Surveillance of Transmitted HIV Drug Resistance in Antiretroviral-Naive Patients Aged less than 25 Years,in Bangkok,Thailand

Abstract

Emergence of transmitted HIV drug resistance (TDR) is a concern after global scale-up of antiretroviral therapy (ART). World Health Organization had developed threshold survey method for surveillance of TDR in resource-limited countries. ART in Thailand has been scaling up for >10 years. To evaluate the current TDR in Thailand, a cross-sectional study was conducted among antiretroviral-naive HIV-infected patients aged <25 years who newly visited infectious disease clinic in a university hospital, in 2011. HIV genotypic-resistance test was performed. World Health Organization 2009 surveillance drug-resistance mutations were used to define TDR. Of 50 patients, the prevalence of TDR was 4%. Of 2 patients with TDR, 1 had K103N and the other had Y181C mutations. Transmitted HIV drug resistance is emerging in Thailand after a decade of rapid scale-up of ART. Interventions to prevent TDR at the population level are essentially needed in Thailand. Surveillance for TDR in Thailand has to be regularly performed.

Introduction

Emergence of transmitted HIV resistance (TDR) is a concern after global scale-up of antiretroviral therapy (ART). Transmitted HIV resistance is associated with poor treatment outcomes and/or clinical complication. ^{1 –5} Transmitted HIV resistance is anticipated in the areas where ART has been widely available for years. The prevalence of TDR has been reported in the United States and Europe, ranging from 6.2% to 21%. ^{6 –9} In resource-limited settings, TDR has been reported from sub-Saharan Africa after scale-up of ART and showed the prevalence from 3.5% to 11.6%, depending on the countries. ¹⁰ The higher prevalence of TDR in Uganda than in other African countries is probably related to its earlier start of ART scale-up. In the countries scaling up ART, the World Health Organization (WHO) recommends the surveillance of TDR. ¹¹ The WHO HIV drug-resistance threshold survey method had been developed for surveillance of TDR in resource-limited countries. To minimize costs, WHO suggests that each survey requires ≤47 specimens from individuals consecutively diagnosed with HIV to categorize resistance to each relevant drug class as <5%, 5% to 15%, or >15%. ¹¹

In Thailand, ART has reduced mortality and morbidity since its introduction in the country. ^{12 –14} Scaling up of ART started since 2001 and the National AIDS Program (NAP) continues to expand. According to the Joint United Nations Programme on HIV/AIDS 2010 report, the number of people receiving ART in December 2009 is 216 118 persons, and the life years gained among adults due to ART between 1996 and 2009 is 389 000. ¹⁵ The first threshold survey in Thailand had been done in Bangkok, involving blood donors and counseling and testing center clients during 2005 to 2006. ¹⁶ The findings showed no mutations associated with TDR. A multinational study in Asia including Thailand has demonstrated the prevalence of primary HIV drug resistance among antiretroviral-naive patients at 13.8%. ¹⁷ Although this study did not use surveillance drug-resistance mutations (SDRMs) recommended by WHO for surveillance of TDR, ¹⁸ it brings a concern of TDR in Thailand. Recently, a prospective observational study conducted among antiretroviral-naive Thai patients with chronic HIV infection has demonstrated that the prevalence of primary HIV drug resistance was 4.9%. ¹⁹ To evaluate the current situation of TDR in Thailand, especially in the patient care center, this study was conducted using WHO threshold survey for resource-limited settings.

Methods

A cross-sectional study was conducted among antiretroviral-naive HIV-infected patients who newly visited an infectious disease clinic in a university hospital between January and December 2011. According to the WHO threshold survey methods to minimize inclusion of antiretroviral-experienced individuals and individuals infected before ART was available, ¹¹ the patients eligibility criteria included (1) laboratory confirmation of HIV infection, (2) age <25 years at HIV diagnosis, (3) if female, no previous pregnancy, and (4) CD4 count >500 cells/mm³. Eligible patients were consecutively enrolled from an infectious clinic during the study period. Ethics approvals were obtained from local institutional review boards. Informed consent was obtained prior to genotypic-resistance testing.

