Antiretroviral Therapy Drug Resistance Research Articles

Analysis of ART effects and drug resistance in adult HIV/AIDS patients in Meigu County, Liangshan Prefecture, China

Background objectiveThis study aimed to understand the basic situation of adults with human immunodeficiency virus (HIV) receiving antiretroviral therapy (ART) in Meigu County, Liangshan Yi Autonomous Prefecture. The information of patients who had been on ART for more than 6 months, the effect of ART, the possible reasons for ART failure, knowledge of drug resistance among patients with ART failure and the possible reasons for the emergence of drug resistance were analyzed.MethodsA total of 2753 people living with HIV (PLWH) were collected for HIV-1 RNA virus nucleic acid testing. Plasma specimens with HIV-1 RNA ≥ 1000 copies/mL were sent to the laboratory for nucleic acid extraction, PCR, electrophoresis and sequencing, and the sequencing results were submitted to the HIV drug resistance database of Stanford University for subtyping to determine the drug resistance mutation sites and drug sensitivity levels.ResultsA total of 2753 patients were enrolled in this study. Antiviral therapy failed in 288 patients and was successfully amplified in 245, of which 111 had resistance genes. The resistance rate to failure of viral suppression was 45.3% (111/245). The highest rates of resistance to NNRTIs were found for efavirenz (EFV) and nevirapine (NVP) (42.9%), and the highest rates of resistance to NRTIs were found for 3TC and emtricitabine (FTC) (15.9%). The most common NNRTI resistance mutation site was K103N (20.8%), followed by V179D (9.4%) and V106M (7.8%); the most common NRTI resistance mutation site was M184V/I/MV (14.3%), followed by K65R (6.9%); three PI-associated resistance mutation sites were identified. The subtype of the resistant strain was CRF07-BC in almost all patients (98.9%).ConclusionsCompared with the previous low ART efficacy in the county, this study showed that the overall virological failure (VF) resistance rate in the county is still low, dominated by resistance to EFV, NVP, 3TC, FTC, and didanosine (DDI). Due to economic constraints, the core regimen is still 3TC + TDF, but before initiating ART, testing for HIV-1 subtypes and resistance should be conducted to avoid resistance that can lead to VF, especially for patients with high risk factors for resistance as shown by epidemiologic investigations.

Cannabis Use Is Associated With Decreased Antiretroviral Therapy Adherence Among Older Adults With HIV.

Conflicting evidence exists on the impact of cannabis use on antiretroviral therapy (ART) adherence among people with human immunodeficiency virus (PWH). We leveraged data collected among older PWH to characterize longitudinal associations between cannabis use and ART adherence. AIDS Clinical Trials Group (ACTG) A5322 study participants were categorized as <100% (≥1 missed dose in past 7 days) or 100% (no missed doses) ART adherent. Participants self-reported current (past month), intermittent (past year but not past month), and no cannabis (in past year) use at each study visit. Generalized linear models using generalized estimating equations were fit and inverse probability weighting was used to adjust for time-varying confounders and loss to follow-up. Among 1011 participants (median age, 51 years), 18% reported current, 6% intermittent, and 76% no cannabis use at baseline; 88% reported 100% ART adherence. Current cannabis users were more likely to be <100% adherent than nonusers (adjusted risk ratio [aRR], 1.53 [95% CI, 1.11-2.10]). There was no association between ART adherence and current versus intermittent (aRR, 1.39 [95% CI, .85-2.28]) or intermittent versus no cannabis use (aRR, 1.04 [95% CI, .62-1.73]). Among a cohort of older PWH, current cannabis users had a higher risk of <100% ART adherence compared to nonusers. These findings have important clinical implications as suboptimal ART adherence is associated with ART drug resistance, virologic failure, and elevated risk for mortality. Further research is needed to elucidate the mechanisms by which cannabis use decreases ART adherence in older PWH and to advance the development of more efficacious methods to mitigate nonadherence in this vulnerable population.

High Rate of HIV-1 Drug Resistance in Antiretroviral Therapy-Failure Patients in Liaoning Province, China.

