Rilpivirine resistance may be barrier to long-acting injectable treatment in South Africa

Hryshchyshen Serhii/

One in eight people (12%) starting antiretroviral treatment in a South African clinic would have been unable to benefit from injectable treatment that includes rilpivirine due to pre-existing resistance to the drug, South African researchers report.

In people experiencing failure of a non-nucleoside reverse transcriptase inhibitor (NNRTI) regimen, rilpivirine resistance was widespread. Close to half (44%) had high-level resistance to rilpivirine and overall, three-quarters showed some degree of resistance to rilpivirine.

The NNRTI rilpivirine (Edurant) is a component of several fixed-dose combinations (Eviplera, Odefsey, Juluca). Rilpivirine has been replaced in first-line treatment by more potent combinations containing an integrase inhibitor and its use has been limited in lower- and middle-income countries owing to the availability of more affordable fixed-dose combinations containing generic versions of another NNRTI, efavirenz.


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).


In pharmacology, a medication which maintains its effects over a long period of time, such as an injection or implant.

integrase inhibitors (INI, INSTI)

A class of antiretroviral drugs. Integrase strand transfer inhibitors (INSTIs) block integrase, which is an HIV enzyme that the virus uses to insert its genetic material into a cell that it has infected. Blocking integrase prevents HIV from replicating.


In HIV, different strains which can be grouped according to their genes. HIV-1 is classified into three ‘groups,’ M, N, and O. Most HIV-1 is in group M which is further divided into subtypes, A, B, C and D etc. Subtype B is most common in Europe and North America, whilst A, C and D are most important worldwide.

first-line therapy

The regimen used when starting treatment for the first time.

But rilpivirine is being reappraised as a component of treatment in lower- and middle-income settings because it is now available as a long-acting injectable treatment (Rekambys, also marketed as Cabenuva) in combination with integrase inhibitor cabotegravir (Vocabria). The injectable regimen can be given once every two months.

For the time being, the injectable combination is unaffordable in lower- and middle-income settings. But there is interest in the potential for providing long-acting injectable treatment, particularly for people who have difficulties in taking daily medication.

However, a high prevalence of NNRTI resistance could be a barrier to offering long-acting injectable treatment containing rilpivirine.

Antiretroviral treatment based on the NNRTI efavirenz was the preferred option until transition to the integrase inhibitor dolutegravir after 2016. People who experience failure of an NNRTI-based regimen are likely to develop some degree of cross-resistance to NNRTIs. Once acquired, NNRTI resistance is persistent and NNRTI-resistant virus can be transmitted to others. People who acquire NNRTI-resistant virus through sex or other routes will not benefit from NNRTI-based treatment.

In a new analysis, South African researchers investigated what proportion of people with HIV in a typical urban HIV clinic population might be eligible for injectable treatment containing rilpivirine, based on drug resistance profiles.

They carried out genotypic resistance testing on samples from 277 previously untreated people with HIV and 1,372 people experiencing the failure of an NNRTI-based regimen.

Previously untreated people had a median age of 34 years and just over half (58%) were female. Seventeen percent had viral mutations associated with NNRTI resistance and 12% had at least one mutation associated with rilpivirine resistance. Almost 10% had intermediate-level rilpivirine resistance and 2% had high-level resistance. As this group of people had no previous treatment experience and were too old to have been born with HIV and exposed to the NNRTI nevirapine in infancy, they probably acquired NNRTI-resistant virus through sexual transmission.

Treatment-experienced people had a median age of 37 years and 63% were female. Ninety-five percent of this group had at least one NNRTI resistance mutation and 74% had at least one rilpivirine resistance mutation. Forty-four percent had high-level resistance to rilpivirine and 28% had intermediate-level resistance to the drug.

Response to the injectable regimen is suboptimal in people with the HIV-1 A1/A6 subtype, chiefly found in Eastern Europe. Less than 1% of each group had subtype A virus.

Although failure of NNRTI-based treatment will become less common as dolutegravir replaces efavirenz in first-line treatment, the previous widespread use of NNRTI-based treatment in lower- and middle-income countries means that many people with HIV have experienced failure of an NNRTI-based regimen – and may have spent a prolonged period on failing treatment, increasing the chance of high-level resistance to other NNRTIs.

The study investigators say that screening for NNRTI resistance in lower- and middle-income countries is logistically and technically challenging and that rilpivirine resistance “has significant implications for operational implementation of long-acting cabotegravir plus rilpivirine.”


Steegen K et al. Impact of rilpivirine cross-resistance on long-acting cabotegravir-rilpivirine in low and middle income countries. AIDS, published online 6 February 2023.

DOI: 10.1097/QAD.0000000000003505