Frailty-Related Factors among Women Living with and without HIV Aged 40 Years and Older. The Women's Interagency HIV Study.

BACKGROUND: Frailty is a clinical, geriatric syndrome linked to disability and mortality; and may be associated with a variety of factors among underrepresented and underserved women living with HIV (WLWH) and without HIV (WLWOH) transitioning through the adult life course. OBJECTIVES: Determine whether a published set of factors associated cross-sectionally with frailty in WLWH and similar WLWOH at average age 39 years in 2005/2006 were associated with frailty in 2018/2019 among women who initiated frailty assessments at age ≥40 years, or whether a new set of factors were associated with frailty. DESIGN: Cross-sectional analyses within a longitudinal cohort study. SETTING: The multi-center Women's Interagency HIV Study (WIHS). PARTICIPANTS: 1285 participants (951 WLWH, 334 WLWOH), median age 53 years (interquartile range 47-58 years). MEASUREMENTS: The Fried Frailty Phenotype (FFP) in association with 23 factors representing HIV serostatus, other infections, sociodemographic factors, health behaviors, and chronic diseases. RESULTS: Frailty prevalence was 11.1% in 2018/2019 (12.6% among WLWOH, 9.6% among WLWH, p=0.121). The published 2005/2006 final multivariable stepwise regression model contained 9 predictors of frailty. When refit to women in 2018/2019, only age ≥50 years and annual income ≤$12,000 were independently positively associated with frailty; other significant 2005/2006 factors, HIV serostatus, CD4+ count <500 cells/mL among WLWH, smoking, drinking, FIB-4 and eGFR, were not. A newly-derived stepwise model considering all 23 predictors measured in 2018/2019, showed independent positive associations between frailty and age ≥50 years, annual income ≤$12,000, obesity (body mass index (BMI) ≥30kg/m2), and history of tuberculosis and cancer. CONCLUSION: Different chronic and infectious disease factors were associated with frailty among WLWH and WLWOH over the adult life course. Understanding factors associated with frailty by adult life stage, allows identification and implementation of novel, temporal interventions to alleviate frailty-associated outcomes and enhance quality of life among WLWH and WLWOH.

Effects of recombinant human interleukin 7 on T-cell recovery and thymic output in HIV-infected patients receiving antiretroviral therapy: results of a phase I/IIa randomized, placebo-controlled, multicenter study.

BACKGROUND: The immune deficiency of human immunodeficiency virus (HIV) infection is not fully corrected with ARV therapy. Interleukin-7 (IL-7) can boost CD4 T-cell counts, but optimal dosing and mechanisms of cellular increases need to be defined. METHODS: We performed a randomized placebo-controlled dose escalation (10, 20 and 30 µg/kg) trial of 3 weekly doses of recombinant human IL-7 (rhIL-7) in ARV-treated HIV-infected persons with CD4 T-cell counts between 101 and 400 cells/µL and plasma HIV levels <50 copies/mL. Toxicity, activity and the impact of rhIL-7 on immune reconstitution were monitored. RESULTS: Doses of rhIL-7 up to 20 µg/kg were well tolerated. CD4 increases of predominantly naive and central memory T cells were brisk (averaging 323 cells/µL at 12 weeks) and durable (up to 1 year). Increased cell cycling and transient increased bcl-2 expression were noted. Expanded cells did not have the characteristics of regulatory or activated T cells. Transient low-level HIV viremia was seen in 6 of 26 treated patients; modest increases in total levels of intracellular HIV DNA were proportional to CD4 T-cell expansions. IL-7 seemed to increase thymic output and tended to improve the T-cell receptor (TCR) repertoire in persons with low TCR diversity. CONCLUSIONS: Three weekly doses of rhIL-7 at 20 µg/kg are well tolerated and lead to a dose-dependent CD4 T-cell increase and the broadening of TCR diversity in some subjects. These data suggest that this rhIL-7 dose could be advanced in future rhIL-7 clinical studies. CLINICAL TRIALS REGISTRATION: NCT0047732.

GABAergic and glycinergic inhibition modulate monaural auditory response properties in the avian superior olivary nucleus.

