Maximal Viral Suppression Research Articles

Viral Suppression Levels in Men Who Have Sex With Men and Transgender Women With Newly Diagnosed HIV and Alcohol Use Disorder in Peru: Results From a Randomized, Double-Blind, Placebo-Controlled Trial Using Oral Naltrexone.

Alcohol use disorders (AUDs) are common in men who have sex with men (MSM) and transgender women (TGW) in Peru and undermine antiretroviral therapy (ART) adherence. Oral naltrexone (NTX) is an evidence-based treatment for AUD that has not been assessed in cotreating AUD in MSM/TGW with HIV. A multi-site, randomized, double-blind, placebo-controlled trial among MSM/TGW with AUD and newly diagnosed with HIV in Lima, Peru. Newly diagnosed MSM/TGW with HIV and AUD were prescribed a single-treatment regimen of EFV/TDF/FTC from 2014 to 2015 and randomized 2:1 to oral NTX (N = 103) or placebo (N = 53) for 24 weeks. The primary and secondary outcomes were proportion achieving viral suppression (VS: HIV-1 RNA < 400 copies/mL) or maximal viral suppression (MVS: HIV-1 RNA < 40 copies/mL) at 24 weeks. There were no significant differences between the arms in VS (81.6% NTX arm vs 75.5% placebo arm; P = 0.37) or MVS (61.2% NTX arm vs 66.0% placebo arm; P = 0.48). Adherence to study medication was low (mean = 34.6%) overall with only 21.4% of participants meeting recommended adherence levels (≥80% daily doses/month). Participants allocated to NTX had significantly lower adherence compared with placebo for both the first and second 12-week study periods, respectively (44.0% vs 35.2%, P = 0.04; 31.4% vs 35.2%, P = 0.03). Findings are inconclusive regarding the use of NTX for treatment of AUD in MSM/TGW newly diagnosed with HIV. VS and MVS levels were high irrespective of allocation. Adherence to study medication was low, requiring further exploration of strategies to optimize adherence to NTX as AUD treatment.

Determinants of HIV Treatment Adherence in Ethnically Diverse and Economically Disadvantaged Patients in a Tertiary Hospital, Nigeria

Antiretroviral Therapy (ART) Has Decreased The Mortality And Morbidity Of HIV/AIDS, And High Adherence To ART (&gt;95%) Is Necessary For A Good Therapeutic Outcome. Non-Adherence Can Lead To Drug-Resistant HIV Caused By Failure To Achieve Maximal Viral Suppression. Little Is Known About Adherence To ART And Its Determinants Among Ethnically Diverse And Economically Disadvantaged Patients. The Purpose Of The Study Was To Identify The Level Of Adherence And Describe Factors That Influence ART Adherence Among Ethnically Diverse And Economically Disadvantaged Patients. This Is With A View To Providing Information That Could Help Health Care Providers Understand Patient Motivations For Discontinuing Their Antiretroviral Treatment And Helping Patients Collaboratively Develop Treatment Regimens That Facilitate Adherence And Optimize The Outcomes Of HIV/AIDS Therapy. A Cross-Sectional Descriptive Survey Was Used. Data Were Collected Among 400 HIV-Infected Patients On ARV Who Received Pretreatment And Ongoing Adherence Counseling And Education Since 2010 Using A Self-Administered Questionnaire. The Data Were Analyzed Using Statistical Package For Social Sciences (SPSS). Findings Showed That The Self-Reported Adherence To The Specific Timing For Taking The Medications (Medication Schedule) Was Significantly Low (8.3%). The Major Factors For Non-Adherence To Medication Reported In This Study Were Being Busy At Work Or School, Forgetfulness, Fasting And Travelling Away From Home. Also, Employment Status Was Associated With Poor Adherence, Which May Be Corroborated By The Major Reason For Non-Adherence (Busy At Work Or School). This Study Is One Of The First Steps In The Exploration Of The Relationship Of Factors Responsible And Medication Adherence Among HIV Patients. This Study Used Three Different Measures Of Medication Adherence. These Are Patients’ Knowledge Of The Benefits Of Taking The Drugs, Adherence To A Medication Schedule, And The Number Of Prescribed Doses Of Medications Missed. Health Care Providers Must Identify Possible Barriers To Adherence At The Earliest And Provide Appropriate Solutions. These Factors Should Be Considered When Designing And Implementing Adherence Interventions.

