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1.  National Prevalence and Trends of HIV Transmitted Drug Resistance in Mexico 
PLoS ONE  2011;6(11):e27812.
Background
Transmitted drug resistance (TDR) remains an important concern for the management of HIV infection, especially in countries that have recently scaled-up antiretroviral treatment (ART) access.
Methodology/Principal Findings
We designed a study to assess HIV diversity and transmitted drug resistance (TDR) prevalence and trends in Mexico. 1655 ART-naïve patients from 12 Mexican states were enrolled from 2005 to 2010. TDR was assessed from plasma HIV pol sequences using Stanford scores and the WHO TDR surveillance mutation list. TDR prevalence fluctuations over back-projected dates of infection were tested. HIV subtype B was highly prevalent in Mexico (99.9%). TDR prevalence (Stanford score>15) in the country for the study period was 7.4% (95% CI, 6.2∶8.8) and 6.8% (95% CI, 5.7∶8.2) based on the WHO TDR surveillance mutation list. NRTI TDR was the highest (4.2%), followed by NNRTI (2.5%) and PI (1.7%) TDR. Increasing trends for NNRTI (p = 0.0456) and PI (p = 0.0061) major TDR mutations were observed at the national level. Clustering of viruses containing minor TDR mutations was observed with some apparent transmission pairs and geographical effects.
Conclusions
TDR prevalence in Mexico remains at the intermediate level and is slightly lower than that observed in industrialized countries. Whether regional variations in TDR trends are associated with differences in antiretroviral drug usage/ART efficacy or with local features of viral evolution remains to be further addressed.
doi:10.1371/journal.pone.0027812
PMCID: PMC3217006  PMID: 22110765
2.  Increase of Transmitted Drug Resistance among HIV-Infected Sub-Saharan Africans Residing in Spain in Contrast to the Native Population 
PLoS ONE  2011;6(10):e26757.
Background
The prevalence of transmitted HIV drug resistance (TDR) is stabilizing or decreasing in developed countries. However, this trend is not specifically evaluated among immigrants from regions without well-implemented antiretroviral strategies.
Methods
TDR trends during 1996–2010 were analyzed among naïve HIV-infected patients in Spain, considering their origin and other factors. TDR mutations were defined according to the World Health Organization list.
Results
Pol sequence was available for 732 HIV-infected patients: 292 native Spanish, 226 sub-Saharan Africans (SSA), 114 Central-South Americans (CSA) and 100 from other regions. Global TDR prevalence was 9.7% (10.6% for Spanish, 8.4% for SSA and 7.9% for CSA). The highest prevalences were found for protease inhibitors (PI) in Spanish (3.1%), for non-nucleoside reverse transcriptase inhibitors (NNRTI) in SSA (6.5%) and for nucleoside reverse transcriptase inhibitors (NRTI) in both Spanish and SSA (6.5%). The global TDR rate decreased from 11.3% in 2004–2006 to 8.4% in 2007–2010. Characteristics related to a decreasing TDR trend in 2007-10 were Spanish and CSA origin, NRTI- and NNRTI-resistance, HIV-1 subtype B, male sex and infection through injection drug use. TDR remained stable for PI-resistance, in patients infected through sexual intercourse and in those carrying non-B variants. However, TDR increased among SSA and females. K103N was the predominant mutation in all groups and periods.
Conclusion
TDR prevalence tended to decrease among HIV-infected native Spanish and Central-South Americans, but it increased up to 13% in sub-Saharan immigrants in 2007–2010. These results highlight the importance of a specific TDR surveillance among immigrants to prevent future therapeutic failures, especially when administering NNRTIs.
doi:10.1371/journal.pone.0026757
PMCID: PMC3201965  PMID: 22046345
3.  Low Prevalence of Transmitted HIV Type 1 Drug Resistance Among Antiretroviral-Naive Adults in a Rural HIV Clinic in Kenya 
Abstract
Low levels of HIV-1 transmitted drug resistance (TDR) have previously been reported from many parts of sub-Saharan Africa (sSA). However, recent data, mostly from urban settings, suggest an increase in the prevalence of HIV-1 TDR. Our objective was to determine the prevalence of TDR mutations among HIV-1-infected, antiretroviral (ARV)-naive adults enrolling for care in a rural HIV clinic in Kenya. Two cross-sectional studies were carried out between July 2008 and June 2010. Plasma samples from ARV-naive adults (>15 years old) at the time of registering for care after HIV diagnosis and before starting ARVs were used. A portion of the pol subgenomic region of the virus containing the protease and part of the reverse transcriptase genes was amplified and sequenced. TDR mutations were identified and interpreted using the Stanford HIV drug resistance database and the WHO list for surveillance of drug resistance strains. Overall, samples from 182 ARV-naive adults [mean age (95% CI): 34.9 (33.3–36.4) years] were successfully amplified and sequenced. Two TDR mutations to nucleoside reverse transcriptase inhibitors [n=1 (T215D)] and protease inhibitors [n=1 (M46L)] were identified, giving an overall TDR prevalence of 1.1% (95% CI: 0.1–3.9). Despite reports of an increase in the prevalence of HIV-1 TDR in some urban settings in sSA, we report a prevalence of HIV-1 TDR of less than 5% at a rural HIV clinic in coastal Kenya. Continued broader surveillance is needed to monitor the extent of TDR in sSA.
doi:10.1089/aid.2012.0167
PMCID: PMC3537300  PMID: 22900472
4.  Prevalence of WHO Transmitted Drug Resistance Mutations by Deep Sequencing in Antiretroviral-Naïve Subjects in Hunan Province, China 
PLoS ONE  2014;9(6):e98740.
Background
There are few data on the prevalence of WHO transmitted drug resistance mutations (TDRs) that could affect treatment responses to first line antiretroviral therapy (ART) in Hunan Province, China.
Objective
Determine the prevalence of WHO NRTI/NNRTI/PI TDRs in ART-naïve subjects in Hunan Province by deep sequencing.
Methods
ART-naïve subjects diagnosed in Hunan between 2010–2011 were evaluated by deep sequencing for low-frequency HIV variants possessing WHO TDRs to 1% levels. Mutations were scored using the HIVdb.stanford.edu algorithm to infer drug susceptibility.
Results
Deep sequencing was performed on samples from 90 ART-naïve subjects; 83.3% were AE subtype. All subjects had advanced disease (average CD4 count 134 cells/mm3). Overall 25.6%(23/90) of subjects had HIV with major WHO NRTI/NNRTI TDRs by deep sequencing at a variant frequency level ≥1%; 16.7%(15/90) had NRTI TDR and 12.2%(11/90) had a major NNRTI TDR. The majority of NRTI/NNRTI mutations were identified at variant levels <5%. Mutations were analyzed by HIVdb.stanford.edu and 7.8% of subjects had variants with high-level nevirapine resistance; 4.4% had high-level NRTI resistance. Deep sequencing identified 24(27.6%) subjects with variants possessing either a PI TDR or hivdb.stanford.edu PI mutation (algorithm value≥15). 17(19.5%) had PI TDRs at levels >1%.
