Publications (21)141.12 Total impact
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Article: Impact of Minority Nonnucleoside Reverse Transcriptase Inhibitor Resistance Mutations on Resistance Genotype after Virologic Failure.
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ABSTRACT: Drug-resistant HIV-1 minority variants increase the risk of virologic failure for first-line NNRTI-based regimens. We performed a pooled analysis to evaluate the relationship between NNRTI-resistant minority variants and the likelihood and types of resistance mutations detected at virologic failure. In multivariable logistic regression analysis, higher NNRTI minority variant copy numbers, non-white race, and nevirapine use were associated with a higher risk of NNRTI resistance at virologic failure. Among participants on efavirenz, K103N was the most frequently observed resistance mutation at virologic failure regardless of the baseline minority variant. However, the presence of baseline Y181C minority variant was associated with a higher probability of Y181C detection after virologic failure. NNRTI regimen choice and pre-existing NNRTI-resistant minority variants were both associated with the probability and type of resistance mutations detected after virologic failure.The Journal of Infectious Diseases 12/2012; · 6.41 Impact Factor -
Article: Relationship between minority nonnucleoside reverse transcriptase inhibitor resistance mutations, adherence, and the risk of virologic failure.
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ABSTRACT: To evaluate the risk of virologic failure conferred by suboptimal adherence to nonnucleoside reverse transcriptase inhibitors (NNRTIs) and minority NNRTI resistance mutations. Pooled analysis of the risk of virologic failure conferred by minority NNRTI resistance mutations and NNRTI adherence from three studies of treatment-naïve individuals initiating an NNRTI-based regimen. Participants from each study were categorized into both adherence quartiles (Q1-Q4) and four strata: at least 95%, 80-94%, 60-79%, and below 60%. Weighted Cox proportional hazard models were used to estimate the risk of virologic failure. The majority of participants (N = 768) had high measured adherence, but those in the lowest adherence quartile had the highest proportion of participants with virologic failure and the risk of virologic failure increased step-wise with adherence below 95%. Detection of minority NNRTI drug resistance mutations increased the proportion of participants with virologic failure across adherence quartiles (Cochran-Mantel-Haenszel P < 0.001) and adherence strata [Cochran-Mantel-Haenszel P < 0.001; <60% adherence, hazard ratio 1.7 (1.1-2.7), P = 0.02; 60-79% adherence, hazard ratio 1.2 (0.5-3.2), P = 0.67; 80-94% adherence, hazard ratio 2.5 (0.98-6.3), P = 0.06; ≥95% adherence, hazard ratio 3.6 (2.3-5.6), P < 0.001]. On multivariate analysis, the effect of minority variants was also most prominent at higher levels of medication adherence. The presence of minority NNRTI resistance mutations and NNRTI adherence were found to be independent predictors of virologic failure, but also modify each other's effects on virologic failure. In addition to the focus on medication adherence counseling, ultrasensitive HIV-1 drug resistance assays could play a role in optimizing the success rates of first-line antiretroviral therapy.AIDS (London, England) 01/2012; 26(2):185-92. · 4.91 Impact Factor -
Article: Epidemiology, seasonality, and predictors of outcome of AIDS-associated Penicillium marneffei infection in Ho Chi Minh City, Viet Nam.
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ABSTRACT: Penicillium marneffei is an important human immunodeficiency virus (HIV)-associated opportunistic pathogen in Southeast Asia. The epidemiology and the predictors of penicilliosis outcome are poorly understood. We performed a retrospective study of culture-confirmed incident penicilliosis admissions during 1996-2009 at the Hospital for Tropical Diseases in Ho Chi Minh City, Viet Nam. Seasonality of penicilliosis was assessed using cosinor models. Logistic regression was used to assess predictors of death or worsening disease based on 10 predefined covariates, and Cox regression was performed to model time-to-antifungal initiation. A total of 795 patients were identified; hospital charts were obtainable for 513 patients (65%). Cases increased exponentially and peaked in 2007 (156 cases), mirroring the trends in AIDS admissions during the study period. A highly significant seasonality for penicilliosis (P<.001) but not for cryptococcosis (P=.63) or AIDS admissions (P=.83) was observed, with a 27% (95% confidence interval, 14%-41%) increase in incidence during rainy months. All patients were HIV infected; the median CD4 cell count (62 patients) was 7 cells/μL (interquartile range, 4-24 cells/μL). Hospital outcome was an improvement in 347 (68%), death in 101 (20%), worsening in 42 (8%), and nonassessable in 23 (5%) cases. Injection drug use, shorter history, absence of fever or skin lesions, elevated respiratory rates, higher lymphocyte count, and lower platelet count independently predicted poor outcome in both complete-case and multiple-imputation analyses. Time-to-treatment initiation was shorter for patients with skin lesions (hazard ratio, 3.78; 95% confidence interval, 2.96-4.84; P<.001). Penicilliosis incidence correlates with the HIV/AIDS epidemic in Viet nam. The number of cases increases during rainy months. Injection drug use, shorter history, absence of fever or skin lesions, respiratory difficulty, higher lymphocyte count, and lower platelet count predict poor in-hospital outcome.Clinical Infectious Diseases 04/2011; 52(7):945-52. · 9.15 Impact Factor -
Article: Low-frequency HIV-1 drug resistance mutations and risk of NNRTI-based antiretroviral treatment failure: a systematic review and pooled analysis.
