RESUMO
Access to Hepatis C treatment in Sub-Saharan Africa is a clinical, public health and ethical concern. The multi-country open-label trial TAC ANRS 12311 allowed assessing the feasibility, safety, efficacy of a specific care model of HCV treatment and retreatment in patients with hepatitis C in Sub Saharan Africa. Between November 2015 and March 2017, with follow-up until mid 2019, treatment-naïve patients with HCV without decompensated cirrhosis or liver cancer were recruited to receive 12 week-treatment with either sofosbuvir + ribavirin (HCV genotype 2) or sofosbuvir + ledipasvir (genotype 1 or 4) and retreatment with sofosbuvir + velpatasvir + voxilaprevir in case of virological failure. The primary outcome was sustained virological response at 12 weeks after end of treatment (SVR12). Secondary outcomes included treatment adherence, safety and SVR12 in patients who were retreated due to non-response to first-line treatment. The model of care relied on both viral load assessment and educational sessions to increase patient awareness, adherence and health literacy. The study recruited 120 participants, 36 HIV-co-infected, and 14 cirrhotic. Only one patient discontinued treatment because of return to home country. Neither death nor severe adverse event occurred. SVR12 was reached in 107 patients (89%): (90%) in genotype 1 or 2, and 88% in GT-4. All retreated patients (n = 13) reached SVR12. HCV treatment is highly acceptable, safe and effective under this model of care. Implementation research is now needed to scale up point-of-care HCV testing and SVR assessment, along with community involvement in patient education, to achieve HCV elimination in Sub-Saharan Africa.
Assuntos
Antivirais , Hepacivirus , Sofosbuvir , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , África Central , África Ocidental , Ácidos Aminoisobutíricos , Antivirais/uso terapêutico , Antivirais/efeitos adversos , Benzimidazóis/uso terapêutico , Benzimidazóis/efeitos adversos , Benzopiranos , Carbamatos/uso terapêutico , Ciclopropanos/uso terapêutico , Ciclopropanos/efeitos adversos , Quimioterapia Combinada , Estudos de Viabilidade , Fluorenos/uso terapêutico , Fluorenos/efeitos adversos , Genótipo , Hepacivirus/genética , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Prolina/análogos & derivados , Prolina/uso terapêutico , Quinoxalinas , Ribavirina/uso terapêutico , Ribavirina/efeitos adversos , Sofosbuvir/uso terapêutico , Sofosbuvir/efeitos adversos , Sulfonamidas/uso terapêutico , Sulfonamidas/efeitos adversos , Resposta Viral Sustentada , Resultado do TratamentoRESUMO
BACKGROUND: Due to the low number of individuals with HIV-2, no randomised trials of HIV-2 treatment have ever been done. We hypothesised that a non-comparative study describing the outcomes of several antiretroviral therapy (ART) regimens in parallel groups would improve understanding of how differences between HIV-1 and HIV-2 might lead to different therapeutic approaches. METHODS: This pilot, phase 2, non-comparative, open-label, randomised controlled trial was done in Burkina Faso, Côte d'Ivoire, Senegal, and Togo. Adults with HIV-2 who were ART naive with CD4 counts of 200 cells per µL or greater were randomly assigned 1:1:1 to one of three treatment groups. A computer-generated sequentially numbered block randomisation list stratified by country was used for online allocation to the next available treatment group. In all groups, tenofovir disoproxil fumarate (henceforth tenofovir) was dosed at 245 mg once daily with either emtricitabine at 200 mg once daily or lamivudine at 300 mg once daily. The triple nucleoside reverse transcriptase inhibitor (NRTI) group received zidovudine at 250 mg twice daily. The ritonavir-boosted lopinavir group received lopinavir at 400 mg twice daily boosted with ritonavir at 100 mg twice daily. The raltegravir group received raltegravir at 400 mg twice daily. The primary outcome was the rate of treatment success at week 96, defined as an absence of serious morbidity event during follow-up, plasma HIV-2 RNA less than 50 copies per mL at week 96, and a substantial increase in CD4 cells between baseline and week 96. This trial is registered at ClinicalTrials.gov, NCT02150993, and is closed to new participants. FINDINGS: Between Jan 26, 2016, and June 29, 2017, 210 participants were randomly assigned to treatment groups. Five participants died during the 96 weeks of follow-up (triple NRTI group, n=2; ritonavir-boosted lopinavir group, n=2; and raltegravir group, n=1), eight had a serious morbidity event (triple NRTI group, n=4; ritonavir-boosted lopinavir group, n=3; and raltegravir group, n=1), 17 had plasma HIV-2 RNA of 50 copies per mL or greater at least once (triple NRTI group, n=11; ritonavir-boosted lopinavir group, n=4; and raltegravir group, n=2), 32 (all in the triple NRTI group) switched to another ART regimen, and 18 permanently discontinued ART (triple NRTI group, n=5; ritonavir-boosted lopinavir group, n=7; and raltegravir group, n=6). The Data Safety Monitoring Board recommended premature termination of the triple NRTI regimen for safety reasons. The overall treatment success rate was 57% (95% CI 47-66) in the ritonavir-boosted lopinavir group and 59% (49-68) in the raltegravir group. INTERPRETATION: The raltegravir and ritonavir-boosted lopinavir regimens were efficient and safe in adults with HIV-2. Both regimens could be compared in future phase 3 trials. The results of this pilot study suggest a trend towards better virological and immunological efficacy in the raltegravir-based regimen. FUNDING: ANRS MIE.
