Summary of findings
Description of the condition
Although there have been important advances in preventing new human immunodeficiency virus (HIV) infections and lowering the number of acquired immunodeficiency syndrome (AIDS)-related deaths, the number of people living with HIV continues to increase. In 2008, the number reached an estimated 33.4 million, which was 20% higher than in 2000; the prevalence was roughly three-fold higher than it was in 1990 (UNAIDS 2009). Also in 2008, approximately 2.7 million people became newly infected HIV patients, and about 2 million died from AIDS-related illnesses worldwide (UNAIDS 2009;Appendix 1). In 2012, there was an estimated 35.3 million people living with HIV, 2.3 million new HIV infections, 1.6 million AIDS deaths in 2012 globally (UNAIDS 2013; Appendix 1).The continuing rise in the number of people living with HIV is due to factors such as the beneficial effects of antiretroviral therapy (ART) and population growth. Recent epidemiological data indicated that the spread of HIV appeared to have peaked globally in 1996, when 3.5 million new HIV infections occurred (UNAIDS 2009).
Description of the intervention
Highly active antiretroviral therapy (HAART) is the main treatment for HIV infection and has significantly demonstrated efficacy in suppressing HIV replication and improving survival of people living with HIV infection and AIDS (Mocroft 1998; Palella 1998; Pujari 2004; Sivadasan 2009). Antiretroviral agents are drawn from four treatment classes: nucleoside reverse transcriptase inhibitors (NRTI), nonnucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors, and fusion inhibitors (Murga 2006). Standard ART consists of at least three antiretroviral drugs to maximally suppress the HIV virus and stop the progression of the disease. Although very large reductions in death rates have been seen with use of a potent antiretroviral regimen, there is no cure for HIV infection. Drug toxicity of HAART may be life-threatening, disfiguring or distressing, thus adversely affecting quality of life and the potential for optimum adherence to antiretroviral therapy. Lack of adherence ultimately leads to the emergence of resistance to antiretroviral drugs, and treatment failure (Sivadasan 2009). Therefore, new agents and treatment strategies that can be deployed in novel combination regimens need to be developed (Murga 2006).
PRO 140 (a humanized form of the PA14 antibody, a monoclonal CCR5 antibody) is a chemokine receptor CCR5 monoclonal antibody that broadly and potently inhibits CCR5-tropic (R5) HIV-1 at concentrations that do not antagonize the natural activity of CCR5 in vitro (Rusert 2005; Shearer 2006). PRO 140 may be an effective new treatment drug because it has the potential to address the limitations of currently available therapies for HIV-infected patients, including the emergence of multidrug resistant viruses, significant side effects, drug-drug or drug-food interactions, and often complex daily treatment regimens (Richard 2006). PRO 140 has emerged as an important target for novel HIV-1 therapies and has entered testing. In a 39-person safety and efficacy study (Jacobson 2008), the drug reduced HIV viral loads by an average maximal decrease of 1.83 log
How the intervention might work
The basic mechanism of PRO 140 is to stop HIV from entering cells and stop viral replication. Entry of HIV-1 proceeds through a cascade of events mediated by the HIV-1 envelope glycoproteins gp120 and gp41. The glycoprotein gp120 sequentially binds CD4 and then CCR5 or another coreceptor molecule, thereby triggering gp41-mediated fusion of the viral and cellular membranes (Murga 2006). CCR5 is a requisite fusion coreceptor used by the virus as a portal by which to enter and infect healthy cells. PRO 140 is an anti-CCR5 monoclonal antibody that potently inhibits HIV-1 entry and replication at concentrations that do not affect CCR5's chemokine receptor activity in vitro (Trkola 2001). PRO 140 inhibits entry of HIV into cells by preventing virus-cell binding at a distinct site on the CCR5 co-receptor without interfering with the natural activity of CCR5. It binds an extracellular (not a transmembrane) site, inhibiting HIV via a competitive, rather allosteric, mechanism (AIDS info).
Why it is important to do this review
Although HAART showed improved efficacy in HIV-infected patients, multidrug resistance or treatment related toxicities are the main problems in the treatment. Therefore, new antiretroviral drugs are needed, such as PRO 140, that have no multidrug resistance or toxicities for HIV-infected patients. This review is necessary because we must make clear the exact efficacy and safety of PRO 140 for HIV-infected patients based on available RCTs.