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ABSTRACT: Presence of low-frequency, or minority, human immunodeficiency virus type 1 (HIV-1) drug resistance mutations may adversely affect response to antiretroviral treatment (ART), but evidence regarding the effects of such mutations on the effectiveness of first-line ART is conflicting. To evaluate the association of preexisting drug-resistant HIV-1 minority variants with risk of first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral virologic failure. Systematic review of published and unpublished studies in PubMed (1966 through December 2010), EMBASE (1974 through December 2010), conference abstracts, and article references. Authors of all studies were contacted for detailed laboratory, ART, and adherence data. Studies involving ART-naive participants initiating NNRTI-based regimens were included. Participants were included if all drugs in their ART regimen were fully active by standard HIV drug resistance testing. Cox proportional hazard models using pooled patient-level data were used to estimate the risk of virologic failure based on a Prentice weighted case-cohort analysis stratified by study. Individual data from 10 studies and 985 participants were available for the primary analysis. Low-frequency drug resistance mutations were detected in 187 participants, including 117 of 808 patients in the cohort studies. Low-frequency HIV-1 drug resistance mutations were associated with an increased risk of virologic failure (hazard ratio (HR], 2.3 [95% confidence interval {CI}, 1.7-3.3]; P < .001) after controlling for medication adherence, race/ethnicity, baseline CD4 cell count, and plasma HIV-1 RNA levels. Increased risk of virologic failure was most strongly associated with minority variants resistant to NNRTIs (HR, 2.6 [95% CI, 1.9-3.5]; P < .001). Among participants from the cohort studies, 35% of those with detectable minority variants experienced virologic failure compared with 15% of those without minority variants. The presence of minority variants was associated with 2.5 to 3 times the risk of virologic failure at either 95% or greater or less than 95% overall medication adherence. A dose-dependent increased risk of virologic failure was found in participants with a higher proportion or quantity of drug-resistant variants. In a pooled analysis, low-frequency HIV-1 drug resistance mutations, particularly involving NNRTI resistance, were significantly associated with a dose-dependent increased risk of virologic failure with first-line ART.JAMA The Journal of the American Medical Association 04/2011; 305(13):1327-35. · 30.03 Impact Factor -
Article: Prevalence of low-level HIV-1 variants with reverse transcriptase mutation K65R and the effect of antiretroviral drug exposure on variant levels.
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ABSTRACT: It has been reported that treatment-naive individuals infected with HIV-1 subtype C may be more likely to harbour viral variants possessing a K65R reverse transcriptase gene mutation. The objectives of this study were to determine the prevalence of low-level K65R variants within different HIV-1 subtypes and to assess the effects of antiretroviral exposure on K65R variant levels. Treatment-naive individuals infected with different HIV-1 subtypes were genotyped by ultra-deep sequencing. Samples were evaluated for low-level variants to 0.4% or 1% levels depending upon viral load. Estimated mutational load was calculated by multiplying the percentage of the variant by the plasma viral load. A total of 411 treatment-naive individuals were evaluated by ultra-deep sequencing to 1% levels; 4 subjects (0.97%) had K65R variants at ≥1% or had a very high mutation load. All four subjects had variants with linked drug resistance mutations suggesting transmitted resistant variants. 147 ARV-naive subjects were sequenced to 0.4% levels; 8.8% (13/147) had K65R low-level variants identified: 2.2% (2/92) in subtype B, 35.7% (10/28) in subtype C (P<0.001 for B versus C) and 3.7% (1/27) in non-B/C subtypes. The 13 ARV-naive subjects with K65R variants at <1% received tenofovir plus emtricitabine plus a ritonavir-boosted protease inhibitor (TDF+FTC+PI/r) and 5 subsequently experienced virological failure. There was no enhancement in K65R levels by percentage or mutational load compared to pre-therapy levels. Low-level K65R variants were more frequently identified in subtype C. K65R variants at >1% levels likely represent transmitted resistant variants. The clinical implication of low-level K65R variants below 1% in treatment-naive subjects who receive TDF+FTC+PI/r remains to be determined as the majority are very low-level and did not increase after antiretroviral exposure.Antiviral therapy 01/2011; 16(6):925-9. · 3.16 Impact Factor -
Article: Development of an electronic medical record-based clinical decision support tool to improve HIV symptom management.
