Barriers and facilitators to HIV pre-exposure prophylaxis uptake among transgender women in Colombia: A qualitative analysis using the COM-B model.

Transgender women [TGW] in Colombia are disproportionately affected by HIV due to their low sociodemographic conditions, varied risk behaviours, difficulty accessing health services, and discrimination. Offering pre-exposure prophylaxis [PrEP] as part of a combination of prevention strategies is an appropriate option for this population to reduce their risk of HIV infection. However, little is known about how to implement a PrEP program for TGW in Colombia. Between June and October 2020, we conducted individual interviews with 16 TGW from four different cities in Colombia. The interviews assessed contextual influences, knowledge, skills, perceptions, and beliefs. We used qualitative thematic analysis to identify themes and the Capability, Opportunity, Motivation, and Behavior framework to further delineate barriers and possible interventions. After delineating the main themes across the three subdomains of the model, nine barriers were identified: one related to capability, knowledge, and perception of PrEP; six related to opportunity, which includes, family relations, sexual work environment, stable partner relations, interactions with healthcare workers, health service provision, and community interactions and opportunities; and two related to motivation, mental health, and concerns about medication side effects. Mapping barriers with interventions generated the following intervention functions: education, training, enablement, and environmental structure; and the following policy functions: communication/marketing, legislation, and changes in service provision. Examples of possible interventions are presented and discussed.

Scales to Assess Knowledge, Motivation, and Self-Efficacy for HIV PrEP in Colombian MSM: PrEP-COL Study.

OBJECTIVE: We evaluated the construct validity Spanish version of knowledge, stigma, norms, and self-efficacy scales regarding PrEP in MSM. METHODS: Sample of 287 MSM. Exploratory confirmatory factor analysis and item response theory were used to validate the constructs. Correlations and confidence interval-based estimation of relevance analyses were conducted to correlate the scales with willingness and intention to use PrEP. RESULTS: Attitude, stigma, and descriptive and subjective norms scales showed good construct validity and were related to intention and willingness to use PrEP. However, the knowledge scale and self-efficacy scales require further refinement. CONCLUSIONS: The study provides useful information for assessing information, motivation, and self-efficacy related to PrEP use. Our results could be used to test the scales and the theoretical model in other contexts to confirm their usefulness.

Psychometric properties of a Spanish version of the 10-item Berger's stigma scale in Colombia: a validation study / Propiedades psicométricas de una versión en español de la escala de Berger de diez ítems en Colombia: un estudio de validación

Introduction: HIV-related stigma is detrimental to people living with HIV (PLH), and reducing it is essential for achieving an HIV/AIDS-free generation. Abbreviated stigma scales can improve the feasibility of surveys that broadly explore factors affecting PLH. This study tested the psychometric properties of a Spanish translation of the abbreviated 10-item Berger's HIV stigma scale. Methods:We recruited a sample of 105 PLH regularly attending a specialized clinic in Cali, Colombia. English-to-Spanish and Spanish-to-English back translation was performed of the Berger's 10-item HIV stigma scale.Exploratory and confirmatory factor analyses were carried out to assess its validity. Pre- and post-test reliability (15 days) was estimated with the intra-class correlation coefficient (ICC). Results: The Confirmatory Factor Analysis (CFA) was used to confirm a two-factor solution with three poor items removed, resulting in a 7-item HIV Stigma Scale. The resulting 7-item HIV stigma scale had a Cronbach's alpha of 0.73 with an ICC of 0.83 (CI 95%: 0.75­0.89). One factor loaded three items related to negative self-image (internalised stigma), and the other four items were related to personalized (enacted) HIV stigma. Both factors were related to depression and adherence to antiretroviral therapy. Conclusion: The Spanish translation of the 10-item HIV stigma scale did not perform well due to problems in items 4, 5, and 6. Rather, a modified 7-item version had a good fit with a two-factor loading in which both HIV stigma factors correlated significantly with depression and HIV medication adherence.

