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1.  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
2.  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
3.  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
4.  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
5.  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
6.  Transmitted Drug Resistance and Phylogenetic Relationships among Acute and Early HIV-1 Infected Individuals in New York City 
Background
Transmitted drug resistance (TDR) is critical to managing HIV-1 infected individuals as well as being a public health concern. Here we report on TDR prevalence and include analyses of phylogenetic clustering of HIV-1 in a predominantly MSM cohort diagnosed during acute/recent HIV-1 infection (AHI) in New York City.
Methods
Genotypic resistance testing was conducted on plasma samples of 600 individuals with AHI (1995–2010). Sequences were used for resistance and phylogenetic analyses. Demographic and clinical data were abstracted from medical records. TDR was defined according to IAS USA and Stanford HIV database guidelines. Phylogenetic and other analyses were conducted using PAUP*4.0 and SAS, respectively.
Results
The mean duration since HIV-1 infection was 66.5 days. TDR prevalence was 14.3%, and stably ranged between 10.8% and 21.6% (Ptrend=0.42). NRTI resistance declined from 15.5% to 2.7% over the study period (Ptrend=0.005). M41L (3.7%), T215Y (4.0%), and K103N/S (4.7%) were the most common mutations. K103N/S prevalence increased from 1.9% to 8.0% between 1995 and 2010 (Ptrend=0.04). Using a rigorous definition of clustering, 19.3% (112/581) of subtype B viral sequences co-segregated into transmission clusters, and clusters increased over time. There were fewer and smaller transmission clusters than had been reported in a similar cohort in Montreal, but similar to reports from elsewhere.
Conclusions
TDR is stable in this cohort and remains a significant concern to both individual patient management and the public health.
doi:10.1097/QAI.0b013e31825a289b
PMCID: PMC3427460  PMID: 22592583
Transmitted Drug Resistance; TDR; HIV-1; Acute infection; phylogenetic analysis; MSM; NYC
7.  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
8.  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
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.  Transmitted Drug Resistance Among Antiretroviral-Naive Patients with Established HIV Type 1 Infection in Santo Domingo, Dominican Republic and Review of the Latin American and Caribbean Literature 
Abstract
Emergence of HIV resistance is a concerning consequence of global scale-up of antiretroviral therapy (ART). To date, there is no published information about HIV resistance from the Dominican Republic. The study's aim was to determine the prevalence of transmitted drug resistance (TDR) to reverse transcriptase and protease inhibitors in a sample of chronically HIV-1-infected patients in one clinic in Santo Domingo. The data are presented in the context of a review of the TDR literature from Latin America and the Caribbean. Genotype testing was successfully performed on 103 treatment-naive adults planning to initiate antiretroviral therapy; the World Health Organization (WHO) list of surveillance drug resistance mutations (SDRM) was used to determine the presence of TDR mutations. WHO SDRM were identified in eight patients (7.8%); none had received sdNVP. There were no significant differences in epidemiologic or clinical variables between those with or without WHO SDRM. The prevalence of WHO SDRM was 1.0% and 6.8% for nucleoside reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors, respectively. No WHO SDRMs for protease inhibitors were identified. Among 12 studies of TDR in the region with a sample size of at least 100 subjects, the reported prevalence of SDRM ranged from 2.8% to 8.1%. The most commonly identified SDRM was K103N. This information adds to our understanding of the epidemiology of TDR in the region and the possible role such mutations could play in undermining first-line treatment. Ongoing surveillance is clearly needed to better understand the TDR phenomenon in the Caribbean.
