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Background: People living with human immunodeficiency virus (HIV) with immuno-virological discordant responses are at an increased risk to develop acquired immunodeficiency syndrome (AIDS) and severe non AIDS events which are risk factors for death. This study was aimed to assess prevalence of immuno- virological discordant responses and associated risk factors among highly active antiretroviral therapy (HAART) users in Tigray, Northern Ethiopia., Methods: A cross sectional study was conducted from September to December 30, 2016 on 260 people living with HIV who started first line HAART from January 2008 to March 2016 at Mekelle hospital and Ayder comprehensive specialized hospital. Baseline and follow-up clinical data and CD4+ result were collected from patient charts. Besides, socio-demographic data and blood samples for CD4 + count and viral load measurement were collected during data collection period. Fisher's exact test, bivariate and multivariate logistic regressions were used for data analysis. P-value < 0.05 with 95% CI was considered as statistically significant., Result: Among the 260 study participants, 8.80% (95% Confidence Interval (CI) =8.77-8.84%) and 2.70% (95% CI = 2.68-2.72%) had virological and immunological discordant responses, respectively with an overall immuno-virological discordance response of 11.50% (95% CI = 11.46-11.54%). The median age of the study participants at HAART initiation was 35 (IQR: 28-44 years). More than half (58.1%) of the study participants were females. Age at or below 35 years old at HAART initiation (AOR ((95% CI) = 4.25(1.48-12.23), p = 0.007)), male gender ((Adjusted Odds Ratio (AOR) (95% CI) =1.71(1.13-1.10), p = 0.029)), type of regimen given ((AOR(95% CI) = 0.30 (0.10-0.88), p = 0.028)) and good treatment adherence ((AOR (95% CI) = 0.12 (0.030-0.0.48), p = 0.003)) were associated risk factors for virological discordant response. Likewise, immunological discordant response was associated with tuberculosis co-infections (p = 0.016), hepatitis B virus co-infections (p = 0.05) and low CD4+ count (≤100 cells/μl) at baseline (p = 0.026)., Conclusions: Over all, immuno-virological discordance response was 11.5% in the study area. Males, low baseline CD4+ count, poor/fair treatment adherence, and TB and HBV co-infections were significantly associated with higher immuno-virological discordance. We recommend that decision of patient treatment outcome, regimen change and patient management response should be done using trends of both viral load and CD4+ count concurrently.

Objectives: Understanding the determinants of HIV immune control is important for seeking viable HIV prevention, treatment and curative strategies. The antigen-specific roles of CD8 T cells in controlling primary HIV infection have been well documented, but their abilities to control the latent HIV reservoir is less well studied., Methods: The scientific literature on this issue was searched on PubMed., Results: Recent reports have demonstrated that CD8 T cells are also involved in the control of viral replication in HIV-infected individuals receiving antiretroviral therapy (ART). However, based on accumulating evidence, the antiviral role of CD8 T cells in ART patients may not be achieved via an antigen-specific manner as HIV-specific CD8 T cells can sense, but not effectively eliminate, cells harbouring intact provirus without first being activated. Our recent study indicated that virtual memory CD8 T cells, a semi-differentiated component of CD8 T cells, may be involved in the mechanism restraining the HIV DNA reservoir in ART patients., Conclusions: In this review, we summarize recent findings on the role of CD8 T cells in controlling HIV, highlighting differences between conventional antigen-specific and innate-like CD8 T cells. A better understanding of the roles of CD8 T cells during HIV infection should benefit the informed design of immune-based treatment strategies., (© 2020 British HIV Association.)

HIV reservoirs persist despite successful antiretroviral therapy (ART) and are a major obstacle to the eradication and cure of HIV. The mature monocyte subset, CD14 + CD16 + , contributes to viral reservoirs and HIV-associated comorbidities. Only a subset of monocytes harbors HIV (HIV + ), while the rest remain uninfected, exposed cells (HIV exp ). We developed an innovative single cell RNA sequencing (scRNAseq) pipeline that detects HIV and host transcripts simultaneously, enabling us to examine differences between HIV + and HIV exp mature monocytes. Using this, we characterized uninfected, HIV + , and HIV exp primary human mature monocytes with and without ART. We showed that HIV + mature monocytes do not form their own cluster separately from HIV exp but can be distinguished by significant differential gene expression. We found that ART decreased levels of unspliced HIV transcripts potentially by modulating host transcriptional regulators shown to decrease viral infection and replication. We also identified and characterized mature monocyte subpopulations differentially impacted by HIV and ART. We identified genes dysregulated by ART in HIV exp monocytes compared to their uninfected counterpart and, of interest, the junctional protein ALCAM, suggesting that ART impacts monocyte functions. Our data provide a novel method for simultaneous detection of HIV and host transcripts. We identify potential targets, such as those genes whose expression is increased in HIV + mature monocytes compared to HIV exp , to block their entry into tissues, preventing establishment/replenishment of HIV reservoirs even with ART, thereby reducing and/or eliminating viral burden and HIV-associated comorbidities. Our data also highlight the heterogeneity of mature monocyte subsets and their potential contributions to HIV pathogenesis in the ART era. IMPORTANCE HIV enters tissues early after infection, leading to establishment and persistence of HIV reservoirs despite antiretroviral therapy (ART). Viral reservoirs are a major obstacle to the eradication and cure of HIV. CD14 + CD16 + (mature) monocytes may contribute to establishment and reseeding of reservoirs. A subset of monocytes, consisting mainly of CD14 + CD16 + cells, harbors HIV (HIV + ), while the rest remain uninfected, exposed cells (HIV exp ). It is important to identify cells harboring virus to eliminate reservoirs. Using an innovative single-cell RNA sequencing (scRNAseq) pipeline to detect HIV and host transcripts simultaneously, we characterized HIV + and HIV exp primary human mature monocytes with and without ART. HIV + mature monocytes are not a unique subpopulation but rather can be distinguished from HIV exp by differential gene expression. We characterized mature monocyte subpopulations differently impacted by HIV and ART, highlighting their potential contributions to HIV-associated comorbidities. Our data propose therapeutic targets to block HIV + monocyte entry into tissues, preventing establishment and replenishment of reservoirs even with ART., (Copyright © 2020 León-Rivera et al.)

Approximately 20% of people with HIV in the United States prescribed antiretroviral therapy are not virally suppressed. Thus, optimal management of virologic failure has a critical role in the ability to improve viral suppression rates to improve long-term health outcomes for those infected and to achieve epidemic control. This article discusses the causes of virologic failure, the use of resistance testing to guide management after failure, interpretation and relevance of HIV drug resistance patterns, considerations for selection of second-line and salvage therapies, and management of virologic failure in special populations., (Copyright © 2019 Elsevier Inc. All rights reserved.)

