Active intravenous drug use during chronic hepatitis C therapy does not reduce sustained virological response rates in adherent patients

Reluctance has been expressed about treating chronic hepatitis C in active intravenous (IV) drug users (IDUs), and this is found in both international guidelines and routine clinical practice. However, the medical literature provides no evidence for an unequivocal treatment deferral of this risk group. We retrospectively analyzed the direct effect of IV drug use on treatment outcome in 500 chronic hepatitis C patients enrolled in the Swiss Hepatitis C Cohort Study. Patients were eligible for the study if they had their serum hepatitis C virus (HCV) RNA tested 6 months after the end of treatment and at least one visit during the antiviral therapy, documenting the drug use status. Five hundred patients fulfilled the inclusion criteria (199 were IDU and 301 controls). A minimum exposure to 80% of the scheduled cumulative dose of antivirals was reached in 66.0% of IDU and 60.5% of controls (P = NS). The overall sustained virological response (SVR) rate was 63.6%. Active IDU reached a SVR of 69.3%, statistically not significantly different from controls (59.8%). A multivariate analysis for treatment success showed no significant negative influence of active IV drug use. In conclusion, our study shows no relevant direct influence of IV drugs on the efficacy of anti-HCV therapy among adherent patients.

Influence of noninjecting and injecting drug use on mortality, retention in the cohort, and antiretroviral therapy, in participants in the Swiss HIV Cohort Study.

OBJECTIVES We studied the influence of noninjecting and injecting drug use on mortality, dropout rate, and the course of antiretroviral therapy (ART), in the Swiss HIV Cohort Study (SHCS). METHODS Cohort participants, registered prior to April 2007 and with at least one drug use questionnaire completed until May 2013, were categorized according to their self-reported drug use behaviour. The probabilities of death and dropout were separately analysed using multivariable competing risks proportional hazards regression models with mutual correction for the other endpoint. Furthermore, we describe the influence of drug use on the course of ART. RESULTS A total of 6529 participants (including 31% women) were followed during 31 215 person-years; 5.1% participants died; 10.5% were lost to follow-up. Among persons with homosexual or heterosexual HIV transmission, noninjecting drug use was associated with higher all-cause mortality [subhazard rate (SHR) 1.73; 95% confidence interval (CI) 1.07-2.83], compared with no drug use. Also, mortality was increased among former injecting drug users (IDUs) who reported noninjecting drug use (SHR 2.34; 95% CI 1.49-3.69). Noninjecting drug use was associated with higher dropout rates. The mean proportion of time with suppressed viral replication was 82.2% in all participants, irrespective of ART status, and 91.2% in those on ART. Drug use lowered adherence, and increased rates of ART change and ART interruptions. Virological failure on ART was more frequent in participants who reported concomitant drug injections while on opiate substitution, and in current IDUs, but not among noninjecting drug users. CONCLUSIONS Noninjecting drug use and injecting drug use are modifiable risks for death, and they lower retention in a cohort and complicate ART.

Antiplatelet therapy duration following bare metal or drug-eluting coronary stents: the dual antiplatelet therapy randomized clinical trial