The superior olivary nucleus (SON) is the primary source of inhibition in the avian auditory brainstem. While much is known about the role of inhibition at the SON's target nuclei, little is known about how the SON itself processes auditory information or how inhibition modulates these properties. Additionally, the synaptic physiology of inhibitory inputs within the SON has not been described. We investigated these questions using in vivo and in vitro electrophysiological techniques in combination with immunohistochemistry in the chicken, an organism for which the auditory brainstem has otherwise been well characterized. We provide a thorough characterization of monaural response properties in the SON and the influence of inhibitory input in shaping these features. We found that the SON contains a heterogeneous mixture of response patterns to acoustic stimulation and that in most neurons these responses are modulated by both GABAergic and glycinergic inhibitory inputs. Interestingly, many SON neurons tuned to low frequencies have robust phase-locking capability and the precision of this phase locking is enhanced by inhibitory inputs. On the synaptic level, we found that evoked and spontaneous inhibitory postsynaptic currents (IPSCs) within the SON are also mediated by both GABAergic and glycinergic inhibition in all neurons tested. Analysis of spontaneous IPSCs suggests that most SON cells receive a mixture of both purely GABAergic terminals, as well as terminals from which GABA and glycine are coreleased. Evidence for glycinergic signaling within the SON is a novel result that has important implications for understanding inhibitory function in the auditory brainstem.

Evaluation of a rapid, point-of-care test device for the diagnosis of hepatitis C infection.

BACKGROUND: Despite considerable evolution in the quality of laboratory-based testing for detection of HCV, the availability of rapid, point-of-care tests may increase diagnoses by increasing opportunities for testing outside of traditional laboratory settings. OBJECTIVES: We evaluated the performance of a new, rapid HCV test that can be used with venous blood, finger stick blood, serum, plasma, or oral fluid and compared it to FDA-approved laboratory methods. STUDY DESIGN: HCV positive subjects as well as subjects at low risk for HCV were tested with the rapid test using all 5 specimen types and results compared to FDA-approved laboratory methods. In addition, performance was assessed in commercially available seroconversion panels. RESULTS: Sensitivity and specificity of the rapid test was equivalent to laboratory EIA and performance was comparable across all 5 specimen types. CONCLUSIONS: The OraQuick HCV Rapid Antibody Test appears suitable as an aid in the diagnosis of HCV infection.

Evaluating an impression cytology grading system (IC score) in patients with dry eye syndrome.

PURPOSE: To evaluate the IC score, a newly developed grading system for the morphological alterations of the ocular surface as a diagnostic tool in relation to type and severity of dry eye disease. METHODS: Impression cytological specimens of 309 patients with simple dry eye (S-DE), 50 patients with Sjögren's syndrome and dry eye (SS-DE), and 39 patients with connective tissue disease and dry eye (CTD-DE) were examined. In all, 10 different morphological parameters were judged with points (IC subscores) and summarized to the IC score. IC score and subscores were correlated to tear function test results and with each other. RESULTS: SS-DE patients had the highest IC scores and IC subscores. IC scores and IC subscores correlated significantly with the fluorescein staining of the cornea in all three patient groups. They were correlated to the rose bengal score in SS-DE and S-DE patients. The analysis of the IC subscores showed that there are significant correlations between most of the morphological alterations investigated. This underlines the importance of each parameter for the summarized IC score. CONCLUSION: The IC score provides detailed information about the morphological alterations of the bulbar conjunctiva. It has proven to be useful for the differentiation of dry eye diseases and might help in the investigation of the pathogenesis of these diseases as well as for follow-up and therapy control.

Multidrug-resistant tuberculous meningitis in patients with AIDS.

We present clinical manifestations, bacteriologic characteristics, and outcomes for eight patients with multidrug-resistant (MDR) tuberculous meningitis and AIDS. All developed meningitis as a terminal complication of previously diagnosed MDR-TB despite anti-tuberculosis therapy. Seven patients presented with fever, five with headache, four with altered mentation, two with focal deficits and one with seizures. CSF examination revealed pleocytosis, hypoglychorrhachia and elevated protein. Mycobacterium tuberculosis resistant to at least isoniazid and rifampin was isolated from all patients. Intracerebral mass lesions were detected in three patients, hydrocephalus in three, meningeal enhancement in five, and infarcts in two. Seven patients died 1-16 weeks after the diagnosis of meningitis; the eighth was lost to follow-up. MDR tuberculous meningitis is a difficult-to-treat infection with a high fatality rate.

