Effectiveness of EFV compared to NVP in the suppression of HIV infection when used as part of initial three-drug combination

Research question

For people living with HIV who have never received antiretroviral therapy (ART), which drug is more effective in suppressing HIV infection in combination with two nucleoside reverse transcriptase inhibitors (NRTI): efavirenz (EFV) or nevirapine (NVP)?

Background

The introduction of highly active ART as treatment for HIV infection has greatly reduced mortality and morbidity for adults and adolescents living with HIV around the world. The recommended initial treatments for HIV infection include two drugs from a class of drugs known as NRTI and one from a related class of drugs called non-nucleoside reverse transcriptase inhibitors (NNRTI). The two NNRTIs most commonly used are NVP and EFV. However, NVP can cause liver damage and severe rash, both of which can be fatal. EFV may also cause a rash, impair mental function, and cause foetal malformations.

Main results

Cochrane researchers examined the available literature up to 12 August 2016 and identified 12 randomized controlled trials, with a total of 3278 people, that met the inclusion criteria of this review. None of the included trials included children. Four trials included people who were also receiving treatment for tuberculosis. There was little or no difference in suppression of HIV infection (high quality evidence), probably little or no difference in mortality, progression to AIDS, stopping treatment early and changes in blood cells affected by HIV (moderate quality evidence). There may be little or no difference in treatment failure (low quality evidence). We are uncertain whether there is a difference in side-effects (very low quality evidence). No studies were found that looked at sexual transmission of HIV. Development of drug resistance is probably slightly less in the EFV group (moderate quality evidence). When the side effects were examined individually, EFV probably caused more impaired mental function (6% in the EFV group and 2% in the NVP group; moderate quality evidence), while NVP probably caused more people to have a rash (3% in the EFV group and 6% in the NVP group; moderate quality evidence), caused more people to have reduced white blood cells (2% in the EFV group and 5% in the NVP group; high quality evidence), and signs of liver damage (6% in the EFV group and 11% in the NVP group; high quality evidence). There was probably little or no difference in increases in liver enzymes and levels of cholesterol (moderate quality evidence). There may be little or no difference in digestive side-effects, fever, enzymes from the liver and pancreas, and fat in the blood (low quality evidence). People on NVP were probably more likely to die when given a once-daily regimen (2% in the EFV group and 4% in the NVP group; moderate quality evidence). In people who were taking treatment for tuberculosis compared to those who were not, there was probably little or no difference in suppression of HIV, deaths, progression to AIDS or stopping treatment early (moderate to high quality evidence).

Conclusion

EFV and NVP are similarly effective in viral suppression, preventing HIV progression and reducing mortality. EFV is more likely to affect mental function, while NVP is more likely to cause signs of liver damage, reduced white blood cells and rash.

Authors' conclusions: 

Both drugs have similar benefits in initial treatment of HIV infection when combined with two NRTIs. The adverse events encountered affect different systems, with EFV more likely to cause central nervous system adverse events and NVP more likely to raise transaminases, cause neutropenia and rash.

Read the full abstract...
Background: 

The advent of highly active antiretroviral therapy (ART) has reduced the morbidity and mortality due to HIV infection. The World Health Organization (WHO) ART guidelines focus on three classes of antiretroviral drugs, namely nucleoside or nucleotide reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors. Two of the most common medications given as first-line treatment are the NNRTIs, efavirenz (EFV) and nevirapine (NVP). It is unclear which NNRTI is more efficacious for initial therapy. This systematic review was first published in 2010.

Objectives: 

To determine which non-nucleoside reverse transcriptase inhibitor, either EFV or NVP, is more effective in suppressing viral load when given in combination with two nucleoside reverse transcriptase inhibitors as part of initial antiretroviral therapy for HIV infection in adults and children.

Search strategy: 

We attempted to identify all relevant studies, regardless of language or publication status, in electronic databases and conference proceedings up to 12 August 2016. We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov to 12 August 2016. We searched LILACS (Latin American and Caribbean Health Sciences Literature) and the Web of Science from 1996 to 12 August 2016. We checked the National Library of Medicine (NLM) Gateway from 1996 to 2009, as it was no longer available after 2009.

Selection criteria: 

We included all randomized controlled trials (RCTs) that compared EFV to NVP in people with HIV without prior exposure to ART, irrespective of the dosage or NRTI's given in combination.