Introducción: el estigma asociado al VIH atenta contra la salud de las personas que viven con VIH (PVV), así que reducirlo es esencial para erradicar el VIH/SIDA. Las escalas abreviadas para estigma pueden facilitar la ejecución de encuestas amplias sobre factores que afectan a las PVV. Este estudio examinó las propiedades psicométricas de una traducción al español de la escala de Berger de 10 ítems. Métodos: se reclutaron 105 PVV en una clínica de VIH en Cali, Colombia. La escala de Berger de 10 ítems se tradujo del inglés al español y después del español al inglés. La validez de constructo se evaluó con análisis factoriales (exploratorios/confirmatorios). La confiabilidad pre y postest (15 días) se estimó con el coeficiente de correlación intraclase (CCI). Resultados: el análisis factorial confirmó una solución de dos factores carente de tres ítems de pobre desempeño, resultando en una escala final de siete ítems, la cual tuvo un coeficiente alfa de Cronbach de 0,73 y un CCI de 0,83 (IC 95%: 0,75-0,89). Un factor cargó tres ítems relacionados con autoimagen negativa (estigma internalizado), y otros cuatro ítems relacionados con el estigma personalizado (estigma declarado/ejercido por terceros). Ambos factores estuvieron asociados a depresión y baja adherencia a tratamiento antirretroviral. Conclusión: la escala de 10 ítems en español para estigma asociado al VIH tuvo pobre desempeño por problemas con los ítems 4, 5 y 6. En cambio, una versión modificada de siete ítems tuvo mejor desempeño, cargando dos factores correlacionados significativamente con depresión y adherencia al tratamiento antirretroviral.

Resistencia a fármacos en pacientes en tratamiento antirretroviral, Cali, Colombia, 2008-2010 / HIV drug resistance in ART-experienced patients in Cali, Colombia, 2008-2010

Introducción. En Colombia se ha publicado poco sobre farmacorresistencia del VIH en pacientes que reciben tratamiento antirretroviral. Las guías de VIH de Colombia de 2006, no recomiendan el uso de los estudios de genotipo de resistencia en pacientes nunca expuestos a medicamentos antirretrovirales ni después del primer fracaso terapéutico. Objetivo. Determinar la frecuencia de mutaciones de resistencia y el grado de sensibilidad/resistencia del VIH a los antirretrovirales en pacientes que han recibido tratamiento antirretroviral. Materiales y métodos. Se reclutó una muestra no probabilística de 170 pacientes con infección por VIH que recibían tratamiento antirretroviral, experimentaban fracaso virológico y que tenían estudios de genotipo de resistencia. Se estudió la farmacorresistencia del VIH en dos grupos: estudios de genotipo de resistencia tempranos Vs . tardíos. Resultados. El tipo de resistencia más frecuente en pacientes bajo tratamiento antirretroviral, afectó a los inhibidores no nucleosídicos (76 %). El grupo de estudio tardío tuvo mayor riesgo de resistencia a inhibidores nucleosídicos y a los inhibidores de proteasa, mayor número de mutaciones de resistencia y mayor complejidad de las resistencias, que el grupo de estudio temprano. También, se encontró un alto grado (30 %) de resistencia cruzada a los inhibidores nucleosídicos en el grupo de estudio tardío. Los medicamentos menos afectados fueron tenofovir y darunavir. Conclusiones. Los resultados de este estudio sugieren que practicar estudios de genotipo de resistencia tardíos se asocia con altos niveles de resistencia, lo cual puede restringir el uso de un gran número de antirretrovirales esenciales en esquemas subsiguientes. Es necesario revisar las actuales recomendaciones sobre el uso de dichos exámenes en las guías colombianas de manejo de VIH.

Introduction: Little has been published in Colombia on HIV drug resistance in patients taking antiretroviral treatment (ART). Currently, the Colombian guidelines do not recommend the use of genotypic antiretroviral resistance tests (GART) for treatment-naive patients or for those experiencing a first therapeutic failure. Objective: To determine the frequency of relevant resistance mutations and the degree of susceptibility/ resistance of HIV to antiretroviral drugs (ARVs) in ART-experienced patients. Materials and methods: A non-random sample of 170 ART-experienced HIV patients with virologic failure and who underwent GART was recruited. A study of HIV drug resistance was carried out in two groups of patients: one group that underwent early GART and the other group that received late GART testing. Results: The most frequent type of resistance affected the non-nucleoside class (76%). The late-GART group had higher risk of nucleoside analog and protease inhibitor drug resistance, a higher number of resistance mutations and more complex mutational profiles than the early-GART group. A high cross resistance level (30%) was found in the nucleoside analog class. The least affected medications were tenofovir and darunavir. Conclusions: Our results suggest that performing GART late is associated with levels of ARV resistance that could restrict the use of an important number of essential ARV in subsequent regimens. There is a need to revise the current recommendations to include GART prior to start of treatment and after the first virologic failure.