Conclusions
ART-naïve subjects from Hunan Province China infected predominantly with subtype AE frequently possessed HIV variants with WHO NRTI/NNRTI TDRs by deep sequencing that would affect the first line ART used in the region. Specific mutations conferring nevirapine high-level resistance were identified in 7.8% of subjects. The majority of TDRs detected were at variant levels <5% likely due to subjects having advanced chronic disease at the time of testing. PI TDRs were identified frequently, but were found in isolation and at low variant frequency. As PI/r use is infrequent in Hunan, the existence of PI mutations likely represent AE subtype natural polymorphism at low variant level frequency.
doi:10.1371/journal.pone.0098740
PMCID: PMC4045886  PMID: 24896087
5.  First Line Treatment Response in Patients with Transmitted HIV Drug Resistance and Well Defined Time Point of HIV Infection: Updated Results from the German HIV-1 Seroconverter Study 
PLoS ONE  2014;9(5):e95956.
Background
Transmission of drug-resistant HIV-1 (TDR) can impair the virologic response to antiretroviral combination therapy. Aim of the study was to assess the impact of TDR on treatment success of resistance test-guided first-line therapy in the German HIV-1 Seroconverter Cohort for patients infected with HIV between 1996 and 2010. An update of the prevalence of TDR and trend over time was performed.
Methods
Data of 1,667 HIV-infected individuals who seroconverted between 1996 and 2010 were analysed. The WHO drug resistance mutations list was used to identify resistance-associated HIV mutations in drug-naïve patients for epidemiological analysis. For treatment success analysis the Stanford algorithm was used to classify a subset of 323 drug-naïve genotyped patients who received a first-line cART into three resistance groups: patients without TDR, patients with TDR and fully active cART and patients with TDR and non-fully active cART. The frequency of virologic failure 5 to 12 months after treatment initiation was determined.
Results
Prevalence of TDR was stable at a high mean level of 11.9% (198/1,667) in the HIV-1 Seroconverter Cohort without significant trend over time. Nucleotide reverse transcriptase inhibitor resistance was predominant (6.0%) and decreased significantly over time (OR = 0.92, CI = 0.87–0.98, p = 0.01). Non-nucleoside reverse transcriptase inhibitor (2.4%; OR = 1.00, CI = 0.92–1.09, p = 0.96) and protease inhibitor resistance (2.0%; OR = 0.94, CI = 0.861.03, p = 0.17) remained stable. Virologic failure was observed in 6.5% of patients with TDR receiving fully active cART, 5,6% of patients with TDR receiving non-fully active cART and 3.2% of patients without TDR. The difference between the three groups was not significant (p = 0.41).
Conclusion
Overall prevalence of TDR remained stable at a rather high level. No significant differences in the frequency of virologic failure were identified during first-line cART between patients with TDR and fully-active cART, patients with TDR and non-fully active cART and patients without TDR.
doi:10.1371/journal.pone.0095956
PMCID: PMC4006817  PMID: 24788613
6.  Surveillance of Transmitted HIV-1 Drug Resistance in Gauteng and KwaZulu-Natal Provinces, South Africa, 2005–2009 
Surveillance of human immunodeficiency virus type 1 transmitted drug resistance (TDR) was conducted among pregnant women in South Africa over a 5-year period after the initiation of a large national antiretroviral treatment program. Analysis of TDR data from 9 surveys conducted between 2005 and 2009 in 2 provinces of South Africa suggests that while TDR remains low (<5%) in Gauteng Province, it may be increasing in KwaZulu-Natal, with the most recent survey showing moderate (5%–15%) levels of resistance to the nonnucleoside reverse transcriptase inhibitor drug class.
doi:10.1093/cid/cir1017
PMCID: PMC3572869  PMID: 22544199
7.  HIV drug resistance surveillance in low- and middle-income countries: 2004 to 2010 
Background
At the end of 2011, over 8 million people were receiving antiretroviral therapy (ART) in low- and middle-income countries (LMIC), a 26-fold increase from 2003. Some degree of HIV drug resistance (HIVDR) will emerge among populations on combination ART even when high levels of adherence are achieved. In 2004, the World Health Organization (WHO) initiated global HIVDR surveillance to monitor emergence and transmission of HIVDR in countries scaling-up ART.
Methods
WHO HIVDR surveillance strategy was designed to inform public health decision-making regarding choice of ART and to identify ART programme factors which could be adjusted to minimize HIVDR emergence. The strategy includes (1) surveillance of transmitted HIVDR (TDR) in recently infected populations, (2) surveillance of acquired HIVDR (ADR) in populations on ART and (3) monitoring of early warning indicators (EWI) of HIVDR which are ART programme factors favouring HIVDR emergence. Surveys used standardized protocols. Epidemiological and sequence data were quality assured.
Results
TDR: Eighty-two surveys were conducted in 30 countries in 2004 to 2010, assessing 3588 recently infected individuals. Pooled analysis indicates an overall prevalence of 3.1% TDR to at least one drug class, 1.6% to non-nucleoside reverse transcriptase inhibitor (NNRTI), 1.3% to nucleoside reverse transcriptase inhibitor (NRTI) and 0.7% to protease inhibitor (PI). Levels of NNRTI resistance, particularly in the areas surveyed in Africa, increased over time, reaching 3.4% (95% CI=1.8 to 5.2%) in 2009. Greater ART coverage was associated, though modestly, with increased prevalence of TDR to NNRTI (P-value adjusted for region=0.039). ADR: Thirty-six ADR surveys assessing 6370 people in 12 LMIC were conducted in 2007 to 2010. HIVDR prevalence to any drug among those initiating ART ranged from 4.8% (95% CI=3.8 to 6.0%) in 2007 to 6.8% (95% CI=4.8 to 9.0%) in 2010. Ninety per cent of patients alive and on therapy at 12 months achieved viral load <1000 c/mL. Among people with virological failure, 72% had HIVDR to at least one drug. EWI: EWIs were monitored at 2017 clinics in 50 countries assessing 131,686 people since 2004. Overall, 75% of clinics met the target of 100% of patients receiving appropriate ART; 69% of clinics met the <20% target for lost to follow-up at 12 months; and only 65% of clinics provided a continuous supply of ART during a 12-month period.
