Antiretroviral drug resistance among antiretroviral-naïve persons with ...

16 downloads 0 Views 65KB Size Report
Report of sexual partners with potential HIV and ARV drug exposures can prompt baseline ARV-DR ... system [14], provided there was a history compatible with.
DOI: 10.1111/j.1468-1293.2008.00562.x HIV Medicine (2008), 9, 322–325

r

2008 British HIV Association

SHORT COMMUNICATION

Antiretroviral drug resistance among antiretroviral-naı¨ve persons with recent HIV infection in Thailand A Apisarnthanarak,1 T Jirayasethpong,2 C Sa-nguansilp,3 H Thongprapai,3 C Kittihanukul,3 A Kamudamas,4 A Tungsathapornpong5 and LM Mundy6 1 Department of Medicine, Division of Infectious Diseases, Thammasat University Hospital, Pratumthani, Thailand, 2Division of Infectious Diseases, Rajvithee Hospital, Bangkok, Thailand, 3Health Concept International Ltd., Pratumthani, Thailand, 4 Division of Obstetrics and Gynaecology, Thammasat University Hospital, Pratumthani, Thailand, 5Paediatric Division, Thammasat University Hospital, Pratumthani, Thailand and 6Department of Public Health and St Louis University School of Public Health, St Louis, MO, USA Objectives

To evaluate the prevalence and patterns of antiretroviral (ARV) drug resistance (ARV-DR) among ARV drug-naı¨ve, recently infected persons with HIV in the 4-year interval (2003–2006) after the inception of the National Access to ARV Programme for People who have AIDS in Thailand. Methods

Cross-sectional study of patients with recent HIV infection for HIV risks, ARV-DR risks and baseline ARV-DR. Results

Seven of the 305 patients (2%) had baseline ARV-DR. Via contract tracing, all seven patients with transmitted ARV-DR identified sexual partners with prior ARV treatment failure and had documented low (o75%) ARV adherence. Annual ARV-DR increased from 0 to 5.2% (P 5 0.06) between 2003 and 2006. Conclusions

Report of sexual partners with potential HIV and ARV drug exposures can prompt baseline ARV-DR testing of at-risk individuals, while behavioural interventions for adherence and safer sex are refined to minimize the emergence of resistance to generic, fixed-dose combination stavudine, lamivudine and nevirapine (GPO-VIR) therapy. Keywords: antiviral drug resistance, drug-naı¨ve, HIV, recent infection, Thailand Received: 21 November 2007, accepted 1 February 2008 apine (GPO-VIR), in April 2002. Subsequent GPO-VIR resistance has been reported in treatment-experienced patient populations [10–12]. We prospectively evaluated the prevalence and patterns of ARV-DR among ARV-naı¨ve persons with recent HIV infection in medical care during the years 2003–2006 in order to inform decision-making for baseline genotypic testing prior to initiation of ARV therapy (ART).

Introduction Susceptibility to antiretroviral (ARV) drugs is a critical component of HIV-1 treatment success and survival [1–3]. In Europe and North America, the estimated prevalence of primary ARV drug-resistant (ARV-DR) HIV infection is 5– 26.7% in the ARV era, prompting international recommendations for baseline ARV-DR testing prior to initiation of therapy [4–9]. The Ministry of Public Health in Thailand created the National Access to ARV Programme for People who have AIDS (NAPHA), giving access to generic, fixeddose, twice-daily stavudine, lamivudine (3TC) and nevir-

Patients and methods Study design, participants, setting and definitions

Correspondence: Anucha Apisarnthanarak, Department of Medicine, Division of Infectious Diseases, Thammasat University Hospital, Pratumthani, Thailand 12120. Tel: 1 66 81 987 2030; fax: 1 66 2 332 8522; e-mail: [email protected]

We conducted a prospective study from 1 January 2003 to 31 December 2006 at the HIV Clinic of Thammasat University Hospital. Thammasat University Hospital is a

