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Short-Duration, Single-Drug Interruption Strategy
Reported by Jules Levin
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One of the more interesting stories coming out of the 12th HIV Drug Resistance Workshop (June 2003, Cabos, Mexico) was a study on short-duration, single-drug interruption. Frank Malderelli from the HIV Drug Resistance Program at the Natl Cancer Institute reported in an oral presentation viral load response and resistance after patients discontinued either efavirenz or d4T from their regimen. The progressive Steve Deeks reported resistance data as a follow-up to his initial report of clinical response to single class interruption, which he reported at the Retrovirus Conference in Feb 2003.
Before telling the single-drug interruption story I'll recap other key stories coming out of the Workshop. Jon Mellors reported that commercial genotype testing failed to detect NNRTI resistance mutations in NNRT-naive and NNRTI-experienced patients who experienced viral failure after receiving efavirenz in ACTG Study 398; but sensitive genotype testing with single genome sequencing detected the NNRTI resistance, and phenotypic resistance was also detected by a new sensitive phenotype test. Researchers started to discuss characterization of tenofovir resistance in treatment-naive patients, as there were several abstracts and some discussion about this. Several abstracts reported data on transmission of drug resistance in the USA (CDC study in 10 cities in a diverse population), Europe, France, and Canada; and there was an interesting study by Susan Little on the persistence of transmitted drug resistance in newly infected. There were a few studies and a good amount of discussion about super-infection, which relates to transmission of drug resistance. Studies provided confirmatory clinical data that 3TC does have viral benefit even if the 3TC resistance mutation M184 is present. And there were several updates on resistance for new drugs at various stages of clinical development including TMC-114, TMC-125, tipranavir, and the new Roche PI. Reports on most of these subjects were emailed out to our readers and are always posted at the NATAP website . Continuing coverage by researchers and myself are forthcoming.
Regarding single-drug interruption, Malderelli said that it's difficult to extrapolate from genotypic and phenotypic test results and interpretations. Individual drug activity may be obscured by combination therapy. Single-drug interruption strategy proposes a way to detect if a specific drug has antiviral activity in a patient with detectable viral load. By peeling away one drug at a time this study suggests you can tell if a drug has activity for a patient.
The "Shortstop" study strategy was to establish baseline viral RNA with 6 viral RNA determinations over 10 days. Drug was discontinuedÑeither efavirenz for 3 weeks or d4T for 2 weeks. The effect on HIV was determined by 7 viral RNA determinations.Primary study outcomes were HIV-RNA and regression analysis Secondary study analysis was resistance testing--Single Genome Sequencing--and drug level monitoring.
RESULTS
There were 5 patients. Malderelli reported that two patients discontinued EFV and 3 discontinued d4T. The authors summarized that short-term single drug discomtinuation strategy was useful to evaluate the presence of antiviral activity in patients. 2 of 2 patients discontinuing efavirenz had no significant change in viral load. No change in genotype during discontinuation. And no residual activity for EFV in the setting of critical resistance mutations. 3 of 3 patients who discontinued d4T had increased viral load. They had residual antiviral activity present despite the presence of NAMs. Rebound viremia was not due to wild-type virus. Follow-up of the 5 patients as you can see below is only about 40 days. The study is short-term, preliminary, and a pilot study. Although the findings are interesting and appear to show promise for the utility of this concept, I think it's premature to use this approach in the clinic until further longer-term study is conducted for resistance and viral effectiveness.
Patient 1 had viral load of 5400 copies/ml, CD4 of 910, and was on d4T/ddI/EFV, and discontinued EFV. Pt 2 had viral load of 9300 c/ml, CD4 of 560, was on d4T/3TC/EFV and discontinued EFV. Pt 3 had VL of 8600 c/ml, CD4 of 600, was on d4T/3TC/RTV/SQV, and discontinued d4T. Pt 4 had 5200 c/ml VL, CD4 of 380, was on d4T/3TC/ABC/EFV, and discontinued d4T. Pt 5 had VL of 61,000 c/ml, CD4 of 650, was on d4T/3TC/IDV, and discontinued d4T.
