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EACS 2015: Dual Therapy with Protease Inhibitors and Lamivudine Suppresses HIV

Dual antiretroviral regimens consisting of only a boosted HIV protease inhibitor (lopinavir/ritonavir or atazanavir) and a single inexpensive and well-tolerated NRTI may be enough to achieve and maintain HIV suppression in a most patients starting antiretroviral therapy (ART) for the first time or switching from a standard triple regimen, according to a pair of studies presented at the EACS 15th European AIDS Conference last month in Barcelona.

As people with HIV continue to face decades of treatment, researchers have attempted to find regimens that are better tolerated, simper, and more convenient. Non-standard antiretroviral therapy may be especially beneficial for people who have highly drug-resistant virus or cannot tolerate drug side effects.

Using a single potent drug would reduce pill burden, toxicities, and cost, but boosted protease inhibitor monotherapy studies to date have generally been disappointing. Adding a second well-tolerated and inexpensive drug could improve efficacy without adding much toxicity or cost. 

Lopinavir/ritonavir + Lamivudine

Maria Jose Rolon, Pedro Cahn, and fellow investigators with the GARDEL Study Group compared the safety and efficacy of first-line therapy using a dual combination of lopinavir/ritonavir (Kaletra or Aluvia) plus lamivudine (3TC or Epivir) versus a standard triple combination of lopinavir/ritonavir plus 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs).

The Phase 3 GARDEL trial (NCT01237444) included 426 previously untreated people with HIV in Argentina, Chile, Mexico, Peru, Spain, and the U.S. After the initial 48-week randomized treatment period, 306 participants continued on in the extension phase through week 96.

Nearly 85% of participants were men, with a median age of about 35 years. The median baseline CD4 cell count was approximately 325 cells/mm³ and 43% had high viral load (HIV RNA >100,000 copies/mL). At baseline they had no known NRTI or protease inhibitor resistance mutations.

Participants in this open-label study were randomly assigned to receive 400/100 mg lopinavir/ritonavir plus 150 mg lamivudine twice-daily, or else lopinavir/ritonavir plus a 2-NRTI fixed-dose coformulation -- either abacavir/lamivudine (Epzicom or Kivexa; 9%), tenofovir/emtricitabine (Truvada; 37%), or zidovudine/lamivudine (Combivir; 54%). NRTIs were chosen by investigators based on national treatment guidelines in effect at the time; while Combivir is no longer recommended in the U.S. and Europe, it is still used in middle- and lower-income countries.

Zidovudine causes many adverse side effects including mitochondrial toxicity, peripheral neuropathy, and lipoatrophy, while tenofovir can cause kidney toxicity and bone loss and abacavir has been linked to heart attacks in some studies, so omitting these NRTIs could improve tolerability for many people with HIV.

Results

• As Cahn reported at the 2013 EACS conference, at 48 weeks 88% of people taking the dual regimen and 84% taking the triple regimen had undetectable viral load (<50 copies/mL) in an intention-to-treat analysis, showing that the simplified regimen was non-inferior to standard therapy.
• At 96 weeks, 90% of participants on dual therapy and 84% of those on triple therapy maintained viral suppression -- not a significant difference.
• People with high baseline viral load had similar response rates, 91% vs. 81%, respectively.
• In an observed or as-treated analysis, corresponding response rates were 93% and 97%.
• Mean CD4 cell gains were similar in the 2 treatment arms, 300 and 310 cells/mm³, respectively.
• There were 8 cases (4.85%) of virological failure in the dual therapy arm and 6 (4.26%) in the triple therapy arm.
• 4 people on the dual regimen and 3 on the triple regimen had treatment-emergent M184V resistance mutations, which confers resistance to lamivudine and emtricitabine.
• This was the only NRTI resistance mutation selected, and no emergent protease inhibitor resistance mutations were found.
• Treatment continued to be generally safe and well-tolerated.
• There were fewer treatment discontinuations overall in the dual versus triple therapy arm during the extension phase -- 12 (7%) vs 18 (13%) -- but the difference did not reach statistical significance.
• The same was the case for discontinuations related to drug toxicity or tolerability -- 1 vs 4 patients, respectively -- which again was not significant.
• New grade 2-3 (moderate to severe) adverse events were reported with similar frequency in the dual and triple therapy arms (100 vs 110, respectively).
• No serious adverse events related to study drugs and no AIDS-defining events were reported between week 48 and week 96.
• The most common side effects in both arms were hyperlipidemia, diarrhea, and nausea.

