Most people taking second-line ART in sub-Saharan Africa achieve viral suppression but there's a need for third-line treatment options

Approximately 85% of people switched to protease inhibitor-based second-line antiretroviral (ART) in sub-Saharan Africa achieve and maintain an undetectable viral load with their new regimen, according to research in the online edition of Clinical Infectious Diseases.

Non-standard first-line treatment, poor adherence and previous resistance to protease inhibitors were also associated with the virological failure of second-line treatment. Genotypic resistance testing on people with a viral load above 1000 copies/ml showed that a fifth had major resistance to drugs in the protease inhibitor class and that resistance to nucleoside reverse transcriptase inhibitors (NRTIs) was widespread.

“This study found high VL suppression rates with second-line PI-based ART in sub-Saharan Africa. However, 1 in 4 participants had a detectable VL (> 400 copies/ml at any point during 2-3 years of follow-up, and 1 in 5 had a VL > 1000 copies/ml,” write the authors. “These findings indicate that future treatment of individuals with failure of second-line ART requires third-line drug options…which are currently unavailable and/or unaffordable in the public sector in sub-Saharan Africa.”

Expanded access to ART in sub-Saharan Africa means that an increasing number of people will experience virological failure and require second-line treatment based on the protease inhibitors lopinavir/ritonavir or atazanavir/ritonavir.

However, there are limited data on longer-term outcomes of people taking second-line therapy in southern Africa and the extent to which third-line regimens – which are for the most part unavailable in poorer settings – will be required.

Investigators from the Pan-African Study to Evaluate Resistance Monitoring (PASER-M) cohort therefore designed a study to establish rate of virological failure among people taking second-line ART; the risk factors for viral breakthrough; and the rate and pattern on major protease inhibitor resistance mutations.

The study population comprised 227 adults who experienced the virological failure of their first-line ART and switched to a second-line combination based on a protease inhibitor. All received second-line treatment for at least 180 days. Most of the participants were women (51%) and the median age at switch to second-line therapy was 39 years. Study participants had received first-line therapy for a median of 26 months, the majority (84%) treated with a standard non-nucleoside reverse transcriptase inhibitor (NNRTI)-based combination. Six individuals (3%), however, had prior use of a protease inhibitor.

At the time of the switch, 81% of people had a viral load above 1000 copies/ml and genotypic resistance testing showed that 88% had at least one drug-resistant mutation present, with five people having some resistance to a protease inhibitor. Overall, 73% of participants were predicted to be sensitive to their new regimen.

Viral load results after changing therapy were available for 205 people.

Monitoring at months 12, 24 and 36 showed that 85%, 85% and 89%, respectively, had a viral load below 400 copies/ml.

Overall, a quarter of inidividuals had a detectable viral load at some point during follow-up, but 76% of these subsequently re-established virological control.

Factors associated with second-line treatment failure were treatment with non-standard NNRTI-based first-line ART (p < 0.001), non-standard protease inhibitor-based ART (p = 0.001), resistance to a protease inhibitor at the time of treatment change (p < 0.001) and adherence below 95% to second-line treatment (p = 0.025).

Of the 43 individuals with a viral load above 1000 copies/ml, 32 (74%) had genotypic resistance data. Major drug resistance was detected in 69% of these people and 22% had mutations conferring resistance to protease inhibitors. However, the majority of these mutations were associated with resistance to older protease inhibitors.

After up to three years of follow-up, five out of the seven people with resistance to protease inhibitors were still alive and receiving second-line ART; one person had died of an AIDS-related illness; the remaining person had switched to a third-line regimen.

“Our data show that the majority of patients receiving PI-based second-line ART in HIV treatment programs in sub-Saharan Africa achieve virological suppression,” conclude the authors. “As more persons start ART and VL monitoring is expanded, the number in need of second- and third-line regimens is expected to increase. There is a real and growing need for expanded access to third-line drug options, ideally guided by genotypic resistance testing.”