Pt 1 (d4T/ddI/EFV) stopped EFV at day 8 and viral load remained without significant change during follow-up, which was 25 days. The mutation profile was the same on the triple regimen and on the double nuke regimen after stopping EFV: D67N, T69N, K70R, V106I, Y188L, T215F, K219Q.
Pt 2, (d4T/3TC/EFV) discontinued EFV at day 9, and viral load remained stable during follow-up, which was 30 days. The mutation profile also did not change from the time of discontinuation to after discontinuation at the end of the 30 day follow-up: K101P, K103N, M184V. There was no increase in 103K by alliele specific PCR.
Pt 3 (d4T/3TC/RTV/SQV) discontinued d4T at day 10, and viral load increased from 5,000 to 48,000 c/ml (p<0.0004). D4T was restarted at day 22 and viral load declined towards baseline. The M184V mutation was present when d4T was stopped and at day 40, 20 weeks after d4T was restarted and VL had declined. No other mutations were reported.
Pt 4 also stopped d4T (d4T, 3TC/ABC/EFV) at day 10, viral load increased, and d4T was restarted 15 days later. VL was resuppressed after restarting d4T at day 25, but VL started to increase after about 10 days. The mutation profile for this pt was the same at the time of discontinuing d4T at day 10 and after VL increased and d4T was restarted at day 25: M41L, D67N, L100I, K103N, V118I, M184V, L210W, T215Y. So during the 15 days of d4T interruption VL increased but resistance mutations did not appear to change during the follow-up period.
Pt 5 (d4T/3TC/indinavir) stopped d4T at day 9, and viral load started to increase from 45,280 to 98,000 c/ml at day 23 (p<0.002). At baseline, day 0, d4T fold change was 9.3 (I think IC50) and RT resistance mutations were M41L, D67N, V75M, V118I, M184V, L210W, T215Y. At day 23 after 2 weeks of increasing VL an additional RT mutation (F77F/L) was reported plus the same profile seen previously.
Short duration, single drug discontinuation to assess the activity of individual drugs in patients failing antiretroviral therapy
Frank Maldarelli 1 , S Palmer 1 , M Kearney 1 , J Falloon 3 , RT Davey 3 , A Powers 3 , S Vogel 3 , A Pau 4 , R Dewar 2 , JA Metcalf 2 , J Mellors 5 and
J Coffin 1 1 HIV Drug Resistance Program, NCI, NIH; 2 NIAID/CCMD Clinic, NIH; 3 Laboratory of Immunoregulation, NIAID, NIH; 4 CC Pharmacy, NIH; and 5 Division of Infectious Diseases, University of Pittsburgh, Pittsburgh, Pa., USA
BACKGROUND: The relationship of in vivo drug activity, and HIV-1 genotype and phenotype is incompletely understood. For non-nucleoside reverse transcriptase inhibitors (NNRTIs), loss of therapeutic activity in vivo is strongly associated with specific mutations. In contrast, for certain NRTIs, such as
stavudine (d4T), the effect of specific mutations on in vivo activity is poorly defined. To investigate the extent to which resistance mutations affect antiviral activity in vivo, we discontinued single drugs for short dura-tions
in patients failing combination antiretroviral therapy.
METHODS: Patients with HIV RNA greater than 5000 copies/ml plasma, CD4 T cell count greater than 50 cells/µl and adherent to a d4T- or efavirenz (EFV)-containing multidrug regimen were enrolled. Following a 10-day baseline sampling period, d4T or EFV was interrupted, maintaining the remainder of the
regimen. Longitudinal samples were obtained during the 14 day (d4T) or 21 day (EFV) interruption period. Following drug interruption, patients had the option of restarting the discontinued antiretroviral with additional sampling. Analysis included HIV-1 RNA measurements by bDNA assay and composite genotype
determination.
