HIV Drug Resistance Workshop: population surveys of resistance

Yasmin Halima
Published: 29 June 2004

Many guidelines now include recommendation for resistance testing before patients begin antiretroviral therapy where the prevalence of population resistance is known to be 10% or more.

However, transmitted resistance may wane over time to levels below the threshold of current resistance assays. These low levels of resistance are likely to be archived and re-emerge upon initiation of treatment, potentially comprising the efficacy and durability of the regimen.

Detecting resistance in treatment-naive patients

The Centers for Disease Surveillance and Control in Atlanta are developing the use of real-time PCR-based point mutation assays specifically to detect the NNRTI-associated mutation K103N and the 3TC associated mutation M184V, on the basis that epidemiological studies confirm these to be the most notable of transmitted mutations.

They compared the results of the real-time PCR which was able to detect resistant viruses below 0.06% (103N) and 0.2% (184V) of the virus population against standard sequence analysis and found significant discrepancies in the comparative findings. Whist none of the 184V showed up in the standard genotype, they had a detection rate of 97% and for the 103N. Similarly, while only one sample identified 103N in the genotypic analysis, the PCR tested positive in 98% of the same sample. These findings may have significant implications for selecting more sensitive resistance testing techniques when a patient is starting treatment or at other times in the patient’s treatment history where detecting lower levels of existing mutations may be important in the selection, or indeed preservation of future treatment options (Johnson).

V118I - is it or isn't transmitted

At last year’s Resistance Workshop, Deenan Pillay from University College London asked the assembled experts whether they defined the V118I RT mutation as a significant mutation or not. Even amongst the experts there was dissent with half of the delegation ascribing significance to this mutation whilst the other half dismissed its clinical significance. The V118I is an interesting mutation; patients on NRTI therapy experiencing a viral rebound often display V118I in association with other NRTI changes.

However, V118I has also been reported as the only mutation in treatment-naïve patients and it has been speculated that this mutation is a consequence of transmitted drug resistance.

Dr Pillay in conjunction with the MRC (UK) and Chelsea and Westminster Hospital in London considered whether this mutation may have an impact on response to first-line therapy by identifying patients with (25 patients) and without (25 patients) V118I. Patients were matched for CD4 cell count and their first-line regimens. Most commonly prescribed treatments in both groups were AZT/3TC/EFV (8 patients in each groups), AZT, 3TC, efavirenz (EFV) tenofovir (TDF) (4 patients) and AZT, 3TC, nevirapine (NVP) (3 patients). Around 25% of patients changed therapy by 9 months into therapy. The study found no significant differences in patients with or without the presence of V118I and therefore no evidence that this mutation at baseline may go on to compromise treatment with NRTIs. The authors conclude that V118I should not be included within the definition of transmitted mutations considered to be clinically significant (Pillay).

Risk of resistance with long-term treatment

Another UK-based study assessed the time to accumulation of resistance in patients receiving three or more drugs and resistance testing as part of their routine care from six clinics in London and Brighton between 1996 and 2003. Of the 4457 patients, 56% started with NNRTI treatment, 41% with PI treatment. The cumulative risk of virologic failure was 41% after six years of HAART. The risk of one major mutation was 10% by year 2, 20% by year 4 and 27% by year 6. The rate of accumulation differed according to class of drugs administered: by year 6, M184V/I mutation occurred in 17% of patients, one or more TAMs (thymidine analogue mutations) in 15% and NNRTI resistance in 13% and PI mutations in 9%. Although there were some differences observed when the results were stratified by use of NNRTI as compared to PI therapy, this may not be significant (Phillips).

Resistance tests still under-utilised in the UK?

Finally, a study by the UK Collaborative Group on HIV Drug Resistance and UK Collaborative HIV Cohort Study of 10,314 patients on therapy monitored since 1998 found quite alarmingly, that resistance testing was performed in only 16% of treatment switches. 5,977 patients had never had a resistance test, 2,655 had only one test, 997 patients had two tests and 685 (of 10,314 patients) had 3 or more resistance tests. Using a method to determine all patients treated, still alive and referring to all previous tests by taking account of archived resistant virus, the estimated number of patients with triple-class resistance rose from 312 in 2000 to 453 in 2001, 511 at 2002 and 421 in 2003, suggesting that triple-class resistance has been stable over this time period. The study concludes that these values are likely to be underestimated due to the low rate of testing at time of treatment failure (Pillay).

Read related reports from the XIII International HIV Drug Resistance Workshop, June 8-12, Tenerife, Spain

Take home messages

What were the key messages from this year's Resistance Workshop?

Entry and attachment inhibitors

As researchers learn more about the ways in which HIV develops resistance to entry and attachment inhibitors, the future shape of therapy with these new classes of drugs becomes clearer.

New concepts for the clinician

This year's workshop heard more about the clinical relevance of replication capacity and hypersusceptibility, and began to debate the potential therapeutic exploitation of interactions between resistance mutations.

Prevention of mother to child transmission

The threat of nevirapine resistance is forcing a rethink of strategies to prevent mother to child transmission. The workshop learnt more about resistance patterns, and why differences in HIV-1 subtype may need to be taken into account when thinking about preventing mother to child transmission.

Non-B HIV subtypes

As treatment access expands and the proportion of patients in Europe with non-B subtypes grows, understanding differences in resistance patterns between B and non-B HIV subtypes becomes more and more important.

References

Johnson JA et al. Real-time PCR assays identify transmitted drug-resistant HIV-1 previously undetected by conventional nucleotide sequencing.

(Abstract 76) Antiviral Therapy 2004, 9:S87.

Pillay D et al. Transmission of HIV-1 containing V118I in reverse transcriptase does not compromise response to first-line therapy. (Abstract 106) Antiviral Therapy 2004, 9:S117.

Phillips AN et al. Risk of development of drug resistance in patients starting antiretroviral therapy with three or more drugs in routine clinical practice. (Abstract 135) Antiviral Therapy 2004, 9:S151.

Pillay D et al. Estimating resistance in drug experienced patients in the UK. (Abstract 77) Antiviral Therapy 2004, 9:S88.

Community Consensus Statement on Access to HIV Treatment and its Use for Prevention

Together, we can make it happen

We can end HIV soon if people have equal access to HIV drugs as treatment and as PrEP, and have free choice over whether to take them.

Launched today, the Community Consensus Statement is a basic set of principles aimed at making sure that happens.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap
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