Prevalence of transmitted drug resistance globally: highest in Australia, US and some European countries but between-country differences in all regions
Simon Collins, HIV i-Base
The XXIV International Drug Resistance Workshop provided a focus for many reports on the prevalence of transmitted HIV drug resistance (TDR) in different countries, although the size and approach to collecting this data varied considerably between studies.
Some of the highest rates reported were in the US, Europe and Central America. Within all regions, including countries in sub-Sahara Africa, wide difference were reported.
Global differences in TDR, together with the disparity in access to resistance testing, was highlighted in a study of baseline data from 4,685 participants enrolled from 2009-2013 in the international START study.  START has already randomised 4600 treatment-naive individuals with CD4 counts >500 cells/mm3 to either immediate ART or deferred ART (when CD4 count drops to 350 cells/mm3).
The overall prevalence of TDR from samples tested was 10.1%, most commonly to NNRTIs (4.5% and NRTIs (4%) and was higher in Australia (17.5%) and the US (12.6%) than Europe (8.8%), but within Europe, differences ranged from16.7% in France and 12.6% in Spain to 4.7% in the UK. Given surveillance studies in the UK have consistently report rates that are at least twice as high, this low percentage has yet to be explained.
However, access to resistance testing varied considerably: 89% in Australia, 86% in Europe, 81% in the US, 22% in Asia, 1.8% in South America and 0.1% in Africa.
This highlights the important of the range of national studies on transmitted drug resistance that were presented at the workshop from other global regions.
In Africa, some countries, with established access to ART for a decade or longer, reported relatively low levels of TDR – defined by the WHO as less than 5% – including Uganda, Mozambique and South Africa.
A study from the Rakai cohort in Uganda in 76 people with recent HIV infection reported than only two people had a single NNRTI mutation each (K101E and K103N), and one individual had a single PI mutation (M46I). Free ART has been widely available in Uganda since 2004. 
A surveillance review in antenatal clinics in Maputo and Beira in 2007, 2009 and 2011 reported that transmitted drug resistance was below WHO surveillance threshold of 5%, although details of the numbers of people tested and the incidence of class resistance was not reported. The study concluded that transmitted drug resistance may be decling over time. By 2011, more than 270,000 people were on ART. 
In South Africa, several studies presented different results from this country that now has more than two million people on ART.
A national surveillance study from all nine provinces provided an analysis of TDR in 2012. This group tested 770 samples from women younger than 21 years old during their first pregnancy, 532 of which (69%) were successfully genotyped. Overall, the prevalence (95% CI) of resistance by drug class was estimated at 5.4% (3.7 to 7.6%) for the NNRTI, 1.1% (0.5 to 2.4%) for NRTI and 0.9% (0.3 to 2.6%) for PI associated drug resistance. However, four provinces had a prevalence of NNRTI resistance that was greater than 5%. 
Results were also reported from three rounds of an annual population based HIV surveillance programme in rural KwaZulu-Natal from 2010-2012. The 701 treatment-naive participants were estimated to have been HIV positive for at least two years. Prevalence of any significant drug resistance was 5% (36/701). These were predominantly NNRTI (n=35): K103N (n=27), V106M (n=3) and G190A (n= 2). NRTI mutations were detected in 11 (1.6%) of the participants, 9 of whom had only one NRTI mutation. TDR was increasing over time (p=0.02). 
The clinical importance of TDR was highlighted in a study from six African countries including South Africa that looked at 2-year and 3-year treatment outcomes from treatment-naive patients at 13 clinic sites. Genotype results from 2,579 participants (94% of the cohort) showed TDR in 5% (n=139). 
Pretreatment resistance increased the risk of three categories of treatment failure.
- Switching with drug resistance (HR 7.8 (95% CI: 3.9 to 15.6) during 3 years.
- Virologic failure (OR 2.9 (95% CI: 1.4 to 5.8) after 2 years and 2.8 (95% CI: 1.1 to7.2) after 3 years.
- Acquired drug resistance (OR 2.5 (95% CI: 1.2 to 5.4) after 2 years and OR 5.0 (95% CI: 1.8 to 14.3) after 3 years of first-line ART.
Although pretreatment drug resistance was not associated with mortality or new AIDS events, this may be a marker of relatively short follow up.
In a small study from Ethiopia where ART has been available in public health programmes since 2003, rates of TDR were higher and have been rising. Genotype results were available for 38/48 newly-diagnosed treatment-naive individuals at a single clinic in the city of Gondar (24/38 were recently infected). Major mutations were found in 4 (11%) people (PRO 46I, 82L; RT 106M, 190A) and 8 additional patients (22%) had other significant mutations (PR 10I/V, 35G, 58E; RT 62V, 108I, 103E, 138A). The authors concluded that the 17% resistance from samples in 2013 compared to 6% in 2008/9 and only 2% in 2003. 
In a cohort of 553 treatment-naive adults in Kenya, 75/553 (14%) had pre-treatment drug resistance detected at baseline. Of these 75 participants with resistance, 97% had resistance to NNRTIs (75% with K103N, 22% with Y181C, 13% with G190A), and 17% with resistance to 3TC (M184V). In the multivariate analysis, younger age was associated with higher relative risk of resistance (16% per 5 year decrease). 