HIV replication within tissues may increase in response to a reduced exposure to antiretroviral drugs. Traditional approaches to measuring drug concentrations in tissues are unable to characterize a heterogeneous drug distribution. Here, we used mass spectrometry imaging (MSI) to visualize the distribution of six HIV antiretroviral drugs in gut tissue sections from three species (two strains of humanized mice, macaques, and humans). We measured drug concentrations in proximity to CD3 + T cells that are targeted by HIV, as well as expression of HIV or SHIV RNA and expression of the MDR1 drug efflux transporter in gut tissue from HIV-infected humanized mice, SHIV-infected macaques, and HIV-infected humans treated with combination antiretroviral drug therapy. Serial 10-μm sections of snap-frozen ileal and rectal tissue were analyzed by MSI for CD3 + T cells and MDR1 efflux transporter expression by immunofluorescence and immunohistochemistry, respectively. The tissue slices were analyzed for HIV/SHIV RNA expression by in situ hybridization and for antiretroviral drug concentrations by liquid chromatography-mass spectrometry. The gastrointestinal tissue distribution of the six drugs was heterogeneous. Fifty percent to 60% of CD3 + T cells did not colocalize with detectable drug concentrations in the gut tissue. In all three species, up to 90% of HIV/SHIV RNA was found to be expressed in gut tissue with no exposure to drug. These data suggest that there may be gut regions with little to no exposure to antiretroviral drugs, which may result in low-level HIV replication contributing to HIV persistence., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Objective: Definitions of virological response vary from <50 up to 1000 copies of HIV-RNA/mL. Our previous models estimate the probability of HIV drug combinations reducing the viral load to <50 copies/mL, with no indication of whether higher thresholds of response may be achieved. Here, we describe the development of models that predict absolute viral load over time., Methods: Two sets of random forest models were developed using 50,270 treatment change episodes from more than 20 countries. The models estimated viral load at different time points following the introduction of a new regimen from variables including baseline viral load, CD4 count, and treatment history. One set also used genotypes in their predictions. Independent data sets were used for evaluation., Results: Both models achieved highly significant correlations between predicted and actual viral load changes (r = 0.67-0.68, mean absolute error of 0.73-0.74 log10 copies/mL). The models produced curves of virological response over time. Using failure definitions of <100, 400, or 1000 copies/mL, but not 50 copies/mL, both models were able to identify alternative regimens they predicted to be effective for the majority of cases where the new regimen prescribed in the clinic failed., Conclusions: These models could be useful for selecting the optimum combination therapy for patients requiring a change in therapy in settings using any definition of virological response. They also give an idea of the likely response curve over time. Given that genotypes are not required, these models could be a useful addition to the HIV-TRePS system for those in resource-limited settings.

The HIV accessory protein Nef modulates key immune evasion and pathogenic functions, and its encoding gene region exhibits high sequence diversity. Given the recent identification of early HIV-specific adaptive immune responses as novel correlates of HIV reservoir size, we hypothesized that viral factors that facilitate the evasion of such responses-namely, Nef genetic and functional diversity-might also influence reservoir establishment and/or persistence. We isolated baseline plasma HIV RNA-derived nef clones from 30 acute/early-infected individuals who participated in a clinical trial of early combination antiretroviral therapy (cART) (<6 months following infection) and assessed each Nef clone's ability to downregulate CD4 and human leukocyte antigen (HLA) class I in vitro We then explored the relationships between baseline clinical, immunological, and virological characteristics and the HIV reservoir size measured 48 weeks following initiation of suppressive cART (where the reservoir size was quantified in terms of the proviral DNA loads as well as the levels of replication-competent HIV in CD4 + T cells). Maximal within-host Nef-mediated downregulation of HLA, but not CD4, correlated positively with post-cART proviral DNA levels (Spearman's R  = 0.61, P  = 0.0004) and replication-competent reservoir sizes (Spearman's R  = 0.36, P  = 0.056) in univariable analyses. Furthermore, the Nef-mediated HLA downregulation function was retained in final multivariable models adjusting for established clinical and immunological correlates of reservoir size. Finally, HIV subtype B-infected persons ( n  = 25) harbored significantly larger viral reservoirs than non-subtype B-infected persons (2 infected with subtype CRF01&#95;AE and 3 infected with subtype G). Our results highlight a potentially important role of viral factors-in particular, HIV subtype and accessory protein function-in modulating viral reservoir establishment and persistence. IMPORTANCE While combination antiretroviral therapies (cART) have transformed HIV infection into a chronic manageable condition, they do not act upon the latent HIV reservoir and are therefore not curative. As HIV cure or remission should be more readily achievable in individuals with smaller HIV reservoirs, achieving a deeper understanding of the clinical, immunological, and virological determinants of reservoir size is critical to eradication efforts. We performed a post hoc analysis of 30 participants of a clinical trial of early cART who had previously been assessed in detail for their clinical, immunological, and reservoir size characteristics. We observed that the HIV subtype and autologous Nef-mediated HLA downregulation function correlated with the viral reservoir size measured approximately 1 year post-cART initiation. Our findings highlight virological characteristics-both genetic and functional-as possible novel determinants of HIV reservoir establishment and persistence., (Copyright © 2019 American Society for Microbiology.)

Objective: To evaluate the effect of primary resistance and selected polymorphic amino-acid substitutions in HIV reverse transcriptase and protease on the CD4 cell count and viral load set point before the start of antiretroviral treatment., Design: Prospective cohort study., Methods: A total of 6180 individuals with a resistance test prior to starting antiretroviral treatment accessing care in HIV clinics across Europe who had at least one viral load and one CD4+ test available were included in the analysis. The impact of amino-acid substitutions variants on viral load and CD4+ trends was investigated using linear mixed models. Clusters of mutations were studied using principal component analysis., Results: Overall, the detection of any primary resistance was not associated with either the speed of CD4+ cell decline or the viral load set point. However, transmitted nucleoside reverse transcriptase inhibitor and protease inhibitor resistance appeared to be weakly associated with lower viral load set points, as were the polymorphic G16E or Q92K protease mutations. There was some evidence suggesting that these effects varied according to HIV subtype, with the effects of transmitted nucleoside reverse transcriptase inhibitor and protease resistance being particularly marked among individuals with a subtype B virus. A cluster of five polymorphic protease substitutions at position 20, 13, 36, 69 and 89 was associated with less steep CD4+ cell declines and lower viral load set points., Conclusion: Although we found little evidence for an association between primary resistance and CD4+ speed of decline and viral load set point, the potential role of polymorphic protease (alone or in clusters) and their interplay with HIV subtype needs to be further evaluated.

