One in six people not on treatment in a large South African household survey already had drug-resistant HIV and more than half of those on treatment had resistance to at least one drug, researchers from the Human Sciences Research Council, Pretoria, the National Institute for Communicable Diseases, Johannesburg, the US Centres for Diseases Control and Prevention and the University of Cape Town reported at the recent Conference on Retroviruses and Opportunistic Infections 2019 in Seattle.
The sobering assessment of the extent of antiretroviral drug resistance in the South African population led researchers to call for prioritisation of integrase inhibitor use in first-line regimens and the stepping up of adherence support for people on antiretroviral treatment. Earlier switches from failing regimens are also needed to prevent the development of further drug resistance.
With over 4.4m people already on treatment, South Africa’s HIV treatment programme is the largest in the world. South Africa aims to enrol a further 2m people on treatment by the end of 2020 and plans to introduce dolutegravir-based first-line treatment during 2019. Dolutegravir has a higher barrier to resistance than other drugs but some South African clinicians think it should be preserved for use in third-line treatment.
Like other countries, South Africa is also considering how to deal with the potential for neural tube defects in infants exposed to dolutegravir at the time of conception. Some countries have decided not to prescribe dolutegravir to women of childbearing age, but policymakers need to balance this against the need for the most effective regimen.
As part of the Fifth South African National HIV Prevalence, Incidence and Behaviour Survey in 2017, researchers undertook HIV drug resistance testing for the first time. The survey involves dried blood spot testing of a representative cross-section of the South African population and so can include people who are not accessing care or who are disengaged from care.
The survey identified 2,294 people with HIV in 2017, of whom 1,107 had unsuppressed viral load. Drug resistance testing was successful in 697 (in the remainder, samples were either insufficient, viral loads too low for testing or PCR amplification failed).
Drug resistance mutations were identified in 200 people (27.4% of those tested for resistance). The most common form of resistance was to the non-nucleoside reverse transcriptase inhibitor (NNRTI) class (18.9% of all samples tested). 7.8% of the sample had resistance to both NNRTIs and to at least one drug in the NRTI class, and 0.5% had resistance to NNRTIs, NRTIs and protease inhibitors.
Over half of all those who tested positive for traces of antiretroviral drugs in their blood (tested to verify treatment status, as the Household Survey is not linked to clinic records) had at least one drug resistance mutation (55.7%), most commonly to drugs in both the NNRTI and NRTI class (40.4%).
Among people who reported never having taken antiretrovirals and who tested negative for antiretrovirals at sampling, 15.3% had drug resistance, all to the NNRTI class (viruses with resistance to NNRTIs are more likely to be transmitted than viruses with other drug-resistant mutations).
Among those who reported being on antiretroviral treatment but who tested negative for antiretrovirals at sampling, 75.9% had drug resistance, predominantly to NNRTIs (56.4%) or to NNRTIs and NRTIs (14.3%).
The researchers found no difference in the prevalence of drug resistance by age or sex.
South Africa’s antiretroviral treatment (ART) programme is the largest globally with >4 million HIV-infected persons receiving standardized treatment regimens. Monitoring levels of HIV drug resistance (HIVDR) is a priority activity for the country. HIVDR testing was included for the first time in the 5th national HIV household survey conducted in 2017.
Multi-stage stratified cross-sectional random sampling was used to select households for participation nationally. Dried blood spots were tested to determine HIV status, estimated recency of infection, exposure to antiretroviral drugs (ARVs), and HIVDR in addition to behavioral data from all household members who agreed to participate. HIVDR testing was conducted on HIV-positive samples with viral load ≥1000 copies/ml using next generation sequencing methodologies.
Of 1107 HIV positive samples from virally unsuppressed participants, 697 (63%) were successfully amplified by polymerase chain reaction and sequenced. Drug resistant mutations (DRM) were identified in 27.4% (95% CI 22.8-32.6) of samples: 18.9%(95% CI 14.8-23.8) had resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) only, 7.8% (95% CI 5.6-10.9) had dual resistance to NNRTIs and nucleoside reverse transcriptase inhibitors(NRTIs), and 0.5% (95% CI 0.1-2.1) had resistance to second-line regimens that include protease inhibitors (PIs),NNRTIs, and NRTIs). Table 1 shows HIVDR by exposure to ARVs, sex, and age. NNRTI-only resistance was found in 14.3% ARV+ve and 20.0% ARV-ve samples (p=0.311), while dual NNRTI and NRTI resistance occurred in 40% ARV+ve and 2.1% ARV–ve samples (pThese findings demonstrate high proportions of DRM among virally unsuppressed HIV-infected persons in South Africa. While these results include treatment defaulters, potential pretreatment HIVDR levels are concerning. Programmatic implications include stronger adherence support to reduce ARV defaulting, and strengthened first line ART regimens by including integrase strand transfer inhibitors (INSTIs) as a part of first line treatment. These findings support the national transition to include Dolutegravir as part of first-line ART in South Africa.
Sizulu Moyo, Gillian Hunt, Zuma Khangelani, Nompumelelo P Zungu, Edmore Marinda, Musa Mabaso, Karidia Diallo, Cheryl Dietrich, Thomas Rehle