This study aimed to monitor the prevalence of HIV-1 drug resistance and risk factors associated with drug resistance in antiretroviral therapy (ART)-failure individuals in Liaoning Province, China. Plasma samples were collected from HIV-1-positive individuals who experienced ART failure in Liaoning Province between April 2018 and September 2019. Genotype resistance test was performed using an in-house assay on these collected samples. Factors associated with drug resistance were identified by logistic regression analysis. We collected a total of 468 ART-failure individuals, of which 256 were successfully included in the final study. Of these, the most predominant genotype was CRF01_AE, accounting for 77.73%. The resistance rate to any of the three classes of antiretroviral drugs (non-nucleoside reverse transcriptase inhibitors [NNRTIs], nucleoside reverse transcriptase inhibitors [NRTIs], and protease inhibitors [PIs]) was 64.84%. Among 256 ART-failure patients, 62.89% showed drug resistance to NNRTIs, 50.39% to NRTIs, and 3.13% to PIs. G190S (31.25%) and Y181C (25.78%) mutations were the most common NNRTIs resistance mutations. K65R (29.69%), M184V (28.52%) were the most common NRTIs resistance mutations. Factors associated with drug resistance included current ART regimen and viral load. The high drug resistance rate among ART-failure individuals in Liaoning Province needs more attention. Corresponding strategies for the risk factors associated with HIV drug resistance can better control and prevent the prevalence of resistance.

Managing HIV-associated inflammation and ageing in the era of modern ART.

This paper aims to address the concerns around ongoing immune activation, inflammation, and resistance in those ageing with HIV that represent current challenges for clinicians. Presentations at a symposium addressing issues of ageing with HIV infection were reviewed and synthesised. The changing natural history and demographics of human immunodeficiency virus (HIV)-infected individuals means new challenges in contemporary management. In the early years of the epidemic,management was focussed on acute, potentially life-threatening AIDS-related complications. From initial monotherapy with first-generation antiretroviral therapy (ART), the development of combination highly active ART (HAART) allowed HIV control but ART toxicities, treatment adherence and drug resistance emerged as major issues. Today, the availability of potent and tolerable ART has made viral suppression achievable in most people living with HIV (PLHIV), and clinicians are confronted with managing a chronic condition among an ageing population. The combination of diseases of ageing and the co-morbidities associated with HIV-infection, even when well controlled, results in a complex set of challenges for many older PLHIV. There is a growing appreciation that many non-AIDS-related co-morbidities are caused, at least in part, by persistent, low-grade immune activation, inflammation, and hypercoagulability, despite suppressive ART. In order to further improve HIV management, it is important to understand the enduring effects of chronically suppressed HIV infection, the potential contribution of these factors to the ageing process, the possibility of drug resistance, and the impact of different treatment strategies, including early ART initiation.

HIV-1 Drug Resistance in ART-Naïve Individuals in Myanmar.

BackgroundEstimating the prevalence and characterizing the transmission of HIV-1 drug resistance in treatment-naïve individuals are very important in the prevention and control of HIV/AIDS. As one of the areas most affected by HIV/AIDS, few data are currently available for HIV-1 drug resistance in antiretroviral therapy (ART)-naïve individuals in Myanmar, which borders Yunnan, China.MethodsHIV-1 pol sequences from ART-naïve HIV-1-infected individuals during 2008 and 2014 in Myanmar were retrieved from our previous studies. HIV-1 transmitted drug resistance (TDR) and susceptibility to antiretroviral drugs were predicted using the Stanford HIVdb program. HIV-1 transmission cluster (TC) was determined by Cluster Picker.ResultsA total of 169 partial pol sequences from ART-naïve HIV-1 positive Burmese were analyzed. The prevalence of TDR was 20.1%. CRF01_AE and BC recombinants appeared to have a higher prevalence of TDR than other subtypes. The V179D/T was found to be very common in the China–Myanmar border region and was involved in half of the transmission clusters formed by HIV-1 drug-resistance strains in this region. Comparison showed that drug-resistance mutation profile in Myanmar was very similar to that in Dehong prefecture of Yunnan. By further phylogenetic analysis with all available sequences from the China–Myanmar border region, four HIV-1 drug-resistance-related TCs were identified. Three of them were formed by Burmese long-distance truck drivers and the Burmese staying in Yunnan, and another was formed by Burmese injection drug users staying in Myanmar and Yunnan. These results suggest a potential transmission link of HIV-1 drug resistance between Myanmar and Yunnan.ConclusionGiven the high prevalence of TDR in Myanmar, and the potential risk of cross-border transmission of HIV-1 drug-resistant strains between Myanmar and Yunnan, China, ongoing monitoring of HIV-1 drug resistance in ART-naïve individuals will provide a guideline for clinical antiretroviral treatment and benefit the prevention and control of HIV/AIDS in this border region.

