Investigación original / Original research HIV transmitted drug resistance in adult and pediatric populations in Panama Juan Castillo,1 Griselda Arteaga,1 Yaxelis Mendoza,1 Alexander A. Martínez,1 Rigoberto Samaniego,2 Dora Estripeaut,3 Kathleen R. Page,4 Rebecca E. Smith,1 Nestor Sosa,1 and Juan M. Pascale1 Suggested citation Castillo J, Arteaga G, Mendoza Y, Martínez AA, Samaniego R, Estripeaut D, et al. HIV transmitted drug resistance in adult and pediatric populations in Panama. Rev Panam Salud Publica. 2011;30(6): 649–56. ABSTRACT Objective. To investigate the prevalence of transmitted drug-resistant HIV among adults in Panama by using a modified World Health Organization Threshold Survey (WHO-TS) and to investigate rates of initial resistance among HIV-positive infants in Panama. Methods. At the Gorgas Memorial Institute, 47 HIV-positive adults were genotyped for mutations associated with transmitted drug resistance (TDR) in the reverse transcriptase and protease genes of HIV-1, according to WHO-TS guidelines, modified to include patients ≤ 26 years old. Prevalence rates for drug-resistance mutations against three classes of antiretroviral drugs—nucleoside analog reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors—were calculated as low (< 5.0%), moderate (5.0%–15.0%), and high (> 15.0%). Twenty-five infant patients were also geno- typed and prevalence rates for drug-resistance mutations were calculated. Results. TDR among Panamanian adults was moderate: 6 of 47 HIV-positive adults showed one or more mutations associated with TDR. Horizontal TDR mutations were moder- ate for NRTIs and NNRTIs and low for protease inhibitors. Vertical transmission of HIV in Panama has decreased for 2002–2007, but vertical HIV TDR prevalence is moderate (12.0%) and is emerging as a problem due to incomplete antiretroviral coverage in pregnancy. Conclusions. The prevalence of HIV TDR indicated by this study, combined with known rates of HIV infection in Panama, suggests more extensive surveys are needed to identify risk factors associated with transmission of HIV drug resistance. Specific WHO-TS guidelines for monitoring vertical transmission of drug-resistant HIV should be established. Key words HIV-1; drug resistance; infectious disease transmission, vertical; protease inhibitors; antiretroviral therapy, highly active; Panama. Throughout the developing world, ac- drugs, and the opportunity to perform cess to antiretroviral therapy (ART) for drug-resistance genotyping is restricted 1 Instituto Conmemorativo Gorgas de Estudios de la Salud, Panama City, Panama. Send correspon- treatment of HIV infections is increasing. (1). In Latin America, there are a num- dence to: Juan M. Pascale, [email protected] As a consequence, drug-resistant HIV ber of studies of secondary drug resis- 2 Hospital Santo Tomás, Departmento de Enferme- dades Infecciosas, Panama City, Panama. (HIVDR) is emerging and diminishing tance, initial drug resistance (IDR), and 3 Hospital del Niño, Departmento de Enfermedades treatment options. In developing coun- primary or transmitted drug resistance Infecciosas, Panama City, Panama. tries, first-line options for treatment are (TDR) (2–15), but discerning continental 4 Johns Hopkins University School of Medicine, Di- vision of Infectious Diseases, Baltimore, Maryland, limited, second-line treatment regimens trends for antiretroviral (ARV) resis- United States of America. are much more expensive than first-line tance in this region is complex. Rev Panam Salud Publica 30(6), 2011 649 Original research Castillo et al. • HIV transmitted drug resistance in Panama Prolonging the lifetimes of ARVs is tally and perinatally (22). Babies born to Samples were collected March 2008 to vital to the sustainability of HIV treat- mothers not taking ART prenatally and October 2010 at the clinic of the Gorgas ment programs in developing nations perinatally should receive AZT, 3TC, Memorial Institute for Health Studies (1). Recommendations for limiting and nevirapine (22). (ICGES), where all HIV patients in Pan- HIVDR in resource-limited countries are Despite broad and prolonged ART ama City were referred for baseline viral defined in the World Health Organiza- coverage in Panama, few studies have ex- load measurement after their initial HIV tion (WHO) global strategy for preven- amined HIVDR prevalence (2) and there diagnoses elsewhere. tion and assessment of HIVDR (16). are no reports of HIV TDR from hori- In this descriptive study, plasma Surveillance of HIV TDR in recently zontal or vertical transmission. HIVDR samples for 47 HIV-positive, ART-naive infected individuals is key to the WHO studies in this country are important, adults from the general population were strategy (16). but financial, human, and laboratory ca- collected and genotyped for drug re- HIV/AIDS was first observed in Pan- pacities to manage HIVDR are limited in sistance at ICGES and their resistance ama in 1984. There are approximately developing countries. In recognition