doi:10.1089/aid.2010.0355
PMCID: PMC3380383  PMID: 21851324
11.  Short Communication: Prevalence of HIV Type 1 Transmitted Drug Resistance in Slovenia: 2005–2010 
Abstract
Slovenia is a small European country with a total of 547 HIV-infected individuals cumulatively reported by the end of 2011. However, the estimated incidence rate of HIV infections increased from 7.0 per million in 2003 to 26.8 per million in 2011. In this study, we assessed the prevalence of transmitted drug resistance (TDR) in the past 6 years (2005–2010) and analyzed the time trend of the proportion of men having sex with men (MSM) and HIV-1 subtype B among newly diagnosed individuals in a 15-year period (1996–2010) in Slovenia. Among 150 patients included in the study, representing 63% of HIV-1 newly diagnosed patients in 2005–2010, TDR was found in seven patients (4.7%). The prevalence of TDR to nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors was 2% (3/150), 2% (3/150), and 0.7% (1/150), respectively. The majority of patients were infected with subtype B (134/150, 89%), while subtype A was detected in 6.0% (9/150), subtype D in 1.3% (2/150), and subtype G and CRF02_AG in 0.7% (one patient each). Three of 150 sequences could not be typed. Infection with subtype B was found to be significantly associated with male gender, Slovenia being reported as the country of the patient's nationality and origin of the virus, CDC class A, mode of transmission with homosexual/bisexual contact, sex with an anonymous person, and a higher CD4+ count. Among patients carrying the subtype B virus, an MSM transmission route was reported in 87% of patients. Although the prevalence of TDR in Slovenia is still below the European average, active surveillance should be continued, especially among MSM, the most vulnerable population for HIV-1 infection in this part of Europe.
doi:10.1089/aid.2012.0152
PMCID: PMC3552160  PMID: 22860694
12.  Programmatically Selected Multidrug-Resistant Strains Drive the Emergence of Extensively Drug-Resistant Tuberculosis in South Africa 
PLoS ONE  2013;8(8):e70919.
Background
South Africa shows one of the highest global burdens of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB). Since 2002, MDR-TB in South Africa has been treated by a standardized combination therapy, which until 2010 included ofloxacin, kanamycin, ethionamide, ethambutol and pyrazinamide. Since 2010, ethambutol has been replaced by cycloserine or terizidone. The effect of standardized treatment on the acquisition of XDR-TB is not currently known.
Methods
We genetically characterized a random sample of 4,667 patient isolates of drug-sensitive, MDR and XDR-TB cases collected from three South African provinces, namely, the Western Cape, Eastern Cape and KwaZulu-Natal. Drug resistance patterns of a subset of isolates were analyzed for the presence of commonly observed resistance mutations.
Results
Our analyses revealed a strong association between distinct strain genotypes and the emergence of XDR-TB in three neighbouring provinces of South Africa. Strains predominant in XDR-TB increased in proportion by more than 20-fold from drug-sensitive to XDR-TB and accounted for up to 95% of the XDR-TB cases. A high degree of clustering for drug resistance mutation patterns was detected. For example, the largest cluster of XDR-TB associated strains in the Eastern Cape, affecting more than 40% of all MDR patients in this province, harboured identical mutations concurrently conferring resistance to isoniazid, rifampicin, pyrazinamide, ethambutol, streptomycin, ethionamide, kanamycin, amikacin and capreomycin.
Conclusions
XDR-TB associated genotypes in South Africa probably were programmatically selected as a result of the standard treatment regimen being ineffective in preventing their transmission. Our findings call for an immediate adaptation of standard treatment regimens for M/XDR-TB in South Africa.
doi:10.1371/journal.pone.0070919
PMCID: PMC3751934  PMID: 24058399
13.  Population uptake of antiretroviral treatment through primary care in rural South Africa 
BMC Public Health  2010;10:585.
Background
KwaZulu-Natal is the South African province worst affected by HIV and the focus of early modeling studies investigating strategies of antiretroviral treatment (ART) delivery. The reality of antiretroviral roll-out through primary care has differed from that anticipated and real world data are needed to inform the planning of further scaling up of services. We investigated the factors associated with uptake of antiretroviral treatment through a primary healthcare system in rural South Africa.
Methods
Detailed demographic, HIV surveillance and geographic information system (GIS) data were used to estimate the proportion of HIV positive adults accessing antiretroviral treatment within northern KwaZulu-Natal, South Africa in the period from initiation of antiretroviral roll-out until the end of 2008. Demographic, spatial and socioeconomic factors influencing the likelihood of individuals accessing antiretroviral treatment were explored using multivariable analysis.