Dolutegravir-Based Regimen for Maintenance of Viral Suppression in People Living with HIV: 48-Week Results in Real-Life Setting.

To evaluate the efficacy, safety, and tolerability of switching to a dolutegravir (DTG)-based regimen in a cohort of virological suppressed HIV-infected patients who have previously been treated with different antiretroviral combination. The dynamics of total HIV-DNA and levels of high-sensitivity c-reactive protein, interleukin-6, soluble-CD14, and D-Dimer were also analyzed. Ninety-six individuals who switched to a DTG-containing regimen were followed up for 48 weeks. HIV RNA, CD4+ T cell count, weight, and levels of laboratory parameters were recorded at baseline, after 24 and 48 weeks of treatment for all study participants. In a subgroup of patients, HIV DNA and inflammation/coagulation marker levels were also analyzed until week 24. Ninety-three out of 96 patients maintained virological suppression, including patients who switched to dual-therapy from triple-drug combination. Eighteen out of 96 patients had residual viremia at baseline, of which 13 reached the maximal viral suppression at W48. Serum creatinine levels showed a significant increase at weeks 24 and 48. A progressive reduction of total cholesterol was observed from week 24 and up to week 48. No variation in body mass index was detected. HIV DNA, inflammation, and coagulation marker levels did not significantly change during follow-up. Switching to a DTG-based regimen may be a key option for achieving and maintaining maximal virological suppression, even in patients showing residual viremia at baseline. Furthermore, the improvement in blood lipid profile and the overall tolerability observed in this study strongly support the use of these regimens in the aging HIV population.

1008. Disease Severity Impact on Long-Term Virologic Response to Ibalizumab in Expanded Access Protocol (TMB-311)

BackgroundThe principal goal of antiretroviral therapy (ART) is durable suppression of HIV RNA. In treatment-experienced (TE) patients, ongoing viremia can lead to further accumulation of drug resistance, increased morbidity and mortality. ART efficacy often depends on HIV disease severity; therefore, we sought to assess its impact on long-term virologic suppression in patients treated with Ibalizumab (IBA), the first long-acting, post-attachment inhibitor approved for multi-drug resistant (MDR) HIV-1 treatment.MethodsIn TMB-301, a Phase 3 study, 40 TE patients with viral load (VL) >1000 copies/mL (c/mL) received an intravenous (IV) loading dose of IBA (2000mg) followed by maintenance doses (800mg IV) every 2 weeks combined with an optimized background regimen. Patients who completed TMB-301 in the US (n=27) continued to an expanded access protocol TMB-311. To determine the impact of baseline (BL) disease on long-term virologic response, we conducted an on-treatment analysis stratified by BL VL and CD4 count up to week 96. Differences in the proportion of suppressed (< 50 c/mL) individuals among the strata were assessed by Fisher’s exact test.ResultsMedian BL VL and CD4 count were 35,350 c/mL and 73 cells/mL, respectively. The number of patients in the VL strata were 11, 17 and 12 for VL < 10,000, 10,000-70,000, and >70,000 c/mL, respectively. There were 12, 10, 5 and 13 patients in the subgroups with CD4 count < 10, 10-100, >100-200 and >200 cells/µL. Population disease severity was reflected by four deaths (unrelated to study drug). Overall, the proportion of suppressed patients increased from 55% at week 24 (n=31) to 75% for patients remaining on treatment for 96 weeks (n=20). Median VL decrease was 2.9 log10 c/mL. Notably, no statistically significant differences were found across groups. Among patients with advanced HIV disease, 66.7% with CD4 count < 10 cells/mL and 71.4% with VL >70,000 c/mL at BL remained fully suppressed at week 96.ConclusionIn TE patients with advanced HIV disease, maximal viral suppression with IBA was observed regardless of BL CD4 or VL strata if patients remained on treatment. This demonstrates that TE patients across the spectrum of HIV disease, can achieve viral suppression by using drugs with a new mechanism of action.Disclosures Princy Kumar, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Jason Leider, MD, PhD, THERA (Speaker’s Bureau) Jihad Slim, MD, Abbvie (Speaker’s Bureau)Gilead (Speaker’s Bureau)Jansen (Speaker’s Bureau)Merck (Speaker’s Bureau)ViiV (Speaker’s Bureau) Graeme Moyle, MD, Theratechnologies (Consultant) Maurice Leonard, PhD, Theratechnologies Europe Ltd (Employee, Shareholder) R Brandon Cash, PharmD, Theratechnologies (Employee) Steven Weinheimer, PhD, TaiMed Biologics USA (Employee) Pedro Mesquita, PhD, Theratechnologies, Inc. (Employee)

