[Show abstract][Hide abstract] ABSTRACT: Increased use of nonnucleoside reverse transcriptase inhibitors (NNRTIs) in pregnant and breastfeeding women will result in fewer children infected with human immunodeficiency virus (HIV). However, among children infected despite prevention of mother-to-child transmission (PMTCT), a substantial proportion will acquire NNRTI-resistant HIV, potentially compromising response to NNRTI-based antiretroviral therapy (ART). In countries scaling up PMTCT and pediatric ART programs, it is crucial to assess the proportion of young children with drug-resistant HIV to improve health outcomes and support national and global decision making on optimal selection of pediatric first-line ART. This article summarizes a new World Health Organization surveillance protocol to assess resistance using remnant dried blood spot specimens from a representative sample of children aged <18 months being tested for early infant diagnosis.
[Show abstract][Hide abstract] ABSTRACT: In 2004, the World Health Organization performed a survey to assess transmitted drug resistance in Mexico City among drug-naive persons with newly diagnosed human immunodeficiency virus (HIV) infection and likely to be recently infected who were attending 3 voluntary counseling and testing sites. A parallel study comparing 2 alternative methods of enrolling survey participant was conducted in 9 voluntary counseling and testing sites in central Mexico. In study arm 1, subject information, consent and blood specimens were obtained during the HIV diagnostic testing visit. In study arm 2, consent and blood specimens were obtained at the return visit, only from those who were HIV infected. This survey classified nonnucleoside reverse-transcriptase inhibitor and nucleoside reverse-transcriptase inhibitor transmitted drug resistance as <5% and 5%-15%, respectively. Arm 2 yielded major advantages in cost and workload, with no evidence of increased sampling bias.
[Show abstract][Hide abstract] ABSTRACT: The World Health Organization developed a set of human immunodeficiency virus drug resistance (HIVDR) early warning indicators (EWIs) to assess antiretroviral therapy clinic and program factors associated with HIVDR. EWIs are monitored by abstracting data routinely recorded in clinical records, and the results enable clinics and program managers to identify problems that should be addressed to minimize preventable emergence of HIVDR in clinic populations. As of June 2011, 50 countries monitored EWIs, covering 131 686 patients initiating antiretroviral treatment between 2004 and 2009 at 2107 clinics. HIVDR prevention is associated with patient care (appropriate prescribing and patient monitoring), patient behavior (adherence), and clinic/program management efforts to reduce treatment interruptions (follow up, retention on first-line ART, procurement and supply management of antiretroviral drugs). EWIs measure these factors and the results have been used to optimize patient and population treatment outcomes.
[Show abstract][Hide abstract] ABSTRACT: In 2004, Malawi began scaling up its national antiretroviral therapy (ART) program. Because of limited treatment options, population-level surveillance of acquired human immunodeficiency virus drug resistance (HIVDR) is critical to ensuring long-term treatment success. The World Health Organization target for clinic-level HIVDR prevention at 12 months after ART initiation is ≥ 70%. In 2007, viral load and HIVDR genotyping was performed in a retrospective cohort of 596 patients at 4 ART clinics. Overall, HIVDR prevention (using viral load ≤ 400 copies/mL) was 72% (95% confidence interval [CI], 67%-77%; range by site, 60%-83%) and detected HIVDR was 3.4% (95% CI, 1.8%-5.8%; range by site, 2.5%-4.7%). Results demonstrate virological suppression and HIVDR consistent with previous reports from sub-Saharan Africa. High rates of attrition because of loss to follow-up were noted and merit attention.
[Show abstract][Hide abstract] ABSTRACT: HIV drug resistance (HIVDR) testing is not routinely available in many resource-limited settings, therefore, antiretroviral therapy (ART) program and site factors known to be associated with HIVDR should be monitored to optimize the quality of patient care and minimize the emergence of preventable HIVDR.
In 2009, Namibia selected 5 World Health Organization Early Warning Indicators (EWIs) and piloted abstraction at 9 ART sites: "ART prescribing practices, patients lost to follow-up at 12 months, patient retention on first-line ART at 12 months, on-time antiretroviral drug pick-up, and antiretroviral drug-supply continuity".
