Search

The availability of an increasing number of antiretroviral agents and the rapid evolution of new information have introduced substantial complexity into treatment regimens for persons infected with human immunodeficiency virus (HIV). In 1996, the Department of Health and Human Services and the Henry J. Kaiser Family Foundation convened the Panel on Clinical Practices for the Treatment of HIV to develop guidelines for clinical management of HIV-infected adults and adolescents (CDC. Report of the NIH Panel To Define Principles of Therapy of HIV Infection and Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. MMWR. 1998;47[RR-5]:1-41). This report, which updates the 1998 guidelines, addresses 1) using testing for plasma HIV ribonucleic acid levels (i.e., viral load) and CD4+ T cell count; 2) using testing for antiretroviral drug resistance; 3) considerations for when to initiate therapy; 4) adherence to antiretroviral therapy; 5) considerations for therapy among patients with advanced disease; 6) therapy-related adverse events; 7) interruption of therapy; 8) considerations for changing therapy and available therapeutic options; 9) treatment for acute HIV infection; 10) considerations for antiretroviral therapy among adolescents; 11) considerations for antiretroviral therapy among pregnant women; and 12) concerns related to transmission of HIV to others. Antiretroviral regimens are complex, have serious side effects, pose difficulty with adherence, and carry serious potential consequences from the development of viral resistance because of nonadherence to the drug regimen or suboptimal levels of antiretroviral agents. Patient education and involvement in therapeutic decisions are critical. Treatment should usually be offered to all patients with symptoms ascribed to HIV infection. Recommendations for offering antiretroviral therapy among asymptomatic patients require analysis of real and potential risks and benefits. In general, treatment should be offered to persons who have <350 CD4+ T cells/mm3 or plasma HIV ribonucleic acid (RNA) levels of >55,000 copies/mL (by b-deoxyribonucleic acid [bDNA] or reverse transcriptase-polymerase chain reaction [RT-PCR] assays). The recommendation to treat asymptomatic patients should be based on the willingness and readiness of the person to begin therapy; the degree of existing immunodeficiency as determined by the CD4+ T cell count; the risk for disease progression as determined by the CD4+ T cell count and level of plasma HIV RNA; the potential benefits and risks of initiating therapy in an asymptomatic person; and the likelihood, after counseling and education, of adherence to the prescribed treatment regimen. Treatment goals should be maximal and durable suppression of viral load, restoration and preservation of immunologic function, improvement of quality of life, and reduction of HIV-related morbidity and mortality. Results of therapy are evaluated through plasma HIV RNA levels, which are expected to indicate a 1.0 log10 decrease at 2-8 weeks and no detectable virus (<50 copies/mL) at 4-6 months after treatment initiation. Failure of therapy at 4-6 months might be ascribed to nonadherence, inadequate potency of drugs or suboptimal levels of antiretroviral agents, viral resistance, and other factors that are poorly understood. Patients whose therapy fails in spite of a high level of adherence to the regimen should have their regimen changed; this change should be guided by a thorough drug treatment history and the results of drug-resistance testing. Because of limitations in the available alternative antiretroviral regimens that have documented efficacy, optimal changes in therapy might be difficult to achieve for patients in whom the preferred regimen has failed. These decisions are further confounded by problems with adherence, toxicity, and resistance. For certain patients, participating in a clinical trial with or without access to new drugs or using a regimen that might not achieve complete suppression of viral replicatioing a regimen that might not achieve complete suppression of viral replication might be preferable. Because concepts regarding HIV management are evolving rapidly, readers should check regularly for additional information and updates at the HIV/AIDS Treatment Information Service website ( http://www.hivatis.org ). [ABSTRACT FROM AUTHOR]

The availability of an increasing number of antiretroviral agents and the rapid evolution of new information has introduced substantial complexity into treatment regimens for persons infected with human immunodeficiency virus (HIV). In 1996, the Department of Health and Human Services and the Henry J. Kaiser Family Foundation convened the Panel on Clinical Practices for the Treatment of HIV to develop guidelines for clinical management of HIV-Infected adults and adolescents (CDC. Report of the NIH Panel To Define Principles of Therapy of HIV Infection and Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. MMWR 1998;47[RR-5]:1-41). This report, which updates the 1998 guidelines, addresses 1) using testing for plasma HIV ribonucleic acid levels (i.e., viral load) and CD4+ T cell count; 2) using testing for antiretroviral drug resistance; 3) considerations for when to initiate therapy; 4) adherence to antiretroviral therapy; 5) considerations for therapy among patients with advanced disease; 6) therapy-related adverse events; 7) interruption of therapy; 8) considerations for changing therapy and available therapeutic options; 9) treatment for acute HIV infection; 10) considerations for antiretroviral therapy among adolescents; 11) considerations for antiretroviral therapy among pregnant women; and 12) concerns related to transmission of HIV to others.Antiretroviral regimens are complex, have serious side effects, pose difficulty with adherence, and carry serious potential consequences from the development of viral resistance because of nonadherence to the drug regimen or suboptimal levels of antiretroviral agents. Patient education and involvement in therapeutic decisions is critical. Treatment should usually be offered to all patients with symptoms ascribed to HIV infection. Recommendations for offering antiretroviral therapy among asymptomatic patients require analysis of real and potential risks and benefits. Treatment should be offered to persons who have <350 CD4+ T cells/mm3 or plasma HIV ribonucleic acid (RNA) levels of >55,000 copies/mL (by b-deoxyribonucleic acid [bDNA] or reverse transcriptase-polymerase chain reaction [RT-PCR] assays). The recommendation to treat asymptomatic patients should be based on the willingness and readiness of the person to begin therapy; the degree of existing immunodeficiency as determined by the CD4+ T cell count; the risk for disease progression as determined by the CD4+ T cell count and level of plasma HIV RNA; the potential benefits and risks of initiating therapy in an asymptomatic person; and the likelihood, after counseling and education, of adherence to the prescribed treatment regimen.Treatment goals should be maximal and durable suppression of viral load, restoration and preservation of immunologic function, improvement of quality of life, and reduction of HIV-related morbidity and mortality. Results of therapy are evaluated through plasma HIV RNA levels, which are expected to indicate a 1.0 log10 decrease at 2-8 weeks and no detectable virus (<50 copies/mL) at 4-6 months after treatment initiation. Failure of therapy at 4-6 months might be ascribed to nonadherence, inadequate potency of drugs or suboptimal levels of antiretroviral agents, viral resistance, and other factors that are poorly understood. Patients whose therapy fails in spite of a high level of adherence to the regimen should have their regimen changed; this change should be guided by a thorough drug treatment history and the results of drug-resistance testing. Because of limitations in the available alternative antiretroviral regimens that have documented efficacy, optimal changes in therapy might be difficult to achieve for patients in whom the preferred regimen has failed. These decisions are further confounded by problems with adherence, toxicity, and resistance. For certain patients, participating in a clinical trial with or without access to new drugs or using a regimen that might not achieve complete suppression of viral replication might be preferable. Because concepts regarding HIV management are evolving rapidly, readers should check regularly for additional information and updates at the HIV/AIDS Treatment Information Service website (http://www.hivatis.org). [ABSTRACT FROM AUTHOR]

Description: In March 2020, the White House Coronavirus Task Force determined that clinicians in the United States needed expert treatment guidelines to optimally manage patients with COVID-19, a potentially life-threatening disease caused by a new pathogen for which no specific treatments were known to be effective., Methods: The U.S. Department of Health and Human Services requested that the National Institutes of Health (NIH) take the lead in expeditiously convening a panel of experts to create "living" guidelines that would be widely accessible and capable of frequent updating as important new information became available., Recommendations: The purpose of this article is to expand on the experiences of the NIH COVID-19 Treatment Guidelines Panel (the Panel) over the past 4 years, summarize the Panel's final recommendations for COVID-19, highlight some challenges and unanswered questions about COVID-19 management, and inform future responses to public health emergencies. The Panel was formed in March 2020, and the first iteration of the guidelines was released in April 2020. Now that the public health emergency has ended, the NIH COVID-19 Treatment Guidelines have sunsetted. This role will now fall to professional societies and organizations, such as the American College of Physicians, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the World Health Organization, all of which have been active in this area., Competing Interests: Disclosures: Disclosure forms are available with the article online.