Resistencia transmitida del virus de la inmunodeficiencia humana en pacientes sin exposición previa a tratamiento antirretroviral, Cali, Colombia, 2010 / Transmitted HIV Resistance in ART-Naïve Patients in Cali, Colombia, 2010

Introducción: En Colombia, existe poca información publicada sobre farmacorresistencia transmitida en el virus de inmunodeficiencia humana (VIH), y actualmente, las pruebas genotípicas de resistencia no son recomendadas por las guías colombianas para pacientes nunca expuestos ( naïve ) a terapia antirretroviral (TAR). Se condujo un estudio para determinar la frecuencia de resistencias transmitidas en pacientes naïve a TAR, quienes fueron atendidos en una clínica especializada en VIH/síndrome de inmunodeficiencia adquirida en Cali, Colombia. Metodología: Se realizó un estudio transversal en 152 pacientes adultos elegibles, con infección confirmada por VIH, naïve a TAR, con pruebas genotípicas de resistencia disponibles, y que accedieron a participar. El período de reclutamiento fue de 2008 a 2010. Las mutaciones de resistencias incluidas en el análisis fueron las definidas por la Organización Mundial de la Salud 2009 e International AIDS Society-USA 2010. Adicionalmente, se recolectó información sociodemográfica y condiciones relacionadas con el VIH. Resultados: La edad promedio fue 32 ± 10,2 años, 76% fueron hombres. La frecuencia de resistencia primaria fue de 6,6% (según la lista de Bennett-Organización Mundial de la Salud 2009), pero se encontró algún nivel de resistencia hasta en un 11,8% de los casos (al considerar mutaciones de la lista International AIDS Society-USA 2010). Las mutaciones más comunes fueron K103N/S (2%), F77L (2%) y M46L (2%). Mutaciones a los inhibidores no nucleosídicos de transcriptasa reversa fueron encontradas en 5,3%, mutaciones a los inhibidores no nucleosídicos de transcriptasa reversa en 3,9% y mutaciones a inhibidor de proteasa en 2% de las secuencias. El único factor relacionado con la resistencia primaria fue la duración de la infección por VIH. Conclusiones: La frecuencia de resistencia transmitida es similar a la encontrada en estudios previos en Colombia y en otros países con amplio uso de antirretrovirales, y está por encima del umbral sobre el cual sería costo-efectivo incluir el estudio genotípico de resistencias como test de rutina antes de la iniciación de la TAR, especialmente en pacientes con infección por VIH de menos de un año de duración.

Introduction: In Colombia, little has been published on HIV-transmitted drug resistance, and genotype resistance testing (GART) is not recommended for antiretroviral therapy (ART)-Naïve patients, according to Colombian HIV guidelines. We conducted a study to determine the frequency of HIV-transmitted drug resistance from a sample of ART-Naïve patients attending an HIV clinic in Cali, Colombia. Methodology: A cross-sectional study was carried out on 152 eligible adult patients with confirmed HIV infection who were ART-Naïve, had HIV GART results, and who agreed to participate. The recruitment period was from 2008 to 2010. Resistance mutations included in the analysis are those defined by the WHO- 2009 and IAS-USA, 2010. Additional data was collected, including socio-demographic characteristics and HIV-related conditions. Results: The mean age was 32 ±10.2 years; 76% were men. Frequency of transmitted drug resistance was 6.6%, but some level of resistance was found in up to 11.8% of total cases (if IAS-USA 2010 mutations were also included). The most common mutations were K103N/S (2%), F77L (2%) and M46L (2%). NNRTI mutations were found in 5.3%, NRTI mutations in 3.9% and PI mutations in 2% of the sequences. The only factor associated with primary resistance was the duration of HIV infection.

[HIV drug resistance in ART-experienced patients in Cali, Colombia, 2008-2010]. / Resistencia a fármacos en pacientes en tratamiento antirretroviral, Cali, Colombia, 2008-2010.

