Nigeria: Drug resistance data show merits of using tenofovir in first-line ART regimens

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.

Seventy 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 samples.

World 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.

However, 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.)

To date subtype B has been the most common in Europe, the Americas, Japan and Australia. Subtype G and CRF A/G has been seen in West and East Africa as well as Central Europe.

HIV 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.

The 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.

The 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.

Inclusion 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.

Care 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).

First-line regimens were categorised according to NRTI type: AZT, d4T and tenofovir.

The 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.

Among 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).

Of those genotyped 14% were on AZT, 21% on d4T, 13% on TDF and 52% on more than one NRTI.

94% 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 tenofovir resistance.

Those 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.

A similar prevalence of K65R in persons experiencing failure of tenofovir-based regimens has been reported in other studies among non-B subtypes.

The 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 suggest adherence.”

Those 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.

In 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).

CD4 cell counts over 100 were independently protective of multiple NRTI mutations.

97% of those genotyped had at least one NNRTI mutation and 47% had two or more etravirine-associated mutations.

The authors conclude, “It is imperative that viral load testing is conducted in order to maintain effective second-line options in low resource settings.”