of levels were evaluated (24). A median of 3 20 000 HIV-positive persons in a concen- this problem and as a pillar of the WHO months had elapsed between initial HIV trated epidemic (17) and there have been global strategy against HIVDR (16), the diagnosis and genotyping. Mean CD4+ a total of 10 381 AIDS cases since 1984.5 WHO Threshold Survey (WHO-TS) sur- count was 400 cells per μL. At ICGES, In 2006, 0.5% of pregnant women were veillance and classification strategy was two of the WHO-TS mandatory eligibil- HIV positive, and the share dropped to developed (23, 24). WHO-TS allows for ity criteria for patient inclusion were 0.3% for 2007–2009.5 low-cost classification of the prevalence met: laboratory confirmation of HIV- Panama has provided free diagno- of HIV TDR in adults to individual drugs positive status and, if female, no previ- sis, monitoring, and ART to 70.0% of or drug classes as low (< 5.0%), moderate ous pregnancies (23). The third criterion, all eligible patients since 1999 and to (5.0%–15.0%), or high (> 15.0%) (24). patient age < 25 years, was extended all patients since 2001 (18). Currently, Forty-one WHO-TS studies have been to ≤ 26 years: patients ≥ 25 years had a 4 463 (19) to 8 700 (Panama Ministry conducted in Africa, Asia, and Mexico confirmed HIV-negative serology in the of Health, personal communication, 30 (1, 23, 25–32).6 An adaptation of the previous 3 years. The sample collection March 2011) adult and minor patients WHO-TS strategy was used in Brazil period was extended from the recom- receive ART. In the absence of a national (33). Combined analysis of WHO-TS mended 12 months. database of patients receiving ARV, from 20 countries showed a low overall 70.0%–80.0% are estimated to receive level of HIV TDR (3.7%), although 17.0% Infant samples first-line therapy, 15.0%–20.0% receive of surveys showed moderate levels of second-line therapy, and 5.0%–10.0% re- HIV TDR (1). In Central America, the All infant patients from the general ceive salvage therapy (Panama Ministry WHO-TS has not been applied. population with an HIV-positive diag- of Health, personal communication, 30 Our first objective is to apply WHO- nosis in the Panama City region attend March 2011). TS, with modifications, to investigate ICGES for molecular confirmation of First-line ART for adults in Panama HIV TDR among Panamanian adults. HIV status and measurement of viral follows WHO guidelines (20): one non- For the second objective, we investigate load. Twenty-five infant patients were nucleoside reverse transcriptase inhibi- IDR in Panama, for the first time at the confirmed as HIV positive at ICGES and tor (NNRTI), efavirenz, combined with molecular level (34). While WHO clearly their samples, collected February 2007 two nucleoside analog reverse transcrip- describes its goal in surveying IDR (35), to October 2009, were genotyped. Some tase inhibitors (NRTIs), for which recom- it does not have a formal IDR surveil- data were available on the ART regi- mendations have recently changed (21, lance strategy. mens of the children and their mothers. 22). Since 2007, NRTIs were lamivudine (3TC) and zidovudine (AZT) (21) and, MATERIALS AND METHODS Genotyping methods since July 2011, tenofovir with 3TC or emtricitabine. Current recommenda- WHO-TS methodology and An in-house method was used to gen- tions for second-line therapy are two its adaptations otype and analyze reverse transcriptase NRTIs with a ritonavir-boosted protease and protease genes for specific muta- inhibitor, usually lopinavir (22). Since The WHO-TS strategy (23, 24) focuses tions associated with drug resistance in 2007, Panama’s ART to prevent mother- on regions where ART has been avail- HIV-1. HIV-1 RNA was extracted with to-child-transmission has involved AZT able to ≥ 20.0% of eligible individuals for the QIAamp viral RNA mini kit (Qiagen) and 3TC, with lopinavir (21, 22). From ≥ 3 years; this study focuses on Panama and reverse-transcribed, amplified, and 2007 to July 2011, ART for infants born City. WHO-TS methodology requires sequenced with the primers indicated in to HIV-positive mothers was AZT until collection and analysis of 47 eligible Table 1 (36). 6 weeks of age (21). Current guidelines specimens, preferably within 12 months. recommend this regimen only for babies Analysis born to mothers receiving ART prena- 6 Bertagnolio S, Kelley K, Saadani Hassani A, Obeng-Aduasare Y, Jordan M. World Health Or- Sequences were edited and analyzed 5 Nuñez Maitin AE, Mastelari M, Guerrero G, Pas- ganization surveys of transmitted and acquired with Sequencher software, version 4.5. cale JM. Panama HIV/AIDS epidemiological situ- HIV drug resistance in resource limited settings Consensus sequences were analyzed ation: 1984–2009 [conference presentation]. At: [conference presentation]. At: 18th Conference on XVIII International AIDS Conference, Vienna, Retroviruses and Opportunistic Infections, Boston, with the Stanford University Calibrated 18–23 July 2010. 27 February to 2 March 2011.