3TC treatment preserves and promotes NNRTI resistance

Keith Alcorn
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This article is more than 22 years old.

Treatment with 3TC in the presence of viral rebound is likely to promote NNRTI resistance in people receiving non-nucleoside reverse transcriptase inhibitors at the same time, and treatment with 3TC after NNRTI treatment ceases is also likely to preserve NNRTI resistance mutations, according to findings presented at the Sixth International Congress on Drug Therapy in HIV Infection last week in Glasgow.

The study was carried out by Dr Alan Winston and colleagues at the Chelsea and Westminster Hospital, London.

Forty four individuals with two resistance tests and evidence of NNRTI resistance on the first test were assessed to see what happened to NNRTI resistance by the time of the second test.

Glossary

nucleoside

A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 

second-line treatment

The second preferred therapy for a particular condition, used after first-line treatment fails or if a person cannot tolerate first-line drugs.

p-value

The result of a statistical test which tells us whether the results of a study are likely to be due to chance and would not be confirmed if the study was repeated. All p-values are between 0 and 1; the most reliable studies have p-values very close to 0. A p-value of 0.001 means that there is a 1 in 1000 probability that the results are due to chance and do not reflect a real difference. A p-value of 0.05 means there is a 1 in 20 probability that the results are due to chance. When a p-value is 0.05 or below, the result is considered to be ‘statistically significant’. Confidence intervals give similar information to p-values but are easier to interpret. 

reverse transcriptase

A retroviral enzyme which converts genetic material from RNA into DNA, an essential step in the lifecycle of HIV. Several classes of anti-HIV drugs interfere with this stage of HIV’s life cycle: nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). 

drug resistance

A drug-resistant HIV strain is one which is less susceptible to the effects of one or more anti-HIV drugs because of an accumulation of HIV mutations in its genotype. Resistance can be the result of a poor adherence to treatment or of transmission of an already resistant virus.

Half of the group continued NNRTI treatment to the time of the second test.

In patients who were receiving 3TC treatment at the time of the second resistance test, 15% showed reduced evidence of genotypic resistance to NNRTIs, compared to 27% of the cohort as a whole. This difference was non-significant. However, patients receiving 3TC treatment at the time of the second resistance test were significantly more likely to show signs of increased genotypic resistance to NNRTIs (35% vs 18% of the total cohort, and 13% of patients who continued NNRTI treatment, p=0.02). Patients currently receiving 3TC were also significantly more likely to have the M184V mutation associated with 3TC treatment (70% vs 37%, p=0.031). This pattern was not observed with any other nucleoside analogue.

The authors of the study say that “The presence of M184V may push viral evolution to select further development of NNRTI mutations”.

In contrast, a number of recent studies have suggested that nucleoside analogue resistance (including 3TC resistance) in the absence of NNRTI resistance mutations may lead to a state of NNRTI hypersusceptibility in a substantial minority of patients. See

Resistance to NNRTIs elsewhere on this website for further information on this topic.

If these findings are replicated in larger cohort analyses, they are likely to further discourage the practice of maintaining 3TC treatment in patients who have failed their first 3TC-containing regimen. A randomised study presented at the XI International HIV Drug Resistance Workshop this summer showed that individuals who maintained 3TC treatment had a twofold higher risk of virological failure (defined as rebound above 2,000 copies/ml) when compared with individuals who replaced 3TC with ddI (Winter).

A study called COLATE is currently testing whether it is better to continue with 3TC in second-line treatment or drop 3TC treatment. This study is testing 3TC in combination with a protease inhibitor rather than an NNRTI.

References

Winston A et al. The effects of continuing therapy on NNRTI-associated mutations over time. Sixth International Congress on Drug Therapy in HIV Infection, Glasgow, abstract P210, 2002.

Winter MA et al. Clinical impact of the M184V mutation on switching to didanosine or maintaining lamivudine treatment in nucleoside-experienced patients. Antiviral Therapy 7: S101, 2002.

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