Conclusion
Expansion of ART in LMIC has resulted in an overall increase in HIVDR, particularly to NNRTI in Africa. EWIs reveal important gaps in service delivery and programme performance. While these data call for continued and improved scale up of surveillance, they also suggest that resistance is under control in the areas surveyed, and the majority of patients initiating or switching therapy are likely to respond to currently available first- and second-line therapy.
doi:10.7448/IAS.15.6.18083
PMCID: PMC3512549
8.  Effect of misclassification of antiretroviral treatment status on the prevalence of transmitted HIV-1 drug resistance 
Background
Estimates of the prevalence of transmitted HIV drug resistance (TDR) in a population are derived from resistance tests performed on samples from patients thought to be naïve to antiretroviral treatment (ART). Much of the debate over reliability of estimates of the prevalence of TDR has focused on whether the sample population is representative. However estimates of the prevalence of TDR will also be distorted if some ART-experienced patients are misclassified as ART-naïve.
Methods
The impact of misclassification bias on the rate of TDR was examined. We developed methods to obtain adjusted estimates of the prevalence of TDR for different misclassification rates, and conducted sensitivity analyses of trends in the prevalence of TDR over time using data from the UK HIV Drug Resistance Database. Logistic regression was used to examine trends in the prevalence of TDR over time.
Results
The observed rate of TDR was higher than true TDR when misclassification was present and increased as the proportion of misclassification increased. As the number of naïve patients with a resistance test relative to the number of experienced patients with a test increased, the difference between true and observed TDR decreased. The observed prevalence of TDR in the UK reached a peak of 11.3% in 2002 (odds of TDR increased by 1.10 (95% CI 1.02, 1.19, p(linear trend) = 0.02) per year 1997-2002) before decreasing to 7.0% in 2007 (odds of TDR decreased by 0.90 (95% CI 0.87, 0.94, p(linear trend) < 0.001) per year 2002-2007. Trends in adjusted TDR were altered as the misclassification rate increased; the significant downward trend between 2002-2007 was lost when the misclassification increased to over 4%.
Conclusion
The effect of misclassification of ART on estimates of the prevalence of TDR may be appreciable, and depends on the number of naïve tests relative to the number of experienced tests. Researchers can examine the effect of ART misclassification on their estimates of the prevalence of TDR if such a bias is suspected.
doi:10.1186/1471-2288-12-30
PMCID: PMC3364874  PMID: 22416878
9.  Transmitted Drug Resistance in Persons with Acute/Early HIV-1 in San Francisco, 2002-2009 
PLoS ONE  2010;5(12):e15510.
Background
Transmitted HIV-1 drug resistance (TDR) is an ongoing public health problem, representing 10–20% of new HIV infections in many geographic areas. TDR usually arises from two main sources: individuals on antiretroviral therapy (ART) who are failing to achieve virologic suppression, and individuals who acquired TDR and transmit it while still ART-naïve. TDR rates can be impacted when novel antiretroviral medications are introduced that allow for greater virologic suppression of source patients. Although several new HIV medications were introduced starting in late 2007, including raltegravir, maraviroc, and etravirine, it is not known whether the prevalence of TDR was subsequently affected in 2008–2009.
Methodology/Principal Findings
We performed population sequence genotyping on individuals who were diagnosed with acute or early HIV (<6 months duration) and who enrolled in the Options Project, a prospective cohort, between 2002 and 2009. We used logistic regression to compare the odds of acquiring drug-resistant HIV before versus after the arrival of new ART (2005–2007 vs. 2008–2009). From 2003–2007, TDR rose from 7% to 24%. Prevalence of TDR was then 15% in 2008 and in 2009. While the odds of acquiring TDR were lower in 2008–2009 compared to 2005–2007, this was not statistically significant (odds ratio 0.65, 95% CI 0.31–1.38; p = 0.27).
Conclusions
Our study suggests that transmitted drug resistance rose from 2003–2007, but this upward trend did not continue in 2008 and 2009. Nevertheless, the TDR prevalence in 2008–2009 remained substantial, emphasizing that improved management strategies for drug-resistant HIV are needed if TDR is to be further reduced. Continued surveillance for TDR will be important in understanding the full impact of new antiretroviral medications.
doi:10.1371/journal.pone.0015510
PMCID: PMC3000814  PMID: 21170322
10.  Low Prevalence of Transmitted Drug Resistance in Patients Newly Diagnosed with HIV-1 Infection in Sweden 2003–2010 
PLoS ONE  2012;7(3):e33484.
Transmitted drug resistance (TDR) is a clinical and epidemiological problem because it may contribute to failure of antiretroviral treatment. The prevalence of TDR varies geographically, and its prevalence in Sweden during the last decade has not been reported. Plasma samples from 1,463 patients newly diagnosed with HIV-1 infection between 2003 and 2010, representing 44% of all patients diagnosed in Sweden during this period, were analyzed using the WHO 2009 list of mutations for surveillance of TDR. Maximum likelihood phylogenetic analyses were used to determine genetic subtype and to investigate the relatedness of the sequences. Eighty-two patients showed evidence of TDR, representing a prevalence of 5.6% (95% CI: 4.5%–6.9%) without any significant time trends or differences between patients infected in Sweden or abroad. Multivariable logistic regression showed that TDR was positively associated with men who have sex with men (MSM) and subtype B infection and negatively associated with CD4 cell counts. Among patients with TDR, 54 (68%) had single resistance mutations, whereas five patients had multi-drug resistant HIV-1. Phylogenetic analyses identified nine significantly supported clusters involving 29 of the patients with TDR, including 23 of 42 (55%) of the patients with TDR acquired in Sweden. One cluster contained 18 viruses with a M41L resistance mutation, which had spread among MSM in Stockholm over a period of at least 16 years (1994–2010). Another cluster, which contained the five multidrug resistant viruses, also involved MSM from Stockholm. The prevalence of TDR in Sweden 2003–2010 was lower than in many other European countries. TDR was concentrated among MSM, where clustering of TDR strains was observed, which highlights the need for continued and improved measures for targeted interventions.
doi:10.1371/journal.pone.0033484
PMCID: PMC3308981  PMID: 22448246
11.  How far will we need to go to reach HIV-infected people in rural South Africa? 
BMC Medicine  2007;5:16.
Background
The South African Government has outlined detailed plans for antiretroviral (ART) rollout in KwaZulu-Natal Province, but has not created a plan to address treatment accessibility in rural areas in KwaZulu-Natal. Here, we calculate the distance that People Living With HIV/AIDS (PLWHA) in rural areas in KwaZulu-Natal would have to travel to receive ART. Specifically, we address the health policy question 'How far will we need to go to reach PLWHA in rural KwaZulu-Natal?'.