IMPORTANCE Despite antirestenotic efficacy of coronary drug-eluting stents (DES) compared with bare metal stents (BMS), the relative risk of stent thrombosis and adverse cardiovascular events is unclear. Although dual antiplatelet therapy (DAPT) beyond 1 year provides ischemic event protection after DES, ischemic event risk is perceived to be less after BMS, and the appropriate duration of DAPT after BMS is unknown. OBJECTIVE To compare (1) rates of stent thrombosis and major adverse cardiac and cerebrovascular events (MACCE; composite of death, myocardial infarction, or stroke) after 30 vs 12 months of thienopyridine in patients treated with BMS taking aspirin and (2) treatment duration effect within the combined cohorts of randomized patients treated with DES or BMS as prespecified secondary analyses. DESIGN, SETTING, AND PARTICIPANTS International, multicenter, randomized, double-blinded, placebo-controlled trial comparing extended (30-months) thienopyridine vs placebo in patients taking aspirin who completed 12 months of DAPT without bleeding or ischemic events after receiving stents. The study was initiated in August 2009 with the last follow-up visit in May 2014. INTERVENTIONS Continued thienopyridine or placebo at months 12 through 30 after stent placement, in 11,648 randomized patients treated with aspirin, of whom 1687 received BMS and 9961 DES. MAIN OUTCOMES AND MEASURES Stent thrombosis, MACCE, and moderate or severe bleeding. RESULTS Among 1687 patients treated with BMS who were randomized to continued thienopyridine vs placebo, rates of stent thrombosis were 0.5% vs 1.11% (n = 4 vs 9; hazard ratio [HR], 0.49; 95% CI, 0.15-1.64; P = .24), rates of MACCE were 4.04% vs 4.69% (n = 33 vs 38; HR, 0.92; 95% CI, 0.57-1.47; P = .72), and rates of moderate/severe bleeding were 2.03% vs 0.90% (n = 16 vs 7; P = .07), respectively. Among all 11,648 randomized patients (both BMS and DES), stent thrombosis rates were 0.41% vs 1.32% (n = 23 vs 74; HR, 0.31; 95% CI, 0.19-0.50; P < .001), rates of MACCE were 4.29% vs 5.74% (n = 244 vs 323; HR, 0.73; 95% CI, 0.62-0.87; P < .001), and rates of moderate/severe bleeding were 2.45% vs 1.47% (n = 135 vs 80; P < .001). CONCLUSIONS AND RELEVANCE Among patients undergoing coronary stent placement with BMS and who tolerated 12 months of thienopyridine, continuing thienopyridine for an additional 18 months compared with placebo did not result in statistically significant differences in rates of stent thrombosis, MACCE, or moderate or severe bleeding. However, the BMS subset may have been underpowered to identify such differences, and further trials are suggested. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00977938.

Combination therapy for multidrug-resistant cytomegalovirus disease

Multidrug-resistant (MDR) cytomegalovirus (CMV) emerged after transient responses to ganciclovir, foscarnet, and cidofovir in a CMV-seropositive recipient who underwent allogeneic hematopoietic stem cell transplantation from a CMV-seronegative donor. Experimental treatments using leflunomide and artesunate failed. Re-transplantation from a CMV-seropositive donor supported by adoptive transfer of pp65-specific T cells and maribavir was followed by lasting suppression. This case illustrates that successful MDR CMV therapy may require individualized multidisciplinary approaches. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Ability to Work and Employment Rates in Human Immunodeficiency Virus (HIV)-1-Infected Individuals Receiving Combination Antiretroviral Therapy: The Swiss HIV Cohort Study

Background.  Limited data exist on human immunodeficiency virus (HIV)-infected individuals' ability to work after receiving combination antiretroviral therapy (cART). We aimed to investigate predictors of regaining full ability to work at 1 year after starting cART. Methods.  Antiretroviral-naive HIV-infected individuals <60 years who started cART from January 1998 through December 2012 within the framework of the Swiss HIV Cohort Study were analyzed. Inability to work was defined as a medical judgment of the patient's ability to work as 0%. Results.  Of 5800 subjects, 4382 (75.6%) were fully able to work, 471 (8.1%) able to work part time, and 947 (16.3%) were unable to work at baseline. Of the 947 patients unable to work, 439 (46.3%) were able to work either full time or part time at 1 year of treatment. Predictors of recovering full ability to work were non-white ethnicity (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.20-3.54), higher education (OR, 4.03; 95% CI, 2.47-7.48), and achieving HIV-ribonucleic acid <50 copies/mL (OR, 1.83; 95% CI, 1.20-2.80). Older age (OR, 0.55; 95% CI, .42-.72, per 10 years older) and psychiatric disorders (OR, 0.24; 95% CI, .13-.47) were associated with lower odds of ability to work. Recovering full ability to work at 1 year increased from 24.0% in 1998-2001 to 41.2% in 2009-2012, but the employment rates did not increase. Conclusions.  Regaining full ability to work depends primarily on achieving viral suppression, absence of psychiatric comorbidity, and favorable psychosocial factors. The discrepancy between patients' ability to work and employment rates indicates barriers to reintegration of persons infected with HIV.