Records supported monitoring of 3 of 5 selected EWIs. Nine of 9 (100%) sites met the target of 100% initiated on appropriate first-line regimens. Eight of 9 (89%) sites met the target of ≤20% lost to follow-up, although 20.8% of ART starters (range: 4.6%-44.6%) had a period of absence without documented ART coverage of 2.3 months (range: 1.5-3.9 months). Six of 9 (67%) sites met the target of 0% switched to a second-line regimen.
EWI monitoring directly resulted in public health action which will optimize the quality of care, specifically the strengthening of ART record systems permitting monitoring of 5 EWIs in future years and protocols for improved ART patient defaulter tracing.
[Show abstract][Hide abstract] ABSTRACT: Programs that monitor local, national, and regional levels of transmitted HIV-1 drug resistance inform treatment guidelines and provide feedback on the success of HIV-1 treatment and prevention programs. To accurately compare transmitted drug resistance rates across geographic regions and times, the World Health Organization has recommended the adoption of a consensus genotypic definition of transmitted HIV-1 drug resistance. In January 2007, we outlined criteria for developing a list of mutations for drug-resistance surveillance and compiled a list of 80 RT and protease mutations meeting these criteria (surveillance drug resistance mutations; SDRMs). Since January 2007, several new drugs have been approved and several new drug-resistance mutations have been identified. In this paper, we follow the same procedures described previously to develop an updated list of SDRMs that are likely to be useful for ongoing and future studies of transmitted drug resistance. The updated SDRM list has 93 mutations including 34 NRTI-resistance mutations at 15 RT positions, 19 NNRTI-resistance mutations at 10 RT positions, and 40 PI-resistance mutations at 18 protease positions.
PLoS ONE 02/2009; 4(3):e4724. DOI:10.1371/journal.pone.0004724 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Transmitted HIV-1 drug resistance can compromise initial antiretroviral therapy (ART); therefore, its detection is important for patient management. The absence of drug-associated selection pressure in treatment-naïve persons can cause drug-resistant viruses to decline to levels undetectable by conventional bulk sequencing (minority drug-resistant variants). We used sensitive and simple tests to investigate evidence of transmitted drug resistance in antiretroviral drug-naïve persons and assess the clinical implications of minority drug-resistant variants.
We performed a cross-sectional analysis of transmitted HIV-1 drug resistance and a case-control study of the impact of minority drug resistance on treatment response. For the cross-sectional analysis, we examined viral RNA from newly diagnosed ART-naïve persons in the US and Canada who had no detectable (wild type, n = 205) or one or more resistance-related mutations (n = 303) by conventional sequencing. Eight validated real-time PCR-based assays were used to test for minority drug resistance mutations (protease L90M and reverse transcriptase M41L, K70R, K103N, Y181C, M184V, and T215F/Y) above naturally occurring frequencies. The sensitive real-time PCR testing identified one to three minority drug resistance mutation(s) in 34/205 (17%) newly diagnosed persons who had wild-type virus by conventional genotyping; four (2%) individuals had mutations associated with resistance to two drug classes. Among 30/303 (10%) samples with bulk genotype resistance mutations we found at least one minority variant with a different drug resistance mutation. For the case-control study, we assessed the impact of three treatment-relevant drug resistance mutations at baseline from a separate group of 316 previously ART-naïve persons with no evidence of drug resistance on bulk genotype testing who were placed on efavirenz-based regimens. We found that 7/95 (7%) persons who experienced virologic failure had minority drug resistance mutations at baseline; however, minority resistance was found in only 2/221 (0.9%) treatment successes (Fisher exact test, p = 0.0038).
These data suggest that a considerable proportion of transmitted HIV-1 drug resistance is undetected by conventional genotyping and that minority mutations can have clinical consequences. With no treatment history to help guide therapies for drug-naïve persons, the findings suggest an important role for sensitive baseline drug resistance testing.