An Overview of Antiretroviral Agents for Treating HIV Infection in Paediatric Population.

Paediatric Acquired ImmunoDeficiency Syndrome (AIDS) is a life-threatening and infectious disease in which the Human Immunodeficiency Virus (HIV) is mainly transmitted through Mother-To- Child Transmission (MTCT) during pregnancy, labour and delivery, or breastfeeding. This review provides an overview of the distinct therapeutic alternatives to abolish the systemic viral replication in paediatric HIV-1 infection. Numerous classes of antiretroviral agents have emerged as therapeutic tools for downregulation of different steps in the HIV replication process. These classes encompass Non- Nucleoside Analogue Reverse Transcriptase Inhibitors (NNRTIs), Nucleoside/Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs/NtRTIs), INtegrase Inhibitors (INIs), Protease Inhibitors (PIs), and Entry Inhibitors (EIs). Co-administration of certain antiretroviral drugs with Pharmacokinetic Enhancers (PEs) may boost the effectiveness of the primary therapeutic agent. The combination of multiple antiretroviral drug regimens (Highly Active AntiRetroviral Therapy - HAART) is currently the standard therapeutic approach for HIV infection. So far, the use of HAART offers the best opportunity for prolonged and maximal viral suppression, and preservation of the immune system upon HIV infection. Still, the frequent administration of high doses of multiple drugs, their inefficient ability to reach the viral reservoirs in adequate doses, the development of drug resistance, and the lack of patient compliance compromise the complete HIV elimination. The development of nanotechnology-based drug delivery systems may enable targeted delivery of antiretroviral agents to inaccessible viral reservoir sites at therapeutic concentrations. In addition, the application of Computer-Aided Drug Design (CADD) approaches has provided valuable tools for the development of anti-HIV drug candidates with favourable pharmacodynamics and pharmacokinetic properties.

Correlates of viral suppression among HIV-infected men who have sex with men and transgender women in Lima, Peru

ABSTRACTIn Peru, HIV is concentrated among men who have sex with men (MSM) and transgender women (TGW). Between June 2015 and August 2016, 591 HIV-positive MSM and TGW were recruited at five clinical care sites in Lima, Peru. We found that 82.4% of the participants had achieved viral suppression (VS; VL < 200) and 73.6% had achieved maximal viral suppression (MVS; VL < 50). Multivariable modeling indicated that patients reporting transportation as a barrier to HIV care were less likely to achieve VS (aOR = 0.47; 95% CI = 0.30–0.75) and MVS (aOR = 0.56; 95% CI = 0.37–0.84). Alcohol use disorders were negatively associated with MVS (aOR = 0.62; 95% CI = 0.30–0.75) and age was positively associated with achieving MVS (aOR = 1.29; 95% CI = 1.04–1.59). These findings underscore the need for more accessible HIV care with integrated behavioral health services in Lima, Peru.

