Impacto de la viremia de bajo grado en el riesgo de fallo virológico en pacientes con infección por VIH-1 / Impact of low-grade viremia on the risk of virological failure in patients with HIV-1 infection on antiretroviral therapy

Resumen Introducción: Cargas virales (CV) entre 20-200 copias/mL se consideran cargas virales de bajo grado (CVBG). Su implicancia clínica y manejo no han sido definidos. Objetivo: Evaluar el impacto de CVBG en el riesgo de desarrollo posterior de fallo virológico (FV). Pacientes y Métodos: Se incluyeron pacientes ≥ 18 años, desde enero de 2009 a diciembre de 2019, con infección por VIH-1 con CV< 20 copias/mL, por un mínimo de seis meses y/o en dos muestras consecutivas bajo tratamiento anti-retroviral . Se realizó seguimiento de las CV estrati ficándolas: CV < 20 copias/mL, CVBG (20-50 copias/mL y 51-200 copias/mL) y FV. Mediana de seguimiento 25 meses (IQR 15-31). Resultados: Fueron incluidos 1.416 pacientes con CV < 20 copias/ mL bajo TARV. De ellos, 797 permanecieron con CV< 20 copias/mL durante el seguimiento, 144 presentaron CV entre 20-50 copias/mL, 384 entre 51-200 copias/mL y 91 presentaron FV sin CVBG previa. De los 528 pacientes que tuvieron CVBG, 110 (20,1%) fallaron, riesgo 3,45 veces superior respecto a los que no tuvieron CVBG previa. El riesgo de FV fue 3,27 mayor para aquellos que tuvieron CVBG entre 51-200 copias/mL vs 20-50 copias/mL. Discusión: El estudio permite relacionar la CVBG con el FV posterior, siendo el mayor riesgo CVBG entre 51-200 copias/mL.

Abstract Background: Viral loads (VL) between 20-200 copies/mL are considered low-grade viral loads (LGVL). Its clinical implications and management have not been defined. Aim: To evaluate the impact of LGVL on the risk of subsequent development of virological failure (VF). Methods: Patients ≥ 18 years, with HIV-1 infection who had VL < 20 copies/mL for at least six months and/or in two consecutive samples under antiretroviral therapy (ART) were included, between January 1st, 2009 and December 31, 2019. Follow-up of the VLs was carried out stratifying them in VL < 20 copies/mL, LGVL (20-50 copies/mL and 51-200 copies/mL) and VF. Median follow-up 25 months (IQR 15-31). Results: 1,416 patients were included who reached VL < 20 copies/ml under ART, 797 patients remained with CV < 20 copies/mL during follow-up, 144 patients had VL between 21-50 copies/mL, 384 between 51-200 copies/mL and 91 had VF without previous LGVL. Out of 528 patients who had LGVL, 110 failed, risk 3.45 times higher than those who had no previous LGVL. Risk 3.27 times higher of VF for those who had LGVL between 51-200 copies/mL compared to 20-50 copies/mL. Discussion: The study allows to relate the LGVL with VF. This association was observed more frequently with LGVL between 51-200 copies/mL

Optimal antiretroviral therapy adherence as evaluated by CASE index score tool is associated with virological suppression in HIV-infected adults in Dakar, Senegal.

