People living with HIV in Nigeria, at high risk for virological failure, on a tenofovir (TDF)-based
first-line regimen, had fewer nucleoside reverse transcriptase inhibitor (NRTI)
drug-resistant mutations and more fully active NRTI drug options for
second-line treatment, researchers report in the advance online edition of AIDS.
per cent of those on tenofovir-based regimens had at least two choices of NRTIs
to include in second-line regimens compared to 40% of those on zidovudine (AZT)-based regimens, a significant difference (p=0.04), Mary-Ann Etiebet and
colleagues write in this retrospective genotypic analysis of 175 archived blood
Health Organization (WHO) guidelines now recommend using tenofovir or AZT as
the preferred nucleoside analogue (NRTI) for use in combination with 3TC or FTC
in first-line regimens. The findings from Nigeria reinforce the World Health Organization recommendation that tenofovir may
be a better option for first-line regimens because it maintains susceptibility
to thymidine analogue NRTIs (AZT and d4T) in second-line treatment.
there are limited data comparing drug resistance patterns associated with tenofovir or AZT-based
first-line treatment regimens and their effects on responses to second-line
regimens in resource-poor settings.
Nigeria has the
second highest burden of HIV worldwide. Its HIV epidemic is dominated by
subtypes G and circulating recombinant form 02_AG (CRF). (CRFs refer to two
viruses of different subtypes meeting in the cell of an infected person so
creating a new hybrid virus.)
date subtype B has been the most common in Europe, the Americas, Japan
Subtype G and CRF A/G has been seen in West and East Africa as well as Central Europe.
drug resistance testing is not available in resource-poor settings. The authors
note evidence suggesting that genetic differences among non-B subtypes exposed
to ART may contribute to their pattern of drug resistance. So mutations among Nigeria’s
diverse HIV subtype population could be cross-resistant to second-line options.
authors undertook a cross-sectional study performing genotypic sequencing
analysis on stored blood samples from patients on non-nucleoside reverse
transcriptase inhibitor (NNRTI) regimens who got targeted viral load testing to
confirm treatment failure.
study was undertaken at the Institute for Human Virology-Nigeria (IHVN)
supported sites. The IHVN provides ART to over 60,000 public sector patients
through the AIDS Care and Treatment in Nigeria (ACTION) programme.
criteria comprised: having had a viral load test between November 2006 and
December 2007; being over 18 years of age, on an NNRTI-based regimen and not
having received any protease inhibitor (PI)-based treatment.
and treatment protocols followed Nigerian national guidelines. Six first-line
regimens were prescribed through the programme: zidovudine, lamivudine and
nevirapine or efavirenz; (AZT/3TC/NVP or EFV) stavudine, lamivudine and
nevirapine or efavirenz (d4T/3TC/NVP or EFV and tenofovir, emtracitabine and
nevirapine or efavirenz (TDF/3TC/NVP or EFV).
regimens were categorised according to NRTI type: AZT, d4T and tenofovir.
viral loads of blood samples from 349 adult patients were measured; those over
1000 copies/ml were then genotyped, 30 of which did not amplify.
the 175 samples genotyped most were subtypes G (42.9%) and CRF02_AG (33.7%);
patients were on ART for a median of 27 months with a median CD4 cell count of 128
cellsmm3 (IQR: 60-229).
those genotyped 14% were on AZT, 21% on d4T, 13% on TDF and 52% on more than
had at least one NRTI mutation and 62% at least one thymidine analogue mutation
conferring resistance to d4T or AZT. 90% of patients had the M184V/I mutation
associated with 3TC resistance and 14% the K65R mutation associated with
on tenofovir-based regimens were significantly more likely to have resistance
patterns that preserved sensitivity to d4T or AZT compared to those on AZT- or
d4T-based regimens, p<0.02); and 57% (13/23) had the K65R mutation,
relatively uncommon in subtype B viruses.
similar prevalence of K65R in persons experiencing failure of tenofovir-based
regimens has been reported in other studies among non-B subtypes.
authors note that tenofovir is partially active and is enhanced when K65R co-occurs
with the M184V mutation. “M184V was the most frequent mutation among tenofovir-based
regimens (14/23) and the only one associated with a lower mean viral load.
Viruses with M184V have a decreased replicative capacity and its presence may
on tenofovir-based regimens were less likely to have thymidine analogue
mutations; 12% of patients with the K65R mutation developed these resistance mutations
compared with 70% without this mutation.
multivariate analysis TDF-based regimens were less likely to have three or more
NRTI mutations after adjusting for subtype, previous ART use, CD4 cell count
and viral load (OR=0.04, p<0.001).
cell counts over 100 were independently protective of multiple NRTI mutations.
of those genotyped had at least one NNRTI mutation and 47% had two or more
authors conclude, “It is imperative that viral load testing is conducted in
order to maintain effective second-line options in low resource settings.”