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ABSTRACT: Common symptoms associated with HIV disease and its management are often underrecognized and undertreated. A clinical decision support tool for symptom management was developed within the Veterans Health Administration electronic medical record (EMR), aiming at increasing provider awareness of and response to common HIV symptoms. Its feasibility was studied in March to May 2007 by implementing it within a weekly HIV clinic, comparing a 4-week intervention period with a 4-week control period. Fifty-six patients and their providers participated in the study. Patients' perceptions of providers' awareness of their symptoms, proportion of progress notes mentioning any symptom(s) and proportion of care plans mentioning any symptom(s) were measured. The clinical decision support tool used portable electronic "tablets" to elicit symptom information at the time of check-in, filtered, and organized that information into a concise and clinically relevant EMR note available at the point of care, and facilitated clinical responses to that information. It appeared to be well accepted by patients and providers and did not substantially impact workflow. Although this pilot study was not powered to detect effectiveness, 25 (93%) patients in the intervention group reported that their providers were very aware of their symptoms versus 27 (75%) control patients (p = 0.07). The proportion of providers' notes listing symptoms was similar in both periods; however, there was a trend toward including a greater number of symptoms in intervention period progress notes. The symptom support tool seemed to be useful in clinical HIV care. The Veterans Health Administration EMR may be an effective "laboratory" for developing and testing decision supports.AIDS patient care and STDs 07/2009; 23(7):521-9. · 2.68 Impact Factor -
Article: Raltegravir with unboosted atazanavir 300 mg twice daily in antiretroviral treatment-experienced participants.
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ABSTRACT: Raltegravir (RAL) is an HIV integrase inhibitor characterized by potent antiretroviral activity, few adverse effects, and lack of cross-resistance to other antiretroviral (ARV) agents. RAL is emerging as a component of effective alternative ARV therapy for those who experience therapeutic failure or intolerance to reverse transcriptase inhibitors (NRTI and NNRTI) and ritonavir (RTV)-boosted protease inhibitor (PI) containing regimens. The combination of RAL with atazanavir (ATV) without a concomitant NRTI-based backbone or the inclusion of RTV may provide an alternative strategy for those unable to tolerate these latter ARV agents. In this report the authors present a case series of treatment-experienced patients managed with RAL + ATV given without a boosting dose of RTV. All patients tolerated this regimen over a course of 25 to 82 weeks, and had good virologic and immunologic outcome with a decrease in HIV RNA levels to <50 copies/mL and a mean CD4 count increase of 234 cells/mm(3).Journal of the International Association of Physicians in AIDS Care (JIAPAC) 03/2009; 8(2):87-92. -
Article: Low-abundance drug-resistant viral variants in chronically HIV-infected, antiretroviral treatment-naive patients significantly impact treatment outcomes.
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ABSTRACT: Minor (i.e., <20% prevalence) drug-resistant human immunodeficiency virus (HIV) variants may go undetected, yet be clinically important. To compare the prevalence of drug-resistant variants detected with standard and ultra-deep sequencing (detection down to 1% prevalence) and to determine the impact of minor resistant variants on virologic failure (VF). The Flexible Initial Retrovirus Suppressive Therapies (FIRST) Study (N = 1397) compared 3 initial antiretroviral therapy (ART) strategies. A random subset (n = 491) had baseline testing for drug-resistance mutations performed by use of standard sequencing methods. Ultra-deep sequencing was performed on samples that had sufficient viral content (N = 264). Proportional hazards models were used to compare rates of VF for those who did and did not have mutations identified. Mutations were detected by standard and ultra-deep sequencing (in 14% and 28% of participants, respectively; P < .001). Among individuals who initiated treatment with an ART regimen that combined nucleoside and nonnucleoside reverse-transcriptase inhibitors (hereafter, "NNRTI strategy"), all individuals who had an NNRTI-resistance mutation identified by ultra-deep sequencing experienced VF. When these individuals were compared with individuals who initiated treatment with the NNRTI strategy but who had no NNRTI-resistance mutations, the risk of VF was higher for those who had an NNRTI-resistance mutation detected by both methods (hazard ratio [HR], 12.40 [95% confidence interval {CI}, 3.41-45.10]) and those who had mutation(s) detected only with ultra-deep sequencing (HR, 2.50 [95% CI, 1.17-5.36]). Ultra-deep sequencing identified a significantly larger proportion of HIV-infected, treatment-naive persons as harboring drug-resistant viral variants. Among participants who initiated treatment with the NNRTI strategy, the risk of VF was significantly greater for participants who had low- and high-prevalence NNRTI-resistant variants.The Journal of Infectious Diseases 03/2009; 199(5):693-701. · 6.41 Impact Factor -
Article: Low-abundance HIV drug-resistant viral variants in treatment-experienced persons correlate with historical antiretroviral use.