A variety of interventions to induce a functional cure of HIV are being explored, with the aim being to allow patients to cease antiretroviral therapy (ART) for prolonged periods of time or for life. These interventions share the goal of inducing ART-free remission from HIV pathogenesis and disease progression but achieve this in quite different ways, by reducing the size of the latent reservoir (for example, small-molecule stimulation of latently infected cells), reducing the number of target cells available for the virus (for example, gene therapy) or improving immune responses (for example, active or passive immunotherapy). Here, we consider a number of these alternative strategies for inducing post-treatment control of HIV and use mathematical modelling to predict the scale of the challenge inherent in these different approaches. For many approaches, over 99.9% efficacy will likely be required to induce durable ART-free remissions. The efficacy of individual approaches is currently far below what we predict will be necessary, and new technologies to achieve lifelong functional cure are needed.

Introduction: We evaluated HIV drug resistance in adults who received early vs. delayed antiretroviral therapy (ART) in a multinational trial [HIV Prevention Trials Network (HPTN) 052, enrollment 2005-2010]. In HPTN 052, 1763 index participants were randomized to start ART at a CD4 cell count of 350-550 cells/mm (early ART arm) or <250 cells/mm (delayed ART arm). In May 2011, interim study results showed benefit of early ART, and all participants were offered ART regardless of CD4 cell count; the study ended in 2015., Methods: Virologic failure was defined as 2 consecutive viral loads >1000 copies/mL >24 weeks after ART initiation. Drug resistance testing was performed for pretreatment (baseline) and failure samples from participants with virologic failure., Results: HIV genotyping results were obtained for 211/249 participants (128 early ART arm and 83 delayed ART arm) with virologic failure. Drug resistance was detected in 4.7% of participants at baseline; 35.5% had new resistance at failure. In univariate analysis, the frequency of new resistance at failure was lower among participants in the early ART arm (compared with delayed ART arm, P = 0.06; compared with delayed ART arm with ART initiation before May 2011, P = 0.032). In multivariate analysis, higher baseline viral load (P = 0.0008) and ART regimen (efavirenz/lamivudine/zidovudine compared with other regimens, P = 0.024) were independently associated with higher risk of new resistance at failure., Conclusions: In HPTN 052, the frequency of new drug resistance at virologic failure was lower in adults with early ART initiation. The main factor associated with reduced drug resistance with early ART was lower baseline viral load.

Background: Despite being used by more than 18 million people our understanding of the extent of the effects of antiretrovirals on the human body and other organisms remains incomplete. In addition, the direct effect of antiretrovirals on the gut microbiota of HIV-infected individuals has been largely overlooked in microbiome studies concerned with HIV-infected individuals., Methods: Here we tested 25 antiretrovirals on Bacillus subtilis and Escherichia coli using a broth microdilution assay to assess whether these drugs have an antibacterial effect., Results: We found that several widely used antiretroviral drugs have in vitro antibacterial activity against both gram-positive and gram-negative commensal bacteria. Efavirenz inhibited the growth of B. subtilis with a minimum inhibitory concentration (MIC) of 16 µg/ml (in all three replicates), while 2',3'-dideoxyinosine and zidovudine inhibited the growth of E. coli with an MIC of 16-32 µg/ml and 0.016-0.125 µg/ml (respectively)., Conclusions: Given the large and increasing number of individuals on antiretrovirals, and the lifelong nature of HIV treatment, this proof-of-concept report could have several potential implications, including an impact of antiretrovirals on bacterial coinfections, as well as potentials for drug discovery and repositioning.

Introduction: HIV genotyping is often unavailable in low and middle-income countries due to infrastructure requirements and cost. We compared genotype resistance testing in patients with virologic failure, by amplification of HIV pol gene, followed by "in-house" sequencing and commercial sequencing., Methods: Remnant plasma samples from adults and children failing second-line ART were amplified and sequenced using in-house and commercial di-deoxysequencing, and analyzed in Harare, Zimbabwe and at Stanford, U.S.A, respectively. HIV drug resistance mutations were determined using the Stanford HIV drug resistance database., Results: Twenty-six of 28 samples were amplified and 25 were successfully genotyped. Comparison of average percent nucleotide and amino acid identities between 23 pairs sequenced in both laboratories were 99.51 (±0.56) and 99.11 (±0.95), respectively. All pairs clustered together in phylogenetic analysis. Sequencing analysis identified 6/23 pairs with mutation discordances resulting in differences in phenotype, but these did not impact future regimens., Conclusions: The results demonstrate our ability to produce good quality drug resistance data in-house. Despite discordant mutations in some sequence pairs, the phenotypic predictions were not clinically significant., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Adherence to antiretroviral medication leads to HIV suppression and decreased morbidity and mortality. In resource- limited settings, the dependence on paper medical charts and unstable electronic health records creates a challenge to monitoring medication adherence. A pharmacy-based strategy that utilizes existing cellular phone infrastructure may lead to a more stable system to monitor adherence., Objectives: To develop and evaluate the usability of a smartphone-based software application (app) for tracking antiretroviral medication refill data in a resource-limited setting., Methods: A pharmacy-based smartphone app for tracking HIV medication adherence was developed through a multi-step rapid prototyping process. The usability of the app was assessed during the daily activities of pharmacy dispensers at HIV clinics in and around Gaborone, Botswana using a validated computer usability survey., Results: The study demonstrated the effective development of and favorable end-user responses to a pharmacy-based HIV medication adherence app. End users had suggestions for minor changes to improve the app's functionality., Conclusions: In resource-limited settings where electronic health record support is limited, such a system was feasible and appealing. In the future, this system may allow for improved HIV medication adherence tracking and be applied to medications beyond antiretrovirals., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Schattauer GmbH.)

Background: There are limited data on primary human immunodeficiency virus drug resistance (HIVDR) in pediatric populations. This study aimed to assess the prevalence of primary HIVDR and associated risk factors among children initiating first-line antiretroviral therapy (ART) in Uganda., Methods: At three Ugandan clinics, children (age <12 years) requiring ART were recruited between January 2010 and August 2011. Before starting ART, blood was collected for viral load and pol gene sequencing. Drug resistance mutations were determined using the 2010 International AIDS Society-USA mutation list. Risk factors for HIVDR were assessed with multivariate regression analysis., Results: Three hundred nineteen HIV-infected children with a median age of 4.9 years were enrolled. Sequencing was successful in 279 children (87.5%). HIVDR was present in 10% of all children and 15.2% of children <3 years. Nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTI (NNRTI), and dual-class resistance was present in 5.7%, 7.5%, and 3.2%, respectively. HIVDR occurred in 35.7% of prevention of mother-to-child transmission (PMTCT)-exposed children, 15.6% in children with unknown PMTCT history, and 7.7% among antiretroviral-naive children. History of PMTCT exposure [adjusted odds ratio (AOR): 2.6, 95% CI: 1.3-5.1] or unknown PMTCT status (AOR: 3.8, 95% CI: 1.1-13.5), low CD4 (AOR: 2.2, 95% CI: 1.3-3.6), current breastfeeding (AOR: 7.4, 95% CI: 2.6-21), and current maternal ART use (AOR: 6.4, 95% CI: 3.4-11.9) emerged as risk factors for primary HIVDR in multivariate analysis., Conclusion: Pretreatment HIVDR is high, especially in children with PMTCT exposure. Protease inhibitor (PI)-based regimens are advocated by the World Health Organization, but availability in children is limited. Children with (unknown) PMTCT exposure, low CD4 count, current breastfeeding, or maternal ART need to be prioritized to receive PI-based regimens.

