RESUMEN
The nucleos(t)ide analogs require phosphorylation to the pharmacologically active anabolites in cells. We investigated the hypothesis that single-nucleotide polymorphisms (SNPs) in genes that encode transporters and phosphodiesterase (PDE) enzymes involved in tenofovir (TFV), disoproxil fumarate (TDF), and lamivudine (3TC) disposition will be associated with concentrations of their phosphate anabolites and virologic response. Individuals with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) coinfection receiving TDF/3TC-containing antiretroviral therapy were enrolled. Steady-state TFV diphosphate (TFV-DP) and 3TC triphosphate (3TC-TP) concentrations in peripheral blood mononuclear cells (PBMCs) and dried blood spot samples were quantified. The relationship between genetic variants and TFV-DP and 3TC-TP concentrations as well as with virologic response were examined using multivariable linear regression. Of the 136 participants (median age 43 years; 63% females), 6.6% had HBV non-suppression, and 7.4% had HIV non-suppression. The multidrug resistance protein 2 (encoded by ABCC2 rs2273697) SNP was associated with 3TC-TP concentrations in PBMCs. The human organic anion transporter-1 (encoded by SLC28A2) rs11854484 SNP was associated with HIV non-suppression, and when evaluated together with SNPs with marginal associations (ABCC2 rs717620 and PDE1C rs30561), participants with two or three variants compared to those with none of these variants had an adjusted odds ratio of 48.3 (confidence interval, 4.3-547.8) for HIV non-suppression. None of the SNPs were associated with HBV non-suppression. Our study identified ABCC2 SNP to be associated with 3TC-TP concentrations in PBMCs. Also, a combination of genetic variants of drug transporters and PDE was associated with HIV non-suppression.
Asunto(s)
Fármacos Anti-VIH , Coinfección , Infecciones por VIH , Lamivudine , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos , Polimorfismo de Nucleótido Simple , Tenofovir , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , Femenino , Masculino , Adulto , Lamivudine/uso terapéutico , Polimorfismo de Nucleótido Simple/genética , Tenofovir/uso terapéutico , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/farmacocinética , Persona de Mediana Edad , Coinfección/tratamiento farmacológico , Coinfección/genética , Leucocitos Mononucleares/metabolismo , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/efectos de los fármacos , Organofosfatos/uso terapéutico , Organofosfatos/farmacocinética , Hepatitis B/tratamiento farmacológico , Hepatitis B/genética , Adenina/análogos & derivados , Adenina/uso terapéutico , Adenina/farmacocinética , Polifosfatos/metabolismo , Farmacogenética/métodosRESUMEN
OBJECTIVE: Concentrations of tenofovir diphosphate (TFV-DP) and lamivudine triphosphate (3TC-TP) in cells are correlates of medication adherence and antiviral activity. However, studies have yet to characterize the simultaneous relationship between TFV-DP and 3TC-TP concentrations with HIV and hepatitis B virus (HBV) suppression. METHODS: Individuals with HIV/HBV coinfection on tenofovir disoproxil fumarate (TDF)-containing antiretroviral therapy (ART) were enrolled. Peripheral blood mononuclear cells (PBMCs) and dried blood spots (DBS) samples were collected and steady-state TFV-DP and 3TC-TP concentrations quantified using validated methods. The relationship between patient factors, TFV-DP, and 3TC-TP concentrations in PBMCs and DBS with HBV and HIV viral suppression were examined. RESULTS: Of 138 participants on TDF-containing ART for a median duration (range) of 6 (0.75-15) years, the median age was 43âyears and 64% were women. Overall, 128 (92.8%) and 129 (93.5%) had suppressed HIV and HBV viral loads, respectively. Of the 128 participants with suppressed HIV, 122 (95.3%) had suppressed HBV. Self-reported ART adherence, recent change to dolutegravir-based ART, TFV-DP, and 3TC-TP concentrations in PBMCs and DBS were associated with HIV RNA suppression, while HBe antigen positivity, HIV suppression, and TFV-DP concentrations in DBS were associated with HBV DNA suppression (including six persons with HBV nonsuppression and HIV suppression). CONCLUSION: Long-term TDF/3TC-conatining ART was highly efficacious in individuals with HIV/HBV coinfection. Higher TFV-DP concentrations were predictive of suppression for both viruses. Persistent HBV viremia on TDF/3TC-containg ART requires additional research, but may represent poor adherence and the need for adherence interventions or novel antivirals.
Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH , Coinfección , Citidina Trifosfato/análogos & derivados , Didesoxinucleótidos , Infecciones por VIH , Organofosfatos , Humanos , Femenino , Adulto , Masculino , Virus de la Hepatitis B , Fármacos Anti-VIH/uso terapéutico , Leucocitos Mononucleares , Coinfección/tratamiento farmacológico , Lamivudine/uso terapéutico , Tenofovir/uso terapéutico , Viremia/tratamiento farmacológicoRESUMEN
OBJECTIVES: Though antiretroviral therapy (ART) has reduced HIV infection into a manageable chronic disease, it does not provide for a cure. HIV cure trials may carry risks for patients who are generally doing well on ART, making it imperative that their input is sought as various types of cure methods and trials are designed. Few studies have sought the views of African patients on HIV cure studies. The objective of this study was to determine the views and preferences of people living with HIV (PLWH) in Ghana on cure research. METHODS: We used a questionnaire to interview 251 PLWH in Ghana about their willingness to engage in HIV cure research. We investigated their motivations, the types of cure they would prefer and which risks were acceptable to them. RESULTS: Most participants were enthusiastic about participating in cure research and driven by both altruistic and personal motives. Patients preferred a cure where they would continue follow-up with their doctor (88%) compared to being assured that they have been completely cured and did not need further follow-up (11%). The vast majority of the respondents were risk averse. Most patients (67%) would decline to interrupt ART as part of a protocol for HIV cure research. In bivariate analysis, participants above the age of 40 years were more likely to agree to treatment interruption during cure studies (OR 2.77; 95% CI 1.21-.6.34. p â= â0.0159). CONCLUSIONS: Our results show that preferred cure modalities and risk tolerance for patients in Africa may be different from those of other parts of the world. Extensive social science and behavioural studies are needed on the continent to help inform future cure trials.
RESUMEN
Hepatitis B virus (HBV) exhibits a high degree of heterogeneity with at least 10 genotypes (A-J) identified to date. Intergenotypic recombination is relatively common. Previously, we investigated HBV drug resistance in HIV/HBV co-infected individuals in Ghana. After identifying multiple circulating genotypes and a novel D/E recombinant, we sought to determine if additional individuals were also infected with recombinant HBV. Partial genome sequences from three individuals were initially identified as genotype A4. Full-length HBV genomes were obtained using rolling circle amplification followed by PCR and shown to cluster with known A/E recombinant viruses. Similar recombination breakpoints were observed in these three individuals suggesting local spread of this novel recombinant HBV in Ghana.
Asunto(s)
Genotipo , Virus de la Hepatitis B/clasificación , Virus de la Hepatitis B/genética , Hepatitis B/virología , Recombinación Genética , Adulto , Análisis por Conglomerados , Femenino , Ghana , Virus de la Hepatitis B/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Filogenia , Secuenciación Completa del GenomaRESUMEN
BACKGROUND: Incomplete hepatitis B virus (HBV) suppression during antiretroviral therapy (ART) in HIV and HBV coinfected patients is common, but underlying factors are not fully elucidated. We hypothesize that genetic factors that influence nucleoside analog pharmacokinetics will affect HBV treatment response. METHODS: HIV/HBV coinfected patients on tenofovir disoproxil fumarate/lamivudine (TDF/3TC)-containing ART were enrolled. Selected ABCC4 single nucleotide polymorphisms (SNPs) with known effects on nucleoside pharmacokinetics were genotyped using TaqMan assays. Relationship between ABCC4 SNPs and unsuppressed HBV DNA (HBV DNA ≥20 IU/mL) were examined. RESULTS: Of the 50 participants on TDF/3TC-containing ART for a median (range) of 1.5 (1-7.4) years, 20 (40%) had unsuppressed HBV DNA. Participants with unsuppressed compared with those with suppressed HBV DNA were more likely to have negative HBe antibody, lower body mass index, and lower CD4 count at enrollment. Carriers of ABCC4 rs11568695 (G3724A) variant allele were more likely than noncarriers to have unsuppressed HBV (61.1% vs. 29.0%, P = 0.038). Among 36 patients with suppressed HIV RNA (presumed good ART adherence), ABCC4 rs11568695 variant carriers were more likely than noncarriers to have unsuppressed HBV (58.8% vs. 20.0% P = 0.021). Logistic regression analysis that included genetic and nongenetic factors identified ABCC4 rs11568695 variant allele, body mass index, and male sex as predictors of unsuppressed HBV DNA. CONCLUSIONS: We identified a novel association between ABCC4 rs11568695 SNP and poor HBV treatment response. If confirmed in further studies, ABCC4 genotyping could be used to identify individuals who may need intensified HBV therapy.