Establishment of intracellular tenofovir-diphosphate as the key determinant for in vitro-in vivo translation of antiviral efficacy

In vitro evaluation of tenofovir disproxil fumarate (TDF) and tenofovir alafenamide (TAF) revealed comparable antiviral effects with respect to the tenofovir-diphosphate (TFV-DP) level in human peripheral blood mononuclear cells (PBMCs), despite the EC50 values determined based on prodrug concentrations were nearly two orders of magnitude apart. In vivo EC50 obtained from meta-analyses were in good agreement with the in vitro results, indicating intracellular TFV-DP can be employed for in vitro-in vivo translation of viral inhibition for tenofovir prodrugs. Current analysis indicated that the intracellular concentrations of TFV-DP achieving maximal antiviral effect in vitro can be directly translatable in the clinic to accomplish maximal viral load suppression attainable by tenofovir-prodrugs.

Determinants of adherence to antiretroviral therapy among HIV-positive adults in sub-Saharan Africa: a systematic review

ObjectiveThe rapid scale up of antiretroviral treatment (ART) in sub-Saharan Africa (SSA) has resulted in an increased focus on patient adherence. Non-adherence can lead to drug-resistant HIV caused by failure...

Measuring Adherence to HIV Pre-Exposure Prophylaxis through Dried Blood Spots.

An important recent development in the field of HIV/AIDS care and treatment is the discovery that taking an antiretroviral medication 2–24 h before high risk sexual activity followed by daily doses for 2 days significantly lowers risk for HIV transmission (1). This strategy, called preexposure prophylaxis or PrEP,3 is naturally changing behavior amongst high-risk groups who are HIV negative. The particular approach of taking pills just before and after a high-risk encounter is known as “on demand” or “intermittent” use and has important practical implications. The conventional dictate for antiretroviral therapy has been that maximal viral suppression occurs when patients take at least 90% of their doses. For PrEP, although the recommendation is still that largest protection is upon daily dosing, high-risk individuals may take the medication around only high-risk encounters. To understand how we can know when PrEP users have adequate protection to guide clinical, or in this case, preclinical care, we spoke with Dr. Peter Anderson, professor of pharmaceutical sciences at the University of Colorado, who has had a long interest in nucleoside analogs and has developed an assay to measure adherence to PrEP. To determine if an HIV positive patient is taking …

Systemic Immune Activation and HIV Shedding in the Female Genital Tract.

Plasma HIV RNA is the most significant determinant of cervical HIV shedding. However, shedding is also associated with sexually transmitted infections (STIs) and cervical inflammation. The mechanism by which this occurs is poorly understood. There is evidence that systemic immune activation promotes viral entry, replication, and HIV disease progression. We hypothesized that systemic immune activation would be associated with an increase in HIV genital shedding. Clinical assessments, HIV RNA in plasma and genital secretions, and markers of immune activation (CD38(+)DR(+) and CD38(-)DR(-)) on CD4(+) and CD8(+) T cells in blood were evaluated in 226 HIV+ women enrolled in the Women's Interagency HIV Study. There were 569 genital evaluations of which 159 (28%) exhibited HIV RNA shedding, defined as HIV viral load >80 copies per milliliter. We tested associations between immune activation and shedding using generalized estimating equations with logit link function. In the univariate model, higher levels of CD4(+) and CD8(+) T-cell activation in blood were significantly associated with genital tract shedding. However, in the multivariate model adjusting for plasma HIV RNA, STIs, and genital tract infections, only higher levels of resting CD8(+) T cells (CD38(-)DR(-)) were significantly inversely associated with HIV shedding in the genital tract (odds ratios = 0.44, 95% confidence interval: 0.21 to 0.9, P = 0.02). The association of systemic immune activation with genital HIV shedding is multifactorial. Systemic T-cell activation is associated with genital tract shedding in univariate analysis but not when adjusting for plasma HIV RNA, STIs, and genital tract infections. In addition, women with high percentage of resting T cells are less likely to have HIV shedding compared with those with lower percentages. These findings suggest that a higher percentage of resting cells, as a result of maximal viral suppression with treatment, may decrease local genital activation, HIV shedding, and transmission.

Pharmacokinetic enhancers in HIV therapeutics.

