Rilpivirine versus efavirenz for initial therapy in treatment‐naive, HIV‐1‐infected patients
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To evaluate the effectiveness of rilpivirine compared to efavirenz as first‐line treatment in patients with HIV infection.
Background
Description of the condition
HIV continues to be a major global public health issue, having claimed more than 25 million lives over the past three decades. There were approximately 34 million people living with HIV in 2011 with Sub‐Saharan Africa being the most affected region. Sixty‐nine percent of all people living with HIV are living in this region (UNAIDS 2012). HIV targets the immune system and weakens the host's surveillance and defence systems against infections and some types of cancer. As the virus destroys and impairs the function of immune cells, infected individuals gradually become immunodeficient (WHO 2011). Immunodeficiency results in increased susceptibility to a wide range of infections and diseases that people with healthy immune systems can fight. The most advanced stage of HIV infection is Acquired Immunodeficiency Syndrome (AIDS), which can take from 2 to 15 years to develop depending on the individual. AIDS is defined by the development of certain cancers, infections, or other severe clinical manifestations (WHO 2011).
Description of the intervention
The introduction of highly active antiretroviral therapy (HAART) in 1996 has converted HIV infection from an almost universally fatal illness to a chronic manageable disease. Over the years, different classes of antiretroviral agents have been developed which include Nucleoside reverse transcriptase inhibitors (NRTI), Non‐nucleoside reverse transcriptase inhibitor (NNRTI), protease inhibitors (PI) and integrase inhibitors (InSTI). The WHO recommends initiation of HAART in resource‐constrained countries with one NNRTI and two NRTI as the first line therapy while protease inhibitors are an option for inclusion in first line regimen in high‐income countries (Gilks 2006). HAART aims to improve quality of life, reduce HIV‐related morbidity and mortality, provide maximal and durable suppression of viral load, restore and/or preserve immune function (Meintjes 2012). For patients to be able to benefit from these gains in the long term, antiretroviral medicines must be convenient, safe, tolerable, effective, and affordable. The main drug‐related challenges to remaining on a particular regimen include side effects, interactions with other medications, safety during pregnancy, dosing schedules, pill burden, and degree of robustness against development of drug resistance (Mills 2006).
Rilpivirine is a second‐generation Non‐nucleoside reverse transcriptase inhibitor with high potency, long half‐life and reduced side‐effect compared with other NNRTIs (Pozniak 2007).
How the intervention might work
The mode of action of rilpivirine is at the stage of viral genome replication, inhibiting HIV reverse transcriptase by binding to a hydrophobic pocket near the active site of the enzyme and thus preventing transcription of viral RNA (Ford 2011). Rilpivirine is active against HIV‐1 in a variety of NNRTI resistant clinical isolates, and the relatively high potency of rilpivirine compared with the older generation of NNRTIs is thought to be due to its internal conformational flexibility (“wiggling”) and the plasticity of its interaction with the binding site (“jiggling"). The “wiggling” and “jiggling” degrees of freedom enable the drug to escape the effects of resistance mutations. A possible explanation for this phenomenon is that very potent and resilient diarylpyrimidine compounds in rilpivirine can bind in multiple modes within the highly flexible NNRTI binding site of the enzyme reverse transcriptase (Janssen 2005).
Why it is important to do this review
Consolidated guidelines on use of ARV drugs by WHO recommend the use of efavirenz, a non‐nucleoside reverse transcriptase inhibitor (NNRTI), as part of the standard first‐line regimen (WHO 2013). Efavirenz is potent and tolerated but its use is limited by its low genetic barrier to development of resistance, its potential for central nervous system toxicity, concerns about safety in the first trimester of pregnancy and its relatively high cost (Ford 2010). Among the alternative NNRTIs, rilpivirine has received attention as a potentially important drug for use in resource‐limited settings because of its low manufacturing cost, its ability to be co‐formulated with other antiretroviral, and its favourable safety profile (Ford 2011). Unlike efavirenz, rilpivirine does not appear to cause birth defects in animal experiments. Rilpivirine remains in the blood for prolonged periods, with a half‐life of 45 hours. This means that it can be taken once daily (Hosein 2010). The side effects of efavirenz, most especially the central nervous system toxicities is affecting compliance among patients on the medication thus increasing the rate of treatment failure and increasing resistant strains of the virus.The side effect profile of rilpivirine is at least equivalent to and potentially even better than nevirapine and efavirenz, the two most common antiretroviral medications used in resource‐limited settings (Cohen 2010).
Objectives
To evaluate the effectiveness of rilpivirine compared to efavirenz as first‐line treatment in patients with HIV infection.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials
Types of participants
HIV infected adults and children treated with HAART without prior exposure to ART. Pregnant or lactating women will be excluded, likewise children under 5 years of age because the WHO guidelines for under fives are different.