Cognitive-Behavioural Analysis System of Psychotherapy (CBASP), a drug, or their combination: differential therapeutics for persistent depressive disorder: a study protocol of an individual participant data network meta-analysis.

INTRODUCTION Despite important advances in psychological and pharmacological treatments of persistent depressive disorders in the past decades, their responses remain typically slow and poor, and differential responses among different modalities of treatments or their combinations are not well understood. Cognitive-Behavioural Analysis System of Psychotherapy (CBASP) is the only psychotherapy that has been specifically designed for chronic depression and has been examined in an increasing number of trials against medications, alone or in combination. When several treatment alternatives are available for a certain condition, network meta-analysis (NMA) provides a powerful tool to examine their relative efficacy by combining all direct and indirect comparisons. Individual participant data (IPD) meta-analysis enables exploration of impacts of individual characteristics that lead to a differentiated approach matching treatments to specific subgroups of patients. METHODS AND ANALYSIS We will search for all randomised controlled trials that compared CBASP, pharmacotherapy or their combination, in the treatment of patients with persistent depressive disorder, in Cochrane CENTRAL, PUBMED, SCOPUS and PsycINFO, supplemented by personal contacts. Individual participant data will be sought from the principal investigators of all the identified trials. Our primary outcomes are depression severity as measured on a continuous observer-rated scale for depression, and dropouts for any reason as a proxy measure of overall treatment acceptability. We will conduct a one-step IPD-NMA to compare CBASP, medications and their combinations, and also carry out a meta-regression to identify their prognostic factors and effect moderators. The model will be fitted in OpenBUGS, using vague priors for all location parameters. For the heterogeneity we will use a half-normal prior on the SD. ETHICS AND DISSEMINATION This study requires no ethical approval. We will publish the findings in a peer-reviewed journal. The study results will contribute to more finely differentiated therapeutics for patients suffering from this chronically disabling disorder. TRIAL REGISTRATION NUMBER CRD42016035886.

Tackling ErbB2: ErbB2-targeting peptide therapy and combination therapy with trastuzumab plus PI3K inhibitors

ErbB2 is an excellent target for cancer therapies because its overexpression was found in about 30% of breast cancers and correlated with poor prognosis of the patients. Unfortunately, current therapies for ErbB2-positive breast cancers remain unsatisfying due to side effects and resistance, and new therapies for ErbB2 overexpressing breast cancers are needed. Peptide/protein therapy using cell-penetrating peptides (CPPs) as carriers is promising because the internalization is highly efficient and the cargos can be bioactive. The major obstacle in using CPPs for therapy is their lack of specificity. We sought to develop a peptide carrier specifically introducing therapeutics to ErbB2-overexpressing breast cancer cells. By modifying the TAT-derived CPP, and attaching anti-HER2/neu peptide mimetic (AHNP), we developed the peptide carrier (P3-AHNP) specifically targeted ErbB2-overexpressing breast cancers in vitro and in vivo. A STAT3 SH2 domain-binding peptide conjugated to this peptide carrier (P3-AHNP-STAT3BP) was delivered preferentially into ErbB2-overexpressing breast cancer cells in vitro and in vivo. P3-AHNP-STAT3BP inhibited growth and induced apoptosis in vitro, with ErbB2-overexpressing 435.eB cells being more sensitive than the ErbB2-lowexpressing MDA-MB-435 cells. P3-AHNP-STAT3BP preferentially accumulated and inhibited growth in 435.eB xenografts, comparing with MDA-MB-435 xenografts or normal tissues with low levels of ErbB2. This ErbB2-targeting peptide delivery system provided the basis for future development of novel cancer target-specific treatments with low toxicity to normal cells. ^ Another urgent issue in treating ErbB2-positive breast cancers is trastuzumab resistance. Trastuzumab is the only FDA-approved ErbB2-targeting antibody for treatment of metastatic breast cancers overexpressing ErbB2, and has remarkable therapeutic efficacy in certain patients. The overall trastuzumab response rate, however, is limited, and understanding the mechanisms of trastuzumab resistance is needed to overcome this problem. We report that PTEN activation contributes to trastuzumab's anti-tumor activity. Trastuzumab treatment quickly inactivated Src, which reduced PTEN tyrosine phosphorylation, increased PTEN membrane localization and its phosphatase activity in cancer cells. Reducing PTEN expression in breast cancer cells by antisense oligonucleotides conferred trastuzumab resistance in vitro and in vivo. Importantly, PI3K inhibitors sensitized PTEN-deficient breast cancers to the growth inhibition by trastuzumab in vitro and in vivo, suggesting that combination therapies with PI3K inhibitors plus trastuzumab could overcome trastuzumab resistance. ^