Maximal and durable viral load suppression is one of the most important goals of HIV therapy and is directly related to adequate drug exposure. Protease inhibitors (PIs), an important component of the antiretroviral armada, were historically associated with poor oral bioavailability and high pill burden. However, because the PIs are metabolized by cytochrome P450 (CYP) 3A enzymes, intentional inhibition of these enzymes leads to higher drug exposure, lower pill burden, and therefore simplified dosing schedules with this class of drug. This is the basis of pharmacokinetic enhancement. In HIV therapy, two pharmacokinetic enhancers or boosting agents are used: ritonavir and cobicistat. Both agents inhibit CYP3A4, with cobicistat being a more specific CYP inhibitor than ritonavir. Unlike ritonavir, cobicistat does not have antiretroviral activity. Cobicistat has been evaluated in clinical trials and was recently approved in the USA as a fixed-dose combination with the integrase inhibitor, elvitegravir and two nucleos(t)ide analogs. Additional studies are examining cobicistat in fixed-dose combinations with various PIs. In this review, we summarize current knowledge of these agents and clinically relevant drug regimens and ongoing trials. Studies with elvitegravir and the novel PI TMC319011 are also discussed.

Deep Sequencing of HIV: Clinical and Research Applications

Human immunodeficiency virus (HIV) exhibits remarkable diversity in its genomic makeup and exists in any given individual as a complex distribution of closely related but nonidentical genomes called a viral quasispecies, which is subject to genetic variation, competition, and selection. This viral diversity clinically manifests as a selection of mutant variants based on viral fitness in treatment-naive individuals and based on drug-selective pressure in those on antiretroviral therapy (ART). The current standard-of-care ART consists of a combination of antiretroviral agents, which ensures maximal viral suppression while preventing the emergence of drug-resistant HIV variants. Unfortunately, transmission of drug-resistant HIV does occur, affecting 5% to >20% of newly infected individuals. To optimize therapy, clinicians rely on viral genotypic information obtained from conventional population sequencing-based assays, which cannot reliably detect viral variants that constitute <20% of the circulating viral quasispecies. These low-frequency variants can be detected by highly sensitive genotyping methods collectively grouped under the moniker of deep sequencing. Low-frequency variants have been correlated to treatment failures and HIV transmission, and detection of these variants is helping to inform strategies for vaccine development. Here, we discuss the molecular virology of HIV, viral heterogeneity, drug-resistance mutations, and the application of deep sequencing technologies in research and the clinical care of HIV-infected individuals.

Residual Viremia in an RT-SHIV Rhesus Macaque HAART Model Marked by the Presence of a Predominant Plasma Clone and a Lack of Viral Evolution

Highly active antiretroviral therapy (HAART) significantly reduces HIV-1 replication and prevents progression to AIDS. However, residual low-level viremia (LLV) persists and long-lived viral reservoirs are maintained in anatomical sites. These reservoirs permit a recrudescence of viremia upon cessation of therapy and thus HAART must be maintained indefinitely. HIV-1 reservoirs include latently infected resting memory CD4+ T-cells and macrophages which may contribute to residual viremia. It has not been conclusively determined if a component of LLV may also be due to residual replication in cells with sub-therapeutic drug levels and/or long-lived chronically infected cells. In this study, RT-SHIVmac239 diversity was characterized in five rhesus macaques that received a five-drug HAART regimen [tenofovir, emtricitabine, zidovudine, amdoxovir, (A, C, T, G nucleoside analogs) and the non-nucleoside reverse transcriptase (RT) inhibitor efavirenz]. Before maximal viral load suppression, longitudinal plasma viral RNA RT diversity was analyzed using a 454 sequencer. After suppression, LLV RT diversity (amino acids 65-210) was also assessed. LLV samples had viral levels less than our standard detection limit (50 viral RNA copies/mL) and few transient blips <200 RNA copies/mL. HAART was discontinued in three macaques after 42 weeks of therapy resulting in viral rebound. The level of viral divergence and the prevalence of specific alleles in LLV was similar to pre-suppression viremia. While some LLV sequences contained mutations not observed in the pre-suppression profile, LLV was not characterized by temporal viral evolution or apparent selection of drug resistance mutations. Similarly, resistance mutations were not detected in the viral rebound population. Interestingly, one macaque maintained a putative LLV predominant plasma clone sequence. Together, these results suggest that residual replication did not markedly contribute to LLV and that this model mimics the prevalence and phylogenetic characteristics of LLV during human HAART. Therefore, this model may be ideal for testing HIV-1 eradication strategies.