PLoS Medicine 08/2008; 5(7):e158. DOI:10.1371/journal.pmed.0050158 · 14.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In lower-income countries, WHO recommends a population-based approach to antiretroviral treatment with standardised regimens and clinical decision making based on clinical status and, where available CD4 cell count, rather than viral load. Our aim was to study the potential consequences of such monitoring strategies, especially in terms of survival and resistance development.
A validated computer simulation model of HIV infection and the effect of antiretroviral therapy was used to compare survival, use of second-line regimens, and development of resistance that result from different strategies-based on viral load, CD4 cell count, or clinical observation alone-for determining when to switch people starting antiretroviral treatment with the WHO-recommended first-line regimen of stavudine, lamivudine, and nevirapine to second-line antiretroviral treatment.
Over 5 years, the predicted proportion of potential life-years survived was 83% with viral load monitoring (switch when viral load >500 copies per mL), 82% with CD4 cell count monitoring (switch at 50% drop from peak), and 82% with clinical monitoring (switch when two new WHO stage 3 events or a WHO stage 4 event occur). Corresponding values over 20 years were 67%, 64%, and 64%. Findings were robust to variations in model specification in extensive univariable and multivariable sensitivity analyses. Although survival was slightly longer with viral load monitoring, this strategy was not the most cost effective.
For patients on the first-line regimen of stavudine, lamivudine, and nevirapine the benefits of viral load or CD4 cell count monitoring over clinical monitoring alone are modest. Development of cheap and robust versions of these assays is important, but widening access to antiretrovirals-with or without laboratory monitoring-is currently the highest priority.
The Lancet 04/2008; 371(9622):1443-51. DOI:10.1016/S0140-6736(08)60624-8 · 45.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Antiretroviral treatment (ART) for HIV is being scaled up rapidly in resource-limited countries. Treatment options are simplified and standardized, generally with one potent first-line regimen and one potent alternate first-line regimen recommended. Widespread HIV drug resistance (HIVDR) was initially feared, but reports from resource-limited countries suggest that initial ART programmes are as effective as in resource-rich countries, which should limit HIV drug resistance if programme effectiveness continues during scale-up. ART interruptions must be minimized to maintain viral suppression on the first-line regimen for as long as possible. Lack of availability of appropriate second-line drugs is a concern, as is the additional accumulation of resistance mutations in the absence of viral load testing to determine failure. The World Health Organization (WHO) recommends a minimum-resource strategy for prevention and assessment of HIVDR in resource-limited countries. The WHO's Global Network HIVResNet provides standardized tools, training, technical assistance, laboratory quality assurance, analysis of results and recommendations for guidelines and public health action. National strategies focus on assessments to guide immediate public health action to improve ART programme effectiveness in minimizing HIVDR and to guide regimen selection. Globally, WHO HIVResNet collects and analyses data to support evidence-based international policies and guidelines. Financial support is provided by major international organizations and technical support from HIVDR experts worldwide. As of December 2007, 25 countries were planning or implementing the strategy; seven countries report results in this supplement.
[Show abstract][Hide abstract] ABSTRACT: The World Health Organization (WHO) HIV drug resistance (HIVDR) threshold survey method was developed for surveillance of transmitted HIVDR in resource-limited countries. The method is being implemented with minimal resources as a routine public health activity to produce comparable results in multiple countries and areas within countries. Transmitted drug resistant HIV strains will be seen first in cities or health districts where antiretroviral treatment (ART) has been widely available for years. WHO recommends countries begin surveillance in these areas.
Each survey requires < or =47 specimens from individuals consecutively diagnosed with HIV to categorize resistance to each relevant drug class as <5%, 5-15% or >15%. Use of routinely collected information and remnant specimens is recommended to minimize costs. Site and individual eligibility criteria are designed to minimize inclusion of ARV-experienced individuals and individuals infected before ART was available.
Surveys have been implemented in 21 countries. In this supplement, seven countries report results of <5% transmitted HIVDR in areas where ART has been available for the longest time period. The main challenges in implementation are acquiring sufficient numbers of eligible specimens and optimizing specimen handling.
