Robert L Murphy

Publications of Robert L Murphy

• Host Gene Expression Changes Correlating With Anti-HIV-1 Effects in Human Subjects After Treatment With Peginterferon Alfa-2a.

  Authors: Jonathan J Hubbard, Teresa Greenwell-Wild, Lisa Barrett, Jun Yang, Richard A Lempicki, Sharon M Wahl, David M Asmuth, Robert L Murphy, Richard B Pollard, Shyam Kottilil

  The Journal of infectious diseases. 03/2012; 205(9):1443-7.

  We investigated whether interferon-inducible genes (IFIGs) with known anti-human immunodeficiency virus (HIV) activity in vitro were associated with in vivo virological response in HIV infection.We investigated whether interferon-inducible genes (IFIGs) with known anti-human immunodeficiency virus (HIV) activity in vitro were associated with in vivo virological response in HIV infection. Nine untreated HIV-1-infected volunteers were treated for 12 weeks with peginterferon alfa-2a. A subset of IFIGs (23 of 47) increased compared with baseline through 6 weeks beyond therapy, and 10 of the 23 IFIGs significantly inversely correlated (r = -0.7; P < .05) with virological response. The strength of peginterferon alfa-2a-induced IFIG response significantly correlated with declines in HIV load during treatment (r(2) = 0.87, p = .003). This study links HIV virological response to a specific IFIG subset, a potential prognostic indicator in peginterferon alfa-2a-treated patients with HIV infection.

• Combination nucleoside/nucleotide reverse transcriptase inhibitors for treatment of HIV infection.

  Authors: Maxwell O Akanbi, Kimberly Scarci, Babafemi Taiwo, Robert L Murphy

  Expert opinion on pharmacotherapy. 01/2012; 13(1):65-79.

  INTRODUCTION: The combination of two nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs) and a third agent from another antiretroviral class is currently recommended for initialINTRODUCTION: The combination of two nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs) and a third agent from another antiretroviral class is currently recommended for initial antiretroviral therapy. In general, N(t)RTIs remain relevant in subsequent regimens. There are currently six nucleoside reverse transcriptase inhibitors and one nucleotide reverse transcriptase inhibitor drug entities available, and several formulations that include two or more N(t)RTIs in a fixed-dose combination. These entities have heterogeneous pharmacological and clinical properties. Accordingly, toxicity, pill burden, dosing frequency, potential drug-drug interaction, preexisting antiretroviral drug resistance and comorbid conditions should be considered when constructing a regimen. This approach is critical in order to optimize virologic efficacy and clinical outcomes. AREAS COVERED: This article reviews N(t)RTI combinations used in the treatment of HIV-infected adults. The pharmacological properties of each N(t)RTI, and the clinical trials that have influenced treatment guidelines are discussed. EXPERT OPINION: It is likely that N(t)RTIs will continue to dominate the global landscape of HIV treatment and prevention, despite emerging interest in N(t)RTI-free combination therapy. Clinical domains where only few alternatives to N(t)RTIs exist include treatment of HIV/HBV coinfection and HIV-2. There is a need for novel N(t)RTIs with enhanced safety and resistance profiles compared with current N(t)RTIs.

• Immunologic criteria are poor predictors of virologic outcome: implications for HIV treatment monitoring in resource-limited settings.

  Authors: Holly E Rawizza, Beth Chaplin, Seema T Meloni, Geoffrey Eisen, Tara Rao, Jean-Louis Sankalé, Abdoulaye Dieng-Sarr, Oche Agbaji, Daniel I Onwujekwe, Wadzani Gashau, Reuben Nkado, Ernest Ekong, Prosper Okonkwo, Robert L Murphy, Phyllis J Kanki

  Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 12/2011; 53(12):1283-90.

  Viral load (VL) quantification is considered essential for determining antiretroviral treatment (ART) success in resource-rich countries. However, it is not widely available in resource-limitedViral load (VL) quantification is considered essential for determining antiretroviral treatment (ART) success in resource-rich countries. However, it is not widely available in resource-limited settings where the burden of human immunodeficiency virus infection is greatest. In the absence of VL monitoring, switches to second-line ART are based on World Health Organization (WHO) clinical or immunologic failure criteria. We assessed the performance of CD4 cell criteria to predict virologic outcomes in a large ART program in Nigeria. Laboratory monitoring consists of CD4 cell count and VL at baseline, then every 6 months. Failure was defined as 2 consecutive VLs >1000 copies/mL after at least 6 months of ART. Virologic outcomes were compared with the 3 WHO-defined immunologic failure criteria. A total of 9690 patients were included in the analysis (median follow-up, 33.2 months). A total of 1225 patients experienced failure by both immunologic and virologic criteria, 872 by virologic criteria only, and 1897 by immunologic criteria only. The sensitivity of CD4 cell criteria to detect viral failure was 58%, specificity was 75%, and the positive-predictive value was 39%. For patients with both virologic and immunologic failure, VL criteria identified failure significantly earlier than CD4 cell criteria (median, 10.4 vs 15.6 months; P < .0001). Because of the low sensitivity of immunologic criteria, a substantial number of failures are missed, potentially resulting in accumulation of resistance mutations. In addition, specificity and predictive values are low, which may result in large numbers of unnecessary ART switches. Monitoring solely by immunologic criteria may result in increased costs because of excess switches to more expensive ART and development of drug-resistant virus.

