NNRTIs and protease inhibitors both good for first ART, channelling affects choices

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) and boosted protease inhibitors work equally well for people starting HIV treatment for the first time, with similar viral suppression, CD4 cell gains, and disease progression, according to a large meta-analysis presented at IDWeek 2014 earlier this month in Philadelphia, United States. A related study shed light on factors affecting choice of initial antiretroviral regimen.

ART meta-analysis

Alvaro Borges from the University of Copenhagen and colleagues with the METART Global Consortium performed a systematic review and meta-analysis of randomised clinical trials (RCTs) of first-line antiretroviral therapy (ART) containing NNRTIs and ritonavir-boosted protease inhibitors.

Some prior studies have suggested that NNRTIs may enable more rapid viral suppression while protease inhibitors may lead to faster CD4 T-cell recovery and have a high barrier to drug resistance, but data have not been consistent.

The investigators searched established medical databases such as PubMed to identify randomised clinical trials comparing NNRTI-based versus boosted protease inhibitor-based initial ART regimens. NNRTI recipients used either efavirenz (Sustiva, also in the Atripla co-formulation) or nevirapine (Viramune), while most protease inhibitor recipients used lopinavir/ritonavir (Kaletra) or ritonavir-boosted atazanavir (Reyataz); newer drugs were not well-represented.

Glossary

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

meta-analysis

When the statistical data from all studies which relate to a particular research question and conform to a pre-determined selection criteria are pooled and analysed together.

depression

A mental health problem causing long-lasting low mood that interferes with everyday life.

virological suppression

Halting of the function or replication of a virus. In HIV, optimal viral suppression is measured as the reduction of viral load (HIV RNA) to undetectable levels and is the goal of antiretroviral therapy.

formulation

The physical form in which a drug is manufactured or administered. Examples of formulations include tablets, capsules, powders, and oral and injectable solutions. A drug may be available in multiple formulations.

A meta-analysis was performed using intent-to-treat results. The primary endpoint was progression to AIDS or death, with secondary endpoints including AIDS alone, death alone, and treatment discontinuation, as well as virological suppression and CD4 cell gains at 48 weeks. The researchers calculated risk ratios (RRs) and mean differences (MDs) in outcomes, as appropriate. Due to data limitations, not all trials were included in every analysis.

Results

The meta-analysis included 27 randomised clinical trials with a total combined enrolment of 9515 participants.

Among the 4848 people assigned to NNRTI-based regimens, 3636 used efavirenz and 1212 used nevirapine.

Among 4667 people assigned to protease inhibitors, 2661 used lopinavir/ritonavir, 1498 used boosted atazanavir, and 508 used other boosted protease inhibitors.

A total of 308 participants taking NNRTIs and 301 taking protease inhibitors experienced progression to AIDS or death during their trials, not a statistically significant difference (RR 1.03).

There were 256 deaths among NNRTI recipients and 249 among protease inhibitor recipients, again not a significant difference (RR 1.03).

193 NNRTI recipients and 184 protease inhibitor recipients progressed to AIDS, also not a significant difference (RR 1.06).

At week 48, there was no difference in virological suppression between NNRTI and protease inhibitor recipients (RR 1.03).

There was also no notable difference in CD4 cell increases (MD -6.95 cells).

Rates of treatment discontinuation overall and due to toxicities were statistically similar in the NNRTI and protease inhibitor groups (RR 1.15 and 1.25, respectively).

However, likelihood of discontinuation due to trial-defined virological failure was significantly higher among NNRTI recipients (RR 1.89).

"In a comprehensive meta-analysis of RCTs, we found no difference in clinical outcomes between subjects randomised to NNRTI- or protease inhibitor/ritonavir-based initial ART," the researchers concluded.

They added that a meta-analysis of individual patient data is warranted to explore differences in specific adverse event profiles and dynamics of viral suppression and CD4 cell recovery associated with particular NNRTIs and protease inhibitors.

Channelling factors

In the second study, Michael Saag from the University of Alabama at Birmingham and colleagues looked at factors that affect how providers select initial antiretroviral drug classes for specific patients, for example, whether doctors prescribe certain drugs for patients with co-existing conditions or at risk for specific side-effects.

The researchers used data from the Centers for AIDS Research Network of Integrated Clinical Systems, or CNICS, an electronic medical records database integrating clinical data from eight prominent HIV clinics at academic medical centres (University of Alabama at Birmingham, University of California at San Francisco and San Diego, University of North Carolina, University of Washington, Case Western Reserve, Harvard, and Johns Hopkins).

This analysis included 1215 patients who started combination ART consisting of three or more drugs – containing an NNRTI, boosted protease inhibitor, or the integrase inhibitor raltegravir (Isentress) – between July 2009 and December 2012.

More than 80% of participants were men, more than half were white, one-third were black, 19% were Hispanic, and the median age was 38 years. Two-thirds were gay/bisexual men and 14% were people who inject drugs. One-quarter started ART with a CD4 count <200 cells/mm3, indicating advanced disease, while a similar proportion started with >500 cells/mm3. A majority had more than two co-morbid conditions, the most common being depression (34%), substance use (33%), other psychiatric conditions (26%), high blood pressure (23%), and hepatitis C virus co-infection (16%). About 60% were on public insurance such as Medicaid, nearly one-third had private insurance, and 14% were uninsured.

NNRTI regimens were most commonly used (53%), while 37% of regimens contained a boosted protease inhibitor and 9% contained raltegravir. Factors suspected of being associated with regimen choice were explored individually and in three separate multivariate logistic regression models.

Results

Women were significantly less likely than men to receive NNRTIs and more likely to receive protease inhibitors (adjusted odds ratio [OR] 0.5 and 2.1, respectively).

There were no significant differences in antiretroviral prescription according to age.

People with prior ART experience were somewhat more likely to receive protease inhibitors or raltegravir, but the difference did not reach statistical significance.

People with hepatitis C or other liver conditions were less likely to receive NNRTIs (adjusted OR 0.6), which have been associated with liver toxicity.

People with depression or other psychiatric conditions were less likely to receive NNRTIs (adjusted OR 0.6) and more likely to receive protease inhibitors or raltegravir, due to the well-known neuropsychiatric side-effects of efavirenz.

People with cardiovascular or cerebrovascular conditions were three times more likely to receive raltegravir (adjusted OR 2.7), which is not associated with lipid elevation or other relevant side-effects.

"The choice of initial regimen is associated with several demographic and clinical factors, which is sometimes referred to as 'channelling'," the researchers concluded. "As more choices for HIV therapy become available, factors that impact initial regimen selection will likely become even more heterogeneous over time," they predicted.

References

Borges A, Lundh A, Tendal B et al. Systematic review and meta-analysis of randomized controlled trials (RCTs) comparing initial non-nucleoside reverse transcriptase inhibitor (NNRTI)- versus ritonavir boosted protease inhibitor (PI/r)-based anti-retroviral therapy (ART). IDWeek 2014. Philadelphia, October 8-12, 2014. Abstract 536.

Saag M, Westfall A, Cole S et al. Factors associated with the selection of initial antiretroviral therapy: real-world channeling. IDWeek 2014. Philadelphia, October 8-12, 2014. Abstract 1555.