Development Of HIV Drug Resistance Research Articles

Risk assessment of first-line treatment failure in untreated HIV patients in Northwestern Federal District of the Russian Federation

The HIV infection epidemic in Russia continues to evolve, and HIV infection cases have been registered in all territorial entities of the Russian Federation. 2021 Treatment coverage was 82.2% and 56.4% individuals under dispensary observation and living with diagnosed HIV infection. 79.9% receiving ART subjects were shown to achieve undetectable viral load. Highly active antiretroviral therapy (HAART) currently represents a combination of three (less frequently four) antiretroviral drugs targeting pathways involved in various stages of HIV replication in vivo. Treatment failure is a problem facing doctors and patients using HAART. The most common cause of therapeutic failure is the development of HIV drug resistance. The emergence of resistance is associated with processes involving mutation occurring in the viral genome influenced by evolutionary factors. Therefore, it is important clinically and programmatically to learn more about the rate of first-line treatment failure, the rate of switching to a second-line ART regimen, and to identify patients at risk to develop strategies for preventing development of further failure cases. The study was aimed at analyzing ineffectiveness of first-line ART therapy in patients in Northwestern Federal District of the Russian Federation. Materials and methods. Sequencing reactions were performed using the AmpliSens HIV Resist-Seq. Assembly of consensus sequences from fragments obtained during sequencing was carried out using Unipro UGENE software. Isolate genotyping was performed using the MEGA-X software with the Neighbor-joining algorithm. Results. The HIV pol genes in 239 patients with first-line ART failure and 100 nave patients were sequenced; all sequences genotyped as HIV-1 subsubtype A6. According to analysis, 82% of patients had at least one significant mutation associated with drug resistance for the corresponding viral subtype. In total, we encountered 87 different drug resistance mutations. Conclusion. We have shown increased proportion of patients with first-line ART failure among all patients with treatment failure. The main cause for such changes is probably related to the prevalence of primary drug resistance, estimated here at 8%. Specific differences were found between drug resistance mutation profiles in patients without suppressed viral load and patients with virological breakthrough. The overall results of the study indicate a need to diagnose and characterize HIV drug resistance prior to initiation of therapy in order to avoid ineffective first-line antiretroviral treatment.

Detection of Patient HIV-1 Drug Resistance Mutations in Russia's Northwestern Federal District in Patients with Treatment Failure.

Highly active antiretroviral therapy (HAART) is currently a combination of three (less frequently four) antiretroviral drugs; these target pathways involved in various stages of HIV replication in the body. Treatment failure is a problem facing doctors and patients using HAART. The most common cause of therapeutic failure is the development of HIV drug resistance. The emergence of resistance is associated with processes involving mutation occurring in the viral genome under the influence of evolutionary factors. Sequencing reactions were performed using the AmpliSens HIV Resist-Seq. Assembly of consensus sequences from fragments obtained during sequencing was carried out using Unipro UGENE softwar. Isolate genotyping was performed using the MEGA-X software with the Neighbor-joining algorithm. According to the analysis, 72.05% of patients had at least one significant mutation associated with drug resistance for the corresponding viral subtype. HIV-1 A6 remains the predominant HIV-1 genetic variant in Russia’s Northwestern Federal District. Among samples with drug resistance mutations, in all cases, mutations associated with pharmacological resistance to two or three drug groups were found. Given the high incidence of resistance mutations in patients on ineffective ART, surveillance of HIV-1 drug resistance, in both ART-receiving and ART-naive individuals, appears necessary. A lack of vigilance and control measures may lead to the spread of primary ART-resistant HIV strains.

Attitudes towards, knowledge about, and confidence to prescribe antiretroviral pre-exposure prophylaxis among healthcare providers in Thailand.

