The scope of the antimicrobial resistance challenge.

Each year, an estimated 7·7 million deaths are attributed to bacterial infections, of which 4.95 million are associated with drug-resistant pathogens, and 1·27 million are caused by bacterial pathogens resistant to the antibiotics available. Access to effective antibiotics when indicated prolongs life, reduces disability, reduces health-care expenses, and enables access to other life-saving medical innovations. Antimicrobial resistance undoes these benefits and is a major barrier to attainment of the Sustainable Development Goals, including targets for newborn survival, progress on healthy ageing, and alleviation of poverty. Adverse consequences from antimicrobial resistance are seen across the human life course in both health-care-associated and community-associated infections, as well as in animals and the food chain. The small set of effective antibiotics has narrowed, especially in resource-poor settings, and people who are very young, very old, and severely ill are particularly susceptible to resistant infections. This paper, the first in a Series on the challenge of antimicrobial resistance, considers the global scope of the problem and how it should be measured. Robust and actionable data are needed to drive changes and inform effective interventions to contain resistance. Surveillance must cover all geographical regions, minimise biases towards hospital-derived data, and include non-human niches.

Clinical Impact of Pretreatment Human Immunodeficiency Virus Drug Resistance in People Initiating Nonnucleoside Reverse Transcriptase Inhibitor-Containing Antiretroviral Therapy: A Systematic Review and Meta-analysis.

BACKGROUND: Increased access to antiretroviral therapy (ART) has resulted in rising levels of pretreatment human immunodeficiency virus drug resistance (PDR). This is the first systematic review and meta-analysis to assess the impact of PDR on treatment outcomes among people initiating nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART, including the combination of efavirenz (EFV), tenofovir (TDF), and lamivudine or emtricitabine (XTC). METHODS: We systematically reviewed studies and conference proceedings comparing treatment outcomes in populations initiating NNRTI-based ART with and without PDR. We conducted subgroup analyses by regimen: (1) NNRTIs + 2 nucleoside reverse transcriptase inhibitors (NRTIs), (2) EFV + 2 NRTIs, or (3) EFV/TDF/XTC; by population (children vs adults); and by definition of resistance (PDR vs NNRTI PDR). RESULTS: Among 6197 studies screened, 32 were analyzed (31 441 patients). We found that individuals with PDR initiating NNRTIs across all the subgroups had increased risk of virological failure compared to those without PDR. Risk of acquisition of new resistance mutations and ART switch was also higher in people with PDR. CONCLUSIONS: This review shows poorer treatment outcomes in the presence of PDR, supporting the World Health Organization's recommendation to avoid using NNRTIs in countries where levels of PDR are high.

Guidelines are needed for studies of pre-treatment HIV drug resistance: a methodological study.

BACKGROUND: The expansion of access to antiretroviral therapy (ART) has been accompanied by an increase in pre-treatment drug resistance (PDR). While it is critical to monitor the increasing prevalence of PDR across countries and populations to inform optimal regimen selection, the completeness of reporting is often suboptimal, limiting the interpretation and generalizability of the results. Indeed, there is no formal guidance on how studies investigating the prevalence of drug resistance should be reported. Thus, we sought to determine the completeness of reporting in studies of PDR and the factors associated with sub-optimal reporting to ascertain the need for guidelines. METHODS: As part of a systematic review on the global prevalence of PDR in key populations (men who have sex with men, sex workers, transgender people, people who inject drugs and people in prisons), we searched 10 electronic databases until January 2019. We extracted information on selected study characteristics useful for interpreting prevalence data. Data were extracted in duplicate. Analyses of variance and correlation were used to explore factors that may explain the number of items reported. RESULTS: We found 650 studies of which 387 were screened as full text and 234 were deemed eligible. The included studies were published between 1997 and 2019 and included a median of 239 (quartile 1 = 101; quartile 3 = 778) participants. Most studies originated from high-income countries (125/234; 53.0%). Of 23 relevant data items, including study design, setting, participant sociodemographic characteristics, HIV risk factors, type of resistance test conducted, definition of resistance, the mean (standard deviation) number of items reported was 13 (2.2). We found that more items were reported in studies published more recently (r = 0.20; p < 0.002) and in studies at low risk of bias (F [2231] = 8.142; p < 0.001). CONCLUSIONS: Incomplete reporting in studies on PDR makes characterising levels of PDR in subpopulations across countries challenging. Hence, guidelines are needed to define a minimum set of variables to be included in such studies.

