Therefore, clarification of the role of this simplified antiretroviral therapy on prolonged suppression of HIV replication is of considerable importance. Since all three drug components of Trizivir® are of the same class, its use (if proven to be effective) potentially preserves other classes of antiretroviral agents for later use thereby avoiding resistance to NNRTIs and PIs at the same time and allows for effective second line treatment regimens (Staszewski 2001). However, there are concerns about hypersensitivity reactions to abacavir (Staszewski 1998), one of the components of Trizivir®.
The aim of this review is to combine all high quality randomised controlled trials comparing Trizivir® with HAART to assess the antiviral potency and tolerability of the simplified triple nucleoside combination in initial therapy for HIV/AIDS.
Objectives
The primary objective of this review will be to evaluate the antiviral efficacy of co‐formulated zidovudine‐lamivudine‐abacavir (Trizivir®) for initial treatment of HIV/AIDS. The secondary objectives will be to evaluate the safety and tolerability of the triple drug combination.
Methods
Criteria for considering studies for this review
Types of studies
Only randomised controlled trials with a minimum follow‐up time of six months will be included.
Types of participants
HIV‐infected, antiretroviral‐naive patients aged at least 16 years.
Types of interventions
Treatment of HIV/AIDS with Trizivir® as initial therapy compared with highly active antiretroviral therapy.
Types of outcome measures
The primary outcome measure is suppression of viral activity, as defined by authors.
The secondary outcome measures include:
1‐ CD4 cell count
2‐ Development of severe adverse events
3‐ Clinical lipodystrophy manifestations
4‐ Total cholesterol
5‐ Triglyceride level
5‐ Treatment adherence
Search methods for identification of studies
PubMed, EMBASE, Cochrane Database of Systematic Reviews, and the York Database of Abstracts of Reviews of Effectiveness (DARE) will be searched for previous reviews and meta‐analyses of antiretroviral therapy for treatment of HIV/AIDS that have included Trizivir®. Reports of relevant trials that are referred to in these reviews will be obtained.
We shall then carryout an exhaustive search of CENTRAL/CCTR, PubMed, EMBASE, and AIDSearch for randomised controlled trials of Trizivir® for initial treatment of HIV/AIDS, using standardised methodological filters (Higgins 2005). The search strategy planned for PubMed is as as follows:
#1: Search HIV Infections[MeSH]
#2: Search HIV[MeSH]
#3: Search hiv[tw]
#4: Search hiv‐1*[tw] OR hiv‐2*[tw]
#5: Search hiv1[tw] OR hiv2[tw]
#6: Search hiv infect*[tw]
#7: Search human immunodeficiency virus[tw] OR human immunedeficiency virus[tw] OR human immunodeficiency virus[tw] OR human immune‐deficiency virus[tw] OR ((human immun*) AND (deficiency virus[tw]))
#8: Search acquired immunodeficiency syndrome[tw] OR acquired immunedeficiency syndrome[tw] OR acquired immunodeficiency syndrome[tw] OR acquired immune‐deficiency syndrome[tw] OR ((acquired immun*) AND (deficiency syndrome[tw]))
#9: Search #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8
#10: Search Antiretroviral Therapy, Highly Active[MeSH]
#11: Search Antiretroviral Agents[MeSH] OR Antiviral Agents[MeSH:NoExp]
#12: Search ((anti) AND (hiv[tw])) OR antiretroviral*[tw] OR ((anti) AND (retroviral*[tw]))
#13: Search HAART[tw]
#14: Search ((anti) AND (acquired immunodeficiency[tw])) OR ((anti) AND (acquired immunedeficiency[tw])) OR ((anti) AND (acquired immunodeficiency[tw])) OR ((anti) AND (acquired immune‐deficiency[tw])) OR ((anti) AND (acquired immun*) AND (deficiency[tw]))
#15: Search #10 OR #11 OR #12 OR #13 OR #14
#16: Search TRIZIVIR
#17: Search ZIDOVUDINE AND LAMIVUDINE AND ABACAVIR
#18: Search #16 OR #17
#19: Search randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized controlled trials [mh] OR random allocation [mh] OR double‐blind method [mh] OR single‐blind method [mh] OR clinical trial [pt] OR clinical trials [mh] OR ("clinical trial" [tw]) OR ((singl* [tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR blind* [tw])) OR ( placebos [mh] OR placebo* [tw] OR random* [tw] OR research design [mh:noexp] OR comparative study [mh] OR evaluation studies [mh] OR follow‐up studies [mh] OR prospective studies [mh] OR control* [tw] OR prospectiv* [tw] OR volunteer* [tw]) NOT (animals [mh] NOT human [mh])
#20: Search #9 AND #15 AND #18 AND #19
An identical search strategy will be used for all electronic databases. The "Related articles" feature of PubMed will also be used.