INTRODUCTION: Little has been published in Colombia on HIV drug resistance in patients taking antiretroviral treatment (ART). Currently, the Colombian guidelines do not recommend the use of genotypic antiretroviral resistance tests (GART) for treatment-naive patients or for those experiencing a first therapeutic failure. OBJECTIVE: To determine the frequency of relevant resistance mutations and the degree of susceptibility/ resistance of HIV to antiretroviral drugs (ARVs) in ART-experienced patients. MATERIALS AND METHODS: A non-random sample of 170 ART-experienced HIV patients with virologic failure and who underwent GART was recruited. A study of HIV drug resistance was carried out in two groups of patients: one group that underwent early GART and the other group that received late GART testing. RESULTS: The most frequent type of resistance affected the non-nucleoside class (76%). The late-GART group had higher risk of nucleoside analog and protease inhibitor drug resistance, a higher number of resistance mutations and more complex mutational profiles than the early-GART group. A high cross resistance level (30%) was found in the nucleoside analog class. The least affected medications were tenofovir and darunavir. CONCLUSIONS: Our results suggest that performing GART late is associated with levels of ARV resistance that could restrict the use of an important number of essential ARV in subsequent regimens. There is a need to revise the current recommendations to include GART prior to start of treatment and after the first virologic failure.

In vitro and structural evaluation of PL-100 as a potential second-generation HIV-1 protease inhibitor.

OBJECTIVES: HIV-1 protease inhibitors (PIs) are key components of HIV therapy. PL-100 is a novel lysine sulphonamide that demonstrates potent antiviral activity against multiresistant HIV-1 strains as well as a higher genetic barrier for development of resistance mutations compared with first-generation PIs. In the present study, we compared the antiviral activity of PL-100 against HIV-1 subtype B with that of darunavir. METHODS: We used tissue culture experiments to evaluate the in vitro development of resistance to PL-100 and tested the antiviral activity of several clinically approved PIs against PL-100-selected resistant variants. Structural modelling was also used to compare the binding of PL-100 and darunavir to the HIV-1 protease (PR) enzyme. RESULTS: PL-100-resistant variants that emerged within 8-48 weeks showed low- to high-level resistance (3.5- to 21.6-fold) to PL-100, but commonly retained susceptibility to darunavir, which, in contrast, did not select for resistance mutations over a period of 40 weeks. Structural modelling demonstrated that binding of PL-100 was predominantly based on polar interactions and delocalized hydrophobic interactions through its diphenyl groups, while darunavir has numerous interactions with PR that include hydrogen bonding to PR backbone oxygens at amino acid positions A28, D29 and D30 via di-tetrahydrofuran (di-THF) groups. CONCLUSIONS: Hydrogen-bonding contacts and the di-THF group in darunavir, as well as the hydrophobic nature of PL-100, contribute to PI binding and a high genetic barrier for resistance. Redesigning the structure of PL-100 to include a di-THF group might improve it.

The role of polymorphisms at position 89 in the HIV-1 protease gene in the development of drug resistance to HIV-1 protease inhibitors.

OBJECTIVES: Relatively little is known about the development of resistance to protease inhibitors (PIs) in non-B subtypes. In subtype B viruses, L89 is commonly found at position 89 in the HIV protease (PR) gene, whereas M89 is commonly observed as a polymorphism in other subtypes. We compared the frequencies of substitutions at position 89 in PR in tissue culture selections and in clinical databases of PI-naive and PI-experienced populations. METHODS: Representative subtype A/CRF01_AE (n = 2 and 3) and subtype C (n = 5) isolates were cultured in MT-2 cells and cord blood mononuclear cells (CBMCs), respectively, under increasing drug pressure with PIs, and drug resistance mutations were identified. RESULTS: The M89 natural polymorphism in non-B subtypes commonly led to the appearance of an M89T mutation in selections with atazanavir in subtypes A/AE and C, and was accompanied by other previously recognized atazanavir mutations. The M89T mutation contributed to phenotypic resistance to atazanavir and cross-resistance to lopinavir and nelfinavir, but not to other PIs. A shift from a L89 natural polymorphism to L89I/M arose in two of five subtype C selections with PIs. M89I/V/T mutations were acquired by 10%-11% of individuals harbouring non-B subtypes who were failing PI-based regimens, but were rarely observed in drug-naive persons and in patients failing non-PI-based regimens. CONCLUSIONS: The M/L89 natural polymorphism present in non-B subtypes may lead to the M89T mutational pathway conferring resistance to atazanavir, lopinavir and nelfinavir.