Drivers of HIV-1 drug resistance to non-nucleoside reverse-transcriptase inhibitors (NNRTIs) in nine southern African countries: a modelling study.

INTRODUCTION: The rise of HIV-1 drug resistance to non-nucleoside reverse-transcriptase inhibitors (NNRTI) threatens antiretroviral therapy's long-term success (ART). NNRTIs will remain an essential drug for the management of HIV-1 due to safety concerns associated with integrase inhibitors. We fitted a dynamic transmission model to historical data from 2000 to 2018 in nine countries of southern Africa to understand the mechanisms that have shaped the HIV-1 epidemic and the rise of pretreatment NNRTI resistance. METHODS: We included data on HIV-1 prevalence, ART coverage, HIV-related mortality, and survey data on pretreatment NNRTI resistance from nine southern Africa countries from a systematic review, UNAIDS and World Bank. Using a Bayesian hierarchical framework, we developed a dynamic transmission model linking data on the HIV-1 epidemic to survey data on NNRTI drug resistance in each country. We estimated the proportion of resistance attributable to unregulated, off-programme use of ART. We examined each national ART programme's vulnerability to NNRTI resistance by defining a fragility index: the ratio of the rate of NNRTI resistance emergence during first-line ART over the rate of switching to second-line ART. We explored associations between fragility and characteristics of the health system of each country. RESULTS: The model reliably described the dynamics of the HIV-1 epidemic and NNRTI resistance in each country. Predicted levels of resistance in 2018 ranged between 3.3% (95% credible interval 1.9-7.1) in Mozambique and 25.3% (17.9-33.8) in Eswatini. The proportion of pretreatment NNRTI resistance attributable to unregulated antiretroviral use ranged from 6% (2-14) in Eswatini to 64% (26-85) in Mozambique. The fragility index was low in Botswana (0.01; 0.0-0.11) but high in Namibia (0.48; 0.16-10.17), Eswatini (0.64; 0.23-11.8) and South Africa (1.21; 0.83-9.84). The combination of high fragility of ART programmes and high ART coverage levels was associated with a sharp increase in pretreatment NNRTI resistance. CONCLUSIONS: This comparison of nine countries shows that pretreatment NNRTI resistance can be controlled despite high ART coverage levels. This was the case in Botswana, Mozambique, and Zambia, most likely because of better HIV care delivery, including rapid switching to second-line ART of patients failing first-line ART.

Low-Abundance Drug-Resistant HIV-1 Variants in Antiretroviral Drug-Naive Individuals: A Systematic Review of Detection Methods, Prevalence, and Clinical Impact.

BACKGROUND: The presence of high-abundance drug-resistant HIV-1 jeopardizes success of antiretroviral therapy (ART). Despite numerous investigations, the clinical impact of low-abundance drug-resistant HIV-1 variants (LA-DRVs) at levels <15%-25% of the virus population in antiretroviral (ARV) drug-naive individuals remains controversial. METHODS: We systematically reviewed 103 studies assessing prevalence, detection methods, technical and clinical detection cutoffs, and clinical significance of LA-DRVs in antiretroviral drug-naive adults. RESULTS: In total, 14 919 ARV drug-naive individuals were included. Prevalence of LA-DRVs (ie, proportion of individuals harboring LA-DRVs) was 0%-100%. Technical detection cutoffs showed a 4 log range (0.001%-10%); 42/103 (40.8%) studies investigating the impact of LA-DRVs on ART; 25 studies included only individuals on first-line nonnucleoside reverse transcriptase inhibitor-based ART regimens. Eleven of those 25 studies (44.0%) reported a significantly association between preexisting LA-DRVs and risk of virological failure whereas 14/25 (56.0%) did not. CONCLUSIONS: Comparability of the 103 studies is hampered by high heterogeneity of the studies' designs and use of different methods to detect LA-DRVs. Thus, evaluating clinical impact of LA-DRVs on first-line ART remains challenging. We, the WHO HIVResNet working group, defined central areas of future investigations to guide further efforts to implement ultrasensitive resistance testing in routine settings.