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Coinfección/tratamiento farmacológico , Infecciones por VIH/tratamiento farmacológico , Hepatitis B/tratamiento farmacológico , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Polimorfismo de Nucleótido Simple , Tenofovir/uso terapéutico , Adulto , ADN Viral/análisis , Femenino , Infecciones por VIH/virología , Hepatitis B/virología , Virus de la Hepatitis B/efectos de los fármacos , Humanos , Modelos Logísticos , Masculino , Persona de Mediana EdadRESUMEN
Human pegivirus (HPgV) is a positive single-stranded RNA virus in the Flaviviridae family. Phylogenetic analysis reveals the presence of multiple HPgV genotypes with distinct geographic locations. HPgV is of interest because of its potential beneficial impact on HIV disease progression. Despite this, the effects of HPgV in the context of other viral infections, such as hepatitis B virus (HBV), are poorly understood, and data from resource-limited settings are scarce. Therefore, we conducted a cross-sectional analysis of HPgV in HIV/HBV co-infected patients in Ghana. Sera from 100 HIV/HBV co-infected individuals were evaluated for HPgV RNA, and the genotype determined by sequencing the 5' untranslated region. HPgV RNA was detected in 27 samples (27%). Of these, 26 were genotyped successfully with 23 belonging to HPgV genotype 1 and 3 belonging to HPgV genotype 2. The presence of HPgV RNA had no statistically significant impact on CD4 cell count or HBV DNA titers in the HIV/HBV co-infected patients. However, there was a trend towards decreased HBV DNA levels in HPgV RNA-positive patients with CD4 cell count < 200 (p = 0.0626). HPgV co-infection is common in Ghana. The effect of HPgV on HIV or HBV disease among HIV/HBV co-infected patients was minimal. However, decreased HBV DNA levels in HPgV RNA-positive patients with low CD4 cell counts highlight the need for prospective studies of HPgV in HIV and hepatitis co-infected patients, especially in those with advanced HIV disease, to study further the effects of HPgV on liver disease.
Asunto(s)
Coinfección/epidemiología , Infecciones por Flaviviridae/complicaciones , Virus GB-C , Infecciones por VIH/complicaciones , Hepatitis B/complicaciones , Hepatitis Viral Humana/complicaciones , Adulto , Coinfección/virología , Femenino , Infecciones por Flaviviridae/epidemiología , Ghana/epidemiología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
INTRODUCTION: This study sought to identify common causes of death as well as the factors associated with the high inpatient mortality rate of HIV-infected patients at the Korle-Bu Teaching Hospital (KBTH). METHODS: The retrospective study reviewed the medical records of 547 HIV-infected adults aged 18 years or older admitted to the KBTH between the months of January 2012 and October 2013. Using standardized abstraction forms, clinical and demographic data of eligible patients was collected. Data was summarized using descriptive statistics. Demographic and clinical characteristics of patients who died within 7 days (early) and after (late) admission were compared using Rank Sum tests or Chi-square tests. RESULTS: Of 547 eligible patients during the period, 222 (40.6%) died during hospitalization, with 124 (55.9%) of them dying within a week of admission. Of the 222 patients who died, 190 (85.6%) were previously known HIV-positive. Yet, 141 (63.5%) of the 222 patients who died had no prior highly active antiretroviral therapy (HAART). The most common admitting diagnoses were anemia (34.2%), cerebral toxoplasmosis (29.3%), and pneumonia (25.7%); the most common causes of death were tuberculosis (34.7%), anemia (30.2%) and cerebral toxoplasmosis (27.5%). Tuberculosis was the only factor significantly associated with early death (P<0.05). CONCLUSION: The inpatient mortality rate among HIV-infected adults admitted to the KBTH is high. A majority of the patients were not receiving HAART despite known HIV diagnosis. Earlier initiation of HAART may lower the risk of opportunistic infections and HIV mortality rates. Additionally, a high index of suspicion and initiation of empiric treatment for TB may reduce early deaths.
Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Causas de Muerte , Infecciones por VIH/mortalidad , Mortalidad Hospitalaria , Infecciones Oportunistas Relacionadas con el SIDA/epidemiología , Adolescente , Adulto , Terapia Antirretroviral Altamente Activa/métodos , Femenino , Ghana/epidemiología , Infecciones por VIH/tratamiento farmacológico , Hospitalización , Hospitales de Enseñanza , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Tiempo , Adulto JovenRESUMEN
Globally, there are approximately 240 million people chronically infected with hepatitis B virus (HBV)-a major cause of hepatocellular carcinoma. Ten different HBV genotypes (A-J) have been identified with distinct geographic distributions. Novel variants generated by recombination between different HBV genotypes have been documented worldwide and represent an important element of genetic variability with possible clinical implications. Here, the complete genome sequence of an HBV genotype D/E recombinant from Ghana is reported. The full-length sequence was obtained using rolling circle amplification followed by PCR and sequenced using next-generation sequencing (NGS). A consensus sequence was extracted from the NGS data and underwent phylogenetic analysis to determine genotype, as well as the recombination pattern. Subsequently, the sequence was compared to recombinants described previously in Africa. Based on MCMC phylogenetic analysis, SimPlot recombination analyses, and intragroup genetic distance, the isolate 007N full-length genome is unique compared to other reported D/E recombinants in Africa.
Asunto(s)
Virus de la Hepatitis B/genética , Hepatitis B/virología , Recombinación Genética , África , Genoma Viral , Genotipo , Virus de la Hepatitis B/clasificación , Virus de la Hepatitis B/aislamiento & purificación , Humanos , FilogeniaRESUMEN
BACKGROUND: The presence of HBV resistance mutations upon initiation or during antiretroviral therapy (ART) in HIV-coinfected patients is an important determinant of treatment response. The main objective of the study was to determine the prevalence of HBV resistance mutations in antiretroviral treatment-naive and treatment-experienced HBV-HIV-coinfected Ghanaian patients with detectable HBV viraemia. METHODS: HBV-HIV-coinfected patients who were ART-naive or had received at least 9 months of lamivudine (3TC)-containing ART were enrolled in a cross-sectional study. Demographic and clinical data were collected and HBV DNA quantified. Partial HBV sequences were amplified by PCR and sequenced bi-directionally to obtain a 2.1-2.2 kb fragment for phylogenetic analysis of HBV genotypes and evaluation of drug resistance mutations. RESULTS: Of the 100 HBV-HIV-coinfected study patients, 75 were successfully PCR-amplified, and 63 were successfully sequenced. Of these 63 patients, 27 (42.9%) were ART-experienced and 58 (92.1%) had HBV genotype E. No resistance mutations were observed in the 36 ART-naive patients, while 21 (77.8%) of 27 treatment-experienced patients had resistance mutations. All patients with resistance mutations had no tenofovir in their regimens, and 80% of them had HIV RNA <40 copies/ml. The 3TC resistance mutations rtL180M and rtM204V were observed in 10 (47.6%) of the 21 patients, while 5 patients (23.8%) had rtV173L, rtL180M and rtM204V mutations. CONCLUSIONS: A high proportion of HBV-HIV-coinfected patients with detectable viraemia on 3TC-containing ART had resistance mutations despite good ART adherence as determined by HIV RNA suppression. This study emphasizes the need for dual therapy as part of a fully suppressive ART in all HBV-HIV-coinfected patients in Ghana.