Predictors of virologic and clinical outcomes in HIV-1-infected patients receiving concurrent treatment with indinavir, zidovudine, and lamivudine. AIDS Clinical Trials Group Protocol 320.

BACKGROUND: A substantial proportion of patients with HIV infection will not respond to antiretroviral therapy. Early predictors of response to treatment are needed to identify patients who are at risk for treatment failure. OBJECTIVE: To determine predictors of virologic and clinical response to indinavir, zidovudine, and lamivudine therapy. DESIGN: Observational analysis of one treatment group in a phase III trial. SETTING: 40 AIDS Clinical Trials units. PATIENTS: 489 patients receiving indinavir, zidovudine, and lamivudine who had 1) a CD4 count of 0.200 x 10(9) cells/L or less after 8 or more weeks of study therapy and 2) plasma HIV-1 RNA measurements obtained at baseline and week 8. MEASUREMENTS: HIV-1 RNA level and CD4 cell count at weeks 0, 4, 8, 24, and 40. Clinical progression was defined as a new AIDS-defining illness or death. RESULTS: Patients' levels of HIV-1 RNA at the 8th study week of therapy predicted whether patients would achieve virologic suppression to below 500 (or 50) copies/mL at study week 24. An HIV-1 RNA level less than 500 copies/mL at week 24 was achieved in 71% of patients whose level at week 8 had been less than 500 copies/mL, 53% of those with a level of 500 copies/mL or more and at least 2-log(10) copies/mL reduction since baseline, 29% of those with a level of 500 copies/mL or more with a 1- to 1.99-log(10) copies/mL reduction, and 9% of those with a level of 500 copies/mL or greater and less than 1-log(10) copies/mL reduction since baseline (P < 0.001). HIV-1 RNA level at week 8 also predicted clinical progression. HIV-1 disease progressed in 2.2% of the patients with a week-8 HIV-1 RNA level less than 500 copies/mL, 2.3% of patients with 500 copies/mL or greater and at least 2-log(10) copies/mL reduction since baseline, 4.9% of patients with 500 copies/mL or greater and 1- to 1.99-log(10) copies/mL reduction since baseline, and 10.6% of patients with 500 copies/mL or greater and less than 1-log(10) copies/mL decrease since baseline (P = 0.009). After adjustment for HIV-1 RNA level, patients with a higher week-8 CD4 cell count were more likely to have a week-24 HIV-1 RNA level less than 500 copies/mL (relative risk for patients with a week-8 CD4 count >/= 0.10 x 10(9) cells/L, 1.47 [95% CI, 1.00 to 2.16] compared with <0.050 x 10(9) cells/L; relative risk for patients with a week-8 CD4 count of 0.05 to 0.099 x 10(9) cells/L, 0.98 [CI, 0.61 to 1.57] compared with <0.050 x 10(9) cells/L). After adjustment for HIV-1 RNA level, patients with a week-8 CD4 count of 0.05 x 10(9) cells/L or greater (compared with <0.05 x 10(9) cells/L) had a decreased hazard for clinical progression (hazard ratio, 0.25 [CI, 0.09 to 0.67]). CONCLUSIONS: The HIV-1 RNA level and CD4 cell count achieved at 8 weeks of treatment are important predictors of subsequent virologic and clinical outcomes.

Do HIV type 1 RNA levels provide additional prognostic value to CD4(+) T lymphocyte counts in patients with advanced HIV type 1 infection?