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ABSTRACT: It is largely unknown how frequently low-abundance HIV drug-resistant variants at levels under limit of detection of conventional genotyping (<20% of quasi-species) are present in antiretroviral-experienced persons experiencing virologic failure. Further, the clinical implications of low-abundance drug-resistant variants at time of virologic failure are unknown. Plasma samples from 22 antiretroviral-experienced subjects collected at time of virologic failure (viral load 1380 to 304,000 copies/mL) were obtained from a specimen bank (from 2004-2007). The prevalence and profile of drug-resistant mutations were determined using Sanger sequencing and ultra-deep pyrosequencing. Genotypes were interpreted using Stanford HIV database algorithm. Antiretroviral treatment histories were obtained by chart review and correlated with drug-resistant mutations. Low-abundance drug-resistant mutations were detected in all 22 subjects by deep sequencing and only in 3 subjects by Sanger sequencing. In total they accounted for 90 of 247 mutations (36%) detected by deep sequencing; the majority of these (95%) were not detected by standard genotyping. A mean of 4 additional mutations per subject were detected by deep sequencing (p<0.0001, 95%CI: 2.85-5.53). The additional low-abundance drug-resistant mutations increased a subject's genotypic resistance to one or more antiretrovirals in 17 of 22 subjects (77%). When correlated with subjects' antiretroviral treatment histories, the additional low-abundance drug-resistant mutations correlated with the failing antiretroviral drugs in 21% subjects and correlated with historical antiretroviral use in 79% subjects (OR, 13.73; 95% CI, 2.5-74.3, p = 0.0016). Low-abundance HIV drug-resistant mutations in antiretroviral-experienced subjects at time of virologic failure can increase a subject's overall burden of resistance, yet commonly go unrecognized by conventional genotyping. The majority of unrecognized resistant mutations correlate with historical antiretroviral use. Ultra-deep sequencing can provide important historical resistance information for clinicians when planning subsequent antiretroviral regimens for highly treatment-experienced patients, particularly when their prior treatment histories and longitudinal genotypes are not available.PLoS ONE 01/2009; 4(6):e6079. · 4.09 Impact Factor -
Article: Hepatitis C protease and polymerase inhibitors in development.
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ABSTRACT: Hepatitis C infection (HCV) remains a global problem and the current anti-HCV therapies available in the clinic have sustained virologic response rates (SVR) of only about 50%, especially in HCV genotype 1-infected subjects. The SVR is even lower in HIV-HCV co-infected patients, estimated at only about 30-40%. However, exciting new research is under way to find new anti-HCV therapies. Presently, efforts to develop new anti-HCV agents for HCV-infected persons who fail pegylated interferon and ribavirin-based therapies have focused on inhibitors of key HCV enzymes such as the HCV NS3 protease and the NS5B polymerase. There are two protease inhibitors, telaprevir (VX-950, Vertex) and boceprevir (SCH 503034, Schering-Plough); and three polymerase inhibitors, valopicitabine (NM283, Idenix), R1626 (Roche), and HCV-796 (Viropharma) that have advanced to late-stage clinical trials. Of these aforementioned agents, telaprevir is the most advanced in clinical development. Early trial results on efficacy, safety, and HCV drug-resistance profiles of these novel agents will be discussed in this review paper.AIDS patient care and STDs 07/2008; 22(6):449-57. · 2.68 Impact Factor -
Article: Attitudes toward needle-sharing and HIV transmission risk behavior among HIV+ injection drug users in clinical care.