Assuntos
Fármacos Anti-HIV , Emtricitabina , Infecções por HIV , HIV-2 , Ritonavir , Tenofovir , Humanos , Infecções por HIV/tratamento farmacológico , Adulto , Masculino , Feminino , HIV-2/efeitos dos fármacos , Tenofovir/uso terapêutico , Tenofovir/efeitos adversos , Projetos Piloto , Contagem de Linfócito CD4 , Emtricitabina/uso terapêutico , Emtricitabina/administração & dosagem , Emtricitabina/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/administração & dosagem , Resultado do Tratamento , Ritonavir/uso terapêutico , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos , Lopinavir/uso terapêutico , Lopinavir/efeitos adversos , Lopinavir/administração & dosagem , Raltegravir Potássico/uso terapêutico , Raltegravir Potássico/efeitos adversos , Raltegravir Potássico/administração & dosagem , Lamivudina/uso terapêutico , Lamivudina/administração & dosagem , Lamivudina/efeitos adversos , Carga Viral/efeitos dos fármacos , Terapia Antirretroviral de Alta Atividade , Pessoa de Meia-Idade , Zidovudina/uso terapêutico , Zidovudina/efeitos adversos , Zidovudina/administração & dosagem , Quimioterapia Combinada , HIV-1/efeitos dos fármacosRESUMO
OBJECTIVES: Widespread testing and treatment are essential to eliminate hepatitis B virus (HBV) infection as a public health concern. However, in resource-limited countries, access to HBV PCR is limited. In this study, we developed a quantitative HBV PCR assay on open molecular platforms and evaluate its performance in diagnosing clinically significant HBV DNA thresholds as defined by the WHO (2000 IU/mL, 20 000 IU/mL, and 200 000 IU/mL). METHODS: We implemented our HBV PCR test in seven African and Asian countries and France, using either an in-house laboratory method or a European conformity for in vitro diagnostic (CE-IVD) marked version of the PCR (Generic HBV Charge Virale, Biocentric). Results were compared with reference tests (Roche Cobas AmpliPrep/Cobas TaqMan and Abbott RealTime on Abbott m2000). RESULTS: There was a good agreement between the HBV DNA results of 1015 samples tested by the PCR on open polyvalent platforms and the results from reference tests (mean difference (bias ± standard deviation [SD]): -0.3 ± 0.7 log10 IU/mL and -0.2 ± 0.9 log10 IU/mL when compared with Roche and Abbott tests, respectively). Kappa-Cohen agreements between the HBV PCR on open polyvalent platforms and the Roche/Abbott assays appeared almost perfect for HBV DNA levels ranged from >20 000 to 200 000 IU/mL and >200 000 IU/mL, substantial and moderate for HBV DNA levels ranged from 2000 to 20 000 IU/mL when compared with Abbott and Roche, respectively. The assay's performance was consistent across genotypes A, B, C, D, and E. DISCUSSION: This field evaluation showed that our HBV PCR test is a valuable alternative to proprietary PCR systems. PCR assays on open platforms contribute to expanding clinical laboratory solutions for diagnosing individuals who meet the viral load criteria for antiviral therapy (>20 000 IU/mL) and mother-to-child prophylaxis (>200 000 IU/mL).