Background: Manipur is one of the highest HIV prevalence states of India because of its geographical location at the international border near the golden triangle of South-East Asia, but no study on drug resistance associated mutations (DRAMs) has been reported yet., Objective: A population-based study on DRAMs of HIV-1 among the anti-retroviral therapy (ART) exposed HIV-1 infected individuals of Manipur was conducted., Methods: 110 HIV-1 positive individuals who had initially exposed to first line anti-HIV drugs were recruited for the surveillance of DRAMs. Reverse transcriptase and protease genes of HIV-1 were amplified, sequenced and analyzed., Results: Significant prevalence of DRAMs of HIV-1 was found among the ART exposed HIV-1 infected individuals of Manipur. The results revealed that 37%, 29% and 7% individuals harbor HIV-1 strains mutated at the target sites of nonnucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors and protease inhibitors respectively. Predominant DRAMs at RT genes were M184V, T215Y, M41L and V108I and H221Y while at PR genes were M46I and I47V. Among the high risk groups, intravenous drug users have the highest number of DRAMs followed by heterosexual individuals. Analysis of viral subtype based on pol gene revealed 83% subtype C, 11.8% recombinant forms and 5.2% subtype B., Conclusion: DRAMs at the target sites of reverse transcriptase inhibitors are high and these were found to have developed resistance to the primary ART drugs that are used in Manipur. The findings of this study will help the clinicians to guide patients during the course of ART treatment regimes.

Objective: Efavirenz-based antiretroviral therapy is recommended for prevention of mother-to-child transmission of HIV with two programmatic options: lifelong therapy for all women or treatment until cessation of breastfeeding. However, the risk of HIV resistance emerging after discontinuing efavirenz-based antiretroviral therapy is unclear. We review present knowledge surrounding the emergence of resistance after stopping efavirenz-based antiretroviral regimens., Design: An expert review., Methods: A literature review was conducted to identify studies assessing risk for emergence of efavirenz-related resistance following discontinuation of efavirenz-based antiretroviral regimens containing either lamivudine and zidovudine or tenofovir disoproxil fumarate and lamivudine. Discontinuation strategies including the use of 'pharmacologic tails' are discussed in the light of what is known about the pharmacology of the drugs., Results: We found no head-to-head comparisons between zidovudine, lamivudine and efavirenz and tenofovir disoproxil fumarate, lamivudine and efavirenz. The risk for HIV resistance exists, even with a 5-7 day tail of zidovudine and lamivudine. For tenofovir disoproxil fumarate, lamivudine and efavirenz, we found no clinical data to inform a recommendation for a tail., Conclusion: In order to prevent emergence of resistance, a tail of at least 2 weeks in duration may be required when discontinuing efavirenz in a regimen containing zidovudine and lamivudine. Studies are needed to characterize the risk of resistance among women who discontinue tenofovir disoproxil fumarate, lamivudine and efavirenz.

Background: Fixed-dose combination antiretroviral therapy administered as a single-tablet regimen (STR) may improve virologic suppression rates. The effect of STRs on development of resistance when virologic failure occurs on STRs is not known., Objectives: To compare the rate of emergent drug resistance mutations (DRMs) on first-line therapy with coformulated tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)/efavirenz (EFV) as an STR versus TDF, lamivudine (3TC) or FTC, and EFV given as non-STR., Methods: Patients from eight cohorts and four randomized clinical trials who received first-line antiretroviral therapy with Atripla (STR group) or with TDF + FTC/3TC + EFV (non-STR group) were eligible if a genotypic resistance test was available immediately after the first episode of viral failure. The DRM list from the 2013 version of IAS-USA was used., Results: One hundred and eighty-six patients were included in the final analysis, 122 (65.6%) from eight cohorts and 64 (34.1%) from four randomized clinical trials. The overall proportion of patients with at least one DRM at viral failure was 67.7%, including 53.4% (31 of 58) in the STR group vs. 74.2% (95 of 128) in the non-STR group (P = 0.005). Among patients exclusively from cohorts, at least one DRM was detected in 53.4% (31 of 58) in the STR group vs. 78.1% (50 of 64) in the non-STR group (P = 0.004). DRMs for individual drugs were: TDF, 15.5 vs. 16.4% (P = 0.87); 3TC/FTC, 31 vs. 35.2% (P = 0.58); and NNRTI, 51.7 vs. 65.6% (P = 0.07). The proportion of patients with an M184V/I among the 128 patients who received FTC was 32.8 vs. 36.2% among the 58 treated with 3TC (P = 0.65)., Conclusions: Compared to patients receiving the STR-Atripla, those receiving the same components individually in a non-STR regimen have a statistically significantly increased risk of selecting for DRMs associated with their drugs on failure.

Fragment-based drug discovery has been applied with varying levels of success to a number of proteins involved in the HIV (Human Immunodeficiency Virus) life cycle. Fragment-based approaches have led to the discovery of novel binding sites within protease, reverse transcriptase, integrase, and gp41. Novel compounds that bind to known pockets within CCR5 have also been identified via fragment screening, and a fragment-based approach to target the TAR-Tat interaction was explored. In the context of HIV-1 reverse transcriptase (RT), fragment-based approaches have yielded fragment hits with mid-μM activity in an in vitro activity assay, as well as fragment hits that are active against drug-resistant variants of RT. Fragment-based drug discovery is a powerful method to elucidate novel binding sites within proteins, and the method has had significant success in the context of HIV proteins.

Objectives: To identify factors associated with detectable viral load and the emergence of drug resistance in a cohort of HIV-infected pregnant women in Malawi receiving antiretroviral combination regimens for the prevention of mother-to-infant transmission., Methods: The study included 260 treatment-naive women who had received a three-drug nevirapine-based regimen from week 25 of gestational age until 6 months after delivery. HIV RNA was determined at month 6 and drug resistance was assessed if viral load was >50 copies/mL. Attendance at the scheduled follow-up visits was used as an indirect measure of treatment adherence., Results: The rate of detectable HIV RNA at 6 months was 9.6% (25/260). The only significant predictor of this occurrence was the presence of ≥1 missed visit during follow-up (P = 0.012). Resistance was assessed in 19 of these women: 7 (37%) had a wild-type virus and the other 12 (63%) had resistance-associated mutations (nucleoside reverse transcriptase inhibitor, 7/12; non-nucleoside reverse transcriptase inhibitor, 11/12). Three of 12 cases (25%) in which mutations were detected had a viral load <1000 copies/mL. The emergence of resistance was not correlated with the presence of baseline mutations in either plasma or archived DNA., Conclusions: In this cohort of women, detectable HIV RNA 6 months post-partum was infrequent and associated with low adherence to the treatment programme. Mutations were present in 63% of the women with detectable viral load at 6 months who had samples available for resistance testing. The impact of resistance on treatment re-initiation in women discontinuing drugs after the risk of transmission has ceased can be limited.