Our objective was to assess whether HIV-1 RNA levels provide additional prognostic information beyond CD4(+) T lymphocyte counts in the prediction of subsequent HIV-1 disease progression among patients with advanced HIV-1 disease. In a nested case-control study conducted in patients with baseline CD4(+) T lymphocyte counts < 300 cells/mm(3) and receiving nucleoside reverse transcriptase inhibitors, 102 patients who progressed to an AIDS-defining event or death were matched within 10 CD4(+) T lymphocyte cells/mm(3) to patients who did not progress. The relationship between plasma HIV-1 RNA levels and HIV-1 disease progression was studied using conditional logistic regression analysis, which adjusts for the matching by baseline CD4(+) T lymphocytes. We observed a 0.10 log(10) copies/ml difference in baseline HIV-1 RNA levels between cases and their matched controls (p = 0.027). The relative risk for HIV-1 disease progression increased with increasing baseline HIV-1 RNA levels (odds ratio [OR] for a 3-fold higher HIV-1 RNA level, 1.42; 95% confidence interval [CI], 1.08--1.86), and remained important when also controlling for clinical status at baseline and CD4(+) T lymphocytes at 2 months (p = 0.038). Higher baseline HIV-1 RNA levels were associated with HIV-1 disease progression among patients with a baseline CD4(+) T lymphocyte count of 100 cells/mm(3) or greater (OR, 1.80; 95% CI, 1.15--2.81), but not among patients with a baseline CD4(+) T lymphocyte count < 100 cells/mm(3) (OR, 1.09; 95% CI, 0.73--1.63). We concluded that HIV-1 RNA levels predict subsequent HIV-1 disease progression independent of CD4(+) T lymphocyte counts. The magnitude and importance of the prognostic information contained in the HIV-1 RNA levels appear to depend on the CD4(+) T lymphocyte counts.

Patterns of plasma human immunodeficiency virus type 1 RNA response to antiretroviral therapy.

Early identification of treatment failure among human immunodeficiency virus (HIV) type 1--infected patients receiving antiretroviral therapy could enable clinicians to modify inadequate regimens and to improve treatment response. Clinical definitions of treatment failure, however, may not be ideally suited for this purpose. This study empirically characterizes the patterns of HIV-1 RNA response to antiretroviral therapy in patients in 4 AIDS clinical trials. The approach assumed 2 patterns of HIV-1 response: "on track," for eventual suppression to HIV-1 RNA levels below the limit of quantification, and "off track," for deviation from this response. The results of this on- or off-track classification generally agreed with the protocol-defined outcomes of virologic success and failure, thus validating these commonly used definitions. Overall, only a minority of patients went off track because of suboptimal HIV-1 RNA response by the first follow-up visit. Most patients who went off track did so at later time points and had sharp unexpected rebounds without prior indication of a suboptimal response.

Amprenavir in combination with lamivudine and zidovudine versus lamivudine and zidovudine alone in HIV-1-infected antiretroviral-naive adults. Amprenavir PROAB3001 International Study Team.

OBJECTIVES: To compare the antiviral activity and safety of a new protease inhibitor, amprenavir (141W94) in combination with lamivudine and zidovudine, versus lamivudine and zidovudine alone in HIV-1 infected, antiretroviral-naive subjects. DESIGN: Subjects (n=232) with a CD4 T cell count of > or =200 cells/mm3, plasma HIV-1 RNA levels of > or =10000 copies/ml, and < or =4 weeks of prior nucleoside antiretroviral therapy, were stratified according to baseline plasma HIV-1 RNA level (10000-30000; 30000-100000; or >100000 copies/ml). Subjects received double-blind treatment with either 1200 mg amprenavir twice daily in combination with lamivudine (150 mg twice daily) and zidovudine (300 mg twice daily) (amprenavir/lamivudine/zidovudine) or matched placebo, lamivudine and zidovudine for 16 weeks. Thereafter, subjects with confirmed plasma HIV-1 RNA levels of > or =400 copies/ml could add open-label amprenavir or switch to other antiretrovirals and continue treatment for up to a minimum of 48 weeks. The primary endpoint of the study was defined as the proportion of subjects with plasma HIV-1 RNA of <400 copies/ml at 48 weeks. RESULTS: At 48 weeks, a significantly greater proportion of amprenavir/lamivudine/zidovudine subjects had plasma HIV-1 RNA levels <400 copies/ml than lamivudine/ zidovudine subjects in the overall population: 41 versus 3% (intent-to-treat missing equals failure analysis) (P<0.001); 93 versus 42% (as-treated analysis) (P<0.001); and within each of the three randomization strata (P<0.001). Subjects on amprenavir/lamivudine/zidovudine experienced longer time to event (permanent discontinuation of randomized therapy or viral rebound) than those on lamivudine/zidovudine (median of 33 versus 13 weeks; P<0.001). A significantly greater incidence of drug-related nausea, vomiting, rash and oral/perioral paresthesia was observed with amprenavir/lamivudine/zidovudine than with lamivudine/zidovudine. CONCLUSIONS: Amprenavir, in combination with lamivudine and zidovudine, has potent and durable antiviral activity in antiretroviral-naive subjects over 48 weeks. Amprenavir was safe and generally well tolerated.