HIV pre-exposure prophylaxis (HIV-PrEP) is an effective method for preventing HIV transmission, and it is recommended in several international guidelines. Perceptions and knowledge about HIV-PrEP prescription among healthcare providers have not been investigated in Thailand where HIV-PrEP is a novel healthcare topic. The objective of study was to determine healthcare providers’ attitudes towards, knowledge about, and confidence to prescribe HIV-PrEP in Thailand.A questionnaire was administered to Thai healthcare providers during May 1, 2017 to September 5, 2018.Of the 500 questionnaires that were distributed, 460 were returned (92%). Respondents included 336 physicians (48 infectious disease [ID] physicians, 288 non-ID physicians) and 124 non-physicians (70 nurses, 35 pharmacists, and 19 others). Eighty one percent of respondents had a positive attitude towards HIV-PrEP. Multivariate analysis revealed being a non-ID physician, having prior knowledge about HIV-PrEP, believing that HIV-PrEP can reduce the number of new patients, and believing that HIV-PrEP is not associated with a higher incidence of other sexually transmitted infections were all factors significantly associated with having a positive attitude towards HIV-PrEP. The issue of most concern to respondents who had a negative attitude toward HIV-PrEP was poor patient adherence to antiviral medications. Only 57% of respondents had confidence to prescribe HIV-PrEP. Factors associated with confidence to prescribe HIV-PrEP included being an ID physician, believing that HIV-PrEP can reduce the number of new patients, believing in the safety of antiviral medications, and believing that HIV-PrEP is not associated with increased development of HIV drug resistance. The results of HIV-PrEP knowledge testing (8 questions) were categorized into good score (≥7/8) and fair score (≤6/8). Fifty five percent of participants had a good score result. Using multivariate analysis, the factors associated with a good score result were ID physician, having HIV-PrEP prescription experience, and believing that HIV-PrEP can reduce the number of new patients.Most Thai healthcare providers (81%) reported having a positive attitude towards HIV-PrEP. Successful HIV-PrEP implementation in Thailand will require steps to mitigate the described barriers, and training for healthcare providers, which will strengthen knowledge and improve both experience with and confidence to prescribe HIV-PrEP.

Development of HIV Drug Resistance in a Cohort of Adults on First-Line Antiretroviral Therapy in Tanzania during the Stavudine Era

As more HIV patients start combination antiretroviral therapy (cART), the emergence of HIV drug resistance (HIVDR) is inevitable. This will have consequences for the transmission of HIVDR, the success of ART, and the nature and trend of the epidemic. We recruited a cohort of 223 patients starting or continuing their first-line cART in Tanzania towards the end of the stavudine era in 2010. Patients were then followed for one year. Of those with a viral load test at baseline and follow-up time, 34% had a detectable viral load at the one-year endpoint. For 41 patients, protease and reverse transcriptase genotyping were successful. Eighteen samples were from cART-naïve patients, and 23 samples were taken under therapy either at baseline for cART-experienced patients or from follow-up samples for both cART–naïve and cART–experienced patients. The isolates were subtype A, followed by C and D in 41.5%, 22%, and 12.2% of the patients, respectively. No transmitted HIVDR was detected, as scored using the surveillance drug resistance mutations (DRMs) list. However, in 3 of the 18 samples from cART-naïve patients, the clinical Rega interpretation algorithm scored 44D or 138A as non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated polymorphisms. The most observed nucleoside reverse transcriptase inhibitor (NRTI) mutation was 184V. The mutation was found in 16 patients, causing resistance to lamivudine and emtricitabine. Nineteen patients had NNRTI resistance mutations, the most common of which was 103N, observed in eight patients. These high levels of resistance call for regular drug resistance surveillance in Tanzania to inform the control of the emergence and transmission of HIVDR.

Progressive emergence of an S153F plus R263K combination of integrase mutations in the proviral DNA of one individual successfully treated with dolutegravir.

The development of HIV drug resistance against the integrase strand transfer inhibitor dolutegravir is rare. We report here the transient detection, by near full-genome ultradeep sequencing, of minority HIV-1 subtype B variants bearing the S153F and R263K integrase substitutions in the proviral DNA from blood cells of one patient who successfully initiated dolutegravir-based ART, over 24 weeks. Our objective was to study the effects of these substitutions. Strand transfer and DNA-binding activities of recombinant integrase proteins were measured in cell-free assays. Cell-based resistance, infectivity and replicative capacities were measured using molecular clones. Structural modelling was performed to understand experimental results. R263K emerged first, followed by the addition of S153F at Week 12. By Week 24, both mutations remained present, but at lower prevalence. We confirmed the coexistence of S153F and R263K on single viral genomes. Combining S153F or S153Y with R263K decreased integration and viral replicative capacity and conferred high levels of drug resistance against all integrase inhibitors. Alone, S153Y and S153F did little to infectivity or dolutegravir resistance. We identified altered DNA binding as a mechanism of resistance. The patient remained with undetectable viral loads at all timepoints. Drug-resistant minority variants have often been reported under suppressive ART. Our study adds to these observations by unravelling a progression towards higher levels of resistance through a novel pathway despite continuous undetectable viral loads. Poorly replicative HIV drug-resistant minority proviral variants did not compromise viral suppression in one individual treated with dolutegravir.

