Therapy with newer, safer antiretrovirals an option for the majority of HIV-positive patients

Clinical trial needed
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The majority of people taking antiretroviral therapy (ART) that includes drugs associated with long-term side-effects may have the option of switching to a novel regimen that uses newer and safer anti-HIV drugs, according to Australian research published in PLOS ONE. The single-site study showed that up to 89% of study participants had the option of changing to a combination that includes three active newer agents with improved safety and side-effect profiles.

The drugs associated with long-term side-effects evaluated in this study comprise the core antiretroviral drugs prescribed to the majority of people taking antiretroviral treatment today.

But the authors acknowledge “most of the regimens considered as ‘viable’ in this study have not been rigorously tested in clinical trials and might be regarded as unconventional.” Nevertheless, they stress “the growing interest in testing novel combinations of ART agents, which exclude nucleoside(tide) and older non-nucleoside reverse transcriptase inhibitors (N(t)RTIs and NNRTIs, respectively), as well as ritonavir (booster dose).”



Term used to indicate how well a particular drug is tolerated when taken by people at the usual dosage. Good tolerability means that drug side-effects do not cause people to stop using the drug.


A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 


Fat or fat-like substances found in the blood and body tissues. Lipids serve as building blocks for cells and as a source of energy for the body. Cholesterol and triglycerides are types of lipids.


Relating to the heart and blood vessels.


When HIV selectively attaches to a particular coreceptor on the surface of a host CD4 cell. HIV can attach to either the CCR5 coreceptor (R5-tropic) or the CXCR4 coreceptor (X4-tropic) or both (dual-tropic).

Most people taking HIV therapy have an excellent life expectancy. However, there is concern about the safety and tolerability of many routinely used anti-HIV drugs. Investigators at St Vincent’s Hospital, Sydney, Australia, called these the “RATE” drugs: ritonavir (Norvir), which is associated with drug interactions, diarrhoea and lipid disturbances; abacavir (Ziagen), which can involve a hypersensitivity reaction, has reduced potency at higher viral loads and may involve a risk of cardiovascular disease; tenofovir (Viread), which can cause bone and kidney problems; and efavirenz (Sustiva), associated with neuropsychiatric side-effects and increased lipids. Moreover, these drugs are usually used in combination, compounding their toxicity profiles.

A number of alternative antiretroviral drugs have recently become available that appear to be safer and more tolerable than the RATE drugs. These include rilpivirine (Edurant), etravirine (Intelence), atazanavir (Reyataz), raltegravir (Isentress), maraviroc (Celsentri or Selzentry), and also the older NRTI lamivudine (Epivir).

Investigators wanted to assess the proportion of people taking current RATE regimens who could potentially switch to a viable RATE-sparing regimen.

The authors examined the treatment history and resistance profiles of 120 people receiving therapy containing two or more RATE drugs at St Vincent’s Hospital. For each person, the investigators calculated the potential activity of newer, alternative drugs.

The study participants had been taking antiretroviral therapy for a median of eight years and 17% had a history of exposure to the integrase inhibitor raltegravir.

Tropism testing – which can predict susceptibility to maraviroc – was unavailable for 54% of individuals and unsuccessful for 8% of participants.

Assuming that people with unknown maraviroc activity were susceptible to the drug, then 98% had an option of at least one RATE-sparing regimen with two active drugs, with 89% able to construct a regimen with three newer drugs. The proportions decreased to 94% and 87%, respectively, assuming maraviroc inactivity when susceptibility to the drug was unknown.

A literature review provided evidence supporting the viability of many of the RATE-sparing regimens. The only exception was regimens that combined raltegravir with drugs with a low genetic barrier to resistance.

Analysis of the nationally representative Australian HIV Observational Cohort (AHOD) showed that 57% of people were taking regimens that included two or more RATE agents and could therefore potentially benefit from switching to a non-RATE regimen.

“Our analysis of patients in one hospital-based clinic suggests that most patients receiving >2 RATE agents would be expected to have at least one viable RATE-sparing regimen switch option containing 2 or 3 fully-active agents,” write the authors. “This remained the case when we restricted our assessment to only those regimen options which have shown promise in publicly presented studies.”

They believe there is a “clear need for trials to rigorously evaluate RATE-sparing regimens, not only to demonstrate their virological success but also their expected greater tolerability and safety.” The investigators suggest such a study should target patients with a high risk of chronic illness who would therefore most benefit from RATE-sparing therapy.  


Achhra AC et al. Moving away from ritonavir, abacavir, tenofovir, and efavirenz (RATE)-agents that concern prescribers and patients: a feasibility study and call for a trial. PLOS ONE 9(6): e99530. DOI: 10.1371/journal.pone.0099530, 2014.