A template-dependent dislocation mechanism potentiates K65R reverse transcriptase mutation development in subtype C variants of HIV-1.

Numerous studies have suggested that the K65R reverse transcriptase (RT) mutation develops more readily in subtype C than subtype B HIV-1. We recently showed that this discrepancy lies partly in the subtype C template coding sequence that predisposes RT to pause at the site of K65R mutagenesis. However, the mechanism underlying this observation and the elevated rates of K65R development remained unknown. Here, we report that DNA synthesis performed with subtype C templates consistently produced more K65R-containing transcripts than subtype B templates, regardless of the subtype-origin of the RT enzymes employed. These findings confirm that the mechanism involved is template-specific and RT-independent. In addition, a pattern of DNA synthesis characteristic of site-specific primer/template slippage and dislocation was only observed with the subtype C sequence. Analysis of RNA secondary structure suggested that the latter was unlikely to impact on K65R development between subtypes and that Streisinger strand slippage during DNA synthesis at the homopolymeric nucleotide stretch of the subtype C K65 region might occur, resulting in misalignment of the primer and template. Consequently, slippage would lead to a deletion of the middle adenine of codon K65 and the production of a -1 frameshift mutation, which upon dislocation and realignment of the primer and template, would lead to development of the K65R mutation. These findings provide additional mechanistic evidence for the facilitated development of the K65R mutation in subtype C HIV-1.

Tissue culture drug resistance analysis of a novel HIV-1 protease inhibitor termed PL-100 in non-B HIV-1 subtypes.

PL-100 is a novel HIV-1 protease inhibitor (PI) that maintains activity against viruses that are resistant to other PIs. To further characterize this compound, we used it to select for drug resistance in tissue culture, using two non-B HIV-1 subtypes, viz. subtype C and a CRF01_AE recombinant virus. PL-100 selected for both minor and major PI resistance mutations along either of two distinct pathways. One of these involved the V82A and L90M resistance mutations while the other involved a mutation at position T80I, with other mutations being observed at positions M46I/L, I54M, K55R, L76F, P81S and I85V. The resistance patterns in both subtype C and CRF01_AE were similar and an accumulation of at least three mutations in the flap and active sites were required in each case for high-level resistance to occur, demonstrating that PL-100 has a high genetic barrier against the development of drug resistance.

Differences in resistance mutations among HIV-1 non-subtype B infections: a systematic review of evidence (1996-2008).

Ninety percent of HIV-1-infected people worldwide harbour non-subtype B variants of HIV-1. Yet knowledge of resistance mutations in non-B HIV-1 and their clinical relevance is limited. Although a few reviews, editorials and perspectives have been published alluding to this lack of data among non-B subtypes, no systematic review has been performed to date.With this in mind, we conducted a systematic review (1996-2008) of all published studies performed on the basis of non-subtype B HIV-1 infections treated with antiretroviral drugs that reported genotype resistance tests. Using an established search string, 50 studies were deemed relevant for this review.These studies reported genotyping data from non-B HIV-1 infections that had been treated with either reverse transcriptase inhibitors or protease inhibitors. While most major resistance mutations in subtype B were also found in non-B subtypes, a few novel mutations in non-B subtypes were recognized. The main differences are reflected in the discoveries that: (i) the non-nucleoside reverse transcriptase inhibitor resistance mutation, V106M, has been seen in subtype C and CRF01_AE, but not in subtype B, (ii) the protease inhibitor mutations L89I/V have been reported in C, F and G subtypes, but not in B, (iii) a nelfinavir selected non-D30N containing pathway predominated in CRF01_AE and CRF02_AG, while the emergence of D30N is favoured in subtypes B and D, (iv) studies on thymidine analog-treated subtype C infections from South Africa, Botswana and Malawi have reported a higher frequency of the K65R resistance mutation than that typically seen with subtype B.Additionally, some substitutions that seem to impact non-B viruses differentially are: reverse transcriptase mutations G196E, A98G/S, and V75M; and protease mutations M89I/V and I93L.Polymorphisms that were common in non-B subtypes and that may contribute to resistance tended to persist or become more frequent after drug exposure. Some, but not all, are recognized as minor resistance mutations in B subtypes. These observed differences in resistance pathways may impact cross-resistance and the selection of second-line regimens with protease inhibitors. Attention to newer drug combinations, as well as baseline genotyping of non-B isolates, in well-designed longitudinal studies with long duration of follow up are needed.