A 57-year-old man presented with subacute progression of cognitive impairment (MMSE 22/30). He had been diagnosed as AIDS two years before and taking atazanavir, abacavir, and lamivudine. HIV RNA of plasma had been negative. On admission, HIV RNA was 4,700 copy/ml and 5,200 copy/ml in plasma and in cerebrospinal fluid respectively, suggesting treatment failure of cART. The brain magnetic resonance imaging showed high intensity areas in the white matter of the both frontal lobes and brain stem. The drug-resistance test revealed the resistance of lamivudine and abacavir. We introduced the CNS penetration effectiveness (CPE) score to evaluate the drug penetration of HIV drugs. As the former regimen had low points (7 points), we optimized the regimen to raltegravir, zidovudine, and darunavir/ritonavir (scoring 10 points). His cognitive function improved as normal (MMSE 30/30) in 2 weeks and HIV-RNA became undetectable both in plasma and CSF in a month. In spite of the cognitive improvement, the white matter hyperintensity expanded. To rule out malignant lymphoma or glioblastoma, the brain biopsy was performed from the right frontal lobe. It revealed microglial hyperplasia and diffuse perivascular infiltration by CD8+/CD4-lymphocytes. No malignant cells were found and the polymerase chain reaction analyses excluded other viruses. Considering the drug penetration to the central nervous system is important for treating HIV encephalopathy.

Objective: To assess opportunities for transmitted drug resistance (TDR), we examined sexual risk behaviours, HIV viraemia and antiretroviral resistance among patients in care., Design: A retrospective, cross-sectional analysis of clinical cohort data., Methods: For 244 UNC Center for AIDS Research HIV Clinical Cohort participants, demographic and behavioural data were obtained during in-person interviews between 2000 and 2011. Genotypic resistance tests were interpreted using WHO surveillance drug resistance mutations (SDRMs). Log-linear binomial regression was used to evaluate associations with TDR risk, defined as unprotected sex in the prior 6 months, HIV RNA at least 400 copies/ml and at least one SDRM., Results: Participants included 91 (37%) women and 153 men, of whom 92 (60%) were MSM. Median age was 43 years; 70% were Black (n = 171). Most (97%) were antiretroviral-experienced; 44% had exposure to more than four regimens. Among 204 individuals on antiretrovirals, 42% reported suboptimal adherence and 29% were viraemic. Over half of participants had at least one SDRM (n = 131); 26 (11%) had triple-class resistance. Overall, 70% were sexually active, and 55% used condoms inconsistently. Thirty (12%) reported unprotected sex during periods of drug-resistant viraemia. Higher TDR risk was associated with prior homelessness [adjusted prevalence ratio (aPR) 2.20, 95% confidence interval (CI) 1.16-4.18], active substance use (aPR 3.12, 95% CI 1.47-6.62) and nonsignificantly with MSM (aPR 1.75, 95% CI 0.93-3.28)., Conclusion: A small but significant proportion of clinic patients with drug-resistant HIV engage in sexual behaviours that place others at risk for TDR. Targeted efforts in secondary prevention could have an impact on TDR incidence, over time.

Heterosexual transmission accounts for the majority of new human immunodeficiency virus (HIV) cases worldwide. The current approach to investigate HIV heterosexual transmission in animals involves application of virus stock to the vaginal surface, a method that does not reproduce the physiological conditions of vaginal intercourse that influence the rate of transmission. We have previously described efficient infection of conventional mice using EcoHIV/NL4-3 and EcoHIV/NDK, chimeric HIV molecular clones constructed to express all HIV structural and regulatory genes except envelope, which is replaced by a rodent-tropic envelope gene. Here we investigated whether EcoHIV/NDK-infected male mice transmit virus to females during coitus, and the sensitivity of this transmission to HIV pre-exposure prophylaxis and the estrus state. Our general approach was to allow mating between EcoHIV/NDK-infected male mice and uninfected females for 1-7 nights. At 1-6 weeks after mating, mice were euthanized and virus burdens were measured by quantitative PCR (qPCR) amplification of HIV RNA or DNA in peritoneal macrophages, inguinal lymph node cells, spleen cells or vas deferens, or by ELISA for antibodies to HIV Gag. We found that 70-100% of female mice mated to EcoHIV/NDK-infected males acquired infection. Pericoital treatment of females with either 2',3'-dideoxcytidine (ddC) or tenofovir largely prevented their EcoHIV/NDK infection by mating (P<0.05 and P<0.003, respectively). In males, T cells were dispensable for virus transmission. The rate of EcoHIV/NDK sexual transmission to females in estrus declined sharply (P=0.003) but their infection by injection was unaffected, indicating that the local environment in the female reproductive tract influences susceptibility to HIV. We conclude that this system of EcoHIV/NDK transmission during mouse mating reproduces key features of heterosexual transmission of HIV in humans and can be used to investigate its biology and control.

Objectives: To study the dynamics of HIV drug resistance (HIVDR) and its association with virologic and immunologic failure as well as mortality among patients on combination antiretroviral therapy (cART) in China., Design: We recruited 365 patients on cART in two rural Chinese counties in 2003-2004 and followed them every 6 months until May 2010., Methods: Virologic failure, HIVDR, immunologic failure and death were documented. We used Kaplan-Meier and the proportional hazards models to identify the timing of the events, and risk factors for mortality., Results: At the end of study, patients had been followed for 1974.3 person-years, a median of 6.1 years. HIVDR mutations were found in 235 (64.4%) patients and 75 died (20.5%, 3.8/100 person-years). Median time from cART to detection of virologic failure was 17.5 months, to HIVDR 36.6 months and to immunologic failure 55.2 months (≈ 18-month median interval between each adverse milestone). Being male, having a baseline CD4 cell count of less than 50 cells/μl and HIVDR were associated with higher mortality. Patients who developed HIVDR in the first year of treatment had higher mortality than those developing HIVDR later (adjusted hazard ratio 1.90, 95% confidence interval 1.01-3.48)., Conclusion: HIVDR was common and was associated with higher mortality among Chinese patients on cART, particular when HIVDR was detected early in therapy. Our study reinforces the importance of improving patient adherence to cART in order to delay the emergence of HIVDR and obviate the need to switch to costly second-line drug regimens too early.