Background: People living with HIV (PLWH) with multidrug-resistant (MDR) viruses have limited therapeutic options and present challenges regarding clinical management. Recent studies have shown that passive transfer of combination broadly neutralizing antibodies (bNAbs) against HIV and anti-domain 1 CD4 antibody UB-421 can sustain virologic suppression in PLWH in the absence of antiretroviral therapy (ART). Yet studies addressing the therapeutic potential of these antibodies and/or detailed characterization of immunologic and virologic parameters in PLWH with MDR HIV are lacking., Methods: We examined levels of immune activation and exhaustion markers on CD8 + T cells and the intact HIV proviral DNA burden in 11 PLWH with MDR viruses. For comparison purposes, we included a control group consisting of 27 ART-naïve viremic PLWH. In addition, we determined the sensitivity of infectious viral isolates obtained from the participants against eight bNAbs (3BNC117, 10-1074, VRC01, VRC07, N6, 10E8, PGDM1400, and PGT121) and two anti-CD4 antibodies (ibalizumab and UB-421) using a TZM-bl-based neutralization/suppression assay., Findings: The level of intact HIV proviral DNA was comparable between the two groups (P = 0.29). The levels of activation and exhaustion markers PD-1 (P = 0.0019), TIGIT (P = 0.0222), 2B4 (P = 0.0015), CD160 (P = 0.0015), and CD38 + /HLA-DR + (P = 0.0138) were significantly lower in the MDR group. The infectious viral isolates from each study participant with MDR HIV were resistant to at least 2 bNAbs; however, they were sensitive to at least one of the CD4-binding and non-CD4-binding site antibodies. The majority of participants had ibalizumab-sensitive viruses although the isolates from some participants showed reduced sensitivity to ibalizumab. Notably, none of the 93 viral isolates obtained from the participants were resistant to UB-421., Interpretation: Our data suggest that combination therapy with HIV-specific bNAbs and/or UB-421 in the presence of optimized background therapy could potentially provide sustained virologic suppression in PLWH with MDR HIV. However, this therapeutic strategy needs to be evaluated in human clinical trials., Funding: Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health., Competing Interests: Declaration of interests We declare no competing interests., (Published by Elsevier B.V.)

Background: Once-weekly isoniazid with rifapentine (HP) for 3 months is a recommended treatment for latent tuberculosis infection in persons with HIV. HP reduces exposures of certain antiretroviral medications, resulting in limited options for the concomitant use of these therapies. Here, we examined the pharmacokinetics (PK), safety, and tolerability of darunavir/cobicistat with HP., Methods: This was an open-label, fixed sequence, two-period crossover study in persons without HIV. Participants received darunavir 800 mg/cobicistat 150 mg once-daily alone for 4 days, then continued darunavir/cobicistat once-daily for days 5-19 with HP coadministration on days 5, 12, and 19. Intensive PK assessments were performed on days 4, 14, and 19. PK parameters were determined using noncompartmental methods. Geometric mean ratios with 90% confidence intervals (CIs) were calculated and compared between phases using mixed-effects models., Results: Thirteen participants were enrolled. Two withdrew after day 4, and one withdrew after day 14. Of the 3 withdrawals, 2 were attributed to drug-related adverse events. Darunavir area under the concentration-time curve, maximum concentrations (Cmax), and concentrations at 24 hours postdose (C24h) were reduced by 71%, 41%, and 96% ∼48-72 hours after HP administration (day 14), respectively, and 36%, 17%, and 89% with simultaneous HP administration (day 19), respectively. On day 14, 45% of the predose and 73% of C24h concentrations were below the darunavir EC50 (0.055 µg/mL)., Conclusions: Darunavir exposures were significantly decreased with HP coadministration. Temporal relationships between HP coadministration and the extent of induction or mixed inhibition/induction of darunavir metabolism were apparent. Coadministration of darunavir/cobicistat with 3HP should be avoided., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