The primary objective of this review was to assess the efficacy and safety of PRO 140 in HIV-infected patients (including adults and children). The second objective was to assess clinical disease progression and immunologic (CD4 count/percentage) and virologic (plasma HIV RNA viral load) markers of PRO 140.
Criteria for considering studies for this review
Types of studies
We only included RCTs and quasi-RCTs. It is impossible for PRO 140 to be administered to HIV-infected patients in cluster-randomized trials or cross-over trials; therefore, we only included individual RCTs with parallel design that compared PRO 140 with placebo or other HIV medications (including other CCR5 antagonists), or different doses for HIV-infected patients.
Types of participants
Individuals infected with HIV regardless of age, race/ethnicity, sexual orientation (gay/homosexual, bisexual, heterosexual), gender identity (including transsexuals), nationality, etc.
Types of interventions
PRO 140 administrated intravenously or subcutaneously, as compared with placebo or other antiretroviral drugs, including other CCR5 antagonists such as vicriviroc and the entry inhibitors enfuvirtide and maraviroc. Comparisons between different doses or administrations of PRO 140 were considered. We excluded interventions that combined PRO 140 with other therapies for HIV patients.
- PRO 140 versus placebo.
- Different doses or administrations of PRO 140.
- PRO 140 versus other HIV medications (including other CCR5 antagonists).
Types of outcome measures
- Clinical laboratory results (including change of log
10HIV RNA viral load from baseline, maximum change in viral load following initiation of treatment, antiviral response which was defined as a ≧ 1.0 log 10copies/mL reduction in HIV RNA level at any time after treatment, change of CD4 +cell count from baseline, and other parameters following PRO 140 administration, etc.).
- Number of subjects with ≦ 400 copies/mL HIV RNA.
- Survival rates.
- Safety and tolerability parameters (including adverse events).
- Progression to AIDS.
- Any death.
- Quality of life: ability to perform daily activities, cognitive function, etc.
Search methods for identification of studies
We searched databases including The Cochrane Central Register of Controlled Trials (The Cochrane Library 2014, Issue 4), MEDLINE (PubMed, January 1966 to April 2014), EMBASE (January 1978 to April 2014) and ISI Web of Knowledge (January 1966 to April 2014) for randomized trials in HIV-infected patients who were treated with PRO 140 to the date of the search. We conducted all searches on 17 May 2010 and updated them on 30 April 2014. We did not impose any language restrictions. We combined the MEDLINE search string with the Cochrane Highly Sensitive Search Strategy for identifying RCTs in all the databases (Higgins 2011). The detailed search strategies for each database searched were presented in Appendix 2.
Searching other resources
Online trial searches
We searched the following databases for ongoing RCTs.
- ClinicalTrials.gov (http://clinicaltrials.gov/).
- Current Controlled Trials (http://www.controlled-trials.com/isrctn/).
- WHO International Clinical Trials Registry Platform (ICTRP) (http://www.who.int/ictrp/en/).
- Chinese Clinical Trial Registry (www.chictr.org).
- Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au/default.aspx).
- Clinical Trials Registry - India (CTRI) (http://ctri.nic.in/Clinicaltrials/login.php).
- Association of the British Pharmaceutical Industry (ABPI) Pharmaceutical Industry Clinical Trials database (http://www.abpi.org.uk/our-work/library/Pages/default.aspx).
In addition, we searched the reference lists of related literature reviews and eligible articles. We performed a handsearch for abstracts published from 1995 to 2008 for presentations at the International Conference on HIV/AIDS in Africa (ICASA). We also searched abstracts from other important HIV meetings conducted by the Conference on Retroviral and Opportunistic Infections (CROI), European Aids Clinical Society (EACS), and International AIDS Society (IAS).
Data collection and analysis
Selection of studies
Two reviewers (L Li and JH Tian) independently screened all titles and abstracts of the citations identified through the searches. If both reviewers believed that the abstracts were potentially relevant, they screened the full-text articles independently to determine whether the study was eligible for inclusion or not. We applied inclusion and exclusion criteria using a standard form to determine eligibility based on the types of participants, interventions, outcome measures and study designs to select studies. We rejected studies on initial screening if it could be determined that they were not RCTs or relevant to PRO 140 for HIV infections. We excluded other papers that did not meet the inclusion criteria after applying prespecified eligibility criteria (see Figure 1). A third review author (KH Yang) was available to resolve any disagreements.
|Figure 1. Study flow diagram.|
Data extraction and management
In keeping with the guidance of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), we used a standardized study record form in data extraction. Two non-blinded authors (P Zhang and WQ Jia) independently extracted the data using a standardized data extraction form. We gathered the following information from each included study.