The primary outcome of interest was virological success. Other primary outcomes included mortality, clinical progression to AIDS, severe adverse events, and discontinuation of therapy for any reason. Secondary outcomes were change in CD4 count, treatment failure, development of ART drug resistance, and prevention of sexual transmission of HIV.

Data collection and analysis: 

Two review authors assessed each reference for inclusion using exclusion criteria that we had established a priori. Two review authors independently extracted data from each included trial using a standardized data extraction form. We analysed data on an intention-to-treat basis. We performed subgroup analyses for concurrent treatment for tuberculosis and dosage of NVP. We followed standard Cochrane methodological procedures.

Main results: 

Twelve RCTs, which included 3278 participants, met our inclusion criteria. None of these trials included children. The length of follow-up time, study settings, and NRTI combination drugs varied greatly. In five included trials, participants were receiving concurrent treatment for tuberculosis.

There was little or no difference between EFV and NVP in virological success (RR 1.04, 95% CI 0.99 to 1.09; 10 trials, 2438 participants; high quality evidence), probably little or no difference in mortality (RR 0.84, 95% CI 0.59 to 1.19; 8 trials, 2317 participants; moderate quality evidence) and progression to AIDS (RR 1.23, 95% CI 0.72 to 2.11; 5 trials, 2005 participants; moderate quality evidence). We are uncertain whether there is a difference in all severe adverse events (RR 0.91, 95% CI 0.71 to 1.18; 8 trials, 2329 participants; very low quality evidence). There is probably little or no difference in discontinuation rate (RR 0.93, 95% CI 0.69 to 1.25; 9 trials, 2384 participants; moderate quality evidence) and change in CD4 count (MD −3.03; 95% CI −17.41 to 11.35; 9 trials, 1829 participants; moderate quality evidence). There may be little or no difference in treatment failure (RR 0.97, 95% CI 0.76 to 1.24; 5 trials, 737 participants; low quality evidence). Development of drug resistance is probably slightly less in the EFV arms (RR 0.76, 95% CI 0.60 to 0.95; 4 trials, 988 participants; moderate quality evidence). No studies were found that looked at sexual transmission of HIV.

When we examined the adverse events individually, EFV probably is associated with more people with impaired mental function (7 per 1000) compared to NVP (2 per 1000; RR 4.46, 95% CI 1.65 to 12.03; 6 trials, 2049 participants; moderate quality evidence) but fewer people with elevated transaminases (RR 0.52, 95% CI 0.35 to 0.78; 3 trials, 1299 participants; high quality evidence), fewer people with neutropenia (RR 0.48, 95% CI 0.28 to 0.82; 3 trials, 1799 participants; high quality evidence), and probably fewer people withrash (229 per 100 with NVP versus 133 per 1000 with EFV; RR 0.58, 95% CI 0.34 to 1.00; 7 trials, 2277 participants; moderate quality evidence). We found that there may be little or no difference in gastrointestinal adverse events (RR 0.76, 95% CI 0.48 to 1.21; 6 trials, 2049 participants; low quality evidence), pyrexia (RR 0.65, 95% CI 0.15 to 2.73; 3 trials, 1799 participants; low quality evidence), raised alkaline phosphatase (RR 0.65, 95% CI 0.17 to 2.50; 1 trial, 1007 participants; low quality evidence), raised amylase (RR 1.40, 95% CI 0.72 to 2.73; 2 trials, 1071 participants; low quality evidence) and raised triglycerides (RR 1.10, 95% CI 0.39 to 3.13; 2 trials, 1071 participants; low quality evidence). There was probably little or no difference in serum glutamic oxaloacetic transaminase (SGOT; MD 3.3, 95% CI -2.06 to 8.66; 1 trial, 135 participants; moderate quality evidence), serum glutamic- pyruvic transaminase (SGPT; MD 5.7, 95% CI -4.23 to 15.63; 1 trial, 135 participants; moderate quality evidence) and raised cholesterol (RR 6.03, 95% CI 0.75 to 48.78; 1 trial, 64 participants; moderate quality evidence).

Our subgroup analyses revealed that NVP slightly increases mortality when given once daily (RR 0.34, 95% CI 0.13 to 0.90; 3 trials, 678 participants; high quality evidence). There were little or no differences in the primary outcomes for patients who were concurrently receiving treatment for tuberculosis.

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