Virological Failure, HIV-1 Drug Resistance and Early Mortality in Adults Admitted to Hospital in Malawi: A Nested Observational Cohort Study

Background: Antiretroviral therapy (ART) scale-up in sub-Saharan Africa (SSA) combined with weak routine virological monitoring has driven increasing HIV drug resistance. We investigated ART failure, drug resistance and early mortality among hospital inpatients in Malawi. Methods: An observational cohort study nested in a trial of urine-based TB screening in unselected HIV-positive adults followed up for 2 months. Patients taking ART for ≥6 months at hospital admission had frozen plasma samples tested for HIV-1 viral load. Those with HIV-1 RNA ≥1000 copies/ml had drug resistance testing by ultra-deep sequencing, with drug resistance defined as intermediate or high-level resistance using the Stanford HIVDR Algorithm Findings: Of 1316 patients recruited in the Malawi trial site between October 2015 and September 2017, 786 had taken ART for ≥6 months of whom 252/786 (32.1%) patients had viral load ≥1000 copies/ml (virological failure). Mean age was 38 years, 61.5% were female and median CD4 count was 60 cells/µL. Of 237 (94.0%) patients with HIV drug resistance results available, 195 (82.3%) had resistance to lamivudine, 128 (54.0%) to tenofovir and 219 (92.4%) to efavirenz. Resistance to at least 2 drugs was common (196/237, 82.7%) and this was associated with increased 2-month mortality (adjusted hazard ratio 1.7, 95% CI 1.2-2.4, p=0.004). Interpretation: HIV virological failure and HIV multidrug resistance were common in HIV-positive inpatients, and associated with increased early mortality. Targeted interventions including adherence support, rapid viral load testing and routine access to drug resistance testing are urgently needed. Enabling prompt diagnosis and switching to alternative ART could reduce early mortality among HIV-positive inpatients. Funding Statement: The Screening for TB to Reduce AIDS Related Mortality in Hospitalised Patients (STAMP) trial was funded by the Joint Global Health Trials Scheme of the UK Department of Health and Social Care, the Department for International Development, the Global Challenges Research Fund, the Medical Research Council and Wellcome Trust (MR/M007375/1). AGW has received a Royal College of Physicians London James Maxwell Grant Prophit Fellowship, and ELC has received a Wellcome Trust Fellowship (WT200901/Z/16/Z). Declaration of Interests: The authors declare no conflicts of interest exist. Ethics Approval Statement: All patients provided informed written consent for participation and sample storage. Retrospective HIV viral load and drug resistance testing was approved by the research ethics committee of the London School of Hygiene and Tropical Medicine, and the University of Malawi College of Medicine Research and Ethics Committee (COMREC).

A15 Archived ART resistance in the latent reservoir of virally suppressed Ugandans

The increased access of antiretroviral therapy (ART) has drastically improved the health of infected individuals. However, increased levels of ART resistance globally threaten ART effectiveness. Resistance monitoring is currently limited to viremic individuals or prior to ART initiation. The archival nature of the HIV latent reservoir (LR) of virally suppressed patients allows examination for the persistence of ART-resistant latent viral variants. Whole blood samples were collected longitudinally in Rakai, Uganda, from 70 virally suppressed HIV-1 infected individuals. The quantitative viral outgrowth assay was performed to measure the frequency of replication-competent latently infected resting-memory CD4 + (rCD4) T-cells. RNA was extracted from HIV p24-positive outgrowth supernatant, and the reverse transcriptase (RT) region was sequenced using a validated site-specific next-generation sequencing assay (Illumina, San Diego, CA). Consensus sequences containing >2.5 per cent of the total raw amplicons of each outgrowth well were analyzed for ART drug resistance mutations using the Stanford Database. The presence of clonal sequence is expressed as both percent clonality and Shannon Entropy. Replication-competent virus was cultured from 52/70 (74.3%) individuals, of which, RT-pol sequence data were obtained from 49/52 (94.3%) individuals. The presence of ART-resistant virus was found in the LR from one individual on second-line therapy that included a protease inhibitor. There were 20 and 44 total prominent consensus sequences from all wells at years 1 and 3 of follow-up, respectively. ART-resistant mutations for both RT-inhibitor drug classes were found in 30 per cent and 27.3 per cent of the total prominent consensus sequences of this one individual from years 1 and 3, respectively. The major ART resistance profile in this individual included: M184V, Y188L, K191E, and G190A. The percentage of total outgrowth that was clonal (percent clonality) increased from year 1 to year 3 (38.1–81.8%) and Shannon Entropy decreased (0.722–0.576). The presence of archived replication-competent ART-resistant virus in the LR was found in only one individual. There were two ART-resistant prominent consensus sequences isolated at year 3 that were not sampled 2 years earlier. The persistence of resistant, intact replication-competent proviral sequences in the LR of this individual seem to be supported by clonal expansion.

