Jonathan M Schapiro

Azienda Ospedaliera Universitaria Senese, Siena, Tuscany, Italy

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Publications (93)485.67 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Analysis of potentially different impact of Lopinavir/Ritonavir (LPV/r) on non-B subtypes is confounded by dissimilarities in the conditions existing in different countries. We retrospectively compared its impact on populations infected with subtypes B and C in Israel, where patients infected with different subtypes receive the same treatment. Clinical and demographic data were reported by physicians. Resistance was tested after treatment failure. Statistical analyses were conducted using SPSS. 607 LPV/r treated patients (365 male) were included. 139 had HIV subtype B, 391 C, and 77 other subtypes. At study end 429 (71%) were receiving LPV/r. No significant differences in PI treatment history and in median viral-load (VL) at treatment initiation and termination existed between subtypes. MSM discontinued LPV/r more often than others even when the virologic outcome was good (p = 0.001). VL was below detection level in 81% of patients for whom LPV/r was first PI and in 67% when it was second (P = 0.001). Median VL decrease from baseline was 1.9±0.1 logs and was not significantly associated with subtype. Median CD4 increase was: 162 and 92cells/µl, respectively, for patients receiving LPV/r as first and second PI (P = 0.001), and 175 and 98, respectively, for subtypes B and C (P<0.001). Only 52 (22%) of 237 patients genotyped while under LPV/r were fully resistant to the drug; 12(5%) were partially resistant. In48%, population sequencing did not reveal resistance to any drug notwithstanding the virologic failure. No difference was found in the rates of resistance development between B and C (p = 0.16). Treatment with LPV/r appeared efficient and tolerable in both subtypes, B and C, but CD4 recovery was significantly better in virologically suppressed subtype-B patients. In both subtypes, LPV/r was more beneficial when given as first PI. Mostly, reasons other than resistance development caused discontinuation of treatment.
    PLoS ONE 01/2014; 9(1):e86239. · 3.73 Impact Factor
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    ABSTRACT: Background The World Health Organization Antiretroviral Treatment Guidelines recommend phasing-out stavudine because of its risk of long-term toxicity. There are two mutational pathways of stavudine resistance with different implications for zidovudine and tenofovir cross-resistance, the primary candidates for replacing stavudine. However, because resistance testing is rarely available in resource-limited settings, it is critical to identify the cross-resistance patterns associated with first-line stavudine failure. Methods We analyzed HIV-1 resistance mutations following first-line stavudine failure from 35 publications comprising 1,825 individuals. We also assessed the influence of concomitant nevirapine vs. efavirenz, therapy duration, and HIV-1 subtype on the proportions of mutations associated with zidovudine vs. tenofovir cross-resistance. Results Mutations with preferential zidovudine activity, K65R or K70E, occurred in 5.3% of individuals. Mutations with preferential tenofovir activity, ≥two thymidine analog mutations (TAMs) or Q151M, occurred in 22% of individuals. Nevirapine increased the risk of TAMs, K65R, and Q151M. Longer therapy increased the risk of TAMs and Q151M but not K65R. Subtype C and CRF01_AE increased the risk of K65R, but only CRF01_AE increased the risk of K65R without Q151M. Conclusions Regardless of concomitant nevirapine vs. efavirenz, therapy duration, or subtype, tenofovir was more likely than zidovudine to retain antiviral activity following first-line d4T therapy.
