Protease inhibitor-based treatment did not result in superior rates of viorologic suppression after two years when compared to NNRTI-based treatment when tested in a randomised study in the Democratic Republic of
the Congo, researchers reported at the 19th Conference
on Retroviruses and Opportunistic Infections in Seattle last week.
outcomes by intent to treat analysis for patients in the Lubumbashi trial on a first line protease-inhibitor (PI)-based regimen were almost identical to those on a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based
regimen at 96 weeks (63% and 64% with viral load below 50 copies/ml
the results of this two-year prospective randomised trial Nathan Clumeck of the
Saint-Pierre University Hospital, Brussels, noted that those on the NNRTI-based
regimen had statistically significantly higher rates of virological failure (27
(12.9%) compared to 13 (6%) for LPV/r), as well as a higher incidence of
resistance mutations in both RTI classes. This may hinder the effectiveness of
second-line treatment with a PI as well as having the potential for increased
However this difference in virologic outcomes was offset by a higher rater of loss to follow-up in the protease inhibitor group.
World Health Organization (WHO) recommends using NNRTIS (nevirapine or
efavirenz) with tenofovir/emtricitabine (TDF/FTC) or zidovudine/lamivudine
(AZT/3TC) as the preferred first-line therapy in resource-poor settings.
Reasons include low cost, ease of use of fixed-dose combinations and no need to
refrigerate. However the advantages come with the primary disadvantage of a low
genetic barrier to the development of resistance in cases of treatment
interruption. This is particularly important with low adherence or stock-outs.
rationale and advantages of a PI-based regimen for first-line include a high
genetic barrier; the possibility for more treatment options at the time of
failure; LPV/r is in tablet form so refrigeration is unnecessary. Nonetheless
disadvantages include higher cost, more pills and metabolic changes, as well as
the potential for drug-drug interactions.
authors decided that in spite of the higher cost and other concerns they would
test the hypothesis that PI-based regimens would be better than NNRTI-based
regimens in resource-poor settings.
Therapeutic failures at 96 weeks were defined as:
WHO clinical stage 3 or 4
Confirmed virological failure (viral load over 1000
Stopping or changing treatment because of toxicity
for enrolment included being over 18 and ART-naïve; women who had taken
single-dose nevirapine were included as long as they had taken the dose more
than a year previously; WHO criteria were used for starting ART (WHO clinical
stage 4, or stage 3 and CD4 under 350 cells/mm3 or CD4 under 200
cells/mm3 regardless of clinical stage).
primary reason for exclusion was tuberculosis (TB) at screening. Dr. Clumeck
noted this is important given that the high death rates in all developing
countries within the first six months of treatment are due primarily to TB.
Other criteria for exclusion included being pregnant or breastfeeding and
abnormal liver enzymes and haemoglobin levels.
patients were first randomised to LPV/r (n=216) or NVP (n=209) and then
secondly to TDF/FTC or AZT/3TC. All got cotrimoxazole prophylaxis.
were no differences between the groups at baseline. Approximately 70% were
women; the majority were WHO clinical stage 3. One woman within the LPV/r arm
and two women within the NVP arm had previous exposure to NVP. Median CD4 cell
counts at baseline were in the region of 170 cells/mm3.
Approximately 30% had CD4 counts under 100 cells/mm3 and
approximately 50% had a viral load above 100,000 copies/ml.
week 96 there was no statistically significant difference in the proportions
with viral load below 50 copies/ml between the two arms but differences in
virological failure were statistically significant.
in CD4 cell counts were not statistically significant, but there was a trend
toward a higher response in the PI arm.
the 40 patients with virological failure (13 in the PI arm and 27 in the NVP
arm) 32 had genotyping done at the time of failure.
mutations were found in 86% of those in the NVP arm and none in the PI arm.
There were no major PI mutations in either arm.
mutations, namely M184V and K56R, were more frequent in the NVP arm compared to
the LPV/r arm, occurring in 73% (16/22) and 20% (2/10), respectively.
resistance mutations were available for 36 of the 40 with virological failure.
Three out of the 25 in the NVP arm had drug resistance mutations for NNRTI and
all failed at week 24. None of the 11 in the LPV/r had drug resistance.
those who failed 13 switched (1 in the LPV/r arm and 12 in the NVP arm) and 9
succeeded in re-suppressing viral load to under 50 copies/mL, one with a
NVP-based regimen and eight with LPV/r-based regimen.
both regimens and their backbones were equally well tolerated.
Dr. Clumeck concluded the significantly higher rate of virological failure and
higher incidence of resistance mutations in both RTI classes of those on an
NNRTI-NRTI first-line regimen in resource-poor settings warrants the evaluation
over the long-term of the cost-effectiveness of a PI-based regimen for first-line
use in these settings.