Integrase strand transfer inhibitor (INSTI)-resistance mutations for the surveillance of transmitted HIV-1 drug resistance.

BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are expected to be widely adopted globally, requiring surveillance of resistance emergence and transmission. OBJECTIVES: We therefore sought to develop a standardized list of INSTI-resistance mutations suitable for the surveillance of transmitted INSTI resistance. METHODS: To characterize the suitability of the INSTI-resistance mutations for transmitted HIV-1 drug resistance (TDR) surveillance, we classified them according to their presence on published expert lists, conservation in INSTI-naive persons, frequency in INSTI-treated persons and contribution to reduced in vitro susceptibility. Mutation prevalences were determined using integrase sequences from 17302 INSTI-naive and 2450 INSTI-treated persons; 53.3% of the INSTI-naive sequences and 20.0% of INSTI-treated sequences were from non-B subtypes. Approximately 10% of sequences were from persons who received dolutegravir alone or a first-generation INSTI followed by dolutegravir. RESULTS: Fifty-nine previously recognized (or established) INSTI-resistance mutations were present on one or more of four published expert lists. They were classified into three main non-overlapping groups: 29 relatively common non-polymorphic mutations, occurring in five or more individuals and significantly selected by INSTI treatment; 8 polymorphic mutations; and 22 rare mutations. Among the 29 relatively common INSTI-selected mutations, 24 emerged as candidates for inclusion on a list of INSTI surveillance drug-resistance mutations: T66A/I/K, E92G/Q, G118R, F121Y, E138A/K/T, G140A/C/S, Y143C/H/R/S, S147G, Q148H/R/K, N155H, S230R and R263K. CONCLUSIONS: A set of 24 non-polymorphic INSTI-selected mutations is likely to be useful for quantifying INSTI-associated TDR. This list may require updating as more sequences become available from INSTI-experienced persons infected with HIV-1 non-subtype B viruses and/or receiving dolutegravir.

Prevalence of pretreatment HIV drug resistance in Cameroon following a nationally representative WHO survey.

Background: Pretreatment HIV drug resistance (PDR) has the potential to affect treatment outcome and mortality. We present here the first nationally representative PDR study conducted in Cameroon. Methods: From February to July 2015, HIV-infected ART initiators were recruited from 24 randomly selected clinics situated in both urban and rural regions. Dried blood spot specimens were collected from study participants at these clinics and centralized in a reference laboratory in Yaoundé, Cameroon, for drug resistance testing. HIV drug resistance mutations were identified using the Stanford algorithm. Results: Overall, from the 379 participants recruited, 321 pol sequences were successfully interpreted. Two hundred and five sequences were from patients attending urban ART clinics and 116 from patients seen at rural facilities. Nine percent of sequences (29/321) were from participants reporting previous exposure to antiretrovirals. PDR prevalence among all initiators was 10.4% (95% CI 5.4%-19.1%), with 14.2% (95% CI 6.6%-27.9%) reported in urban areas and 4.3% (95% CI 1.2%-14.3%) in rural areas. Among participants with no prior exposure to antiretrovirals, PDR prevalence was 10.4% (95% CI 4.7%-21.5%) overall, with 13.5% (95% CI 5.1%-31.5%) and 5.3% (95% CI 1.4%-17.5%) reported in urban and rural areas, respectively. Conclusions: Our findings indicate that at least 10% of patients initiating ART in Cameroon carry viruses with PDR and may be at risk of premature ART failure. The high level of NNRTI-associated resistance is of particular concern and supports introduction of drugs with a higher genetic barrier to resistance.

The World Health Organization's Response to Emerging Human Immunodeficiency Virus Drug Resistance and a Call for Global Action.

The global community, including the World Health Organization (WHO), has committed to ending the AIDS epidemic and to ensuring that 90% of people living with human immunodeficiency virus (HIV) are diagnosed, 90% start treatment, and 90% achieve and maintain virological suppression. The emergence of HIV drug resistance (HIVDR) as antiretroviral treatment programs expand could preclude the 90-90-90 targets adopted by the United Nations General Assembly at the High-Level Meeting on Ending AIDS from being achieved. The Global Action Plan on HIVDR is a call for collective action grounded on normative guidance providing a standardized and robust approach to monitoring, preventing, and responding to HIVDR over the next 5 years (2017-2021). WHO is committed to supporting country, global, regional, and national partners to implement and monitor the progress of the Global Action Plan. This article outlines the key components of WHO's strategy to tackle HIVDR and the role the organization takes in leading the global response to HIVDR.