322

ARV drug resistance in ARV-naı¨ve patients 323

tertiary-care, 450-bed referral hospital in central Thailand, serving a 250-km radius of urban and rural regions. There are an estimated 450 HIV-related hospital admissions and 3850 HIV-related out-patient visits annually [13]. Screened patients were eligible to opt in for ARV-DR testing if they met one of the following criteria: (i) detectable HIV-1 RNA in blood plasma and a negative or intermediate Western blot assay for anti-HIV-1 antibody, with subsequent antibody seroconversion; or (ii) a positive enzyme immunoassay (EIA) with Western blot confirmation within 12 months of a documented negative HIV-1 antibody result; or (iii) an optical density signal to cut-off ratio of o0.75 according to a less sensitive or standard dual EIA testing system [14], provided there was a history compatible with recent HIV infection [15]; or (iv) detection of HIV-RNA in the absence of positive antibody test, or an incident detection of low-affinity antibody in a ‘detuned’ assay [14] if there was history compatible with acute HIV infection [15]. Inclusion criteria were patients of age  15 years (inclusive of prenatal HIV-1 screening), recent HIV infection (  12 months after infection), ARV-naı¨ve (inclusive of post-exposure prophylaxis) according to selfreport and medical chart review, CD4 count 4200 cells/mL and no identifiable AIDS-defining condition. This study was approved by the Institutional Review Board of Thammasat University Hospital.

Data collection After gaining informed consent, demographic, clinical and laboratory data were collected. Adherence was assessed routinely by scheduled pill counts at each routine medical encounter. The pharmacist calculated the ratio of pills taken divided by the total number of pills prescribed for the interval period. Laboratory data included HIV quantification via HIV-RNA polymerase chain reaction (PCR) using Roche Amplicor version 1.5 (Roche Diagnostic Systems, Meylan, France); HIV-1 Genotyping Assay (Trugene, Visible Genetics, Toronto, ON, Canada) was performed in patients who had viral load 41000 HIV-1 RNA copies/mL; reverse-transcriptase genotypic resistance was assessed by a method validated for HIV clade B [16]. We defined ARVDR using the criteria established by the International AIDS Society-USA [17]. As a component of contact tracing, third-party consent was obtained from the identified sexual partners of participants with ARV-DR for participation in this study if the partner received care within the same university-based HIV clinic. After consent, the HIV status, clinical, laboratory data and ARV use (regimen and adherence levels) of the index patient’s identified sexual partner(s) were obtained from standardized interviews and structured medical chart reviews. Adherence to ART was

r

2008 British HIV Association HIV Medicine (2008) 9, 322–325

harvested for these individuals from the archived scheduled pill counts recorded in the medical charts.

Data analysis Data analysis was performed using SPSS version 12 (SPSS, Chicago, IL, USA). Descriptive statistics were used to classify patient characteristics and ARV-DR prevalence and patterns. Trend analysis was performed to evaluate ARV-DR from the years 2003 to 2006 using simple linear regression. All P-values were two-tailed; Po0.05 was considered statistically significant.

Results Study cohort There were 305 ARV-naı¨ve enrolled patients with recent HIV infection from 12 provinces in central Thailand between 1 January 2003 and 31 December 2006. At baseline, the overall median age was 24 years, the median duration of known HIV infection was 3 months and there were 169 (55%) women – 130 of whom (77%) were pregnant (Table 1). The majority of participants (n 5 215, 70%) reported HIV-related heterosexual risks and 23 (8%) reported male-to-male transmission risks; the median CD4 count was 545 cells/mL (range 356–901 cells/mL). Notably, 115 participants (38%) reported a sexual partner with HIV infection who was receiving ART; 104 (90%) were on nonnucleoside reverse transcriptase inhibitor (NNRTI)based regimens and 11 (10%) were on protease inhibitor (PI)-based regimens. The incidence of ARV-DR was 0% (n 5 0/75) in 2003, 1.2% (n 5 1/78) in 2004, 2.6% (n 5 2/76) in 2005 and 5.2% Table 1 Demographic and clinical characteristics of 305 recently infected, antiretroviral drug-naı¨ve patients with HIV

Characteristic Age: median (range) Sex Female Pregnant CD4 (cells/mL): median (range) HIV risks Heterosexual Male-to-male Injecting drug use Other/unknown Sexual partners taking ARV NNRTI-based regimens PI-based regimens

Number (%) (n 5 305) 24 (15–51) 169 (55) 130 (43) 545 (356–901) 215 23 35 32

(70) (8) (11) (10)

104 (34) 11 (4)

ARV, antiretroviral therapy; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor.

324 A Apisarnthanarak et al.

Table 2 Virological, immunological and partner characteristics of seven participants with detected antiretroviral (ARV) drug resistance

Study participant

CD4 (cells/lL)

Duration of HIV (months)

ARV drug resistance mutation

Sexual partners’ ARV use* at time of VF and AL

1 2 3 4 5 6 7

404 516 610 495 554 901 859

6 3 2 4 1 1 1

K103N, M184V Y181C, M184V Y181C K103N, M184V Y181C, M184V Y181C, M184V Y181C, M184V

VF VF VF VF VF VF VF

on on on on on on on

GPO-VIR, AL 44% GPO-VIR, AL 65% GPO-VIR, AL 74% EFV-based regimen, AL 70% GPO-VIR, AL 55% GPO-VIR, AL 45% GPO-VIR, AL 60%

*Including evidence of clinical, immunological and virological failure, treatment regimen(s) and adherence level as measured by ‘scheduled’ pill counts. EFV, efavirenz; GPO-VIR, generic, fixed-dose, twice-daily stavudine, lamivudine and nevirapine; VF, virological failure, as defined by failure to achieve undetectable viral load within 6 months of initiation of ARV; AL, ARV adherence level.