When looking at drug resistance in people on treatment, several studies reported high levels of drug resistance, associated with limited access to viral load testing. This has been a long standing concern for all settings where lack of viral load testing means that first-line combination is continued until clinical failure.
In Ghana, in a cohort of 175 patients receiving long-term NNRTI-based ART, one third were found to have detectable viral load. This was detectable below vs above 1000 copies/mL in 19% vs 4%, respectively, with drug resistance in 18% (2/11) vs 83% (19/23). Almost all patients with viral load above 1000 copies/mL (median 4.1 log: IQR: 3.8-4.3) also had dual NRTI/NNRTI resistance. In the 151 people with low or undetectable viral load, viral rebounded to >1000 copies/mL in 11% of people over 20 months, by which time the majority of these patients also acquired dual NRTI and NNRTI resistance. 
In the first study of drug resistance in Liberia, out of 90 patients at a single clinic in Monrovia on first-line NNRTI-based treatment for median 42 months (IQR: 22-55 months), only 27% had undetectable viral load <50 copies/mL. In those with detectable viral load, 63% had NRTI, 70% had NNRTI and 60% had dual class resistance. Two people had PI mutations (M46L and D30N). 
A multinational study of six countries in Central America reported rates of TDR in more than 3600 people who were recently diagnosed between 2010-2014 in Mexico (n=1476), Guatemala (n=1180), Panama (n=238), Nicaragua (n=222), Honduras (n=294) and Belize (n=100). Belize showed the highest prevalence (19.0%), followed by Nicaragua (14.9%), Panama (12.2%), Honduras (9.9%), Mexico (7.7%) and Guatemala (7.1%). In all countries, resistance was generally highest to NNRTIs, then NRTIs with lower rates of PI-associated mutations. 
One of the highest rates of TDR however was reported from the US National Surveillance System in a recent study of 9,629 MSM diagnosed from 2010-12 in eight sites (Colorado, Connecticut, Los Angeles county, Michigan, New York, South Carolina, Texas, and Washington). 
In this analysis, 18.9% men had TDR to any class: 16.2% to 1 drug class, 2.3% to 2 drug classes, and 0.4% to 3 drug classes. TDR by class was NNRTI (9.9%), NRTI (6.8%) and PI (5.3%).
Men aged 20-29 years accounted for 40% of TDR (with a prevalence of 19.4%). However, younger men aged 13–19 years, who accounted for only 6.6% of infections, had the highest prevalence of 23.4%. Although TDR was significantly different by race/ethnicity these rates were 20.1% for black MSM, 18.5% for Hispanic/Latino and 17.5% for white MSM.
Taken together these studies highlight the need to know (1) the prevalence of transmitted drug resistance in various populations in different countries and regions and (2) the prevalence of developed drug resistance in different regions. The results then need to relate to aspects of care such as availability of viral load testing and frequency of follow up visits.
The studies give a limited view, with different sampling rates and sizes and little information on the populations studied. They highlight the importance of increasing availability to viral load testing. It would be of interest to have more results from people who have advanced clinically.
Unless stated otherwise, references are to the Programme and Abstracts of the XXIV International HIV Drug Resistance Workshop, 21-22 February 2015, Seattle, Washington.
- Baxter JD et al. Global HIV-1 transmitted drug resistance in the INSIGHT Strategic Timing of AntiRetroviral Treatment Study. Abstract 67.
- Reynolds SJ et al. Low rates of transmitted drug resistance among newly identified HIV-1 seroconverters in rural Rakai, Uganda. Abstract 60.
- Bila D et al. Three consecutively surveillance rounds reveal a decrease in transmitted drug resistance in Mozambique. Abstract 56.
- Hunt G et al. National surveillance of HIV-1 transmitted drug resistance in South Africa in 2012. Abstract 77.
- Manasa J et al. Increase in HIV primary drug resistance in a demographic surveillance area in Rural KwaZulu- Natal South Africa. Abstract 73.
- Boender TS et al. Pretreatment HIV drug resistance increases regimen switch in Sub-Saharan Africa. Poster abstract 3.
- Olshtain-Pops E K et al. High HIV drug resistance in naive, recently diagnosed patients in Gondar. Abstract 23.
- Silverman RA et al. Higher risk of pre-treatment HIV drug resistance among younger ART-naive Adults in Kenya. Abstract 86.
- Beloukas A et al. Prevalence of resistance-associated mutations at viral load below 1000 copies/mL during long-term first-line NNRTI-based antiretroviral therapy in Ghana. Poster abstract 2.
- Loubet P. High level of acquired HIV drug resistance in patients failing on first-line regimen in Liberia. Abstract 15.
- Avila-Ríos S et al. HIV drug resistance in antiretroviral treatment-naive individuals in the Mesoamerican Region, 2010-2014. Abstract 65.
- Ocfemia MCB et al. Epidemiology of HIV-1 transmitted drug resistance among men who have sex with men in the United States. Oral abstract 81.