While the coronavirus disease 2019 (COVID-19) pandemic continues to present global challenges, sufficient time has passed to reflect on lessons learned and use those insights to inform policy and approaches to prepare for the next pandemic. In May 2022, the Duke Clinical Research Institute convened a think tank with thought leaders from academia, clinical practice, the pharmaceutical industry, patient advocacy, the National Institutes of Health, the US Food and Drug Administration, and the Centers for Disease Control and Prevention to share, firsthand, expert knowledge of the insights gained from the COVID-19 pandemic and how this acquired knowledge can help inform the next pandemic response. The think tank focused on pandemic preparedness, therapeutics, vaccines, and challenges related to clinical trial design and scale-up during the early phase of a pandemic. Based on the multi-faceted discussions, we outline 10 key steps to an improved and equitable pandemic response., Competing Interests: Potential conflicts of interest. A. F. H. reports contracts with Pfizer and Merck and consulting fees from Merck. B. L. is an employee of and owns stock in Moderna and reports support for travel to a meeting from Moderna. C. W. W. reports consulting fees from Arena Pharmaceuticals, BioFire, FHI Clinical, Giner, Karius, and SeLux Diagnostics; grants or contracts (paid to institution) from Defense Advanced Research Projects Agency, National Institutes of Health (NIH)-Antibacterial Resistance Leadership Group/National Institute of Allergy and Infectious Diseases/NIH Vaccine and Treatment Evaluation Units/National Institute of Mental Health/National Institute of General Medical Sciences, Sanofi, Najit, the Centers for Disease Control and Prevention (CDC), Patient-Centered Outcomes Research, United States Army Medical Research Acquisition Activity, Department of Defence, Abbott, and Pfizer; support for attending meetings and/or travel from the American Society for Microbiology (ASM); participation on a data and safety monitoring board (DSMB) or advisory board for IDbyDNA, Janssen, Regeneron, Roche Molecular Sciences; a leadership or fiduciary role for ASM and the American Society of Tropical Medicine and Hygiene; being employed by Duke University, Durham Veterans Affairs Hospital, Biomeme, and Equity/Founder of Predigen, Inc; and planned, issued, or pending patents for biomarkers for the molecular classification of bacterial infection, methods to diagnose and treat acute respiratory infections, gene expression signatures useful to predict or diagnose sepsis and methods of using the same, host-based molecular signatures of human infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 (coronavirus disease 2019 [COVID-19]), methods of identifying infectious disease and assays for identifying infectious disease, and nasopharyngeal protein biomarkers of acute respiratory virus infection and methods of using same. H. C. and S. C. B. are employees of and hold or may hold stock in AstraZeneca. J. W. reports being an employee of and owns stock/stock options in and received equipment, materials, drugs, medical writing, gifts, and other services from Johnson & Johnson and, as CMO, has been deposed in litigation; patents issued that do not relate to the current article (available on request); and a role on the Brooklyn College Cancer Center Advisory Board, a Brooklyn College Foundation Trustee, and on the Fellowships at Auschwitz for the Study of Professional Ethics, Academic Committee. J. R. D. is an employee and shareholder in Eli Lilly and Company. L. H. C. reports consulting fees from Regeneron for the NFL Players Association and grants or contracts from NIH for PCORI. L. S. reports stock/stock options in Novartis. L. R. is an employee of and owns stock/stock options in and received support for attending meetings and/or travel from Bayer AG. M. S. reports consulting fees from AbbVie, Assembly Bio, Antios, Arbutus, Gilead Sciences, Precision Bio, and GSK for scientific advisory boards and participation on a DSMB for Gilead Sciences and AbbVie and a role as editor of the Journal Viral Hepatitis. O. V. is an employee of Boehringer Ingelheim. P. P. has a patent pending for sotrovimab and is an employee and shareholder of Vir Biotechnology. S. N. reports consulting fees from Pardes Biosciences, Theratechnologies, and Silverback Therapeutics; stock/stock options in Vir Biotechnology; grants or contracts (paid to institution) from Gilead Sciences and AbbVie; participation on an advisory board for Vir Biotechnology, a DSMB for Personal Health Insights, Inc; and serving on an event adjudication committee for Bristol–Myers Squibb/PRA. M. A. M. reports consulting fees from Abcam; stock/stock options in Grid Therapeutics; a role as an advisory board member for GSK Belimumab Pregnancy Registry; and funding to Duke from NIAD (U01 AI151378): Centers for Research in Emerging Infectious Disease (CREID) Network Coordinating Center, HHS 75N93019C00050: Duke Collaborative Influenza Vaccine Innovation Centers (CIVICs) A: Vaccine Center, HHS 75N93019C00054: Duke CIVICs C: Clinical Core, U19 AI144177: A Global Syphilis Vaccine Targeting Outer Membrane Proteins Of Treponema pallidum, 2P01 AI089618: Structure-Function Analysis Of Infection- And Vaccine-Induced B Cell Repertoires. S. E. T. reports royalties from UptoDate; grants or contracts (paid to institution) from the CDC; payment or honoraria (to author) from the Infectious Disease Society of America (IDSA) and Emerson Hospital; support from DCRI to attend the meeting upon which this article was based. L. R. B. is involved in human immunodeficiency virus (HIV) and SARS-CoV-2 vaccine clinical trials conducted in collaboration with the NIH, HIV Vaccine Trials Network, COVID Vaccine Prevention Network, International AIDS Vaccine Initiative, Crucell/Janssen, Moderna, Military HIV Research Program, the Gates Foundation, and Harvard Medical School. reports participation on a DSMB for NIH and AMDAC Committee for the FDA (research funded by the NIH, Welcome Trust, and the Gates Foundation). R. T. G. reports a leadership or fiduciary role on the NIH COVID Treatment Guidelines Panel and IDSA COVID Treatment Guidelines Panel. R. G. reports grants (to institution) from NIH/NIAID, book chapter royalties from Elsevier, and section editor royalties from UpToDate. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Nuclear localization signal (NLS) of HIV-1 integrase (IN) is implicated in nuclear import of HIV-1 preintegration complex (PIC). Here, we established a multiclass drug-resistant HIV-1 variant (HIV KGD ) by consecutively exposing an HIV-1 variant to various antiretroviral agents including IN strand transfer inhibitors (INSTIs). HIV KGD was extremely susceptible to a previously reported HIV-1 protease inhibitor, GRL-142, with IC 50 of 130 femtomolar. When cells were exposed to HIV KGD IN-containing recombinant HIV in the presence of GRL-142, significant decrease of unintegrated 2-LTR circular cDNA was observed, suggesting that nuclear import of PIC was severely compromised by GRL-142. X-ray crystallographic analyses revealed that GRL-142 interacts with NLS's putative sequence (DQAEHLK) and sterically blocks the nuclear transport of GRL-142-bound HIV KGD 's PIC. Highly INSTI-resistant HIV-1 variants isolated from heavily INSTI-experienced patients proved to be susceptible to GRL-142, suggesting that NLS-targeting agents would serve as salvage therapy agents for highly INSTI-resistant variant-harboring individuals. The data should offer a new modality to block HIV-1 infectivity and replication and shed light on developing NLS inhibitors for AIDS therapy.

The development of the National Institutes of Health (NIH) COVID-19 Treatment Guidelines began in March 2020 in response to a request from the White House Coronavirus Task Force. Within 4 days of the request, the NIH COVID-19 Treatment Guidelines Panel was established and the first meeting took place (virtually-as did subsequent meetings). The Panel comprises 57 individuals representing 6 governmental agencies, 11 professional societies, and 33 medical centers, plus 2 community members, who have worked together to create and frequently update the guidelines on the basis of evidence from the most recent clinical studies available. The initial version of the guidelines was completed within 2 weeks and posted online on 21 April 2020. Initially, sparse evidence was available to guide COVID-19 treatment recommendations. However, treatment data rapidly accrued based on results from clinical studies that used various study designs and evaluated different therapeutic agents and approaches. Data have continued to evolve at a rapid pace, leading to 24 revisions and updates of the guidelines in the first year. This process has provided important lessons for responding to an unprecedented public health emergency: Providers and stakeholders are eager to access credible, current treatment guidelines; governmental agencies, professional societies, and health care leaders can work together effectively and expeditiously; panelists from various disciplines, including biostatistics, are important for quickly developing well-informed recommendations; well-powered randomized clinical trials continue to provide the most compelling evidence to guide treatment recommendations; treatment recommendations need to be developed in a confidential setting free from external pressures; development of a user-friendly, web-based format for communicating with health care providers requires substantial administrative support; and frequent updates are necessary as clinical evidence rapidly emerges.

Background: Direct oral anticoagulants (DOACs) have become first-line treatment for venous thrombotic events. DOAC prescribing trends among people living with human immunodeficiency virus (PWH) are not well described. The coadministration of DOACs with the antiretroviral (ARV) pharmacokinetic boosters ritonavir (RTV) or cobicistat (COBI) may be complicated by pharmacokinetic interactions., Methods: A longitudinal cohort study was conducted using the D.C. Cohort Database in Washington, D.C., from January 2011 to March 2017, to describe oral anticoagulant prescribing among PWH ≥ 18 years old and the prevalence of DOAC use with RTV or COBI. Data collection included demographic and clinical characteristics, ARV and anticoagulant prescriptions, and International Classification of Diseases Ninth and Tenth Edition diagnosis codes., Results: Among 8315 PWH, there were 236 anticoagulant prescriptions (96 DOAC, 140 warfarin) for 206 persons. PWH prescribed anticoagulants were predominantly Black (82%) and male (82%), with a mean age at anticoagulant initiation of 56 years. DOAC use increased from 3% of total anticoagulant prescribing in 2011 to 43% in 2016, accounting for 64% of all newly recorded anticoagulant prescriptions by 2016. There were 19 bleeding events recorded among 16 individuals. Despite the Food and Drug Administration label recommendation to avoid rivaroxaban with boosted ARVs, 41% remained on boosted ARVs after rivaroxaban initiation., Conclusions: DOAC use increased substantially in PWH by 2016. Although rivaroxaban is not recommended with RTV or COBI, concomitant use was recorded in 41% of rivaroxaban recipients in this cohort. As DOAC usage increases, clinicians need to be aware of potential DOAC/ARV interactions in order to select the most appropriate oral anticoagulant and monitoring plan for PWH., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)

Eight-day inpatient directly observed therapy confirmed nonadherence as the major cause of virologic failure for 9 (45%) of 20 highly treatment-experienced persons with human immunodeficiency virus, extensive antiretroviral drug resistance, and high self-reported adherence rates, preventing unnecessary regimen changes., (Published by Oxford University Press for the Infectious Diseases Society of America 2019.)