- Administrative details - titles, authors, publication, year of publication, volume number, issue number, and page numbers (if published); or titles, conductors, year in which the study was conducted (if not published); and details of other relevant papers.
- Details of study - study design, inclusion and exclusion criteria, number of participants, characteristics of participants (including age, sex, CD4-cell count; prior use of antiretroviral drugs); number excluded, number enrolled, number analyzed; dropouts and losses; type, duration, frequency and completeness of follow-up; country and location of the study.
- Details of intervention - doses, and routes of administration.
- Details of outcomes - primary and secondary outcomes.
Any disagreements about data extraction were resolved by the adjudication of a third reviewer (KH Yang).
Assessment of risk of bias in included studies
Two review authors (L Li and P Zhang) independently assessed the quality of each included trial according to the Cochrane Collaboration's tool for assessing risk of bias (Chapter 8 of Higgins 2011). We resolved discrepancies through discussion. If there was insufficient information about the study methods, we contacted the first author or the corresponding author for further information. If the trial authors did not respond within four or more weeks, we assessed risk of biases from the available information. We assessed these items as 'low risk' of bias, 'unclear risk' of bias, or 'high risk' of bias (see Appendix 3).
Measures of treatment effect
In keeping with the guidance of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), we defined measures of treatment effects as follows.
For dichotomous outcomes, results were expressed as odds ratios (ORs) with 95% confidence intervals (CIs). For continuous variables, we used recommended methods to collect and combine the data. We used the mean difference (MD), or a standardized mean difference (SMD) if different scales. For quality of life, we measured it as ordinal data, which was reported qualitatively.
Unit of analysis issues
PRO 140 cannot be administered to HIV-infected patients in cluster-randomized trials or cross-over trials; therefore, we only included individual RCTs with parallel design. As a result, individual participants were the unit of analysis.
Dealing with missing data
We tried our best to contact the authors (by email, telephone or fax when available) of the original studies for missing data. If all the authors of the study did not respond within four or more weeks, we extracted all the available data from the published report. We used sensitivity analyses to explore the impact of missing data in the assessment of treatment effect. If data were missing because of drop-out of participants or loss to follow-up, we conducted a primary analysis based on intention-to-treat analysis.
Assessment of heterogeneity
We examined heterogeneity among trials using the Chi
Assessment of reporting biases
If it was possible, we had planned to assess reporting biases by using funnel plots in our review.
We used the Review Manager software (RevMan 2012) provided by the Cochrane Collaboration for statistical analysis on an intention-to-treat basis. Meta-analysis was considered to measure the appropriate measure of effect if the search yielded a group of trials sufficiently homogeneous in terms of measured outcomes. According to the level of heterogeneity between trials, we used either fixed- or random-effects models where appropriate, and after careful consideration we pooled the outcomes and examined the differences between the two models. If significant heterogeneity existed and the reasons for heterogeneity could not be found, we reported the results qualitatively. For dichotomous outcomes, we expressed results as ORs with 95% CI. We pooled data using the fixed-effect model but also considered the random-effects model to ensure robustness of the model. If there were continuous scales of measurement, we used the MD to assess the effects of treatment, or the SMD if different scales had been used.
Subgroup analysis and investigation of heterogeneity
Subgroup analyses were planned to explore possible sources of heterogeneity, including routes of administration, dose, duration of therapy, and the different kinds of patients (adults or children). If significant heterogeneity existed, the causes of heterogeneity would be investigated. If the trends of all subgroups were the same, we would combine the results of subgroup analyses to find the overall trend of the interventions. If not, we would combine the overall results.
Sensitivity analyses would have been made to explore the influence of possible sources and studies of low methodological quality. If significant heterogeneity had existed after subgroup and sensitivity analysis, at the same time the reasons for heterogeneity could not be found, we would have had to report the results qualitatively.
Description of studies
Results of the search
After comprehensive searches (conducted on 17 May 2010 and updated on 30 April 2014), we found 381 citations identified through electronic databases (Cochrane Central Register of Controlled Trials (CENTRAL): 75 citations; MEDLINE (PubMed): 31 citations; EMBASE: 213 citations; and ISI Web of Science: 15 citations. We identified additional records (46 citations) through other sources (WHO ICTRP: four citations; ClinicalTrials.gov: 33 citations; Current Controlled Trials: one citation, and reference tracking eight citations).