Randomized study of saquinavir with ritonavir or nelfinavir together with delavirdine, adefovir, or both in human immunodeficiency virus-infected adults with virologic failure on indinavir: AIDS Clinical Trials Group Study 359.

This study compared antiretroviral activity among 6 "salvage" therapy regimens. The study was a prospective, randomized, 2x3 factorial, multicenter study of the AIDS Clinical Trials Group. The study enrolled 277 human immunodeficiency virus (HIV)-infected patients naive to nonnucleoside analogues who had taken indinavir >6 months. The patients had 2000-200,000 HIV RNA copies/mL. Patients received saquinavir with ritonavir or nelfinavir together with delavirdine and/or adefovir and were followed for safety and antiretroviral response between baseline and week 16. At week 16, 30% (77/254) of patients had

Concentration-targeted phase I trials of atevirdine mesylate in patients with HIV infection: dosage requirements and pharmacokinetic studies. The ACTG 187 and 199 study teams.

RATIONALE: To determine the dosage requirements and pharmacokinetics of atevirdine, a non-nucleoside reverse transcriptase inhibitor and its N-dealkylated metabolite (N-ATV) during phase I studies in patients receiving atevirdine alone or in combination with zidovudine. DESIGN: Two open label, phase I studies conducted by the adult AIDS Clinical Trials Group (ACTG) in which atevirdine was administered every 8 h with weekly dosage adjustments to attain targeted trough plasma atevirdine concentrations. SETTING: Five Adult AIDS Clinical Trials Units. PATIENTS: Fifty patients (ACTG 199; n = 20 and ACTG 187; n = 30) with HIV-1 infection and < or =500 CD4+ lymphocytes/mm3. INTERVENTION: ACTG 199; 12 weeks of therapy with atevirdine (dose-adjusted to achieve plasma trough atevirdine concentrations of 5-10 microM) and zidovudine (200 mg every 8 h). ACTG 187: 12 weeks of atevirdine monotherapy with atevirdine doses adjusted to achieve escalating, targeted trough plasma concentration ranges (5-13, 14-22, and 23-31 microM). MEASUREMENTS: ACTG 199: atevirdine, N-ATV and zidovudine trough determinations weekly (all patients) and intensive pharmacokinetics (selected patients) prior to and at 6 and 12 weeks during combination therapy. ACTG 187: atevirdine and N-ATV trough concentrations over a 12 week period. Intensive pharmacokinetic studies were conducted prior to and at 4 and/or 8 weeks during atevirdine monotherapy in female patients. RESULTS: Atevirdine plasma concentrations demonstrated considerable interpatient variability which was minimized by the adjustment of maintenance doses (range: 600-3900 mg/day) to achieve the desired trough concentrations. In ACTG 187, the mean number of weeks to attain the target value, and the percentage of patients who attained the target, was group I (5-11 microM): 2.7+/-2.4 weeks (92%); group II (12-21 microM): 2.6+/-1.8 (64%); and group III (22-31 microM): 7.0+/-5.6 weeks (27%). In ACTG 199 it was 3.2+/-5.2 weeks (95%) to achieve a 5-10 microM trough. Atevirdine demonstrated a mono- or bi-exponential decline among most of the patients studied after the first dose. During multiple-dosing a number of patterns of atevirdine disposition were observed including; rapid absorption with Cmax at 0.5-1 h, delayed absorption with Cmax at 3-4 h; minimal Cmax to Cmin fluctuation and Cmax to Cmin ratios of > 4. N-ATV (an inactive metabolite) patterns were characterized on day one by rapid appearance of the metabolite which peaked at 2-3 h after the dose and declined in a mono- or bi-exponential manner. At steady-state N-ATV patterns demonstrated minimal Cmax to Cmin fluctuations with some of the patients having more stable plasma N-ATV concentrations, while others had greater fluctuations week to week. CONCLUSIONS: Considerable interpatient variability was noted in the pharmacokinetics of atevirdine. The variation in drug disposition was reflected in the range of daily doses required to attain the targeted trough concentrations. Atevirdine metabolism did not appear to reach saturation during chronic dosing in many of our patients, as reflected by the pattern of N-ATV/ATV ratios in plasma and saturation was not an explanation for the variation in dosing requirements. No apparent differences were noted between males and females, and atevirdine did not appear to influence zidovudine disposition.