Background: Tuberculosis (TB) and HIV co-infection remains a major public health problem. In spite of different initiatives implemented to tackle the disease, many countries have not reached TB control targets. One of the major attributing reasons for this failure is infection with HIV. This study aims to determine the effect of HIV infection on the survival of TB patients., Findings: A retrospective cohort study was employed to compare the survival between HIV positive and HIV negative TB patients (370 each) during an eight month directly observed treatment short-course (DOTS) period. TB patient's HIV status was considered as an exposure and follow up time until death was taken as an outcome. All patients with TB treatment outcomes other than death were censored, and death was considered as failure. Cox proportional hazard regression model was used to determine the hazard ratio (HR) of death for each main baseline predictor. TB/HIV co-infected patients were more likely to die; adjusted Hazard Rate (AHR) =1.6, 95%CI (1.01, 2.6) during the DOTS period. This risk was statistically higher among HIV patients during the continuation phase (p=0.0003), as a result HIV positive TB patients had shorter survival (Log rank test= 6.90, df= 2, p= 0.008). The adjusted survival probability was lower in HIV positive TB patients (< 15%) than HIV negative TB patients (> 85%) at the end of the DOTS period (8th month)., Conclusion: TB treatment survival was substantially lower in HIV infected TB patients, especially during the continuation phase. Targeted and comprehensive management of TB/HIV with a strict follow up should be considered through the entire TB treatment period.

Objective: The objective of this study was the analysis of the prevalence and type of primary resistance to antiretroviral drugs in patients diagnosed with HIV infection, and to determine the most appropriate empirical treatment to obtain a virological and immunological response., Patients and Methods: An observational analysis of patients with a de novo diagnosis of HIV infection during the period 2008-2010. Clinical, immunological and virological characteristics, including genotype analysis of resistance to antiretrovirals, were considered as independent variables. The dependent variable was an undetectable HIV viral load after six months of treatment. Data are provided as median (interquartile range) and absolute number (percentage)., Results: Seventy-three patients with a de novo diagnosis of HIV infection were included [53 males (73%); 36 (30-46) years-old; prior use of intravenous drugs: 5 patients (7%); hepatitis C virus co-infection: 13 individuals (18%)]. Ten patients (14%) showed symptoms attributable to acute HIV infection. A CD4+ T cell count lower than 350 mm(3) was detected in a 37% (n=27) of all patients. The initiation of antiretroviral therapy followed the GESIDA recommendations (no therapy: 20 patients; tenofovir+emtricitabine+efavirenz: 28 patients; abacavir+lamivudine+efavirenz: 1 patient; tenofovir+emtricitabine+protease inhibitors: 5 patients; abacavir+lamivudine+protease inhibitors: 1 patient; 18 patients were lost in the follow-up). After starting antiretroviral therapy, the resistance analyses detected the existence of primary resistance to antiretrovirals in 12.7% (confidence interval 95%: 3-22) of the patients, distributed as follows: isolated resistance to, nucleosides was detected in 2% (M184V), to nevirapine/efavirenz in 9% (K103N), and combined resistance to nucleosides and non-nucleosides in 2%; there were no cases of resistance to protease inhibitors. Consequently, antiretroviral therapy was changed in 5 (14%) out of 35 patients, attaining an undetectable HIV viral load at 6 months in all of them. The primary resistance to antiretrovirals was not related with epidemiological, virological (including infection by non B subtype) or immunological variables., Conclusions: In the present study, a change in the epidemiological pattern of de novo diagnosis of HIV infection in our area has been observed. The existence of resistance mutations in more than 5% of the new cases is noteworthy. This finding must be considered in order to establish the rules of empirical treatment in our area., (Copyright © 2011 Elsevier España, S.L. All rights reserved.)

We have studied transmitted drug resistance (TDR) in 1.864 antiretroviral-naïve patients entering CoRIS (Spain) during 2007-2010. An overall 8.58% TDR was observed (3.92%, nucleoside reverse transcriptase inhibitors (NRTIs); 3.86%, non-nucleoside reverse transcriptase inhibitors (NNRTIs); 2.31%, protease inhibitors), with a significant decreasing trend over time for NNRTIs (5.53%, 2007; 2.45%, 2010; p for trend = 0.044). Non-B subtype prevalence was 15.93%, with a significant increase (11.95%, 2007; 18.14%, 2010; p for trend = 0.018), mainly related to immigration. Having no formal education increased the risk of TDR to NNRTIs (OR, 7.26), and carrying a non-B subtype reduced the risk of TDR to NRTIs (OR, 0.27). These findings may have important implications for treatment guidelines and laboratory testing recommendations., (© 2012 The Authors. Clinical Microbiology and Infection © 2012 European Society of Clinical Microbiology and Infectious Diseases.)

The associations of acute HIV infection (AHI) and other predictors with transmitted drug resistance (TDR) prevalence were assessed in a cohort of HIV-infected, antiretroviral-naïve patients. AHI was defined as being seronegative with detectable HIV RNA. Binomial regression was used to estimate prevalence ratios and 95% confidence intervals for associations with TDR. Among 43 AHI patients, TDR prevalence was 20.9%, whereas prevalence was 8.6% among 677 chronically infected patients. AHI was associated with 1.9 times the prevalence of TDR (95% confidence intervals: 1.0 to 3.6) in multivariable analysis. AHI patients may represent a vanguard group that portends increasing TDR in the future.

Despite the high inhibition of viral replication achieved by current anti-HIV drugs, many patients fail treatment, often with emergence of drug-resistant virus. Clinical observations show that the relationship between adherence and likelihood of resistance differs dramatically among drug classes. We developed a mathematical model that explains these observations and predicts treatment outcomes. Our model incorporates drug properties, fitness differences between susceptible and resistant strains, mutations and adherence. We show that antiviral activity falls quickly for drugs with sharp dose-response curves and short half-lives, such as boosted protease inhibitors, limiting the time during which resistance can be selected for. We find that poor adherence to such drugs causes treatment failure via growth of susceptible virus, explaining puzzling clinical observations. Furthermore, our model predicts that certain single-pill combination therapies can prevent resistance regardless of patient adherence. Our approach represents a first step for simulating clinical trials of untested anti-HIV regimens and may help in the selection of new drug regimens for investigation.

This study reports on the drug resistance profiles for HIV-infected adults in Jamaica using genotypic methods. The genetic diversity of HIV-1 found in these patients was also determined using phylogenetic analysis. Epidemiological data were documented for each patient, blood was collected by venous puncture, and plasma was separated and stored. Viral RNA was extracted and analyzed for mutations in the viral genome by the amplification of the protease and reverse transcriptase (Pro-RT) regions using a nested PCR method. The rate of drug resistance among treatment-experienced individuals was 35%, while treatment-naive individuals showed a prevalence of 29%. The overall prevalence of drug resistance mutations in Jamaicans was consistent with the increased use of antiretroviral drugs in the region, with many of the mutations detected reducing susceptibility to the drugs commonly used to treat Jamaican patients. These results indicate the need for regular drug resistant surveillance to guide treatment strategies.