HIV integrase mutation T97A emerges after suboptimal therapy with integrase strand transfer inhibitors (INSTIs), but the contribution of T97A to dolutegravir resistance remains uncertain. Here we report >10-fold increase in dolutegravir resistance after the single addition of T97A in 2 individuals with prior INSTI resistance receiving dolutegravir salvage therapy.

The presence of non-B HIV subtypes in the USA has been documented during the epidemic, although the timing of early introductions of different subtypes remains uncertain. Subtype C, the most common HIV variant worldwide, was first reported in the USA in 1996-97, after subtype C had expanded greatly in sub-Saharan Africa. In this study, we report a patient with subtype C infection acquired by mother-to-child transmission, born in the USA in 1990 to a Washington, D.C. resident who never traveled outside the USA, demonstrating that subtype C was present in the USA much earlier. Comparative analysis of the sequence from this patient and subtype C sequences in the USA and elsewhere suggest multiple independent introductions of this subtype into the USA have taken place, many of which are traced to sub-Saharan or East Africa. These data indicate subtype C HIV was already present in the USA years earlier than previously reported, and during the early period of subtype C expansion.

Background: Once-weekly isoniazid and rifapentine for 3 months is a treatment option in persons with human immunodeficiency virus and latent tuberculosis infection. This study aimed to examine pharmacokinetic drug-drug interactions between this regimen and dolutegravir, a first-line antiretroviral medication., Methods: This was a single-center, open-label, fixed-sequence, drug-drug interaction study in healthy volunteers. Subjects received oral dolutegravir 50 mg once daily alone (days 1-4) and concomitantly with once-weekly isoniazid 900 mg, rifapentine 900 mg, and pyridoxine 50 mg (days 5-19). Dolutegravir concentrations were measured on days 4, 14, and 19, and rifapentine, 25-desacetyl-rifapentine, and isoniazid concentrations were measured on day 19. Cytokines and antidrug antibodies to isoniazid and rifapentine were examined at select time points., Results: The study was terminated following the development of flu-like syndrome and elevated aminotransferase levels in 2 of 4 subjects after the third isoniazid-rifapentine dose. Markedly elevated levels of interferon-γ, CXCL10, C-reactive protein, and other cytokines were temporally associated with symptoms. Antidrug antibodies were infrequently detected. Dolutegravir area under the curve (AUC) was decreased by 46% (90% confidence interval, 27-110%; P = .13) on day 14. Rifapentine and 25-desacetyl rifapentine levels on day 19 were comparable to reference data, whereas isoniazid AUCs were approximately 67%-92% higher in the subjects who developed toxicities., Conclusions: The combined use of dolutegravir with once-weekly isoniazid-rifapentine resulted in unexpected and serious toxicities that were mediated by endogenous cytokine release. Additional investigations are necessary to examine the safety and efficacy of coadministering these medications., Clinical Trials Registration: NCT02771249.

Background: Clinical trials frequently enroll subjects from different study sites. Few such studies provide analysis by individual site. Between 2004-2007, the South African Military Health System (SAMHS) established 6 research sites (3 urban, 3 rural) to build capacity for clinical research and HIV care. We explore differences in clinical, virologic and CD4 outcomes by site in the context of a randomized controlled trial., Methods: Phidisa-II is the first randomised controlled trial conducted in the South African military setting, which compared 4 antiretroviral regimens in treatment-naïve advanced HIV subjects. Primary study outcome was first AIDS event or death. Kaplan-Meier curves for AIDS events and mortality were compared across sites. Hazard rates were adjusted for baseline risk factors to assess the independent effect of site. Secondary outcomes of CD4 count and viral responses are also compared across study sites., Results: 1,771 subjects [average age=35.4 ± 5.5 years old, 68% male, with median CD4 count=105 (IQR 41, 157) cells/mm3 and HIV RNA=144,000 (IQR 53,900-305,000)copies/mL] enrolled in 3 urban and 3 rural sites. Sites varied considerably in resources and diagnostic capacities. After adjusting for baseline characteristics, study site was found to be a factor significantly associated with mortality (p=0.008), with Urban 2 and Rural 2 sites had the lowest mortality. Site was also associated with the adjusted hazard for AIDS events (p=0.038). At 24 months, CD4 count was similar across sites, but HIV suppression rate varied considerably (range 40-70%)., Conclusion: Site heterogeneity was found in primary clinical outcomes of mortality and AIDS event rates, but there were no clear patterns for differences between the rural versus urban sites. Site differences were also found in the proportion of confirmed AIDS events. Factors within study sites that may have contributed to poorer outcomes need further investigation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: The current study was conducted to determine if efavirenz (EFV) or atazanavir/ritonavir (ATV/r)-based combination antiretroviral therapy (cART) impacted steady-state atovaquone plasma concentrations in human immunodeficiency virus (HIV)-infected patients receiving treatment doses of atovaquone., Methods: Thirty HIV-infected volunteers were recruited, 10 taking no cART and 10 each taking cART that included EFV or ATV/r. Subjects were randomly assigned to atovaquone 750 mg twice daily (BID) for 14 days followed by atovaquone 1500 mg BID for 14 days, or vice-versa, with a washout period in between. On day 14 of each phase, blood was sampled for pharmacokinetic studies, and the area under the concentration-time curve (AUCτ) and average concentration (C avg) were calculated and compared using an unpaired t test., Results: Twenty-nine subjects completed both dosing cohorts. Subjects receiving EFV-based cART had 47% and 44% lower atovaquone AUCτ than subjects not receiving cART at atovaquone doses of 750 mg BID and 1500 mg BID, respectively (P≤ .01). Only 5 of 10 subjects receiving EFV-based cART plus atovaquone 750 mg BID had an atovaquone C avg>15 µg/mL, which has previously been associated with successful treatment of Pneumocystis jirovecipneumonia. AUCτ and Cavg did not significantly differ for concurrent ATV/r for 750 mg BID or 1500 mg BID when compared to the group not receiving cART. Nine of 10 subjects not receiving cART, 8 of 10 subjects receiving ATV/r, and 2 of 10 subjects receiving EFV in combination with atovaquone 750 mg BID achieved an atovaquone C avg>18.5 µg/mL, a concentration that has previously been associated with successful treatment of Toxoplasmaencephalitis (TE)., Conclusions: These data suggest that the currently recommended dose of atovaquone 750 mg BID for treatment of mild to moderate PCP may not be adequate in patients receiving concurrent EFV. Furthermore, doses lower than the currently recommended dose of 1500 mg BID may achieve plasma concentrations adequate to treat TE in HIV-infected patients not receiving EFV., Clinical Trials Registration: NCT01479361., (Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

We describe a patient with two recent episodes of tenofovir disoproxil fumarate (TDF)-associated acute kidney injury and six-class drug-resistant HIV infection who achieved and maintained viral suppression without worsening kidney function on a regimen including tenofovir alafenamide (TAF) through 48 weeks of therapy. The safety and efficacy of TAF in patients with TDF-associated renal tubulopathy and multiple drug resistant HIV has not yet been described. TAF may represent a useful option to maximally suppress HIV in patients with these complications.

