Current Opinion in HIV & AIDS:
15 MILLION ON ART BY 2015: A REALISTIC TARGET OR JUST A DREAM?: Edited by Joep M.A. Lange
Transmitted HIV drug resistance in Asia
Sohn, Annette H.a; Srikantiah, Padminib; Sungkanuparph, Somnuekc; Zhang, Fujied
aTREAT Asia/amfAR, The Foundation for AIDS Research, Bangkok, Thailand
bHIV/AIDS Division, San Francisco General Hospital, University of California, San Francisco, San Francisco, USA
cDepartment of Medicine, Division of Infectious Diseases, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
dDivision of Treatment and Care, National Centre for AIDS/STD Control and Prevention, Chinese Centre for Disease Control and Prevention, Beijing, China
Correspondence to Annette H. Sohn, MD, TREAT Asia/amfAR, 388 Sukhumvit Road, Suite 2104, Klongtoey, Bangkok 10110, Thailand. Tel: +66 2 663 7561; fax: +66 2 663 7562; e-mail: firstname.lastname@example.org
Purpose of review: Surveillance for transmitted HIV drug resistance is essential to assessing the longer term sustainability and durability of first-line antiretroviral therapy (ART). Increases in pre-ART resistance would compromise the ability to achieve optimal and durable treatment outcomes using currently recommended antiretrovirals.
Recent findings: In the Asia region, many countries have conducted studies of transmitted resistance among recently HIV-infected and pre-ART patients. Data vary by methodology and resistance interpretation systems. Studies in some high-income settings have shown stabilizing or declining rates (e.g. Taiwan, Hong Kong), and increasing rates in others (e.g. Japan). In low-income and middle-income Asian countries, resistance has primarily been reported to be below WHO thresholds for moderate resistance (i.e. <5%). However, studies have identified an increased risk of resistance associated with male-to-male sex and/or higher rates among cohorts of MSM. Some countries still lack systematically collected transmitted resistance data.
Summary: To date, there does not appear to be a need for baseline resistance testing in most Asian settings for which there are data. However, MSM appear to be at higher risk of transmitted resistance and may benefit from enhanced resistance assessments and prevention interventions.
There were an estimated 4.8 million people living with HIV in the Asia-Pacific region at the end of 2010 . Asian countries have been implementing national HIV treatment programmes since as early as 2000 [2▪▪,3]. The combination of less potent regimens used in some settings in the early 2000s with the greater duration of antiretroviral penetration into Asian communities led to concerns over the development of both pretreatment HIV drug resistance (HIVDR; transmitted resistance) and acquired resistance associated with treatment failure. Preexisting HIVDR in patients at the time of antiretroviral therapy (ART) initiation due to transmitted drug-resistant virus leads to shorter times to treatment failure after starting first-line ART, and a subsequent risk of further transmitting resistance to uninfected individuals [4,5▪▪].
Challenges in assessing transmitted HIVDR data from individual studies include the variation in methodologies used to sample ART-naive patients, and the different ways in which resistance is interpreted. Patients surveyed may be classified as recently infected – whether by younger age, recent negative HIV test or other factors – or chronically infected, which generally applies to patients meeting CD4 cell count-based criteria for initiating ART. Resistance is also interpreted using multiple methods, the most common being the International AIDS Society-USA mutation list (IAS-USA) , the Stanford University HIV Drug Resistance Database programme (HIVdb)  and the WHO drug mutation list for transmitted resistance . Each of these lists serves different and potentially overlapping purposes. The interpretation best suited to clinical management of an individual patient is not necessarily optimal for global resistance surveillance [8,9].
This review will focus on how recent transmitted HIVDR patterns in adults with HIV in Asia vary between high-income, low-income, and middle-income settings. Data related to HIVDR in Asian countries were selected from recent publications indexed in PubMed and conference abstracts from the Conference on Retroviruses and Opportunistic Infections and the International AIDS Society. Country-specific commentary will highlight HIVDR patterns in the larger treatment programmes in the region.
REGIONAL-LEVEL HIV DRUG RESISTANCE SURVEILLANCE AND MONITORING ACTIVITIES AND LABORATORY QUALITY ASSURANCE
Since 2003, the WHO has developed a global framework and methodology for addressing HIVDR, and implemented surveillance and monitoring activities . Transmitted resistance is defined as when individuals are newly infected with already resistant virus. Surveys of transmitted HIVDR have been conducted in the region using the WHO methodology in Cambodia, China, India, Indonesia, Thailand and Vietnam [5▪▪,11,12▪,13▪]. Only samples genotyped within WHO-accredited laboratories are considered eligible for contribution to the WHO global HIVDR database . The following Asian countries have accredited national-level laboratories: China (Beijing, Shanghai, Shenyang), India (Chennai, Pune) and Thailand (Bangkok, Nonthaburi). Two regional-level laboratories (Melbourne, Sydney) are authorized to test samples submitted from other countries in the Asia-Pacific .