    The Journal of Infectious Diseases 06/2013; 207 Suppl 2:S70-7. · 5.85 Impact Factor
  • Andrea De Luca, Raphael L Hamers, Jonathan M Schapiro
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    ABSTRACT: Antiretroviral treatment (ART) is expanding to human immunodeficiency virus type 1 (HIV-1)-infected persons in low-middle income countries, thanks to a public health approach. With 3 available drug classes, 2 ART sequencing lines are programmatically foreseen. The emergence and transmission of viral drug resistance represents a challenge to the efficacy of ART. Knowledge of HIV-1 drug resistance selection associated with specific drugs and regimens and the consequent activity of residual drug options are essential in programming ART sequencing options aimed at preserving ART efficacy for as long as possible. This article determines optimal ART sequencing options for overcoming HIV-1 drug resistance in resource-limited settings, using currently available drugs and treatment monitoring opportunities. From the perspective of drug resistance and on the basis of limited virologic monitoring data, optimal sequencing seems to involve use of a tenofovir-containing nonnucleoside reverse-transcriptase inhibitor-based first-line regimen, followed by a zidovudine-containing, protease inhibitor (PI)-based second-line regimen. Other options and their consequences are explored by considering within-class and between-class sequencing opportunities, including boosted PI monotherapies and future options with integrase inhibitors. Nucleoside reverse-transcriptase inhibitor resistance pathways in HIV-1 subtype C suggest an additional reason for accelerating stavudine phase out. Viral load monitoring avoids the accumulation of resistance mutations that significantly reduce the activity of next-line options. Rational use of resources, including broader access to viral load monitoring, will help ensure 3 lines of fully active treatment options, thereby increasing the duration of ART success.
    The Journal of Infectious Diseases 06/2013; 207 Suppl 2:S63-9. · 5.85 Impact Factor
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    ABSTRACT: Single-nucleotide polymorphisms (SNPs) near the IL28B gene were identified as major predictors of treatment response (sustained virologic response - SVR) and spontaneous clearance of HCV. Haemophilia patients have the highest prevalence of HCV, and are a unique target for genetic studies. The Israeli population is ethnically heterogeneous; therefore, genetic variability is anticipated. To determine the IL28B haplotypes in HCV-infected haemophilia patients and association with SVR and spontaneous viral clearance. IL28B polymorphism at SNPs rs12979860 and rs8099917 was determined in sera obtained from 130 HCV-infected haemophilia patients. The frequency of the various haplotypes was analysed according to treatment response, spontaneous HCV clearance, viral load and degree of fibrosis. The CC haplotype at SNP rs12979860 was found in 31% of patients, whereas the TT genotype at SNP rs8099917 was detected in 57% of cases. SVR was achieved in 70% of patients carrying the CC haplotype (P = 0.0196 vs. CT/TT), and 50% of the TT genotype at SNP rs8099917 (P = 0.0227 vs. TG/GG). Thirty-five percent of patients carrying the CC haplotype and 26% with the TT genotype at SNP rs8099917 showed spontaneous clearance of HCV infection (P = 0.00262 vs. CT/TT; and P = 0.00371 vs. TG/GG respectively). The C-allele frequency was exceptionally high (71%) in immigrants from the Asian republics of Russia. In HCV-infected haemophilia patients, SVR was more commonly achieved among patients who had the CC (rs12979860) or TT (rs8099917) genotype. Likewise, patients who possess harbour the CC or TT genotypes were more likely to clear HCV infection spontaneously. A unique distribution of the CC genotype was observed in some ethnic groups.