Costs and cost-efficacy analysis of the 2017 GESIDA/Spanish National AIDS Plan recommended guidelines for initial antiretroviral therapy in HIV-infected adults

IntroductionGESIDA and the Spanish National AIDS Plan panel of experts have recommended preferred (PR), alternative (AR) and other regimens (OR) for antiretroviral therapy (ART) as initial therapy in HIV-infected patients for 2017. The objective of this study was to evaluate the costs and the efficiency of initiating treatment with PR and AR. MethodsEconomic assessment of costs and efficiency (cost-efficacy) based on decision tree analyses. Efficacy was defined as the probability of reporting a viral load <50copies/mL at week 48, in an intention-to-treat analysis. Cost of initiating treatment with an ART regimen was defined as the costs of ART and its consequences (adverse effects, changes of ART regimen and drug resistance studies) during the first 48 weeks. The payer perspective (National Health System) was applied considering only differential direct costs: ART (official prices), management of adverse effects, resistance studies and HLA B*5701 screening. The setting was Spain and the costs correspond to those of 2017. A deterministic sensitivity analysis was conducted, building three scenarios for each regimen: base case, most favourable and least favourable. ResultsIn the base case scenario, the cost of initiating treatment ranged from 6882 euro for TFV/FTC/RPV (AR) to 10,904 euros for TFV/FTC+RAL (PR). The efficacy varied from 0.82 for TFV/FTC+DRV/p (AR) to 0.92 for TAF/FTC/EVG/COBI (PR). The efficiency, in terms of cost-efficacy, ranged from 7923 to 12,765 euros per responder at 48 weeks, for ABC/3TC/DTG (PR) and TFV/FTC+RAL (PR), respectively. ConclusionConsidering ART official prices, the most efficient regimen was ABC/3TC/DTG (PR), followed by TFV/FTC/RPV (AR) and TAF/FTC/EVG/COBI (PR).

Costs and cost-efficacy analysis of the 2017 GESIDA/Spanish National AIDS Plan recommended guidelines for initial antiretroviral therapy in HIV-infected adults

IntroductionGESIDA and the Spanish National AIDS Plan panel of experts have recommended preferred (PR), alternative (AR) and other regimens (OR) for antiretroviral therapy (ART) as initial therapy in HIV-infected patients for 2017. The objective of this study was to evaluate the costs and the efficiency of initiating treatment with PR and AR. MethodsEconomic assessment of costs and efficiency (cost-efficacy) based on decision tree analyses. Efficacy was defined as the probability of reporting a viral load <50copies/mL at week 48, in an intention-to-treat analysis. Cost of initiating treatment with an ART regimen was defined as the costs of ART and its consequences (adverse effects, changes of ART regimen and drug resistance studies) during the first 48 weeks. The payer perspective (National Health System) was applied considering only differential direct costs: ART (official prices), management of adverse effects, resistance studies and HLA B*5701 screening. The setting was Spain and the costs correspond to those of 2017. A deterministic sensitivity analysis was conducted, building three scenarios for each regimen: base case, most favourable and least favourable. ResultsIn the base case scenario, the cost of initiating treatment ranged from 6882 euro for TFV/FTC/RPV (AR) to 10,904 euros for TFV/FTC+RAL (PR). The efficacy varied from 0.82 for TFV/FTC+DRV/p (AR) to 0.92 for TAF/FTC/EVG/COBI (PR). The efficiency, in terms of cost-efficacy, ranged from 7923 to 12,765 euros per responder at 48 weeks, for ABC/3TC/DTG (PR) and TFV/FTC+RAL (PR), respectively. ConclusionConsidering ART official prices, the most efficient regimen was ABC/3TC/DTG (PR), followed by TFV/FTC/RPV (AR) and TAF/FTC/EVG/COBI (PR).

Evaluation of mHealth strategies to optimize adherence and efficacy of Option B+ prevention of mother-to-child HIV transmission: Rationale, design and methods of a 3-armed randomized controlled trial