OBJECTIVE: To determine the prevalence and factors associated with optimal antiretroviral therapy (ART) adherence and virological failure (VLF) among HIV-infected adults enrolled in the national ART programme at the teaching hospital of Fann, Dakar, Senegal. METHODS: Cross-sectional study from 1 September 2013 to 30 January 2014. OUTCOMES: (1) optimal ART adherence by the Center for Adherence Support Evaluation (CASE) Index Score (>10) and (2) VLF (HIV RNA > 1000 copies/ml). Diagnostic accuracy of CASE Index Score assessed using sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV) and corresponding 95% confidence intervals (CIs). Multivariate logistic regression analysis was performed to identify independent factors associated with optimal adherence and VLF. RESULTS: Of 98 HIV-infected patients on ART, 68% were female. The median (IQR) age was 42 (20-50) years. A total of 57 of 98 (60%) were on ART more than 3 years, and majority (88%) were on NNRTI-based first-line ART regimen. A total of 79 of 98 (80%) patients reported optimal ART adherence, and only five of 84 (5.9%) had documented VLF. Patients with VLF were significantly more likely to have suboptimal ART adherence (17.7% vs. 2.9%; P = 0.02). CASE Index Score showed the best trade-off in Se (78.9%, 95% CI: 54.4-93.9%), Sp (20.0%, 95% CI: 11.1-31.7), PPV (22.4, 95% CI: 13.1-34.2%) and NPV (76.5%, 95% CI: 50.1-93.2), when used VLF threshold of HIV RNA >50 copies/ml. Factors independently associated with VLF were CASE Index Score <10 ([aOR] = 13.0, 95% CI: 1.1-147.9; P = 0.04) and being a boosted PI-based ART regimen ([aOR] = 27.0, 95% CI: 2.4-309.4; P = 0.008). CONCLUSIONS: Optimal ART adherence is achievable in a high proportion of HIV-infected adults in this study population. CASE Index Score was independently associated with virological outcomes, supporting usefulness of this low-cost ART adherence monitoring tool in this setting.

Intensive adherence counselling for HIV-infected individuals failing second-line antiretroviral therapy in Johannesburg, South Africa.

OBJECTIVE: In resource-limited settings, where genotypic drug resistance testing is rarely performed and poor adherence is the most common reason for treatment failure, programmatic approaches to handling treatment failure are essential. This study was performed to describe one such approach to adherence optimisation. METHODS: This was a single-arm study of patients on second-line protease inhibitor (PI)-based antiretroviral therapy (ART) with a HIV-1 RNA ≥400 copies/ml in Johannesburg, South Africa, between 1 March 2012 and 1 December 2013. Patients underwent enhanced adherence counselling. Those with improved adherence and a repeat viral load of >1000 copies/ml underwent HIV-1 drug resistance testing. We describe results using simple proportions and 95% confidence intervals. RESULTS: Of the 400 patients who underwent targeted adherence counselling after an elevated viral load on second-line ART, 388 (97%) underwent repeat viral load testing. Most of these (n = 249; 64%, 95% CI 59-69) resuppressed (<400 copies/ml) on second line. By the end of follow-up (1 March 2014), among the 139 (36%, 95% CI: 31-41%), who did not initially resuppress after being targeted, 106 had a viral load >400 copies/ml, 11 switched to third line, 5 were awaiting third line, 4 had died and 13 were lost to follow-up. Among the unsuppressed, 48 successfully underwent resistance testing with some resistance detected in most (41/48). CONCLUSIONS: Most (64%) second-line treatment failure in this clinic is related to adherence and can be overcome with careful adherence support. Controlled interventions are needed to determine what the optimal approach is to improving second-line outcomes and reducing the need for third-line ART.

Virological efficacy with first-line antiretroviral treatment in India: predictors of viral failure and evidence of viral resuppression.