Impact of HIV Drug Resistance on HIV/AIDS-Associated Mortality, New Infections, and Antiretroviral Therapy Program Costs in Sub-Saharan Africa.

To inform the level of attention to be given by antiretroviral therapy (ART) programs to HIV drug resistance (HIVDR), we used an individual-level model to estimate its impact on future AIDS deaths, HIV incidence, and ART program costs in sub-Saharan Africa (SSA) for a range of program situations. We applied this to SSA through the Spectrum-Goals model. In a situation in which current levels of pretreatment HIVDR are over 10% (mean, 15%), 16% of AIDS deaths (890 000 deaths), 9% of new infections (450 000), and 8% ($6.5 billion) of ART program costs in SSA in 2016-2030 will be attributable to HIVDR.

Human Immunodeficiency Virus (HIV) Drug Resistance in African Infants and Young Children Newly Diagnosed With HIV: A Multicountry Analysis.

BACKGROUND: Programs for the prevention of mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV) have been scaled up in many low- and middle-income countries. However, HIV drug resistance (HIVDR) data among HIV-1-infected young children remain limited. METHODS: Surveys of pretreatment HIVDR among children aged <18 months who were diagnosed with HIV through early infant diagnosis were conducted in 5 sub-Saharan African countries (Mozambique, Swaziland, South Africa, Uganda, and Zimbabwe) between 2011 and 2014 following World Health Organization (WHO) guidance. Deidentified demographic and clinical data were used to explore risk factors associated with nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance. RESULTS: Among the 1450 genotypes analyzed, 1048 had accompanying demographic and clinical data. The median age of children was 4 months; 50.4% were female. HIV from 54.1% showed resistance to 1 or more antiretroviral (ARV) drugs, with 53.0% and 8.8% having resistance to 1 or more NNRTI or nucleoside reverse transcriptase inhibitors, respectively. NNRTI resistance was particularly high in children exposed to ARV drugs through PMTCT; adjusted odds ratios were 1.8 (95% confidence interval [CI], 1.3-2.6) for maternal exposure only and 2.4 (CI, 1.6-3.6) for neonatal exposure only. CONCLUSIONS: Protease inhibitor-based regimens in children aged <3 years are currently recommended by WHO, but the implementation of this recommendation is suboptimal. These results reinforce the urgent need to overcome barriers to scaling up pediatric protease inhibitor-based regimens in sub-Saharan Africa and underscore the need to accelerate the study and approval of integrase inhibitors for use in young children.

Monitoring HIV Drug Resistance: Early Warning Indicators to Assess Performance of Thailand's Antiretroviral Treatment Program.

OBJECTIVE: To describe trends in Thailand's antiretroviral treatment (ART) program performance assessed by HIV drug resistance early warning indicators (EWIs), as recommended by WHO, between 2009 and 2013. MATERIAL AND METHOD: Seven EWIs were monitored, viral load (VL) testing coverage, VL suppression, retention in ART, lost to follow-up (LTFU), antiretrovirals (ARVs) dispensing practices, on-time pill pick-up, and pharmacy stock-outs. Data from ART adult patients in National Health Security Office Scheme were analyzed except for pharmacy stock-outs, which were reported from hospitals. Aggregated averages were calculated for each EWI. Chi-square for trend was applied to measure significant changes. RESULTS: By September 2013, 174,284 adults were receiving ART at 929 hospitals. Over time, improvement in VL testing coverage (53.8% in 2009 to 79.8% in 2013) was observed. VL suppression and on-time pill pick up rates were well above 90%. Rates of retention in ART declined from 84.0 to 82.9%, whereas LTFU rates increased from 8.3 to 9.2% (p<0.001). Prescriptions with inappropriate ARVs decreased from 0.32 to 0.10% (p<0.001). Of reporting hospitals, 96.1%, 96.3%, and 96.2% observed no ARVs stock-out between 2011 and 2013. CONCLUSION: EWI is a useful tool to monitor ART program performance and to identify area where improvement is needed.