BackgroundLifelong antiretroviral therapy (ART) (Option B+) is recommended for all HIV-infected pregnant/postpartum women, but high adherence is required to maximize HIV prevention potential and maintain maternal health. Mobile health (mHealth) interventions may provide treatment adherence support for women during, and beyond, the pregnancy and postpartum periods. Methods and designWe are conducting an unblinded, triple-arm randomized clinical trial (Mobile WACh X) of one-way short message service (SMS) vs. two-way SMS vs. control (no SMS) to improve maternal ART adherence and retention in care by 2years postpartum. We will enroll 825 women from Nairobi and Western Kenya. Women in the intervention arms receive weekly, semi-automated motivational and educational SMS and visit reminders via an interactive, human-computer hybrid communication system. Participants in the two-way SMS arm are also asked to respond to a question related to the message. SMS are based in behavioral theory, are tailored to participant characteristics through SMS tracks, and are timed along the pregnancy/postpartum continuum. After enrollment, follow-up visits are scheduled at 6weeks; 6, 12, 18, and 24months postpartum. The primary outcomes, virological failure (HIV viral load ≥1000copies/mL), maternal retention in care, and infant HIV infection or death, will be compared in an intent to treat analysis. We will also measure ART adherence and drug resistance. DiscussionPersonalized and tailored SMS to support HIV-infected women during and after pregnancy may be an effective strategy to motivate women to adhere to ART and remain in care and improve maternal and infant outcomes.

Can research at the end of life be a useful tool to advance HIV cure?

OPINION Can research at the end of life be a useful tool to advance HIV cure? Sara Gianella a , Jeff Taylor b , Timothy R. Brown c , Andy Kaytes b , Cristian L. Achim a , David J. Moore a , Susan J. Little a , Ronald J. Ellis a and Davey M. Smith a,d AIDS 2017, 31:1–4 Keywords: end of life, eradication, HIV cure, last gift, legacy, peri-mortem research model, research Modern antiretroviral therapy (ART) has saved millions of years of life [1], but it cannot eradicate latently infected cells [2,3]. The replication-competent provirus that remains during ART represents the major barrier to curing HIV [4]. Most of this latent reservoir resides in solid tissues and not in circulating blood, and we have yet to fully define the sanctuary sites of HIV persistence [5]. Timothy Ray Brown (known by many as the ‘Berlin Patient’) may be the closest to an HIV cure after being treated with an allogeneic hematopoietic stem cell transplant from a donor who was homozygous for the CCR5D32 deletion [6]. Unfortunately, this remarkable success has not been reproduced, and robust viral replication resumes almost universally following treat- ment interruption [7–9]. Even if strategies currently in development succeed in purging HIV from circulating CD4 þ T cells, residual virus can remain in the central nervous system (CNS), gut-associated lymphoid tissue (GALT), genital tract, adipose tissue, and others [9–12]. Thus, cure efforts must tackle the eradication of HIV reservoirs in anatomic compartments and sanctuaries throughout the body. The earliest stages of HIV infection are characterized by high levels of viral replication and little immune response [13,14]. This window of uncontrolled replication allows the virus to seed reservoirs throughout the body, as early as within 2 weeks of HIV infection [15], and to persist indefinitely throughout the lifespan of HIV-infected individuals [10]. These proviral reservoirs continue to expand and diversify until viral replication is successfully suppressed with ART. Despite extensive investigations, we still do not fully understand the dynamics of the total body HIV reservoir and how sub-reservoirs in various compart- ments relate to one another. For example, it remains unclear what factors govern the size and the activity of replication-competent HIV DNA in the CNS compared to the genital tract and blood. Most studies that have explored nonblood reservoirs among persons living with HIV infection have been limited to small samples of cerebrospinal fluid (CSF), genital secretion, gut, and shallow lymph nodes [10,16]. Studies using macaque models with simian immunodeficiency viruses (SIVs) have been enlightening for reservoirs in different tissues [17–23], but while SIV shares a high degree of structural and sequence identity to HIV, studies of SIV will not suffice to test eradication strategies for humans. For example, the Merck adenovirus type 5 (Ad5) trivalent HIV-1 vaccine trial (STEP trial) did not show efficacy in preventing HIV infection or slowing disease progression [24], despite promising results in various macaques’ trials [25–27]. As the field tackles the ambitious goal of eradicating HIV from the human body, we will need to test the effectiveness of cure interventions in living persons. a University of California, San Diego, La Jolla, b Community Advisory Board (CAB) AntiViral Research Center (AVRC), c Las Vegas, Nevada, and d Veterans Affairs San Diego Healthcare System, San Diego, California, USA. Correspondence to Sara Gianella, University of California San Diego, 9500 Gilman Drive, MC 0679, La Jolla, CA 92093-0679, USA. Tel: +1 858 642 1620; fax: +1 858 552 7445; e-mail: gianella@ucsd.edu Received: 18 August 2016; revised: 23 September 2016; accepted: 27 September 2016. DOI:10.1097/QAD.0000000000001300 ISSN 0269-9370 Copyright Q 2016 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Genetic diversity of human immunodeficiency viruses and antiretroviral therapy