OBJECTIVE: Combination antiretroviral therapy (ART) has improved in efficacy, durability and tolerability. Virological efficacy studies in India are limited. We determined incidence and predictors of virological failure among patients initiating first-line ART and described virological resuppression after confirmed failure, with the goal of informing national policy. METHODS: Therapy-naïve patients initiated on first-line ART as per national guidelines were monitored every 3 months for adherence and virological response over 2 years. Genotyping on baseline samples was performed to assess primary drug resistance. Multivariate Cox regression analysis was used to assess predictors of virological failure. RESULTS: Virological failure rate among 599 eligible patients was 10.7 failures per 100 person-years. Cumulative failure incidence was 13.2% in the first year and 16.5% over 2 years. Patients initiated on tenofovir had a significantly lower rate of virological failure than those on stavudine or zidovudine (6.7 vs. 11.9 failures per 100 person-years, P = 0.013). Virological failure was independently associated with age <40 years, mean adherence <95%, non-tenofovir-containing regimens and presence of primary drug resistance. In a subset of 311 patients who were reassessed after treatment failure, 19% (11/58) patients resuppressed their viral load to <400 copies/ml after confirmed virological failure. CONCLUSIONS: Our results support the inclusion of tenofovir as first-line ART in resource-limited settings and a role for regular adherence counselling and virological monitoring for enhanced treatment success. Detection of early virological failure should provide an opportunity to augment adherence counselling and repeat viral load testing before therapy switch is considered.

Evaluación de resistencia genotípica del VIH-1 en pacientes con fallo virológico de Guatemala / Evaluation of genotypic resistance of HIV-1 in patients with virologic failure Guatemala

La resistencia a la terapia antirretroviral (TARV) es un factor determinante para el fallo virológico en pacientes con VIH. El objetivo de este estudio fue identificar los patrones genotípicos de resistencia en pacientes con fallo virológico. Fueron incluidos pacientes de las diferentes unidades de atención integral de VIH en Guatemala, de quienes se sospechaba resistencia y que necesitaban cambios en la TARV por fallo virológico, se requirió haber evaluado la adherencia y una carga viral ≥1,000 copias/ml. La información clínica y demográfica fue recolectada a través de la forma de solicitud. El análisis de resistencia se realizó a través de la metodología TRUGENE® HIV-1. La muestra se restringió a 25 pacientes por motivos de accesibilidad. El 68% de las muestras analizadas presentaron resistencia; por familia de ARV la resistencia fue de 88.2% para ITINN, 70.5% para ITIAN y 17.6% para IP. Se identificaron 79 mutaciones entre el grupo de estudio, el 46.8% de fueron asociadas a ITINN, 76.6% a ITIAN y 26.6% a IP. Para ITIAN las mutaciones más frecuentes fueron la M184V 43%, M184I 14% y K219E 10%; el 23.8% fueron mutaciones TAMs. Para ITINN fueron la V179D 16%, K103N 14%, G190A 14% y Y181C 14%. Para los IP la mutación más frecuente fue la M36I con 29%. La resistencia identificada en este grupo, fue menor a lo reportado en otros países latinoamericanos; sin embargo es similar a lo reportado por OMS en países con bajo o medio ingreso económico.

ARV drug resistance is one of the leading causes of virologic failure among HIV patients on HAART. Theobjective of this study was to determine genotypic resistance profiles among HIV patients on virologic failure. Patients from one HIV clinic in Guatemala on whom ARV drug resistance was suspected and needed a change in their ARV regimen due to virologic failure were included. In order to perform the genotype, the patient had to demonstrate good adherence to therapy and a confirmed viral load ≥1,000 copies/ml. Demographics andclinical data were collected through the resistance-testing questionnaire. The TRUGENE® HIV-1 methodology was used for resistance analysis. The patient sample was restricted to 25 patients due to accessibility, 68% presented resistance to at least one ARV drug. By ARV class, 88.2% presented resistance to NNRTIs, 70.5% to NRTIs and 17.6% to IPs. We found 79 mutations among the samples analyzed. Of the mutations found, 46.8% were associated with NNRTI resistance, 76.6% to NRTI resistance and the remainder 26.6% to PI resistance. The most frequent NRTI associated mutations were M184V 43%, M184I 14% and K219E 10%; 23.8% were TAM. The NNRTI associated mutations were V179D 16%, K103N 14%, G190A 14% and Y181C 14%. For the PI the most frequent mutation was M36I with 29%. The resistance found in this study was lower to that reported in other Latin American studies, however, it is similar to what is reported by WHO in low and middle income countries.

