Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study

OBJECTIVES: Efavirenz is an effective antiretroviral agent, but central nervous system side effects occur commonly, and population (racial) differences in pharmacokinetics and response have been reported. Efavirenz is metabolized by cytochrome P4502B6 (CYP2B6). We investigated whether polymorphisms in CYP2B6, CYP3A4, CYP3A5, and MDR1 were associated with efavirenz central nervous system side effects and pharmacokinetics. DESIGN: Twenty-four week cohort from a randomized study. METHODS: Adult AIDS Clinical Trials Group study A5097s examined relationships between central nervous system side effects and efavirenz plasma concentration-time profiles in HIV-infected subjects. Efavirenz plasma pharmacokinetics were estimated by a population-based method. Central nervous system symptoms were assessed by questionnaires and neuropsychological testing. RESULTS: Study subjects included 89 (57%) European-Americans, 50 (32%) African-Americans, and 15 (10%) Hispanics. The CYP2B6 T/T genotype at position 516 (GlnHis) was more common in African-Americans (20%) than in European-Americans (3%), and was associated with greater efavirenz plasma exposure (P < 0.0001). The median efavirenz [area-under-the-curve] (0-24 h) according to G/G, G/T, and T/T genotype was 44 (n = 78), 60 (n = 60), and 130 (n = 14) mug.h/ml, respectively (P < 0.0001). The CYP2B6 G516T genotype was also associated with central nervous system symptoms at week 1 (P = 0.036). Analysis of DNA from other subjects confirmed population differences in frequency of the G516T variant. No associations were apparent with the other polymorphisms studied. CONCLUSIONS: A CYP2B6 allelic variant that is more common in African-Americans than in Europeans-Americans was associated with significantly greater efavirenz plasma exposure during HIV therapy. Inter-individual differences in metabolism may, in part, explain susceptibility to efavirenz central nervous system side effects.     

Virologic and CD4+ cell responses to new nucleoside regimens: switching to stavudine or adding lamivudine after prolonged zidovudine treatment of human immunodeficiency virus infection. ACTG 302 Study Team. AIDS Clinical Trials Group

Clinical benefit of zidovudine alone in the treatment of HIV infection wanes after several years, with decreasing CD4+ cell numbers and increasing HIV RNA in plasma. To develop treatment strategies following prolonged zidovudine treatment, 92 subjects from the AIDS Clinical Trials Group (ACTG) 175 study after a median of 3.6 years of zidovudine monotherapy were randomized to treatment with stavudine or zidovudine and lamivudine. Evaluation of long-term changes, the average of 40- and 48-week HIV plasma RNA, demonstrated that lamivudine and zidovudine provided significantly greater virologic suppression compared with stavudine (mean decrease 0.70 versus 0.18 1og10 copies/ml,p = 0.003). Twenty-nine percent of zidovudine plus lamivudine recipients had HIV RNA levels below 500 copies per milliliter at 48 weeks as compared with 4% of stavudine recipients (p = 0.02). Both regimens significantly increased CD4+ cell numbers, the means of weeks 40 and 48 rose to 49 and 36 CD4+ cells per cubic millimeter among zidovudine plus lamivudine and stavudine recipients, respectively. Treatments were well tolerated and only 3 of 92 subjects died or developed AIDS within 48 weeks. In zidovudine-experienced subjects, addition of lamivudine resulted in significantly decreased plasma HIV RNA levels at 48 weeks compared with treatment with stavudine alone.     

Influence of prior antiretroviral experience on adherence and responses to new highly active antiretroviral therapy regimens

The impact of prior antiretroviral experience on adherence and clinical outcomes in patients initiating a new highly active antiretroviral therapy (HAART) regimen is not well defined. We performed an observational cohort analysis of antiretroviral-experienced or -naive HIV-infected patients prescribed a new HAART regimen (3538 patients) and enrolled in Kaiser Permanente Northern California from 1997 through 2002. Outcomes evaluated were HAART adherence and changes in HIV RNA level and CD4 T-cell counts over 12 and 24 months. The antiretroviral-naive group had a significantly greater odds of achieving >/=95% adherence to the HAART regimen over 12 months (adjusted odds ratio [OR] = 1.88, p < 0.001) and over 24 months (OR = 1.66, p < 0.001). The odds of achieving HIV RNA levels below limits of quantification also was higher among patients who were antiretroviral naive; over 24 months OR = 6.88, p < 0.001. Adjusted change in CD4 T-cell count was also greater among naive patients over 24 months (+67 cells/muL, p < 0.001), compared to antiretroviral-experienced patients. Years of antiretroviral experience did not affect adherence or any outcome measure. Adjusting for HAART adherence did not significantly affect HIV RNA results but did lessen CD4 T-cell count differences between antiretroviral-naive and -experienced patients. Thus, antiretroviral naive patients have improved HAART adherence, HIV RNA control, and CD4 T-cell count increases compared to antiretroviral-experienced patients regardless of years of antiretroviral experience. These findings should help direct HAART adherence efforts in HIV care clinics.     