The lecture is devoted to the analysis of the state-of-the-art of the impact of genetic diversity of human immunodeficiency (HIV) viruses on the pattern of infection and the efficiency of antiretroviral therapy (ART). It provides brief information on the origin and evolution of HIV and on the current classification of their genetic variants. The molecular epidemiological situation of HIV infection in Russia and nearby states and the major molecular HIV variants that are dominant in these countries, as well as their origin and prevalence trends are characterized. How the diversity of HIV can affect the efficiency of diagnosis, the transmission of the virus, and the pattern of HIV pathogenesis are briefly reviewed. The comparative data available in the world's scientific literature on these topics are given. More detailed attention is given to the possible causes of varying therapeutic effects against different HIV subtypes, as well as to the specific features of the formation and phenotyping manifestation of ART drug resistance mutations. There is evidence for the necessity of forming a unified follow-up system for treated HIV-infected patients during ART scaling, including in an effort to evaluate the impact of the specific features of the HIV genome on the efficiency of treatment regimens used in Russia.

Pooled Nucleic Acid Testing to Detect Antiretroviral Treatment Failure in HIV-Infected Patients in Mozambique.

In resource-limited settings, viral load monitoring of HIV-infected patients receiving antiretroviral therapy (ART) is not readily available because of high costs. Here, we compared the accuracy and costs of quantitative and qualitative pooled methods with standard viral load testing. Blood was collected prospectively from 461 patients receiving first-line ART in Mozambique who had not been evaluated previously with viral load testing. Screening for virologic failure of ART was performed quantitatively (ie, standard viral loads) and qualitatively [one and 2 rounds of polymerase chain reaction (PCR)]. Individual samples and minipools of 5 samples were then analyzed using both methods. The relative efficiency, accuracy, and costs of each method were calculated based on viral load thresholds for ART failure. Standard viral load testing of individual samples revealed a high rate of ART failure (19%-23%) across all virologic failure thresholds, and the majority of the patients (93%) with viral loads >1500 copies per milliliter had genotypic resistance to drugs in their ART regimen. Pooled quantitative screening and deconvolution testing had positive and negative predictive values exceeding 95% with cost savings of $11,250 compared with quantitative testing of each sample individually. Pooled qualitative screening and deconvolution testing had a higher cost savings of $30,147 for 1 PCR round and $25,535 for 2 PCR rounds compared with quantitative testing each sample individually. Both pooled qualitative PCR methods had positive and negative predictive values ≥90%, but the pooled 1-round PCR method had a sensitivity of 64%. Given the high rate of undiagnosed ART failure and drug resistance in this cohort, it is clear that virologic monitoring is urgently needed in this population. Here, we compared alternative methods of virologic monitoring with standard viral load testing of individual samples and found these methods to be cost saving and accurate. The test characteristics of each method will likely need to be considered for each local population before it is adopted.

Adolescent antiretroviral management: Understanding the complexity of non-adherence.

This case-based discussion highlights challenges in adolescent antiretroviral management, focusing on non-disclosure of status and the subsequent impact of suboptimal treatment adherence. Despite the scale-up of antiretroviral therapy (ART) and recommendations made by the World Health Organization (WHO) for ART for all human immunodeficiency virus (HIV)-infected paediatric patients, ART coverage in adolescents lags behind that in adults. Challenges of sustaining lifelong ART in children and adolescents require consideration of specific behavioural, physiological and psychosocial complexities associated with this special group. To preserve future drug options and sustain lifelong access to therapy, addressing non-adherence to treatment is critical to minimising acquisition of ART drug resistance and treatment failure. We review the psychosocial and developmental components that influence the course of the disease in adolescents and consider the complexities arising from perinatal exposure to ART and the growing risk of transmitted ART drug resistance in high-burden resource-limited settings.

Comparison of home and hospital deaths among patients on anti-retroviral therapy (ART): A clinical and verbal autopsy study