Methods
We developed a model to quantify treatment accessibility in rural areas; the model incorporates heterogeneity in spatial location of HCFs and patient population. We defined treatment accessibility in terms of the number of PLWHA that have access to an HCF. We modeled the treatment-accessibility region (i.e. catchment area) around an HCF by using a two-dimensional function, and assumed that treatment accessibility decreases as distance from an HCF increases. Specifically, we used a distance-discounting measure of ART accessibility based upon a modified form of a two-dimensional gravity-type model. We calculated the effect on treatment accessibility of: (1) distance from an HCF, and (2) the number of HCFs.
Results
In rural areas in KwaZulu-Natal even substantially increasing the size of a small catchment area (e.g. from 1 km to 20 km) around an HCF would have a negligible impact (~2%) on increasing treatment accessibility. The percentage of PLWHA who can receive ART in rural areas in this province could be as low as ~16%. Even if individuals were willing (and able) to travel 50 km to receive ART, only ~50% of those in need would be able to access treatment. Surprisingly, we show that increasing the number of available HCFs for ART distribution ~ threefold does not lead to a threefold increase in treatment accessibility in rural KwaZulu-Natal.
Conclusion
Our results show that many PLWHA in rural KwaZulu-Natal are unlikely to have access to ART, and that the impact of an additional 37 HCFs on treatment accessibility in rural areas would be less substantial than might be expected. There is a great length to go before we will be able to reach many PLWHA in rural areas in South Africa, and specifically in KwaZulu-Natal.
doi:10.1186/1741-7015-5-16
PMCID: PMC1906822  PMID: 17577418
12.  Transmitted Antiretroviral Drug Resistance in New York State, 2006-2008: Results from a New Surveillance System 
PLoS ONE  2012;7(8):e40533.
Background
HIV transmitted drug resistance (TDR) is a public health concern because it has the potential to compromise antiretroviral therapy (ART) at the population level. In New York State, high prevalence of TDR in a local cohort and a multiclass resistant case cluster led to the development and implementation of a statewide resistance surveillance system.
Methodology
We conducted a cross-sectional analysis of the 13,109 cases of HIV infection that were newly diagnosed and reported in New York State between 2006 and 2008, including 4,155 with HIV genotypes drawn within 3 months of initial diagnosis and electronically reported to the new resistance surveillance system. We assessed compliance with DHHS recommendations for genotypic resistance testing and estimated TDR among new HIV diagnoses.
Principal Findings
Of 13,109 new HIV diagnoses, 9,785 (75%) had laboratory evidence of utilization of HIV-related medical care, and 4,155 (43%) had a genotype performed within 3 months of initial diagnosis. Of these, 11.2% (95% confidence interval [CI], 10.2%–12.1%) had any evidence of TDR. The proportion with mutations associated with any antiretroviral agent in the NNRTI, NRTI or PI class was 6.3% (5.5%–7.0%), 4.3% (3.6%–4.9%) and 2.9% (2.4%–3.4%), respectively. Multiclass resistance was observed in <1%. TDR did not increase significantly over time (p for trend = 0.204). Men who have sex with men were not more likely to have TDR than persons with heterosexual risk factor (OR 1.0 (0.77–1.30)). TDR to EFV+TDF+FTC and LPV/r+TDF+FTC regimens was 7.1% (6.3%–7.9%) and 1.4% (1.0%–1.8%), respectively.
Conclusions/Significance
TDR appears to be evenly distributed and stable among new HIV diagnoses in New York State; multiclass TDR is rare. Less than half of new diagnoses initiating care received a genotype per DHHS guidelines.
doi:10.1371/journal.pone.0040533
PMCID: PMC3412856  PMID: 22879878
13.  Genetic diversity and drug resistance among newly diagnosed and antiretroviral treatment-naive HIV-infected individuals in western Yunnan: a hot area of viral recombination in China 
BMC Infectious Diseases  2012;12:382.
Background
The emergence of an HIV-1 epidemic in China was first recognized in Dehong, western Yunnan. Due to its geographic location, Dehong contributed greatly in bridging HIV-1 epidemics in Southeast Asia and China through drug trafficking and injection drug use; and also extensively to the HIV genetic diversity in Yunnan and China. We attempt to monitor HIV-1 in this area by studying the HIV-1 genetic distribution and transmitted drug resistance (TDR) in various at-risk populations.
Methods
Blood samples from a total of 320 newly HIV-1 diagnosed individuals, who were antiretroviral therapy (ART)-naive, were collected from January 2009 to December 2010 in 2 counties in Dehong. HIV-1 subtypes and pol gene drug resistance (DR) mutations were genotyped.
Results
Among 299 pol sequences successfully genotyped (93.4%), subtype C accounted for 43.1% (n=129), unique recombinant forms (URFs) for 18.4% (n=55), CRF01_AE for 17.7% (n=54), B for 10.7% (n=32), CRF08_BC for 8.4% (n=25) and CRF07_BC for 1.7% (n=5). Subtype distribution in patients infected by different transmission routes varied. In contract to the previous finding of CRF01_AE predominance in 2002-2006, subtype C predominated in both injecting drug users (IDUs) and heterosexually transmitted populations in this study. Furthermore, we found a high level of BC, CRF01_AE/C and CRF01_AE/B/C recombinants suggesting the presence of active viral recombination in the area. TDR associated mutations were identified in 4.3% (n=13) individuals. A total of 1.3% of DR were related to protease inhibitors (PIs), including I85IV, M46I and L90M; 0.3% to nucleoside reverse transcriptase inhibitors (NRTIs), including M184I; and 2.7% to non-nucleoside reverse transcriptase inhibitors (NNRTIs), including K103N/S, Y181C, K101E and G190A.
Conclusion
Our work revealed diverse HIV-1 subtype distributions and intersubtype recombinations. We also identified a low but significant TDR mutation rate among ART-naive patients. These findings enhance our understanding of HIV-1 evolution and are valuable for the development and implementation of a comprehensive public health approach to HIV-1 DR prevention and treatment in the region.
doi:10.1186/1471-2334-12-382
PMCID: PMC3552723  PMID: 23270497
HIV-1; Genetic diversity; Drug resistance; Injecting drug use; Dehong; China
14.  Evolution of Primary HIV Drug Resistance in a Subtype C Dominated Epidemic in Mozambique 
PLoS ONE  2013;8(7):e68213.
Objective
In Mozambique, highly active antiretroviral treatment (HAART) was introduced in 2004 followed by decentralization and expansion, resulting in a more than 20-fold increase in coverage by 2009. Implementation of HIV drug resistance threshold surveys (HIVDR-TS) is crucial in order to monitor the emergence of transmitted viral resistance, and to produce evidence-based recommendations to support antiretroviral (ARV) policy in Mozambique.