The role of lipopolysaccharide as a marker of immune activation in HIV-1 infected patients: a systematic literature review

BackgroundRecent observational studies suggest a role for lipopolysaccharide (LPS) as a marker of immune activation in HIV-infected patients, with potential repercussions on the effectiveness of antiretroviral regimens.ObjectA systematic review of LPS as a marker of immune activation in HIV-1 infected patients.Data sourcesMEDLINE register of articles and international conference proceedings.Review methodsCase–control studies comparing the role of plasma LPS as a marker of immune activation in HIV-infected patients versus HIV negative subjects.Data synthesisTwo hundred and six articles were selected using MEDLINE, plus 51 studies presented at international conferences. Plasma LPS is a marker of immune activation in HIV-infected patients, determining the entry of central memory CD4+ T cells into the replication cycle and finally generating cell death. Plasma LPS probably results from immune-mediated alterations of the intestinal barrier, which can occur soon after HIV seroconversion. LPS is a likely marker of disease progression, as it drives chronic monocyte activation, and some studies suggest that hyperexpression of CCR5 receptors, related to LPS plasma levels, could be responsible for monocyte trafficking in the brain compartment and for the appearance of HIV-associated neurocognitive disorders. Long-term combination antiretroviral therapy (cART) generally reduces LPS concentrations, but rarely to the same levels as in the control group. This phenomenon probably depends on ongoing but incomplete repair of the mucosal barrier. Only in patients achieving maximal viral suppression (i.e. viral load < 2.5 cp/ml) are LPS levels comparable to healthy donors. In successfully treated patients who did not restore CD4+ T cells, one hypothesis is that the degree of residual microbial translocation, measured by LPS, alters the turnover of CD4+ T cells.ConclusionsLPS is a marker of microbial translocation, responsible for chronic immune activation in HIV-infected patients. Even in successfully treated patients, LPS values are rarely normal. Several studies suggest a role for LPS as a negative predictive marker of immune restoration in patients with blunted CD4 T cell gain.

CC3-02: Risk Factors for Short-term Virologic Outcomes Among HIV-infected Patients Undergoing Regimen Switch of Combination Antiretroviral Therapy

Abstract We investigated risk factors for unfavorable virologic responses among HIV-infected patients who recently switched antiretroviral regimens. We identified HIV-infected patients who switched antiretroviral regimens (defined as adding ≥2 new medications) between 2001 and 2008 at Kaiser Permanente California. Virological response, measured after 6 months on the new regimen, was classified as (1) maximal viral suppression (HIV RNA 5000/ml). Potential risk factors examined included (1) HIV disease factors, e.g., prior AIDS, CD4 cell count; (2) history of antiretroviral use, e.g., therapy classes of the newly switched regimen, medication adherence, and virologic failure at previous regimens; and (3) novel patient-level factors including comorbidities and healthcare utilization. Adjusted odds ratios (aOR) for LLV and advanced virologic failure were obtained from multivariable nominal logistic regression models. A total ...

Influence of provider experience on antiretroviral adherence and viral suppression