The above search strategy will be supplemented by searching reference lists of identified articles and abstracts or proceedings of the International Conference on AIDS, the Conference on Retroviruses and Opportunistic Infections, and the International AIDS Society (IAS) Conference on HIV Pathogenesis and Treatment. Investigators of identified trials and other content experts, and pharmaceutical companies will be contacted to locate any further trials (completed or ongoing, published or not) that may not yet be included in the electronic databases or presented at the conferences. Relevant editorials, expert opinions and letters to the editor will also be scrutinised for any additional relevant studies or unpublished data.
There will be no language restrictions to our search.
Data collection and analysis
CSW and MSS shall conduct the literature search, with the help of the Trials Search Coordinator of the Cochrane HIV/AIDS Group (http://www.igh.org/Cochrane/). Studies identified by the search strategy will be scrutinised independently for eligibility by three authors (MSS, EJK, and CSW). Studies will be included if they are randomised controlled trials (study design) comparing Trizivir® with HAART (intervention) in antiretroviral‐naive, HIV infected adults (participants). MSS, EJK and CSW will then independently assess included studies for methodological quality. Quality assessment will be based on the method of assigning participants to interventions, according to standard Cochrane criteria (Higgins 2005). Authors assessing study eligibility and quality will not be blinded to the names of the trial investigators, their institutions, journals of publication, and results of the study.
After quality assessment, the three authors (MSS, EJK, CSW) will abstract the data. We will design forms for data abstraction and for requesting additional information from the investigators. On data abstraction forms will be noted the review title, study reference and publication status, date of abstraction, and author's initials. Data will be abstracted under the following subheadings in the form: methods (method of randomisation and allocation concealment, blinding of those receiving and providing care and assessing outcomes, losses to follow‐up and how they were handled), participants (setting, number of patients randomised, baseline plasma HIV‐1 RNA level), interventions (length of treatment, comparison group), outcomes (new plasma HIV‐1 RNA level, CD4+ cell count, Cholesterol level, metabolic abnormalities, clinical lipodystrophy manifestations, other side effects), and other notes. If data are available on outcome measures at two or more periods, the more complete or later one will be taken into account. The data abstracted for dichotomous variables will be the number of affected participants and the number of participants in the comparison group; and for continuous variables, the mean, the standard deviation and the number of participants in the comparison group. Attempts shall be made to get missing data from the trial investigators.
Disagreement amongst the three authors assessing the eligibility and quality of trials and abstracting data will be resolved by discussion. If the disagreement should persist, JDS will arbitrate.
Meta‐analysis will be undertaken using RevMan 4.2. Study results for dichotomous data will be expressed as relative risk (RR) and 95% confidence intervals (CI), and combined using a fixed effect (Mantel‐Haenszel) method. Heterogeneity between studies will be examined by graphical inspection of results followed by a chi‐square test of homogeneity. We plan to use sensitivity analyses to explore the effect of trial quality, baseline plasma HIV‐1 RNA level, type of comparison group, and virological endpoint on the estimated effect size. When a significant statistical association is found, we shall calculate the absolute risk reduction (or increase) with the number needed to treat (NNT) or harm (NNH), as appropriate.