Methods
World Health Organization (WHO) methodology was used to evaluate transmitted drug resistance (TDR) in newly diagnosed HIV-1 infected pregnant women attending ante-natal clinics in Maputo and Beira to non-nucleoside reverse transcriptase inhibitors (NNRTI), nucleoside reverse transcriptase inhibitors (NRTI) and protease inhibitors (PI). Subtypes were assigned using REGA HIV-1 subtyping tool and phylogenetic trees constructed using MEGA version 5.
Results
Although mutations associated with resistance to all three drug were detected in these surveys, transmitted resistance was analyzed and classified as <5% in Maputo in both surveys for all three drug classes. Transmitted resistance to NNRTI in Beira in 2009 was classified between 5–15%, an increase from 2007 when no NNRTI mutations were found. All sequences clustered with subtype C.
Conclusions
Our results show that the epidemic is dominated by subtype C, where the first-line option based on two NRTI and one NNRTI is still effective for treatment of HIV infection, but intermediate levels of TDR found in Beira reinforce the need for constant evaluation with continuing treatment expansion in Mozambique.
doi:10.1371/journal.pone.0068213
PMCID: PMC3728366  PMID: 23935858
15.  Short Communication: HIV Type 1 Transmitted Drug Resistance and Evidence of Transmission Clusters Among Recently Infected Antiretroviral-Naive Individuals from Ugandan Fishing Communities of Lake Victoria 
Abstract
Human immunodeficiency virus type 1 (HIV-1) prevalence and incidence in the fishing communities on Lake Victoria in Uganda are high. This population may play a role in driving the HIV epidemic in Uganda including the spread of transmitted drug resistance (TDR). We report data on TDR in this population among antiretroviral (ARV)-naive, recently infected individuals about 5 years after ARV scaling-up in Uganda. We identified phylogenetic transmission clusters and combined these with volunteer life histories in order to understand the sexual networks within this population. From a prospective cohort of 1,000 HIV-negative individuals recruited from five communities, 51 seroconverters were identified over a period of 2 years. From these, whole blood was collected and population sequencing of the HIV-1 pol gene (protease/reverse transcriptase) was performed from plasma. Drug resistance mutations (DRMs) were scored using the 2009 WHO list for surveillance of TDR. TDR prevalence categories were estimated using the WHO recommended truncated sampling technique for the surveillance of TDR for use in resource-limited settings (RLS). Of the samples 92% (47/51) were successfully genotyped. HIV-1 subtype frequencies were 15/47 (32%) A1, 20/47 (43%) D, 1/47 (2%) C, 1/47 (2%) G, and 10/47 (21%) unique recombinant forms. Nonnucleoside reverse transcriptase inhibitor (NNRTI) drug resistance mutation K103N was identified in two individuals and V106A in one (6%) suggesting that the level of TDR was moderate in this population. No nucleoside/tide reverse transcriptase inhibitor (NRTI) or protease inhibitor (PI) DRMs were detected. In this study, we identified five transmission clusters supported by high bootstrap values and low genetic distances. Of these, one pair included the two individuals with K103N. Two of the genotypic clusters corresponded with reported sexual partnerships as detected through prior in-depth interviews. The level of TDR to NNRTIs in these ARV-naive individuals was moderate by WHO threshold survey categorization. The transmission clusters suggest a high degree of sexual partner mixing between members of these communities.
doi:10.1089/aid.2012.0123
PMCID: PMC3636596  PMID: 23173702
16.  Trends and Predictors of Transmitted Drug Resistance (TDR) and Clusters with TDR in a Local Belgian HIV-1 Epidemic 
PLoS ONE  2014;9(7):e101738.
We aimed to study epidemic trends and predictors for transmitted drug resistance (TDR) in our region, its clinical impact and its association with transmission clusters. We included 778 patients from the AIDS Reference Center in Leuven (Belgium) diagnosed from 1998 to 2012. Resistance testing was performed using population-based sequencing and TDR was estimated using the WHO-2009 surveillance list. Phylogenetic analysis was performed using maximum likelihood and Bayesian techniques. The cohort was predominantly Belgian (58.4%), men who have sex with men (MSM) (42.8%), and chronically infected (86.5%). The overall TDR prevalence was 9.6% (95% confidence interval (CI): 7.7–11.9), 6.5% (CI: 5.0–8.5) for nucleoside reverse transcriptase inhibitors (NRTI), 2.2% (CI: 1.4–3.5) for non-NRTI (NNRTI), and 2.2% (CI: 1.4–3.5) for protease inhibitors. A significant parabolic trend of NNRTI-TDR was found (p = 0.019). Factors significantly associated with TDR in univariate analysis were male gender, Belgian origin, MSM, recent infection, transmission clusters and subtype B, while multivariate and Bayesian network analysis singled out subtype B as the most predictive factor of TDR. Subtype B was related with transmission clusters with TDR that included 42.6% of the TDR patients. Thanks to resistance testing, 83% of the patients with TDR who started therapy had undetectable viral load whereas half of the patients would likely have received a suboptimal therapy without this test. In conclusion, TDR remained stable and a NNRTI up-and-down trend was observed. While the presence of clusters with TDR is worrying, we could not identify an independent, non-sequence based predictor for TDR or transmission clusters with TDR that could help with guidelines or public health measures.
doi:10.1371/journal.pone.0101738
PMCID: PMC4086934  PMID: 25003369
17.  Clinically Relevant Transmitted Drug Resistance to First Line Antiretroviral Drugs and Implications for Recommendations 
PLoS ONE  2014;9(3):e90710.
Background
The aim was to analyse trends in clinically relevant resistance to first-line antiretroviral drugs in Spain, applying the Stanford algorithm, and to compare these results with reported Transmitted Drug Resistance (TDR) defined by the 2009 update of the WHO SDRM list.
Methods
We analysed 2781 sequences from ARV naive patients of the CoRIS cohort (Spain) between 2007–2011. Using the Stanford algorithm “Low-level resistance”, “Intermediate resistance” and “High-level resistance” categories were considered as “Resistant”.
Results
70% of the TDR found using the WHO list were relevant for first-line treatment according to the Stanford algorithm. A total of 188 patients showed clinically relevant resistance to first-line ARVs [6.8% (95%Confidence Interval: 5.8–7.7)], and 221 harbored TDR using the WHO list [7.9% (6.9–9.0)]. Differences were due to a lower prevalence in clinically relevant resistance for NRTIs [2.3% (1.8–2.9) vs. 3.6% (2.9–4.3) by the WHO list] and PIs [0.8% (0.4–1.1) vs. 1.7% (1.2–2.2)], while it was higher for NNRTIs [4.6% (3.8–5.3) vs. 3.7% (3.0–4.7)]. While TDR remained stable throughout the study period, clinically relevant resistance to first line drugs showed a significant trend to a decline (p = 0.02).
