South Africa reports successful third-line HIV treatment programme

Despite 57% already having resistance to darunavir

People with resistance to first- and second-line antiretroviral drugs can still achieve high rates of viral suppression in the first year on third-line regimens according to a South African study published in the January issue of the Journal of Acquired Immune Deficiency Syndromes.

Third-line therapy was defined in the study to be any treatment regimen that included one of darunavir, raltegravir, or etravirine after documented resistance and failure of a regimen based on a protease inhibitor (PI).

The study provides the first evidence to show the effectiveness of third-line antiretroviral therapy (ART) use in the first year in a large cohort of a public sector programme and in a resource limited setting. However, it does not show what happens to people after the initial year so more analysis needs to be done to determine the effectiveness of the programme.


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.

protease inhibitor (PI)

Family of antiretrovirals which target the protease enzyme. Includes amprenavir, indinavir, lopinavir, ritonavir, saquinavir, nelfinavir, and atazanavir.


A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 

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.

In this study, 83% and 79% of people achieved virological suppression of below 1000 copies/ml and below 400 copies/ml respectively after six months. Dr Michelle Moorhouse of the Wits Reproductive Health and HIV Institute says this demonstrates that good virological suppression rates on third-line regimens are achievable in resource-limited settings, despite high levels of resistance.

South Africa has about 3.4 million people accessing ART, the largest number of HIV-positive individuals on antiretrovirals in the world, so understanding how to handle drug resistance is crucial in its control of the HIV epidemic. With the removal of the CD4 count thresholds as a criterion for ART initiation and due to increased acquired resistance, the numbers of people switching to third-line regimens is increasing.

The World Health Organization (WHO) recommends that national ART programmes in resource-limited settings develop policies for access to third-line ART, using drugs such as ritonavir-boosted darunavir, integrase inhibitors, etravirine and nucleoside analogues.

South Africa is one of the few countries in sub-Saharan Africa which has a national third-line ART public programme and a policy for people who have failed both first-line and second-line ART.

South Africa uses the WHO recommended first-line ART, based on a non-nucleoside reverse transcriptase inhibitor (NNRTI). Following virological failure and without resistance testing, patients are switched to a PI based regimen. About 145,000 people (4% of those on ART) are on second-line regimens.

Access to third-line ART in South Africa must be approved by a national committee that assesses eligibility and makes a recommendation for an individual regimen based on information received. The third-line committee is virtual and operates by email consensus.

The criteria for third-line includes one year or longer on PI-based ART with virological failure, despite adherence optimisation, and a genotypic antiretroviral resistance test showing PI resistance.

Between August 2013 and July 2014, 144 people were approved and enrolled into the third-line ART programme for which at least one viral load test was done at least six months after third line approval.

Their median age was 41 years, 60% were women and 40% men (a ratio of women to men similar to most cohorts in sub-Saharan Africa). The median CD4 count and viral load were 172 cells/mm3 and 14,759 copies/ml respectively. Two-thirds of the patients started ART before 2008 and 45% started second-line ART before 2012, while the start date was unknown for 49%.

There was a high proportion of people with resistance to the drugs used in first- and second-line ART regimens, probably due to delayed switching to second-line ART after first-line failure. Of the 144 patients, 97% and 98% had resistance to lopinavir and atazanavir, respectively.

Moreover, 57% had resistance to darunavir at third-line initiation, mainly low- and intermediate-level resistance. The likely reason for resistance to darunavir is that people may experience prolonged virological failure while on a second-line PI-based regimen before being referred for assessment of eligibility for third-line ART. In addition, before third-line ART was available in South Africa, people were maintained on failing PI-based regimens because there were no further options.

Similarly, resistance to etravirine was noted in just over a third of people (37%, 52/140), consisting mainly of low- and intermediate-level resistance.

All patients were initiated on a regimen containing darunavir, as well as raltegravir for 101 people, and also etravirine for 33 people. Most regimens also included nucleoside analogues.

Among those with at least one viral load at least six months after third-line approval, 83% (98/118) were suppressed to below 1000 copies/ml and 79% (93/118) to below 400 copies/ml. The rates of virological suppression to below 400 copies/ml were similar to those seen in people on third-line ART within South African private sector HIV disease management programmes.

The main limitations of the study were the relatively small sample size, short duration of follow-up, and missing data in those people for whom no viral loads after third-line initiation are available. A further limitation was the lack of data regarding outcomes beyond viral load, such as mortality and retention in care.

Furthermore, the lack of accurate data of numbers of people on second-line ART and those with confirmed virological failure made it difficult to contextualise the scope of PI resistance and need for third-line ART.


Moorhouse M et al. Third-Line Antiretroviral Therapy Program in the South African Public Sector: Cohort Description and Virological Outcomes. Journal of Acquired Immune Deficiency Syndromes 80: 73-78, 2019. (Full text freely available).