The rapid advances in drug discovery and the development of antiretroviral therapy is unprecedented in the history of modern medicine. The administration of chronic combination antiretroviral therapy targeting different stages of the human immunodeficiency virus' replicative life cycle allows for durable and maximal suppression of plasma viremia. This suppression has resulted in dramatic improvement of patient survival. This article reviews the history of antiretroviral drug development and discusses the clinical pharmacology, efficacy, and toxicities of the antiretroviral agents most commonly used in clinical practice to date., (Published by Elsevier Inc.)

In May 2013, a revised and updated version of the Centers for Disease Control and Prevention/National Institutes of Health/HIV Medicine Association Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents was released online. These guidelines, since their inception in 1989, have been widely accessed in the United States and abroad. These guidelines have focused on the management of HIV/AIDS-related opportunistic infections that occur in the United States. In other parts of the world, the spectrum of complications may be different and the resources available for diagnosis and management may not be identical to those in the United States. The sections that have been most extensively updated are those on immune reconstitution inflammatory syndrome, tuberculosis, hepatitis B, hepatitis C, human papillomavirus, and immunizations. The guidelines will not be published in hard copy form. This document will be revised as needed throughout each year as new data become available.

Background: This study compared the effectiveness of a Specially Designed Paste Carrier technique with the Syringe-Spreader technique and the Syringe-Lentulo spiral technique in the intracanal placement of calcium hydroxide., Methods: Three groups, each containing 15 single-rooted human anterior teeth were prepared using standardized Mtwo rotary instruments to a master apical file size 40 with 0.04 taper. Each group was filled with calcium hydroxide paste using: Syringe and #25 finger spreader (Group 1); Syringe and #4 rotary Lentulo spiral (Group 2), Specially Designed Paste Carrier (Group 3). Using pre-filling and post-filling radiographs in buccolingual and mesiodistal planes, the radiodensities at 1 mm, 3 mm, 5 mm, and 7 mm from the apical foramen were analyzed by ANOVA and Bonferroni post hoc tests., Results: Overall, The Specially Designed Paste Carrier technique showed a statistically significantly higher mean radiodensity than the two other compared techniques. No significant difference was detected between the Syringe-Lentulo spiral and the Syringe-Spreader techniques., Conclusion: The Specially Designed Paste Carrier technique was more effective than the Syringe-Spreader technique and the Syringe-Lentulo spiral technique in the intracanal placement of calcium hydroxide.

Background: Venous thrombotic events (VTE) occur at high ratesin HIV/AIDS patients and are likely under-diagnosed in rural sub-Saharan Africa., Objective: To describe clinical presentations and challenges in the management of VTE in patients with advanced HIV/AIDS., Design: Case series from patients enrolled in a prospective observational cohort study., Settings: A clinical research centre in rural Kericho, Kenya., Subjects: Two hundred patients with median age 38 (30-47) years, BMI 16.9 (12.4-20.3) kg/m2, haemoglobin 9.3 (6.8-13.4) g/dL, CD4+ T-cell count 27 (4-77) cells/mm and plasma HIV RNA 5.23 (3.70-5.88) log10 copies/mL., Interventions: VTE cases were diagnosed by clinical presentation and Doppler/ radiographic confirmation. Anti-coagulation therapy was managed by a multidisciplinary team; patients were initiated on enoxaparin or heparin followed by warfarin., Results: Over two years,11patients (5.5%) experienced VTE. All but one (10/11,90.9%) case occurred within six months of starting ART. Nine patients had peripheral VTE (five popliteal, four femoral) and two had cerebral sinus thromboses. VTE was diagnosed 52 (1-469) days after ART initiation, and 81.8% of cases were outpatients at presentation. All patients received at least one concomitant medication that could significantly interact with warfarin (efavirenz, nevirapine, lopinavir/ritonavir, rifampicin, trimethoprim-sulfamethoxazole, and fluconazole). A median of 39 (10-180) days and eight (4-22) additional clinic visits were required to achieve/maintain a therapeutic INR of 2-3. Two minor bleeding complications occurred. No recurrent VTE cases were observed., Conclusion: Consideration of VTE and preparedness for management in patients with advanced HIV/AIDS starting ART is critical in sub-Saharan Africa. Overcoming challenges in anti-coagulation is possible in rural settings using a multidisciplinary team approach.

Objective: To identify an alternative inhaled corticosteroid to fluticasone propionate that can be safely coadministered with HIV protease inhibitors, the safety and pharmacokinetics of beclomethasone dipropionate (BDP) and its active metabolite, beclomethasone 17-monopropionate (17-BMP), in combination with ritonavir (RTV) and darunavir/ritonavir (DRV/r) were assessed., Design: Open-label, prospective, randomized pharmacokinetic and pharmacodynamic study in healthy volunteers., Methods: Thirty healthy volunteers received inhaled 160 μg bid BDP for 14 days and were then randomized (1:1:1) into 3 groups: group 1 (control) remained on BDP alone for 28 days, group 2 received 100 mg bid BDP + RTV for 28 days, and group 3 received 600/100 mg bid BDP + DRV/r for 28 days. Pharmacokinetic sampling for 17-BMP was performed on days 14 and 28, and pharmacokinetic parameter values were compared within patients and between groups. Cortisol stimulation testing was also performed on days 1, 14, 28, and 42 and compared within and between groups., Results: Geometric mean ratios (day 28:day 14) (90% confidence interval) for 17-BMP area under the concentration-time curve in groups 1, 2, and 3, respectively, were 0.93 (0.81 to 1.06, P = 0.27), 2.08 (1.52 to 2.65, P = 0.006), and 0.89 (0.68 to 1.09, P = 0.61). There were no significant reductions in serum cortisol levels within or between groups (P > 0.05)., Conclusions: DRV/r did not increase 17-BMP exposure, whereas RTV alone produced a statistically significant but clinically inconsequential 2-fold increase in 17-BMP exposure. Adrenal suppression was not observed in any of the study groups. These data suggest that BDP can be safely coadministered with DRV/r and likely other RTV-boosted protease inhibitors.

Current product labels for maraviroc and raltegravir provide no dosing guidance for patients with end-stage liver disease and worsening renal function. We describe a 41-year-old man with human immunodeficiency virus (HIV) infection and rapidly progressive liver failure and vanishing bile duct syndrome at presentation. Despite discontinuation of all potential offending drugs, the patient's liver function continued to deteriorate. To achieve and maintain HIV suppression while awaiting liver transplantation, a regimen consisting of maraviroc, raltegravir, and enfuvirtide was started. These agents were chosen because the patient was not exposed to them before the onset of liver failure. While receiving product label-recommended twice-daily dosing of these drugs, he achieved and maintained HIV suppression. During a complicated and prolonged hospitalization, the patient also developed renal dysfunction. As hepatic metabolism is the primary route of clearance of maraviroc and raltegravir, we predicted that using approved doses of these drugs could result in significant drug accumulation. Since the safety profiles of supratherapeutic concentrations of these agents are not well defined, we chose to use therapeutic drug monitoring to guide further dosing. The reported concentrations showed severely impaired metabolic clearance of both drugs, with markedly prolonged elimination half-lives of 189 hours for maraviroc and 61 hours for raltegravir. Previously reported half-lives for maraviroc and raltegravir in HIV-infected patients with normal hepatic and renal function are 14-18 hours and 9-12 hours, respectively. Based on these results, the dosing intervals were extended from twice/day to twice/week for maraviroc and every 48 hours for raltegravir. Unfortunately, the patient's clinical condition continued to deteriorate, and he eventually died of complications related to end-stage liver disease. This case illustrates the difficulties in managing antiretroviral therapy in an HIV-infected patient with combined severe liver and renal failure. Prolonged excessively high exposure to maraviroc and raltegravir is likely to result in some level of concentration-dependent toxicity. Until more data are available, therapeutic drug monitoring remains the only evidence-based approach to optimize dosage selection of these drugs in this patient population., (© 2012, Pharmacotherapy Publications, Inc.)

