Boosted protease inhibitor and lamivudine provides effective maintenance treatment

HIV maintenance treatment with two drugs, a boosted protease inhibitor and lamivudine, is just as effective as three-drug treatment with a boosted protease inhibitor in people who already have fully suppressed viral load, a meta-analysis of clinical trials presented today at the 16th European AIDS Conference (EACS 2017) shows.

The findings, presented by Dr José Perez-Molina of Hospital Universitario Ramón y Cajal, Madrid, on behalf of the GESIDA network of Spanish HIV researchers, also showed that the strategy was equally effective in men and women, and in people with HIV and hepatitis C co-infection.

A boosted protease inhibitor combined with lamivudine has the potential to reduce the cost of long-term treatment as boosted protease inhibitors come off patent over the next two years in higher-income countries. Lamivudine is already available in a cheap generic formulation.

Simplifying antiretroviral therapy so that a boosted protease inhibitor or an integrase inhibitor is taken with lamivudine holds several other attractions:

• The simplified regimen may reduce the risk of toxicities potentially associated with use of a second nucleoside or nucleotide analogue: cardiovascular disease in the case of abacavir, and kidney injury or bone loss in the case of tenofovir disoproxil. Lamivudine has few side-effects and is well tolerated by the vast majority of people. Long-term follow-up data on this question are lacking.
• Lamivudine does not interact with drugs used to treat other conditions, reducing the potential for problematic drug interactions between an antiretroviral regimen and other medications, which is especially important in older people with HIV.
• Virologic rebound after failure of the simplified regimen will not result in cross-resistance to tenofovir, so preserving this drug as a future option. Rebounding virus may also remain sensitive to abacavir, although this depends on previous treatment history.

Four randomised trials comparing maintenance treatment with a boosted protease inhibitor and lamivudine to three-drug treatment have reported results. These studies are:

• ATLAS, comparing atazanavir/ritonavir and lamivudine to atazanavir/ritonavir plus two nucleoside reverse transcriptase inhibitors (NRTIs).
• DUAL, comparing darunavir/ritonavir and lamivudine to darunavir/ritonavir plus tenofovir/emtricitabine or abacavir/lamivudine.
• SALT, comparing atazanavir/ritonavir and lamivudine to atazanavir/ritonavir plus two NRTIs.
• OLE, comparing lopinavir/ritonavir and lamivudine to lopinavir/ritonavir plus two NRTIs.

The researchers combined the databases of the four studies to carry out an individual-patient meta-analysis. The purpose of doing so was to find out if the strategy of using two drugs was inferior to three-drug treatment, regardless of drug, using new US Food and Drug Administration (FDA) guidelines defining when a switch regimen can be considered virologically non-inferior (4% margin of non-inferiority). They also investigated whether any boosted protease inhibitor was inferior to others when used as part of a two-drug regimen.

The total population comprised 1051 people.

At week 48 there was no significant difference in the proportion of people with a viral load below 50 copies/ml (undetectable). 84.7% of people taking dual therapy had viral load < 50 copies/ml compared to 83.2% of people taking a three-drug combination, a difference favouring dual therapy of 1.47% (95% confidence interval -2.9% to 5.8%).

Similarly, there was no difference in the proportion of people who had a detectable viral load (> 50 copies/ml) at week 48 (this measure is used to distinguish between people who had experienced viral rebound and those who had stopped treatment for other reasons). Four per cent of people taking dual therapy and 3.04% of people taking three-drug therapy had a detectable viral load, a difference of 0.9% (95% CI -1.3% to 3.2%).

On both measures examined, the meta-analysis showed much narrower confidence limits than individual clinical trials. The confidence limits represent the upper and lower limits within which the estimate is likely to fall on 95 out of 100 calculations.

The analysis also found no difference in outcome for either measure when the three boosted protease inhibitors used in these studies were compared. Gender and the presence of hepatitis C infection during the study period had no impact on the outcomes.

Asked whether the results of the meta-analysis supported the use of a boosted protease and lamivudine as maintenance therapy, José Perez-Molina said “If they don’t have previous drug resistance or active hepatitis B I think these data are very strong. I think if a drug is not needed we should not use it.”

Resistance after the failure of dual regimens

Although virologic rebound during treatment with a two-drug regimen is rare, it can lead to the development of drug resistance. Professor Vincent Calvez of the Pitie-Salpetriere Hospital, Paris, reported on patterns of drug resistance seen in people who experienced virologic rebound on two-drug regimens (100 people) or three-drug regimens (300 people).

Lamivudine resistance occurred most frequently after the failure of a two-drug regimen consisting of dolutegravir and lamivudine or lopinavir/ritonavir and lamivudine (33% and 21% of virologic rebound patients respectively).

Resistance to a non-nucleoside reverse transcriptase inhibitor (NNRTI) occurred in between one-third and half of patients after the failure of an NNRTI-containing regimen. Although numbers were small, NNRTI resistance occurred more often after the failure of a three-drug regimen in combination with two NRTIs than when an NNRTI was combined with an integrase inhibitor.

Resistance to a boosted protease inhibitor was rare; only 14 out of 172 virologic failures in people taking a boosted protease inhibitor resulted in the development of resistance to a protease inhibitor. In contrast 50 out of 121 virologic failures on an NNRTI-containing regimen resulted in resistance to an NNRTI.