Immunogenetics of CD4 lymphocyte count recovery during antiretroviral therapy: An AIDS Clinical Trials Group study

During antiretroviral therapy, CD4 lymphocyte count increases are modest in some patients despite virologic control. We explored whether polymorphisms in genes important for T cell expansion, survival, and apoptosis are associated with the magnitude of CD4 lymphocyte count recovery during antiretroviral therapy. We studied treatment-naive individuals who achieved sustained control of plasma viremia (<400 HIV-1 RNA copies/mL) for at least 48 weeks after initiation of antiretroviral therapy and compared genotypes among individuals who had an increase of either <200 or > or =200 CD4 cells/mm3 from baseline. A total of 137 single-nucleotide polymorphisms across 17 genes were characterized in 873 study participants. In multivariate analyses that controlled for clinical variables, polymorphisms in genes encoding tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), TNF- alpha , Bcl-2-interacting molecule (Bim), interleukin (IL)-15, and IL-15 receptor alpha chain (IL-15R alpha ) were associated with the magnitude of the increase in CD4 lymphocyte count, as were haplotypes in genes encoding interferon- alpha , IL-2, and IL-15R alpha (P < .05, for each). Multifactor dimensionality reduction identified a gene-gene interaction between IL-2/IL-15 receptor common beta chain and IL-2/IL-7/IL-15 receptor common gamma chain. Immune recovery during antiretroviral therapy is a complex phenotype that is influenced by multiple genetic variants. Future studies should validate these tentative associations and define underlying mechanisms.     

Self-reported adherence to antiretroviral medications among participants in HIV clinical trials: the AACTG adherence instruments. Patient Care Committee & Adherence Working Group of the Outcomes Committee of the Adult AIDS Clinical Trials Group (AACTG)

This paper describes the AACTG Adherence Instruments, which are comprised of two self-report questionnaires for use in clinical trials conducted by the Adult AIDS Clinical Trials Group (AACTG). The questionnaires were administered to 75 patients at ten AACTG sites in the USA. All patients were taking combination antiretroviral therapy (ART), including at least one protease inhibitor. Eleven per cent of patients reported missing at least one dose the day before the interview, and 17% reported missing at least one dose during the two days prior. The most common reasons for missing medications included 'simply forgot' (66%) and a number of factors often associated with improved health, including being busy (53%), away from home (57%) and changes in routine (51%). Less adherent patients reported lower adherence self-efficacy (p = 0.006) and were less sure of the link between non-adherence and the development of drug resistance (p = 0.009). They were also more likely to consume alcohol, to be employed outside the home for pay and to have enrolled in clinical trials to gain access to drugs (all p < 0.05). Twenty-two per cent of patients taking drugs requiring special instructions were unaware of these instructions. Each questionnaire took approximately ten minutes to complete. Responses to the questionnaires were favourable. These questionnaires have been included in six AACTG clinical trials to date and have been widely disseminated to investigators both in the USA and abroad.     

基于国产司他夫定和齐多夫定的抗HIV治疗优化方案的探索

目的探索基于国产仿制高效抗反转录病毒治疗药物司他夫定（D4T）胶囊、齐多夫定（AZT）片为初始治疗方案的优化治疗策略,以达到良好的治疗效果,降低药物不良反应发生率,合理地使用国产仿制药物,最终能长期可持续的治疗。方法选择75例无机会性感染的、CD4＋T淋巴细胞〈350×106/L的、完成96周随访的艾滋病病毒（HIV）感染者/艾滋病（AIDS）患者,随机分为A组27例,服用D4T＋拉米夫定（3TC）＋奈韦拉平（NVP）/依非韦伦（EFV））;B组27例,服用AZT＋3TC＋NVP/EFV;C组21例,前24周服用D4T＋3TC＋NVP/EFV,24周后服用AZT＋3TC＋NVP/EFV。观察3组的治疗效果及D4T、AZT的不良反应发生规律。结果治疗96周前后,A组患者的CD4＋T淋巴细胞计数中位数分别是219（15～332）×106/L和420（203～635）×106/L,B组分别为224（28～332）×106/L和366（178～724）×106/L,C组分别为153（19～350）×106/L和411（95～728）×106/L。A、B、C 3组患者血浆HIV RNA〈40拷贝/mL的比率分别为92.6%、96.3%、100%。A组D4T的不良反应发生率高达81.5%,主要发生在治疗36周之后;B组AZT的不良反应发生率高达48.2%,主要发生在治疗前12周内;C组在服用D4T24周后改服AZT,D4T的不良反应发生率为0,AZT的相关不良反应发生率为9.5%,明显低于A组（P〈0.05）和B组（P〈0.05）。结论 D4T治疗24周后更换为AZT的优化方案与长期服用D4T或AZT方案,均能获得满意的治疗效果,但不良反应发生概率优化方案明显低于长期D4T或AZT方案治疗者,可做为目前国产仿制药物初始治疗的优化方案。     

