Monoclonal CCR5 antibody for treatment of people with HIV infection
Abstract
Background
A monoclonal CCR5 antibody, PRO 140 (a humanised form of the PA14 antibody), inhibits CCR5‐tropic (R5) HIV‐1. This may be an effective new treatment for HIV‐infected patients, with the potential to address the limitations of currently available therapies.
Objectives
We aimed to assess the efficacy and safety of PRO 140 for HIV‐1‐infected patients in randomised controlled trials (RCTs).
Search methods
Databases including Cochrane's CENTRAL, PubMed, EMBASE and ISI Web of Knowledge, online trials registries and other sources were searched. The reference lists of related literature and presentations from major HIV/AIDS conferences were also screened.
Selection criteria
RCTs and quasi‐RCTs comparing PRO 140 with placebo or other antiretroviral drugs, or different doses for individuals infected with HIV.
Data collection and analysis
Two reviewers (L Li and TT Sun) independently screened all retrieved citations and selected relevant citations. Data were extracted independently by two authors (P Zhang and WQ Jia). Any disagreements when selecting studies and extracting data were adjudicated the review mentor (KH Yang). RevMan software was used for statistical analysis based an intention‐to‐treat analysis. Heterogeneity was examined using the I2 statistic. I2 estimates greater than 50% were regarded as moderate or high levels. According to the level of heterogeneity, either fixed or random effects models were used. If significant heterogeneity existed and the reasons could not be found, we reported the results qualitatively.
Main results
We included 2 trials comparing PRO 140 with placebo in adult patients with HIV infection. Our review indicates that PRO 140 may offer significant dose‐dependent HIV‐1 RNA suppression with tolerable side effects. PRO 140 2mg/Kg, 5 mg/Kg, 162mg weekly, 324 mg biweekly, 324 mg weekly showed statistically significant differences in the changes of HIV RNA level. Both HIV‐1 RNA levels of PRO 140 2mg/Kg, 5mg/Kg on day 10 and PRO 140 162mg weekly, 324 mg biweekly, 324 mg weekly on day 22 were significantly reduced. PRO 140 0.5mg/Kg, 2mg/Kg, 5mg/Kg, 162 mg weekly; 324 mg biweekly; 324 mg weekly demonstrated greater antiviral response. Only PRO 140 324 mg weekly showed more patients with ≦400 copies/mL HIV‐1 RNA. Only PRO 140 5 mg/Kg showed greater change in CD4+ cell count on day 8. Headache, lymphadenopathy, diarrhoea, fatigue, and hypertension were reported to be the most frequent adverse events.
Authors' conclusions
Limited evidence from two small trials suggests that PRO 140 might demonstrate potent, dose‐dependent, highly significant antiviral activity. The evidence is insufficient, so recommendations cannot yet be made. Larger, longer‐term, double‐blind RCTs are required to provide conclusive evidence.
PICOs
Plain language summary
PRO 140 for treatment of people with HIV infection
PRO 140 is a laboratory‐made antibody that blocks the CCR5 receptor on CD4 cells. By blocking CCR5, PRO 140 prevents the HIV virus from infecting healthy cells. PRO 140 may be an effective new treatment drug for HIV‐infected patients because it has the potential to address the limitations of currently available therapies. PRO 140 has emerged as an important new therapy and has entered testing. this review included two small randomised controlled trials (RCTs).
Even though available evidence from the two trials suggests that PRO 140 may be effective, the number of patients in these two studies was very small, and the results of these two studies may be influenced by potential biases. PRO 140 has been granted fast‐track approval status by the United States Food and Drug Administration, but the efficacy of PRO 140 still needs to be proven in large, long‐term high‐quality RCTs. The two studies reviewed here only evaluated the short time (59 days) efficacy. The long time efficacy was not evaluated, and adverse events data were not reported adequately for each group. So, we can not judge the effects and safety of PRO 140 from these two small trials, and any recommendations cannot yet be made for applying this evidence. Whether PRO 140 could be used in clinical practice as first‐line treatment for HIV depends on the results of high‐quality future RCTs.