• Abacavir/lamivudine versus tenofovir DF/emtricitabine as part of combination regimens for initial treatment of HIV: final results.

  Authors: Paul E Sax, Camlin Tierney, Ann C Collier, Eric S Daar, Katie Mollan, Chakra Budhathoki, Catherine Godfrey, Nasreen C Jahed, Laurie Myers, David Katzenstein, Awny Farajallah, James F Rooney, Belinda Ha, William C Woodward, Judith Feinberg, Karen Tashima, Robert L Murphy, Margaret A Fischl

  The Journal of infectious diseases. 10/2011; 204(8):1191-201.

  AIDS Clinical Trials Group A5202 compared blinded abacavir/lamivudine (ABC/3TC) to tenofovir DF/emtricitabine (TDF/FTC) with efavirenz (EFV) or atazanavir/ritonavir (ATV/r) in human immunodeficiencyAIDS Clinical Trials Group A5202 compared blinded abacavir/lamivudine (ABC/3TC) to tenofovir DF/emtricitabine (TDF/FTC) with efavirenz (EFV) or atazanavir/ritonavir (ATV/r) in human immunodeficiency virus (HIV)-infected treatment-naive patients, stratified by screening HIV RNA (< or ≥ 10(5) copies/mL). Due to higher virologic failure with ABC/3TC in the high HIV RNA stratum, blinded treatment was stopped in this group, but study follow-up continued for all patients. Primary endpoints were times to virologic failure, regimen modification, and safety event. In the low HIV RNA stratum, time to virologic failure was similar for ABC/3TC vs TDF/FTC with ATV/r (hazard ratio [HR] 1.25, 95% confidence interval [CI] 0.76, 2.05) or EFV (HR 1.23, 95% CI 0.77, 1.96), with significantly shorter times to regimen modification for ABC/3TC with EFV or ATV/r and to safety events with EFV. Prior to stopping blinded treatment in the high stratum, higher virologic failure rates were seen with ABC/3TC with EFV (HR 2.46, 95% CI 1.20, 5.05) or ATV/r (HR 2.22, 95% CI 1.19, 4.14). In the low HIV RNA stratum, times to virologic failure for ABC/3TC or TDF/FTC were not different with EFV or ATV/r. In the high stratum, virologic failure rate was significantly higher for ABC/3TC than for TDF/FTC when given with either EFV or ATV/r.

• Atazanavir/ritonavir-based combination antiretroviral therapy for treatment of HIV-1 infection in adults.

  Authors: Chad J Achenbach, Kristin M Darin, Robert L Murphy, Christine Katlama

  Future virology. 02/2011; 6(2):157-177.

  In the past 15 years, improvements in the management of HIV infection have dramatically reduced morbidity and mortality. Similarly, rapid advances in antiretroviral medications have resulted in theIn the past 15 years, improvements in the management of HIV infection have dramatically reduced morbidity and mortality. Similarly, rapid advances in antiretroviral medications have resulted in the possibility of life-long therapy with simple and tolerable regimens. Protease inhibitors have been important medications in regimens of combination antiretroviral therapy for the treatment of HIV. One of the recommended and commonly used therapies in this class is once-daily-administered atazanavir, pharmacologically boosted with ritonavir (atazanavir/r). Clinical studies and practice have shown these drugs, in combination with other antiretroviral agents, to be potent, safe and easy to use in a variety of settings. Atazanavir/r has minimal short-term toxicity, including benign bilirubin elevation, and has less potential for long-term complications of hyperlipidemia and insulin resistance compared with other protease inhibitors. A high genetic barrier to resistance and a favorable resistance profile make it an excellent option for initial HIV treatment or as the first drug utilized in the protease inhibitors class. Atazanavir/r is also currently being studied in novel treatment strategies, including combinations with new classes of antiretrovirals to assess nucleoside reverse transcriptase inhibitor-sparing regimens. In this article we review atazanavir/r as a treatment for HIV infection and discuss the latest information on its pharmacology, efficacy and toxicity.

