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EACS 2017: Boosted Protease Inhibitor + Lamivudine Effective for HIV Maintenance Treatment

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HIV maintenance treatment with 2 drugs, a boosted protease inhibitor and lamivudine, is just as effective as 3-drug treatment with a boosted protease inhibitor for people who already have fully suppressed viral load, according to a meta-analysis of clinical trials presented last weekat the 16th European AIDS Conference (EACS 2017) in Milan.

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

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 2 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/nucleotide analogue: cardiovascular disease in the case of abacavir (Ziagen), and kidney impairment or bone loss in the case of tenofovir DF (Viread). 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 interactions between an antiretroviral regimen and other medications, which is especially important for older people with HIV.
  • Virological rebound after failure of the simplified regimen will not result in cross-resistance to tenofovir, thus preserving this drug as a future treatment option. Rebounding virus may also remain sensitive to abacavir, although this depends on previous treatment history.

Four randomized trials comparing maintenance treatment with a boosted protease inhibitor and lamivudine to 3-drug treatment have reported results to date:

  • ATLAS, comparing ritonavir-boosted atazanavir (Reyataz) plus lamivudine to atazanavir/ritonavir plus 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs);
  • DUAL, comparing ritonavir-boosted darunavir (Prezista) plus lamivudine to darunavir/ritonavir plus tenofovir/emtricitabine or abacavir/lamivudine;
  • SALT, comparing atazanavir/ritonavir plus lamivudine to atazanavir/ritonavir plus 2 NRTIs;
  • OLE, comparing lopinavir/ritonavir (Kaletra) plus lamivudine to lopinavir/ritonavir plus 2 NRTIs.

The researchers combined the data from the 4 studies to carry out an individual-patient meta-analysis. The total population comprised 1051 people.

The purpose of doing so was to find out if the strategy of using 2 drugs was inferior to 3-drug treatment, regardless of drug, using new U.S. 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 2-drug regimen.

At week 48 there was no significant difference in the proportion of people with undetectable viral load. 84.7% of people taking dual therapy had viral load below 50 copies/mL compared to 83.2% of those taking a 3-drug combination, a difference of 1.47% favoring dual therapy.

Similarly, there was no difference in the proportion of people who had a detectable viral load at week 48 (this measure is used to distinguish between people who experienced viral rebound and those who stopped treatment for other reasons). 4% of people taking dual therapy and 3.04% of people taking 3-drug therapy had a detectable viral load, a difference of 0.9%.

On both measures examined, the meta-analysis showed much narrower confidence limits than individual clinical trials, due in part to a larger number of participants. 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 outcomes for either measure when the 3 boosted protease inhibitors used in these studies were compared. Gender and the presence of hepatitis C 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 inhibitor and lamivudine as maintenance therapy, 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 Dual Regimen Failure

Although virological rebound during treatment with a 2-drug regimen is rare, it can lead to the development of drug resistance. Vincent Calvez of Pitie-Salpetriere Hospital in Paris reported on patterns of drug resistance seen in people who experienced virological rebound on 2-drug regimens (100 people) or 3-drug regimens (300 people).

Lamivudine resistance occurred most frequently after the failure of a 2-drug regimen consisting of dolutegravir (Tivicay) plus lamivudine or lopinavir/ritonavir plus lamivudine (33% and 21% of virological 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 3-drug regimen containing 2 NRTIs than when an NNRTI was combined with an integrase inhibitor.

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

10/31/17

Sources

JA Perez-Molina et alIndividual patient data meta-analysis of randomized controlled trials of dual therapy with a boosted protease inhibitor plus lamivudine for maintenance of virological suppression (Gesida Study 9717). 16th European AIDS Conference. Milan, October 25-27, 201

V Calvez et al. Antiretroviral resistance selected at failure in HIV infected patients treated by triple and dual therapies. 16th European AIDS Conference. Milan, October 25-27, 2017. Abstract PS1/4.