Conclusions
Prevalence of clinically relevant resistance to first line ARVs in Spain is decreasing, and lower than the one expected looking at TDR using the WHO list. Resistance to first-line PIs falls below 1%, so the recommendation of screening for TDR in the protease gene should be questioned in our setting. Cost-effectiveness studies need to be carried out to inform evidence-based recommendations.
doi:10.1371/journal.pone.0090710
PMCID: PMC3956602  PMID: 24637804
18.  Prevalence and Clinical Significance of HIV Drug Resistance Mutations by Ultra-Deep Sequencing in Antiretroviral-Naïve Subjects in the CASTLE Study 
PLoS ONE  2010;5(6):e10952.
Background
CASTLE compared the efficacy of atazanavir/ritonavir with lopinavir/ritonavir, each in combination with tenofovir-emtricitabine in ARV-naïve subjects from 5 continents.
Objectives
Determine the baseline rate and clinical significance of TDR mutations using ultra-deep sequencing (UDS) in ARV-naïve subjects in CASTLE.
Methods
A case control study was performed on baseline samples for all 53 subjects with virologic failures (VF) at Week 48 and 95 subjects with virologic successes (VS) randomly selected and matched by CD4 count and viral load. UDS was performed using 454 Life Sciences/Roche technology.
Results
Of 148 samples, 141 had successful UDS (86 subtype B, 55 non-B subtypes). Overall, 30.5% of subjects had a TDR mutation at baseline; 15.6% only had TDR(s) at <20% of the viral population. There was no difference in the rate of TDRs by B (30.2%) or non-B subtypes (30.9%). VF (51) and VS (90) had similar rates of any TDRs (25.5% vs. 33.3%), NNRTI TDRs (11.1% vs.11.8%) and NRTI TDRs (24.4% vs. 25.5%). Of 9 (6.4%) subjects with M184V/I (7 at <20% levels), 6 experienced VF. 16 (11.3%) subjects had multiple TAMs, and 7 experienced VF. 3 (2.1%) subjects had both multiple TAMs+M184V, and all experienced VF. Of 14 (9.9%) subjects with PI TDRs (11 at <20% levels): only 1 experienced virologic failure. The majority of PI TDRs were found in isolation (e.g. 46I) at <20% levels, and had low resistance algorithm scores.
Conclusion
Among a representative sample of ARV-naïve subjects in CASTLE, TDR mutations were common (30.5%); B and non-B subtypes had similar rates of TDRs. Subjects with multiple PI TDRs were infrequent. Overall, TDRs did not affect virologic response for subjects on a boosted PI by week 48; however, a small subset of subjects with extensive NRTI backbone TDR patterns experienced virologic failure.
doi:10.1371/journal.pone.0010952
PMCID: PMC2880604  PMID: 20532178
19.  The prevalence of transmitted antiretroviral drug resistance in treatment naïve HIV-infected individuals in China 
Background
Transmission of HIV drug resistance (TDR) gives rise to reduced efficacy of initial antiretroviral treatment, and has become a public health concern.
Methods
A nationwide survey on TDR was conducted in antiretroviral therapy naïve HIV-1 infected individuals from September 2004 to October 2005 in China. Drug resistance genotyping was performed on subjects’ plasma samples. Drug resistance mutations were determined and scored by Stanford HIV Drug Resistance algorithm.
Results
Sequences were obtained from 676 individuals, of which 61.2% were former plasma and blood donors, 17.3% were infected sexually, and 17.2% were intravenous drug users. Subtype B’ HIV-1 strains were found in 73.5%, CRF01_AE in 13.9%, CRF07_BC in 6.2%, CRF08_BC in 2.7%, subtype C in 1.04%, subtype B in 0.9%, CRF02_AG in 0.4% and B’/C intersubtype recombinant strains in 1.3% of the subjects. Twenty-six (3.8%) were found to harbor drug resistance strains. The rates of resistance to PIs, NRTIs and NNRTIs were 0.4%, 1.6% and 2.1%, respectively. Though there was no significant difference in TDR rates between 2004 and 2005 (2.9% vs. 4.4%), an increased trend was observed in the rate of high-level drug resistance (0.8% in 2004 vs. 3.0% in 2005, P = 0.0634).
Conclusions
The rate of TDR was relatively low in China, as compared with those in developed countries. Surveys among recently HIV-infected subjects should be preformed continually to ensure the success of the scale-up antiretroviral treatment.
doi:10.1097/QAI.0b013e3181c7d363
PMCID: PMC3422681  PMID: 20104099
treatment naïve; transmitted HIV-1 drug resistance; prevalence
20.  Prevalence of Transmitted HIV Drug Resistance Among Newly Diagnosed Antiretroviral Therapy–Naive Pregnant Women in Lilongwe and Blantyre, Malawi 
In 2006, a survey of transmitted human immunodeficiency virus (HIV) drug resistance (TDR) was conducted in Lilongwe, Malawi. The survey followed the World Health Organization method to classify TDR to nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) among primigravid women aged <25 years. Results of the 2006 survey showed <5% TDR in all drug classes. In 2009, TDR surveys using the same method were repeated in Lilongwe and expanded to Blantyre. Findings show that in Lilongwe TDR to NRTIs and PIs was <5%, whereas TDR to NNRTIs was 5%–15%. In Blantyre, TDR was <5% to all drug classes. Observed moderate TDR in Lilongwe is cause for concern and signals the need for closer monitoring of Malawi’s antiretroviral therapy program.
doi:10.1093/cid/cir993
PMCID: PMC3338309  PMID: 22544197
21.  Transmitted HIV Drug Resistance in Treatment-Naive Romanian Patients 
Journal of medical virology  2013;85(7):1139-1147.