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ABSTRACT: Risky behavior related to injection drug use accounts for a considerable proportion of incident HIV infection in the United States. Large numbers of injection drug users (IDUs) currently receive antiretroviral therapy in clinical settings and are accessible for risk-reduction interventions to reduce transmission of drug-resistant HIV and spread of HIV to uninfected others. The current study examined attitudes toward needle- or equipment-sharing among 123 HIV-positive IDUs in clinical care in an effort to understand the dynamics of such behavior and to create a basis for clinic-based risk-reduction interventions. Results indicate that at baseline, participants who reported extremely negative attitudes toward needle-sharing were less likely to have shared during the past month than those with less-extreme negative attitudes. Demographic, behavioral, and attitudinal variables were entered into a logistic regression model to examine needle-sharing group membership among HIV-positive IDUs. Being female and having less-extreme negative attitudes toward sharing were independent and significant correlates of sharing behavior. Interventions targeting needle-sharing attitudes deployed within the clinical care setting may be well-positioned to reduce HIV transmission among HIV-positive IDUs.AIDS Care 05/2008; 20(4):462-9. · 1.60 Impact Factor -
Article: Directly administered antiretroviral therapy for HIV-infected drug users does not have an impact on antiretroviral resistance: results from a randomized controlled trial.
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ABSTRACT: Directly administered antiretroviral therapy (DAART) is an effective intervention that improves clinical outcomes among HIV-infected drug users. Its effects on antiretroviral drug resistance, however, are unknown. We conducted a community-based, prospective, randomized controlled trial of DAART compared with self-administered therapy (SAT). We performed a modified intention-to-treat analysis among 115 subjects who provided serum samples for HIV genotypic resistance testing at baseline and at follow-up. The main outcomes measures included total genotypic sensitivity score, future drug options, number of new drug resistance mutations (DRMs), and number of new major International AIDS Society (IAS) mutations. The adjusted probability of developing at least 1 new DRM did not differ between the 2 arms (SAT: 0.41 per person-year [PPY], DAART: 0.49 PPY; adjusted relative risk [RR] = 1.04; P = 0.90), nor did the number of new mutations (SAT: 0.76 PPY, DAART: 0.83 PPY; adjusted RR = 0.99; P = 0.99) or the probability of developing new major IAS new drug mutations (SAT: 0.30 PPY, DAART: 0.33 PPY; adjusted RR = 1.12; P = 0.78). On measures of GSS and FDO, the 2 arms also did not differ. In this trial, DAART provided on-treatment virologic benefit for HIV-infected drug users without affecting the rate of development of antiretroviral medication resistance.JAIDS Journal of Acquired Immune Deficiency Syndromes 01/2008; 46(5):555-63. · 4.43 Impact Factor -
Article: Adherence, virological and immunological outcomes for HIV-infected veterans starting combination antiretroviral therapies.
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ABSTRACT: We aimed to determine adherence, virological, and immunological outcomes one year after starting a first combination antiretroviral therapy (ART) regimen. Observational; synthesis of administrative, laboratory, and pharmacy data. Antiretroviral regimens were divided into efavirenz, nevirapine, boosted protease inhibitor (PI), and single PI categories. Propensity scores were used to control for confounding by treatment assignment. Adherence was estimated from pharmacy refill records. Veterans Affairs Healthcare System, all sites. HIV-infected individuals starting combination ART with a low likelihood of previous antiretroviral exposure. None. The proportion of antiretroviral prescriptions filled as prescribed, a change in log HIV-RNA, the proportion with log HIV-RNA viral suppression, a change in CD4 cell count. A total of 6394 individuals unlikely to have previous antiretroviral exposure started combination ART between 1996 and 2004, and were eligible for analysis. Adherence overall was low (63% of prescriptions filled as prescribed), and adherence with efavirenz (67%) and nevirapine (65%) regimens was significantly greater than adherence with boosted PI (59%) or single PI (61%) regimens (P < 0.001). Efavirenz regimens were more likely to suppress HIV-RNA at one year (74%) compared with nevirapine (62%), boosted PI (63%), or single PI (53%) regimens (all P < 0.001), and this superiority was maintained when analyses were adjusted for baseline clinical characteristics and propensity for treatment assignment. Efavirenz also yielded more favorable immunological outcomes. HIV-infected individuals initiating their first combination ART using an efavirenz-based regimen had improved virological and immunological outcomes and greater adherence levels.AIDS 08/2007; 21(12):1579-89. · 6.24 Impact Factor -
Article: Natural polymorphism of the HIV-1 integrase gene and mutations associated with integrase inhibitor resistance.