The Th17 subset is preferentially depleted as compared to the Th1 subset in chronically HIV-infected patients, even after successful antiretroviral therapy. In this study, we have established an in vitro system utilizing primary human CD4 T cell cultures that recapitulates the dramatic loss of Th17 response upon HIV-1 infection that is accompanied with a less profound Th1 decrease. With this experimental system, we showed that blocking viral entry with CCR5 ligands or TAK779 reduced the infection and enhanced Th17 response but not Th1 response. Antiretroviral drug 3TC (lamivudine), given at the time of infection, completely prevented the loss of Th17 and Th1 responses but was ineffective when given after infection was already established. Only when Th17 differentiation cytokines were given along with 3TC to the cultures with established HIV infection was Th17 response fully restored and virus replication kept suppressed. Finally, a significant increase of Th17 response was achieved in peripheral lymphocytes of HIV-infected patients on antiretroviral therapy after treatment with Th17 differentiation cytokines. These data demonstrate the presence of CD4 T cells remaining capable of mounting Th17 response during HIV infection and indicate the potential use of immunotherapeutic modalities to supplement antiretroviral drugs for restoring Th17 response in chronically HIV-infected patients.

We studied drug resistance mutations (DRMs) in 2623 pol sequences. Out of 94,828 amino acid substitutions that were detected, 8749 corresponded to nucleoside reverse transcriptase inhibitor (NRTI), 3765 to nonnucleoside reverse transcriptase inhibitor (NNRTI), and 7141 to protease inhibitor (PI) resistance-associated mutations. The most common DRMs were L10I, I54V, L90M, V82A, A71V, L10V, M46I, M184V, M41L, T215Y, D67N, L210W, K70R, N348I, V118I, K103N, Y181C, G190A, K101E, V108I, L100I, V90I, K101Q, and A98G. As expected, DRMs frequencies depended on viral genotype. The amounts of NRTI and PI resistance mutations among B and BF sequences from children were higher than among sequences from adults. The frequencies of PI and NRTI resistance mutations among B and BF sequences from adult men were higher than among sequences from women. Some of these observations can be explained in light of the available epidemiological information, but some cannot, indicating that further studies are needed to understand the antiretroviral resistance epidemics in Argentina.

In 2006, a survey of transmitted human immunodeficiency virus (HIV) drug resistance (TDR) was conducted in Lilongwe, Malawi. The survey followed the World Health Organization method to classify TDR to nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) among primigravid women aged <25 years. Results of the 2006 survey showed <5% TDR in all drug classes. In 2009, TDR surveys using the same method were repeated in Lilongwe and expanded to Blantyre. Findings show that in Lilongwe TDR to NRTIs and PIs was <5%, whereas TDR to NNRTIs was 5%-15%. In Blantyre, TDR was <5% to all drug classes. Observed moderate TDR in Lilongwe is cause for concern and signals the need for closer monitoring of Malawi's antiretroviral therapy program.

Burkina Faso began rapid antiretroviral therapy (ART) scale-up in 2003 and by December 2009, 26,448 individuals were on treatment. With rapid scale-up of ART, some degree of human immunodeficiency virus transmitted drug resistance (TDR) is inevitable. Following World Health Organization methods, between June 2008 and July 2009, Burkina Faso assessed TDR in primigravid pregnant women aged <25 years attending antenatal care clinics in Ouagadougou, Burkina Faso. TDR was classified as moderate (5%-15%) for both nucleoside reverse-transcriptase inhibitors and nonnucleoside reverse-transcriptase inhibitors. The observed moderate TDR in Ouagadougou is a cause for concern and calls for closer monitoring of Burkina Faso's ART program.

During 2007-2008, surveillance of transmitted human immunodeficiency virus (HIV) drug resistance (TDR) was performed following World Health Organization guidance among clients with newly diagnosed HIV infection attending voluntary counseling and testing (VCT) sites in Ho Chi Minh City (HCMC), Vietnam. Moderate (5%-15%) TDR to nonnucleoside reverse-transcriptase inhibitors (NNRTIs) was observed among VCT clients aged 18-21 years. Follow-up surveillance of TDR in HCMC and other geographic regions of Vietnam is warranted. Data generated will guide the national HIV drug resistance surveillance strategy and support selection of current and future first-line antiretroviral therapy and HIV prevention programs.

Human immunodeficiency virus drug resistance (HIVDR) in cohorts of patients initiating antiretroviral therapy (ART) at clinics in Chennai and Mumbai, India, was assessed following World Health Organization (WHO) guidelines. Twelve months after ART initiation, 75% and 64.6% of participants at the Chennai and Mumbai clinics, respectively, achieved viral load suppression of <1000 copies/mL (HIVDR prevention). HIVDR at initiation of ART (P <.05) and 12-month CD4 cell counts <200 cells/μL (P <.05) were associated with HIVDR at 12 months. HIVDR prevention exceeded WHO guidelines (≥ 70%) at the Chennai clinic but was below the target in Mumbai due to high rates of loss to follow-up. Findings highlight the need for defaulter tracing and scale-up of routine viral load testing to identify patients failing first-line ART.

The World Health Organization (WHO) has developed a global laboratory network to support human immunodeficiency virus drug resistance genotyping for public health surveillance in resource-limited countries. Blinded proficiency panels are an essential part of a genotyping quality-assurance program and are used to monitor the reliability of genotyping data in the WHO laboratory network. Laboratories in Europe, North America, Asia, Africa, and the Caribbean have tested panels annually since 2007; 103 of 131 submissions (79%) had >99% nucleotide sequence identity and resistance mutation concordance, compared with consensus. Most errors were associated with mixtures in the test specimen, leading to subjectivity in base-calling or amplification bias. Overall, genotyping assays used by the WHO laboratory network are reliable.

Cytomegalovirus (CMV) retinitis is the most common ocular opportunistic complication and a serious cause of vision loss in immunocompromised patients. Even though, a rise in human immunodeficiency virus (HIV) infected individuals seems to be a major factor responsible for the prevalence of CMV retinitis, the introduction of highly active antiretroviral therapy (HAART) significantly reduced the incidence and severity of CMV retinitis. Thorough evaluation of the patient's immune status and an exact classification of the retinal lesions may provide better understanding of the disease etiology, which would be necessary for optimizing the treatment conditions. Current drugs such as ganciclovir, valganciclovir, cidofovir and foscarnet have been highly active against CMV, but prolonged therapy with these approved drugs is associated with dose-limiting toxicities thus limiting their utility. Moreover development of drug-resistant mutants has been observed particularly in patients with acquired immunodeficiency syndrome (AIDS). Continuous efforts by researchers in the industry and academia have led to the development of newer candidates with enhanced antiviral efficacy and apparently minimal side effects. These novel compounds can suppress viral replication and prevent reactivation in the target population. Though some of the novel therapeutics possess potent viral inhibitory activity, these compounds are still in stages of clinical development and yet to be approved. This review provides an overview of disease etiology, existing anti-CMV drugs, advances in emerging therapeutics in clinical development and related recent patents for the treatment of CMV retinitis.