Additional regional data on HIVDR in Asia are from TREAT Asia/amfAR's study to evaluate transmitted and acquired resistance (TASER), conducted from 2006 to 2011, using protocols with a modified WHO methodology . External laboratory quality assurance was provided for HIV genotyping through the TREAT Asia Quality Assurance Scheme (TAQAS), facilitated by the National Serology Reference Laboratory, Australia . Participating laboratories linked to TASER clinical sites were located in Hong Kong China SAR, Indonesia (Jakarta, Bali), Malaysia (Kuala Lumpur, Kota Bharu), the Philippines (Manila) and Thailand (Bangkok, Chiang Mai) .
HIV DRUG RESISTANCE IN HIGH-INCOME ASIAN SETTINGS
Rates of transmitted HIVDR in some high-income Asian settings are beginning to stabilize or decrease. In Taiwan, an analysis of 1349 samples collected from ART-naive, recently and chronically infected patients over an 11-year period at the largest national HIV referral hospital demonstrated an increase in transmitted HIVDR using the IAS-USA mutation lists  from 6.1% during 2000–2002 to 12.3% in 2003–2006, followed by a decrease to 5.1% in 2007–2010 (P ≤ 0.05) . A similar decrease in transmitted HIVDR was observed in a study of anonymous HIV testing programmes in Southern Taiwan. In a sample of 78 HIV-positive patients out of 3697 screened, 11.5% were found to have resistant virus, with annual resistance prevalence falling from 17.6% in 2007 to 13% in 2008 and 8% in 2009 . Most reported their risk for infection as male-to-male sex (85%), and almost all had subtype B (99%).
In a 5-year study from 2003 to 2007 at the largest HIV clinical centre in Hong Kong China SAR, 3.6% of 731 newly diagnosed patients were found to have mutations from the IAS-USA list, and 10.7% had low-level to high-level resistance by the Stanford HIVdb algorithm [7,22]. Patients were predominantly male (87%), reporting male-to-male (44%) or heterosexual (43%) sex as their primary risk factor for HIV infection, and subtypes were split between B (42%) and CRF01_AE (43%). Within this patient population, nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance (5.1%) was most common, compared with nucleoside reverse transcriptase inhibitors (NRTIs; 3.3%) and protease inhibitors (3.0%). Moreover, rates of resistance decreased over time to 7.6% by 2007.
However, this is not the situation in Japan. Investigators there have been conducting national surveillance in newly diagnosed patients since 2003 . Rates of patients having at least one major resistance mutation by Stanford HIVdb criteria have increased from 5.9% in 2003 to 8.3% in 2008, to 11.9% in 2010 [24,25]. The patient population is composed almost entirely of men (93%) who have sex with men (MSM; 65%), with subtype B infection (89%) . Although the use of protease inhibitors has been identified as a possible reason for the lower rates of transmitted HIVDR in Hong Kong , it has not led to the same outcome in Japan, where some centres are using second-generation protease inhibitors in their standard first-line regimens (i.e. darunavir; S. Oka, personal communication).
Clinical centres in higher income settings may be able to conduct pre-ART genotyping to assess for resistance, similar to the current United States guidelines , and more easily individualize treatment regimens than in less well resourced centres in the region.
HIV DRUG RESISTANCE IN LOW-INCOME AND MIDDLE-INCOME ASIAN SETTINGS
WHO conducted a global meta-regression analysis of studies on transmitted HIVDR in low-income and middle-income countries (LMICs), excluding WHO surveys, in recently infected patients and pre-ART chronically infected patients published between 2003 and 2010 [2▪▪]. Overall aggregated rates of having at least one drug-resistance mutation reported were lowest in 2005 (1.9%) and highest in 2009 (6.6%), with the most recent data from 2010 (2.1%). NRTI resistance varied from 0 to 2.3%, NNRTI resistance from 0.9 to 3.3% and protease inhibitor resistance from 0 to 0.9%. Within Asia, studies were included from Cambodia (N = 2), China (N = 11), India (N = 8), Thailand (N = 7) and Vietnam (N = 6). Rates of resistance across the Asian studies were all less than 5% within the last 5 years of the analysis (Table 1).