Results
Mean uptake of ART among HIV positive resident adults was 21.0% (95%CI 20.1-21.9). Uptake among HIV positive men (19.2%) was slightly lower than women (21.8%, P = 0.011). An individual's likelihood of accessing ART was not associated with level of education, household assets or urban/rural locale. ART uptake was strongly negatively associated with distance from the nearest primary healthcare facility (aOR = 0.728 per square-root transformed km, 95%CI 0.658-0.963, P = 0.002).
Conclusions
Despite concerns about the equitable nature of antiretroviral treatment rollout, we find very few differences in ART uptake across a range of socio-demographic variables in a rural South African population. However, even when socio-demographic factors were taken into account, individuals living further away from primary healthcare clinics were still significantly less likely to be accessing ART
doi:10.1186/1471-2458-10-585
PMCID: PMC3091553  PMID: 20920267
14.  Targeting the hotspots: investigating spatial and demographic variations in HIV infection in small communities in South Africa 
Background
In South Africa, the severity of the HIV/AIDS epidemic varies according to geographical location; hence, localized monitoring of the epidemic would enable more effective prevention strategies. Our objectives were to assess the core areas of HIV infection in KwaZulu-Natal, South Africa, using epidemiological data among sexually active women from localized communities.
Methods
A total of 5753 women from urban, peri-rural and rural communities in KwaZulu-Natal were screened from 2002 to 2005. Each participant was geocoded using a global information system, based on residence at time of screening. The Spatial Scan Statistics programme was used to identify areas with disproportionate excesses in HIV prevalence and incidence.
Results
This study identified three hotspots with excessively high HIV prevalence rates of 56%, 51% and 39%. A total of 458 sexually active women (19% of all cases) were included in these hotspots, and had been exclusively recruited by the Botha's Hill (west of Durban) and Umkomaas (south of Durban) clinic sites. Most of these women were Christian and Zulu-speaking. They were also less likely to be married than women outside these areas (12% vs. 16%, p = 0.001) and more likely to have sex more than three times a week (27% vs. 20%, p < 0.001) and to have had more than three sexual partners (55% vs. 45%, p < 0.001). Diagnosis of genital herpes simplex virus type 2 was also more common in the hotspots. This study also identified areas of high HIV incidence, which were broadly consistent with those with high prevalence rates.
Conclusions
Geographic excesses of HIV infections at rates among the highest in the world were detected in certain rural communities of Durban, South Africa. The results reinforce the inference that risk of HIV infection is associated with definable geographical areas. Localized monitoring of the epidemic is therefore essential for more effective prevention strategies - and particularly urgent in a region such as KwaZulu-Natal, where the epidemic is particularly rampant.
doi:10.1186/1758-2652-13-41
PMCID: PMC2984578  PMID: 20979651
15.  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
16.  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
17.  HIV Drug Resistance Surveillance Using Pooled Pyrosequencing 
PLoS ONE  2010;5(2):e9263.
Background
Surveillance for HIV transmitted drug resistance (TDR) is performed using HIV genotype results from individual specimens. Pyrosequencing, through its massive parallel sequencing ability, can analyze large numbers of specimens simultaneously. Instead of using pyrosequencing conventionally, to sequence a population of viruses within an individual, we interrogated a single combined pool of surveillance specimens to demonstrate that it is possible to determine TDR rates in HIV protease from a population of individuals.