Transmitted, pre-treatment and acquired antiretroviral drug resistance among men who have sex with men and transgender women living with HIV in Nigeria.

Across sub-Saharan Africa, men who have sex with men (MSM) and transgender women (TGW) have disproportionately poor HIV treatment outcomes. Stigma and criminalization create barriers to health-care engagement and adherence to antiretroviral therapy (ART), potentially promoting the development of HIV drug resistance (HIVDR). We evaluated transmitted, pre-treatment and acquired HIVDR among MSM and TGW in Lagos and Abuja, Nigeria. Adults with HIV RNA ≥1,000 copies/ml in the TRUST/RV368 cohort, including incident cases diagnosed via 3-monthly screening, underwent HIVDR testing using the Sanger sequencing method. Major mutations conferring resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) were identified from the 2017 IAS-USA list. World Health Organization surveillance drug resistance mutations (SDRMs) were identified in ART-naive participants. From March 2013 to June 2017, 415 participants with median age 24 (interquartile range [IQR] 21-27) years, CD4+ T-cell count 370 (IQR 272-502) cells/mm3, and HIV RNA 4.73 (IQR 4.26-5.15) log10 copies/ml underwent HIVDR testing. SDRMs were observed in 36 of 373 ART-naive participants (9.7%, 95% confidence interval [95% CI 6.8, 13.1%]), including 8 of 39 incident cases (20.5%, [95% CI] 9.3, 36.5%). Among 42 ART-experienced participants, NNRTI resistance was detected in 18 (42.9%, 95% CI 27.7, 59.0%) and NRTI resistance in 10 (23.8%, 95% CI 12.0, 39.4%). No PI resistance was detected. The high prevalence of transmitted and acquired drug resistance among Nigerian MSM and TGW living with HIV suggests the need for programmatic solutions to improve uninterrupted access to ART and timely switch to second-line regimens in cases of viral failure.

A4 Development of HIV drug resistance in HIV-infected patients failing second line regimen in Zimbabwe: A public health concern

A4 Development of HIV drug resistance in HIV-infected patients failing second line regimen in Zimbabwe: A public health concern

Universal antiretroviral therapy for HIV-infected children: a review of the benefits and risks to consider during implementation.

Background: The 2016 World Health Organization (WHO) consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, recommended to start all HIV-infected children on antiretroviral therapy (ART). Here, we explore the possible benefits and risks of implementing universal ART for all HIV-infected children and adolescents and outline some of the key considerations that led to the 2016 revision of WHO guidelines.Methods: We conducted a review of the published data from 2000 to 2016, to ascertain the clinical and programmatic benefits, as well as the risks of implementing universal ART for all children.Results and discussion: Universal ART for all children has the potential to increase treatment coverage, which in 2015 was only 51% globally, as well as providing several biological benefits, by preventing: premature death/loss to follow-up, progressive destruction of the immune system, poor growth and pubertal delay, poor neuro-cognitive outcomes and future burden to the health care system with complications of untreated HIV-infection. However, the strategy could be associated with risks, notably development of HIV drug resistance, antiretroviral drug toxicities and increased costs to an already stretched health system.Conclusion: Overall, our findings suggest that the benefits could outweigh the risks and support universal ART for all HIV-infected children, but recognize that national programmes will need to put measures in place to minimize the risks if they choose to implement the strategy.

Development of HIV drug resistance and therapeutic failure in children and adolescents in rural Tanzania: an emerging public health concern.