Changes in human immunodeficiency virus type 1 virus load during mobilization and harvesting of hemopoietic progenitor cells. Adult AIDS Clinical Trials Group 285 Study Team

Genetic modification of hemopoietic progenitor cells ex vivo, followed by the infusion of the genetically modified cells into the human immunodeficiency virus-1 (HIV-1) infected donor, has been proposed as a treatment for HIV-1 infection. The current study was undertaken to evaluate the effect of hemopoietic stem cell mobilization and harvesting on HIV-1 replication in persons with HIV-1 infection. Eighteen HIV-1-infected persons received recombinant granulocyte colony-stimulating factor (G-CSF; Filgrastim) 10 microg/kg per day, for 7 days. On days 4 and 5, peripheral blood mononuclear cells were harvested by leukapheresis. The CD4+ lymphocyte count at entry was >500/microL for 6 subjects, 200 to 500/microL for 6 subjects, and <200/microL for 6 subjects. For 9 of 18 subjects, plasma HIV-1 RNA levels increased 4- to 100-fold (>0.6 log(10)) above baseline between days 4 and 7 and returned to baseline by day 27. Significant increases of plasma HIV-1 RNA levels occurred in 5 subjects despite 3-drug antiretroviral therapy. Changes in CD4+ and CD34+ cells during mobilization and harvesting were similar in all subjects whether they had or did not have increased plasma HIV-1 RNA levels. Thus, mobilization and harvesting of bone marrow progenitor cells from persons infected with HIV-1 induced a transient increase in viral replication in some patients but was not associated with adverse effects. (Blood. 2000;95: 48-55)     

Immunization against influenza: comparison of various topical and parenteral regimens containing inactivated and/or live attenuated vaccines in healthy adults

Methods for enhancing immune responses to influenza were explored in 2 double-blind, placebo-controlled trials. Intranasal (inl) immunization with monovalent, live attenuated, cold-adapted recombinant (CR) or inactivated influenza virus (MIV) vaccine and intramuscular (im) immunization with MIV were evaluated in various combinations. Healthy susceptible adults were assigned randomly to receive 10(7.1) TCID(50) of CR (A/H1N1 or A/H3N2), homologous MIV (15 microg), or placebo inl and placebo or homologous MIV im (6 groups in each study). Serum antibody responses were greatest in groups given im vaccine (with or without inl vaccine). A 2-fold increase in nasal wash antibody response frequencies was seen in groups given combined inl (CR or MIV) and im vaccine, compared with subjects given a single im (MIV) or inl (CR or MIV) vaccine. Combined inl and im immunization is a promising approach for enhancing both local and systemic immune responses against influenza.     

Late presenters in the era of highly active antiretroviral therapy: uptake of and responses to antiretroviral therapy

OBJECTIVES: To investigate the characteristics and clinical, immunological and virological outcomes for individuals presenting for care with low CD4 cell counts. METHODS: Individuals aged > 16 years presenting for care for the first time were identified between 1 January 1996 and 31 December 2002. Late presenters were those with CD4 cell count < 50 x 10(6) cells/l. Follow-up was until last contact, death or 31 December 2002. RESULTS: Late presenters formed 15.3% (110) of the group; they were more likely to be female (35% versus 24%), heterosexual (53% versus 38%), and of Black-African ethnicity (39% versus 27%) than other individuals. Over a median follow-up of 2.5 years, 13% of late presenters died. Ninety-nine patients started antiretroviral treatment; Of the 11 patients who did not start antiretroviral treatment, eight died within 3 months of presentation. Among those starting treatment, 87 (87.9%) achieved a viral load < 400 copies/ml and median CD4 cell counts increased from 43 x 10(6) cells/l at 0-2 months after presentation to 204 x 10(6) cells/l at 1 year. Over the first year, 71 patients attended at least one outpatient visit (median, 4.5; range, 0-39), 21 attended at least one day case visit (median, 0; range, 0-15) and 49 were admitted as an inpatient (median, 0; range, 0-4). CONCLUSIONS: Those presenting for care with very low CD4 cell counts may make large demands on clinical resources, particularly over the first few months. While some patients do have a poor outcome on highly active antiretroviral therapy, many will benefit from this therapy and will experience good immunological and virological responses.     