    Haemophilia 08/2012; · 3.17 Impact Factor
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    ABSTRACT: To assess the most frequent resistance-associated mutations (RAMs) to lopinavir/ritonavir in a cohort of patients attended in daily practice. We retrospectively identified 195 multitreated subjects with virological failure. Patients were classified as follows: (i) 71 (36.4%) never received lopinavir/ritonavir (lopinavir/ritonavir naive); (ii) 75 (38.5%) had previously failed on lopinavir/ritonavir; and (iii) 49 (25.1%) were on lopinavir/ritonavir at failure. RAM patterns were assessed. Medians, IQRs, percentages, Kruskal-Wallis, χ(2) or Fisher's exact test, and multinomial logistic regression were used whenever appropriate. L10I/F, K20R, L24I, L33F, M36I, M46I/L, I47V, G48V, F53L, I54V, A71V, G73S, V82A, I84V and L90M (all with P ≤ 0.037) were protease RAMs overexpressed in patients with lopinavir/ritonavir failure. L10I, M36I, M46I, I54V, L63P, A71V, V82A, I84V and L90M were the most common in lopinavir/ritonavir-naive patients. Other IAS-USA RAMs for lopinavir/ritonavir (L10R/V, K20M, V32I, I47A, I50V, I54L/A/M/T/S, A71T, L76V and V82F/T/S) were not associated with previous or current failure to lopinavir/ritonavir. Lopinavir/ritonavir failure was associated with the number of protease RAMs (OR = 1.146, 95% CI = 1.287, 1.626), higher exposure to protease inhibitors, and the presence of E44D, L33F, I54V and I84V. In multitreated patients with previous or current lopinavir/ritonavir failure, some protease mutations are selected at significantly greater rates. L10I, M36I, I54V, L63P, A71V, V82A and L90M were found in >50% of cases. Thus, their presence should be expected when genotypic testing results are not available. The number of protease RAMs and higher prior exposures to protease inhibitors were significantly associated with lopinavir/ritonavir failure.
    Journal of Antimicrobial Chemotherapy 03/2012; 67(6):1462-9. · 5.34 Impact Factor
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    ABSTRACT: HIV subtype-specific data on mutation type, rate, and accumulation following HAART treatment failure are limited. We studied patterns and accrual of drug resistance mutations in a Cambodian CRF01_AE-infected cohort continuing a virologically failing first-line, nonnucleoside reverse transcriptase inhibitor- (NNRTI-) based, HAART. Between 2005 and 2007, 837 adult HIV-infected patients had regular plasma HIV-1 RNA viral load measurements at Sihanouk Hospital Centre of Hope (SHCH), Cambodia. Drug resistance testing was performed in all patients with HIV-1 RNA >1000 copies/ml after at least 6 months of HAART. Seventy-one patients with a mean age of 34 years, of whom 68% were male, were retrospectively assessed at virological failure. The median duration of antiretroviral therapy was 12.3 (IQR 7.1-18.23) months, the median CD4 cell count was 173 (IQR 118-256) cells/mm(3), and the mean plasma HIV-1 RNA viral load was 3.9 log (SD 0.72) at failure. NNRTI mutations, M184I/V mutation, thymidine analogue mutations, and K65R were observed in 78.9%, 69%, 20%, and 12.7% of patients, respectively. For 33 patients, genotypic testing was carried out on at least two occasions before the switch to second-line HAART after a median duration of 5.8 (IQR 4.3-6.1) months of virological failure: 54.5% of patients accumulated new mutations with a rate of 1.6 mutations per person-year. Accumulation was seen both for nucleoside and nonnucleoside reverse transcriptase inhibitors, and also in patients with low-level viremia. Subtype-specific data on mutation type, rate, and accumulation after HAART failure are urgently needed to optimize treatment strategies in resource-limited settings.