After screening based on titles and abstracts, we identified 17 potential citations for further review, as we excluded 148 citations which were duplicates, 109 citations which were not relevant to PRO 140, 77 citations which were not relevant to HIV/AIDS, and 29 citations which were not clinical trials. We excluded seven citations that were in vitro studies (Ketas 2003; Ketas 2007; Morrow 2003; Murga 2006; Pugach 2008; Rusert 2005; Shearer 2006), four citations which were not clinical trials (Boesecke 2012; Khatib 2010; Tenorio 2011; Trkola 2001), and one citation that were not published ( NCT01272258). We have tried to contacted the investigators of the three trials, but they did not respond. We ultimately included three trials (six citations, Jacobson 2008; Jacobson 2010a; Jacobson 2010b). (See Figure 1 for flowchart of screening process).
We included three RCTs (Jacobson 2008; Jacobson 2010a; Jacobson 2010b), which fulfilled our inclusion criteria. The characteristics of the included trials are presented in Characteristics of included studies. The baseline characteristics of treated subjects for each study are in Appendix 4, Appendix 5 and Appendix 6.
Based on titles and abstracts, 148 citations which were duplicates, 109 citations which were not relevant to PRO 140, 77 citations which were not relevant to HIV/AIDS, and 29 citations which were not clinical trials were excluded. Based on full-texts, we excluded seven citations that were in vitro studies (Ketas 2003; Ketas 2007; Morrow 2003; Murga 2006; Pugach 2008; Rusert 2005; Shearer 2006), four citations which were not clinical trials (Boesecke 2012; Khatib 2010; Tenorio 2011; Trkola 2001), and one citation that were not published (NCT01272258). See Characteristics of excluded studies.
Risk of bias in included studies
|Figure 2. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.|
We tried to contact all the authors of the original studies for information about missing risk of bias data, but they did not respond. We analyzed the studies based on available information. All studies (Jacobson 2008; Jacobson 2010a; Jacobson 2010b) mentioned randomization and double-blinded, but any details about the methods were not mentioned. Allocation concealment, incomplete outcome data, and selective reporting were also not specified. There may be potential conflicts of interest in all studies (Jacobson 2008; Jacobson 2010a; Jacobson 2010b), as some of the authors are current or past employees of Progenics Pharmaceuticals, the producer of PRO 140. As such, they may hold stock in the company.
All studies (Jacobson 2008; Jacobson 2010a; Jacobson 2010b) mentioned randomization, but they did not describe the method in detail. These three studies did not mention allocation concealment. The study authors did not respond to our requests for clarification.
Incomplete outcome data
Unclear. The study authors did not respond to our requests for clarification.
Unclear. The study authors did not respond to our requests for clarification.
Other potential sources of bias
There may be potential conflicts of interest in all studies (Jacobson 2008; Jacobson 2010a; Jacobson 2010b), as some of the authors are current or past employees of Progenics Pharmaceuticals, the producer of PRO 140. The three included studies were supported by the US National Institutes of Health (Public Health Service grant AI066329).
Effects of interventions
See: Summary of findings for the main comparison PRO 140 compared to placebo for treatment of people with HIV infection; Summary of findings 2 PRO 140 compared to placebo for treatment of people with HIV infection
Changes in HIV-1 RNA level
Single IV infusion of PRO 140 0.5 mg/kg did not show any beneficial effects (MD -0.19, 95% CI -0.42 to 0.04) in the maximum changes in HIV-1 RNA level after the 58-day follow-up period. The other doses (single IV infusion of PRO 140 2 mg/kg, 5 mg/kg, 10 mg/kg, 162 mg weekly, 324 mg weekly, 324 mg biweekly) showed significantly statistical differences between the subjects who were treated with PRO 140 and patients treated with placebo ( Analysis 1.1;Figure 3).
|Figure 3. Forest plot of comparison: 1 PRO 140 versus placebo, outcome: 1.1 Individual nadir changes in HIV-1 RNA level.|
One trial (Jacobson 2008) reported the changes in HIV-1 RNA levels on day 10. There was not a significantly statistical difference in the reductions of HIV-1 RNA level on day 10 between patients with single IV infusion of PRO 140 0.5 mg/kg and placebo (MD -0.24, 95% CI -0.61 to 0.13). The other two doses (single IV infusion of PRO 140 2 mg/kg, 5 mg/kg) showed that PRO 140 significantly reduced HIV-1 RNA level on day 10 ( Analysis 1.2;Figure 4).