Nonnucleoside reverse transcriptase inhibitor-drug resistance mutations (DRM) are increasingly reported in Africans failing their first antiretroviral regimen. The Phidisa II trial randomized treatment-naive participants to lopinavir/ritonavir or efavirenz with stavudine + lamivudine or zidovudine + didanosine. We report the prevalence of DRM in subjects who achieved HIV RNA <400 copies per milliliter at 6 months, but subsequently had 2 consecutive HIV RNA >1000 copies per milliliter. Sixty-eight participants fulfilled the inclusion criteria. nonnucleoside reverse transcriptase inhibitor-DRM were found in 17 of 36 (47.2%) efavirenz recipients, and M184V/I mutation in 14 of 40 (35.0%) lamivudine recipients. No protease inhibitor mutation was identified in 38 lopinavir/ritonavir recipients. This is one of the first studies in Africa confirming the paucity of protease inhibitor-associated DRM despite virologic failure.

Study Objective: To evaluate the effect of a previous single dose of nevirapine given to prevent mother-to-child transmission of human immunodeficiency virus (HIV) on virologic and immunologic measures after months of an antiretroviral regimen containing either efavirenz or lopinavir-ritonavir., Design: Retrospective subgroup analysis of data from the Phidisa II trial., Setting: Six South African research clinics. Patients. A total of 394 women with HIV who completed 6 months of combination antiretroviral regimen containing either efavirenz or lopinavirritonavir as part of the Phidisa II trial., Measurements and Main Results: During the screening process for the Phidisa II study, 478 women were asked about previous nevirapine use: 392 women (82%) were nevirapine naïve, and 86 (18%) had received nevirapine. During the study, patients received either an efavirenz-based or lopinavir-ritonavir- based antiretroviral regimen. After 6 months of treatment, virologic (HIV RNA levels) and immunologic (CD4(+) cell count) responses were measured. These data were compared between women with or without previous nevirapine exposure, and between women who received efavirenz versus lopinavirritonavir. After 6 months of treatment, 394 women (324 nevirapine naïve, 70 exposed to nevirapine) had follow-up HIV RNA results. Two hundred twenty-seven (70.1%) of the nevirapine-naïve patients and 48 (68.6%) of the nevirapine-exposed patients achieved HIV RNA levels lower than 400 copies/ml (p=0.89), with CD4(+) cell count increases of 115.5 and 120.4 cells/mm(3), respectively (p=0. 7). Among the nevirapine-exposed women, 27 (75%) of 36 efavirenz-treated and 21 (61.8%) of 34 lopinavir-ritonavir-treated patients had HIV RNA levels lower than 400 copies/ml at months (p=0.31)., Conclusion: In this retrospective analysis of a small cohort, previous exposure to a single dose of nevirapine did not affect virologic outcomes after 6 months of either an efavirenz-based or lopinavir-ritonavir-based antiretroviral regimen. As efavirenz is one of the first-line combination antiretroviral therapies administered in Africa, it remains an option for women who received single-dose nevirapine.

Here, we describe an HIV-infected patient with pretreatment resistance to raltegravir, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors, and the ultimate ability to achieve viral suppression. Pretreatment integrase resistance testing is not routinely performed because transmitted integrase mutations conferring resistance to raltegravir are currently thought to be negligible. We suggest obtaining a pretreatment integrase genotype in patients with transmitted multiclass drug resistance in order to create an optimal first regimen and increase the chance for virological suppression.

Combination antiretroviral therapy (cART) has improved survival rates in HIV-infected patients; however, patients now experience comorbidities that require pharmacological intervention, thereby increasing the risk of drug-drug interactions (DDIs). HIV protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and the CCR5 antagonist maraviroc are primarily metabolized via the cytochrome P450 (CYP) system and are prone to pharmacokinetic interactions.(1,2) This article addresses some key challenges that prescribers face when using available drug interaction-data resources in making day-to-day clinical decisions.

We report the first case of a human immunodeficiency virus type 1 (HIV-1)-infected individual receiving combination antiretroviral therapy, which included ritonavir, who developed Cushing syndrome with profound complications after epidural triamcinolone injections. This case highlights the potential of ritonavir interactions even with local injections of a corticosteroid.

Purpose of Review: Combination antiretroviral therapy has improved the morbidity and mortality of HIV-infected patients worldwide. As patients live longer, management of HIV infection extends to treatment of a wide spectrum of co-morbid conditions. Pharmacokinetic interactions are common among antiretroviral drugs when they are used in combination and along with treatments for other conditions. This review discusses the clinical significance of drug interactions among antiretroviral drugs and other medications, resources to use in assessing drug interaction potential, and some key principles to follow when managing patients prescribed potentially interacting drugs., Recent Findings: Targeted pharmacokinetic drug interaction studies and extrapolations on the basis of potential mechanism of interactions provide an initial basis for recommendations regarding use of certain drug combinations. Some unexpected interactions have emerged in the literature through case reports in which untoward effects were observed., Summary: Management of patients on multiple drug therapy can be a challenge. The key to safe and effective therapy relies on the clinician's vigilance in their ongoing assessment of interaction potential among drugs prescribed to each patient, the significance for such interactions, the need for modification to therapy, and close follow up to assess safety and toxicity.

Unlabelled: The literature on concurrent tobacco (CCT) use, i.e., regularly using both smoked and chewed tobacco, is sparse., Objectives: This study aims to establish the point prevalence of CCT use in a randomly selected sample of UK-resident Bangladeshi males, compare CCT users with other tobacco users (smokers alone and chewers alone), and model the factors for CCT use and chewing tobacco use alone., Methods: A cross-sectional bilingual interview survey collecting data on age, marital status, social class, employment status, home ownership and overcrowding, self-assessed health and chronic illness episodes, social capital, nicotine dependence, and oral pain was used. Carbon monoxide readings validated smoked tobacco use. Logistic regressions were used for data analysis., Results: The initial response rate was 59 percent. Sample mean age was 40.7 years. CCT prevalence was estimated at 22 percent, practiced by older respondents of limited educational status. CCT users more likely had only average or poor self-rated health and more likely reported current oral pain compared with tobacco smokers. A wife chewing tobacco distinguished CCT users, as compared with tobacco smokers alone., Conclusions: In this sample of adult Bangladeshi males, CCT use was prevalent. CCT users more likely had a partner who was also a tobacco chewer, as compared with tobacco smokers.