Delavirdine susceptibilities and associated reverse transcriptase mutations in human immunodeficiency virus type 1 isolates from patients in a phase I/II trial of delavirdine monotherapy (ACTG 260).

The development of human immunodeficiency virus type 1 resistance to delavirdine (DLV) was studied in subjects receiving DLV monotherapy. Phenotypic resistance developed in 28 of 30 subjects within 8 weeks. K103N and Y181C, which confer nonnucleoside reverse transcriptase inhibitor (NNRTI) cross-resistance, were the predominant reverse transcriptase mutations. P236L, which confers DLV resistance but hypersensitivity to other NNRTIs, developed in <10% of isolates.

Competing drug-drug interactions among multidrug antiretroviral regimens used in the treatment of HIV- infected subjects: ACTG 884.

OBJECTIVE: To evaluate the steady state concentrations of saquinavir, ritonavir, nelfinavir, delavirdine, and adefovir in six different three- and four-drug combination regimens. DESIGN: Randomized, partially double-blinded, multicenter study in a population of indinavir-experienced subjects with virologic failure. The first seven subjects enrolled in each of the six treatment arms from 10 participating sites were entered into this pharmacokinetic evaluation. SETTING: Multicenter study of the AIDS Clinical Trials Group (ACTG). PATIENTS: HIV-infected subjects. INTERVENTIONS: A 12-hour pharmacokinetic study was conducted after 2 weeks of drug administration. MAIN OUTCOME MEASURES: Area under the concentration-time curve with statistical comparisons to evaluate the effect of the second protease inhibitor and the effect of the non-protease inhibitors. RESULTS: There was no difference in saquinavir concentrations according to whether the second protease inhibitor was ritonavir or nelfinavir. Saquinavir concentrations in the groups receiving the combination of delavirdine plus adefovir dipivoxil were reduced by approximately 50% compared with those receiving delavirdine. Delavirdine concentrations were reduced by approximately 50%, in the delavirdine plus adefovir dipivoxil arms compared with the delavirdine arms. CONCLUSIONS: Saquinavir concentrations were significantly lower in the arms containing the combination of delavirdine and adefovir dipivoxil compared with the arms containing delavirdine. Delavirdine concentrations were significantly lower when coadministered with adefovir dipivoxil. These drug-drug interactions were not expected, the mechanism(s) is (are) not clear, and additional studies are warranted. This study illustrates the need to understand more fully the pharmacokinetic characteristics of complex combination antiretroviral regimens prior to use in patient management.

Antiretroviral therapy in adults: updated recommendations of the International AIDS Society-USA Panel.

OBJECTIVE: To update recommendations for antiretroviral therapy for adult human immunodeficiency virus type 1 (HIV-1) infection, based on new information and drugs that are available. PARTICIPANTS: A 17-member international physician panel with antiretroviral research and HIV patient care experience initially convened by the International AIDS Society-USA in December 1995. EVIDENCE: Available clinical and basic science data including phase 3 controlled trials; data on clinical, virologic, and immunologic end points; research conference reports; HIV pathogenesis data; and panel expert opinion. Recommendations were limited to therapies available (US Food and Drug Administration approved) in 1999. CONSENSUS PROCESS: The panel assesses new research reports and interim results and regularly meets to consider how the new data affect therapy recommendations. Recommendations are updated via full-panel consensus. Guidelines are presented as recommendations if the supporting evidence warrants routine use in the particular situation and as considerations if data are preliminary or incomplete but suggestive. CONCLUSIONS: The availability of new antiretroviral drugs has expanded treatment choices. The importance of adherence, emerging long-term complications of therapy, recognition and management of antiretroviral failure, and new monitoring tools are addressed. Optimal care requires individualized management and ongoing attention to relevant scientific and clinical information in the field.