|Figure 4. Forest plot of comparison: 1 PRO 140 versus placebo, outcome: 1.2 Changes in HIV-1 RNA level on day 10.|
One trial (Jacobson 2010b) reported the changes in HIV-1 RNA levels on day 12. The result revealed that single IV infusion of PRO 140 5 mg/kg (MD -1.71, 95% CI -1.96 to -1.46) and 10 mg/kg (MD -1.75, 95% CI -2.00 to -1.50) was associated with reduced HIV-1 RNA levels on day 12. And the combined results showed that PRO 140 could reduce HIV-1 RNA levels on day 12 (MD -1.73, 95% CI -1.91 to -1.55) without any statistical heterogeneity among the studies (I
|Figure 5. Forest plot of comparison: 1 PRO 140 versus placebo, outcome: 1.3 Changes in HIV-1 RNA level on day 12.|
One trial (Jacobson 2010a) reported the changes in HIV-1 RNA levels on day 22. All the doses (162 mg weekly, 324 mg biweekly, 324 mg weekly) showed that PRO 140 significantly reduced HIV-1 RNA levels on day 22. The pooled estimate of PRO 140 in the reductions of HIV-1 RNA level on day 22 was -0.87 (95% CI -1.08 to -0.66) with a high amount of statistical heterogeneity among the studies (I
|Figure 6. Forest plot of comparison: 1 PRO 140 versus placebo, outcome: 1.4 Changes in HIV-1 RNA level on day 22.|
Antiviral response was defined as a >1.0 log
Number of subjects with ≦ 400 copies/mL HIV-1 RNA
There were 0 subjects with ≦ 400 copies/mL HIV-1 RNA for single IV infusion of PRO 140 0.5 mg/kg in both groups. There were significantly statistical differences in the number of subjects with ≦ 400 copies/mL HIV-1 RNA between the PRO 140 324 mg weekly (OR 51.00, 95% CI 2.30 to 1129.95), 5 mg/kg (OR 43.99, 95% CI 4.22 to 459.01; I
Change in CD4
As two studies (Jacobson 2010a; Jacobson 2010b) did not supply sufficient data of the doses of 162 mg weekly, 324 mg biweekly, 324 mg weekly, 5 mg/kg, and 10 mg/kg, we just analyzed the data of PRO 140 in the doses of 0.5 mg/kg, 2 mg/kg, and 5 mg/kg in the changes of CD4
The authors of the three studies did not report enough information about adverse events for each group. In Jacobson 2008, the most frequently reported adverse events were headache in 12 subjects; lymphadenopathy in 11 subjects; and diarrhoea and fatigue in eight subjects. In Jacobson 2010a, the most frequently reported systemic adverse events were diarrhoea (6 of 44), headache (6 of 44), lymphadenopathy (5 of 44), and hypertension (4 of 44). Jacobson 2010b reported that the most frequently reported systemic adverse events were headache in one subject in the 5 mg/kg group and two subjects in the 10 mg/kg group, nasal congestion in two subjects in the placebo group and one subject in the 10 mg/kg group, and pruritus in three subjects in the placebo group. As sufficient data of adverse events to allow for statistical pooling were lacking, we did not pool the data of adverse events.
Other outcomes (including progression to AIDS, any death, quality of life issues, survival rates) were not reported in these three trials.
Summary of main results
This review indicates that PRO 140 might offer significant dose-dependent HIV-1 RNA suppression and tolerable side effects. All the doses except single IV infusion of PRO 140 0.5mg/kg (single IV infusion of PRO 140 2 mg/kg, 5 mg/kg, 10 mg/kg, 162 mg weekly, 324 mg biweekly and 324 mg weekly) showed significantly statistical differences in the nadir changes in HIV-1 RNA level between the two groups. Two doses (single IV infusion of PRO 140 2 mg/kg and 5 mg/kg) showed that PRO 140 significantly reduced HIV-1 RNA levels on day 10. Two doses (single IV infusion of PRO 140 10 mg/kg and 5 mg/kg) showed that PRO 140 significantly reduced HIV-1 RNA levels on day 12. The three doses (162 mg weekly, 324 mg biweekly and 324 mg weekly) showed that PRO 140 significantly reduced HIV-1 RNA levels on day 22. All the doses except single IV infusion of PRO 140 0.5 mg/kg (single IV infusion of PRO 140 2 mg/kg, 5 mg/kg, 10 mg/kg, 162 mg weekly, 324 mg biweekly and 324 mg weekly) demonstrated greater antiviral responses than placebo. Three doses of the PRO 140 group (324 mg weekly, 5 mg/kg, 10 mg/kg) showed more patients with ≦ 400 copies/mL HIV-1 RNA than placebo-treated patients. Only the single IV infusion of PRO 140 showed greater changes in CD4
The authors of the three studies did not report sufficient information about adverse events for each group. As a result, we did not pool the results. Headache, lymphadenopathy, diarrhoea, fatigue, hypertension, nasal congestion and pruritus were reported to be the most frequent adverse events.