Types of interventions
We will consider any triple‐drug antiretroviral combination regimen for initial therapy containing two NRTIs plus either Rilpivirine compared with Efavirenz at any dose.
Types of outcome measures
Primary outcomes
All‐cause mortality
Secondary outcomes
1. Treatment failure ‐ defined as the number of participants with incomplete viral load
suppression (VL >50 copies/ml) or who experienced a virological rebound in the time frame reported by the authors.
2. CD4 cell count ‐ mean change in the concentration of the CD4 count from baseline
3. . Adverse events ‐ according to grade 1 to 4 of the Adverse Event Toxicity Scale (DAIDS 2009) and reported as the proportion of participants that experienced grade 3 and 4 clinical and laboratory adverse events. Using this scale, grade 1 and 2 will denote mild to moderate symptoms, grade 3‐serious symptoms and grade 4, life‐threatening events requiring significant clinical intervention.
4. Development of ART drug resistance
5. Opportunistic infection‐ the incidence of opportunistic infection
6. Adherence
Search methods for identification of studies
Electronic searches
We would develop comprehensive search strategy to identify all relevant studies. The following electronic databases will be searched to identify relevant RCTs:
1. The Cochrane Central Register of Controlled Trials (CENTRAL)
2. MEDLINE (1990 to date)
3. EMBASE (1990 to date)
4. LILACS (1985 to date)
5. CINAHL
6. WHO international clinical trial registry for completed and ongoing trials
The search will include the following MeSH terms in various combinations; Antiretroviral agents; HAART; Rilpivirine; TMC278; Efavirenz; NNRTI; Randomised controlled trials; Controlled trials; adverse effect; resistance; treatment failure etc.
Searching other resources
In addition we searched trials registries via the World Health Organization International Clinical Trials Platform Search Portal (http://apps.who.int/trialsearch/Default.aspx).
We will also searched the following electronic data base:
• AIDSInfo® (http://www.aidsinfo.nih.gov/).
• the International AIDS Society Conference on HIV Pathogenesis and Treatment (2001, 2003, 2005, 2007, 2009)
• International AIDS Conference (2010, 2011, 2012, 2013) will be searched using the International AIDS society. electronic database (available at http://www.iasociety.org/Default.aspx?pageId=7).
• Conference on Retroviruses and Opportunistic Infections(CROI),
• Interscience Conference on Antimicrobial Agents & Chemptherapy (ICAAC),
• The European AIDS Clinical Society (EACS) from 2001 to 2013.
We will handsearch the reference lists of all the relevant reviews and studies for additional studies. Information about trials not registered in MEDLINE, including unpublished ones, will be sought by contacting drug manufacturers, scanning reference list of articles, and contacting authors.
All the search will be made without any language restrictions.
Data collection and analysis
We will summarise data by standard Cochrane Collaboration methodology (Higgins 2011)
Selection of studies
Two authors will independently and manually identify citations and abstract of references to establish the possible relevance of the articles for inclusion into the review. Disagreement or doubt will be resolved by discussion or by one of the editors in the Cochrane HIV group. Studies that potentially meets the inclusion criteria based on the title, abstract or both will be obtained in full and assessed against the inclusion criteria.
Data extraction and management
Two authors will independently extract data from the selected trials using standardised data extraction forms. The following data will be extracted:
• Study details: citation, start and end dates, location, study design and details.
• Participant details: study population eligibility (inclusion and exclusion) criteria, ages, population size, attrition rate, details of HIV diagnosis and disease and any clinical, immunologic or virologic staging or lab information.
• Interventions details: drug names, doses, duration, ancillary testing and monitoring, any other information on adherence or resistance.
• Outcome details: mortality; response to ART [clinical (AIDS and non‐AIDS events), virologic and immunologic]; severe adverse events; development of ART drug resistance;
adherence/tolerability/retention; risk of sexual transmission of HIV.
Any disagreement will be resolved by discussion.
Assessment of risk of bias in included studies
Two authors will independently assess the risk of bias for each trial using a simple form and will follow the domain‐based evaluation as described in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011). We will compare the assessment results and discuss any discrepancies between ourselves. We aim to achieve agreement on the final assessment for each criteria by discussion.
The following domains will be assessed as low risk of bias, unclear risk of bias or high risk of bias;
1. Random sequence generation
2. Allocation concealment
3. Blinding of participants and personnel
4. Blinding of outcome assessor
5. Incomplete outcome data
6. Selective reporting
7. Other bias
We will use the following definitions:
Generation of allocation sequence
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low risk of bias, if the allocation sequence was generated by random number table, computer random number generator, coin tossing, throwing dice, drawing of lots, shuffling cards or envelopes or minimization.
