Drug-resistant virus acquired during HIV infection remains stable and persistent

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A three-year study from an HIV treatment centre in Brighton, East Sussex, has found that drug-resistant strains of HIV remain stable and can persist for “a considerable time” after infection. The study, published in the December 15th issue of the Journal of Acquired Immune Deficiency Syndrome, highlights the implications for both onward transmission of resistant virus, and the importance of performing resistance testing at baseline.

‘Primary’ resistance, which occurs after infection with a drug-resistant strain of HIV, accounts for between ten and 20% of new infections in the UK, Western Europe and North America, and, as was established in two papers in the journal AIDS earlier this year, reported here, patients infected with resistant virus do not tend revert to wild-type virus in the months and years following seroconversion in the absence of antiretroviral drug treatment.

The purpose of this study was to monitor the persistence of resistance-associated mutations after recent HIV infection. The study included 14 patients with primary infection. This was defined as having previously had a negative antibody test within 18 months of seroconversion, along with either laboratory evidence of acute seroconversion (e.g. an evolving antibody response) or by use of the STARHS assay, which can indicate if someone has been infected within the past 170 days. None of the patients were on anti-HIV therapy during the study’s three year follow-up period.

Glossary

seroconversion

The transition period from infection with HIV to the detectable presence of HIV antibodies in the blood. When seroconversion occurs (usually within a few weeks of infection), the result of an HIV antibody test changes from HIV negative to HIV positive. Seroconversion may be accompanied with flu-like symptoms.

 

wild-type virus

The naturally occurring, non-mutated strain of a virus. When exposed to antiretroviral (ARV) drugs, wild-type HIV can develop mutations that make the virus resistant to specific HIV drugs. 

 

strain

A variant characterised by a specific genotype.

 

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). 

protease inhibitor (PI)

Family of antiretrovirals which target the protease enzyme. Includes amprenavir, indinavir, lopinavir, ritonavir, saquinavir, nelfinavir, and atazanavir.

Sequence analysis found that the patients were initially infected with virus showing nucleoside reverse transcriptase inhibitor (NRTI) and protease inhibitor (PI) resistance, or non-nucleoside reverse transcriptase (NNRTI) and PI resistance, or resistance to all three classes (multidrug resistance, MDR). Follow-up ranged from two to 36 months, and it was found that the vast majority of drug resistant viruses persisted over time.

The only exceptions seen to the persistence of drug-resistance virus during follow-up were A62V, Y181C and K219Q when these mutations occurred singly. The authors write: “The disappearance of [these] mutations could be caused by reversion and selection of a fitter virus or, alternatively, by overgrowth of wild-type virus that was present in the original infecting innoculum as a minority population.”

The most commonly-found variants, seen in three and five patients, respectively, were at the M41L and T215 codon, which confers resistance to AZT (zidovudine, Retrovir) and d4T (stavudine, Zerit). The authors note that both mutations remained stable over time, with only one patient seen to have T215Y evolve into T215C.

The two patients who were found to have MDR virus (which persisted for the full 17 and 18 months of follow-up, respectively) had low viral loads (under 5000 copies/ml) and retained CD4 counts over 500 cells/mm3 throughout the study. The authors comment that the MDR virus “showed no change over the period studied. The slow evolution of MDR virus to fitter wild-type virus may be a consequence of the multiple mutations needing replacement in these viruses.”

Two issues are highlighted by this study: the potential for onward transmission of resistant virus from patients not on anti-HIV therapy, and the importance of performing a resistance test at baseline. The authors conclude that resistance testing at baseline “even when evidence of recent infection is not present,” is important even if this “may result in some underestimation of transmitted resistance because of loss of some mutations over time. Nevertheless, it can certainly provide some benefit for the guidance of treatment options and should be considered for all at-risk patient groups.”

References

Pao D et al. Long-term persistence of primary genotypic resistance after HIV-1 seroconversion. JAIDS 37 (5), 2004.