Methodology/Principal Findings
The protease region from 96 treatment naïve, HIV+ serum specimens was genotyped using standard Sanger sequencing method. The 462 bp protease amplicons from these specimens were pooled in equimolar concentrations and re-sequenced using the GS FLX Titanium system. The nucleotide (NT) and amino acid (AA) differences from the reference sequence, along with TDR mutations, detected by each method were compared. In the protease sequence, there were 212 nucleotide and 81 AA differences found using conventional sequencing and 345 nucleotide and 168 AA differences using pyrosequencing. All nucleotide and amino acid polymorphisms found at frequencies ≥5% in pyrosequencing were detected using both methods with the rates of variation highly correlated. Using Sanger sequencing, two TDR mutations, M46L and I84V, were each detected as mixtures at a frequency of 1.04% (1/96). These same TDR mutations were detected by pyrosequencing with a prevalence of 0.29% and 0.34% respectively. Phylogenetic analysis established that the detected low frequency mutations arose from the same single specimens that were found to contain TDR mutations by Sanger sequencing. Multiple clinical protease DR mutations present at higher frequencies were concordantly identified using both methods.
Conclusions/Significance
We show that pyrosequencing pooled surveillance specimens can cost-competitively detect protease TDR mutations when compared with conventional methods. With few modifications, the method described here can be used to determine population rates of TDR in both protease and reverse transcriptase. Furthermore, this pooled pyrosequencing technique may be generalizable to other infectious agents where a survey of DR rates is required.
doi:10.1371/journal.pone.0009263
PMCID: PMC2822863  PMID: 20174661
18.  Transmitted Antiretroviral Drug Resistance among Acute and Recent HIV Infections in North Carolina, 1998 to 2007 
Antiviral therapy  2009;14(5):673-678.
Background
Transmitted drug resistance (TDR) limits antiretroviral options, complicating management of HIV-positive patients. HIV disproportionately affects the Southern United States (US), but available national estimates of TDR prevalence principally reflect large metropolitan centers outside this region.
Methods
The Duke/UNC Acute HIV Program has collected data on acute or recent HIV infections (ARHI) in North Carolina (NC) since 1998. Acute infections represent antibody-negative, RNA-positive subjects; recent infection was determined by history of HIV testing, or concordance between detuned ELISA and antibody avidity assays. Genotypic sequence data from the earliest collected pre-treatment plasma sample were analyzed with the Stanford HIV Database and screened for Surveillance Drug Resistance Mutations (SDRMs).
Results
253 individuals with ARHI between 1998 and May 2007 had complete genotypic sequence data for analysis; 39.5% were acute infections, 78.7% were male, 64.8% were non-white, and 53.8% were men who have sex with men. The overall prevalence of TDR was 17.8%, with SDRMs for non-nucleoside reverse transcriptase inhibitors (NNRTIs) in 9.5% of the cohort. Mutations for nucleos(t)ide RT inhibitors (NRTIs) were detected in 7.5%, and for protease inhibitors (PIs) in 3.2%. K103N was the most common mutation (7.5%). Thymidine analogue mutations were found in 4.7% of samples; the most common PI SDRM was L90M (2.4%). Dual-or triple-class antiretroviral resistance was rare, encountered in only six samples (2.4%).
Conclusions
The prevalence of TDR in NC is similar to estimates from US metropolitan areas. These findings have implications for initial regimen selection and secondary prevention efforts outside of large, metropolitan HIV epicenters.
PMCID: PMC2860724  PMID: 19704170
HIV Infections/epidemiology; HIV Infections/transmission; North Carolina/epidemiology; Drug resistance, viral; Antiretroviral therapy, highly active
19.  Molecular Characteristics of Human Immunodeficiency Virus Type 1 Subtype C Viruses from KwaZulu-Natal, South Africa: Implications for Vaccine and Antiretroviral Control Strategies 
Journal of Virology  2003;77(4):2587-2599.