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ABSTRACT: Two inhibitors of the HIV-1 integrase enzyme (INIs) are in late stage clinical development. To date, approximately 42 mutations within the HIV-1 integrase (IN) gene have been associated with INI drug resistance. Naturally occurring IN gene polymorphisms may have important implications for INI development. In this study, we evaluated clinical HIV-1 strains from INI-naive patients to determine the prevalence of IN gene polymorphisms, and the frequency of naturally occurring amino acid (aa) substitutions at positions associated with INI resistance and at sites crucial for LEDGF/p75 binding and HIV-1 integration. The IN gene from 67 INI-naive, HIV-1 clade B-infected patients were sequenced using standard population-based DNA sequencing methods. In addition, 176 unique full-length HIV-1 clade B IN gene sequences from INI-naive patients obtained from the HIV Los Alamos database were analysed. Analysis of 243 IN genes from HIV-1 clade B, INI-naive clinical strains revealed that 64% of the aa positions were polymorphic. Of the 42 aa substitutions currently associated with INI resistance, 21 occurred as natural polymorphisms: V72I, L74I, T97A, T112I, A128T, E138K, Q148H, V151I, S153Y/A, M154I, N155H, K156N, E157Q, G163R, V165I, V201I, I203M, T206S, S230N and R263K. IN aa positions crucial to LEDGF/P75 binding and HIV-1 integration were well conserved. Major INI mutations within the catalytic domain and extended active sites associated with high level resistance to the compounds in late stage development, especially strand transfer inhibitors (STIs), were infrequent in our study, which may help explain the excellent virological responses demonstrated in clinical trials.Antiviral therapy 02/2007; 12(4):563-70. · 3.16 Impact Factor -
Article: A comparison of three highly active antiretroviral treatment strategies consisting of non-nucleoside reverse transcriptase inhibitors, protease inhibitors, or both in the presence of nucleoside reverse transcriptase inhibitors as initial therapy (CPCRA 058 FIRST Study): a long-term randomised trial.
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ABSTRACT: Long-term data from randomised trials on the consequences of treatment with a protease inhibitor (PI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or both are lacking. Here, we report results from the FIRST trial, which compared initial treatment strategies for clinical, immunological, and virological outcomes. Between 1999 and 2002, 1397 antiretroviral-treatment-naive patients, presenting at 18 clinical trial units with 80 research sites in the USA, were randomly assigned in a ratio of 1:1:1 to a protease inhibitor (PI) strategy (PI plus nucleoside reverse transcriptase inhibitor [NRTI]; n=470), a non-nucleoside reverse transcriptase inhibitor (NNRTI) strategy (NNRTI plus NRTI; n=463), or a three-class strategy (PI plus NNRTI plus NRTI; n=464). Primary endpoints were a composite of an AIDS-defining event, death, or CD4 cell count decline to less than 200 cells per mm3 for the PI versus NNRTI comparison, and average change in CD4 cell count at or after 32 months for the three-class versus combined two-class comparison. Analyses were by intention-to-treat. This study is registered ClinicalTrials.gov, number NCT00000922. 1397 patients were assessed for the composite endpoint. A total of 388 participants developed the composite endpoint, 302 developed AIDS or died, and 188 died. NNRTI versus PI hazard ratios (HRs) for the composite endpoint, for AIDS or death, for death, and for virological failure were 1.02 (95% CI 0.79-1.31), 1.07 (0.80-1.41), 0.95 (0.66-1.37), and 0.66 (0.56-0.78), respectively. 1196 patients were assessed for the three-class versus combined two-class primary endpoint. Mean change in CD4 cell count at or after 32 months was +234 cells per mm3 and +227 cells per mm3 for the three-class and the combined two-class strategies (p=0.62), respectively. HRs (three-class vs combined two-class) for AIDS or death and virological failure were 1.15 (0.91-1.45) and 0.87 (0.75-1.00), respectively. HRs (three-class vs combined two-class) for AIDS or death were similar for participants with baseline CD4 cell counts of 200 cells per mm3 or less and of more than 200 cells per mm3 (p=0.38 for interaction), and for participants with baseline HIV RNA concentrations less than 100 000 copies per mL and 100,000 copies per mL or more (p=0.26 for interaction). Participants assigned the three-class strategy were significantly more likely to discontinue treatment because of toxic effects than were those assigned to the two-class strategies (HR 1.58; p<0.0001). Initial treatment with either an NNRTI-based regimen or a PI-based regimen, but not both together, is a good strategy for long-term antiretroviral management in treatment-naive patients with HIV.The Lancet 12/2006; 368(9553):2125-35. · 38.28 Impact Factor -
Article: The hunt for HIV-1 integrase inhibitors.