Suboptimal Viral Suppression Rates Among HIV-Infected Children in Low- and Middle-Income Countries: A Meta-analysis.

BACKGROUND: The 90-90-90 goal to achieve viral suppression in 90% of all human immunodeficiency virus (HIV)-infected people on antiretroviral treatment (ART) is especially challenging in children. Global estimates of viral suppression among children in low- and middle-income countries (LMICs) are lacking. METHODS: We searched for randomized controlled trials and observational studies and analyzed viral suppression rates among children started on ART during 3 time periods: early (2000-2005), intermediate (2006-2009), and current (2010 and later), using random effects meta-analysis. RESULTS: Seventy-two studies, reporting on 51 347 children (aged <18 years), were included. After 12 months on first-line ART, viral suppression was achieved by 64.7% (95% confidence interval [CI], 57.5-71.8) in the early, 74.2% (95% CI, 70.2-78.2) in the intermediate, and 72.7% (95% 62.6-82.8) in the current time period. Rates were similar after 6 and 24 months of ART. Using an intention-to-treat analysis, 42.7% (95% CI, 33.7-51.7) in the early, 45.7% (95% CI, 33.2-58.3) in the intermediate, and 62.5% (95% CI, 53.3-72.6) in the current period were suppressed. Long-term follow-up data were scarce. CONCLUSIONS: Viral suppression rates among children on ART in LMICs were low and considerably poorer than those previously found in adults in LMICs and children in high-income countries. Little progress has been made in improving viral suppression rates over the past years. Without increased efforts to improve pediatric HIV treatment, the 90-90-90 goal for children in LMIC will not be reached.

Long-term Virological Outcomes of First-Line Antiretroviral Therapy for HIV-1 in Low- and Middle-Income Countries: A Systematic Review and Meta-analysis.

BACKGROUND: More than 11.7 million people are currently receiving antiretroviral therapy (ART) in low- and middle-income countries (LMICs), and focused efforts are needed to ensure high levels of adherence and to minimize treatment failure. Recently, international targets have emphasized the importance of long-term virological suppression as a key measure of program performance. METHODS: We systematically reviewed publications and conference abstracts published between January 2006 and May 2013 that reported virological outcomes among human immunodeficiency virus type 1 (HIV-1)-infected adults receiving first-line ART for up to 5 years in LMICs. Summary estimates of virological suppression after 6, 12, 24, 36, 48, and 60 months of ART were analyzed using random-effects meta-analysis. Intention-to-treat (ITT) analysis assumed all participants who were lost to follow-up, died, or stopped ART as having virological failure. RESULTS: Summary estimates of virological suppression remained >80% for up to 60 months of ART for all 184 included cohorts. ITT analysis yielded 74.7% (95% confidence interval [CI], 72.2-77.2) suppression after 6 months and 61.8% (95% CI, 44.0-79.7) suppression after 48 months on ART. Switches to second-line ART were reported scarcely. CONCLUSIONS: Among individuals retained on ART, virological suppression rates during the first 5 years of ART were high (>80%) and stable. Suppression rates in ITT analysis declined during 4 years.

Geographic and temporal trends in the molecular epidemiology and genetic mechanisms of transmitted HIV-1 drug resistance: an individual-patient- and sequence-level meta-analysis.