Relevant drug to drug interactions between itraconazole and non-nucleoside reverse transcriptase inhibitors in HIV-infected patients on maintenance therapy for disseminated histoplasmosis

Objective. Itraconazole is recommended life-long for preventing relapse of disseminated histoplasmosis in HIV-infected patients. I sought to determine if serum itraconazole levels are affected by the type of Highly Active Anti-Retroviral Therapy (NNRTI or PI) being taken concomitantly to treat HIV. ^ Design. Retrospective cohort. ^ Methods. De-identified data were used from an IRB-approved parent study which identified patients on HAART and maintenance itraconazole for confirmed disseminated histoplasmosis between January 2003 and December 2006. Available itraconazole blood levels were abstracted as well as medications taken by each patient at the time of the blood tests. Mean itraconazole levels were compared using the student's t-test. ^ Results. 11 patients met study criteria. Patient characteristics were: median age 36, 91% men, 18% white, 18% black, 55% Hispanic and 9% Asians, median CD4 cell count 120 cells/mm3. 14 blood levels were available for analysis—8 on PI, 4 on NNRTI and 2 on both. 8/8 itraconazole levels obtained while taking concomitant PI were therapeutic (>0.4 μg/mL) in contrast to 0/4 obtained while taking NNRTI. Two patients switched from NNRTI to PI and reached therapeutic levels. Mean levels on NNRTI (0.05 μg/mL, s.d. 0.0) and on PI (2.45 μg/mL, s.d. 0.21) for these two patients were compared via a paired t-test (t = 16.00, d.f. = 1, P = 0.04). Remaining patient levels were compared using an unpaired t-test. Mean itraconazole on concomitant PI (n = 6) was 1.37 μg/mL (s.d. 0.74), while the mean on concomitant NNRTI was 0.05 μg/mL (s.d. 0.0), t = 2.39, d.f. = 6, P = 0.05. ^ Conclusions. Co-administration of NNRTI and itraconazole results in significant decreases in itraconazole blood levels, likely by inducing the CYP3A4 enzyme system. Itraconazole drug levels should be monitored in patients on concomitant NNRTI. PI-based HAART may be preferred over NNRTI-based HAART when using itraconazole to treat HIV-infected patients with disseminated histoplasmosis. ^

Novel Use of Dual Anti-Inflammatory Therapy to Overcome Drug Resistance and Improve Functional Recovery Following Spinal Cord Injury