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ABSTRACT: Currently, there are three distinct mechanistic classes of antiretrovirals: inhibitors of the HIV- 1 reverse transcriptase and protease enzymes and inhibitors of HIV entry, including receptor and coreceptor binding and cell fusion. A new drug class that inhibits the HIV-1 integrase enzyme (IN) is in development and may soon be available in the clinic. IN is an attractive drug target because it is essential for a stable and productive HIV-1 infection and there is no mammalian homologue of IN. Inhibitors of integrase enzyme (INI) block the integration of viral double-stranded DNA into the host cell's chromosomal DNA. HIV-1 integration has many potential steps that can be inhibited and several new compounds that target specific integration steps have been identified by drug developers. Recently, two INIs, GS-9137 and MK-0518, demonstrated promising early clinical trial results and have been advanced into later stage trials. In this review, we describe how IN facilitates HIV-1 integration, the needed enzyme cofactors, and the resultant byproducts created during integration. Furthermore, we review the different INIs under development, their mechanism of actions, site of IN inhibition, potency, resistance patterns, and discuss the early clinical trial results.AIDS PATIENT CARE and STDs 08/2006; 20(7):489-501. · 2.41 Impact Factor -
Article: A population-based and longitudinal study of sexual behavior and multidrug-resistant HIV among patients in clinical care.
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ABSTRACT: Population-based and longitudinal information regarding sexual risk behavior among patients with multidrug resistant (MDR) HIV and their sexual partners is of great public health and clinical importance. To characterize the HIV sexual risk behaviors of patients with and without drug-resistant HIV in the clinical care setting over time. 393 HIV-positive patients completed questionnaires of self-reported sexual risk behaviors at approximate 6-month intervals extending over 24 months. HIV viral load and genotypic drug resistance obtained during the same time points were matched to the behavioral data. Multidrug resistance was defined as having resistance to 2 or 3 antiretroviral (ARV) drug classes. In serial cross-sectional analyses, 393 patients (44% female and 79% heterosexual) contributed 919 matched behavioral and virologic results over the 24 months of data collection. Of these, 250 patients (64%) reported having sex during at least 1 survey period resulting in greater than 10,000 sexual events with more than 1000 partners. Unprotected sexual behavior was reported by 45% of sexually active patients, resulting in 34% of all sex events that exposed 29% of all partners. Of these patients with unprotected sexual events, 31% had HIV drug resistance--11.6% with resistance to 2 classes of ARVs (2-class), and 1.8% with 3-class ARV resistance at the time of a sexual risk event. Close to 1000 or 28% of all unprotected sexual events involved resistant strains (11% of these with resistance to 2 classes and 0.2% with 3-class resistance, exposing 20% of unprotected sexual partners to resistant HIV (8% to 2-class and 0.6% to 3-class resistance). In longitudinal analysis among the 78 patients who reported a cumulative total of 12 months of sexual history and had resistance testing, 38% reported engaging in unprotected sexual behavior. There was substantial and complex variation in the distribution of unprotected sexual events and in the detection of resistance over time. In this study of HIV sexual risk and resistance over time among HIV-infected patients in clinical care, a substantial proportion engaged in unprotected sex and had drug-resistant HIV, frequently exposing partners to 1- or 2-class resistant HIV strains. However, relatively few exposures involved 3-class resistance. The dynamics of sexual risk behavior and HIV drug resistance are complex and vary over time and urgently require both general and targeted interventions to reduce transmission of resistant HIV.MedGenMed: Medscape general medicine 02/2006; 8(2):72. -
Article: Prevalence and impact of HIV-1 protease codon 33 mutations and polymorphisms in treatment-naive and treatment-experienced patients.