Overall completeness and applicability of evidence
Although PRO 140 has been granted fast-track approval status by the United States FDA, the efficacy of PRO 140 has not yet been proven in large double-blind RCTs. The numbers of patients in these three studies (Jacobson 2008; Jacobson 2010a; Jacobson 2010b) were very small, and the results of these three studies may be influenced by potential biases. Their durations of follow-up were very short, only 58 or 59 days. The long-time efficacy was not evaluated, and the data of adverse events were not reported adequately in each group. Although available evidnece showed that PRO 140 might offer significant short-term dose-dependent HIV-1 RNA suppression with tolerable side effects, but any recommendations could not be made based on these three studies. Whether PRO 140 could be used in clinical practice as front-line treatment for HIV-infected patients or not depends on the effects in the future of large double-blind RCTs.
Quality of the evidence
All studies (Jacobson 2008; Jacobson 2010a; Jacobson 2010b) mentioned randomization and blinding, but any details about the methods were not found. And allocation concealment, incomplete outcome data, and selective reporting were unclear at the same time. The methodological quality of these three studies was low, as there were so many methodological problems, which may reduce the quality of evidence. The big problem was that there may be potential conflicts of interest in these three studies, which make the research results unreliable and unbelievable. The number of patients in these three studies (Jacobson 2008; Jacobson 2010a; Jacobson 2010b) was very small, and the results of these three studies may be influenced by potential biases. Thus, the quality of the evidence from available RCTs was low ( Summary of findings for the main comparison, Summary of findings 2).
Potential biases in the review process
We conducted electronic, online trial and manual searches to search for relevant articles, but there may still have been papers we did not find. This review only includes published data; unpublished data of PRO 140 were not included (although we requested the data from the study authors). As a result, selective biases may exist in our review.
Agreements and disagreements with other studies or reviews
Available published data about PRO 140 in these three studies (Jacobson 2008; Jacobson 2010a; Jacobson 2010b) showed positive results and were consistent with each other. All (Jacobson 2008; Jacobson 2010a; Jacobson 2010b) showed that PRO 140 offered the potential for significant dose-dependent HIV-1 RNA suppression and infrequent patient self-administration. Any studies or reviews disagreeing with such results for PRO 140 have not been published.
Implications for practice
These three small trials suggested PRO 140 may demonstrate potent, dose-dependent, highly significant antiviral activity. But the frequency of adverse effects could not be determined from the evidence available. Meanwhile, the methodological quality of these three studies was low, and the number of patients in these three studies was very small, which made the quality of the evidence from available RCTs low. That is why available evidence is not sufficient and conclusive to determine whether PRO 140 was effective in HIV patients or not. Thus, at this stage, we cannot recommend PRO 140 as a therapy for the treatment of HIV patients based on available insufficient evidence.
Implications for research
This review analyses three small, preliminary phase I/IIa clinical trials. Larger, longer-term, double-blind, randomized phase IIb and III trials need to be performed in order to determine the potential role of PRO 140 as a therapy for HIV infection and to provide conclusive evidence of the efficacy and safety of PRO 140 for HIV patients. Not only should the short-term anti-HIV activity and safety of PRO 140 be evaluated in future studies, but also its long-term efficacy and safety. The methodological quality of these three trials (Jacobson 2008; Jacobson 2010a; Jacobson 2010b) were too low, and therefore the evidence they produced was also of low quality. As a result, in the future the RCTs related to PRO 140 for HIV-infected patients should be well conducted (adapting strict randomization, blinding and allocation concealment methods) and transparently reported with a long follow-up.