Over 1.2 million Americans are currently living with a traumatic spinal cord injury (SCI). Despite the need for effective therapies, there are currently no proven effective treatments that can improve recovery of function in SCI patients. Many therapeutic compounds have shown promise in preclinical models of SCI, but all of these have fallen short in clinical trials. P-glycoprotein (Pgp) is an active transporter expressed on capillary endothelial cell membranes at the blood-spinal cord barrier (BSCB). Pgp limits passive diffusion of blood-borne drugs into the CNS, by actively extruding drugs from the endothelial cell membrane. Pgp can become pathologically up-regulated, thus greatly impeding therapeutic drug delivery (‘multidrug resistance’). Importantly, many drugs that have been evaluated for the treatment of SCI are Pgp substrates. We hypothesized that Pgp-mediated drug resistance diminishes the delivery and efficacy of neuroprotective drugs following SCI. We observed a progressive, spatial spread of Pgp overexpression within the injured spinal cord. To assess Pgp function, we examined spinal cord uptake of systemically-delivered riluzole, a drug that is currently being evaluated in clinical trials as an SCI intervention. Blood-to-spinal cord riluzole penetration was reduced following SCI in wild-type but not Pgp-null rats, highlighting a critical role for Pgp in mediating spinal cord drug resistance after injury. Others have shown that pro-inflammatory signaling drives Pgp up-regulation in cancer and epilepsy. We have detected inflammation in both acutely- and chronically-injured spinal cord tissue. We therefore evaluated the ability of the dual COX-/5-LOX inhibitor licofelone to attenuate Pgp-mediated drug resistance following SCI. Licofelone treatment both reduced spinal cord Pgp levels and enhanced spinal cord riluzole bioavailability following SCI. Thus, we propose that licofelone may offer a new combinatorial treatment strategy to enhance spinal cord drug delivery following SCI. Additionally, we assessed the ability of licofelone, riluzole, or both to enhance recovery of locomotor function following SCI. We found that licofelone treatment conferred a significant improvement in hindlimb function that was sustained through the end of the study. In contrast, riluzole did not improve functional outcome. We therefore conclude that licofelone holds promise as a potential neuroprotective intervention for SCI.

PIM KINASE INHIBITION: SINGLE AGENT AND COMBINATION APPROACHES IN B-CELL LYMPHOMA

Proviral integration site for Moloney murine leukemia virus (Pim) kinases are Ser/Thr/Tyr kinases. They modulate B-cell development but become oncoproteins and promote cancer development once overexpressed. Containing three isoforms, Pim-1, -2 and -3 are known to phosphorylate various substrates that regulate transcription, translation, cell cycle, and survival pathways in both hematological and solid tumors. Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma. Elevated Pim kinase levels are common in MCL, and it negatively correlates with patient outcome. SGI-1776 is a small molecule inhibitor selective for Pim-1/-3. We hypothesize that SGI-1776 treatment in MCL will inhibit Pim kinase function, and inhibition of downstream substrates phosphorylation will disrupt transcriptional, translational, and cell cycle processes while promoting apoptosis. SGI-1776 treatment induced moderate to high levels of apoptosis in four MCL cell lines (JeKo-1, Mino, SP-53 and Granta-519) and peripheral blood mononuclear cells (PBMCs) from MCL patients. Phosphorylation of transcription and translation regulators, c-Myc and 4E-BP1 declined in both model systems. Additionally, levels of short-lived Mcl-1 mRNA and protein also decreased and correlated with decline of global RNA synthesis. Collectively, our investigations highlight Pim kinases as viable drug targets in MCL and emphasize their roles in transcriptional and translational regulation. We further investigated a combination strategy using SGI-1776 with bendamustine, an FDA-approved DNA-damaging alkylating agent for treating non-Hodgkin’s lymphoma. We hypothesized this combination will enhance SGI-1776-induced transcription and translation inhibition, while promoting bendamustine-triggered DNA damage and inducing additive to synergistic cytotoxicity in B-cell lymphoma. Bendamustine alone resulted in moderate levels of apoptosis induction in MCL cell lines (JeKo-1 and Mino), and in MCL and splenic marginal zone lymphoma (a type of B-cell lymphoma) primary cells. An additive effect in cell killing was observed when combined with SGI-1776. Expectedly, SGI-1776 effectively decreased global RNA and protein synthesis levels, while bendamustine significantly inhibited DNA synthesis and generated DNA damage response. In combination, intensified inhibitory effects in DNA, RNA and protein syntheses were observed. Together, these data suggested feasibility of using Pim kinase inhibitor in combination with chemotherapeutic agents such as bendamustine in B-cell lymphoma, and provided foundation of their mechanism of actions in lymphoma cells.