(n 5 4/76) in 2006 (P 5 0.06). Seven patients (2%) had confirmed GPO-VIR drug resistance over the 4-year period (Table 2). Each of these seven participants identified sexual partners who were in HIV care at the study site (and not elsewhere); all reported a single sexual partner and reported no recent (o24 months) sexual encounters with a commercial sex worker. Each identified sexual partner had documented GPO-VIR non-adherence and GPO-VIR treatment failure. Each initial participant with ARV-DR and the identified sexual partner, together, had similar ARV-DR mutations. These mutations were K103N and M184V (two pairs), Y181C and M184V (four pairs) and Y181C (one pair) – compatible with 3TC and NNRTI resistance. No participants had evidence of PI-associated mutations.

Discussion The emergence of ARV-DR worldwide has been linked to consequent morbidity, mortality, excess costs of care and public health concerns [1,4,18]. The first of two major findings of this study is the 4-year temporal trend in ARVDR – rising from 0 to 5.2% in ARV-naı¨ve individuals. Second are data to support a potential risk-based, prioritized approach to baseline ARV-DR testing among ARV drug-naı¨ve, recently infected HIV patients who report a sexual partner with ARV non-adherence or GPO-VIR treatment failure. While the temporal rise in ARV-DR was not statistically significant, the trend is consistent with a short list of observational studies from Thailand that have characterized the emergence of ARV-DR among persons with ARV experience and treatment failure despite a universal ARV access programme [11–12]. Together, these surveillance and cohort studies suggest that additional system-, provider- and patient-level support is needed to secure ARV drug delivery and minimize the emergence of ARV-DR. The prior studies in ARV-experienced patients have identified the need for national surveillance for baseline ARV resistance among HIV drug-naı¨ve patients, while

generic NNRTI-based regimens (GPO-VIR) remain first-line treatment and recommendations for resistance testing are selective [11–12]. While our data do not support routine ARV-DR testing among all ARV-naı¨ve patients in Thailand, our findings suggest that baseline ARV-DR may be justified in newly diagnosed patients with HIV infection who identify an ARV-experienced, HIV-infected sexual partner who acknowledges ARV non-adherence or treatment failure. Furthermore, our data on the prevalence of GPOVIR resistance in recently infected, ART-naı¨ve patients – all of whom identified sexual partners with prior GPO-VIR experience and low adherence – suggest that behavioural support interventions for both ARV adherence and safer sex remain key interventions for population health in the years to come. There are some noteworthy, recognized limitations to our study findings. Firstly, although potential misclassification bias with inclusion of persons with HIV of prolonged duration may exist in this retrospective study, this limitation was minimized: our ARV-DR prevalence estimates were based on objective laboratory-based criteria of recent infection. The inclusion criteria and the cohort’s relatively high median CD4 count (545 cells/mL) also suggest minimization of information and misclassification biases, and the inclusion of patients who acquired HIV in the pre-ART era in Thailand would probably underestimate ARV-DR prevalence. Secondly, our findings represent results from a single university-based referral centre in central Thailand, and may not be generalizable to other regions in Thailand. Nonetheless, there are no known data to suggest regional differentiation in ARV-DR prevalence and patterns. Because GPO-VIR has been implemented as the national regimen of choice, it is likely that similar ARV-DR patterns will emerge elsewhere. Thirdly, a targeted approach to ARV-DR testing may not be relevant beyond Thailand and, as such, may be effective only in geographic regions during the early stage in the epidemic when only a small, clearly demarcated section of the HIV-infected population has ARV access. Lastly, the relatively small

r

2008 British HIV Association HIV Medicine (2008) 9, 322–325

ARV drug resistance in ARV-naı¨ve patients 325

sample size of this cohort may limit our capacity to quantify the true national ARV-DR prevalence. In conclusion, the increasing prevalence of ARV-DR among ARV-naı¨ve persons with recent HIV infection is alarming and supports the existing evidence for ARV-DR surveillance in Thailand. Because GPO-VIR remains the current ARV regimen of choice in Thailand, additional provider-initiated obtainment of potential inadvertent ARV exposures during patient interviews should prompt baseline ARV-DR testing in at-risk individuals prior to ARV initiation, while behavioural interventions that focus on adherence and safer sex are refined to minimize transmission of wild-type and ARV-DR HIV infection.