Assuntos
DNA Viral , Vírus da Hepatite B , Hepatite B , Humanos , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , DNA Viral/genética , África , Hepatite B/diagnóstico , Hepatite B/virologia , Ásia , Sensibilidade e Especificidade , Técnicas de Diagnóstico Molecular/métodos , Feminino , Carga Viral/métodos , Masculino , Reação em Cadeia da Polimerase/métodos , Adulto , Reação em Cadeia da Polimerase em Tempo Real/métodos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Data on HIV-1 controllers in Africa are scarce. We report the proportion of HIV-1 controllers in a group of adults prospectively monitored with frequent viral load measurements as part of a clinical trial in West Africa. METHODS: For the Temprano trial, antiretroviral therapy (ART)-naive HIV-1 infected adults with no criteria for starting ART were randomized to start ART immediately or defer ART until the WHO starting criteria were met. Plasma viral load was measured every 6 months. The trial follow-up was 30âmonths. We considered all Temprano participants randomized to defer ART. Patients with all semestrial viral <2000âcopies/ml and still off ART at month 30 were defined as HIV-1 controllers. Controllers with all viral loads <50âcopies/ml were defined as elite controllers, the rest as viremic controllers. RESULTS: Of the 1023 HIV-1-infected adults randomized in the Temprano deferred-ART group, 18 (1.8%) met the criteria for classification as HIV controllers, of whom seven (0.7%) were elite controllers and 11 (1.1%) viremic controllers. The HIV-1 controllers had low peripheral blood mononuclear cell HIV-1 DNA and low inflammatory marker levels. They maintained high CD4+ cell count and percentages and had a low morbidity rate. DISCUSSION: HIV controllers exist in Africa at a proportion close to that reported elsewhere. They represent a small fraction of all HIV-1-infected patients but raise important questions. Further studies should assess whether starting ART might represent more risk than benefit for some controllers, and where it does, how to identify these patients before they start ART.
Assuntos
Infecções por HIV , HIV-1 , Adulto , Contagem de Linfócito CD4 , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Humanos , Leucócitos Mononucleares , Carga ViralRESUMO
BACKGROUND: Asymptomatic HIV-infected people who start ART early may feel less motivated and neglect compliance. This might promote the emergence of resistance. METHODS: In the Temprano trial, ART-naive HIV-infected adults with high CD4 counts were randomly assigned to start ART immediately (immediate group) or defer ART until the WHO criteria were met (deferred group). All participants were monitored for 30 months. Those in the deferred group who started ART were monitored for longer, until they had completed 30 months on ART. We compared the rate of virological failure and drug resistance between the immediate and deferred groups 30 months after ART initiation. RESULTS: Of the 2056 participants in Temprano, 1033 were assigned to start ART immediately and 1023 to defer ART. Of the latter, 488 started ART during trial follow-up. Patients in the deferred group who started ART had a lower median CD4 count (280 versus 465 cells/mm3) and a higher median plasma HIV-1 RNA (5.1 versus 4.7 log10 copies/mL) at baseline. During follow-up, participants in both groups had similar antiretroviral drug exposure. Thirty months after ART initiation, patients in the deferred group had a higher rate of virological failure (35.3% versus 29.9%, P = 0.04) and a lower genotypic susceptibility score (P = 0.04). CONCLUSIONS: Starting ART early decreases the risk of virological failure and drug resistance in the medium term. This benefit is of particular importance in countries where access to viral load monitoring and the number of antiretroviral drug lines is limited.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Adulto , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Resistência a Medicamentos , Infecções por HIV/tratamento farmacológico , Humanos , Carga Viral , Organização Mundial da SaúdeRESUMO
BACKGROUND: Hepatitis B virus (HBV) co-infection in human immunodeficiency virus (HIV)-positive individuals increases the risk of overall mortality, especially when HBV DNA levels are high. The role of CD4+ cell counts in this association is poorly defined. We aimed to determine whether HIV-HBV co-infection influences changes in CD4+ cell count before and during antiretroviral therapy and whether it affects mortality risk at levels of CD4+. METHODS: 2052 HIV-positive participants from Côte d'Ivoire in a randomized-control trial assessing early or deferred ART were included. HBV-status was determined by hepatitis B surface antigen (HBsAg). Changes in CD4+ cell levels were estimated using a mixed-effect linear model. The incidence rates of all-cause mortality were estimated at CD4+ counts ≤350, 351-500, >500/mm3 and were compared between HBV-status groups as incidence rate ratios (IRR). RESULTS: At baseline, 190 (9%) were HBsAg-positive [135 (71%) with HBV DNA <2000 IU/mL, 55 (29%) ≥2000 IU/mL]. Follow-up was a median 58 months (IQR = 40-69). Between co-infection groups, there were no differences in CD4+ decline before ART initiation and no differences in CD4+ increase after ART initiation. After adjusting for sex, age, baseline HIV RNA level, and early/deferred ART arm, mortality rates were not significantly different between HBsAg-positive versus HBsAg-negative participants across strata of CD4+ levels. However, HBsAg-positive individuals with HBV-DNA ≥2000 IU/mL versus HBsAg-negative individuals had increased mortality rates at ≤350/mm3 (adjusted-IRR = 3.82, 95% CI = 1.11-9.70) and 351-500/mm3 (adjusted-IRR = 4.37, 95% CI = 0.98-13.02), but not >500/mm3 (adjusted-IRR = 1.07, 95% CI = 0.01-4.91). CONCLUSION: Despite no effect of HBV-infection on CD4+ levels, HIV-HBV co-infected individuals with high HBV replication are at higher risk of mortality when CD4+ is <500/mm3.
