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BackgroundLimited data exist comparing viral quasispecies between cerebrospinal fluid (CSF) and plasma compartments during primary HIV infection. Deep sequencing is a new method to examine the HIV plasma and CSF quasispecies.MethodsIn this pilot study, deep sequencing of protease (PR) and reverse transcriptase (RT) was performed in plasma and CSF from participants during primary HIV infection. Estimated mutational load was calculated by mutant variant frequency multiplied by HIV-RNA level.ResultsPaired plasma and CSF samples were studied from five antiretroviral therapy-naïve male participants with median 109 days post estimated transmission, age 32 years, CD4 cell count 580 cells/μL, HIV-RNA 5.18 log10 copies/mL in plasma and 3.67 log10 copies/mL in CSF. Plasma samples averaged 7,124 reads of PR and 2,448 reads of RT, whereas CSF samples averaged 7,082 and 2,792 reads, respectively. A distinct drug-resistance pattern with linked mutations present at significant levels (5-10%) was detected in one participant in CSF. Other low abundance variants (>0.2%) were detected in plasma and CSF of four out of five participants.ConclusionsDeep sequencing of CSF HIV is technically possible with sufficient HIV-RNA levels. Differences between the quasispecies in the two compartments detected in one participant, which were present with a high mutational load in CSF at an estimated 3.6 months after HIV infection, suggest that early CNS compartmentalisation may be revealed by sensitive deep-sequencing methods. The presence of distinct low abundance (

Objectives: The main objective of this analysis was to evaluate the impact of pre‐existing drug resistance by next‐generation sequencing (NGS) on the risk of treatment failure (TF) of first‐line regimens in participants enrolled in the START study. Methods: Stored plasma from participants with entry HIV RNA >1000 copies/mL were analysed using NGS (llumina MiSeq). Pre‐existing drug resistance was defined using the mutations considered by the Stanford HIV Drug Resistance Database (HIVDB v8.6) to calculate the genotypic susceptibility score (GSS, estimating the number of active drugs) for the first‐line regimen at the detection threshold windows of >20%, >5%, and >2% of the viral population. Survival analysis was conducted to evaluate the association between the GSS and risk of TF (viral load >200 copies/mL plus treatment change). Results: Baseline NGS data were available for 1380 antiretroviral therapy (ART)‐naïve participants enrolled over 2009–2013. First‐line ART included a non‐nucleoside reverse transcriptase inhibitor (NNRTI) in 976 (71%), a boosted protease inhibitor in 297 (22%), or an integrase strand transfer inhibitor in 107 (8%). The proportions of participants with GSS <3 were 7% for >20%, 10% for >5%, and 17% for the >2% thresholds, respectively. The adjusted hazard ratio of TF associated with a GSS of 0–2.75 versus 3 in the subset of participants with mutations detected at the >2% threshold was 1.66 (95% confidence interval 1.01–2.74; p = 0.05) and 2.32 (95% confidence interval 1.32–4.09; p = 0.003) after restricting the analysis to participants who started an NNRTI‐based regimen. Conclusions: Up to 17% of participants initiated ART with a GSS <3 on the basis of NGS data. Minority variants were predictive of TF, especially for participants starting NNRTI‐based regimens. [ABSTRACT FROM AUTHOR]

Common symptoms associated with HIV disease and its management are often underrecognized and undertreated. A clinical decision support tool for symptom management was developed within the Veterans Health Administration electronic medical record (EMR), aiming at increasing provider awareness of and response to common HIV symptoms. Its feasibility was studied in March to May 2007 by implementing it within a weekly HIV clinic, comparing a 4-week intervention period with a 4-week control period. Fifty-six patients and their providers participated in the study. Patients' perceptions of providers' awareness of their symptoms, proportion of progress notes mentioning any symptom(s) and proportion of care plans mentioning any symptom(s) were measured. The clinical decision support tool used portable electronic 'tablets' to elicit symptom information at the time of check-in, filtered, and organized that information into a concise and clinically relevant EMR note available at the point of care, and facilitated clinical responses to that information. It appeared to be well accepted by patients and providers and did not substantially impact workflow. Although this pilot study was not powered to detect effectiveness, 25 (93%) patients in the intervention group reported that their providers were very aware of their symptoms versuas 27 (75%) control patients (p = 0.07). The proportion of providers' notes listing symptoms was similar in both periods; however, there was a trend toward including a greater number of symptoms in intervention period progress notes. The symptom support tool seemed to be useful in clinical HIV care. The Veterans Health Administration EMR may be an effective 'laboratory' for developing and testing decision supports.

Hepatitis C infection (HCV) remains a global problem and the current anti-HCV therapies available in the clinic have sustained virologic response rates (SVR) of only about 50%, especially in HCV genotype 1-infected subjects. The SVR is even lower in HIV-HCV co-infected patients, estimated at only about 30-40%. However, exciting new research is under way to find new anti-HCV therapies. Presently, efforts to develop new anti-HCV agents for HCV-infected persons who fail pegylated interferon and ribavirin-based therapies have focused on inhibitors of key HCV enzymes such as the HCV NS3 protease and the NSSB polymerase. There are two protease inhibitors, telaprevir (VX-950, Vertex) and boceprevir (SCH 503034, Schering-Plough); and three polymerase inhibitors, valopicitabine (NM283, Idenix), R1626 (Roche), and HCV-796 (Viropharma) that have advanced to late-stage clinical trials. Of these aforementioned agents, telaprevir is the most advanced in clinical development. Early trial results on efficacy, safety, and HCV drug-resistance profiles of these novel agents will be discussed in this review paper.