    AIDS research and human retroviruses 07/2011; 27(7):727-35. · 2.18 Impact Factor
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    ABSTRACT: Connection domain mutations (CDMs) in HIV-1 reverse transcriptase (RT) alter susceptibility to some nucleoside/nonnucleoside RT inhibitors (NRTIs/NNRTIs). Their effects on susceptibility and virologic responses to etravirine were analyzed. Seventeen CDMs were evaluated: L283I, E312Q, G333D, G333E, G335C, G335D, N348I, A360I, A360T, A360V, V365I, T369I, A371V, A376S, I393L, E399D, and E399G. CDM prevalence and effects on virologic responses were analyzed retrospectively using clinical data. The effects on etravirine susceptibility were assessed in clinical samples and confirmed using site-directed mutants. The most prevalent CDMs (>10%) were A371V, E399D, A376S, N348I, A360T, G333E, and L283I. CDM presence was positively correlated with thymidine analogue-associated mutations, but not with NNRTI resistance-associated mutations (RAMs). The presence or number of CDMs did not significantly reduce etravirine susceptibility, although small reductions were seen in samples with G333D, N348I, A360V, T369I, and A376S. N348I, E399G, and N348I/T369I were associated with reduced etravirine susceptibility when present with K103N, L100I, or Y181C. N348I or T369I was associated with reduced etravirine susceptibility when present with K101P or K103R/V179D. Virologic responses to an etravirine-containing regimen were slightly diminished when G333D, G335D, or A376S was present, but this was not confirmed in subgroups with higher baseline resistance or without etravirine RAMs. CDMs alone do not confer substantial reductions in etravirine susceptibility but can further reduce etravirine susceptibility in combination with certain NNRTI mutations. Since virologic responses to etravirine were not affected by CDMs, the clinical impacts of these mutations on etravirine susceptibility appear to be minimal.
    Antimicrobial Agents and Chemotherapy 04/2011; 55(6):2872-9. · 4.57 Impact Factor
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    ABSTRACT: Viral tropism is the ability of viruses to enter and infect specific host cells and is based on the ability of viruses to bind to receptors on those cells. Testing for HIV tropism is recommended before prescribing a chemokine receptor blocker. In most European countries, HIV tropism is identified with tropism phenotype testing. New data support genotype analysis of the HIV third hypervariable loop (V3) for the identification of tropism. The European Consensus Group on clinical management of tropism testing was established to make recommendations to clinicians and clinical virologists. The panel recommends HIV-tropism testing for the following groups: drug-naive patients in whom toxic effects are anticipated or for whom few treatment options are available; patients who have poor tolerability to or toxic effects from current treatment or who have CNS pathology; and patients for whom therapy has failed and a change in treatment is considered. In general, an enhanced sensitivity Trofile assay and V3 population genotyping are the recommended methods. Genotypic methods are anticipated to be used more frequently in the clinical setting because of their greater accessibility, lower cost, and faster turnaround time than other methods. For the interpretation of V3 loop genotyping, clinically validated systems should be used when possible. Laboratories doing HIV tropism tests should have adequate quality assurance measures. Similarly, close collaboration between HIV clinicians and virologists is needed to ensure adequate diagnostic and treatment decisions.
    The Lancet Infectious Diseases 03/2011; 11(5):394-407. · 19.97 Impact Factor
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    ABSTRACT: Maraviroc-containing regimens are known to achieve virological suppression in many treatment-experienced patients. This study aimed to evaluate a more rigorous methodological approach to resistance-response analysis in large clinical studies and to better establish which subpopulations of patients were most likely to benefit from maraviroc by refining and extending previous subgroup analyses from the MOTIVATE studies. Individual weighted optimized background therapy (OBT) susceptibility scores were calculated by combining genotypic or phenotypic resistance testing with prior drug use information. Virological response (HIV-1 RNA<50 copies/ml at week 48) using each of these methods was compared with a commonly used method of counting active drugs. Baseline predictors of virological response, including weighted or unweighted scoring, maraviroc use, baseline CD4(+) T-cell count, HIV-1 plasma viral load and tropism, were assessed by logistic regression modelling. Genotypic or phenotypic weighted methods were similarly predictive of virological response and better than counting active drugs. Weighted scoring and baseline CD4(+) T-cell count were the strongest predictors of virological response (P<0.0001): ≈70% of maraviroc patients with a weighted score ≥2 had a virological response, rising to ≈80% when the baseline CD4(+) T-cell count was ≥50 cells/mm(3). Approximately 80% of patients with a CD4(+) T-cell count ≥50 cells/mm(3) receiving maraviroc with the equivalent of at least two fully active agents achieved HIV-1 RNA<50 copies/ml at week 48 in the MOTIVATE studies. Genotypic and phenotypic weighted scores were similarly predictive of virological response.