The review authors would like to thank the following people (in addition to the peer referees) for commenting on the draft protocol and full-text: Angela Broad, Tara Horvath, JinHui Tian, and ShaoLiang Sun.
Data and analyses
- Top of page
- Summary of findings [Explanations]
- Authors' conclusions
- Data and analyses
- What's new
- Contributions of authors
- Declarations of interest
- Differences between protocol and review
- Index terms
Appendix 1. Appendix 1
Part 1: Global summary of the AIDS epidemic December 2008 (UNAIDS 2009 )
Part 2: Global summary of the AIDS epidemic in 2012 (UNAIDS 2013)
Appendix 2. Search strategy
#1 PRO 140
#3 #1 or #2
#5 MeSH descriptor HIV explode all trees
#6 HIV infections
#7 MeSH descriptor HIV infections explode all trees
#8 Human immunodeficiency virus
# 10 MeSH descriptor Acquired Immunodeficiency Syndrome explode all trees
#11 Acquired Immunodeficiency Syndrome
#12 #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11
#13 #3 and #12
MEDLINE search strategy (PubMed)
#1 randomized controlled trial [pt]
#2 controlled clinical trial [pt]
#3 randomized [ti/ab]
#4 placebo [ti/ab]
#5 drug therapy [sh]
#6 randomLy [ti/ab]
#7 trial [ti/ab]
#8 groups [ti/ab]
#9 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8
#10 animals [mh] not (humans [mh] and animals [mh])
#11 #9 not #10
#12 PRO 140 [mh]
#13 PA14 [ti/ab]
#14 PRO 140 [ti/ab]
#15 #12 or #13 or #14
#16 HIV [mh]
#17 HIV [ti/ab]
#18 Human immunodeficiency virus [ti/ab]
#19 HIV infections [mh]
#20 HIV infections [ti/ab]
#21 AIDS [mh]
#22 Acquired Immunodeficiency Syndrome [ti/ab]
#23 AIDS [ti/ab]
#24 #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23
#25 #11 and #14 and #24
EMBASE search strategy (via EMBASE.COM)
#1 'randomized controlled trial': it
#2 'controlled clinical trial': it
#3 randomized: ab
#4 placebo: ab
#5 randomLy: ab
#6 trial: ab
#7 groups: ab
#8 #1 or #2 or #3 or #4 or #5 or #6 or #7
#9 'PRO 140'/exp
#10 'PRO 140'
#11 'PA 14'
#12 #9 or #10 or #11
#14 'human immunodeficiency virus'
#15 'human immunodeficiency virus'/exp
#16 'HIV infections'
#17 'human immunodeficiency virus infection'/exp
#19 'Acquired Immunodeficiency Syndrome'
#20 'Acquired Immunodeficiency Syndrome'/exp
#21 #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20
#22 #8 and #12 and #21
ISI Web of Knowledge
#1 Topic= (PRO 140) OR Topic = (PA 14)
#2 Topic= (HIV) OR Topic = (HIV infections) OR Topic = (human immunodeficiency virus) OR Topic = (AIDS) OR Topic = (Acquired Immunodeficiency Syndrome)
#3 Topic= (random*) OR Topic= (groups) OR Topic= (controlled clinical trial) AND Topic= (randomised controlled trial)
# 4 #1 AND #2 AND #3
Appendix 3. Bias assessment
Appendix 4. Baseline characteristics of Jacobson JM 2008 study
Appendix 5. Baseline characteristics of Jacobson JM 2010a study
Appendix 6. Baseline characteristics of Jacobson JM 2010b study
Last assessed as up-to-date: 30 April 2014.
Protocol first published: Issue 3, 2010
Review first published: Issue 12, 2010
Contributions of authors
Declarations of interest
All authors have nothing to declare, none of them was funded.
Differences between protocol and review
Due to few studies we included, we did not assess reporting biases, conduct subgroup analyses of duration of therapy, the different kinds of patients (adults or children), and conduct sensitivity analysis.
Medical Subject Headings (MeSH)
*CCR5 Receptor Antagonists; Anti-HIV Agents [*therapeutic use]; Antibodies, Monoclonal [*therapeutic use]; Antibodies, Monoclonal, Humanized [*therapeutic use]; Drug Administration Schedule; HIV Antibodies [*therapeutic use]; HIV Infections [*drug therapy]; HIV-1 [*genetics]; RNA, Viral [blood]; Randomized Controlled Trials as Topic
MeSH check words