Transmitted HIV drug resistance (TDR) remains an important concern for individuals unexposed to antiretroviral treatment. Data on the prevalence of TDR, available mainly for HIV-1 subtype B, are now also emerging for other subtypes. In Romania, a steady predominance of subtype F was reported among both long-term survivor children and newly infected adults. The pol gene of 61 drug-naïve patients infected with HIV, diagnosed between 1997 and 2011 was sequenced in order to analyze the prevalence of primary resistance mutations and to correlate these with the infecting genotype. Only 5/61 specimens were classified as infected recently using the BED-Capture Enzyme Immunoassay. Subtype F1 was prevalent (80.3%), however, other HIV-1 clades are increasingly identified, especially in the group of subjects infected recently. An HIV transmission cluster, associated to injecting drug use was identified by phylogenetic analysis. The overall prevalence of TDR was 14.75%, mainly associated with NRTI resistance (13.11%), TAMs and M184V being the most common mutations. A declining trend of TDR was recorded from 26.08% in 1997–2004 to 7.89% in 2005–2011. No primary resistance was identified among recent seroconvertors. All HIV-1 strains had minor mutations in the protease and RT genes, often detected at polymorphic positions. The declining rates of TDR might be related to the high efficacy of HAART and to the increasing number of treated patients with virological success who have a low risk of transmission. The recent increase of HIV-1 infections which involve other subtypes impose a continuous surveillance of the genetic composition of the epidemic.
doi:10.1002/jmv.23572
PMCID: PMC3896237  PMID: 23592112
HIV-1; transmitted drug resistance; subtype F; Romania
22.  HIV-1 Genetic Characteristics and Transmitted Drug Resistance among Men Who Have Sex with Men in Kunming, China 
PLoS ONE  2014;9(1):e87033.
Background
Yunnan has been severely affected by HIV/AIDS in China. Recently, the reported prevalence of HIV-1 among men who have sex with men (MSM) in Yunnan was high in China. To monitor dynamic HIV-1 epidemic among Yunnan MSM, HIV-1 genetic characteristics and transmitted drug resistance (TDR) were investigated.
Methods
Blood samples from 131 newly HIV-1 diagnosed MSM were continuously collected at fixed sites from January 2010 to December 2012 in Kunming City, Yunnan Province. Partial gag, pol and env genes were sequenced. Phylogenetic, evolutionary and genotypic drug resistance analyses were performed.
Results
Multiple genotypes were identified among MSM in Kunming, including CRF01_AE (64.9%), CRF07_BC (25.2%), unique recombinant forms (URFs, 5.3%), subtype B (3.1%) and CRF08_BC (1.5%). CRF01_AE and CRF07_BC were the predominant strains. The mean of genetic distance within CRF01_AE were larger than that within CRF07_BC. The estimated introducing time of CRF01_AE in Yunnan MSM (1996.9) is earlier than that of CRF07_BC (2002.8). In this study, subtype B was first identified in Yunnan MSM. CRF08_BC seems to be the distinctive strain in Yunnan MSM, which was seldom found among MSM outside Yunnan. The proportion of URFs increased, which further contributed to genetic diversity among MSM. Strikingly, genetic relatedness was found among these strains with MSM isolates from multiple provinces, which suggested that a nationwide transmission network may exist. TDR-associated mutations were identified in 4.6% individuals. The multivariate analysis revealed that non-native MSM and divorced/widowed MSM were independently associated with a higher TDR rate.
Conclusion
This work revealed diverse HIV-1 genetics, national transmission networks and a baseline level of TDR in MSM. These findings enhance our understanding of the distribution and evolution of HIV-1 in MSM, and are valuable for developing HIV prevention strategies for MSM.
doi:10.1371/journal.pone.0087033
PMCID: PMC3906090  PMID: 24489829
23.  The Prevalence and Drug Sensitivity of Tuberculosis among Patients Dying in Hospital in KwaZulu-Natal, South Africa: A Postmortem Study 
PLoS Medicine  2010;7(6):e1000296.
A postmortem study by Ted Cohen and colleagues reveals a huge toll of tuberculosis among patients dying in hospitals in KwaZulu-Natal, South Africa.
Background
Tuberculosis is the leading cause of death in South Africa by death notification, but accurate diagnosis of tuberculosis is challenging in this setting of high HIV prevalence. We conducted limited autopsies on young adults dying in a single public hospital in the province of KwaZulu-Natal between October 2008 and August 2009 in order to estimate the magnitude of deaths attributable to tuberculosis.
Methods and Findings
We studied a representative sample of 240 adult inpatients (aged 20–45 years) dying after admission to Edendale Hospital. Limited autopsies included collection of respiratory tract secretions and tissue by needle core biopsies of lung, liver, and spleen. Specimens were examined by fluorescent microscopy for acid-fast bacilli and cultured in liquid media; cultures positive for M. tuberculosis were tested for drug susceptibility to first- and second-line antibiotics. Ninety-four percent of our study cohort was HIV seropositive and 50% of decedents had culture-positive tuberculosis at the time of death. Fifty percent of the participants were on treatment for tuberculosis at the time of death and 58% of these treated individuals remained culture positive at the time of death. Of the 50% not receiving tuberculosis treatment, 42% were culture positive. Seventeen percent of all positive cultures were resistant to both isoniazid and rifampin (i.e., multidrug resistant); 16% of patients dying during the initiation phase of their first ever course of tuberculosis treatment were infected with multidrug-resistant bacilli.
Conclusions
Our findings reveal the immense toll of tuberculosis among HIV-positive individuals in KwaZulu-Natal. The majority of decedents who remained culture positive despite receiving tuberculosis treatment were infected with pan-susceptible M. tuberculosis, suggesting that the diagnosis of tuberculosis was made too late to alter the fatal course of the infection. There is also a significant burden of undetected multidrug-resistant tuberculosis among HIV-coinfected individuals dying in this setting. New public health approaches that improve early diagnosis of tuberculosis and accelerate the initiation of treatment are urgently needed in this setting.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, nearly 10 million people develop tuberculosis—a contagious bacterial infection that affects the lungs and other parts of the body—and nearly two million people die from the disease. Tuberculosis is caused by Mycobacterium tuberculosis, which spreads in airborne droplets when people with the disease cough or sneeze. Its characteristic symptoms are a persistent cough, weight loss, and night sweats. Diagnostic tests for tuberculosis include the microscopic examination of sputum samples (mucus brought up from the lungs by coughing) for M. tuberculosis bacilli, and mycobacterial culture (in which bacteriologists try to grow M. tuberculosis from sputum or tissue samples). Although tuberculosis can be cured by taking several powerful antibiotics regularly for at least 6 months, global efforts to control tuberculosis are being thwarted by the emergence of strains of M. tuberculosis that are resistant to several antibiotics (multidrug and extensively drug-resistant tuberculosis) and by the HIV epidemic; people who are infected with HIV, the virus that causes AIDS, are particularly susceptible to tuberculosis because of their weakened immune system.
Why Was This Study Done?
In the past few years, tuberculosis has become the leading recorded cause of death in South Africa, a country where nearly a fifth of adults are infected with HIV. There are 122,000 recorded deaths from tuberculosis (including 94,000 deaths in HIV-positive people) in South Africa every year. However, because the accurate diagnosis of tuberculosis in HIV-positive people can be difficult—they are more likely to have sputum-negative tuberculosis than HIV-negative individuals—the true number of people dying because of tuberculosis is likely to be higher than the recorded number. Public-health experts in South Africa need an accurate picture of the tuberculosis deaths to help them improve tuberculosis control. In this postmortem study, the researchers determine the prevalence (the proportion of a population that has a disease) and drug sensitivity of tuberculosis among patients dying in a public hospital in KwaZulu-Natal, South Africa, to get a better estimate of how many people die because of tuberculosis in this setting.