    Antiviral therapy 01/2011; 16(3):395-404. · 3.07 Impact Factor
  • Y. Maor, J. M. Schapiro, D. Bashari, U. Martinowitz
    Journal of Hepatology - J HEPATOL. 01/2011; 54.
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    ABSTRACT: This December 2010 version of the International AIDS Society-USA (IAS-USA) drug resistance mutations list updates the figures last published in December 2009 (Johnson VA et al, Top HIV Med, 2009;17:138-145). This update includes 9 new mutations- E138G and E138K for etravirine (Haddad M et al, CROI, 2010; Abstract 574, and Vingerhoets J et al, Antivir Ther, 2010;15 [Suppl 2]:A125); E92Q for raltegravir (Geretti AM et al, Antivir Ther, 2010;15 [Suppl 2]:A62; Cooper et al, N Engl J Med, 2008;359:355-365; and Malet I et al, Antimicrob Agents Chemother, 2008;52:1351-1358); and M36L, M36V, H69R, L89I, L89M, and L89V for tipranavir/ritonavir. In addition, the tipranavir/ritonavir N83D mutation designation was changed to boldface to indicate its recognition as a major mutation rather than a minor mutation. The mutations I13V, K20M/R, E35G, and L90M were removed from the tipranavir/ritonavir bar, reflecting new understanding. For etravirine, L100I*, K101P*, and Y181C*/I*/V* are denoted with asterisks (instead of bolded) to reflect that these individual mutations each have the greatest impact (ie, highest weighting scores) on reduced phenotypic susceptibility and impaired clinical response when compared with other etravirine mutations (Haddad M et al, CROI, 2010; Abstract 574). In addition, user notes d, n, r, w, and z were revised.
    Topics in HIV medicine: a publication of the International AIDS Society, USA 12/2010; 18(5):156-63.
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    ABSTRACT: Treatment guidelines recommend dual nucleoside reverse transcriptase inhibitors (NRTI ) as a part of combination antiretroviral therapy. The objective of this study was to assess the relative efficacy and toxicity of the dual NRTI part of the regimen in antiretroviral-naïve HIV-1-infected adults. A systematic review and meta-analysis of randomized controlled trials assessing highly active antiretroviral therapy (HAART) for treatment-naïve HIV-infected adults with a 48-week follow-up were done. We searched the PubMed, CENTRAL, and EMBASE electronic databases up to April 2009. Proceedings from conferences were reviewed. Data were extracted independently by two reviewers. Primary outcome was viral suppression at 48 weeks. The odds ratio (OR) is reported with its corresponding 95% confidence interval (CI). Twenty-two randomized controlled trials, including 8,184 HIV-treatment-naïve patients, were included. The combination didanosine + lamivudine/emtricitabine (four trials, 1,148 patients) was more effective (OR 0.53, 95% CI 0.41-0.68) for viral load (VL) >50 copies/ml and less toxic (OR 0.52, 95% CI 0.36-0.76) for discontinuation due to adverse events (AE) than its comparators. The combination tenofovir + lamivudine/emtricitabine was more effective and less toxic (OR 0.75, 95% CI 0.58-0.96) only in the 144-week follow-up data (two trials, 1,119 patients). Abacavir + lamivudine had similar efficacy to its comparators (OR 0.81, 95% CI 0.8-1.1), but more AIDS-defining events (OR 3.22, 95% CI 1.24, 8.40). The once-daily combination didanosine + lamivudine/emtricitabine was found to be effective and tolerable. This combination, soon to be generic, should be compared to the current standard of care in a large randomized trial. An effective, safe, and inexpensive alternative to current options is needed.