Antiretroviral therapy in 1999 for antiretroviral-naive individuals with HIV infection.

The choice of initial antiretroviral regimen for treating people infected with HIV is crucial to successful long-term control of virus replication. Potent antiretroviral therapy substantially suppresses viral replication as measured by plasma HIV RNA levels to below limits of detection: the current standard of care is usually a combination of at least three drugs and frequently includes a protease inhibitor, or alternatively a non-nucleoside reverse transcriptase inhibitor (nnRTI). Patients who have low CD4+ cell counts (< or = 200 CD4+ cells/mm3) or high plasma HIV RNA levels (> or = 100,000 copies/ml) may not attain maximal suppression of HIV replication when treated with current regimens and may require more aggressive therapy. In contrast, patients with relatively normal CD4+ cell counts and low to non-measurable levels of plasma HIV RNA over prolonged periods (i.e., slow or non-progressors) may not require immediate antiretroviral therapy. These individuals should reconsider treatment when either the CD4+ cell count declines or the HIV RNA level increases. Early and potent antiretroviral therapy should provide more durable virological and clinical benefits for many patients, especially if they receive sufficient counselling and support to aid adherence to the treatment regimen. The optimum time to initiate antiretroviral therapy is not well established, but to maximise the recovery of the immune system and the virological and clinical benefits, initiation of therapy is generally recommended for individuals who have symptoms or those with plasma HIV RNA levels > 5000-10,000 copies/ml, or CD4+ cell counts < 500 cells/mm3. The current choice of initial antiretroviral regimens includes two nucleoside reverse transcriptase inhibitors (nRTI) with a potent, well-tolerated HIV-1 protease inhibitor or nnRTI. Recent short-term activity data (24-week comparative clinical trial data) indicate that regimens combining three nRTI, including abacavir, could also be considered. Other emerging combination regimens for consideration include two HIV-1 protease inhibitors with one or two nRTI, or a combination of drugs from all current categories (e.g., nRTI with a nnRTI and HIV-1 protease inhibitor). The goal of antiretroviral therapy is to maximise suppression of HIV replication and thereby prevent or delay viral resistance, restore immunological function and improve clinical outcome. Since evolution of the virus towards resistance can occur with plasma HIV RNA levels between 50 and 500 copies/ml, current standards for best suppression of HIV replication have shifted to declines in plasma HIV RNA to < 50 copies/ml. In addition, non-adherence to any regimen is associated with the greatest risk for virological failure. Therefore, both the decision to initiate therapy and the choice of initial therapy should be carefully weighted and balanced with the long-term implications of antiretroviral therapy.

Efficacy and safety of delavirdine mesylate with zidovudine and didanosine compared with two-drug combinations of these agents in persons with HIV disease with CD4 counts of 100 to 500 cells/mm3 (ACTG 261). ACTG 261 Team.

To evaluate the antiretroviral activity of delavirdine mesylate, a non-nucleoside reverse transcriptase inhibitor of HIV-1, we performed a phase II, randomized, double-blind, multicenter trial comparing the three-drug combination of delavirdine with zidovudine and didanosine to two-drug combinations of these drugs. Patients with CD4 cell counts between 100 and 500 cells/mm3 without prior or <6 months of monotherapy with zidovudine or didanosine were randomized to one of four arms and observed on a follow-up basis for 48 weeks. In total, 544 patients were evaluated. In those assigned to the three-drug regimen, mean short-term (weeks 4-12) and long-term (weeks 40-48) change in CD4 cells from baseline were 49.3+/-8.1 and 65.4+/-13.4 cells/mm3, respectively; mean short-term and long-term HIV-1 RNA changes from baseline were -1.13 log10+/-0.12 and -0.73+/-0.12 copies/ml, respectively. These responses in CD4 cell counts and HIV-1 RNA levels were better in comparisons with each of the two-drug arms at all study points; however, differences were not consistently significant. Gastrointestinal side effects were experienced by 33% of patients (178 of 544), and 30% (121 of 407) receiving delavirdine experienced rash, only one case of which was severe. In this study, therapy with delavirdine + zidovudine + didanosine was safe and showed modest, but not always significant, antiviral activity and CD4 cell count benefit compared with two-drug regimens with these agents. Key