Design, Synthesis and Development of Transporter Targeting Agents for Image-guided Therapy and Drug Delivery

The purpose of this study was to design, synthesize and develop novel transporter targeting agents for image-guided therapy and drug delivery. Two novel agents, N4-guanine (N4amG) and glycopeptide (GP) were synthesized for tumor cell proliferation assessment and cancer theranostic platform, respectively. N4amG and GP were synthesized and radiolabeled with 99mTc and 68Ga. The chemical and radiochemical purities as well as radiochemical stabilities of radiolabeled N4amG and GP were tested. In vitro stability assessment showed both 99mTc-N4amG and 99mTc-GP were stable up to 6 hours, whereas 68Ga-GP was stable up to 2 hours. Cell culture studies confirmed radiolabeled N4amG and GP could penetrate the cell membrane through nucleoside transporters and amino acid transporters, respectively. Up to 40% of intracellular 99mTc-N4amG and 99mTc-GP was found within cell nucleus following 2 hours of incubation. Flow cytometry analysis revealed 99mTc-N4amG was a cell cycle S phase-specific agent. There was a significant difference of the uptake of 99mTc-GP between pre- and post- paclitaxel-treated cells, which suggests that 99mTc-GP may be useful in chemotherapy treatment monitoring. Moreover, radiolabeled N4amG and GP were tested in vivo using tumor-bearing animal models. 99mTc-N4amG showed an increase in tumor-to-muscle count density ratios up to 5 at 4 hour imaging. Both 99mTc-labeled agents showed decreased tumor uptake after paclitaxel treatment. Immunohistochemistry analysis demonstrated that the uptake of 99mTc-N4amG was correlated with Ki-67 expression. Both 99mTc-N4amG and 99mTc-GP could differentiate between tumor and inflammation in animal studies. Furthermore, 68Ga-GP was compared to 18F-FDG in rabbit PET imaging studies. 68Ga-GP had lower tumor standardized uptake values (SUV), but similar uptake dynamics, and different biodistribution compared with 18F-FDG. Finally, to demonstrate that GP can be a potential drug carrier for cancer theranostics, several drugs, including doxorubicin, were selected to be conjugated to GP. Imaging studies demonstrated that tumor uptake of GP-drug conjugates was increased as a function of time. GP-doxorubicin (GP-DOX) showed a slow-release pattern in in vitro cytotoxicity assay and exhibited anti-cancer efficacy with reduced toxicity in in vivo tumor growth delay study. In conclusion, both N4amG and GP are transporter-based targeting agents. Radiolabeled N4amG can be used for tumor cell proliferation assessment. GP is a potential agent for image-guided therapy and drug delivery.

Brain structural and functional recovery following initiation of combination antiretroviral therapy

NeuroAIDS persists in the era of combination antiretroviral therapies. We describe here the recovery of brain structure and function following 6 months of therapy in a treatment-naive patient presenting with HIV-associated dementia. The patient’s neuropsychological test performance improved and his total brain volume increased by more than 5 %. Neuronal functional connectivity measured by magnetoencephalography changed from a pattern identical to that observed in other HIV-infected individuals to one that was indistinguishable from that of uninfected control subjects. These data suggest that at least some of the effects of HIV on the brain can be fully reversed with treatment.

Concomitant combination therapy for HIV infection preferable over sequential therapy with 3TC and non-nucleoside reverse transcriptase inhibitors