    European Journal of Clinical Microbiology 07/2010; 29(7):779-86. · 3.02 Impact Factor
  • Josep M Llibre, Jonathan M Schapiro, Bonaventura Clotet
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    ABSTRACT: Virological suppression rates achieved with the new antiretroviral drugs in patients with virological failure and resistance to multiple drug classes are nearly matching the rates seen in treatment-naive patients. Knowledge of cross-resistance patterns to drugs of the same class is key for successful use of etravirine, tipranavir, and darunavir in treatment-experienced patients. Determination of human immunodeficiency virus type 1 (HIV-1) tropism is cardinal for maraviroc. The impressive potency of raltegravir must not preclude its use with other active drugs because of its limited genetic barrier. These new agents have demonstrated superiority in virtually all efficacy parameters in their pivotal salvage trials, but comparative data between them are still very scarce. This review discusses the clinical implication of resistance to these new drugs. Specific genotypic resistance scores have been developed for tipranavir and etravirine, and mutations conferring resistance to darunavir are well understood. Determining the most active drugs and successfully combining them is the key challenge in salvage regimens.
    Clinical Infectious Diseases 02/2010; 50(6):872-81. · 9.37 Impact Factor
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    ABSTRACT: The purpose of this study was to develop a tipranavir-weighted mutation score that provides guidance to treating physicians on the relative effect of specific protease mutations on tipranavir activity. Weights were developed using data from RESIST tipranavir-treated patients based on regressions of virological response at weeks 8 and 24, accounting for baseline CD4(+) T-cell count and background regimen activity. The resulting weighted score and cutoffs were validated using a set of cohort patients external to the tipranavir development programme. Response rates were tabulated for the new weighted score and compared with other tipranavir mutation scores used in clinical practice. The final weights were 74P, 82L/T, 83D and 47V (+4), 58E and 84V (+3), 36I, 43T and 54A/M/V (+2), 10V, 33F and 46L (+1), 24I and 76V (-2), 50L/V (-4), and 54L (-6). Tipranavir-weighted score susceptibility categories were susceptible ≤3, partially susceptible >3 but ≤10, and resistant ≥11. Week 48 response rates for RESIST patients were 34.6%, 15.9% and 5.9%, respectively. Using the external cohort data (n=150), the weighted score was highly associated with week 8 viral load reduction (P=0.0027). Only one other score achieved statistical significance. The tipranavir-weighted score developed and externally validated here, in three datasets representing a broad population of treatment-experienced patients, can be used to make clinical decisions about whether to consider tipranavir in a treatment-experienced patient who has limited treatment options.
    Antiviral therapy 01/2010; 15(7):1011-9. · 3.07 Impact Factor
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    Journal of the International AIDS Society 01/2010; 13:1-2. · 3.94 Impact Factor
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    ABSTRACT: The International AIDS Society–USA (IAS–USA) Drug Resistance Mutations Group reviews new data on HIV-1 drug resistance that have been published or presented at recent scientific meetings to maintain a current list of mutations associated with antiretroviral drug re-sistance. This December 2008 version of the IAS–USA drug resistance muta-tions figures updates those published in this journal in March/April 2008 (Johnson VA, Brun-Vézinet F, Clotet B, et al, Top HIV Med, 2008;16:62-68). The compilation includes mutations that may contribute to a reduced virologic response to HIV-1 drugs. It should not be assumed that the list presented here is exhaustive. Drugs that have been approved by the US Food and Drug Administration (US FDA) as well as any drugs available in expanded ac-cess programs are included and listed in alphabetical order by drug class. The figures are designed for practitioners to use in identifying key mutations as-sociated with viral resistance to anti-retroviral drugs and in making thera-peutic decisions. Updates are posted periodically at www.iasusa.org. For more in-depth reading and an exten-sive reference list, see the 2008 IAS– USA panel recommendations for re-sistance testing (Hirsch MS, Gunthard HF, Schapiro JM, et al, Clin Infect Dis, 2008:47:266-285). The mutations listed have been identified by 1 or more of the follow-ing criteria: (1) in vitro passage experi-ments or validation of contribution to resistance by using site-directed