AimTo identify factors associated with home and hospital deaths among human immunodeficiency virus (HIV) infected adult patients in Nigeria. BackgroundCauses of mortality among HIV infected hospitalized patients on anti-retroviral therapy (ART) have been characterized in sub-Saharan Africa. However, majority of deaths occur outside hospitals. Materials and methodsWe undertook a retrospective clinical review on patients who were on ART and died at home or in the hospital. We obtained additional information on those who died at home through verbal autopsy and qualitative interview by our Home Based Care Team (HBCT). ResultsA total of 101 patient deaths over three years were reviewed. Those who died at home (51) or hospital (50) had similar ages, gender, co-morbidities, proportions with stages III/IV disease and opportunistic diseases. The median pre-ART CD4 cell counts for those who died at home and hospital was 108cells/μl and 72.0cells/μl respectively and they had been on similar ART regimens. Adherence was less 14/51 (27.5%) versus 30/50 (60%) (p=0.040) and use of traditional medicines (TM) higher 41/51 (80.4%) versus 16/50 (32%) (p=0.014) among those who died at home. Tuberculosis (TB) was the commonest cause of death accounting for 33/51 (64.7%) and 31/50 (62.0%) (p=0.979) of the home and hospital deaths respectively. Verbal autopsy and qualitative interview also identified TB, poor adherence, ART drug resistance and side effects as well as poverty, stigma, use of TM and spiritual alternatives as important causes of deaths. Tuberculosis is the overall cause of death. ConclusionStrategies for improving adherence, prevention and treatment of TB should be explored.

Population-Based Monitoring of Emerging HIV-1 Drug Resistance on Antiretroviral Therapy and Associated Factors in a Sentinel Site in Cameroon: Low Levels of Resistance but Poor Programmatic Performance

BackgroundScale-up of antiretroviral therapy (ART) in resource-limited settings has drastically reduced HIV-related morbidity and mortality. However, challenges in long-term ART, adherence and HIV drug resistance (HIVDR) itself, require monitoring to limit HIVDR emergence among ART-experienced populations, in order to ensure regimen efficacy.MethodsA longitudinal study was conducted from 2009–2011 in a cohort of 141 HIV-infected adult patients (aged >21) at the national social insurance centre hospital in Yaounde, Cameroon. As per-WHO HIVDR protocol, HIV-1 protease-reverse transcriptase genotyping was performed at baseline and at endpoint (12 months) on first-line ART using ViroSeq™ Genotyping kit.ResultsAt baseline, a prevalence of 3.6% (5/139) HIVDR was observed [protease inhibitors M46I (1/5), G73A (1/5), L90LM (1/5); nucleoside reverse transcriptase inhibitors: M184V (1/5), T215F (1/5); non-nucleoside reverse transcriptase inhibitors: K103N (1/5), Y181Y/C (2/5), M230ML (1/5)]. At endpoint, 54.0% (76) patients were followed-up, 9.2% (13) died, and 3.5% (5) transferred, 38.5% (47) lost to follow-up (LTFU). 69.7% (53/76) of those followed-up had viremia <40 copies/ml and 90.8% (69/76) <1000 copies/ml. 4/7 patients with viremia ≥1000 copies/ml harbored HIVDR (prevalence: 5.3%; 4/76), with M184V/I (4/4) and K103K/N (3/4) being the most prevalent mutations. LTFU was favored by costs for consultation/laboratory tests, drug shortages, workload (physician/patient ratio: 1/180) and community disengagement.ConclusionsLow levels of HIVDR at baseline and at endpoint suggest a probable effectiveness of ART regimens used in Cameroon. However the possible high rate of HIVDR among LTFUs limited the strengths of our findings. Evaluating HIVDR among LTFU, improving adherence, task shifting, subsidizing/harmonizing costs for routine follow-up, are urgent measures to ensure an improved success of the country ART performance.

Oral antiretroviral drugs as public health tools for HIV prevention: global implications for adherence, drug resistance, and the success of HIV treatment programs.

Recent data from studies on treatment as prevention (TasP) and preexposure prophylaxis (PrEP) show that antiretroviral drugs can be used in prevention, as well as in treatment. The movement from first-generation antiretroviral therapy (ART) coformulations based on thymidine analogues to second-generation ART coformulations based on tenofovir may coincide with future prevention strategies that also use tenofovir/emtricitabine, raising concerns regarding drug resistance. In published studies, failure of prophylaxis was associated with poor adherence and low plasma drug levels. Although rates of drug resistance in cases of failed prevention was low, regular human immunodeficiency virus (HIV) testing was undertaken in these clinical trials. Although legitimate concerns exist about ART adherence and drug resistance associated with PrEP and TasP in real-world settings, efforts to curb the continuing HIV epidemic through use of these novel prevention strategies should move forward because the development and approval of newer drugs reserved for prevention might take many more years. Efforts must be made to monitor ART adherence and to intervene through counseling and other means in order to optimize adherence and retention in care, whenever necessary. Finally, further research involving the generalized epidemic is needed to determine when suboptimal drug use may occur and when regular testing and monitoring of the long-term consequences of ART use may not be routine.