All plasma samples, HIV polynucleotide sequencing of reverse transcriptase, and protease region were carried out using TRUGENE HIV Genotypic Assay in conjunction with the Open Gene automated DNA sequencing system (Visible Genetics, Toronto, Canada). Testing involved simultaneous clip sequencing of protease and codons 35 to 244 of the reverse transcriptase from the amplified complementary DNA in both the 3′ and the 5′ directions. Sequences were aligned and compared with an HIV-B-lymphoadenopathy-associated virus type 1 consensus sequence using Visible Genetics Gene Librarian software. ^20,21 Surveillance drug-resistance mutations recommended by WHO for surveillance of TDR in 2009 were used in all analyses. ¹⁸ Transmitted HIV drug resistance in a patient was defined as the presence of at least 1 SDRM.

Results

A total of 50 patients were included in this analysis. The mean (standard deviation) age was 22.2 (3.3) years. In all, 31 (62%) patients were males. Risks of HIV infection were heterosexual (66%), homosexual (30%), and intravenous drug use (4%). Median (range) CD4 count and HIV RNA were 614 (510-787) cells/mm³ and 56 000 (1200-8 50 000) copies/mL, respectively. Of 50 patients, 41 (82%) were infected with HIV subtype CRF01_AE. Other subtypes were B (12%), CRF07_BC (4%), and CRF12_BF (2%).

The prevalence of TDR was 4%. Of these 2 patients with TDR, both had only 1 nonnucleoside reverse transcriptase inhibitor (NNRTI)-SDRM; 1 had K103N and the other had Y181C mutation. Nucleoside reverse transcriptase inhibitor- and protease inhibitor-SDRMs were not observed in this study. Both patients were males; 1 was heterosexual and the other was homosexual. They aged 23 and 24 years old. CD4 counts and HIV RNA of these 2 patients were 522 and 608 cells/mm³ and 1750 and 165 000 copies/mL, respectively.

Discussion

Surveillance of TDR can support implementation of prevention measures at the population level. Transmitted HIV drug resistance represents a challenge for the treatment of HIV infection because it can reduce the efficacy of first-line ART and impact clinical outcomes. ^{1 –5} After a decade of rapid scale-up of ART in Thailand, TDR is inevitably anticipated. The results from the present study have demonstrated that there is an emergence of TDR in Thailand. The prevalence of TDR (4%) is comparable to the prevalence of primary HIV drug resistance in a recent study conducted among antiretroviral-naive Thai patients with chronic HIV infection (4.9%). ¹⁹ Although the prevalence is less than the WHO lower threshold (5%), it raises a concern of HIV care in Thailand. Although patients with TDR had SDRMs only to NNRTI, the treatment response can be markedly impacted. ART regimens in resource-limited settings are usually selected at the national level following a public health approach. In Thailand, the national guidelines recommend using NNRTI-based regimens as the first-line ART. ²² Nonnucleoside reverse transcriptase inhibitor-based regimens generally have low genetic barrier for the development of resistance, and early treatment failure is likely if the regimen does not consist of 3 fully active drugs. ²³ Although we cannot demonstrate how our patients acquired drug-resistance mutations in this study due to the lack of information on the patients’ sexual partners, it is likely that sexual transmission from their treatment-experienced partners may be the case. Our previous study has shown that Y181C and K103N are common drug-resistance mutations after failing the first-line ART in Thailand. ²⁴ To minimize TDR in Thailand, strengthening of HIV care system, supporting patient’s adherence to therapy, and prevention of HIV transmission in both HIV-infected and not infected individuals are crucial. Regular surveillance of TDR in Thailand will inform evidence-based decision making regarding NAP.

In conclusion, TDR is emerging in Thailand after a decade of rapid scale-up of ART. Interventions to prevent the development of HIV drug resistance among treated patients and to prevent transmission of drug-resistant virus are essentially needed in Thailand. To inform the national policy for HIV care, surveillance of TDR in Thailand has to be regularly performed.