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unclear risk of bias, if there is insufficient information about the sequence generation process
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high risk of bias, if a system involving dates, names, or admittance numbers was used for the allocation of patients.
Allocation concealment
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low risk of bias, if the allocation of patient involved a central independent unit, on‐site locked computer, sequentially numbered drug containers of identical appearance prepared by an independent pharmacist or investigator, or opaque sealed envelopes.
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unclear risk of bias, if the trial was described as randomised, but the method used to concealed the allocation was not described.
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high risk of bias, if there is insufficient information about the allocation concealment process to permit judgement.
Blinding
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low risk of bias, if there is no blinding but the outcome and the outcome measurement are not likely to be influenced by lack of blinding, if blinding of participants and key study personnel ensured and unlikely that the blinding could have been broken, if either participants or some key personnel were not blinded but outcome assessment was blinded and the non‐blinding of others unlikely to introduce bias.
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unclear risk of bias, if there are insufficient information to permit judgement or if the study did not address this outcome.
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high risk of bias, if no blinding or incomplete blinding was done and the outcome or outcome measurement is likely to be influenced by lack of blinding, if blinding of key study participants and personnel was done but likely that the blinding could have been broken, if the participants or some key study personnel were not blinded which could have introduced bias.
Incomplete outcome data
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low risk of bias, if there are no missing outcome data, reason for missing outcome data unlikely to be related to true outcome, missing outcome data balanced in numbers across intervention groups.
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unclear risk of bias, if there is insufficient reporting of attrition/exclusions to permit judgement of the study did not address this outcome.
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high risk of bias, if reason for missing outcome data likely to be related to true outcome, imbalance in the numbers or reason for missing data across intervention groups.
Selective outcome reporting
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low risk of bias, if the study protocol is available and all the prespecified outcomes of interest have been reported of if study protocol is not available but published reports include all expected outcomes.
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unclear risk of bias, if there is insufficient information to permit judgement.
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high risk of bias, if not all the prespecified primary outcomes have been reported.
Other potential threats to validity
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low risk of bias, if the study appears to be free of other sources of bias.
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unclear risk of bias, there may be a risk of bias but there is insufficient information to prove it.
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high risk of bias, if there is at least one important risk of bias.
Measures of treatment effect
Statistical analysis will be performed according to the statistical guidelines referenced in the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2011). For dichotomous outcomes, the measure of effect will be expressed as risk ratio (RR) and absolute risk (AR) with 95% confidence intervals (CI); and for continuous outcomes the measure of effect will be expressed as a mean difference (MD) with 95% CI. In the event that continuous data is reported on different continuous scales, outcomes will be standardised, where possible, to calculate the standardised mean difference.
Unit of analysis issues
The unit of analysis will be individuals. A single measurement for each outcome from each participant will be collected and analysed. We do not anticipate cluster trials or cross‐over trials.
Dealing with missing data
Percentage of dropout will be assessed in each trial and per each randomisation arm and we will then determine if an intention to treat analysis has been performed or could be performed with the available published information. When additional information is needed, we will contact the corresponding author of each study by e‐mail.
Assessment of heterogeneity
We will first assess clinical and methodological heterogeneity as described in the Cochrane Handbook for Systematic Reviews of Intervention. We will use the I² statistic to measure statistical heterogeneity among the trials in each analysis. if we identify substantial heterogeneity we will explore it by pre‐specified subgroup analysis. The I² statistic describes the percentage of total variation across trials that is due to heterogeneity rather than sampling error (Higgins 2003). We will consider there to be significant statistical heterogeneity if I²>50% (Higgins 2011).
Assessment of reporting biases
Where reporting bias is suspected, the authors will be contacted to provide missing outcome data. Where this is not possible, and the missing data are thought to introduce serious bias, the impact of including such studies in the overall assessment of results will be explored by a sensitivity analysis.
Data synthesis
We will combine data for outcomes from studies that meet the inclusion criteria in the meta‐analysis using the latest version of Review Manager software, provided the studies are sufficiently similar. Random effects meta‐analysis will be conducted, if appropriate. In instances where data could not be combined in a meta‐analysis, we will provide a narrative summary of the trial findings.
Subgroup analysis and investigation of heterogeneity
If statistical heterogeneity is present, we will attempt to further investigate potentially influential study characteristics by conducting subgroup analysis
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age (children/adolescent/adults)
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sex (males and females)
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baseline CD4 count
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dosage
Sensitivity analysis
If sufficient trials are identified, we plan to conduct a sensitivity analysis comparing the results using all trials as follows: Those RCTs that performed intention‐to treat versus per‐protocol analyses. Attrition bias will also be evaluated, estimated by the percentage of participants lost. Trials with a total attrition of more than 30% or where differences between the groups exceed 10% , or both, will be excluded from meta‐analysis but will be included in the review.