The role of targeted viral load testing in diagnosing virological failure in children on antiretroviral therapy with immunological failure.

OBJECTIVES: To determine the improvement in positive predictive value of immunological failure criteria for identifying virological failure in HIV-infected children on antiretroviral therapy (ART) when a single targeted viral load measurement is performed in children identified as having immunological failure. METHODS: Analysis of data from children (<16 years at ART initiation) at South African ART sites at which CD4 count/per cent and HIV-RNA monitoring are performed 6-monthly. Immunological failure was defined according to both WHO 2010 and United States Department of Health and Human Services (DHHS) 2008 criteria. Confirmed virological failure was defined as HIV-RNA >5000 copies/ml on two consecutive occasions <365 days apart in a child on ART for ≥18 months. RESULTS: Among 2798 children on ART for ≥18 months [median (IQR) age 50 (21-84) months at ART initiation], the cumulative probability of confirmed virological failure by 42 months on ART was 6.3%. Using targeted viral load after meeting DHHS immunological failure criteria rather than DHHS immunological failure criteria alone increased positive predictive value from 28% to 82%. Targeted viral load improved the positive predictive value of WHO 2010 criteria for identifying confirmed virological failure from 49% to 82%. CONCLUSION: The addition of a single viral load measurement in children identified as failing immunologically will prevent most switches to second-line treatment in virologically suppressed children.

Enfuvirtide: el primer paso de una nueva estrategia de tratamiento antirretroviral / Enfuvirtide: the first step for a new strategy of antiretroviral therapy

Enfuvirtide (antes T-20) es el primer inhibidor de la entrada a la célula del HIV-1 en ser aprobado. Es un péptido análogo de la porción HR2 de la glucoproteína de superficie viral gp41. Su mecanismo de acción consiste en la unión competitiva a la porción HR1 de la gp41 para impedir los cambios conformacionales del complejo gp41-gp120 tras la unión del HIV-1 a los receptores celulares, impidiendo así el acercamiento y posterior fusión entre el virus y la célula. Se aplica por vía subcutánea. Los resultados de los principales estudios clínicos (TORO 1 y 2) llevados a cabo en pacientes con fallo virológico, tratamientos previos con antirretrovirales y portadores de cepas virales altamente resistentes, mostraron que quienes recibieron enfuvirtide + HAART optimizado, elegido mediante un test de resistencia, presentaron mayores beneficios que quienes sólo recibieron HAART optimizado, en términos de mejor recuperación inmune y mayor descenso de la carga viral de HIV. Los mejores resultados se observaron en el subgrupo de pacientes con más drogas útiles en el HAART según el test de resistencia, una menor carga viral de HIV y un mayor recuento de linfocitos CD4 basales. El principal efecto adverso es el desarrollo de lesiones por hipersensibilidad en los sitios de aplicación. El alto costo de enfuvirtide se vio compensado por una reducción en los costos de internación.

Enfuvirtide (T-20) is the first approved HIV-1 entry into cells' inhibitor. It is a peptide with an amino acid sequence analogue to HR2 region of the viral surface glycoprotein gp41. Its mechanism of action is the competitive binding to HR1 region of the gp41, preventing the interaction between HR1 and HR2 and impeding the conformational changes in gp41 necessary for fusion of the virus with the cell. Its application is by subcutaneous injection. The main clinical trials of enfuvirtide (TORO 1 and 2) were performed in HIV-infected patients with virological failure, high antiretroviral experience and highly resistant viral isolates. Those trials showed that the addition of enfuvirtide to an optimized HAART (chosen with a resistance test) provided better results than HAART alone, measured by drop in viral load and immunologic benefit. The best results were observed in the subgroup of patients with more useful drugs in HAART (according to the information of the resistance test), a lower viral load, and a higher CD4 cell count at baseline. The most important adverse event is the production of injection drug hypersensitivity reaction in 98% of patients. The high cost is compensated by a reduction in costs derived from admissions.