• Association of ongoing drug and alcohol use with non-adherence to antiretroviral therapy and higher risk of AIDS and death: results from ACTG 362.

  Authors: Susan E Cohn, Hongyu Jiang, J Allen McCutchan, Susan L Koletar, Robert L Murphy, Kevin R Robertson, Annabelle M de St Maurice, Judith S Currier, Paige L Williams

  AIDS care. 02/2011; 23(6):775-85.

  Drug and alcohol use have been associated with a worse prognosis in short-term and cross-sectional analyses of HIV-infected populations, but longitudinal effects on adherence to antiretroviralDrug and alcohol use have been associated with a worse prognosis in short-term and cross-sectional analyses of HIV-infected populations, but longitudinal effects on adherence to antiretroviral therapy (ART) and clinical outcomes in advanced AIDS are less well characterized. We assessed self-reported drug and alcohol use in AIDS patients, and examined their association with non-adherence and death or disease progression in a multicenter observational study. We defined non-adherence as reporting missed ART doses in the 48 hours before study visits. The association between drug use and ART non-adherence was evaluated using repeated measures generalized estimating equation (GEE) models. The association between drug and alcohol use and time to new AIDS diagnosis or death was evaluated via Cox regression models, controlling for covariates including ART adherence. Of 643 participants enrolled between 1997 and 1999 and followed through 2007, at entry 39% reported ever using cocaine, 24% amphetamines, and 10% heroin. Ongoing drug use during study follow-up was reported by 9% using cocaine, 4% amphetamines, and 1% heroin. Hard drug (cocaine, amphetamines, or heroin) users had 2.1 times higher odds (p=0.001) of ART non-adherence in GEE models and 2.5 times higher risk (p=0.04) of AIDS progression or death in Cox models. Use of hard drugs was attenuated as a risk factor for AIDS progression or death after controlling for non-adherence during follow-up (HR = 2.11, p=0.08), but was still suggestive of a possible adherence-independent mechanism of harm. This study highlights the need to continuously screen and treat patients for drug use as a part of ongoing HIV care.

• Novel antiretroviral combinations in treatment-experienced patients with HIV infection: rationale and results.

  Authors: Babafemi Taiwo, Robert L Murphy, Christine Katlama

  Drugs. 09/2010; 70(13):1629-42.

  Novel antiretroviral drugs offer different degrees of improvement in activity against drug-resistant HIV, short- and long-term tolerability, and dosing convenience compared with earlier drugs. ThoseNovel antiretroviral drugs offer different degrees of improvement in activity against drug-resistant HIV, short- and long-term tolerability, and dosing convenience compared with earlier drugs. Those drugs approved more recently and commonly used in treatment-experienced patients include the entry inhibitor enfuvirtide, protease inhibitors (PIs) [darunavir and tipranavir], a C-C chemokine receptor (CCR) type 5 antagonist (maraviroc), an integrase inhibitor (raltegravir) and etravirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI). Novel agents in earlier stages of development include a CCR5 monoclonal antibody (PRO 140) administered subcutaneously once weekly, once-daily integrase inhibitors (elvitegravir and S/GSK1349572), and several nucleoside (nucleotide) reverse transcriptase inhibitors and NNRTIs. Bevirimat, a maturation inhibitor, has compromised activity in the presence of relatively common Gag polymorphisms. Viral suppression is necessary to control the evolution of drug resistance, reduce chronic immune activation that probably underlies the excess morbidity and mortality in HIV-infected patients, and reduce viral transmission, including transmitted drug resistance. In general, the proportion of viraemic patients who achieve suppression increases with the number of active pharmacokinetically compatible antiretroviral drugs in the regimen. In the ANRS139-TRIO trial, 86% of highly treatment-experienced patients treated with darunavir-ritonavir, etravirine and raltegravir had HIV RNA <50 copies/mL at 48 weeks. In patients who had received at least 12 weeks of a stable regimen and had no darunavir resistance-associated mutations, once-daily darunavir boosted with ritonavir 100 mg was virologically noninferior with better lipid effects than with the twice-daily dosing, which requires a 200 mg total daily dose of ritonavir. Raltegravir plus a boosted PI is being investigated for second-line therapy in patients not responding to NNRTI-based first-line treatment in resource-limited settings (RLS). However, concerns about this potential strategy include the low barrier against resistance of raltegravir, limited penetration of some PIs into the CNS and the unknown impact of integrase polymorphisms seen more commonly in non-B subtype HIV-1. In patients who have already achieved viral suppression, novel agents may be used to simplify the dosing schedule, lower costs (such as by switching to boosted PI monotherapy), reduce adverse events or preserve antiretroviral drug options, especially since the absence of an HIV eradication strategy implies the need for life-long combination antiretroviral therapy. Switching enfuvirtide to raltegravir eliminated painful injection-site reactions without compromising virological suppression. Two studies found different virological outcomes when patients were switched from lopinavir/ritonavir to raltegravir, but there was an improvement in the lipid profile. Simplifying to darunavir-ritonavir monotherapy after suppression of plasma HIV RNA to <50 copies/mL has been found to be safe with no emergence of resistance in cases of viral rebound, but longer-term data are needed. The initial suggestion that maraviroc may possess unique CD4+ T-cell boosting effects was not confirmed in several clinical trials. Improved understanding of HIV pathogenesis has opened new frontiers for research such as identifying the sources, consequences and optimal management of residual viraemia in those with plasma HIV RNA <50 copies/mL. Globally, however, one of the most urgent priorities is providing the increasing number of treatment-experienced virologically failing patients in RLS with access to optimal treatment, including those treatments based on novel antiretroviral agents.