Asunto(s)
Coinfección/tratamiento farmacológico , Coinfección/virología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Virus de la Hepatitis B/genética , Hepatitis B/tratamiento farmacológico , Hepatitis B/virología , Fármacos Anti-VIH/uso terapéutico , Antivirales/uso terapéutico , Estudios Transversales , ADN Viral/sangre , ADN Viral/genética , Farmacorresistencia Viral/genética , Genotipo , Ghana , Infecciones por VIH/complicaciones , Hepatitis B/complicaciones , Virus de la Hepatitis B/efectos de los fármacos , Humanos , Lamivudine/uso terapéutico , Mutación , Carga ViralRESUMEN
BACKGROUND: The global burden of Hepatitis B virus (HBV) and HIV co-infection is enormous. The risk of developing cirrhosis and hepatocellular cancer is associated with HBV DNA levels. The main objective of the study was to determine proportion of Hepatitis B viremia in ART-naïve and ART-experienced co-infected Ghanaian patients and factors associated with HBV viremia after at least 36 weeks of lamivudine with or without tenofovir containing ART. METHODS: Hepatitis B and HIV co-infected patients who were ART-naïve or had received at least 9 months of lamivudine-containing ART were enrolled in a cross-sectional study at Korle-Bu Teaching Hospital. Demographic and clinical data were collected and samples obtained for Hepatitis B serology, liver function tests and HBV DNA. Factors associated with viremia were determined using univariate and multivariate logistic regression analysis. RESULTS: Of 3108 HIV-infected patients screened, 257 (8.3%) were HBsAg-positive, of which 235 enrolled. Overall, 152 (64.7%) were ART-experienced and 83 (35.3%) were ART-naïve. Eighty-nine-percent of ART-naïve and 42.1% of ART-experienced patients had HBV DNA > 20 IU/mL. In multivariate analysis of all patients, being ART-naïve (OR 10.1, 95% CI 4.6-21.9) and elevated ALT (OR 3.7, 95% CI 1.8-7.9) were associated with Hepatitis B viremia. In treatment experienced patients, elevated ALT (OR 4.8 CI 2.0-12.1) and male sex (OR 2.1, 95% CI 1.0-4.2) were associated with Hepatitis B viremia. CONCLUSIONS: Majority of ART-naïve (89%) and 42% of ART-experienced patients had detectable hepatitis B viremia > 20 IU/mL. An abnormal serum ALT was significantly associated with hepatitis B viremia in HBV and HIV co-infected patients irrespective of treatment status. Baseline and on-treatment ALT may be a useful non-invasive predictor of Hepatitis B viremia in resource-constrained countries in sub-Saharan Africa where infection is endemic and viral load tests are not widely available.
Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Antivirales/administración & dosificación , Coinfección/tratamiento farmacológico , Infecciones por VIH/tratamiento farmacológico , Hepatitis B/tratamiento farmacológico , Viremia/tratamiento farmacológico , Adolescente , Adulto , Coinfección/epidemiología , Coinfección/virología , Estudios Transversales , Femenino , Ghana/epidemiología , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/fisiología , Hepatitis B/epidemiología , Hepatitis B/virología , Virus de la Hepatitis B/efectos de los fármacos , Virus de la Hepatitis B/fisiología , Humanos , Lamivudine/administración & dosificación , Masculino , Persona de Mediana Edad , Tenofovir/administración & dosificación , Carga Viral , Viremia/epidemiología , Viremia/virología , Adulto JovenRESUMEN
BACKGROUND: In Ghana it is estimated that 1.2% of HIV infections occur in young people aged 15-24 but the representation in our clinics is small. Adherence to treatment, appointment keeping and knowledge of HIV status remains a challenge. Disclosure has been shown to result in better adherence to therapy, good clinical outcomes, psychological adjustment and reduction in the risk of HIV transmission when the young person becomes sexually active. A baseline study was conducted to ascertain if adolescents and young adults knew their HIV status and their knowledge on HIV. Informed consent and assent were obtained from willing participants. Self-administered questionnaires on general knowledge of HIV, HIV treatment and disclosure were collected and analyzed. RESULTS: Thirty-four young persons participated in the study. The mean age was 16.9±SD 2.5 and 62% (21/32) were female. All of them were still in school. Eighty-five percent were aware that young people their age could fall sick, 91% had heard of HIV, 70% knew someone with HIV and 45% thought that adolescents were not at risk of HIV. On modes of HIV transmission, 66.7% knew HIV was transmitted through sex and 63.6% knew about mother to child transmission. Fifty three percent (18/34) knew their HIV status, 50% (17/34) were on antiretroviral and 35% (6/17) of them admitted to missing ARV doses. One person who said he was HIV negative and another who did not know his status were both on ARVs. CONCLUSION: Disclosure of HIV status to adolescents and young people is dependent on a complex mix of factors and most practitioners recommend an age and developmentally appropriate disclosure. Thus it is highly individualized. The knowledge and awareness of HIV was 91% compared to 97% of adults in the most recent Ghana Demographic and Health Survey however only about two thirds had acceptable in depth knowledge on HIV. Only half knew their HIV status which was not the best considering their ages. There is the need to strengthen education to young persons with HIV, support adhere to ARVs for better outcomes and assist care givers to disclose HIV status to them.