Background and aimEarly in the combination antiretroviral therapy (cART) era, provider experience (as measured by panel size) was associated with improved outcomes. We explored that association and other characteristics of provider experience.MethodsWe performed a retrospective cohort analysis in Kaiser Permanente California (an integrated health care system in the United States), examining all human immunodeficiency virus seropositive (HIV+) patients initiating a first cART regimen (antiretroviral therapy [ART]-naïve, N = 7071) or initiating a second or later cART regimen (ART-experienced, N = 3730) from 1996–2006. We measured ART adherence through 12 months (pharmacy fill and refill records) and determined HIV viral load levels below limits of quantification at 12 months. Provider experience, updated annually, was measured as (1) HIV panel size (0–10 patients as reference strata), (2) years treating HIV (less than 1 year as reference), and (3) specialty ( noninfectious disease specialty, non-HIV expert as reference). We assessed associations by utilizing mixed modeling analyses (clustered by provider and medical center), controlling for patient age, sex, race/ethnicity, HIV risk behavior, hepatitis C coinfection, ART regimen class, and calendar year.ResultsAmong the ART-experienced, improved adherence was associated with greater years experience (mean increase 3.1% 2–5 years experience; 3.7% 5–10 years; 2.7% 11–20 years; P = 0.07, categorical). In adjusted analyses, viral suppression among ART-naïve was positively associated with panel size (odds ratio 26–50 patients: 1.31, P = 0.03, categorical), but negatively associated with years experience (18% less for greater than 100 patients; P = 0.003). No provider characteristic was significantly associated with improved adherence among ART-naïve or odds of maximal viral suppression among ART-experienced in adjusted analysis.ConclusionsExcept for panel size and years experience among ART-naïve, provider characteristics did not significantly influence ART adherence or likelihood of viral suppression.

Retention on Buprenorphine Is Associated with High Levels of Maximal Viral Suppression among HIV-Infected Opioid Dependent Released Prisoners

IntroductionHIV-infected prisoners lose viral suppression within the 12 weeks after release to the community. This prospective study evaluates the use of buprenorphine/naloxone (BPN/NLX) as a method to reduce relapse to opioid use and sustain viral suppression among released HIV-infected prisoners meeting criteria for opioid dependence (OD).MethodsFrom 2005–2010, 94 subjects meeting DSM-IV criteria for OD were recruited from a 24-week prospective trial of directly administered antiretroviral therapy (DAART) for released HIV-infected prisoners; 50 (53%) selected BPN/NLX and were eligible to receive it for 6 months; the remaining 44 (47%) selected no BPN/NLX therapy. Maximum viral suppression (MVS), defined as HIV-1 RNA<50 copies/mL, was compared for the BPN/NLX and non-BPN/NLX (N = 44) groups.ResultsThe two groups were similar, except the BPN/NLX group was significantly more likely to be Hispanic (56.0% v 20.4%), from Hartford (74.4% v 47.7%) and have higher mean global health quality of life indicator scores (54.18 v 51.40). MVS after 24 weeks of being released was statistically correlated with 24-week retention on BPN/NLX [AOR = 5.37 (1.15, 25.1)], having MVS at the time of prison-release [AOR = 10.5 (3.21, 34.1)] and negatively with being Black [AOR = 0.13 (0.03, 0.68)]. Receiving DAART or methadone did not correlate with MVS.ConclusionsIn recognition that OD is a chronic relapsing disease, strategies that initiate and retain HIV-infected prisoners with OD on BPN/NLX is an important strategy for improving HIV treatment outcomes as a community transition strategy.

Risk Factors for Short-Term Virologic Outcomes Among HIV-Infected Patients Undergoing Regimen Switch of Combination Antiretroviral Therapy

We investigated risk factors for unfavorable virologic responses among HIV-infected patients who recently switched antiretroviral regimens. We identified HIV-infected patients who switched antiretroviral regimens (defined as adding ≥2 new medications) between 2001 and 2008 at Kaiser Permanente California. Virological response, measured after 6 months on the new regimen, was classified as (1) maximal viral suppression (HIV RNA <75/ml), (2) low-level viremia (LLV; 75-5000/ml), or (3) advanced virologic failure (>5000/ml). Potential risk factors examined included (1) HIV disease factors, e.g., prior AIDS, CD4 cell count; (2) history of antiretroviral use, e.g., therapy classes of the newly switched regimen, medication adherence, and virologic failure at previous regimens; and (3) novel patient-level factors including comorbidities and healthcare utilization. Adjusted odds ratios (aOR) for LLV and advanced virologic failure were obtained from multivariable nominal logistic regression models. A total of 3447 patients were included; 2608 (76%) achieved maximal viral suppression, 420 (12%) had LLV, and 419 (12%) developed advanced virologic failure. Factors positively associated with LLV and advanced virologic failure included number of regimens prior to switch [aOR(per regimen)=1.38 (1.17-1.62) and 1.77 (1.50-2.08), respectively], nucleotide reverse transcriptase inhibitor-only regimens (vs. protease inhibitor-based) [aOR=2.78 (1.28-6.04) and 5.10 (2.38-10.90), respectively], and virologic failure at previous regimens [aOR=3.15 (2.17-4.57) and 4.71 (2.84-7.81), respectively]. Older age, higher CD4 cell count, and medication adherence were protective for unfavorable virologic outcomes. Antiretroviral regimen-level factors and immunodeficiency were significantly associated with virologic failure after a recent therapy switch and should be considered when making treatment change decisions.

