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

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.

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.