• Patient-selected treatment partners did not protect against drug resistance during first-line NNRTI-based HAART in a randomized trial.

  Authors: Babafemi O Taiwo, John A Idoko, Anne-Geneviève Marcelin, Ihedinachi Otoh, Susheel Reddy, Paul G Iyaji, Oche Agbaji, Sudhir Penugonda, Patricia A Agaba, Robert L Murphy

  Journal of acquired immune deficiency syndromes (1999). 08/2010; 54(5):563-5.

• Chicago medical response to the 2010 earthquake in Haiti: translating academic collaboration into direct humanitarian response.

  Authors: Christine Babcock, Carolyn Baer, Jamil D Bayram, Stacey Chamberlain, Jennifer L Chan, Shannon Galvin, Jimin Kim, Melodie Kinet, Rashid F Kysia, Janet Lin, Mamta Malik, Robert L Murphy, C Sola Olopade, Christian Theodosis

  Disaster medicine and public health preparedness. 06/2010; 4(2):169-73.

  On January 12, 2010, a major earthquake in Haiti resulted in approximately 212 000 deaths, 300 000 injuries, and more than 1.2 million internally displaced people, making it the most devastatingOn January 12, 2010, a major earthquake in Haiti resulted in approximately 212 000 deaths, 300 000 injuries, and more than 1.2 million internally displaced people, making it the most devastating disaster in Haiti's recorded history. Six academic medical centers from the city of Chicago established an interinstitutional collaborative initiative, the Chicago Medical Response, in partnership with nongovernmental organizations (NGOs) in Haiti that provided a sustainable response, sending medical teams to Haiti on a weekly basis for several months. More than 475 medical volunteers were identified, of whom 158 were deployed to Haiti by April 1, 2010. This article presents the shared experiences, observations, and lessons learned by all of the participating institutions. Specifically, it describes the factors that provided the framework for the collaborative initiative, the communication networks that contributed to the ongoing response, the operational aspects of deploying successive medical teams, and the benefits to the institutions as well as to the NGOs and Haitian medical system, along with the challenges facing those institutions individually and collectively. Academic medical institutions can provide a major reservoir of highly qualified volunteer medical personnel that complement the needs of NGOs in disasters for a sustainable medical response. Support of such collaborative initiatives is required to ensure generalizability and sustainability.

• Safety, tolerability, and mechanisms of antiretroviral activity of pegylated interferon Alfa-2a in HIV-1-monoinfected participants: a phase II clinical trial.

  Authors: David M Asmuth, Robert L Murphy, Susan L Rosenkranz, Juan J L Lertora, Shyam Kottilil, Yoninah Cramer, Ellen S Chan, Robert T Schooley, Charles R Rinaldo, Nathan Thielman, Xiao-Dong Li, Sharon M Wahl, Jessica Shore, Jennifer Janik, Richard A Lempicki, Yaa Simpson, Richard B Pollard

  The Journal of infectious diseases. 06/2010; 201(11):1686-96.