The WHO HIVDR threshold survey method is feasible in resource-limited countries and produces information relevant to ART and drug resistance prevention planning.
[Show abstract][Hide abstract] ABSTRACT: Surveillance for transmitted HIV-1 drug resistance was conducted among drug-naive HIV-1-infected pregnant women in South Africa, where single-dose nevirapine has been in use since 2001 and a national antiretroviral treatment programme started in 2004.
All subjects were from the Gauteng Province and were part of the 2002 and 2004 annual antenatal HIV seroprevalence survey conducted by the South African National Department of Health. All subjects met the inclusion criteria as set out by the World Health Organisation guidelines for HIV-1 transmitted drug resistance surveillance (women <22 years of age and in first pregnancy). Genotyping was performed on viral RNA by sequencing the protease and reverse transcriptase genes. Samples were also tested for the K103N mutation using a highly sensitive allele-specific real-time PCR assay (AS-PCR).
Of 128 eligible participants from 2002, 65 (51%) samples were successfully amplified. None of them had evidence of resistance mutations by genotyping or by AS-PCR. Of 117 eligible participants from 2004, 48 (41%) samples were successfully amplified. Of these, one had T69D and one had the K70R resistance mutation, to give a total of 2/48 (4.2%) participants with evidence of resistance mutations by genotyping. One sample that was wild-type by genotyping was positive for K103N by AS-PCR. All samples clustered phylogenetically with HIV-1 subtype C, the predominant subtype circulating in South Africa.
Using the threshold survey, resistance prevalence overall and for each drug class in 2002 and 2004 was <5% for the Gauteng province of South Africa. The detection of a low frequency of resistance mutations in the 2004 survey suggests that surveillance should be conducted annually among untreated populations to determine if this increases with time.
[Show abstract][Hide abstract] ABSTRACT: The goal for tuberculosis (TB) elimination in the United States is a TB disease incidence of less than 1 per million U.S. population by 2010, which requires that the latent TB infection (LTBI) prevalence be less than 1% and decreasing.
To estimate the prevalence of LTBI in the U.S. population.
Interviews and medical examinations, including tuberculin skin testing (TST), of 7,386 individuals were conducted in 1999-2000 as part of the National Health and Nutrition Examination Survey (NHANES), a nationally representative sample of the civilian, noninstitutionalized U.S. population. LTBI was defined as a TST measurement of >/=10 mm. Associations of age, race/ethnicity, sex, poverty, and birthplace were assessed. Results among the 24- to 74-year-old subgroup were compared with NHANES 1971-1972 data.
Estimated LTBI prevalence was 4.2%; an estimated 11,213,000 individuals had LTBI. Among 25- to 74-year-olds, prevalence decreased from 14.3% in 1971-1972 to 5.7% in 1999-2000. Higher prevalences were seen in the foreign born (18.7%), non-Hispanic blacks/African Americans (7.0%), Mexican Americans (9.4%), and individuals living in poverty (6.1%). A total of 63% of LTBI was among the foreign born. Among the U.S. born, after adjusting for confounding factors, LTBI was associated with non-Hispanic African-American race/ethnicity, Mexican American ethnicity, and poverty. A total of 25.5% of persons with LTBI had been previously diagnosed as having LTBI or TB, and only 13.2% had been prescribed treatment.
In addition to basic TB control measures, elimination strategies should include targeted evaluation and treatment of individuals in high-prevalence groups, as well as enhanced support for global TB prevention and control.
American Journal of Respiratory and Critical Care Medicine 02/2008; 177(3):348-55. DOI:10.1164/rccm.200701-057OC · 13.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This article describes the development of a novel sequential sampling method for the surveillance of transmitted HIV drug resistance by cross-sectional survey. Two commonly used sequential sampling methods are described and their applicability to the problem of classifying the prevalence of transmitted HIV drug resistance investigated. Both methods are rejected due to insufficient savings in sample size and operational complexity. A novel method is proposed and this is tested using computer-based simulation. This method provides useful sample size savings and operational simplicity and could provide the basis for a rapid and reliable survey method for classifying the prevalence of transmitted HIV drug resistance in circumstances where monitoring HIV drug resistance is an important issue, but resources do not allow fullscale surveillance to be established. The method is currently being used in several such settings.