Global scale-up of antiretroviral therapy (ART) in low- and middle-income countries (LMICs) is an unprecedented public health achievement. With planned efforts of expanded ART access including earlier treatment initiation and the use of antiretroviral (ARV) drugs for prophylaxis, increasing levels of HIV drug resistance (HIVDR) are expected.Several factors may lead to selection and transmission of significant HIVDR in LMICs, which will lead to decreased population-level efficacy of standard first- and second-line ART regimens. These factors include low genetic barrier of some ARVs to resistance development, drug-drug interactions, inappropriate prescribing practices, interruption of drug supply, poor retention in care and lack of routine viral load monitoring.To maximize long-term effectiveness of available ARVs, policy makers and programme managers in LMICs should routinely monitor programme factors associated with emergence and transmission of HIVDR and implement routine HIVDR surveillance following standardized methods. When surveillance results suggest the need for action, specific public health interventions must be taken to adjust ART programme functioning to minimize further emergence and transmission of HIVDR.In this paper, we review ARV drug, HIV, patient and programme-related determinants of HIVDR. Additionally, we summarize the World Health Orgnization's global HIVDR surveillance and prevention strategy and describe resulting public health and policy implications.

Background: More and more antiretroviral therapies are being developed for treatment of HIV infection. The in-vivo efficacy of these drugs is commonly predicted based on in-vitro measures of antiviral effect. One primary in-vitro measure is the IC50, the amount of drug required for 50% inhibition of viral replication. We have previously shown that HIV life-cycle kinetics impact clinically observed HIV viral dynamics. Here we present a mathematical model of how they affect the pharmacodynamics of antiretroviral drugs., Results: We find that experimentally measured antiretroviral IC50s are determined by three factors: (i) intrinsic drug properties (e.g. drug-target binding), (ii) kinetics of the HIV life cycle, and (iii) kinetics of drug-inhibited infected cells. Our model predicts that the IC50 is a declining function of the duration of the drug-susceptible stage in the host cell. We combine our model with known viral life-cycle kinetics to derive a measure of intrinsic properties, reflecting drug action, for known antiretroviral drugs from previously measured IC50s. We show that this measure of intrinsic drug property correlates very well with in vitro-measured antiviral activity, whereas experimentally measured IC50 does not., Conclusions: Our results have implications for understanding pharmacodynamics of and improving activity of antiretroviral drugs. Our findings predict that drug activity can be improved through co-administration of synergistic drugs that delay the viral life cycle but are not inhibitory by themselves. Moreover, our results may easily extend to treatment of other pathogens.

CoRIS is an open multicentre cohort of HIV seroprevalent ARV-naïve subjects who began treatment at 32 Spanish healthcare centres from January 2004. Up to November 2008, a total of 683 FASTA format sequences, encoding the HIV protease and reverse transcriptase (RT) derived from plasma samples at entry into the cohort, had been obtained for examination of transmitted drug resistance (TDR) and HIV clade. TDR was found in 8.5% of the patients (4.4% NRTIs, 4% NNRTIs, 2.2% PIs). The most prevalent resistance mutations were: T215 revertants (3.8%), D67NG (1.3%), K219QENR (1.2%) and M41L (1%), for NRTIs; K103N (3.2%), for NNRTIs; I54VLMSAT, M46I and L90M (0.7%), for PIs. Non-B subtypes were recognized in 104 patients (15.2%) and were more common in Sub-Saharan Africans (15/17, 88.2%), Eastern Europeans (7/12, 58.3%) and Northern Africans (8/16, 50%) than among Spaniards (53/479, 11%) (p<0.001). The most prevalent non-B subtype was CRF02&#95;AG (4.4%), followed by subtype D (1.9%), CRF03&#95;AB (1.5%), CRF07&#95;BC and subtype F1 (1%). A trend was observed for the transmission of non-B subtypes to increase and for TDR to decrease., (Copyright © 2011 Elsevier B.V. All rights reserved.)

As human immunodeficiency virus (HIV) diversity may have an impact on both vaccine efficacy and drug resistance, it is important to have knowledge of circulating genetic variants. With widespread use of antiretroviral (ARV) drugs in Africa, one of the major potential challenges is the risk of emergence of ARV drug-resistant HIV strains. This study aimed to determine the circulating HIV subtypes and recombinant forms, as well as the prevalence of ARV drug resistance mutations, among 75 treatment-naive HIV-infected youths in Dar es Salaam, Tanzania. Gag (n = 48), partial pol (n = 44), and partial env (n = 35) sequencing was performed; all three regions were sequenced in 26 samples. Evidence of infection with recombinant viruses was found in 12 (46%) participants; AC recombinants were the most commonly detected and they were identified in six (23%) participants. Of individuals infected with nonrecombinant strains, subtype A was most commonly detected in seven (27%) participants, followed by subtype C detected in six (23%) participants and subtype D detected in one (4%) participant. Among the pol sequences from 44 individuals, three (7%) had resistance to nucleoside reverse transcriptase (RT) inhibitors and four (9%) had nonnucleoside RT inhibitor resistance mutations. Of these, three (7%) individuals were infected with viruses with cross-resistance mutations to both classes of RT inhibitors. These resistant mutations were all associated with drugs currently used in first-line therapy and in the prevention of vertical transmission. This high prevalence of resistance mutations is of considerable concern in apparently drug-naive populations as it may result in treatment failure and the spread of ARV-resistant strains.

There is a significant prevalence (20%-80% depending on the population and the study) of lipid disorders and other cardiovascular risk factors in people living with HIV infection. This review focuses on HIV and HIV treatment-associated metabolic and cardiovascular concerns, including dyslipidemias, lipodystrophy syndromes, endothelial dysfunctions, and associated metabolic events such as insulin resistance. Emerging hypotheses of the underlying pathophysiology of these issues, with impact on selection of specific antiretroviral treatment (ART) strategies, therapy, and preventive approaches to decreasing cardiovascular risk and other problems associated with these syndromes are discussed. Screening for cardiovascular risk as part of the decision of starting antiretroviral therapy, and during care of patients with HIV regardless of ART therapy status, is suggested with particular areas of focus. Statins, other hyperlipidemic therapies, treatment for specific problems arising due to lipodystrophy, and implications on ART selection to avoid drug interactions and adverse effects are also discussed.

HIV genotypic resistance testing has become a routine test informing the management of HIV-positive patients. This chapter describes the background of this testing and provides a protocol for undertaking the assay by a home-brew method. Methods for interpretation of the data are also outlined.