  To our knowledge, the antiviral activity of pegylated interferon alfa-2a has not been studied in participants with untreated human immunodeficiency virus type 1 (HIV-1) infection but without chronicTo our knowledge, the antiviral activity of pegylated interferon alfa-2a has not been studied in participants with untreated human immunodeficiency virus type 1 (HIV-1) infection but without chronic hepatitis C virus (HCV) infection. Untreated HIV-1-infected volunteers without HCV infection received 180 microg of pegylated interferon alfa-2a weekly for 12 weeks. Changes in plasma HIV-1 RNA load, CD4(+) T cell counts, pharmacokinetics, pharmacodynamic measurements of 2',5'-oligoadenylate synthetase (OAS) activity, and induction levels of interferon-inducible genes (IFIGs) were measured. Nonparametric statistical analysis was performed. Eleven participants completed 12 weeks of therapy. The median plasma viral load decrease and change in CD4(+) T cell counts at week 12 were 0.61 log(10) copies/mL (90% confidence interval [CI], 0.20-1.18 log(10) copies/mL) and -44 cells/microL (90% CI, -95 to 85 cells/microL), respectively. There was no correlation between plasma viral load decreases and concurrent pegylated interferon plasma concentrations. However, participants with larger increases in OAS level exhibited greater decreases in plasma viral load at weeks 1 and 2 (r = -0.75 [90% CI, -0.93 to -0.28] and r = -0.61 [90% CI, -0.87 to -0.09], respectively; estimated Spearman rank correlation). Participants with higher baseline IFIG levels had smaller week 12 decreases in plasma viral load (0.66 log(10) copies/mL [90% CI, 0.06-0.91 log(10) copies/mL]), whereas those with larger IFIG induction levels exhibited larger decreases in plasma viral load (-0.74 log(10) copies/mL [90% CI, -0.93 to -0.21 log(10) copies/mL]). Pegylated interferon alfa-2a was well tolerated and exhibited statistically significant anti-HIV-1 activity in HIV-1-monoinfected patients. The anti-HIV-1 effect correlated with OAS protein levels (weeks 1 and 2) and IFIG induction levels (week 12) but not with pegylated interferon concentrations.

• Assessing the viorologic and adherence benefits of patient-selected HIV treatment partners in a resource-limited setting.

  Authors: Babafemi O Taiwo, John A Idoko, Leah J Welty, Ihedinachi Otoh, Grace Job, Paul G Iyaji, Oche Agbaji, Patricia A Agaba, Robert L Murphy

  Journal of acquired immune deficiency syndromes (1999). 05/2010; 54(1):85-92.

  To determine the efficacy of patient-selected treatment partners on virologic and adherence outcomes during first-line antiretroviral therapy. Randomized controlled trial. SETTING AND ANALYTICALTo determine the efficacy of patient-selected treatment partners on virologic and adherence outcomes during first-line antiretroviral therapy. Randomized controlled trial. SETTING AND ANALYTICAL APPROACH: Between June 2006 and December 2007, 499 HIV-infected adults in Jos, Nigeria, were randomized to standard of care (SOC) or patient-selected treatment partner-assisted therapy (TPA). Each patient was followed for 48 weeks. Virologic outcomes, adherence to drug pick-up, CD4 cell counts, and mortality are reported. At week 24, undetectable viral load was achieved by 61.7% of patients in the TPA arm versus 50.2% of those receiving SOC [odds ratio (OR) = 1.58, 95% CI: 1.11 to 2.26, P < 0.05]. There was no significant difference at week 48: 65.3% versus 59.4% for TPA and SOC, respectively (OR = 1.28, 95% CI: 0.89 to 1.84, P > 0.05). The TPA group had more than 3 times the odds of at least 95% drug pickup adherence through week 24 (OR = 3.06, 95% CI: 1.89 to 4.94, P < 0.01) and almost twice the odds through week 48 (OR = 1.95, 95% CI: 1.29 to 2.93, P < 0.01). At week 48, there were no significant differences in CD4 cell count increases (t = -0.09, df = 404, P > 0.05) or mortality (10.6% vs. 6.1%) between TPA vs. SOC, respectively. Residence-to-clinic distance was significantly associated with virologic and adherence outcomes. Use of patient-selected treatment partners was associated with improved drug pickup adherence and initial virologic success but had no durable effect on attaining undetectable viral load.

• Erratum to: Abacavir/lamivudine fixed-dose combination antiretroviral therapy for the treatment of HIV.

  Authors: Chad J Achenbach, Kimberly K Scarsi, Robert L Murphy

  Advances in therapy. 03/2010;

• Predictors of atypical squamous cell of undetermined significance cervical cytology with high-risk human papilloma virus genotypes.

  Authors: Jonah Musa, Babafemi Taiwo, Susan Goldsmith, Sarah Sutton, Baiba Berzins, Robert L Murphy

  Archives of gynecology and obstetrics. 03/2010; 283(2):343-8.

