Three second-line ART regimens test safe

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Three second-line antiretroviral therapy (ART) regimens are equally safe and effective for patients experiencing virological failure in Africa, investigators report. All three regimens consisted of a ritonavir-boosted protease inhibitor with two nucleoside reverse transcriptase inhibitors (NRTI). After 48 weeks, approximately two-thirds of patients had a viral load below 50 copies/ml with little difference between the three combinations and safety and side-effect profiles were good. However, poorer outcomes were observed among patients with a viral load above 100,000 copies/ml at the time of treatment switch.

Access to ART has expanded rapidly in resource-limited settings in recent years. WHO recommended first-line therapy consists of two NRTIs in combination with a non-nucleoside reverse transcriptase inhibitor (NNRTI). For patients experiencing first-line treatment failure, the World Health Organisation recommend a second-line regimen consisting of a boosted protease inhibitor and two NRTIs. This strategy has been supported by the results of randomised controlled trials. But there is little information to guide the choice of specific drugs for use in second-line therapy.

An international team of investigators therefore designed an open-label study involving adult patients experiencing first-line treatment failure (confirmed viral load above 1000 copies/ml after six months of ART) in Cameroon, Dakar and Burkina Faso. The authors note, “the study was conducted in field conditions very similar to those of national programmes, with late diagnosis of first-line ART and no resistance testing to inform decisions about drug choice.”

A total of 451 patients were recruited to the study. Average CD4 cell count was below 200 cells/mm3. Median viral load was approximately 32,000 copies/ml, with 27% patients having a viral load above 100,000 copies/ml.

Participants were equally randomised to receive one of three regimens:
• tenofovir/emtricitabine with lopinavir/ritonavir
• abacavir, didanosine (ddI) with lopinavir/ritonavir
• tenofovir/emtricitabine with darunavir/ritonavir

The primary outcome was the proportion of patients at week 48 with a viral load below 50 copies/ml. Data were also gathered on viral suppression below 200 and 1,000 copies/ml and the safety and tolerability of each of the regimens.
Overall, 65% of patients had a viral load below 50 copies/ml 48 weeks after switching to second-line treatment.

Outcomes were broadly comparable for the three regimens:
• tenofovir/emtricitabine with lopinavir/ritonavir – 69% suppressed
• abacavir, didanosine with lopinavir/ritonavir – 63% suppressed
• tenofovir/emtricitabine with darunavir/ritonavir – 63% suppressed

A viral load below 200 copies/ml was achieved by 80% of individuals, whereas 90% had a viral load below 1000 copies/ml. Only 38% of patients with a baseline viral load above 100,000 copies/ml achieved a viral load below 50 copies/ml after switching to second-line therapy. This compared to a suppression rate of 75% among patients with lower viral loads. The combination containing darunavir/ritonavir performed especially poorly among patients with a viral load above 100,000 copies/ml, with just 23% having suppression below 50 copies/ml at week 48.

HIV-related events were observed in 70 (16%) patients. These mainly occurred in the first three months after changing treatment. There were six deaths: one due to severe tuberculosis; one because of liver cancer; the other four from unknown causes.

The safety and tolerability of all three regimens was, for the most part, good. Only five patients stopped treatment because of side-effects. There was one unconfirmed abacavir hypersensitivity reaction; two patients taking ddI discontinued treatment because of neuropathy; and a darunavir/ritonavir-treated patient experienced severe kidney failure not connected with the drug. Gastrointestinal side-effects were common and rates were higher among those taking lopinavir/ritonavir (33%) compared to darunavir/ritonavir (17%). Adherence to all three regimens was good.

“Results about second-line regimen efficacy are, for the moment, reassuring,” conclude the investigations. “Our results suggest that patients with high viral load with first-line failure may need special management to avoid early second-line failure.”

Abstract
Objective: WHO recommends ritonavir-boosted protease inhibitor with two nucleoside reverse transcriptase inhibitors in HIV-infected patients failing non-nucleoside reverse transcriptase inhibitor-based first-line treatment. Here, we aimed to provide more evidence for the choice of nucleoside reverse transcriptase inhibitor and boosted protease inhibitor.
Design: ANRS 12169 is a 48-week, randomized, open-label, non-inferiority trial in three African cities, comparing efficacy and safety of three second-line regimens.
Methods: Patients failing non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy with confirmed plasma HIV-1 viral load above 1000 copies/ml were randomly assigned to tenofovir/emtricitabine + lopinavir/ritonavir (control group as per WHO recommendations), abacavir + didanosine + lopinavir/ritonavir (ABC/ddI group) or tenofovir/emtricitabine + darunavir/ritonavir (DRV group) regimens. The primary endpoint was the proportion of patients with plasma vral load below 50 copies/ml at week 48 in the modified intention-to-treat population. Non-inferiority was pre-specified with a 15% margin.
Results: Of the 454 randomized patients, 451 were included in the analysis. Globally, 294 (65.2%) and 375 (83.2%) patients had viral load below 50 and 200 copies/ml, respectively, at week 48. The primary endpoint was achieved in 105 (69.1%) control group patients versus 92 (63.4%) in the ABC/ddI (difference 5.6%, 95% confidence interval –5.1 to 16.4) and 97 (63.0%) in the DRV (difference 6.1%, 95% confidence interval –4.5 to 16.7) groups (non-inferiority not shown). Overall, less number of patients with baseline viral load at least 100 000 copies/ml (n = 122) had a viral load below 50 copies/ml at week 48 (37.7 versus 75.4%; P < 0.001).
Conclusions: The three second-line regimens obtained similar and satisfactory virologic control and confirmed the WHO recommendation (TDF/FTC/LPVr) as a valid option. However, the suboptimal response for patients with high viral load warrants research for improved strategies.

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