Between 2005 and 2009, 24 surveys of transmitted HIVDR were conducted in Asia following WHO guidelines [5▪▪]. These surveys are conducted according to a specific methodology focusing solely on recently infected individuals. Survey sites are advised to recruit from a defined geographic area where ART has been available to at least 20% of eligible patients for at least 3 years. Up to 47 consecutively identified asymptomatic patients with laboratory-confirmed HIV, who are under 25 years of age, and have no history of previous pregnancies, can be enrolled . WHO surveillance conducted among voluntary counselling and testing centre clients in Cambodia (one survey) and Vietnam (one survey) each demonstrated a transmitted HIVDR prevalence between 5 and 15% to at least one drug class. Of the 10 surveys conducted in mainland China between 2008 and 2009, only a 2009 Beijing survey reported resistance between 5 and 15%, all due to the M46L mutation to protease inhibitors [13▪]. All other WHO surveys in the region (in China, India, Indonesia, Thailand, Vietnam) consistently reported less than 5% transmitted HIVDR among the specific populations assessed.
In a preliminary analysis of the TASER study cohort, data were analysed from 682 patients about to start ART from eight sites in Hong Kong China SAR, Malaysia and Thailand . Most were Thai (73%), male (65%), reported heterosexual risk exposures (75%) and were infected with subtype CRF01_AE (78%). Using the IAS-USA mutation list, 14% had more than one resistance-associated mutation to NRTIs (8.4%), NNRTIs (6.5%) and protease inhibitors (0.4%). Only the NRTI mutation K70R (7.6%) and mutations to etravirine (V179D 3.2%, V106I 1.9%) were seen in more than 1% of the patients. Having a lower CD4 cell count (median 66 vs. 108 cells/μl, P < 0.009) was identified as a risk factor for resistance.
A follow-up study of 468 recently and 1340 chronically infected patients enrolled from 2007 to 2010 was conducted in four TASER sites enrolling recently infected patients in Thailand, Hong Kong China SAR and the Philippines, and 11 sites enrolling chronically infected patients in Thailand, Malaysia, Hong Kong China SAR, the Philippines and Indonesia. The analysis cohort included primarily males (recent 92%, chronic 66%) from Thailand (recent 64%, chronic 69%), reporting heterosexual (recent 13%, chronic 72%) and homosexual (recent 81%, chronic 20%) exposure risks, with subtype CRF01_AE (recent 69%, chronic 79%) . Applying the WHO 2009 mutation list, investigators reported that those with recent infection had a higher rate of overall and protease inhibitor specific resistance than those with chronic infection (6.1 vs. 4.0%, P = 0.065; protease inhibitor only 3.9 vs. 1.0%, P < 0.001). The most common NRTI mutations were M184I/V and T215D/E/F/I/S/Y; Y181C (1.3%) was the most common NNRTI mutation, and M46I the most common protease inhibitor mutation (1.5%). Chronically infected patients had similar mutations at lower prevalence (T215D/E/F/I/S/Y 0.8%, Y181C 0.5%, M46I 0.4%). In this population, heterosexual contact was less likely to be associated with transmitted resistance compared with other HIV exposure categories [odds ratio (OR) 0.34, 95% confidence interval (CI) 0.20–0.59, P < 0.001].
Country-specific resistance issues
A number of countries in the region have yet to conduct systematic surveillance of transmitted HIVDR. The lack of access to viral load testing and HIV genotyping in parts of the Asia-Pacific hampers efforts to more accurately assess current resistance trends. The countries highlighted below include those with the largest ART programmes and more extensive resistance monitoring experience in the region.
China's National Free ART Programme has initiated treatment in almost 100 000 people at over 2600 clinical centres since 2002 [29▪]. The adult HIV epidemic reflects a combination of those infected through paid blood donation schemes, sexual risk behaviours and IDU. A national sentinel surveillance study [30▪] of HIVDR was conducted in five provinces or municipalities of ART-naive patients in 2011. Of 627 eligible patients, 77% were male with HIV risk categories reported as 25% IDU, 26% male-to-male sex and 43% heterosexual behaviour. The most common subtypes were CRF07_BC (46%) and CRF01_AE (43%), and the overall prevalence of resistance using the Stanford HIVdb was 2.7%, lower than a previous survey reporting a 3.8% prevalence [30▪,31]. Male-to-male sex was associated with a higher prevalence of resistance (4.3%) and was the only significant factor on logistic regression (crude OR 2.9, 95% CI 1.0–8.5). In comparison, a study of 145 recently diagnosed ART-naive patients in Beijing reported 6.9% resistance to any antiretroviral class using WHO 2009 surveillance criteria . Although not statistically significant, the study similarly found that male-to-male sex as an HIV risk factor was associated with a higher rate of resistance than heterosexual sex (11.6 vs. 7.1%).