Assuntos
Coinfecção , Infecções por HIV , Soropositividade para HIV , Hepatite B , África Subsaariana/epidemiologia , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos , Coinfecção/epidemiologia , DNA Viral , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Hepatite B/complicações , Hepatite B/epidemiologia , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B/genética , HumanosRESUMO
Treatment scale-up is leading to a progressive increase in HIV resistance to antiretrovirals, especially in children. To assess resistance to reverse transcriptase inhibitors (RTIs) in HIV-1 infected children in Côte d'Ivoire, genotypic resistance tests were performed and interpreted using the ANRS algorithm (www.hivfrenchresistance.org). Phylogenetic trees were created using BioEdit v7 and Mega7 software. The frequency of resistance to at least one RTI was 79%. It was 88% for nucleoside reverse transcriptase inhibitors (NRTIs), 71% for non-nucleoside reverse transcriptase inhibitors (NNRTIs), and 63% for both classes (NRTI + NNRTI). The frequency of resistance was 50% for the ZDV + 3TC + EFV combination, 42% for the ABC + 3TC + EFV combination, and 8% for the TDF + 3TC + EFV combination. Frequently encountered resistance mutations were for NRTIs: M184V (88%), TAMs (67%), T215F/I/V/Y (33%), and L74I/V (24%); for NNRTIs: K103N/S (74%), P225H (26%), and G190A/E/Q (24%). The synthesis of phylogenetic analyses showed the predominance of the viral subtype CRF02_AG (85%). These results show a high prevalence of resistance to RTIs in children infected with HIV-1. Hence the interest of a more accessible monitoring of viral load and genotypic resistance tests in HIV-1 infected children undergoing treatment in Côte d'Ivoire.
Assuntos
HIV-1/classificação , HIV-1/efeitos dos fármacos , HIV-1/genética , Mutação , Filogenia , Inibidores da Transcriptase Reversa/farmacologia , Adolescente , Criança , Pré-Escolar , Côte d'Ivoire , Feminino , Genótipo , Infecções por HIV , Transcriptase Reversa do HIV/genética , Humanos , Lactente , Masculino , Estudos ProspectivosRESUMO
BACKGROUND: Whereas 72% of hepatitis C virus (HCV)-infected people worldwide live in low- and middle-income countries (LMICs), only 6% of them have been diagnosed. Innovative technologies for HCV diagnosis provide opportunities for developing testing strategies more adapted to resource-constrained settings. However, studies about their economic feasibility in LMICs are lacking. METHODS: Adopting a health sector perspective in Cameroon, Cote-d'Ivoire, and Senegal, a decision tree model was developed to compare 12 testing strategies with the following characteristics: a one-step or two-step testing sequence, HCV-RNA or HCV core antigen as confirmative biomarker, laboratory or point-of-care (POC) tests, and venous blood samples or dried blood spots (DBS). Outcomes measures were the number of true positives (TPs), cost per screened individual, incremental cost-effectiveness ratios, and nationwide budget. Corresponding time horizon was immediate, and outcomes were accordingly not discounted. Detailed sensitivity analyses were conducted. FINDINGS: In the base-case, a two-step POC-based strategy including anti-HCV antibody (HCV-Ab) and HCV-RNA testing had the lowest cost, 8.18 per screened individual. Assuming a lost-to-follow-up rate after screening > 1.9%, a DBS-based laboratory HCV-RNA after HCV-Ab POC testing was the single un-dominated strategy, requiring an additional cost of 3653.56 per additional TP detected. Both strategies would require 8-25% of the annual public health expenditure of the study countries for diagnosing 30% of HCV-infected individuals. Assuming a seroprevalence > 46.9% or a cost of POC HCV-RNA < 7.32, a one-step strategy based on POC HCV-RNA dominated the two-step POC-based strategy but resulted in many more false-positive cases. CONCLUSIONS: POC HCV-Ab followed by either POC- or DBS-based HCV-RNA testing would be the most cost-effective strategies in the study countries. Without a substantial increase in funding for health or a dramatic decrease in assay prices, HCV testing would constitute an economic barrier to the implementation of HCV elimination programs in LMICs.