Telbivudine: A valuable treatment option in chronic hepatitis B

The last five years have emerged as a new era in the treatment of chronic hepatitis B (CHB). Advances in therapeutics and the approval of new drugs have been accompanied by a better understanding of the natural history and pathogenesis, as well as better diagnostics. In the treatment of CHB, no therapy has been proven to eradicate the virus completely from the human body due to the persistence of the covalently closed circular hepatitis B virus (HBV) DNA in the hepatocytes. Long-term maximal viral suppression is of utmost importance for the prevention of disease progression and hepatocellular cirrhosis development. Telbivudine is one of the more potent options, with phase III studies indicating its antiviral potency with 6- to 6.5-log 10 copies / mL reductions in HBV DNA levels at year one, comparable to other potent agents such as entecavir or tenofovir. The increasing rates of hepatitis B e antigen (HBeAg) seroconversion were achieved in HBeAg-positive patients during periods of up to four years of continuous telbivudine treatment, and seroconversion was durable in most patients throughout a two-year, off-treatment follow-up, indicating the potential for a finite treatment period in this group of patients. Long-term telbivudine treatment offers effective viral suppression to CHB patients, with certain baseline characteristics and on-treatment virological response. It is also one of the few drugs in the treatment of CHB under FDA pregnancy Category B. Telbivudine is well-tolerated, with elevations in creatine phosphokinase being the most common abnormality observed in the clinical trials. Most often, elevations have been asymptomatic. There are few new drugs for hepatitis B in the pipeline, with the agent farthest along in development, clevudine, halted for problems with muscle toxicity. Future research in hepatitis B will focus on the best ways to use the existing therapies, including telbivudine, sequentially or in combination, in order to maximize viral suppression and minimize the development of antiviral resistance.

Low-Level Exposure to HIV Induces Virus-Specific T Cell Responses and Immune Activation in Exposed HIV-Seronegative Individuals

HIV-specific T cells response and T cell activation are frequently seen in exposed seronegative individuals (ESN). In this study, we report HIV-specific response and level of T cell activation in ESN partners of HIV-infected patients presenting low or undetectable levels of HIV-RNA. We evaluated 24 HIV-serodiscordant couples. ESN were classified into three categories of exposure to HIV (very low, low, and moderate-high), considering levels of HIV-RNA in their infected partner and frequency of sexual high-risk practices within the last 12 mo. HIV-specific T cell responses and activation levels in T cell subsets were evaluated by flow cytometry. We reported that 54% of ESN had detectable HIV-specific T cells response, being the highest prevalence seen in the low exposure group (64%). Several T cell subsets were significantly increased in ESN when compared with controls: CD4(+)CD38(+) (p = 0.006), CD4(+)HLA-DR(-)CD38(+) (p = 0.02), CD4(+)CD45RA(+)CD27(+)HLA-DR(-)CD38(+) (p = 0.002), CD8(+)CD45RA(+)CD27(+)CD38(-)HLA-DR(+) (p = 0.02), and CD8(+)CD45RA(+)CD27(-)CD38(+)HLA-DR(+) (p = 0.03). Activation of CD8(+) T cells was increased in ESN with detectable HIV T cell responses compared with ESN lacking these responses (p = 0.04). Taken together, these results suggest that persistent but low sexual HIV exposure is able to induce virus-specific T cells response and immune activation in a high proportion of ESN, suggesting that virus exposure may occur even in conditions of maximal viral suppression in the HIV-infected partner.