RESULTS: Of the five patients enrolled, three discontinued d4T and two discontinued EFV. There were no significant increases in viraemia during the 21-day observation period following EFV interruption. Baseline genotypes in both patients revealed NNRTI resistance mutations (K103N and Y188L). By con-trast, interruption of d4T for 14 days resulted in significant in viraemia in all three patients. Baseline genotypes in two of the patients in this group had multiple mutations associated with d4T resistance (M41L, D67N, V118I, L210W, T215Y). HIV-1 RNA levels were still increasing at the end of the discontinu-ation period, so the full impact of d4T discontinuation could not be determined. HIV-1 RNA levels declined promptly to baseline values in the two patients restarting d4T. No significant changes in CD4 T cell counts were observed during the trial and no adverse events related to drug interruption occurred.
CONCLUSIONS: Persistent antiviral activity of d4T, despite the presence of resistance-conferring mutations, was revealed by interruption of drug. By con-trast, EFV showed no persistent activity in patients with NNRTI resistance mutations. The single drug dis-continuation strategy may be a useful approach to assess persistent antiretroviral activity in patients failing therapy.
Limited genotypic and phenotypic evolution after interruption of a single therapeutic drug class in patients with multidrug-resistant HIV
SG Deeks, EE Paxinos, T Wrin, R Hoh, F Aweeka, JN Martin, CJ Petropoulos and
RM Grant University of California, San Francisco, Calif.; ViroLogic, South San Francisco, Calif.; and Gladstone Institute of Virology and Immunology, Calif., USA
BACKGROUND: We hypothesized that among treated patients with multidrug-resistant HIV, interruption of all drugs from a single therapeutic class ('partial
treatment interruptions', PTI) could: 1) maintain partial viral suppression and its associated immunological benefit; 2) prevent overgrowth of wild-type HIV; 3) delay viral evolution; and 4) reduce drug-toxicity and drug costs. We have previously reported that interruption of protease inhibitor (PI) therapy was often associated with stable viraemia, while interruption of reverse transcriptase inhibitor (RTI) therapy was often associated with rapid rises in viraemia. Here, we describe evolution of viral populations after interruption
of a single therapeutic class.
METHODS: Eligible subjects had >90% adherence, persistent viraemia (>400 copies/ml) and detectable PI levels. Replicative capacity and resistance testing was performed retrospectively with stored plasma. Phylogenies were constructed using parsimony methods.
RESULTS: Nineteen subjects interrupted PI therapy and six interrupted RTI therapy. All patients had evidence of a treatment-mediated benefit prior to PTI
(median 1.2 log copies/ml decrease in viral load relative to pretreatment levels). Wild-type HIV did not emerge during the PTI period. Among the patients who interrupted PIs, we observed no loss of PI mutations during 16-24 weeks of observation. Although most subjects had been exposed to sequential RTI therapy in the pre-HAART era (and potentially harboured RTI-resistant,
PI-susceptible virus), such an archived virus population did not emerge during the first 16-24 weeks of observation; we did, however, observe the emergence
PI-susceptible virus after week 36 in one subject (phylogenetic analyses suggest that loss of resistance was due to escape of an archived virus). Three subjects
who interrupted lamivudine lost the M184V mutations. Phylogenetic data suggest 'back' evolution of virus populations after PTI of reverse transcriptase
inhibitors, and an apparent absence of such evolution within after PI PTI. Finally, loss of resistance was temporally associated with increasing RC and increasing viraemia in most subjects.
CONCLUSION: Interrupting PI therapy in patients with multidrug-resistant HIV is associated with stable viremia and persistent levels of PI resistance. Several
mechanisms may have accounted for the failure of PI resistance to wane. First, the close proximity of RT and protease makes genetic recombination unlikely.
Second, viral evolution in presence of PI therapy is associated with the accumulation of compensatory mutations that increase viral fitness. Back mutations may require remodelling within these regions and an early decrease in relative fitness; this fitness 'valley' prevents reversion. Third, archived RTI-resistant and PI-susceptible virus likely contains fewer RTI-associated
mutations than more recent variants. Thus, the archived virus may be relatively more susceptible to RTIs. Collectively, these data suggest that decreases in replication capacity associated with PI resistance will
persist in the absence of the inhibitor.
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