Objective:To investigate the prevalence and determinants of virologic failure and acquired drug resistance-associated mutations (DRMs) in HIV-infected children and adolescents in rural Tanzania.Design:Prospective cohort study with cross-sectional analysis.Methods:All children 18 years or less attending the paediatric HIV Clinic of Ifakara and on antiretroviral therapy (ART) for at least 12 months were enrolled. Participants with virologic failure were tested for HIV-DRM. Pre-ART samples were used to discriminate acquired and transmitted resistances. Multivariate logistic regression analysis identified factors associated with virologic failure and the acquisition of HIV-DRM.Results:Among 213 children on ART for a median of 4.3 years, 25.4% failed virologically. ART-associated DRM were identified in 90%, with multiclass resistances in 79%. Pre-ART data suggested that more than 85% had acquired key mutations during treatment. Suboptimal adherence [odds ratio (OR) = 3.90; 95% confidence interval (CI) 1.11–13.68], female sex (aOR = 2.57; 95% CI 1.03–6.45), and current nonnucleoside reverse transcriptase inhibitor-based ART (aOR = 7.32; 95% CI 1.51–35.46 compared with protease inhibitor-based) independently increased the odds of virologic failure. CD4+ T-cell percentage (aOR = 0.20; 0.10–0.40 per additional 10%) and older age at ART initiation (aOR = 0.84 per additional year of age; 95% CI 0.73–0.97) were protective (also in predicting acquired HIV-DRM). At the time of virologic failure, less than 5% of the children fulfilled the WHO criteria for immunologic failure.Conclusion:Virologic failure rates in children and adolescents were high, with the majority of ART-failing children harbouring HIV-DRM. The WHO criteria for immunologic treatment failure yielded an unacceptably low sensitivity. Viral load monitoring is urgently needed to maintain future treatment options for the millions of African children living with HIV.

A clinical prediction tool for targeted pre-antiretroviral therapy creatinine testing applied to the TREAT Asia HIV observational database cohort.

A clinical prediction tool for targeted pre-antiretroviral therapy creatinine testing applied to the TREAT Asia HIV observational database cohort.

Viral Load for HIV Treatment Failure Management: A Report of Eight Drug-Resistant Tuberculosis Cases Co-Infected with HIV Requiring Second-Line Antiretroviral Treatment in Mumbai, India

Dear Sir: We read with great interest the report by Satti H, McLaughlin MM, and Seung KJ describing six HIV/drug-resistant tuberculosis (HIV/DR-TB) co-infected patients who failed first-line antiretroviral treatment (ART) in Lesotho.1 We would like to share an experience treating similar patients in Mumbai, India. Although having a lower HIV prevalence compared with many African countries, India has the third largest population living with HIV, after South Africa and Nigeria, with an estimated 2,090,000 people affected in 2011.2 Furthermore, India has the highest burden of TB in the world, representing one-fifth (21%) of the global incidence. Unfortunately, India does not have national data on DR-TB prevalence, but a survey conducted in the States of Gujarat and Maharashtra in 2007 estimated the prevalence of DR-TB to be 3% in new cases and 12–17% in retreatment cases.3 Between October 2006 and July 2013, Medecins Sans Frontieres (MSF) treated 129 DR-TB patients co-infected with HIV at a clinic in Mumbai. The patients were referred to us from government ART centers, public-private ART centers, and a network of community non-governmental organizations. All HIV patients were monitored with viral load (VL) testing at least every 6 months, as recommended by Satti. Patients identified as having virological failure received adherence counseling and subsequently had the VL test rechecked at 3–6 months. Those in whom the VL test did not re-suppress were switched to a second-line ART regimen consisting of a protease inhibitor (PI) and suitable nucleoside(tide) reverse transcriptase inhibitors (NRTIs), based on genotype HIV resistance testing when necessary. Of the 129 DR-TB patients co-infected with HIV, 8 patients required second-line ART4; the median baseline CD4 count of the 8 patients before DR-TB treatment initiation was 102.5 cells/μL. Three of the 8 patients were on first-line ART at the time of DR-TB treatment initiation and had to be switched to second-line ART during the course of DR-TB treatment (Table 1). All 3 had a VL result > 5,000 copies/mL before the switch; subsequent VL testing showed a 2-log decrease in the two patients in whom a result was available. Table 1 CD4 count, viral load, and TB treatment response of patients on second-line ART In the six patients having a CD4 count available at the end of DR-TB treatment, five had an increase compared with baseline. Five out of eight patients had successful outcomes: 3 were cured and 2 successfully completed DR-TB treatment. Two patients were unfortunately lost to follow-up, and there was one death (Case 5). In this latter case, there was extensive pulmonary involvement and additional resistance of the TB strain to fluoroquinolones. We agree with the recommendation of Satti that VL testing be performed routinely in DR-TB patients co-infected with HIV. It allows for early detection of ART adherence problems, which has been shown in other reports to prevent an unnecessary switch to a second-line regimen with enhanced adherence support.5 In those in whom the VL result cannot be re-suppressed (i.e. caused by development of HIV drug resistance), an early switch to a second-line regimen is likely to increase the chances of a more successful outcome. We would like to reinforce an additional point that was implied in their Short Report, that DR-TB and HIV management be integrated in co-infected patients. Such patients are complicated and ideally should be managed in the same health facility by the same team of health care providers. At present, HIV VL testing is reserved only for suspected cases of treatment failure attending public ART centers in Mumbai and is not used for routine monitoring. Such an approach is likely to delay early detection of ART failure and contribute to the poor outcomes being seen in DR-TB patients co-infected with HIV.6 In this and other national HIV/ART programs not yet implementing routine VL testing, we ask that this be prioritized in HIV patients being treated for DR-TB. We also hope to see stronger collaboration between all HIV/ART and DR-TB programs with a view toward eventual integration of services for these complicated patients, to allow for better management.7