The KwaZulu-Natal region of South Africa is experiencing an explosive outbreak of human immunodeficiency virus type 1 (HIV-1) subtype C infections. Understanding the genetic diversity of C viruses and the biological consequences of this diversity is important for the design of effective control strategies. We analyzed the protease gene, the first 935 nucleotides of reverse transcriptase, and the C2V5 envelope region of a representative set of 72 treatment-naïve patients from KwaZulu-Natal and correlated the results with amino acid signature and resistance patterns. Phylogenetic analysis revealed multiple clusters or “lineages” of HIV-1 subtype C that segregated with other C viruses from southern Africa. The same pattern was observed for both black and Indian subgroups and for retrospective specimens collected prior to 1990, indicating that multiple sublineages of HIV-1 C have been present in KwaZulu-Natal since the early stages of the epidemic. With the exception of three nonnucleoside reverse transcriptase inhibitor mutations, no primary resistance mutations were identified. Numerous accessory polymorphisms were present in the protease, but none were located at drug-binding or active sites of the enzyme. One frequent polymorphism, I93L, was located near the protease/reverse transcriptase cleavage site. In the envelope, disruption of the glycosylation motif at the beginning of V3 was associated with the presence of an extra protein kinase C phosphorylation site at codon 11. Many polymorphisms were embedded within cytotoxic T lymphocyte or overlapping cytotoxic T-lymphocyte/T-helper epitopes, as defined for subtype B. This work forms a baseline for future studies aimed at understanding the impact of genetic diversity on vaccine efficacy and on natural susceptibility to antiretroviral drugs.
doi:10.1128/JVI.77.4.2587-2599.2003
PMCID: PMC141090  PMID: 12551997
20.  Prevalence of HIV-1 Drug Resistance after Failure of a First Highly Active Antiretroviral Regimen in KwaZulu Natal, South Africa 
Background
Emergence of human immunodeficiency virus type 1 (HIV-1) drug resistance may limit the benefits of antiretroviral therapy in resource-limited settings. The prevalence of resistance was assessed among patients from KwaZulu Natal (KZN), South Africa following failure of their first highly active antiretroviral therapy (HAART) regimen.
Methods
Genotypic resistance testing was performed on plasma virus from patients experiencing virologic failure (VF) of a first HAART regimen at two clinics in KZN. Clinical and demographic data were obtained from medical records. Regression analysis was performed to determine factors associated with ≥ 1 significant resistance mutation.
Results
Between January 2005 and August 2006, 124 ART-treated adults with virologic failure VF were enrolled. The predominant subtype was HIV-1C. Samples from 83.5% carried ≥ 1 significant resistance mutation. Dual-class resistance was present in 64.3% of subjects; 2.6% had triple-class resistance. The most common mutation was M184V/I (64.3%); K103N was present in 51.3% and V106M in 19.1%. Thymidine analog resistance mutations were found in 32.2% of subjects, and protease resistance mutations in 4.4%.
Conclusions
Antiretroviral drug resistance was detected in more than 80% of South African patients with failure of a first HAART regimen. Patterns of resistance reflected drugs used in first-line regimens and viral subtype. Continued surveillance of resistance patterns is warranted to guide selection of second-line regimens.
doi:10.1086/587109
PMCID: PMC2692213  PMID: 18419495
HIV; drug resistance; antiretrovirals; resource-limited setting
21.  Predictors of Poor CD4 and Weight Recovery in HIV-Infected Children Initiating ART in South Africa 
PLoS ONE  2012;7(3):e33611.
Objective
To identify baseline demographic and clinical risk factors associated with poor CD4 and weight response after initiation of antiretroviral therapy (ART) in a cohort of human immunodeficiency virus (HIV)-infected children in KwaZulu-Natal, South Africa.
Methods
We performed a retrospective cohort study of 674 children initiating antiretroviral therapy at McCord and St. Mary's hospitals in KwaZulu-Natal, South Africa, from August 2003 to December 2008.
We extracted data from paper charts and electronic medical records to assess risk factors associated with CD4 and weight response using logistic regression.