Assuntos
Análise Custo-Benefício , Hepatite C/diagnóstico , Modelos Estatísticos , África Central , África Ocidental , Árvores de Decisões , Estudos de Viabilidade , Humanos , Testes Imediatos/economia , Fatores de TempoRESUMO
BACKGROUND: High HIV-1 DNA levels in peripheral blood mononuclear cells (PBMC) were associated with a higher risk of severe morbidity and a faster decline in CD4 count in ART-naive patients. We report the association between HIV-1 DNA and mortality in HIV-infected adults in a trial of early ART in West Africa. METHODS: In the Temprano trial, HIV-infected adults were randomly assigned to start ART immediately or defer ART. After trial termination, HIV-1 DNA was measured in whole blood samples frozen at baseline. We analyzed the association between baseline PBMC HIV-1 DNA and long-term mortality. FINDINGS: 2019 patients were followed for 9253 patient-years (median 4.9 years). At baseline, the median CD4 count was 462/mm3 [IQR 368-571], the median plasma HIV-1 RNA 4.7 log10 copies/ml [IQR 4.0-5.2], and the median HIV-1 DNA 2.9 log10 copies/million PBMC [IQR 2.5-3.3]. During follow-up, 86 participants died. In univariate analysis, the hazard ratio [HR] of death was 2.67 (95% CI, 1.68-4.22) for patients with HIV-1 DNA ≥3 log10 copies/million PBMC vs. others, and 2.10 (95% CI, 1.38-3.21) for patients with HIV-1 RNA ≥5 log10 copies/ml vs. others. In multivariate Cox regression analysis, HIV-1 DNA levels ≥3 log10 copies/million PBMC were strongly associated mortality (adjusted HR = 2.09, 95% CI 1.24-3.52, p= 0.005) while the association between baseline plasma HIV-1 RNA and mortality was not significant. INTERPRETATION: In these African adults who started ART with high CD4 counts, HIV-1 DNA was a strong independent predictor of death. The HIV reservoir still plays a prognostic role in the early ART era. FUNDING: This trial was supported by the French National Agency for AIDS and viral hepatitis research (ANRS, Paris, France; Grants ANRS 12136, 12224 and 12253).
Assuntos
Fármacos Anti-HIV/uso terapêutico , DNA Viral/genética , Infecções por HIV/mortalidade , HIV-1/genética , Adulto , Fármacos Anti-HIV/farmacologia , Terapia Antirretroviral de Alta Atividade , População Negra/estatística & dados numéricos , Contagem de Linfócito CD4 , Feminino , França/etnologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Leucócitos Mononucleares/virologia , Masculino , Fatores de Risco , Análise de Sobrevida , Resultado do Tratamento , Carga ViralRESUMO
BACKGROUND: Scaling-up the access to hepatitis C virus (HCV) diagnostics for people who use injecting drugs (PWID) is essential to reduce the HCV incidence in low and middle-income countries. METHODS: A decision tree model was developed to compare the cost-effectiveness of 12 strategies for diagnosing HCV in Senegal with a health sector perspective. Strategies included HCV-Ab screening and confirmation of viraemia (based on HCV-RNA or HCV core antigen detection) or only the latter step. Laboratory assays and decentralized tools (point-of-care (POC) tests and dried blood spot (DBS) samples) were included. The base-case assumed a 38.9% seroprevalence, as reported in the PWID population of Dakar. RESULTS: Compared to the cheapest strategy (POC HCV-Ab followed by POC HCV-RNA (S5)), one strategy remained un-dominated in the base-case: POC HCV-Ab followed by venepuncture-based laboratory HCV-RNA (S3). Above a lost to follow-up testing rate of 2.3%, combining POC HCV-Ab with HCV-RNA on DBS (S4) became more cost-effective than S3. Above this threshold, a single-step POC HCV-RNA (S12) was also found un-dominated (ICER to S5=3,297.50). S5, S12 and S4 cost 14.21, 17.03 and 36.55/screened individual. Incremental cost-effectiveness ratios (/additional true positive case) were 2,164.82 (S12 versus S5) and 3,297.50 (S4 versus S12). Whenever HCV seroprevalence reached 55.5%, S12 became more cost-effective than S5. Moreover, S4 required a budget 2 to 2.5 times higher than S5 or S12 for diagnosing 90% of HCV-infected PWID in Dakar. CONCLUSION: A two-step POC-based strategy (S5) would be the most cost-effective option among those proposed in this study for diagnosing HCV in PWID in Senegal. This study illustrates how the lack of secure financing and of data on PWID in LMICs, render difficult to identify the most sustainable strategy in those countries, as well as its implementation.