BACKGROUND: Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes. METHODS AND FINDINGS: We reviewed all GenBank submissions of HIV-1 reverse transcriptase sequences with or without protease and identified 287 studies published between March 1, 2000, and December 31, 2013, with more than 25 recently or chronically infected ARV-naïve individuals. These studies comprised 50,870 individuals from 111 countries. Each set of study sequences was analyzed for phylogenetic clustering and the presence of 93 surveillance drug-resistance mutations (SDRMs). The median overall TDR prevalence in sub-Saharan Africa (SSA), south/southeast Asia (SSEA), upper-income Asian countries, Latin America/Caribbean, Europe, and North America was 2.8%, 2.9%, 5.6%, 7.6%, 9.4%, and 11.5%, respectively. In SSA, there was a yearly 1.09-fold (95% CI: 1.05-1.14) increase in odds of TDR since national ARV scale-up attributable to an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. The odds of NNRTI-associated TDR also increased in Latin America/Caribbean (odds ratio [OR] = 1.16; 95% CI: 1.06-1.25), North America (OR = 1.19; 95% CI: 1.12-1.26), Europe (OR = 1.07; 95% CI: 1.01-1.13), and upper-income Asian countries (OR = 1.33; 95% CI: 1.12-1.55). In SSEA, there was no significant change in the odds of TDR since national ARV scale-up (OR = 0.97; 95% CI: 0.92-1.02). An analysis limited to sequences with mixtures at less than 0.5% of their nucleotide positions­a proxy for recent infection­yielded trends comparable to those obtained using the complete dataset. Four NNRTI SDRMs­K101E, K103N, Y181C, and G190A­accounted for >80% of NNRTI-associated TDR in all regions and subtypes. Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes. In SSA and SSEA, 89% of NNRTI SDRMs were associated with high-level resistance to nevirapine or efavirenz, whereas only 27% of NRTI SDRMs were associated with high-level resistance to zidovudine, lamivudine, tenofovir, or abacavir. Of 763 viruses with TDR in SSA and SSEA, 725 (95%) were genetically dissimilar; 38 (5%) formed 19 sequence pairs. Inherent limitations of this study are that some cohorts may not represent the broader regional population and that studies were heterogeneous with respect to duration of infection prior to sampling. CONCLUSIONS: Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains. A small number of NNRTI-resistance mutations were responsible for most cases of high-level resistance, suggesting that inexpensive point-mutation assays to detect these mutations may be useful for pre-therapy screening in regions with high levels of TDR. In the context of a public health approach to ARV therapy, a reliable point-of-care genotypic resistance test could identify which patients should receive standard first-line therapy and which should receive a protease-inhibitor-containing regimen.

Transmission of drug resistant HIV and its potential impact on mortality and treatment outcomes in resource-limited settings.

Scale-up of antiretroviral therapy in low- and middle-income countries has been achieved by using a public health approach that involved national standard regimens and clinical monitoring in settings where laboratory infrastructure was not available. This strategy potentially allows for long periods of unrecognized viral failure, during which drug-resistant virus can be transmitted and this could compromise the long-term effectiveness of currently available first-line regimens. In response to this concern, the World Health Organization recommends population-based surveys to detect whether the prevalence of resistance in ART-naive people is reaching alerting levels. Whereas adherence counseling has to be an integral component of any treatment program, it is still unclear which threshold of transmitted drug resistance (TDR) should trigger additional targeted public health actions and which action is the most cost-effective. Mathematical models can contribute to answer these questions. In order to estimate the potential long-term impact of TDR on mortality in people on ART we used the Synthesis transmission model. TDR is predicted to have potentially significant impact on future HIV mortality. It is critical to remain vigilant over transmission of drug-resistant HIV.

Nucleoside reverse transcriptase inhibitor resistance mutations associated with first-line stavudine-containing antiretroviral therapy: programmatic implications for countries phasing out stavudine.

BACKGROUND: The World Health Organization Antiretroviral Treatment Guidelines recommend phasing-out stavudine because of its risk of long-term toxicity. There are two mutational pathways of stavudine resistance with different implications for zidovudine and tenofovir cross-resistance, the primary candidates for replacing stavudine. However, because resistance testing is rarely available in resource-limited settings, it is critical to identify the cross-resistance patterns associated with first-line stavudine failure. METHODS: We analyzed HIV-1 resistance mutations following first-line stavudine failure from 35 publications comprising 1,825 individuals. We also assessed the influence of concomitant nevirapine vs. efavirenz, therapy duration, and HIV-1 subtype on the proportions of mutations associated with zidovudine vs. tenofovir cross-resistance. RESULTS: Mutations with preferential zidovudine activity, K65R or K70E, occurred in 5.3% of individuals. Mutations with preferential tenofovir activity, ≥ two thymidine analog mutations (TAMs) or Q151M, occurred in 22% of individuals. Nevirapine increased the risk of TAMs, K65R, and Q151M. Longer therapy increased the risk of TAMs and Q151M but not K65R. Subtype C and CRF01_AE increased the risk of K65R, but only CRF01_AE increased the risk of K65R without Q151M. CONCLUSIONS: Regardless of concomitant nevirapine vs. efavirenz, therapy duration, or subtype, tenofovir was more likely than zidovudine to retain antiviral activity following first-line d4T therapy.