Sequencing of therapy to avoid resistance and the need for new antiretroviral drugs in the treatment of HIV disease.

HIV-1 drug regimens now offer more potent, less toxic and more durable choices. However, strategies addressing convenient sequential use of active antiretroviral combinations are rarely presented in the literature. Studies have seldom directly addressed this issue, despite it being a matter of daily use in clinical practice. This is, in part, because of the complexity of HIV-1 resistance information. Nevertheless, several principles can effectively assist the planning of antiretroviral drug sequencing. The introduction of tenofovir, abacavir and emtricitabine into current nucleoside backbone options, with each of them selecting for an individual pattern of resistance mutations, now permits sequencing in the context of previously popular thymidine analogs (zidovudine and stavudine). Similarly, newer ritonavir-boosted protease inhibitors could be potentially sequenced in a manner that uses the least cross-resistance prone PI at the start of therapy while leaving the most cross-resistance prone drugs for later, as long as there is rationale to employ such a compound because of its utility against commonly observed drug-resistant forms of the virus. The ability to sequence new therapies will be enhanced by availability of new antiretroviral drugs.

Effects of the K65R and K65R/M184V reverse transcriptase mutations in subtype C HIV on enzyme function and drug resistance.

BACKGROUND: We investigated the effects of mutations K65R and K65R plus M184V on enzymatic function and mechanisms of drug resistance in subtype C reverse transcriptase (RT). METHODS: Recombinant subtype C HIV-1 RTs containing K65R or K65R+M184V were purified from Escherichia coli. Enzyme activities and tenofovir (TFV) incorporation efficiency by wild-type (WT) and mutant RTs of both subtypes were determined in cell-free assays. Efficiency of (-) ssDNA synthesis and initiation by subtype C RTs was measured using gel-based assays with HIV-1 PBS RNA template and tRNA3Lys as primer. Single-cycle processivity was assayed under variable dNTP concentrations. Steady-state analysis was performed to measure the relative inhibitory capacity (ki/km) of TFV-disphosphate (TFV-DP). ATP-dependent excision and rescue of TFV-or ZDV-terminated DNA synthesis was monitored in time-course experiments. RESULTS: The efficiency of tRNA-primed (-)ssDNA synthesis by subtype C RTs was: WT > K65R > K65R+M184V RT. At low dNTP concentration, K65R RT exhibited lower activity in single-cycle processivity assays while the K65R+M184V mutant showed diminished processivity independent of dNTP concentration. ATP-mediated excision of TFV-or ZDV-terminated primer was decreased for K65R and for K65R+M184V RT compared to WT RT. K65R and K65R+M184V displayed 9.8-and 5-fold increases in IC50 for TFV-DP compared to WT RT. The Ki/Km of TFV was increased by 4.1-and 7.2-fold, respectively, for K65R and K65R+M184V compared to WT RT. CONCLUSION: The diminished initiation efficiency of K65R-containing RTs at low dNTP concentrations have been confirmed for subtype C as well as subtype B. Despite decreased excision, this decreased binding/incorporation results in diminished susceptibility of K65R and K65R+M184 RT to TFV-DP.

Role of genetic diversity amongst HIV-1 non-B subtypes in drug resistance: a systematic review of virologic and biochemical evidence.