Adaptive Design for Diabetes Clinical Trials: Operational Challenges and Solutions with Implementation of an Adaptive Seamless Phase 2/3 Study

A wide variety of operational issues were encountered with the planning and implementation of an adaptive, dose-finding, seamless phase 2/3 trial for a diabetes therapeutic. Compared with a conventional design, significant upfront planning was required, as well as earlier, more integrated cross-functional coordination. The existing infrastructure necessitated greater flexibility to meet the needs of the adaptive design. Rapid data acquisition, analysis, and reporting were essential to support the successful implementation of the adaptive algorithm. Drug supply for nine treatment arms had to be carefully managed across many sites worldwide. Details regarding these key operational challenges and others will be discussed along with resolutions taken to enable successful implementation of this adaptive, seamless trial.     

Patients’ Views About the Disclosure of Collateral Findings in Pragmatic Clinical Trials: a Focus Group Study

BackgroundPragmatic clinical trials (PCTs) are increasingly being conducted to efficiently generate evidence to inform healthcare decision-making. Despite their growing acceptance, PCTs may involve a variety of ethical issues, including the management of pragmatic clinical trial-collateral findings (PCT-CFs), that is, information that emerges in PCTs that is unrelated to the primary research questions but may have implications for patients, clinicians, and health systems.ObjectiveWe sought to understand patients’ views about PCT-CF disclosure, including how, by whom, and the nature and extent of information provided.DesignProspective, qualitative focus group study.ParticipantsFocus groups were conducted in Baltimore, MD; Houston, TX; and Seattle, WA (overall N = 66), during July and August 2019.ApproachAll groups discussed a hypothetical scenario involving the detection of a PCT-CF of contraindicated medications. Participants were asked about their reactions to the PCT-CF and issues related to its disclosure.Key ResultsReactions to learning about the PCT-CF were mixed, ranging from fear of a significant health problem, anger that the contraindicated medications had gone unnoticed and/or for being included in research without their permission, to gratitude for the information. Preferences for how such disclosures are made varied but were driven by several consistent desires, namely minimizing patient harm and anxiety and demonstrating trust and respect. Many wanted their treating clinician to be informed of the PCT-CF so that they would be prepared to answer patients’ questions and to discuss treatment options.ConclusionsThe detection of PCT-CFs is likely to increase with further expansion of PCTs. As such, clinicians will undoubtedly become involved in the management of PCT-CFs. Our data illustrate some of the challenges clinicians may face when their patients are informed of a PCT-CF and the need to develop guidance for disclosing PCT-CFs in ways that align with patients’ preferences and values.Electronic supplementary materialThe online version of this article (10.1007/s11606-020-06113-5) contains supplementary material, which is available to authorized users.KEY WORDS: pragmatic clinical trial, patient perspective, collateral finding     

T cell responses to recall antigens, alloantigen, and mitogen of HIV-infected patients receiving long-term combined antiretroviral therapy

The effect of highly active antiretroviral therapy (HAART) on T cell responses in 30 HIV-infected patients was studied. Lymphocyte proliferation in response to influenza A virus, HIV-1 p24, gp160, allogeneic leukocytes, and mitogen, as well as influenza-specific cytotoxic T lymphocyte (CTL) responses, were measured. AIDS patients had decreased T cell-proliferative responses to influenza and alloantigen compared with asymptomatic patients. Absence of positive proliferative responses of HIV-infected patients to HIV-1 antigens was not associated with increased interleukin 10 production. Correlation was observed between influenza-specific CTL response and T cell proliferation, as well as CD4+ T lymphocyte counts, indicating the importance of CD4+ helper T cells for generating antiviral CTL responses. Finally, these results show that HAART-treated asymptomatic patients, but not AIDS patients, have T cell responses comparable to those of control individuals. It remains to be determined whether immune-based therapy will contribute any additional benefit to patients who received HAART.