Lamivudine in combination with zidovudine, stavudine, or didanosine in patients with HIV-1 infection. A randomized, double-blind, placebo-controlled trial. National Institute of Allergy and Infectious Disease AIDS Clinical Trials Group Protocol 306 Investigators.

OBJECTIVE: To study the antiviral activity of lamivudine (3TC) plus zidovudine (ZDV), didanosine (ddl), or stavudine (d4T). DESIGN: Randomized, placebo-controlled, partially double-blinded multicenter study. SETTING: Adult AIDS Clinical Trials Units. PATIENTS: Treatment-naive HIV-infected adults with 200-600x10(6) CD4 T lymphocytes/l. INTERVENTIONS: Patients were openly randomized to a d4T or a ddl limb, then randomized in a blinded manner to receive: d4T (80 mg/day), d4T plus 3TC (300 mg/day), or ZDV (600 mg/day) plus 3TC, with matching placebos; or ddl (400 mg/day), ddl plus 3TC (300 mg/day), or ZDV (600 mg/day) plus 3TC, with matching placebos. After 24 weeks 3TC was added for patients assigned to the monotherapy arms. MAIN OUTCOME MEASURE: The reduction in plasma HIV-1 RNA level at weeks 24 and 48. RESULTS: Two hundred ninety-nine patients were enrolled. After 24 weeks the mean reduction in plasma HIV-1 RNA copies/ml from baseline was 0.49 log10 (d4T monotherapy) versus 1.03 log10 (d4T plus 3TC; P = 0.001), and 0.68 log10 (ddl monotherapy) versus 0.82 log10 (ddl plus 3TC; P>0.22). After 48 weeks the mean reduction was 1.08 log10 (d4T plus 3TC) versus 1.01 log10 (ZDV plus 3TC) in the d4T limb (P = 0.66), and 0.94 log10 (ddl plus 3TC) versus 0.88 log10 (ZDV plus 3TC; P = 0.70) in the ddl limb. CONCLUSIONS: 3TC added significantly to the virologic effects of d4T, but not ddl, in treatment-naive patients. 3TC plus d4T produced virologic changes comparable to those of 3TC plus ZDV. These results support the use of 3TC with either ZDV or d4 as a component of initial combination antiretroviral therapy.

ACTG 260: a randomized, phase I-II, dose-ranging trial of the anti-human immunodeficiency virus activity of delavirdine monotherapy. The AIDS Clinical Trials Group Protocol 260 Team.

ACTG 260 was an open-label, four-arm trial designed to study the safety and anti-human immunodeficiency virus (anti-HIV) activity of delavirdine monotherapy at three ranges of concentrations in plasma compared to those of control therapy with zidovudine or didanosine. Delavirdine doses were adjusted weekly until subjects were within their target trough concentration range (3 to 10, 11 to 30, or 31 to 50 microM). A total of 113 subjects were analyzed. At week 2, the mean HIV type 1 (HIV-1) RNA level declines among the subjects in the three delavirdine arms were similar (0.87, 1.08, and 1.02 log10 for the low, middle, and high target arms, respectively), but by week 8, the subjects in the pooled delavirdine arms showed only a 0.10 log10 reduction. In the subjects in the nucleoside arm, mean HIV-1 RNA level reductions at weeks 2 and 8 were 0.67 and 0.55 log10, respectively. Because viral suppression by delavirdine was not maintained, the trial was stopped early. Rash, which was usually self-limited, developed in 36% of subjects who received delavirdine. Delavirdine monotherapy has potent anti-HIV activity at 2 weeks, but its activity is time limited due to the rapid emergence of drug resistance.