Assuntos
Hepatite C/diagnóstico , Programas de Rastreamento/métodos , Modelos Econômicos , Abuso de Substâncias por Via Intravenosa/epidemiologia , Análise Custo-Benefício , Árvores de Decisões , Teste em Amostras de Sangue Seco/economia , Acessibilidade aos Serviços de Saúde , Hepatite C/epidemiologia , Humanos , Programas de Rastreamento/economia , Testes Imediatos/economia , RNA Viral/sangue , Senegal/epidemiologia , Estudos SoroepidemiológicosRESUMO
BACKGROUND: The decision about whether to switch to third-line antiretroviral therapy (ART) in patients with treatment failure on second-line therapy is difficult in settings with little access to genotypic resistance testing. In this study, we used a standardised algorithm including a wide range of adherence-enhancing interventions followed by a new viral load measurement to decide whether to switch to third-line therapy in this situation. The decision, made on the basis of effectiveness of the adherence reinforcement to drive viral resuppression, did not use genotypic resistance testing. METHODS: In this prospective cohort study, adults in four west African countries with treatment failure of a boosted protease inhibitor ART regimen were offered nine adherence reinforcement interventions, and followed up for 64 weeks. We measured viral load at week 12 and used the results to decide ART treatment at week 16: if successful resuppression (plasma HIV-1 RNA <400 copies per mL or had decreased by ≥2 log10 copies per mL compared with baseline), patients continued the same second-line regimen; otherwise they switched to a third-line regimen based on ritonavir-boosted darunavir and raltegravir. The primary endpoint was virological success at week 64 (plasma HIV-1 RNA <50 copies per mL). After study termination we did genotypic resistance testing on frozen plasma samples collected at baseline, and retrospectively determined the appropriateness of the week 16 decision on the basis of the baseline genotypic susceptibility score. FINDINGS: Between March 28, 2013, and May 11, 2015, of the 198 eligible participants, five died before week 16. Of the 193 remaining, 130 (67%) reached viral resuppression and continued with second-line ART, and 63 (33%) switched to third-line ART at week 16. Post-study genotypic resistance testing showed that the baseline genotypic susceptibility score was calculable in 166 patients, of whom 57 (34%) had a score less than 2. We retrospectively concluded that the week 16 decision was appropriate in 145 (75%) patients. At week 64, four patients (2%) were lost to follow-up, ten (5%) had died, and 101 (52%) had a viral load less than 50 copies per mL. INTERPRETATION: Poor adherence is the first problem to tackle in patients for whom second-line ART is failing when resistance tests are not routinely available and is effectively a manageable problem. Lack of access to genotypic resistance testing should not be an obstacle to the prescription of third-line ART in patients who do not achieve viral resuppression after adherence reinforcement. FUNDING: French Agency for Research on AIDS and Viral Hepatitis.
Assuntos
Darunavir/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Raltegravir Potássico/administração & dosagem , Ritonavir/administração & dosagem , Adulto , África Ocidental , Algoritmos , Tomada de Decisão Clínica , Darunavir/efeitos adversos , Darunavir/farmacologia , Quimioterapia Combinada/efeitos adversos , Feminino , HIV-1/crescimento & desenvolvimento , Humanos , Masculino , Adesão à Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Estudos Prospectivos , Raltegravir Potássico/efeitos adversos , Raltegravir Potássico/farmacologia , Ritonavir/efeitos adversos , Ritonavir/farmacologia , Falha de Tratamento , Resultado do Tratamento , Carga Viral/efeitos dos fármacosRESUMO
Background: ART in the developing world has moved to a new era with the WHO recommendation to test and immediately treat HIV-positive individuals. A high frequency of pretreatment HIV drug resistance (PDR) can compromise ART efficacy. Our study presents updated estimates of PDR in seven countries from West Africa (Burkina Faso, Cameroon, Côte d'Ivoire, Mali and Togo) and Southeast Asia (Thailand and Vietnam). Methods: Eligible study participants were adult ART initiators, recruited from December 2015 to November 2016 in major ART clinics in each country. HIV drug resistance (HIVDR) tests were performed for all specimens and interpretation was done using the Stanford algorithm. Results: Overall, 1153 participants were recruited and 1020 nt sequences were generated. PDR frequency among all initiators was 15.9% (95% CI: 13.8%-18.3%) overall, ranging from 9.6% and 10.2% in Burkina Faso and Thailand, respectively, 14.7% in Vietnam, 15.4% in Mali, 16.5% in Côte d'Ivoire and 19.3% in Cameroon, to 24.6% in Togo. The prevalence of NNRTI resistance mutations was 12%; NRTI and PI PDR prevalences were 4% and 3%, respectively. Conclusions: Our study shows that in most countries PDR exceeded 10%, warranting the conduct of nationally representative surveys to confirm this trend. In the meantime, actions to prevent drug resistance, including transition from NNRTIs to more robust drug classes should be urgently implemented.