What Did the Researchers Do and Find?
The researchers collected respiratory tract secretions and lung, liver, and spleen samples from 240 adults who died in the Edendale public hospital in KwaZulu-Natal over a 10-month period in 2008/9. They looked for M. tuberculosis bacilli in the samples, tried to culture M. tuberculosis from them, and tested any bacteria that grew for antibiotic sensitivity. They also collected information on current tuberculosis treatment status, previous tuberculosis treatment, and HIV status for each deceased patient (decedent) from medical records and from relatives. Ninety-four percent of the decedents were HIV positive and 50% had culture-positive tuberculosis at the time of death. Of the 50% of the decedents who were being treated for tuberculosis, 58% were culture positive at the time of death. A similar percentage (42%) of the decedents who were not being treated for tuberculosis were culture positive at the time of death. Seventeen percent of all the positive cultures were multidrug resistant and 16% of patients dying during their first course of tuberculosis treatment were infected with multidrug-resistant bacteria. Seventy percent of decedents who remained culture positive despite receiving tuberculosis treatment were infected with M. tuberculosis strains that were susceptible to all antibiotics.
What Do These Findings Mean?
These findings reveal the immense toll of tuberculosis among HIV-infected individuals in this hospital in KwaZulu-Natal. They show that many patients being treated for tuberculosis were culture positive at death despite being infected with antibiotic-sensitive M. tuberculosis, which suggests that diagnoses of tuberculosis are often made too late to alter the fatal course of infection. These findings also suggest that multidrug-resistant tuberculosis often goes undetected among HIV-infected individuals. Further studies are needed to confirm these findings elsewhere in South Africa and in other countries with a high HIV prevalence. Nevertheless, they suggest that public-health initiatives that improve the early diagnosis of tuberculosis, that introduce routine screening for tuberculosis among HIV-positive patients, and that accelerate the initiation of treatment for both tuberculosis and HIV might reduce the global death toll from tuberculosis.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000296.
The World Health Organization provides information on all aspects of tuberculosis, including information on tuberculosis and HIV, on tuberculosis in South Africa, and on the Stop TB Partnership (some information is in several languages)
The US Centers for Disease Control and Prevention has information about tuberculosis and on tuberculosis and HIV coinfection
The US National Institute of Allergy and Infectious Diseases also has detailed information on all aspects of tuberculosis
Information is available from Avert, an international AIDS charity, on tuberculosis and HIV
doi:10.1371/journal.pmed.1000296
PMCID: PMC2889914  PMID: 20582324
24.  Estimating Trends in the Proportion of Transmitted and Acquired HIV Drug Resistance in a Long Term Observational Cohort in Germany 
PLoS ONE  2014;9(8):e104474.
Objective
We assessed trends in the proportion of transmitted (TDR) and acquired (ADR) HIV drug resistance and associated mutations between 2001 and 2011 in the German ClinSurv-HIV Drug Resistance Study.
Method
The German ClinSurv-HIV Drug Resistance Study is a subset of the German ClinSurv-HIV Cohort. For the ClinSurv-HIV Drug Resistance Study all available sequences isolated from patients in five study centres of the long term observational ClinSurv-HIV Cohort were included. TDR was estimated using the first viral sequence of antiretroviral treatment (ART) naïve patients. One HIV sequence/patient/year of ART experienced patients was considered to estimate the proportion of ADR. Trends in the proportion of HIV drug resistance were calculated by logistic regression.
Results
9,528 patients were included into the analysis. HIV-sequences of antiretroviral naïve and treatment experienced patients were available from 34% (3,267/9,528) of patients. The proportion of TDR over time was stable at 10.4% (95% CI 9.1–11.8; p for trend = 0.6; 2001–2011). The proportion of ADR among all treated patients was 16%, whereas it was high among those with available HIV genotypic resistance test (64%; 1,310/2,049 sequences; 95% CI 62–66) but declined significantly over time (OR 0.8; 95% CI 0.77–0.83; p for trend<0.001; 2001–2011). Viral load monitoring subsequent to resistance testing was performed in the majority of treated patients (96%) and most of them (67%) were treated successfully.
Conclusions
The proportion of TDR was stable in this study population. ADR declined significantly over time. This decline might have been influenced by broader resistance testing, resistance test guided therapy and the availability of more therapeutic options and not by a decline in the proportion of TDR within the study population.
doi:10.1371/journal.pone.0104474
PMCID: PMC4141736  PMID: 25148412
25.  Local phylogenetic analysis identifies distinct trends in transmitted HIV drug resistance: implications for public health interventions 
BMC Infectious Diseases  2013;13:509.
Background
HIV transmitted drug resistance (TDR) surveillance is usually conducted by sampling from a large population. However, overall TDR prevalence results may be inaccurate for many individual clinical setting. We analyzed HIV genotypes at a tertiary care setting in Ottawa, Ontario in order to evaluate local TDR patterns among sub-populations.
Method
Genotyping reports were digitized from ART naïve patients followed at the Immunodeficiency Clinic at the Ottawa Hospital, between 2008 and 2010. Quality controlled, digitized sequence data were assessed for TDR using the Stanford HIV Database. Patient characteristics were analyzed according to TDR patterns. Finally, a phylogenetic tree was constructed to elucidate the observed pattern of HIV TDR.
Results
Among the 155 clinic patients there was no statistically significantly difference in demographics as compared to the Ontario provincial HIV population. The clinic prevalence of TDR was 12.3%; however, in contrast to the data from Ontario, TDR patterns were inverted with a 21% prevalence among MSM and 5.5% among IDU. Furthermore, nearly 80% of the observed TDR was a D67N/K219Q pattern with 87% of these infections arising from a distinct phylogenetic cluster.
Conclusions
Local patterns of TDR were distinct to what had been observed provincially. Phylogenetic analysis uncovered a cluster of related infections among MSM that appeared more likely to be recent infections. Results support a paradigm of routine local TDR surveillance to identify the sub-populations under care. Furthermore, the routine application of phylogenetic analysis in the TDR surveillance context provides insights into how best to target prevention strategies; and how to correctly measure outcomes.
doi:10.1186/1471-2334-13-509
PMCID: PMC3816547  PMID: 24171696
HIV; Surveillance; Drug resistance; Molecular epidemiology; Clusters; Public health

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