The genetic diversity of HIV-1 has required its classification into types and subtypes. There is controversy as to how and to what extent genetic diversity may affect the emergence of antiretroviral drug resistance in HIV-1 subtypes other than B. To better understand the impact of genetic diversity (represented by different HIV-1 subtypes) on resistance to reverse transcriptase and protease inhibitor drugs, a systematic review was conducted on virologic and biochemical evidence obtained from work with non-B HIV-1 subtypes. We searched 11 databases and retrieved 3,486 citations on all aspects of non-B subtype-related resistance research. Twenty-seven studies with virologic and/or biochemical data met the eligibility criteria for our systematic review. Nineteen studies were found that reported phenotypes in non-B subtypes (304 from naive isolates and 242 from drug-exposed isolates) and 11 studies that used molecular biology techniques to study non-B resistance to antiretroviral drugs. Compared to the NL4-3 laboratory strain, lower baseline susceptibilities of recombinant A/G subtype virus to protease inhibitors were observed and a substantial proportion of subtype C isolates displayed higher IC50 at baseline for atazanavir. Some A/G isolates were found to have reduced susceptibility to abacavir. Mutations not typical of B subtypes include the reverse transcriptase mutation V106M and the protease mutations M89I/V and N83T. Virologic and biochemical data suggest that K65R is more likely to emerge in subtype C HIV-1. There is evidence to suggest differential effects of other mutations according to subtype, e.g. the protease inhibitor mutations I93L and M89I/V. Importantly, the most widely used commercial phenotyping systems do not take into account gag variations among natural isolates, which could limit the accuracy of measured susceptibility. Enzymatic and virologic data support the concept that naturally occurring polymorphisms in different non-B subtypes can affect the susceptibility of HIV-1 to different antiretroviral drugs, the magnitude of resistance conferred by major mutations, and the propensity to acquire some resistance mutations. Tools may need to be optimized to accurately measure drug susceptibility of non-B subtypes, especially for protease inhibitors.

Benefits of an educational program for journalists on media coverage of HIV/AIDS in developing countries.

OBJECTIVE: a) To assess the suitability of the curriculum content and didactical quality of information delivered to educate journalists in the J2J program in HIV/AIDS (process evaluation) and b) to explore the effects of such programs on journalists' reporting of HIV/AIDS related information (outcome evaluation). DESIGN: Descriptive study. METHODS: For the process evaluation, each J2J program curriculum was evaluated for accuracy and pertinence by individuals with high familiarity with HIV/AIDS research. For the outcome evaluation, a survey of J2J attendees and evaluations of the program lectures by attendees were performed in chronological order to determine their perception on usefulness of the program. RESULTS: Overall, the J2J curriculum is successful in providing journalists with a clear understanding of the current HIV/AIDS medical research objectives and issues with most journalists reporting an increased ability to better investigate and disseminate accurate information on this subject. Furthermore, the journalists surveyed reported positive community responses directly as a result of the J2J training. CONCLUSION: The J2J program helps to increase global awareness of pertinent HIV/AIDS concepts. Through this professional development strategy, journalists from around the world may help to amplify efforts to prevent new HIV infections and quench the dissemination of inaccurate information and folklore.

Antiretroviral therapy : optimal sequencing of therapy to avoid resistance.

In the second decade of highly active antiretroviral therapy, drug regimens offer more potent, less toxic and more durable choices. However, strategies addressing convenient sequential use of active antiretroviral combinations are rarely presented in the literature. Studies have seldom directly addressed this issue, despite it being a matter of daily use in clinical practice. This is, in part, because of the complexity of HIV-1 resistance information as well as the complexity of designing these types of studies. Nevertheless, several principles can effectively assist the planning of antiretroviral drug sequencing. The introduction of tenofovir disoproxil fumarate, abacavir and emtricitabine into current nucleoside backbone options, with each of them selecting for an individual pattern of resistance mutations, now permits sequencing in the context of previously popular thymidine analogues (zidovudine and stavudine). Similarly, newer ritonavir-boosted protease inhibitors could potentially be sequenced in a manner that uses the least cross-resistance prone protease inhibitor at the start of therapy, while leaving the most cross-resistance prone drugs for later, as long as there is rationale to employ such a compound because of its utility against commonly observed drug-resistant forms of HIV-1.

Protease inhibitor resistance in HIV-infected patients: molecular and clinical perspectives.

The problem of HIV-1 drug resistance has established a need for new compounds that retain activity against mutated resistant viral isolates. Fortunately, a number of new compounds have recently been developed that possess excellent activity against HIV-1 strains that contain as many as eight relevant drug-resistance mutations in the viral protease (PR) gene. These newer protease inhibitors (PI) are characterized by higher genetic barrier for drug resistance, meaning that higher numbers of mutations are required for resistance to develop in comparison with older members of the PI family of drugs. Thus, different PIs can be used sequentially in HIV therapy in a manner that can overcome previous drug resistance and potentially forestall the development of additional resistance mutations in the viral PR. All currently used PIs, in general, require ritonavir to be used as a pharmacological boosting agent. There is a need to develop novel PIs, that will not require such boosting, and that are also characterized by potent antiviral activity and a high genetic barrier for resistance.