Assuntos
Farmacorresistência Viral/genética , Infecções por HIV/epidemiologia , HIV-1/efeitos dos fármacos , Adulto , África Ocidental/epidemiologia , Fármacos Anti-HIV/sangue , Sudeste Asiático/epidemiologia , Feminino , HIV-1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Carga ViralRESUMO
BACKGROUND: Temprano ANRS 12136 was a factorial 2â×â2 trial that assessed the benefits of early antiretroviral therapy (ART; ie, in patients who had not reached the CD4 cell count threshold used to recommend starting ART, as per the WHO guidelines that were the standard during the study period) and 6-month isoniazid preventive therapy (IPT) in HIV-infected adults in Côte d'Ivoire. Early ART and IPT were shown to independently reduce the risk of severe morbidity at 30 months. Here, we present the efficacy of IPT in reducing mortality from the long-term follow-up of Temprano. METHODS: For Temprano, participants were randomly assigned to four groups (deferred ART, deferred ART plus IPT, early ART, or early ART plus IPT). Participants who completed the trial follow-up were invited to participate in a post-trial phase. The primary post-trial phase endpoint was death, as analysed by the intention-to-treat principle. We used Cox proportional models to compare all-cause mortality between the IPT and no IPT strategies from inclusion in Temprano to the end of the follow-up period. FINDINGS: Between March 18, 2008, and Jan 5, 2015, 2056 patients (mean baseline CD4 count 477 cells per µL) were followed up for 9404 patient-years (Temprano 4757; post-trial phase 4647). The median follow-up time was 4·9 years (IQR 3·3-5·8). 86 deaths were recorded (Temprano 47 deaths; post-trial phase 39 deaths), of which 34 were in patients randomly assigned IPT (6-year probability 4·1%, 95% CI 2·9-5·7) and 52 were in those randomly assigned no IPT (6·9%, 5·1-9·2). The hazard ratio of death in patients who had IPT compared with those who did not have IPT was 0·63 (95% CI, 0·41 to 0·97) after adjusting for the ART strategy (early vs deferred), and 0·61 (0·39-0·94) after adjustment for the ART strategy, baseline CD4 cell count, and other key characteristics. There was no evidence for statistical interaction between IPT and ART (pinteraction=0·77) or between IPT and time (pinteraction=0·94) on mortality. INTERPRETATION: In Côte d'Ivoire, where the incidence of tuberculosis was last reported as 159 per 100â000 people, 6 months of IPT has a durable protective effect in reducing mortality in HIV-infected people, even in people with high CD4 cell counts and who have started ART. FUNDING: National Research Agency on AIDS and Viral Hepatitis (ANRS).
Assuntos
Antituberculosos/uso terapêutico , Contagem de Linfócito CD4/estatística & dados numéricos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/mortalidade , Isoniazida/uso terapêutico , Adulto , África Ocidental/epidemiologia , Antirretrovirais/uso terapêutico , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Risco , Resultado do TratamentoRESUMO
BACKGROUND: In sub-Saharan Africa, the burden of human immunodeficiency virus (HIV)-associated tuberculosis is high. We conducted a trial with a 2-by-2 factorial design to assess the benefits of early antiretroviral therapy (ART), 6-month isoniazid preventive therapy (IPT), or both among HIV-infected adults with high CD4+ cell counts in Ivory Coast. METHODS: We included participants who had HIV type 1 infection and a CD4+ count of less than 800 cells per cubic millimeter and who met no criteria for starting ART according to World Health Organization (WHO) guidelines. Participants were randomly assigned to one of four treatment groups: deferred ART (ART initiation according to WHO criteria), deferred ART plus IPT, early ART (immediate ART initiation), or early ART plus IPT. The primary end point was a composite of diseases included in the case definition of the acquired immunodeficiency syndrome (AIDS), non-AIDS-defining cancer, non-AIDS-defining invasive bacterial disease, or death from any cause at 30 months. We used Cox proportional models to compare outcomes between the deferred-ART and early-ART strategies and between the IPT and no-IPT strategies. RESULTS: A total of 2056 patients (41% with a baseline CD4+ count of ≥500 cells per cubic millimeter) were followed for 4757 patient-years. A total of 204 primary end-point events were observed (3.8 events per 100 person-years; 95% confidence interval [CI], 3.3 to 4.4), including 68 in patients with a baseline CD4+ count of at least 500 cells per cubic millimeter (3.2 events per 100 person-years; 95% CI, 2.4 to 4.0). Tuberculosis and invasive bacterial diseases accounted for 42% and 27% of primary end-point events, respectively. The risk of death or severe HIV-related illness was lower with early ART than with deferred ART (adjusted hazard ratio, 0.56; 95% CI, 0.41 to 0.76; adjusted hazard ratio among patients with a baseline CD4+ count of ≥500 cells per cubic millimeter, 0.56; 95% CI, 0.33 to 0.94) and lower with IPT than with no IPT (adjusted hazard ratio, 0.65; 95% CI, 0.48 to 0.88; adjusted hazard ratio among patients with a baseline CD4+ count of ≥500 cells per cubic millimeter, 0.61; 95% CI, 0.36 to 1.01). The 30-month probability of grade 3 or 4 adverse events did not differ significantly among the strategies. CONCLUSIONS: In this African country, immediate ART and 6 months of IPT independently led to lower rates of severe illness than did deferred ART and no IPT, both overall and among patients with CD4+ counts of at least 500 cells per cubic millimeter. (Funded by the French National Agency for Research on AIDS and Viral Hepatitis; TEMPRANO ANRS 12136 ClinicalTrials.gov number, NCT00495651.).
