of Drug-resistant HIV Increases Risk of Treatment Failure
who become infected with HIV that already has at least 1 drug-resistance
mutation are more likely to experience subsequent antiretroviral
treatment failure, according to a presentation at the XVIII
International AIDS Conference (AIDS 2010) last month in Vienna.
Virological failure was more common among people taking NNRTI-based
regimens, suggesting that protease inhibitors may be advisable
if pre-treatment genotypic resistance testing is not available.
that confer resistance to antiretroviral
drugs typically evolve in an individual if viral replication is
not fully suppressed, for example due to suboptimal therapy or poor
adherence. In some cases, however, people can be initially infected
with HIV that has already developed
such mutations, known as primary resistance.
Investigators with the EuroCoord-CHAIN Joint Project Team studied the
impact of transmitted drug resistance on treatment outcomes during the
first year of combination
antiretroviral therapy (ART).
The analysis included 10,458 participants from 25 cohorts making up
4 networks of the EuroCoord project -- CASCADE, COHERE, EuroSIDA, and
PENTA-EPPICC. Patients were taking first-line ART regimens consisting
of 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
plus either a non-nucleoside reverse transcriptase inhibitor (NNRTI)
or a protease inhibitor.
Using the World Health Organization (WHO) 2009 list of HIV drug-resistance
mutations and the Stanford algorithm (v6.0.5), the researchers classified
participants into 3 categories: no resistance mutations, 1 or more mutation
but receiving a fully active regimen, and 1 or more mutation and demonstrating
at least low-level resistance to at least 1 prescribed drug. They then
assessed time to virological failure, or the first of 2 consecutive
viral load measurements > 500 copies/mL after 6 months of therapy.
participants -- 9505, or 90.9% -- had no evidence of resistance
patients (4.5%) had at least 1 resistance mutation but were nevertheless
on a fully active ART regimen consisting of drugs not compromised
remaining 477 patients (4.6%) had 1 or more viral mutations and
were resistant to at least 1 drug in their regimen.
with resistance to at least 1 drug had a 2.6-fold higher risk of
virological failure compared to patients without resistance mutations.
was no significant difference in the likelihood of treatment failure
between patients without transmitted resistance mutations and those
with transmitted resistance but receiving a fully active ART regimen
(hazard ratio 1.2; P = 0.34).
with 1 or more resistance mutations who were taking a NNRTI plus
2 NRTIs and were predicted to be on a fully active regimen tended
to have a higher risk of virological failure compared with patients
on protease inhibitor-based regimens (P = 0.08, not reaching the
statistical significance threshold of 0.05).
responses, or CD4 cell increases, were consistent with virological
findings led the researchers to conclude that "Transmitted drug
resistance caused a poor virological and immunological response when
patients received combination ART containing > 1 drug classified
with at least low-level resistance."
"A higher trend for virological failure was found in [the] presence
of > 1 mutation in patients receiving 2 NRTIs + 1 NNRTI classified
to be fully active," they continued. Thus, first-line combination
ART regimens should be carefully selected using genotypic testing, and
drugs classified as already compromised by low-level resistance should
antiretroviral treatment guidelines recommend genotypic resistance
testing -- or seeing if the viral gene sequence includes known resistance
mutations -- before starting antiretroviral therapy in order to determine
if specific drugs are unlikely to work.
testing, however, may not detect resistant strains that make up only
a small proportion of the total viral population. The greater likelihood
of virological failure, though not significant, indicates that low-level
resistant virus may be more likely in people taking NNRTI-based regimens.
For this reason, the researchers suggested, protease inhibitor-based
regimens may be preferable in areas where pre-treatment resistance testing
is not widely available.
affiliations: INSERM U897, ISPED, Université Victor Segalen,
Centre of Epidemiology and Biostatistics, Bordeaux, France.
L Wittkop, G Chêne, Hannah Castro. Impact of transmitted drug
resistance (TDR) on virological and immunological response to initial
combination antiretroviral therapy (cART) - EuroCoord-CHAIN joint project.
XVIII International AIDS Conference (AIDS 2010). Vienna, July 18-23,