mutagenesis; (2) susceptibility testing of laboratory or clinical isolates; (3) nucleotide sequencing of viruses from patients in whom the drug is failing; (4) correlation studies between genotype at baseline and virologic response in patients exposed to a drug. The avail-ability of more recently approved drugs that cannot be tested as monotherapy precludes assessment of the impact of resistance on antiretroviral activity that is not seriously confounded by activity of other drug components in the background regimen. Readers are encouraged to consult the literature and experts in the field for clarification or more information about specific mutations and their clinical impact. Polymorphisms associated with im-paired treatment responses that occur in wild-type viruses should not be used in epidemiologic analyses to identify transmitted HIV-1 drug resistance. In the context of making clinical decisions regarding antiretroviral ther-apy, evaluating the results of HIV-1 ge-notypic testing includes: (1) assessing whether the pattern or absence of a pattern in the mutations is consistent with the patient's antiretroviral therapy history; (2) recognizing that in the ab-sence of drug (selection pressure), re-sistant strains may be present at levels below the limit of detection of the test (analyzing stored samples, collected under selection pressure, could be use-ful in this setting); and (3) recognizing that virologic failure of the first regi-men typically involves HIV-1 isolates with resistance to only 1 or 2 of the drugs in the regimen (in this setting, resistance most commonly develops to lamivudine or the nonnucleoside ana-logue reverse transcriptase inhibitors [NNRTIs]). The absence of detectable viral resistance after treatment failure may result from any combination of the following factors: the presence of drug-resistant minority viral populations, nonadherence to medications, labora-tory error, lack of current knowledge of the association of certain mutations with drug resistance, the occurrence of relevant mutations outside the regions targeted by routine resistance assays, drug-drug interactions leading to sub-therapeutic drug levels, and possibly compartmental issues, indicating that drugs may not reach optimal levels in specific cellular or tissue reservoirs.
    Topics in HIV medicine: a publication of the International AIDS Society, USA 12/2009; 17(5):138-45.
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    ABSTRACT: Programs that monitor local, national, and regional levels of transmitted HIV-1 drug resistance inform treatment guidelines and provide feedback on the success of HIV-1 treatment and prevention programs. To accurately compare transmitted drug resistance rates across geographic regions and times, the World Health Organization has recommended the adoption of a consensus genotypic definition of transmitted HIV-1 drug resistance. In January 2007, we outlined criteria for developing a list of mutations for drug-resistance surveillance and compiled a list of 80 RT and protease mutations meeting these criteria (surveillance drug resistance mutations; SDRMs). Since January 2007, several new drugs have been approved and several new drug-resistance mutations have been identified. In this paper, we follow the same procedures described previously to develop an updated list of SDRMs that are likely to be useful for ongoing and future studies of transmitted drug resistance. The updated SDRM list has 93 mutations including 34 NRTI-resistance mutations at 15 RT positions, 19 NNRTI-resistance mutations at 10 RT positions, and 40 PI-resistance mutations at 18 protease positions.
    PLoS ONE 02/2009; 4(3):e4724. · 3.73 Impact Factor
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    ABSTRACT: The International AIDS Society-USA (IAS-USA) Drug Resistance Mutations Group reviews new data on HIV-1 drug resistance that have been published or presented at recent scientific meetings to maintain a current list of mutations associated with antiretroviral drug resistance.This December 2008 version of the IAS-USA drug resistance mutations figures updates those published in this journal in March/April 2008 (Johnson VA, Brun-Vezinet F, Clotet B, et al, Top HIV Med, 2008;16:62-68). The compilation includes mutations that may contribute to a reduced virologic response to HIV-1 drugs. It should not be assumed that the list presented here is exhaustive. Drugs that have been approved by the US Food and Drug Administration (US FDA) as well as any drugs available in expanded access programs are included and listed in alphabetical order by drug class. The figures are designed for practitioners to use in identifying key mutations associated with viral resistance to antiretroviral drugs and in making therapeutic decisions.