7 Yerly S, Vora S, Rizzardi P et al. Acute HIV infection: impact on the spread of HIV and transmission of drug resistance. AIDS 2001; 15: 2287–2292. 8 UK Collaborative Group on Monitoring the Transmission of HIV Drug Resistance. Analysis of prevalence of HIV-1 drug resistance in primary infections in the United Kingdom. BMJ 2001; 322: 1087–1088. 9 Briones C, Pe´rez-Olmeda M, Rodriguez C, del Romero J, Hertogs K, Soriano V. Primary genotypic and phenotypic HIV-1 drug resistance in recent seroconverters in Madrid. J Acquir Immune Defic Syndr 2001; 26: 145–150. 10 Sungkanuparph S, Manosuthi W, Kiertiburanakul S, Piyavong B, Chumpathat N, Chantratita W. Options for a second-line antiretroviral regimen for HIV type 1-infected patients whose initial regimen of a fixed-dose combination of stavudine,

Acknowledgements

lamivudine, and nevirapine fails. Clin Infect Dis 2007; 44: 447–452.

This study was supported, in part, by the Thai American Physician Foundation (to A.A.) and, in part, by Health Concept Company Limited (to C.S., H.T. and C.K.).

11 Sukasem C, Churdboonchart V, Chasombat S et al. Surveillance of genotypic resistance mutations in chronic HIV-1 treated individuals after completion of the National Access to Antiretroviral Program in Thailand. Infection 2007; 35: 81–88.

References 1 Smith D, Moini N, Pesano R et al. Clinical utility of HIV standard genotyping among antiretroviral-naı¨ve individuals with unknown duration of infection. Clin Infect Dis 2007; 44: 456–458. 2 De Luca A, Weidler J, Di Giambenedetti S et al. Association of HIV-1 replication capacity with treatment outcomes in patients with virologic treatment failure. J Acquir Immune Defic Syndr

12 Sutthent R, Arworn D, Kaoriangudom S et al. HIV-1 drug resistance in Thailand: before and after National Access to Antiretroviral Program. J Clin Virol 2005; 34: 272–276. 13 Kitkungvan D, Apisarnthanarak A, Plengpart P et al. Fever of unknown origin in patients with human immunodeficiency virus infection in Thailand: an observation study and review of the literature. Int J STD AIDS 2008, in press. 14 Janssen RS, Satten GA, Stramer SL et al. New testing strategy to detect early HIV-1 infection for use in incidence estimates and for clinical and prevention purposes. JAMA 1998; 280:

2007; 45: 411–417. 3 Seyler C, Adje´-Toure´ C, Messou E et al. Impact of genotypic

15 Grant RM, Hecht FM, Warmerdam M et al. Time trends in

drug resistance mutations on clinical and immunological

primary HIV-1 drug resistance among recently infected

outcomes in HIV-infected adults on HAART in West Africa. AIDS 2007; 21: 1157–1164. 4 Little SJ, Holte S, Routy JP et al. Antiretroviral-drug resistance among patients recently infected with HIV. N Engl J Med 2002; 347: 385–394. 5 Little SJ. Is transmitted drug resistance in HIV on the rise? It seems so. BMJ 2001; 322: 1074–1075. 6 Grubb JR, Singhatiraj E, Mondy K, Powderly WG, Overton ET. Patterns of primary antiretroviral drug resistance in antiretroviral-naı¨ve HIV-1-infected individuals in a midwest university clinic. AIDS 2006; 20: 2115–2116.

r

2008 British HIV Association HIV Medicine (2008) 9, 322–325

42–48.

persons. JAMA 2002; 288: 181–188. 16 Kuritzkes DR, Grant RM, Feorino P et al. Performance characteristics of the TRUGENE HIV-1 genotyping kit and the Opengene DNA sequencing system. J Clin Microbiol 2003; 41: 1594–1599. 17 Johnson VA, Brun-Vezinet F, Clotet B et al. Update of the drug resistance mutations in HIV-1: fall 2005. Top HIV Med 2005; 13: 125–131. 18 Sax PE, Islam R, Walensky RP et al. Should resistance testing be performed for treatment-naı¨ve HIV-infected patients? A costeffectiveness analysis. Clin Infect Dis 2005; 41: 1316–1323.