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ABSTRACT: HIV-1 protease gene mutations at codon 33 have been associated with resistance to some but not all protease inhibitors (PIs). Little is known about the difference in prevalence of codon 33 mutations and polymorphisms between treatment-naive and treatment-experienced patients, and the effect of codon 33F on PI phenotypic resistance patterns. Baseline genotypes (TRUGENE) from 772 patients participating in two different randomized clinical trials [504 antiretroviral treatment-naive patients and 268 antiretroviral treatment-experienced patients] were evaluated for the presence of protease codon 33 mutations and polymorphisms. Baseline phenotypes (Antivirogram), including fold-change in resistance for 16 antiretroviral drugs, were available for the 268 treatment-experienced patients. Multivariate linear regression models were used to determine factors associated with phenotypic fold-change for PIs. The prevalence of codon 33 mutations and polymorphisms was 5.2% in the naive cohort (0.2% 33F, 2.5% 33V, 2.5% 331) and 34.7% in the experienced cohort (30.2% 33F, 1.5% 33V, 3.0% 331). In the antiretroviral-experienced cohort (mean = 4.2 prior PIs, 10.6 prior antiretroviral drugs overall), a model adjusting for the presence of specific major protease and multi-PI resistance conferring mutations, the number of other minor PI mutations, prior PI drug exposure (current, prior only, never), and HIV transmission risk factor was used to estimate the phenotypic fold-change in resistance for those with and without mutation 33F. Those with 33F had a significantly higher fold-change for amprenavir (33 vs 19, P<0.0001), ritonavir (162 vs 82, P<0.0001), lopinavir (49 vs 38, P=0.04), and saquinavir (47 vs 41, P=0.02). The presence of the 33F was not a significant predictor of fold change in susceptibility for indinavir or nelfinavir. At protease codon 33, the prevalences of polymorphisms 33V and 331 were similar for PI-naive and PI-experienced patients (<3.0%), but the prevalence of 33F was significantly different (0.2% versus 30.2%). In the treatment-experienced cohort, the differences in phenotypic fold-change for amprenavir, lopinavir, saquinavir, and ritonavir between those with and without 33F persist after adjustment for the presence of other major PI mutations and PI drug exposure history. Given the availability of newer PIs that may select for 33F, monitoring for the presence of this mutation should be ongoing for both treatment-naive and treatment-experienced patients.Antiviral therapy 01/2006; 11(4):457-63. · 3.16 Impact Factor -
Article: HIV drug resistance and HIV transmission risk behaviors among active injection drug users.
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ABSTRACT: HIV(+) injection drug users in clinical care may harbor and transmit drug-resistant HIV. We performed a retrospective study of HIV drug resistance and risk behavior among HIV(+) injection drug users in care to determine the number of needle-sharing events that involved and the proportion of sharing partners exposed to drug-resistant HIV. Among 180 HIV injection drug users, 55 (31%) reported injecting drugs in the previous month, and 22 of these (40%) shared needles and/or works 148 times with 296 partners, of whom 271 (92%) were thought to be HIV(-) or status unknown. Further, 55 (31%) drug users harbored resistant HIV, including 5 (3% of total) who also shared needles and/or works a total of 27 times with 44 partners (18% of all sharing events and 15% of all exposed partners). A small proportion of injection drug users receiving clinical care engage in injection risk behavior and carry resistant HIV; however, because of multiple partners and needle-sharing events, they expose a substantial number of individuals to drug-resistant HIV. Strategies to reduce injection drug use risk behaviors among patients in clinical care are needed to reduce the transmission of sensitive and resistant HIV.JAIDS Journal of Acquired Immune Deficiency Syndromes 10/2005; 40(1):106-9. · 4.43 Impact Factor -
Article: Antiretroviral resistance and high-risk transmission behavior among HIV-positive patients in clinical care.
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ABSTRACT: HIV-positive patients receiving antiretroviral therapy (ART) who engage in HIV transmission behaviors may harbor and transmit drug-resistant HIV. However, little is known about the risk behaviors of these patients, potential partners exposed and the relationship of these to ART resistance. To determine the relationship of HIV drug resistance and continuing HIV transmission risk behavior among HIV-positive patients in care. A retrospective, cross-sectional study of HIV transmission risk behavior and HIV drug resistance data from 333 HIV-positive patients. Among a diverse population of 333 HIV-positive patients, 75 (23%) had unprotected sex during the previous 3-months, resulting in 1126 unprotected sexual events with 191 partners of whom 155 were believed by patients to be HIV-negative or of unknown status. Eighteen of the 75 (24%) had resistant HIV and 207 unprotected sexual events, exposing 18% of the HIV- or status unknown partners. There was no difference in the proportion of patients engaging in unprotected sex who had undetectable viral load (VL) (22%): VL > 400 copies/ml without resistance (20%) and VL > 400 copies/ml with resistance (26%). Resistance and risk behavior was predicted only by lower mental health scores (odds ratio, 10.3; 95% confidence interval, 1.7-18.6). A substantial minority (23%) of patients in clinical care engaged in HIV sexual transmission risk behavior. A small subset of these also had ART-resistant HIV. However, this core group (approximately 5% of all patients) accounted for a large number of high-risk HIV transmission events with resistant virus, exposing a substantial number of partners.AIDS 12/2004; 18(16):2185-9. · 6.24 Impact Factor
Top co-authors
Top Journals
Institutions
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2011–2012
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Harvard University
- Department of Medicine Brigham and Women's Hospital
Boston, MA, USA
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2004–2011
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Yale University
- • Department of Internal Medicine
- • Section of Infectious Diseases
New Haven, CT, USA
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2009
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454 Life Sciences
Branford, CT, USA
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2006–2009
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Yale-New Haven Hospital
New Haven, CT, USA
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