Failure of second-line ART is common in resource-limited countries, but modern third-line regimens work well

Beatriz Grinsztejn at CROI 2018. Photo by Liz Highleyman.

More than half of people in low- and middle-income countries may not maintain viral suppression on second-line antiretroviral therapy (ART), according to a study presented at the 25th Conference on Retroviruses and Opportunistic Infections (CROI 2018) last week in Boston.

This international trial showed that regimens containing boosted darunavir (Prezista) or raltegravir (Isentress) were effective as third-line therapy for people who developed resistance to lopinavir/ritonavir (Kaletra). But the treatment failure rate among people who showed little evidence of resistance and therefore stayed on their second-line regimen was unexpectedly high, said Beatriz Grinsztejn of Instituto Nacional de Infectologia Evandro Chagas in Rio de Janeiro, Brazil.

Treatment of individuals who do not maintain viral suppression on their first antiretroviral regimen can be challenging in resource-limited settings due to uncertainty about viral resistance and limited data about virological response to the remaining available medications. Some have already been exposed to nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors, and drug resistance patterns can be variable and complex.


virological suppression

Halting of the function or replication of a virus. In HIV, optimal viral suppression is measured as the reduction of viral load (HIV RNA) to undetectable levels and is the goal of antiretroviral therapy.

second-line treatment

The second preferred therapy for a particular condition, used after first-line treatment fails or if a person cannot tolerate first-line drugs.

hepatitis B virus (HBV)

The hepatitis B virus can be spread through sexual contact, sharing of contaminated needles and syringes, needlestick injuries and during childbirth. Hepatitis B infection may be either short-lived and rapidly cleared in less than six months by the immune system (acute infection) or lifelong (chronic). The infection can lead to serious illnesses such as cirrhosis and liver cancer. A vaccine is available to prevent the infection.

reverse transcriptase

A retroviral enzyme which converts genetic material from RNA into DNA, an essential step in the lifecycle of HIV. Several classes of anti-HIV drugs interfere with this stage of HIV’s life cycle: nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). 

middle income countries

The World Bank classifies countries according to their income: low, lower-middle, upper-middle and high. There are around 50 lower-middle income countries (mostly in Africa and Asia) and around 60 upper-middle income countries (in Africa, Eastern Europe, Asia, Latin America and the Caribbean).

Study ACTG A5288 was an open-label trial comparing treatment strategies for people with viral loads of 1000 copies/ml or more after at least 24 weeks on a second-line ART regimen containing a protease inhibitor. The aim of the study was to use newer antiretrovirals and contemporary management tools, including virus genotyping, to select appropriate third-line regimens and enable more people to achieve viral suppression.

The study included 545 participants in 10 countries in Africa, Asia, South America and the Caribbean followed from 2013 to 2015. Just under half were women and their median age was 41 years. The median CD4 count was 175 cells/mm3, indicating that many had advanced immune suppression. They had been on ART for an average of about 8 years.

At study enrolment participants were tested for drug resistance using real-time standard genotyping. This showed that 62% had evidence of NRTI resistance (including 56% with the M184V mutation); 64% had NNRTI resistance, though 78% remained susceptible to etravirine (Intelence); and 36% were resistant to protease inhibitors, though 97% remained susceptible to darunavir. Just over 20% were susceptible to all antiretroviral classes, 20% showed resistance to one drug class, 30% were resistant to two classes and 27% were resistant to three classes.

Participants were assigned to a treatment cohort based on their resistance profile.

  • People in Cohort A had no resistance to lopinavir/ritonavir and were susceptible to one or more NRTIs. Just over half of the study participants were eligible for this group. These people remained on their current second-line regimen.
  • Participants in Cohort B were resistant to lopinavir/ritonavir, susceptible to darunavir and etravirine, and had no prior exposure to raltegravir; 28% were eligible for this cohort. They were randomised to receive either the best available NRTIs or etravirine, both with darunavir/ritonavir and raltegravir.
  • People in Cohort B with hepatitis B virus (HBV) co-infection – 1% of total enrolees – were an exception; they were allocated to take darunavir/ritonavir and raltegravir with tenofovir/emtricitabine (the drugs in Truvada), which are active against both HIV and HBV.
  • People in Cohort C were resistant to both lopinavir/ritonavir and etravirine, but were susceptible to darunavir and had no prior exposure to raltegravir; 13% of participants fell into this group. They received the best available NRTIs plus darunavir/ritonavir and raltegravir.
  • Finally, people in Cohort D did not meet the eligibility criteria for Cohorts A, B or C. They took the best antiretrovirals available locally or supplied by the study. This group accounted for just 6% of all participants.

At 48 weeks 64% of all participants had HIV RNA below 200 copies/ml, just missing the study's target of 65% achieving viral suppression. But this differed substantially according to treatment strategy.

Most people assigned to the modern ART regimens in Cohorts B and C did well. The viral suppression rate was 88% in Cohort B for people who used either etravirine or other NRTIs, and all eight people with HIV/HBV co-infection had an undetectable viral load. Similarly, 90% of those in Cohort C achieved viral suppression.

In Cohort A, however, only 44% of those who had minimal or no resistance and stayed on their second-line treatment were virally suppressed at week 48. This reached 74% for those in Cohort D treated with the best available drugs.

Virological failure rates were low (6-8%) in Cohorts B and C, rising to 18% in Cohort D. But 51% of those in Cohort A experienced confirmed virological failure.

Disturbingly, 17% and 15% of people in Cohorts A and D, respectively, had new resistance mutations, further limiting their treatment options. Emergent NRTI resistance was most common (22%), followed by NNRTI (15%) and protease inhibitor (6%) resistance.

Overall, treatment was generally safe and well tolerated and 92% of participants completed follow-up. Serious adverse events were most common (21%) in Cohort A, despite the fact that these participants didn't change treatment. Rates ranged from 11% to 18% in the other cohorts.

The researchers concluded that regimens containing darunavir/ritonavir or raltegravir with or without etravirine were highly effective for participants with lopinavir/ritonavir resistance who presented for third-line ART. But more than half of participants without lopinavir/ritonavir resistance who remained on second-line ART did not achieve viral suppression at week 48, indicating that "this subgroup requires additional interventions to achieve viral suppression."

The researchers added that, "Targeted real-time genotyping to select regimens for third-line ART can appropriately allocate more costly antiretrovirals to those with greater resistance." But it may not perform so well for predicting who could benefit from switching to a new third-line regimen.

Grinsztejn told reporters that a majority of patients assigned to Cohort A had very little resistance and "didn’t have a reason based on genotyping to move to other drugs." But, reassuringly, "those with higher levels of resistance assigned to cohorts receiving newer drugs did well, with over 85% success."


Grinsztejn B et al. Results of ACTG A5288: a strategy study in RLS for 3rd-line ART candidates. 25th Conference on Retroviruses and Opportunistic Infections (CROI 2018), Boston, abstract 30LB, 2018.

View the abstract on the conference website.

Watch the webcast of this presentation on the conference website.

Update: Following the conference presentation, this research was published in a peer-reviewed journal:

Grinsztejn B et al. Third-line antiretroviral therapy in low-income and middle-income countries (ACTG A5288): a prospective strategy study. Lancet HIV 6: PE588-E600, 2019.