Exposure to 3TC of HIV-1 mutant strains containing non-nucleoside reverse transcriptase inhibitor (NNRTI)-specific mutations in their reverse transcriptase (RT) easily selected for double-mutant viruses that had acquired the characteristic 184-Ile mutation in their RT in addition to the NNRTI-specific mutations. Conversely, exposure of 3TC-resistant 184-Val mutant HIV-1 strains to nine different NNRTIs resulted in the rapid emergence of NNRTI-resistant virus strains at a time that was not more delayed than when wild-type HIV-1(IIIB) was exposed to the same compounds. The RTs of these resistant virus strains had acquired the NNRTI-characteristic mutations in addition to the preexisting 184-Val mutation. Surprisingly, when the 184-Ile mutant HIV-1 was exposed to a variety of NNRTIs, the 188-His mutation invariably occurred concomitantly with the 184-Ile mutation in the HIV-1 RT. Breakthrough of this double-mutant virus was markedly accelerated as compared with the mutant virus selected from the wild-type or 184-Val mutant HIV-1 strain. The double (184-Ile + 188-His) mutant virus showed a much more profound resistance profile against the NNRTIs than the 188-His HIV-1 mutant. In contrast with the sequential chemotherapy, concomitant combination treatment of HIV-1-infected cells with 3TC and a variety of NNRTIs resulted in a dramatic delay of virus breakthrough and resistance development.

Reduction of HIV-1 in blood and lymph nodes following potent antiretroviral therapy and the virologic correlates of treatment failure

Potent antiretroviral therapy can reduce plasma HIV RNA levels below the threshold of detection for periods of a year or more. The magnitude of HIV RNA reduction in the lymphoid tissue in patients with suppression of HIV RNA levels in plasma beyond 6 months has not been determined. We evaluated levels of HIV RNA and DNA and characterized resistance mutations in blood and inguinal lymph node biopsies obtained from 10 HIV-infected subjects who received 36–52 weeks of indinavir (IDV)/zidovudine (ZDV)/lamivudine (3TC), IDV, or ZDV/3TC. After 1 year of therapy, viral RNA levels in LN of individuals remained detectable but were log10 = 4 lower than in subjects on the triple drug regimen with interruption of therapy or in those treated with ZDV/3TC alone, who had viral loads in their lymph nodes indistinguishable from those expected for untreated patients. In all cases viral DNA remained detectable in lymph nodes and peripheral blood mononuclear cells (PBMC). When plasma virus suppression was incomplete, lymph node and PBMC cultures were positive and drug resistance developed. These studies indicate that pronounced and sustained suppression of plasma viremia by a potent antiretroviral combination is associated with low HIV RNA levels in the lymph nodes 1 year after treatment. Conversely, the persistence of even modest levels of plasma virus after 1 year of treatment reflects ongoing viral replication, the emergence of drug resistance, and the maintenance of high burdens of virus in the lymph nodes.

Rational interleukin 2 therapy for HIV positive individuals: daily low doses enhance immune function without toxicity.

When administered in high doses to HIV positive (HIV+) individuals, interleukin 2 (IL-2) causes extreme toxicity and markedly increases plasma HIV levels. Integration of the information from the structure-activity relationships of the IL-2 receptor interaction, the cellular distribution of the different classes of IL-2 receptors, and the pharmacokinetics of IL-2 provides for the rationale that low IL-2 doses should circumvent toxicity. Therefore, to identify a nontoxic, but effective and safe IL-2 treatment regimen that does not stimulate viral replication, doses of IL-2 from 62,500 to 250,000 IU/m2/day were administered subcutaneously for 6 months to 16 HIV+ individuals with 200-500 CD4+ T cells/mm3. IL-2 was already detectable in the plasma of most HIV+ individuals even before therapy. Peak plasma IL-2 levels were near saturating for high affinity IL-2 receptors in 10 individuals who received the maximum nontoxic dose, which ranged from 187,500 to 250,000 IU/m2/day. During the 6 months of treatment at this dose range, plasma levels of proinflammatory cytokines remained undetectable, and plasma HIV RNA levels did not change significantly. However, delayed type hypersensitivity responses to common recall antigens were markedly augmented, and there were IL-2 dose-dependent increases in circulating Natural Killer cells, eosinophils, monocytes, and CD4+ T cells. Expanded clinical trials of low dose IL-2 are now warranted, especially in combination with effective antivirals to test for the prevention of immunodeficiency and the emergence of drug-resistant mutants and for the eradication of residual virions.