Currently, there are three distinct mechanistic classes of antiretrovirals: inhibitors of the HIV-1 reverse transcriptase and protease enzymes and inhibitors of HIV entry, including receptor and coreceptor binding and cell fusion. A new drug class that inhibits the HIV-1 integrase enzyme (IN) is in development and may soon be available in the clinic. IN is an attractive drug target because it is essential for a stable and productive HIV-1 infection and there is no mammalian homologue of IN. Inhibitors of integrase enzyme (INI) block the integration of viral double-stranded DNA into the host cell's chromosomal DNA. HIV-1 integration has many potential steps that can be inhibited and several new compounds that target specific integration steps have been identified by drug developers. Recently, two INIs, GS-9137 and MK-0518, demonstrated promising early clinical trial results and have been advanced into later stage trials. In this review, we describe how IN facilitates HIV-1 integration, the needed enzyme cofactors, and the resultant byproducts created during integration. Furthermore, we review the different INIs under development, their mechanism of actions, site of IN inhibition, potency, resistance patterns, and discuss the early clinical trial results.

Background: Population‐based and longitudinal information regarding sexual risk behavior among patients with multidrug resistant (MDR) HIV and their sexual partners is of great public health and clinical importance. Objective: To characterize the HIV sexual risk behaviors of patients with and without drug‐resistant HIV in the clinical care setting over time. Measurements: 393 HIV‐positive patients completed questionnaires of self‐reported sexual risk behaviors at approximate 6‐month intervals extending over 24 months. HIV viral load and genotypic drug resistance obtained during the same time points were matched to the behavioral data. Multidrug resistance was defined as having resistance to 2 or 3 antiretroviral (ARV) drug classes. Results: In serial cross‐sectional analyses, 393 patients (44% female and 79% heterosexual) contributed 919 matched behavioral and virologic results over the 24 months of data collection. Of these, 250 patients (64%) reported having sex during at least 1 survey period resulting in greater than 10,000 sexual events with more than 1000 partners. Unprotected sexual behavior was reported by 45% of sexually active patients, resulting in 34% of all sex events that exposed 29% of all partners. Of these patients with unprotected sexual events, 31% had HIV drug resistance 11.6% with resistance to 2 classes of ARVs (2‐class), and 1.8% with 3‐class ARV resistance at the time of a sexual risk event. Close to 1000 or 28% of all unprotected sexual events involved resistant strains (11% of these with resistance to 2 classes and 0.2% with 3‐class resistance, exposing 20% of unprotected sexual partners to resistant HIV (8% to 2‐class and 0.6% to 3‐class resistance). In longitudinal analysis among the 78 patients who reported a cumulative total of 12 months of sexual history and had resistance testing, 38% reported engaging in unprotected sexual behavior. There was substantial and complex variation in the distribution of unprotected sexual events and in the detection of resistance over time. Conclusion: In this study of HIV sexual risk and resistance over time among HIV‐infected patients in clinical care, a substantial proportion engaged in unprotected sex and had drug‐resistant HIV, frequently exposing partners to 1‐ or 2‐class resistant HIV strains. However, relatively few exposures involved 3‐class resistance. The dynamics of sexual risk behavior and HIV drug resistance are complex and vary over time and urgently require both general and targeted interventions to reduce transmission of resistant HIV., Introduction The transmission of drug‐resistant strains of HIV‐1 to newly infected persons is now a major clinical and public health problem in developed countries with availability of antiretroviral (ARV) therapy [...]

A cross-sectional study is conducted to determine the prevalence of HIV drug resistance in HIV(super +) injection drug users receiving clinical care, the frequency with which they shared needles and perceived serostatus of needle-sharing partners they exposed to drug-resistant HIV. Strategies to reduce injection drug use risk behaviors among patients in clinical care are needed to reduce the transmission of sensitive and resistant HIV.

Acquired resistance to antiretroviral agents is an established sequela of HIV pharmacotherapy. Viral mutations can confer reduced susceptibility to antiretroviral medications, resulting in virologic and clinical failure in more than half of treated patients. Cross-resistance that can develop within each drug class leads to the progressive loss of future therapeutic options for individual patients. Although protease inhibitors (PIs) are a potent class of antiretrovirals, resistance can still develop rapidly, and multiple-PI resistance has become a serious, growing clinical problem. Development of rational treatment strategies that recognize specific patterns of cross-resistance among PIs are needed to help clinicians choose the most appropriate PI. Rational sequencing of PI use should be based on genotypic and phenotypic resistance testing. Maintaining higher drug plasma levels or using specific PI combinations may also diminish PI cross-resistance. New agents that are less likely to induce or be susceptible to cross-resistance will be of value in HIV treatment. This article reviews the acquisition of resistance to currently available PIs, discussing the drug-specific mutational patterns and evidence of clinical cross-resistance. The resistance profiles of two newer PIs, atazanavir and tipranavir, are also presented.