Role of HIV infection duration and CD4 cell level at initiation of combination anti-retroviral therapy on risk of failure.

BackgroundThe development of HIV drug resistance and subsequent virological failure are often cited as potential disadvantages of early cART initiation. However, their long-term probability is not known, and neither is the role of duration of infection at the time of initiation.MethodsPatients enrolled in the UK Register of HIV seroconverters were followed-up from cART initiation to last HIV-RNA measurement. Through survival analysis we examined predictors of virologic failure (2HIV-RNA ≥400 c/l while on cART) including CD4 count and HIV duration at initiation. We also estimated the cumulative probabilities of failure and drug resistance (from the available HIV nucleotide sequences) for early initiators (cART within 12 months of seroconversion).ResultsOf 1075 starting cART at a median (IQR) CD4 count 272 (190,370) cells/mm3 and HIV duration 3 (1,6) years, virological failure occurred in 163 (15%). Higher CD4 count at initiation, but not HIV infection duration at cART initiation, was independently associated with lower risk of failure (p=0.033 and 0.592 respectively). Among 230 patients initiating cART early, 97 (42%) discontinued it after a median of 7 months; cumulative probabilities of resistance and failure by 8 years were 7% (95% CI 4,11) and 19% (13,25), respectively.ConclusionAlthough the rate of discontinuation of early cART in our cohort was high, the long-term rate of virological failure was low. Our data do not support early cART initiation being associated with increased risk of failure and drug resistance.

Research development of HIV drug resistance

Highly active antiretroviral combination therapy significantly reduced the mortality, but in the high-speed copying, high genetic variation and drug selection pressure under the effect of the increasingly serious problem of drug resistance greatly weakened the role of HAART inhibit viral replication and reduce antiviral treatment. This paper reports the latest trends in HIV drug-resistance in order to develop anti-HIV drugs in clinical programs, research and development of new guidance anti-HIV-1 strategy to bring guidance.

Pharmacists’ Research Contributions in the Fight against HIV/AIDs

Pharmacists have made many contributions to HIV/AIDs research and are still showing their significance as members of the healthcare team through innovative clinical trials. Pharmacists are showing advances in several healthcare settings including inpatient, outpatient, and community pharmacies. Because of the complex regimens of highly active antiretroviral therapy (HAART), the increased life span of patients living with HIV, and other concomitant medications taken for comorbid disease states, there is a high risk for health-related complications and the development of adverse events. These adverse events may lead to decreased adherence to HAART, which may cause the development of HIV drug resistance. Pharmacists are providing examples through growing research on how they help combat medication-related errors and also continue to contribute as healthcare providers as a part of a holistic healthcare team.