[Show abstract][Hide abstract] ABSTRACT: The World Health Organization (WHO) estimates that >2 million people will have started antiretroviral therapy (ART) by the end of 2006. As the development of some HIV drug resistance (HIVDR) is inevitable in populations taking ART, the emergence of HIVDR must be balanced against the benefits of providing ART, including improved health outcomes and decreased HIV/AIDS-associated morbidity and mortality. ART programmes should operate to minimize the emergence of HIVDR in populations receiving therapy and HIVDR itself must be monitored to ensure ongoing regimen efficacy. ART regimens in resource-limited settings are usually selected at the national level following a public health approach: generally only one first-line regimen with alternate regimen(s) incorporating within-class drug substitutions are available in the public sector. The WHO has developed a population-based HIVDR assessment and prevention strategy, which includes standardized HIVDR monitoring surveys in populations receiving first-line ART at sentinel sites. The WHO surveys monitor HIVDR prevention in sentinel sites by utilizing a standardized, minimum-resource prospective survey methodology to assess the success of adult and paediatric ART sites in preventing HIVDR emergence during the first year of ART. The surveys also identify associated factors that can be addressed at the level of the ART site or programme. WHO HIVDR monitoring surveys are designed to be integrated easily into a country's ongoing, routine HIV-related evaluation activities. Performed regularly at representative sites, the data generated will inform evidence-based decision making regarding national and global ART regimen selection and minimize the emergence of HIVDR at a population level.
[Show abstract][Hide abstract] ABSTRACT: Programmes that monitor local, national and regional levels of transmitted HIV-1 drug resistance inform treatment guidelines and provide feedback on the success of HIV-1 treatment and prevention programmes. The World Health Organization (WHO) has established a global programme for genotypic surveillance of HIV-1 drug resistance and has recommended the adoption of a consensus definition of genotypic drug resistance. Such a definition is necessary to accurately compare transmitted drug resistance rates across geographical regions and time periods. HIV-1 diversity and the large number of mutations associated with antiretroviral drug resistance complicate the development of a consensus definition for genotypic drug resistance. This paper reviews the data that must be considered to determine which of the many HIV-1 drug resistance mutations are likely to be both sensitive and specific indicators of transmitted drug resistance. The process used to create a previously published list of drug resistance mutations for HIV-1 surveillance is reviewed and alternative approaches to this process are discussed.
[Show abstract][Hide abstract] ABSTRACT: In resource-limited settings where antiretroviral treatment (ART) access is being scaled-up, the World Health Organization (WHO) recommends surveillance of transmitted HIV drug resistance (HIVDR). We used the WHO HIVDR threshold survey method to assess transmitted HIVDR in Dar es Salaam where ART was introduced in 1995 and where approximately 11,000 people are currently on ART.
From November 2005 to February 2006, dried blood spot (DBS) specimens were made from remnant specimens collected during the national HIV serosurvey from 60 primagravidas <25 years old attending six antenatal clinics for routine syphilis testing. Genotyping was performed at the Centers for Disease Control and Prevention, Atlanta, Georgia, USA. Protease and reverse transcriptase drug resistance mutations were identified using the Stanford University HIV drug resistance database. We used the National Institutes of Health genotyping tool for HIV-1 subtyping. HIVDR prevalence categorization was based on the WHO threshold survey binomial sequential sampling method.
Among the 60 eligible specimens collected, 50 DBS were successfully amplified using RT-PCR. Sequencing was performed on the first 39 specimens: 13 (33.3%) were subtype A1, 13 (33.3%) subtype C, and 4 (10.3%) subtype D, the remainder differed in the closest subtype based on protease versus reverse transcriptase. No resistance mutations were seen; HIVDR to all drug classes was categorized as <5%.