Results
From the initial cohort of 901 children <10 years old initiating ART between August 2003 and December 2008, we analyzed 674 children with complete baseline data. Viral suppression rates (<400 copies/ml) were 84% after six months of therapy and 88% after 12 months of therapy. Seventy-three percent of children achieved CD4 recovery after six months and 89% after 12 months. Weight-for-age Z-score (WAZ) improvements were seen in 58% of children after six months of ART and 64% after 12 months. After six months of ART, lower baseline hemoglobin (p = 0.037), presence of chronic diarrhea (p = 0.007), and virologic failure (p = 0.046) were all associated with poor CD4 recovery by multivariate logistic regression. After 12 months of ART, poor CD4 recovery was associated with higher baseline CD4% (p = 0.005), chronic diarrhea (p = 0.02), and virologic failure (p<0.001). Age less than 3 years at ART initiation (p = 0.0003), higher baseline CD4% (p<0.001), and higher baseline WAZ (p<0.001) were all associated with poor WAZ improvements after 6 months by multivariate logistic regression.
Conclusion
The presence of chronic diarrhea at baseline, independent of nutritional status and viral response, predicts poor CD4 recovery. Age at initiation of ART is an important factor in early WAZ response to ART, while viral suppression strongly predicts CD4 recovery but not WAZ improvement.
doi:10.1371/journal.pone.0033611
PMCID: PMC3306429  PMID: 22438965
22.  Risk Factors Associated with Increased Mortality among HIV Infected Children Initiating Antiretroviral Therapy (ART) in South Africa 
PLoS ONE  2011;6(7):e22706.
Objective
To identify demographic and clinical risk factors associated with mortality after initiation of antiretroviral therapy (ART) in a cohort of human immunodeficiency (HIV) infected children in KwaZulu-Natal, South Africa.
Methods
We performed a retrospective cohort study of 537 children initiating antiretroviral therapy at McCord Hospital in KwaZulu-Natal, South Africa. Data were extracted from electronic medical records and risk factors associated with mortality were assessed using Cox regression analysis.
Results
Overall there were 47 deaths from the cohort of 537 children initiating ART with over 991 child-years of follow-up (median 22 months on ART), yielding a mortality rate of 4.7 deaths per 100 child years on ART. Univariate analysis indicated that mortality was significantly associated with lower weight-for-age Z-score (p<0.0001), chronic diarrhea (p = 0.0002), lower hemoglobin (p = 0.002), age <3 years (p = 0.003), and CD4% <10% (p = 0.005). The final multivariable Cox proportional hazards mortality model found age less than 3 years (p = 0.004), CD4 <10% (p = 0.01), chronic diarrhea (p = 0.03), weight-for-age Z-score (<0.0001) and female gender as a covariate varying with time (p = 0.03) all significantly associated with mortality.
Conclusion
In addition to recognized risk factors such as young age and advanced immunosuppression, we found female gender to be significantly associated with mortality in this pediatric ART cohort. Future studies are needed to determine whether intrinsic biologic differences or socio-cultural factors place female children with HIV at increased risk of death following initiation of ART.
doi:10.1371/journal.pone.0022706
PMCID: PMC3146475  PMID: 21829487
23.  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
24.  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
25.  Population Structure of Multi- and Extensively Drug-Resistant Mycobacterium tuberculosis Strains in South Africa 
Journal of Clinical Microbiology  2012;50(3):995-1002.
Genotyping of multidrug-resistant (MDR) Mycobacterium tuberculosis strains isolated from tuberculosis (TB) patients in four South African provinces (Western Cape, Eastern Cape, KwaZulu-Natal, and Gauteng) revealed a distinct population structure of the MDR strains in all four regions, despite the evidence of substantial human migration between these settings. In all analyzed provinces, a negative correlation between strain diversity and an increasing level of drug resistance (from MDR-TB to extensively drug-resistant TB [XDR-TB]) was observed. Strains predominating in XDR-TB in the Western and Eastern Cape and KwaZulu-Natal Provinces were strongly associated with harboring an inhA promoter mutation, potentially suggesting a role of these mutations in XDR-TB development in South Africa. Approximately 50% of XDR-TB cases detected in the Western Cape were due to strains probably originating from the Eastern Cape. This situation may illustrate how failure of efficient health care delivery in one setting can burden health clinics in other areas.
doi:10.1128/JCM.05832-11
PMCID: PMC3295122  PMID: 22170931

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