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Risk Of Developing Resistance Mutations During Treatment Interruptions
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Reported by Jules Levin
"Risk of Developing Selected de Novo (new) Resistance Mutations During Structured Therapy Interruptions (STI) in Chronic HIV-1 Infection"
For several years now increasing numbers of studies have found that HIV drug resistance may emerge during treatment interruptions. Simultaneously, a number of studies have found that HIV drug resistance may be present under the surface but not detected by standard commercially available genotype resistance testing. Studies have also unmasked HIV drug resistance by using sensitive resistance tests even when resistance was not able to be found using standard commercial resistance testing.
RISK OF DEVELOPING RESISTANCE MUTATIONS DURING TREATMENT INTERRUPTIONS
Mireia Arnedo (Clinic Institute of Infectious Diseases and Immunology, University of Barcelona, Spain) presented results from this study at the XIII International HIV Drug Resistance Workshop in Tenerife (June 8-12 2004). Here is his report.
STI may allow viral replication in the presence of drug, leading to the emergence of drug resistance mutations.
112 cycles of STI in a total of 35 patients recruited in 4 STI protocols were studied. Plasma samples were analyzed, at baseline before starting any treatment, before starting the STI protocol and 2 weeks after STI. Proviral DNA was also assessed. All drugs were interrupted at the same time during STI. In a subgroup of 8 patients genotypic and phenotypic analysis were also assessed at peak of viral load after each interruption. Analysis of genotypic resistances were performed using TruGene HIV-1 assay (Visible Genetics). Virtual phenotype was performed for each sample by Virco.
RESULTS
Resistance mutations were selected in 20 out of 112 STI cycles (18%). In 6% mutations were de novo and in 12% from archived mutations. Overall nine out of 35 patients (26%) selected resistance mutations during STI (14% de novo and 12% from archived mutations). Three out of 13 recipients of NNRTI (23%; all de novo) selected resistance mutations to NNRTI. Nine out of 18 recipients of lamivudine (3TC) (50%; 22% de novo and 28% from archived mutations) selected resistance mutations to 3TC. Two out of 35 recipients of NRTI (g%; 3% de novo and 3% from archived mutations) selected resistance mutations to NRTI excluding the M184V mutation.
Finally, no primary mutations to PI were detected. In most cases mutations were selected during first cycle of STI and did not significantly increase during successive cycles. There was good concordance between virtual phenotype and genotype.
The authors concluded that 26% of patients participating in STI protocols selected resistance mutations that were already present before being recruited in about half of them. Among NNRTI and 3TC recipients the percentage was 23% and 50% and again, in both cases, selected mutations were already present before being recruited in about half of them.
Another poster presentation addressed a related question on interruptions.
"Baseline Predictors and Virological Outcome in Subjects Developing Mutations During Intermittent HAART"
genotypic resistance is not always detectable but study finds viral load level predicts resistance during STI
Lucia Palmisano (Istituto Superiore di Sanita, Rome, Italy) and colleagues including Stefano Vella presented results from this study at the Resistance Workshop in Tenerife. Here is his report.
They previously reported that by 21 months followup about 28% of chronically infected subjects, switched from continuous to intermittent HAART, have developed mutations during treatment interruptions. They reported that the risk of developing mutations is 10-fold higher in subjects harboring archived mutations in proviral DNA before interrupting therapy. Here is a report on further data on virologic outcome and baseline viral replication in these subjects, that may contribute to better understand limits and potentials of intermittent therapy in clinical practice.
The relationship between plasma mutations and virologic failure (HIV RNA >400 at any time) was assessed in 108 subjects assigned to arm B of ISS PART study, an ongoing, randomized multi-centere clinical trial comparing continuous (arm A) versus intermittent HAART in HIV+ subjects on first line HAART, all with HIV RNA <400 and CD4 count >350. Intermittent therapy consisted of four cycles 'on/off' (STIs of 1, 1, 2, 2 months, at 3-month intervals). In a subgroup of 49 subjects (24 with plasma mutations during STI), previously studied for PBMC genotype, baseline HIV RNA was measured with a modified ultrasensitive method (limit of detection: 3.5 copies/ml).
RESULTS
The overall prevalence rate of virologic failure in arm B was 18.4%. However, when subjects were stratified according to the presence of plasma mutations during STI, a significantly higher rate was found in those with mutations (12.4% vs 33%, p=0.004). In the subgroup analysis, mean baseline levels of HIV RNA were significantly higher in subjects with plasma mutations, when compared to patients retaining a wild-type virus (4.9 vs 17.5 copies/ml, p=0.03). Baseline RNA was also correlated with the presence of mutations in proviral DNA.
The authors concluded that the present results show that in subjects with undetectable viremia (measured with currently used assays), actual levels of HIV RNA, as well as the presence of mutations in proviral DNA, are predictors of resistance during STIs. Secondly, a correlation exists between actual levels of viremia at baseline and the presence of archived mutations. Third, virologic response to therapy reinstitution is jeopardized by the emergence of mutations during STI.
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