  To investigate epidemiological factors that predicts high-risk human papillomavirus (HR-HPV) types among women with atypical squamous cells of undetermined significance (ASCUS). Case-control study ofTo investigate epidemiological factors that predicts high-risk human papillomavirus (HR-HPV) types among women with atypical squamous cells of undetermined significance (ASCUS). Case-control study of women with ASCUS and 'reflex' HR-HPV DNA test results at the Prentice Ambulatory Care (PAC) outpatient clinic, Northwestern University, Chicago, USA. Univariate analysis and logistic regression were done to generate measures of association between various epidemiological variables and positive HR-HPV. A total of 2,539 women had liquid-based Pap smear and 126 (4.96%) were confirmed ASCUS. Of the 126 with ASCUS, 125 (99.2%) had 'reflex' HR-HPV results. The prevalence of HR-HPV among women with ASCUS was 43.2%. Among the 54 with a positive HR-HPV, 76.0% were women <30 years and 24.0% were ≥ 30 years. The prevalence of HR-HPV was 61.2% among women <30 years versus 22.4% among women ≥ 30 years (P < 0.001). The mean age and standard deviations (SD) was 26.5 (6.2 years) and 34.6 (10.2 years) for women with a positive HR-HPV and negative HR-HPV test, respectively (P < 0.001). Age category <30 years was independently predictive of HR-HPV (adjusted odds ratio 4.6, 95% CI 2.0-10.7; P < 0.001). Age <30 years significantly predicts presence of HR-HPV types among women with diagnosis of ASCUS. A strategy of limiting HPV testing to older women and referral of those <30 years for colposcopic assessment appears more effective.

• Abacavir/lamivudine fixed-dose combination antiretroviral therapy for the treatment of HIV.

  Authors: Chad J Achenbach, Kimberly K Scarsi, Robert L Murphy

  Advances in therapy. 01/2010; 27(1):1-16.

  In the past 15 years, improvements in the treatment of HIV infection have dramatically reduced morbidity and mortality. Nucleoside reverse transcriptase inhibitors are the backbone of combinationIn the past 15 years, improvements in the treatment of HIV infection have dramatically reduced morbidity and mortality. Nucleoside reverse transcriptase inhibitors are the backbone of combination antiretroviral therapy for the treatment of HIV. One of the recommended and commonly used therapies in this class is the once-daily fixed-dose combination of abacavir/lamivudine. Clinical studies and practice have shown these drugs to be potent, safe, and easy to use in a variety of settings; however, several recent reports have challenged the safety and efficacy claims among certain patient populations, including those at risk for cardiovascular disease and in those with high viral loads prior to treatment initiation. We reviewed abacavir/lamivudine as a treatment for HIV and discussed limitations of its use due to these controversial issues.

• Antiviral activity and tolerability of amdoxovir with zidovudine in a randomized double-blind placebo-controlled study in HIV-1-infected individuals.

  Authors: Robert L Murphy, Nancy M Kivel, Carlos Zala, Claudia Ochoa, Phillip Tharnish, Judy Mathew, Maria Luz Pascual, Raymond F Schinazi

  Antiviral therapy. 01/2010; 15(2):185-92.

  Amdoxovir acts synergistically with zidovudine in vitro and the combination prevents or delays the selection of thymidine analogue and K65R mutations. In silico studies have shown that a reduced doseAmdoxovir acts synergistically with zidovudine in vitro and the combination prevents or delays the selection of thymidine analogue and K65R mutations. In silico studies have shown that a reduced dose of zidovudine (200 mg) results in decreased zidovudine-monophosphate levels, associated with toxicity, while maintaining zidovudine-triphosphate levels, which are associated with antiviral effects. Here, we aimed to assess the short-term tolerability and antiviral activity of amdoxovir in combination with reduced and standard doses of zidovudine. The study was a double-blind, placebo-controlled study in HIV-1-infected patients not receiving antiretroviral therapy and with plasma HIV-1 RNA > or =5,000 copies/ml. Patients were randomized to 10 days of twice-daily treatment with 200 mg zidovudine, 300 mg zidovudine, 500 mg amdoxovir, 500 mg amdoxovir plus 200 mg zidovudine or 500 mg amdoxovir plus 300 mg zidovudine. The mean change in viral load (VL) log(10) and area under the virus depletion curve (AUC(VL)) from baseline to day 10 were determined. Laboratory and clinical safety monitoring were performed. Twenty-four patients were enrolled. The mean VL log(10) change was 0.10 with placebo, -0.69 with zidovudine 200 mg, -0.55 with zidovudine 300 mg, -1.09 with amdoxovir, -2.00 with amdoxovir plus zidovudine (200 mg) and -1.69 with amdoxovir plus zidovudine (300 mg). Amdoxovir plus zidovudine (200 mg) was significantly more potent than amdoxovir monotherapy in AUC(VL) and mean VL decline (P=0.019 and P=0.021, respectively), suggesting synergy. There was markedly decreased VL variability with the combination compared with amdoxovir alone. All adverse events were mild to moderate. Conclusion: The combination of amdoxovir plus zidovudine appeared synergistic with reduced VL variability. This combined therapy, including the use of a lower zidovudine dosage, warrants further development for the therapy of HIV infection.

• Management of antiretroviral failure and resistance in developing countries.