    Topics in HIV medicine: a publication of the International AIDS Society, USA 12/2008; 16(5):138-45.
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    ABSTRACT: An abstract is unavailable. This article is available as HTML full text and PDF.
    AIDS 10/2008; 22(16):2053-2067. · 6.41 Impact Factor
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    ABSTRACT: The aim of the study was to compare the efficacy and safety of induction with the addition of enfuvirtide to a newly designed oral, highly active antiretroviral therapy (HAART) regimen versus HAART alone followed by a maintenance phase wherein participants were randomized to either continue/discontinue enfuvirtide while maintaining HAART or continue HAART alone (NCT00487188). Participants with HIV-1 RNA >/=1000 copies/mL, CD4 count >/=200 cells/mm(3) and genotype sensitivity score >/=2 (excluding enfuvirtide) were randomized 2:1 to enfuvirtide+HAART or HAART alone and assessed every 4 weeks. Participants achieving <50 copies/mL on two consecutive visits by week 24 entered a maintenance phase wherein those receiving enfuvirtide+HAART underwent another randomization 1:1 to maintain enfuvirtide+HAART or discontinue enfuvirtide; those receiving HAART alone continued their regimen. Virological and immunological endpoints were analysed at weeks 24 and 48. At 24 weeks, 20/31 (65%) participants in the enfuvirtide+HAART arm versus 8/16 (50%) participants in the HAART arm achieved <50 copies/mL. Median time to achieving <50 copies/mL was 57 versus 141 days in the enfuvirtide+HAART and HAART arms (P = 0.048). Withdrawals were similar between groups. In the maintenance phase, at 48 weeks, 14/19 (74%) in the original enfuvirtide+HAART arm (regardless of second randomization) versus 4/8 (50%) in the HAART arm had <50 copies/mL. During maintenance, there were two virological failures in the enfuvirtide+HAART continuation arm, one in the enfuvirtide discontinuation arm and none in the HAART arm. Although limited by small participant numbers, these results suggest that treatment with enfuvirtide added to HAART may be an option for many patients.
    Journal of Antimicrobial Chemotherapy 10/2008; 62(6):1374-8. · 5.34 Impact Factor

Publication Stats

6k Citations
485.67 Total Impact Points

Institutions

  • 2013
    • Azienda Ospedaliera Universitaria Senese
      Siena, Tuscany, Italy
  • 1996–2013
    • Stanford University
      • • Division of Infectious Diseases
      • • Center for Design Research
      Palo Alto, CA, United States
  • 2004–2012
    • Sheba Medical Center
      • Department of Pathology
      Gan, Tel Aviv, Israel
  • 2002–2012
    • Hospital Universitari Germans Trias i Pujol
      • Department of Clinical Pharmacology
      Badalona, Catalonia, Spain
    • Vanderbilt University
      Nashville, Michigan, United States
  • 2010
    • Autonomous University of Barcelona
      Cerdanyola del Vallès, Catalonia, Spain
  • 2008–2010
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States
    • Tel Aviv Sourasky Medical Center
      Tell Afif, Tel Aviv, Israel
    • Harvard Medical School
      Boston, Massachusetts, United States
    • Ministry of Health (Israel)
      Yerushalayim, Jerusalem District, Israel
  • 2009
    • World Health Organization WHO
      Genève, Geneva, Switzerland
  • 2007
    • Jewish General Hospital
      Montréal, Quebec, Canada
    • Catholic University of the Sacred Heart
      • Institute of Clinical Infectious Diseases
      Roma, Latium, Italy
  • 2006
    • University Medical Center Utrecht
      Utrecht, Utrecht, Netherlands
  • 1999–2000
    • Stanford Medicine
      • Division of Infectious Diseases and Geographic Medicine
      Stanford, California, United States