Resistance testing does not improve viral suppression after first-line failure in South Africa and Uganda

Dr Mark Siedner (top right) presenting to CROI 2021.

Resistance testing to trigger switching to a second-line HIV treatment regimen did not improve virological suppression nine months later in a large randomised study carried out in South Africa and Uganda, Dr Mark Siedner of Massachusetts General Hospital reported to the 2021 virtual Conference on Retroviruses and Opportunistic Infections (CROI) on Monday.

The study findings suggest that implementing resistance testing in resource-limited settings within current algorithms for changing to second-line treatment is unlikely to improve viral suppression and that a continued emphasis on viral-load testing and intensified adherence remains critical in managing first-line treatment failure.

In resource-limited settings, decisions about when to switch from a failing first-line regimen are made using the results of viral-load testing. A change of treatment is recommended if viral load remains above 1000 copies/ml on a second viral-load test after adherence counselling. But prolonged periods of unsuppressed viral load can lead to drug resistance, even when viral load remains below 1000 copies/ml.

Glossary

resistance testing

Laboratory testing to determine if an individual’s HIV strain is resistant to anti-HIV drugs. 

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.

drug resistance

A drug-resistant HIV strain is one which is less susceptible to the effects of one or more anti-HIV drugs because of an accumulation of HIV mutations in its genotype. Resistance can be the result of a poor adherence to treatment or of transmission of an already resistant virus.

first-line therapy

The regimen used when starting treatment for the first time.

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.

Resistance testing can be used to look for drug resistance mutations. If drug resistance is present, an algorithm can predict which drugs are likely to be active against a person’s HIV.

Whereas resistance testing is used routinely in this way in higher-income settings, the cost and logistics of doing genotypic resistance tests that look for specific drug-resistance mutations means that the use of these tests is limited to research studies in lower-income countries. But as the cost of resistance testing goes down, testing may be a cost-effective way to ensure that expensive second-line drugs are used effectively.

A resistance test that shows no drug-resistance mutations may also be a useful prompt for intensifying adherence counselling, showing that improvements in adherence can lead to viral suppression and preservation of first-line treatment.

Siedner said that these uses of resistance testing led investigators to ask, “why don’t we move to an immediate resistance test and switch on the basis of that result?” They designed a study to investigate whether carrying out resistance testing within the current framework of World Health Organization guidelines for switching to second-line treatment resulted in improved outcomes.

REVAMP was a randomised study of resistance testing or standard management in people on failing first-line regimens with viral load over 1000 copies/ml. The study was carried out in South Africa and Uganda, recruiting 840 people without previously documented drug resistance.

Participants were randomised either to undergo resistance testing at baseline, with a subsequent decision about whether to change treatment made by trained clinic staff one to two months after enrolment, or to receive standard management of adherence counselling, followed by a viral load test two to three months later to determine if viral load remained above 1000 copies/ml. People with viral load above 1000 copies/ml after the second viral-load test were switched to second-line treatment whereas those with viral load below this level continued first-line treatment.

Participants were switched to atazanavir/ritonavir or lopinavir/ritonavir and two NRTIs, either recycling tenofovir and lamivudine or switching from tenofovir to zidovudine.

The study population was evenly balanced by sex, had a median age of 37 years and had been taking antiretroviral treatment for a median of three years, in most cases an efavirenz-based regimen (75% in the standard-of-care arm and 71% in the resistance-testing arm).

The primary outcome of the study was the proportion of participants in each arm with viral load below 200 copies/ml nine months after randomisation. The study found no significant difference in this outcome between study arms: 61% in the standard-of-care am and 63% in the resistance-testing arm had a viral load below 200 copies/ml.

Nor was there a difference in the proportions with viral load below 50 copies/ml, or the proportion who achieved viral suppression on their existing first-line regimen.

Sub-group analysis found no significant differences in primary outcome by country, baseline adherence, sex, or baseline CD4 count.

However, standard management did result in a higher frequency of drug resistance in people with viral load above 1000 copies/ml at month 9. Seventy-five per cent of those in the standard-management arm with viral load above the potential switch threshold of 1000 copies/ml had drug resistance, compared to 56% in the resistance-testing arm.

After adherence counselling, 38% of those in the standard-of-care arm with enrolment viral load above 1000 copies/ml had a second viral load result that was below 1000 copies/ml and remained on their existing regimen. Fifty-five per cent still had viral load above 1000 copies/ml and were recommended to switch.

In the resistance-testing arm, 66% had resistance at baseline and were recommended to switch regimen.

The study investigators concluded that resistance testing did not improve the 9-month suppression rate in this study and that interventions to improve the management of virological failure are still urgently needed.

References

Siedner M et al. Randomized trial of resistance testing for virological failure in sub-Saharan Africa. Conference on Retroviruses and Opportunistic Infections, abstract 95, 2021.

Download the abstract eBook from the conference website.