  Authors: Claudia Hawkins, Robert L Murphy

  Current opinion in HIV and AIDS. 11/2009; 4(6):538-44.

  As scale-up of antiretroviral therapy in developing countries continues, an increasing number of patients developing antiretroviral failure and resistance are being identified. This review focuses onAs scale-up of antiretroviral therapy in developing countries continues, an increasing number of patients developing antiretroviral failure and resistance are being identified. This review focuses on the identification and management of these complex patients in settings with limited antiretroviral drug options and resources. The number of patients receiving second-line and salvage therapies remains lower than the number of patients who are eligible for these therapies. This situation is a result of delays in the recognition and management of antiretroviral failure caused by a lack of sensitive diagnostic techniques, and effective and tolerable alternative antiretroviral drugs. Alternative treatment options using currently available therapies in developing countries are suggested for the management of patients with antiretroviral failure and resistance. Strategies to enhance the durability of antiretroviral regimens to minimize the risk of failure are also discussed. The development of antiretroviral failure and drug resistance among HIV-infected patients in developing countries is of increasing concern. Intensive efforts by HIV care and treatment programs are required to ensure the timely and effective diagnosis and management of these patients. Efforts to minimize the risk of failure are also needed given the significant cost and resource limitations in these settings.

• A step ahead on the HIV collaboratory.

  Authors: Robert L Murphy, Brigitte Autran, Christine Katlama, Gilles Brucker, Patrice Debre, Vincent Calvez, Bonaventura Clotet, Nathan Clumeck, Dominique Costagliola, Steven G Deeks [......] Jose Gatell, Ashley Haase, Michel Klein, Adriano Lazzarin, Andrew J McMichael, Laura Papagno, Timothy W Schacker, Simon Wain-Hobson, Bruce D Walker, Michael Youle

  Science (New York, N.Y.). 07/2009; 324(5932):1264-5.

• Greater decrease in bone mineral density with protease inhibitor regimens compared with nonnucleoside reverse transcriptase inhibitor regimens in HIV-1 infected naive patients.

  Authors: Claudine Duvivier, Sami Kolta, Lambert Assoumou, Jade Ghosn, Sylvie Rozenberg, Robert L Murphy, Christine Katlama, Dominique Costagliola

  AIDS (London, England). 04/2009; 27(7):817-24.

  OBJECTIVE: To evaluate the change in bone mineral density (BMD) at specific sites in patients initiating antiretroviral therapy in a substudy of the ANRS 121 trial. METHODS: Antiretroviral-naiveOBJECTIVE: To evaluate the change in bone mineral density (BMD) at specific sites in patients initiating antiretroviral therapy in a substudy of the ANRS 121 trial. METHODS: Antiretroviral-naive patients were randomized (2: 1: 1) into three treatment strategy arms: a nonnucleoside reverse transcriptase inhibitor (NNRTI) and a boosted protease inhibitor (PI/r), a PI/r and two nucleoside reverse transcriptase inhibitors (NRTIs) or an NNRTI and NRTIs. Hip and lumbar spine standardized BMD were evaluated at baseline and week 48 by dual X-ray absorptiometry by a central reading laboratory. RESULTS: Seventy-one patients were enrolled: 36 in the PI/r and NNRTI, 19 in the PI/r and NRTIs and 16 in the NNRTI and NRTIs arms. Baseline characteristics were [median (interquartile range)]: male (77%), age 40 years (33-49), 69% white, 58% smokers, BMI 23 kg/m2 (21-24), CD4 cell count 219 cells/microl (144-285). In the arms with NRTIs, 86% of patients received zidovudine/lamivudine. At baseline, 31% had osteopenia and 3% had osteoporosis. At week 48, there was a mean change in BMD of -4.1 +/- 3.9% at lumbar spine and -2.8 +/- 4.7% at hip (both P< or = 0.001). The decrease of BMD at lumbar spine was significantly worse in the PI/r and NNRTI arm (-4.4 +/- 3.4%) and in the PI/r and NRTIs arm (-5.8 +/- 4.5%) compared with the NNRTI and NRTIs arm (-1.5 +/- 2.9%), P = 0.007 and P = 0.001, respectively. CONCLUSION: BMD was impaired in 34% of patients, before starting any antiretrovirals. After 1 year, the decrease in lumbar spine BMD was more pronounced in patients receiving either PI/r-containing regimen compared with NNRTI and NRTIs. BMD at specific sites should be monitored during lifelong antiretroviral therapy.

• Mitochondrial function, morphology and metabolic parameters improve after switching from stavudine to a tenofovir-containing regimen.