Trends in CD4 counts in HIV-infected patients with HIV viral load monitoring while on combination antiretroviral treatment: results from The TREAT Asia HIV Observational Database

BackgroundThe aim of this study was to examine the relationship between trends in CD4 counts (slope) and HIV viral load (VL) after initiation of combination antiretroviral treatment (cART) in Asian patients in The TREAT Asia HIV Observational Database (TAHOD).MethodsTreatment-naive HIV-infected patients who started cART with three or more and had three or more CD4 count and HIV VL tests were included. CD4 count slopes were expressed as changes of cells per microliter per year. Predictors of CD4 count slopes from 6 months after initiation were assessed by random-effects linear regression models.ResultsA total of 1676 patients (74% male) were included. The median time on cART was 4.2 years (IQR 2.5-5.8 years). In the final model, CD4 count slope was associated with age, concurrent HIV VL and CD4 count, disease stage, hepatitis B or C co-infection, and time since cART initiation. CD4 count continues to increase with HIV VL up to 20 000 copies/mL during 6-12 months after cART initiation. However, the HIV VL has to be controlled below 5 000, 4 000 and 500 copies/mL for the CD4 count slope to remain above 20 cells/microliter per year during 12-18, 18-24, and beyond 24 months after cART initiation.ConclusionsAfter cART initiation, CD4 counts continued to increase even when the concurrent HIV VL was detectable. However, HIV VL needed to be controlled at a lower level to maintain a positive CD4 count slope when cART continues. The effect on long-term outcomes through the possible development of HIV drug resistance remains uncertain.

Resistance considerations in sequencing of antiretroviral therapy in low-middle income countries with currently available options

Access to antiretroviral therapy (ART) has been scaled-up in low-middle income countries (LMICs), where the majority of the world's HIV-1-infected population is living. Concerns towards the emergence and spread of HIV-1 drug resistance exist, given the lack of virological monitoring which may give rise to accumulation of resistance as well as the use of suboptimal ART in pregnant women with the aim to reduce perinatal transmission. Knowledge of the prevalence of transmitted and emerging drug resistance as well as its specific patterns is of help in guiding the selection of appropriate ART types and sequencing strategies. Whereas transmitted drug resistance in LMIC is still limited, resistance in pregnant women as a consequence of suboptimal ART for the prevention of vertical transmission is frequent and dependent on viral subtype and load. Accumulation of drug resistance during first-line ART depends on the frequency of monitoring, whereas mutational patterns are influenced by type of ART and, partly, viral subtype. Optimized ART for prevention of mother-to-child transmission and closer monitoring of ART programs with the inclusion of viral load may help reducing unnecessary development of HIV drug resistance in LMIC and preserve the limited available treatment options.

Cohort profile: the Centers for AIDS Research Network of Integrated Clinical Systems

Highly active antiretroviral therapy (HAART) delays disease progression and death. However, the treatments incompletely control HIV replication, only partially restore immune function, have significant shortand long-term toxicities, and eventually fail in many patients with consequent development of HIV drug resistance. Thus, there is increasing need for information to guide HIV-infected patients and their providers in making decisions regarding optimal use of antiretroviral therapies. Although clinical trials provide valuable information about efficacy and side effects of antiretroviral treatment, they have limited size, duration and power to detect effects on clinical outcomes, focusing instead on surrogate endpoints such as virologic failure, treatment discontinuation or composite outcome measures. Outside the clinical trial setting, there is tremendous heterogeneity among HIV-infected patients. The prevalence and impact of important health conditions such as hepatitis C virus (HCV) co-infection, mental illness and substance abuse likely contribute to increased toxicity and decreased clinical effectiveness of HAART regimens among the broader spectrum of patients treated in routine care. Cohorts with significant diversity in HIV disease severity, comorbidities and demographic distributions are required to provide information regarding long-term outcomes and complications of HIV infection in the modern HAART era. The Centers for AIDS Research (CFAR) Network of Integrated Clinical Systems (CNICS) was created to better define the relationship between patient and treatment factors and long-term clinical outcomes among HIV-infected patients in the HAART era. The CFARs are a national network of centres of excellence for HIV care and research established by the National Institutes of Health (NIH) whose mission is to support a multi-disciplinary environment for basic, clinical, epidemiologic, behavioural and translational research in the prevention, detection and treatment of HIV infection and AIDS. There are 19 CFARs located at academic and research institutions throughout the United States. The objective of the CNICS project is to integrate clinical data from the large and diverse population of HIV-infected persons receiving care at CFAR sites to investigate questions related to HIV disease management that cannot be readily addressed through traditional randomized controlled clinical trials and other cohort studies. Investigators with expertise in basic, clinical, translational and epidemiologic research, in addition to medical informatics, are collaborating on the CNICS project. The potential to build a comprehensive clinical data repository for HIV disease was greatly advanced by the work of CFAR investigators at the participating CNICS sites who had instituted point-of-care electronic medical record systems (EMRs) with the dual purpose of providing real-time clinical information to facilitate the delivery of HIV care and capturing standardized clinical data to support populationbased HIV research. The initial four CNICS sites were Case Western Reserve University, University of * Corresponding author. Center for AIDS Research, University of Washington, 325 9th Ave, MS 359931, Seattle, WA 98104, USA. E-mail: kitahata@u.washington.edu 1 Department of Medicine, University of Washington, Seattle, 98195, USA. 2 Department of Medicine, Case Western Reserve University, Cleveland, 44106, USA. 3 Department of Medicine, University of California, San Diego, 92110, USA. 4 Department of Medicine, Harvard University, Boston, 02115, USA. 5 Department of Medicine, Johns Hopkins University, Baltimore, 21218, USA. 6 Department of Medicine, University of Alabama, Birmingham, 35209, USA. 7 Department of Medicine, University of California, San Francisco, 94143, USA. Published by Oxford University Press on behalf of the International Epidemiological Association