HIV/hepatitis C virus (HCV)-coinfected individuals have accelerated liver disease, increased drug toxicities, and modest responses to peginterferon and ribavirin. Hematologic toxicities necessitating dose reduction or discontinuation are limiting factors to HCV treatment in the coinfected patient. This study aimed to identify predictors for the need of filgrastim and darbepoetin to manage hematologic toxicities so as to maintain patients on full doses of study drugs for the duration of study. The primary study was a single-center, open-label, prospective study to evaluate the safety, efficacy, and viral kinetics of 48-week peginterferon alfa 2b and ribavirin in HIV/HCV-coinfected patients. Complete blood count was monitored at baseline, days 3, 7, 10, 14, and then weekly for the first month, fortnightly until week 8, then monthly from week 12 to 48. Filgrastim was initiated when absolute neutrophil count (ANC) fell below 750 cells/mm(3) and darbepoetin was used when hemoglobin dropped to less than 10 g/dL. All patients experienced decrease in ANC and hemoglobin. Twenty of 30 (66.6%) of patients required hematopoeitic growth factors, 15 (50%) received filgrastim, and 12 (40%) received darbepoetin. Seven (23.3%) required both. Baseline ANC of less than 2250 cells per millimeter and negative rate of change of hemoglobin on day 3 of therapy were excellent predictors for filgrastim and darbepoetin use, respectively. Supplemental growth factors were associated with substantial increase in overall cost for HCV treatment. Larger clinical trials will be needed to address the cost effectiveness of supplemental growth factor use in the HIV/HCV-coinfected patients.

WHO recommends lopinavir/ritonavir as an antiretroviral option in resource-limited countries. Lopinavir/ritonavir is recommended to be stored at 2-8 degrees C until dispensing, and afterwards, may be kept at < or = 25 degrees C for < or = 2 months. Anticipating lopinavir/ritonavir use in countries lacking adequate cold-chains, we assessed its physical and chemical stability at 35 and 45 degrees C. Although maintaining chemical stability for 4 weeks at 35 degrees C, at 45 degrees C the capsules clumped after 7 days, supporting a need for more temperature-stable formulations for hotter climates.

Although it has not been demonstrated yet, phenytoin is expected to reduce efavirenz exposure through coinduction of cytochrome P450 (CYP) 3A4 and CYP2B6. Conversely, efavirenz has been shown in vitro to inhibit the enzymes responsible for phenytoin metabolism, CYP2C9 and CYP2C19. We report a case in which a potential bidirectional drug interaction between phenytoin and efavirenz resulted in lower-than-expected efavirenz concentrations and elevated phenytoin levels. Therapeutic drug monitoring was used in this case to ensure adequate efavirenz exposure.

The availability of antiretroviral therapy has significantly reduced the morbidity and mortality of HIV infection. In addition, improved treatment of opportunistic infections and comorbidities common to patients with HIV is further prolonging the lives of patients. Improvement in the treatment of HIV has led to a significant increase in the number of medications which caregivers are able to utilise to manage HIV/AIDS. Antiretroviral medications, as well as many of the drugs used in the management of opportunistic infections and primary care (e.g., macrolide antibiotics, azole antifungals, cholesterol-lowering medications), are particularly prone to drug interactions. The interpretation of clinically significant interactions is complicated by the rate at which new information on drug metabolism and transport is becoming available. Management of drug interactions in HIV is further confounded by conflicting study results and differences between documented and theoretical inter-actions. The mechanisms and significance of interactions involving antiretrovirals, drugs used for opportunistic infections, and other medications commonly used in HIV patients will be reviewed.

Objective: To explore how dental undergraduates with different levels of emotional intelligence (EI) cope with stress., Design: Qualitative unstructured depth interviews., Setting: A dental teaching hospital in the UK, 2002., Subjects and Methods: Subjects selected from the undergraduate population of a 5-year dental degree course. A questionnaire survey was carried out to determine the EI scores of the subjects. In each year of study, subjects were divided into low and high EI groups at the median score. From each EI group in each year, one male and one female subject were recruited., Data Collection: Unstructured face-to-face interviews., Data Analysis: Transcribing, sifting, indexing and charting data according to key themes., Results: 10 males and 10 females with low and high EI, representing all 5 years of study were interviewed. The experience of stress, expressed in emotional terms, ranged from anger and frustration to hatred. Four sets of coping strategies, adopted at varying degrees according to EI, were identified. High EI students were more likely to adopt reflection and appraisal, social and interpersonal, and organisation and time-management skills. Low EI students were more likely to engage in health-damaging behaviours., Conclusions: Future research needs to establish whether the enhancement of EI in dental students would lead to improved stress-coping, and better physical and psychological health.

The pharmacokinetics of 2,000 mg of sulfadiazine administered twice daily (BID) versus those of 1,000 mg administered four times a day were compared in eight human immunodeficiency virus-infected patients. No differences in pharmacokinetic parameters were detected between the regimens. These data provide a pharmacokinetic rationale for BID dosing of sulfadiazine for the treatment and suppression of toxoplasmosis.

In the late 1980s and early 1990s, when HIV/AIDS had become the leading cause of death in 25- to 44-year-old persons in the United States, it was acceptable to prescribe newer antiretroviral therapy such as zidovudine, which has significant bone marrow toxicities but can potentially improve patient survival. Although current antiretroviral therapy is not likely to eradicate HIV-1 infection, the advances in the use of combination antiretroviral therapy (including protease inhibitors and non-nucleoside reverse transcriptase inhibitors) have dramatically improved the overall survival, immune status, and productivity of HIV-infected individuals in developed countries. Instead of prevention and treatment of HIV-associated complications, many of the patients" clinic visits are focused on finding strategies to manage and prevent antiretroviral therapy-associated complications. Because only a few HIV-infected persons fulfilling stringent inclusion criteria were included in premarketing clinical trials and because the US Food and Drug Administration"s (FDA) accelerated approval process for antiretroviral therapy requires only 24-week safety and efficacy data, newly emerging and previously unrecognized adverse effects of antiretroviral therapy continue to surface when these drugs are administered to a larger patient population for a longer duration. Unfortunately, some of these adverse effects can be unpredictable and serious, and, if not recognized early and managed aggressively, can lead to fatality. This article reviews four of the most serious, life-threatening toxicities associated with antiretroviral therapy.

Objectives: The study objectives were to assess the oral health status of a sample of UK resident Bangladeshi women tobacco-in-paan users and its relationship to participant age and number of daily paan, to determine the prevalence of oral pain at baseline and at the one-week postcessation follow-up, and to explore the relationship between oral health status and changes in self-reported oral pain at baseline and at the one-week postcessation follow-up., Methods: Interviews were conducted in Sylheti using fully structured questionnaires and an oral examination was carried out. A quit date was set and nicotine replacement therapy patches (Nicorette 15 mg, Pfizer) were supplied. Age, number of daily paan, and oral pain characteristics, including intensity, frequency, any provoking factors, and associated symptoms were recorded. Oral mucosal lesions (OMLs) and numbers of teeth decayed, missing, filled, and those with recession, abrasion, loss of attachment (LOA), and tooth wear were charted., Results: Fifty-two women took part. The mean age was 42.8 years and number of daily paan with tobacco was 13. Compared to those aged 18-39 years, those aged 40 years and older had poorer oral health. Older adults were significantly more likely to have higher numbers of teeth with recession, abrasion, and LOA greater than 3.5 mm. They were significantly more likely to have an OML at baseline. The prevalence of self-reported oral pain was 26.9 percent at baseline and 51.9 percent at one-week follow-up. Presence of an OML at baseline was a significant predictor of reports of oral pain at the one-week follow-up. Results of stepwise multiple regression analysis confirmed this finding (OR = 3.66; 95% CI = 1.06, 12.621; P = .04)., Conclusions: Reports of oral pain at follow-up during a tobacco cessation program correlate with the presence of OMLs at baseline. Further investigation of this relationship is needed. Access to appropriate dental care, as an aid to successful tobacco cessation, is indicated.