  Authors: Mariana Gerschenson, Courtney Kim, Baiba Berzins, Babafemi Taiwo, Daniel E Libutti, Julia Choi, Diana Chen, Jill Weinstein, Jessica Shore, Barbara da Silva, Elizabeth Belsey, Grace A McComsey, Robert L Murphy

  The Journal of antimicrobial chemotherapy. 04/2009;

  Objectives HIV-associated lipoatrophy has been associated with mitochondrial dysfunction induced by nucleoside reverse transcriptase inhibitor therapy. We hypothesize that lipid profiles and markersObjectives HIV-associated lipoatrophy has been associated with mitochondrial dysfunction induced by nucleoside reverse transcriptase inhibitor therapy. We hypothesize that lipid profiles and markers of mitochondrial function will improve in HIV-lipoatrophic patients switched to the nucleotide analogue tenofovir. Methods Ten patients receiving stavudine, lamivudine and lopinavir/ritonavir (Kaletra((R))) for over 6 years were switched from stavudine to tenofovir for 48 weeks. Subcutaneous fat tissue biopsies, fasting metabolic tests, HIV RNA, CD4 cell count and whole body dual energy X-ray absorptiometry (DEXA) scans were obtained at study entry and week 48. Mitochondrial DNA (mtDNA) copies/cell and mitochondrial morphology were assessed in adipose tissue biopsies, mtDNA 8-oxo-deoxyguanine in peripheral blood mononuclear cells, and glutathione (GSH) and F2-isoprostane in plasma. Results There was no change in limb fat mass by DEXA; however, trunk fat mass increased by 18.9% (P = 0.01). Fasting total cholesterol decreased by 33 mg/dL (P = 0.005) and serum glucose decreased by 4 mg/dL (P = 0.039). mtDNA copies/cell increased from 386 to 1537 (P < 0.001). Transmission electron microscopy showed that mitochondrial cristae were lacking or poorly defined at study entry, whereas mitochondrial inner structures were more well defined and outer membranes were intact at 48 weeks. Oxidative damage decreased in 8/10 patients, GSH increased and F2-isoprostane decreased. Conclusions The results from this study demonstrate that systemic and peripheral fat mitochondria improve in patients switched to tenofovir following long-term exposure to stavudine, while continuing protease inhibitor therapy.

• Lipoprotein Changes in HIV-Infected Antiretroviral-Naïve Individuals after Starting Antiretroviral Therapy: ACTG Study A5152s Stein: Lipoprotein Changes on Antiretroviral Therapy.

  Authors: James H Stein, Lauren Komarow, Bruno R Cotter, Judith S Currier, Michael P Dubé, Carl J Fichtenbaum, Mariana Gerschenson, Carol K C Mitchell, Robert L Murphy, Kathleen Squires, Robert A Parker, Francesca J Torriani

  Journal of clinical lipidology. 12/2008; 2(6):464-471.

  BACKGROUND: Dyslipidemia is a frequent complication of antiretroviral therapy (ART) for patients with human immunodeficiency virus infection (HIV). The effects of ART on lipoproteins are lessBACKGROUND: Dyslipidemia is a frequent complication of antiretroviral therapy (ART) for patients with human immunodeficiency virus infection (HIV). The effects of ART on lipoproteins are less well-understood, and have not been investigated in a prospective study where assignment to ART is randomized. OBJECTIVE: To evaluate the effects of three class-sparing ART regimens on lipids and lipoproteins. METHODS: This was a substudy of a prospective, multicenter study treatment-naïve HIV-infected individuals randomly assigned to receive a regimen of nucleoside reverse transcriptase inhibitors (NRTIs) + the non-nucleoside reverse transcriptase inhibitor efavirenz, NRTIs + the protease inhibitor lopinavir/ritonavir, or a NRTI-sparing regimen of efavirenz + lopinavir/ritonavir. Lipoproteins were measured by nuclear magnetic resonance spectroscopy. RESULTS: Among the 82 participants, total and small low-density lipoprotein concentrations increased (median, interquartile range) by 152 (-49 - +407, p<0.01) and 130 (-98 - +417, p<0.01) nmol/L, respectively, especially in the arms containing lopinavir/ritonavir (p(KW)<0.04). Very low-density lipoproteins also increased (p<0.01), with a larger increase in the arms that contained lopinavir/ritonavir (p=0.022). High-density lipoproteins increased by 6.0 nmol/L (2.8 - 10.4, p<0.01), but differences between arms were not significant (p(KW)=0.069). Changes were not related to changes in markers of insulin/glucose metabolism. CONCLUSIONS: Total and small low-density lipoprotein concentrations increased, especially in the arms containing lopinavir/ritonavir, as did increases in total very low-density lipoproteins. Adverse changes were especially prominent in the arm with efavirenz + lopinavir/ritonavir.