PRO 140 (a humanized form of the PA14 antibody, a monoclonal CCR5 antibody) 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 because it has the potential to address the limitations of currently available therapies for HIV-infected patients. PRO 140 has emerged as an important new therapy and has entered testing.
We reviewed the efficacy, safety, clinical disease progression and immunologic (CD4 count/percentage) and virologic (plasma HIV RNA viral load) markers of PRO 140 for HIV-infected patients. We included three randomized controlled trials (RCTs). The evidence is current to April, 2014. These three RCTs were of unclear risk of bias, as the details of methodological items were not adequately reported. All patients in these three studies were adult HIV-infected patients, PRO 140 was adminstrated subcutaneous or intravenous infusion with different doses. These three studies adressed the immunologic (CD4 count/percentage) and virologic (plasma HIV RNA viral load) markers. There may be potential conflicts of interest in all studies, as some of the authors are current or past employees of Progenics Pharmaceuticals, the producer of PRO 140.
Our systematic review showed that PRO 140 may offer significant short-term dose-dependent HIV-1 RNA suppression with tolerable side effects. PRO 140 2 mg/kg, 5 mg/kg, 10 mg/kg, 162 mg weekly, 324 mg biweekly, and 324 mg weekly could reduce HIV-1 RNA levels and demonstrate antiviral response. And PRO 140 5 mg/kg showed greater change in CD4+ cell count on day eight. Headache, lymphadenopathy, diarrhoea, fatigue, hypertension, nasal congestion and pruritus were reported to be the most frequent adverse events. Even though available evidence from the three trials suggests that PRO 140 may be effective, the number of patients in these three studies was very small, and the results of these three studies may be influenced by potential biases. So the quality of the evidence from available RCTs was low.
PRO 140 has been granted fast-track approval status by the United States Food and Drug Administration (FDA), but the efficacy of PRO 140 still needs to be proven in large, long-term high quality RCTs. The three studies reviewed here only evaluated the short-term (58 or 59 days) efficacy. The long-term efficacy was not evaluated, and adverse events data were not reported adequately for each group. So 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-infected patients or not depends on the results of high quality future RCTs.
Limited evidence from three small trials suggests that PRO 140 might demonstrate potent, short-term, dose-dependent, highly significant antiviral activity. However, as the evidence is insufficient, recommendations cannot yet be made. Larger, longer-term, double-blind RCTs are required to provide conclusive evidence.
PRO 140 (a humanized form of the PA14 antibody, a monoclonal CCR5 antibody) inhibits CCR5-tropic (R5) type 1 human immunodeficiency virus (HIV). This may be an effective new treatment with the potential to address the limitations of currently available therapies for HIV-infected patients.
We aimed to assess the efficacy, safety, clinical disease progression and immunologic (CD4 count/percentage) and virologic (plasma HIV RNA viral load) markers of PRO 140 for HIV-infected patients in randomized controlled trials (RCTs) and quasi-randomized controlled trials (quasi-RCTs).
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), online trials registries and other sources. We also screened the reference lists of related literature and eligible studies, and presentations from major HIV/AIDS (human immunodeficiency virus/acquired immunodeficiency syndrome) conferences.
We included RCTs and quasi-RCTs comparing PRO 140 with placebo or other antiretroviral drugs, or different doses of PRO 140 for individuals infected with HIV.
Two reviewers (L Li and JH Tian) independently screened all retrieved citations and selected eligible studies. Two authors (P Zhang and WQ Jia) independently extracted data. Any disagreements when selecting studies and extracting data were adjudicated by the review mentor (KH Yang). We used Review Manager (RevMan) software for statistical analysis based on an intention-to-treat analysis. We examined heterogeneity using the Chi2 statistic. We regarded I2 estimates greater than 50% as moderate or high levels of heterogeneity. According to the level of heterogeneity, we used either a fixed or random-effects model.If significant heterogeneity existed and the reasons could not be found, we reported the results qualitatively.
We included three 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 2 mg/kg, 5 mg/kg, 10 mg/kg, 162 mg weekly, 324 mg biweekly, and 324 mg weekly showed statistically significant differences in the changes of HIV-1 RNA levels. HIV-1 RNA levels were reduced by intravenous (IV) infusion of PRO 140 2 mg/kg or 5 mg/kg on day 10, 5 mg/kg or 10 mg/kg on day 12, 162 mg weekly, 324 mg biweekly, or 324 mg weekly on day 22. PRO 140 2 mg/kg, 5 mg/kg, 10 mg/kg, 162 mg weekly, 324 mg biweekly, and 324 mg weekly demonstrated greater antiviral response. PRO 140 324 mg weekly, 5 mg/kg, and 10 mg/kg 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 eight. Headache, lymphadenopathy, diarrhoea, fatigue, hypertension, nasal congestion and pruritus were reported to be the most frequent adverse events.