India's ART scale-up started in 2004, and as of August 2012, there were 540 000 people on ART at 355 public-sector treatment facilities across the country . Although the number of new infections has been reduced by more than 50%, increasing numbers of infections are being seen in MSM, IDUs and male migrants . In a survey using WHO methodology enrolling recently infected primigravida women in Southern India, only one of the patients had a resistance mutation (to NNRTIs), translating to a less than 5% resistance rate . Somewhat different results were seen in a survey of pre-ART transmitted resistance in clinics in Chennai and Mumbai, where 298 patients were enrolled prior to ART initiation [12▪]. Using the Stanford HIVdb, 5.2% of patients in Chennai and 10.4% in Mumbai had at least one resistance mutation. Notably, 90% of these patients in Mumbai had high-level resistance to nevirapine, part of the standard first-line regimen in India and most LMICs. These data reflect the challenges in monitoring resistance across the diverse populations and geographic areas within India's national HIV programme.
Thailand was the first country in the region to initiate active ART scale-up, beginning in 2000. By the end of 2011, over 225 000 people were receiving ART through 943 clinical centres . Key features of the Thai epidemic include their longer experience with ART, and the epidemiologic shift towards infections among MSM, female sex workers and IDUs . Annual surveys of transmitted HIVDR among recently HIV-infected MSM using WHO methodology in Bangkok in 2009 and 2010 showed an increase from 3.9% all-class resistance to 6.8% . This is higher than a survey of patients also in Bangkok, but with predominantly heterosexual risk exposure . In that study of 466 ART-naive patients, the prevalence of all-class resistance also using WHO 2009 surveillance definitions was 4.9%.
Mathematical modelling of transmitted HIVDR in Thailand has shown the potential benefit of combining routine viral load monitoring to detect earlier virologic failure with rapid ART switch to second-line regimens, in order to reduce transmitted resistance on a national level . In the annual viral load testing scenario, the absolute proportion of transmitted resistance was reduced by 5%, representing an 80% relative reduction in baseline resistance. Testing every 6 months would result in a further 28% relative reduction, illustrating the utility of viral load testing as a key component of HIVDR prevention.
Vietnam did not begin national-level scale-up until 2005. By 2011, their HIV care and treatment programme was delivering ART to almost 58 000 adults and over 3000 children . Vietnam's two earlier WHO surveys of transmitted HIVDR reported less than 5% resistance , except for a single result of 5–15% to NNRTIs (Testing on plasma was negative for NNRTI resistance, but positive on a dried blood spot sample). Two multicentre cross-sectional studies from samples collected between 2008 and 2009 showed differing results. A national multicentre study  reported that 6.5% of a subcohort of ART-naive female sex workers and IDUs had at least one major NRTI or NNRTI mutation. Investigators working in Northern Vietnam conducted three annual resistance assessments of ART-naive patients, which went from 2.9% in 2007 to 6.2% in 2008 to 2.0% in 2009 [43▪]. The investigators noted that the fall in resistance occurred in parallel to increases in ART coverage from 30% in 2007 to 54% in 2009. It can be postulated that increased treatment coverage reduces the community viral load and HIV transmission as a result . Continued expansions of ART coverage in Vietnam may change the epidemiology of resistant virus transmission.
Surveillance for HIVDR is essential to assessing the longer term sustainability of currently used first-line ART regimens and programme effectiveness. Surveys of recently infected patients help to track transmitted HIVDR as it is happening, although assessing resistance in chronically infected patients as they are about to start ART informs the impact of resistance on the efficacy of ART regimens currently being used in national programmes.
1. To date, the prevalences of reported resistance do not indicate a need for baseline genotyping.
2. Data in the Asia region have shown both a decline in pre-ART resistance in some high-income settings and increases in key at-risk populations in LMICs.
3. The association between male-to-male sex and resistance seen in multiple countries should be of concern, and leads to greater efforts to track resistance among MSM.
Surveillance and genotyping remain in the early stages in much of the Asia-Pacific. Greater technical resources are still needed in countries lacking the ability to systematically collect resistance data before ART initiation and after treatment failure.
Conflicts of interest
The authors report no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 77).
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antiretroviral therapy; Asia; HIV drug resistance; transmitted resistance; treatment failure
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