rebound occurred in only one in six patients during the first 18 months of
antiretroviral treatment at five major public hospitals in South Africa,
according to an analysis of close to 20,000 patients published in the advance
online edition of the Journal of Acquired
Immune Deficiency Syndromes. However,
the study found big variations between clinics in the speed at which patients
with virologic failure were switched to second-line treatment, despite clear
The median delay between confirmation of failure and switch to second-line treatment was five months, yet time to switching
varied by up to two-fold between cohorts. Lower CD4
cell counts at failure and rapidly declining CD4 cell counts were predictive of
authors found that close to three-quarters of those with confirmation of treatment
failure and at least six months of follow-up switched.
the study period, clinics were following the 2004 South African national
guidelines, which recommended a switch to second-line treatment if patients
with a detectable viral load measurement above 400 copies/ml had a viral load
above 5000 copies/ml three months later, despite intensive adherence support. This
guidance is consistent with WHO guidance on the use of viral load for
determining when to switch to second-line treatment in resource-limited
2010, South African guidance was updated to recommend a switch if viral load was
above 1000 copies/ml three months after the first detectable measurement.
authors chose to describe, for the first time, how WHO guidance works at the
national level and what the impact of different thresholds for determining
virological failure is at the programme level.
this observational cohort study, the authors included adult patients who began
public-sector antiretroviral therapy (ART) between January 2000 and July 2008 at five sites in South Africa
and who had completed at least six months of follow-up. Guidelines at the
time, now revised, included all patients with CD4 cell counts under 250
cells/mm3 or with WHO clinical stage 4 as being eligible for ART. Once on ART,
guidelines supported six-monthly viral load testing and CD4 cell count
In total, 19,645 people were followed for 29,935 person years, with a median of 1.3 years
(1.1-1.4) in the study and 1.8 years on ART and with a median CD4 cell count at the
start of ART of 96 (IQR: 40-159). Eighty-eight per cent achieved viral suppression on first-line
9.9% experienced treatment failure at what was determined to be a common failure
definition (viral load at or above 1000 copies/ml) at a median time from
starting ART of 16 months (IQR: 12-23 months); of which 62% (833/1348) switched
to second-line ART.
a confirmatory threshold of 400 copies/ml, 16.9% (95% CI: 15.4-18.6%) of the
sub-group treated for five years had experienced treatment failure by five
years whereas using a threshold of 10,000 copies/ml only 7.8% (95% CI:
6.6-9.3%) did according to survival analysis.
disease at the start of ART increased the risks of failure by 60% and two or
more treatment interruptions were associated with a seven-fold increased risk
of failure (aHR: 7.25, 95% CI: 4.95-10.6).
findings mirror those found in individual cohorts.
10.1% (9-11.4%) of the combined cohort switched to second-line treatment between six
months and five years on ART. The expected delays between first and second
detectable viral loads and subsequent switching were a median time of 2.7
months (IQR:1.6-4.7) and 4.6 months (IQR: 2.1-8.7), respectively.
public health approach, note the authors, has been shown to successfully identify
those patients with high levels of drug resistance needing to switch to second-line
therapy but with low levels of cross-resistance between first- and second-line
as these findings show, how this approach is applied will have a considerable
impact on the numbers who experience treatment failure and need second-line regimens.
authors note that subsequent changes to South Africa’s guidelines may
affect how these findings are interpreted. The initial nucleoside reverse
transcriptase inhibitor (NRTI) backbone has been changed from stavudine (d4T) and
lamivudine (3TC) to tenofovir and lamivudine. Routine viral load testing is now done
annually rather than six monthly after the first year on ART. Confirmation of
virologic failure was lowered from 5000 to 1000 copies/ml and the
confirmatory test has to be done within three months of the first.
less frequent monitoring may delay identifying those on failing treatment, use of tenofovir in
first-line treatment causes less concern for the accumulation of thymidine
analogue mutations that can compromise second-line regimens.
study found a high proportion of those needing to be switched did switch treatment.
Nonetheless, the nearly five-month delay between confirmation and switching and
the link with a decline in CD4 counts suggest clinical and administrative
factors contributing to the variations among the cohorts, note the authors.
used as a non-nucleoside reverse transcriptase inhibitor (NNRTI), was
associated with virological failure as commonly found in observational studies
and with clinical trial data from African sites, the authors add.
include the absence of appropriate data on prevention of mother-to-child transmission to look at single-dose nevirapine
and treatment failure. There were no data on adherence or prior resistance, two
important potential predictors of failure.
authors conclude “future treatment guidelines should make explicit the
rationale for thresholds chosen to define and confirm virologic failure in
light of our finding these profoundly affect the proportion of patients meeting
failure definitions, and the resultant costs of second-line treatment…Future
research should look at the impact failure definitions and delays in switching
have on treatment outcomes.”