Two-drug maintenance therapy keeps viral load suppressed and may even have advantages over traditional ART

Two-drug antiretroviral therapy (ART) consisting of ritonavir-boosted atazanavir and lamivudine has comparable or better virological efficacy than traditional three-drug therapy based on ritonavir/atazanavir, according to a poster presentation at the recent 15th European AIDS Conference.

The study examined use of the simplified treatment as maintenance therapy for patients who had already achieved sustained virological suppression (below 50 copies/ml) using traditional three-drug ART. Participants were randomised to receive either two-drug treatment or to remain on traditional ART. Follow-up after 48 weeks of therapy showed the simplified therapy was at least non-inferior to three-drug treatment and could even have advantages.

ART has transformed the prognosis of patients with HIV. But it requires high levels of adherence, can cause side effects and is expensive. Reducing the number of drugs in a regimen for patients with virological suppression could help overcome these problems. However, it is essential that virological efficacy is not compromised when the number of drugs in a combination is reduced.

Glossary

non-inferiority trial

A clinical trial which aims to demonstrate that a new treatment is not worse than another. While the two drugs may have comparable results in terms of virological response, the new drug may have fewer side-effects, be cheaper or have other advantages. 

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.

not significant

Usually means ‘not statistically significant’, meaning that the observed difference between two or more figures could have arisen by chance. 

creatinine

Breakdown product of creatine phosphate in muscle, usually produced at a fairly constant rate by the body (depending on muscle mass). As a blood test, it is an important indicator of the health of the kidneys because it is an easily measured by-product of muscle metabolism that is excreted unchanged by the kidneys.

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.

Investigators in Rome therefore wanted to see if ART could be simplified to a two-drug regimen for patients who initiated therapy with a three-drug combination who had sustained virological suppression (at least six months).

The 266 individuals recruited to the study were randomised to receive either ritonavir/atazanavir plus lamivudine or to remain on a three-drug combination of ritonavir/atazanavir with two NRTIs.

The study was designed to see if the simplified regimen was non-inferior in terms of virological efficacy (-12% difference) over 96 weeks. Data were also gathered on discontinuation of therapy for any reason, side-effects and laboratory abnormalities.   

Virological failure was defined as a sustained rebound in viral load to over 1000 copies/ml.

The patients had an average age of 44 years, most (77%) were male, 11% had hepatitis C virus (HCV) co-infection and approximately 10% had a history of injecting drug use. Patients had been taking their current regimen for approximately 29 months and viral load had been undetectable 21-24 months. CD4 count at baseline was over 600 cells/mm3.

Forty-eight week data were reported by the investigators. The simplified regimen was at the very least non-inferior to traditional therapy.

Only 2% of patients taking the two-drug combination experienced virologic failure compared to 6% of those treated with the three-drug regimen (difference non-significant). Patients taking simplified therapy were also less likely than those on the traditional combination to change treatment for any cause (14% vs. 27%, p = 0.042), experience side-effects possibly related to their therapy (2% vs. 5%) and develop adverse events that were not therapy related (2% vs. 3%).

The majority (80%) of patients were taking tenofovir at baseline, a drug associated with declines in kidney function. At week 48, kidney function had improved significantly among patients on the two-drug regimen but declined in those on traditional ART (p < 0.001). Atzanavir can cause benign increases in bilirubin. Here again, the simplified combination had the edge, with bilirubin levels significantly lower at week 48 among those on the two-drug therapy (p = 0.027). Creatinine levels remained stable in both treatment groups, but the lipid metabolism of patients taking two-drug treatment improved slightly whereas these values remained unchanged among patients on three-drug therapy.

The investigators conclude that simplified treatment with ritonavir/atazanavir and lamivudine is at least non-inferior to traditional therapy in terms of virological efficacy and may even have some advantages.

References

DI Giambenedetto S et al. Simplification to atazanavir/ritonavir + lamivudine versus maintaining atazanavir/ritonavir + 2 NRTIs in virologically suppressed HIV-infected patients: 48-week data of the ATLAS-M trial. EACS, 2015.