"Dual therapy with [lopinavir/ritonavir + lamivudine] was non-inferior to triple therapy after 96 weeks of treatment, regardless of baseline viral load," the researchers concluded. "Virological failure, at similarly low levels in both treatment arms, did not result in protease inhibitor resistance development, preserving a wide range of drugs for second line antiretroviral therapy."

Atazanavir/ritonavir + Lamivudine

In a related study, presented in a poster discussion, Simona Di Giambenedetto from Catholic University of Sacred Heart in Rome and colleagues evaluated a dual regimen of ritonavir-boosted atazanavir (Reyataz) plus lamivudine in people simplifying from a 3-drug regimen.

The Phase IV ATLAS-M study included 266 patients. Again, most (78%) were men and the median age was 44 years. The median CD4 count was approximately 600 cells/mm³. At baseline they were taking atazanavir/ritonavir with 2 NRTIs, mostly tenofovir/emtricitabine (79%). They had suppressed viral load (<50 copies/mL) for at least 3 months and no past virological treatment failure.

Participants in this open-label study were randomized to either stay on the same regimen or switch to atazanavir/ritonavir plus lamivudine.

At 48 weeks, 90% of people who switched to dual therapy and 80% who stayed on triple therapy maintained viral suppression in an intention-to-treat analysis, according to the study abstract; 2 people (1.6%) in the dual therapy arm and 6 (4.7%) in the triple therapy arm experienced virological failure. CD4 cell gains were a bit larger in the dual therapy group, but the difference did not reach statistical significance.

Here too, treatment was generally well-tolerated, and clinical and laboratory adverse events occurred at similar overall rates in both treatment arms. However, people in the dual therapy arm saw a greater increase in total and HDL ("good") cholesterol levels. Kidney function showed improvement in the dual therapy arm, attributed to people switching off tenofovir disoproxil fumarate. No significant differences in bilirubin levels or other laboratory parameters were observed.

In this study 48-week data "clearly indicate non-inferiority and suggest a possible superior efficacy of treatment simplification to atazanavir/ritonavir + lamivudine as compared to continuation of atazanavir/ritonavir + 2 NRTIs in virologically suppressed patients," the researchers concluded.

Another set of studies reported at the conference showed that the integrase inhibitor dolutegravir (Tivicay) was able to suppress HIV when used in a dual regimen with lamivudine, and to maintain viral suppression when used as monotherapy.

Taken together, these studies suggest that regimens with a potent anchor drug and a single well-tolerated NRTI may be an option for many people with HIV.

11/23/15

References

P Cahn on behalf of the GARDEL Study Group (MJ Rolon presenting). Durability of Dual Therapy (DT) with Lopinavir/Ritonavir (LPV/r) and Lamivudine (3TC) in Comparison to Standard Triple Drug Therapy (TT): 96-week Results of the GARDEL Study. 15th European AIDS Conference. Barcelona, October 21-24, 2015. Abstract PS10/4.

S Di Giambenedetto, M Fabbiani, E Quiros-Roldan, et al. Simplification to Atazanavir/Ritonavir + Lamivudine versus Maintaining Atazanavir/Ritonavir + 2NRTIs in Virologically Suppressed HIV-infected Patients: 48-weeks Data of the ATLAS-M Trial. 15th European AIDS Conference. Barcelona, October 21-24,2015. Abstract BPD1/6.