Our survey indicates that prevalence of transmitted HIVDR among recently infected pregnant women in Dar es Salaam is low (<5/%). The survey should be repeated during the next HIV sentinel survey in Dar es Salaam and extended to other regions where ART is being scaled up.
[Show abstract][Hide abstract] ABSTRACT: In resource-limited settings where antiretroviral treatment (ART) is being scaled-up, the World Health Organization (WHO) recommends the surveillance of transmitted HIV drug resistance (HIVDR). We used the WHO's HIVDR threshold survey method to assess transmitted HIVDR in three antenatal clinic (ANC) sites along the corridor between the two most populous cities in Swaziland, where ART was introduced in 2003.
From July-August 2006, remnant sera were aliquoted from HIV serosurvey specimens collected from 70 primagravidas <25 years old attending ANC during the national HIV serosurvey. Genotyping was performed at the National Institute for Communicable Diseases, South Africa. Transmitted resistance was defined by the WHO's surveillance list of mutations. HIVDR prevalence was categorized using the WHO's threshold survey binomial sequential sampling method.
Among the 70 eligible specimens, 61 were sequenced--60 (98%) were identified as subtype C and one as subtype B. No major nucleoside or non-nucleoside reverse transcriptase inhibitor mutations occurred among the first 34 consecutive specimens, which supported a transmitted resistance categorization to these drug classes as <5%. One protease inhibitor mutation, M461, was seen among the first 44 specimens, supporting a categorization of PI resistance as <5%.
Our survey indicates that prevalence of transmitted HIVDR among recently infected pregnant women along the Manzini-Mbabane corridor is low (<5%). Surveys will be carried out in this area biannually and may be extended to other areas. Surveys for transmitted resistance make up one element among a spectrum of activities to assess and support minimization of HIVDR.
[Show abstract][Hide abstract] ABSTRACT: To describe surveillance measures to inform HIV drug-resistance prevention, as part of the public health approach to antiretroviral therapy in developing countries.
Neither HIV drug-resistance transmission nor its emergence in treatment is routinely assessed in the developing world, but routine methods should be part of antiretroviral therapy scale-up. Mathematical modelling and experience in resource-rich countries suggest HIV drug-resistance transmission will increase as antiretroviral therapy coverage increases, but its rise will be limited initially. Transmission surveys should begin in geographic areas in each country where antiretroviral therapy coverage is widespread. Reports from resource-limited countries suggest that antiretroviral therapy programs are as effective as in resource-rich countries, which should limit HIV drug resistance if effectiveness is maintained with antiretroviral therapy expansion. Surveillance of HIV drug resistance emerging in treatment and other factors will support implementation of prevention measures on a population level.
Standardized surveillance of transmitted and treatment-associated HIV drug resistance is critical to the success of antiretroviral therapy expansion in developing countries. Routine assessment of prescribing practices, availability of and access to appropriate regimens for adults and children, antiretroviral drug supply continuity, and measures to prevent HIV transmission will supply critical information for HIV drug-resistance prevention.
Current Opinion in Infectious Diseases 01/2007; 19(6):607-14. DOI:10.1097/QCO.0b013e3280109ff1 · 5.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To better understand the molecular epidemiology of tuberculosis (TB) transmission for culture-confirmed patients <5 years of age, data were analyzed from a population-based study conducted in seven U.S. sites from 1996 to 2000. Mycobacterium tuberculosis isolates were genotyped with IS6110-based restriction fragment length polymorphism analysis and spoligotyping. Case-patient data were obtained from the Centers for Disease Control and Prevention s national tuberculosis registry and health department records. Routine public health investigations conducted by local health departments identified suspected source patients for 57 (51%) of 111 culture-confirmed patients <5 years of age. For 8 (15%) of 52 culture-confirmed patients <5 years of age and their suspected source patients with complete genotyping results, genotypes suggested infection with different TB strains. Potential differences between sources for patients <5 years of age and source patients that transmitted TB to adolescent and adult patients were identified.