The Calculated Genetic Barrier for Antiretroviral Drug Resistance Substitutions Is Largely Similar for Different HIV-1 Subtypes

The genetic barrier, defined as the number of mutations required to overcome drug-selective pressure, is an important factor for the development of HIV drug resistance. Because of high variability between subtypes, particular HIV-1 subtypes could have different genetic barriers for drug resistance substitutions. This study compared the genetic barrier between subtypes using some 2000 HIV-1 sequences (>600 of non-B subtype) isolated from anti-retroviral-naive patients in Europe. The genetic barrier was calculated as the sum of transitions (scored as 1) and/or transversions (2.5) required for evolution to any major drug resistance substitution. In addition, the number of minor protease substitutions was determined for every subtype. Few dissimilarities were found. An increased genetic barrier was calculated for I82A (subtypes C and G), V108I (subtype G), V118I (subtype G), Q151M (subtypes D and F), L210W (subtypes C, F, G, and CRF02_AG), and P225H (subtype A) (P < 0.001 compared with subtype B). A decreased genetic barrier was found for I82T (subtypes C and G) and V106M (subtype C) (P < 0.001 vs subtype B). Conversely, minor protease substitutions differed extensively between subtypes. Based on the calculated genetic barrier, the rate of drug resistance development may be similar for different HIV-1 subtypes. Because of differences in minor protease substitutions, protease inhibitor resistance could be enhanced in particular subtypes once the relevant major substitutions are selected.

Epidemiology and Evolution of Antiretroviral Drug Resistance

The development of HIV drug resistance is a formidable obstacle in the long term success of antiretroviral therapeutic regimens. To date, resistance has occurred against all drugs that are in widespread use for treatment of HIV disease. Moreover, HIV drug resistant viruses can be sexually transmitted and it is now estimated that as many as 10% of new HIV infections in Western countries may carry at least one mutation associated with HIV drug resistance. In some cases, newly infected individuals may even harbour viruses that are resistant to two or even three classes of antiretroviral drugs. Studies have shown that mutations which are transmitted from one individual to another may often persist over long periods of time i.e. 2– 7 years. Although many mutations may also revert to wild-type, a danger is that they will have become permanently archived in a patient's long-lived memory Tcells, and that this may preclude future therapeutic options.

Präoperative Risikoabschätzung und perioperatives Management HIV-infizierter Patienten

Due to their impaired immune function, unusual multimorbidity, and extensive concomitant medication HIV-infected patients impose special and specific demands on those who deal with their perioperative care. Beside standardized diagnostic and therapeutic preparations the preoperative knowledge, quantification, and treatment of HIV-associated opportunistic disorders and chronic organ damage are of particular importance. This requires an extended problem-orientated work-up. Furthermore, antiretroviral medication may interact with perioperatively administered pharmaceutics and lead to hardly foreseeable synergistic and antagonistic adverse effects. In contrast, "drug holidays" favor the development of HIV drug resistance. Anesthetic and surgical procedures basically depend on the underlying indication and consequently follow common principles. Laparoscopic techniques do not have any specific advantage in HIV-infected subjects. During their postoperative course, HIV-infected patients have to be more often admitted to intensive care unit and kept on artificial respiration unplannedly. Perioperative morbidity of HIV-infected patients increases with the stage of their disease. It is, however, not significantly elevated compared to that of HIV-negative subjects in similar preoperative health condition.