Genetic Diversity of Simian Immunodeficiency Virus Encoding HIV-1 Reverse Transcriptase Persists in Macaques despite Antiretroviral Therapy

The impact of antiretroviral therapy (ART) on the genetics of simian immunodeficiency virus (SIV) or human immunodeficiency virus (HIV) populations has been incompletely characterized. We analyzed SIV genetic variation before, during, and after ART in a macaque model. Six pigtail macaques were infected with an SIV/HIV chimeric virus, RT-SHIV(mne), in which SIV reverse transcriptase (RT) was replaced by HIV-1 RT. Three animals received a short course of efavirenz (EFV) monotherapy before combination ART was started. All macaques received 20 weeks of tenofovir, emtricitabine, and EFV. Plasma virus populations were analyzed by single-genome sequencing. Population diversity was measured by average pairwise difference, and changes in viral genetics were assessed by phylogenetic and panmixia analyses. After 20 weeks of ART, viral diversity was not different from pretherapy viral diversity despite more than 10,000-fold declines in viremia, indicating that, within this range, there is no relationship between diversity and plasma viremia. In two animals with consistent SIV RNA suppression to <15 copies/ml during ART, there was no evidence of viral evolution. In contrast, in the four macaques with viremias >15 copies/ml during therapy, there was divergence between pre- and during-ART virus populations. Drug resistance mutations emerged in two of these four animals, resulting in virologic failure in the animal with the highest level of pretherapy viremia. Taken together, these findings indicate that viral diversity does not decrease with suppressive ART, that ongoing replication occurs with viremias >15 copies/ml, and that in this macaque model of ART drug resistance likely emerges as a result of incomplete suppression and preexisting drug resistance mutations.

Short Communication: Antiretroviral Therapy Resistance Mutations Present in the HIV Type 1 Subtype CpolandenvRegions from Therapy-Naive Patients in Zambia

The prevalence of antiretroviral therapy (ART) resistance mutations present in HIV-1 subtype C pol and env regions of the proviral DNA was analyzed and compared from therapy-naive individuals before (Cohort A) and after (Cohort B) the availability of free ART in Zambia. Mutations present in sequences published in a previous study from Zambian ART-naive individuals infected with subtype C were analyzed using current parameters for the classification of ART drug resistance and compared with Cohorts A and B. No statistically significant differences were observed when comparing mutations present in the pol and env of these cohorts. However, an increase in the number of minor, borderline, or partial resistance mutations as well as the presence of major resistance mutations were observed in Cohort B. These results suggest there is an increasing trend of drug resistance-associated mutations that could be a result of the availability of free ART in Zambia. Moreover, the high prevalence of resistance mutations observed for maraviroc and vicriviroc in both cohorts may suggest a limited efficacy of entry inhibitors on HIV-1 subtype C.

Effectiveness of antiretroviral therapy and development of drug resistance in HIV-1 infected patients in Mombasa, Kenya

Access to antiretroviral therapy (ART) is increasing in resource-limited settings (RLS) and can successfully reduce HIV-related morbidity and mortality. However, virologic failure and development of viral drug resistance can result in reduced treatment options and disease progression. Additionally, transmission of resistant virus, and particularly multi-drug resistance, could become a public health concern. This study evaluated treatment success and development of ART drug resistance after short-term treatment among patients attending the Comprehensive HIV Care Centre (CCC) of Coast Province General Hospital, Mombasa, Kenya. One hundred and fifty HIV-infected individuals receiving ART were consecutively recruited to participate in the study. After determination of plasma viral load, patients with detectable viral load levels were subjected to genotypic drug resistance testing. At the time of sampling, 132 of the 150 participants were on ART for more than 6 months (median 21 months, IQR = 12–26). An efficient viral load reduction to below 50 copies/ml was observed in 113 (85.6%) of them. Of the 19 patients with a detectable viral load, sequencing of the protease (PR) and reverse transcriptase (RT) gene was successful in 16. Eleven (11) of these 16 patients were infected with a subtype A1 virus. Major PR mutations were absent, but mutations associated with drug resistance in RT were detected in 14 of the 16 patients (87.5%). High-level resistance against at least 2 drugs of the ART regimen was observed in 9/14 (64.3%). The 3TC mutation M184V and the NNRTI mutation K103N were most frequent but also the multi-drug resistance Q151M and the broad NRTI cross-resistance K65R were observed. The results of this study revealed a high rate of treatment success after short term ART in patients treated at a public provincial hospital in a RLS. Nevertheless, the observed high risk of accumulation of resistance mutations among patients failing treatment and the selection of multi-drug resistance mutations in some, remains of great concern for future treatment options and potential transmission to partners.