This study investigated the relationship between emotional intelligence (EI) and perceived stress (PS) in dental undergraduates. All dental undergraduates attending a UK dental school were invited to complete a questionnaire on age, gender, year of study, EI, and PS. Two hundred and thirteen students (48 percent male) participated, a response rate of 70 percent. The mean score for EI was 117.54 (S.D. 14.90) and PS was 17.73 (S.D. 6.49). Factor analysis confirmed four factors previously identified in the literature as comprising emotional intelligence: optimism/mood regulation, utilization of emotions, appraisal of emotions, and social skills. T-tests indicated that females had significantly higher EI scores than males. Mean PS scores were significantly higher for students aged over twenty-one years compared with those aged twenty-one years or less (p < 0.001), female compared to male students (p < 0.05), and those in higher years compared to those in lower years of study (p < 0.001). Correlational analysis showed an inverse relationship between EI and PS. Multiple regression analysis identified year of study, optimism/mood regulation, and gender as independent, significant predictors of PS. In conclusion, low EI scorers report more PS. Future research should investigate the relationships of EI and PS with impact on lifestyle behaviors, academic and clinical performance, and health outcomes.

Objectives: To investigate dental students' perception as to whether PBL can facilitate the development of professional attributes., Design: A cross-sectional survey of second year dental undergraduates in a UK dental school., Method: At the end of a PBL module, all students were asked to complete a fully structured questionnaire. Data were collected on socio-demographics, aspects of the PBL experience and the extent to which students perceived that PBL had facilitated the development of professional attributes., Results: The response rate was 96%. The frequency distributions of the PBL experience and development of professional attributes were skewed to the positive. Non-white students, compared to white students, rated significantly more highly the extent to which they thought PBL had facilitated the development of professional attributes. Differences between male and female students, and mature and less mature students were not significant. Students who rated the PBL experience positively were significantly more likely to rate highly the extent to which they thought PBL had facilitated the development of professional attributes., Conclusions: The factors that affect the relationship between ethnicity and development of professional attributes need further research. To enhance the development of professional attributes, teachers of PBL need to ensure that students find the learning experience worthwhile and stimulating.

This study reports the experience of oral pain and psychological distress following tobacco cessation in Bangladeshi women. A cross-sectional survey was carried out in which telephone interviews were conducted in the Sylheti language by two female Bangladeshi researchers using structured questionnaires. Study participants were 58 Bangladeshi women, aged 22-60 years, who had recently given up chewing paan-with-tobacco. The General Health Questionnaire (GHQ-12) was used to measure psychological distress. A questionnaire on pain description, location, duration, onset, and intensity also was administered. Logistic regression analysis was carried out to explore the relationships between psychological distress and age, chewing characteristics, and the oral pain experience. The response rate was 100%. Of the sample, 22% reported having pain for 2 days and 28% for at least 1 week, 65% reported that the pain started by itself, 69% reported the intensity as mild or discomforting, and 52% experienced psychological distress. Significant predictors for high psychological distress were number of daily paan (odds ratio, OR=1.13), current tooth problem (OR=4.60), pounding pain (OR=6.50), pain onset (OR=3.21), and pain intensity (OR=5.57). The prevalence of oral pain reported for Bangladeshi women following an attempt at chewing tobacco cessation is high. Characteristics of this outcome suggest the pain is of dental origin. These characteristics are correlated to psychological distress. The success of chewing tobacco cessation initiatives in the population may be influenced by oral pain and psychological distress. Further research is needed to explore the etiological factors associated with oral pain in this group of tobacco users.

Purpose: To assess the methodological quality of epidemiological studies on dental pain and review the published literature for its prevalence, and association with age, gender and socio-economic status., Materials and Methods: Medline and reference lists of relevant articles were searched for observational studies published in English from 1966 to 2001 carried out on humans aged 19 years and over. Articles for reading of the full text were selected by two reviewers independently. Selected articles were assessed independently by the two reviewers according to a set of 8 standardized criteria. Inter-rater agreement was measured using the kappa statistic. Disagreements were discussed and a final score for each study agreed. Data on prevalence estimates and their distribution by age, gender and socio-economic factors were extracted., Results: 422 studies were identified, and 23 selected for review. Inter-rater agreement was high for all 8 criteria used (kappa > 0.6). Methodological quality was poor with the number of criteria fulfilled by each study ranging from 1 to 6, median score 3. The prevalence estimates for 5 case definitions identified were: 'toothache' 7-32%, 'pain in teeth with hot, cold or sweet things' 25-38%, 'pain and discomfort needing medication or treatment' 7-9%, 'pain or discomfort in the mouth, teeth or gums' 19-66%, and 'oral and facial pain'40-44%. Younger subjects and those from lower socio-economic groups were more likely to report pain. Gender was not associated with dental pain., Conclusion: Epidemiological data on dental pain are sparse and of poor quality. There is a need for well-designed surveys using randomly selected community samples and standardized measurement criteria to fill this knowledge gap.

Highly active antiretroviral therapy has improved the morbidity and survival of patients with the human immunodeficiency virus (HIV) infection. Currently available antiretroviral agents can suppress viral replication and partially reverse cellular immunity defects in HIV patients. Immune-based therapy with interleukin-2 when used as adjunctive therapy to antiretroviral therapy may further improve immune responses, as demonstrated by an increase in CD4(+) T-lymphocyte counts in recent clinical trials.

Objectives: To report the feedback from general dental practitioners (GDPs) and dental undergraduates who participated in a general dental practice placement scheme., Methods: Subjects All 61 students in a year made 2 to 3 full day visits, individually or in pairs, to 44 general dental practices allocated to them. Thirty four GDPs completed and returned the questionnaire, representing a response rate of 77%. Data collection Formal feedback from the students and GDPs were obtained through 6 structured seminar sessions and a postal questionnaire respectively. Analysis Sifting, indexing and charting the data according to key issues and themes., Results: All 61 students attended the feedback sessions, 34 GDPs (response rate 77%) returned the questionnaire. The two most common themes that students reported having gained insight into were personal/professional development and practice management. The common positive aspects reported by the GDPs included exposure to the General Dental Service (GDS), motivation for undergraduate training and benefits for GDPs. These benefits included encouragement for the GDPs to reflect critically on their clinical practice, focus on their practice facilities and management, and stay in touch with developments in dental education. Through their visits and assignments, students gained skills in observation, interviewing, communication, relation-building and report writing., Conclusions: Placements of dental undergraduates in general dental practices enable students to gain insight into the GDS, develop key transferable skills and undergo professional socialisation. They are also beneficial and enjoyable for the GDPs who participated.

Aims: To explore the subjective experience of a sample of patients attending a dental teaching hospital emergency clinic with toothache., Materials and Methods: Subjects 21 female and 14 male dental patients, of different ages, marital status, employment status and levels of education, presenting with toothache at a dental teaching hospital emergency clinic. Data collection Unstructured in-depth interviews, following a topic guide. Analysis Transcribing, sifting, indexing and charting data according to key issues and themes., Findings: A dimension of toothache pain that emerged was the perceived inability to cope. Patients reported a dependency on a dentist or other person to alleviate their pain, suggesting connotations of helplessness, disempowerment and incapacitation. The perceived inability to cope was also expressed in terms of loss of control, despair and isolation. A number of care-seeking patterns for toothache was identified: repeated visits to the same dentist for emergency care, repeated visits to different dentists, attendance at the dental hospital emergency clinic and consulting non-dental health workers such as doctors and pharmacists., Conclusions: The perceived inability to cope and care-seeking patterns are two unexplored dimensions of the toothache pain experience. Both dimensions may be associated with pain intensity, the clinical conditions that manifest as toothache, quality of treatment provided and management of demand for emergency dental care. A conceptual framework is proposed for future research to investigate these relationships.