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/prevenção & controle , Antirretrovirais/uso terapêutico , Antituberculosos/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1 , Isoniazida/uso terapêutico , Tuberculose/prevenção & controle , Adulto , Antirretrovirais/efeitos adversos , Antituberculosos/efeitos adversos , Doenças Assintomáticas , Contagem de Linfócito CD4 , Côte d'Ivoire , Feminino , Seguimentos , Infecções por HIV/imunologia , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Isoniazida/efeitos adversos , Masculino , Pessoa de Meia-Idade , RNA Viral/análise , Tempo para o Tratamento , Carga ViralRESUMO
This study evaluates HIV infant diagnosis on DBS using Biocentric HIV1-DNA and HIV1-RNA assays, in field conditions in Côte d'Ivoire. Paediatric screening was offered to children≤3 years in clinical sites in Côte d'Ivoire in 2008. For each HIV-infected child, two non-infected children were included and blood samples were collected. HIV-DNA results obtained on EDTA blood samples with Biocentric assay were the reference for HIV infant diagnosis. Plasma and DBS viral loads were measured using HIV-RNA Biocentric assay. DBS samples were also tested for HIV-DNA detection using both Biocentric and Amplicor Roche assays. Sensitivity, specificity and concordance between tests were calculated. Overall samples from 138 HIV-exposed children, 46 infected, 92 non-infected were included. All tests were 100% sensitive and specific including 100% concordance with the two HIV-DNA assays. The median level of HIV-DNA on EDTA samples was 3.15 log10 copies/10(6) PBMCs; the median level of HIV RNA in plasma and DBS were respectively 5.82 and 5.17 log10 copies/ml (Pearson's correlation R2=0.92, p<0.0001). The threshold for detectable HIV-RNA on DBS was 3.3 log10. Although there are differences between viral load measured on DBS and plasma, the two Biocentric assays present very good performances for HIV infant diagnosis on DBS while cheap and feasible.
Assuntos
Sangue/virologia , DNA Viral/isolamento & purificação , Infecções por HIV/diagnóstico , HIV-1/isolamento & purificação , Técnicas de Diagnóstico Molecular/métodos , RNA Viral/isolamento & purificação , Manejo de Espécimes/métodos , Pré-Escolar , Côte d'Ivoire , DNA Viral/genética , Dessecação , Infecções por HIV/virologia , HIV-1/genética , Humanos , Lactente , Plasma/virologia , RNA Viral/genética , Sensibilidade e Especificidade , Carga Viral/métodosRESUMO
BACKGROUND: In sub-Saharan Africa, most HIV-infected patients receive antiretroviral therapy (ART) without virological monitoring. Longitudinal data on secondary resistance are rare. METHODS: We conducted a prospective cohort study of HIV-1-infected adults initiating ART in 3 clinics using computerized monitoring systems. Patients had plasma HIV-1 RNA viral load (VL) tests at months 12 (M12) and 24 (M24) after ART initiation and HIV-1 resistance genotype tests if VL was detectable (≥300 copies/mL). RESULTS: Overall, 1573 patients initiated ART with stavudine/zidovudine plus lamivudine plus nevirapine/efavirenz. At M12 and M24, 944 and 844 patients, respectively, remained in active follow-up. Among them, 25% (M12) and 27% (M24) had detectable VLs and 12% (M12) and 19% (M24) had virus resistant to at least 1 antiretroviral drug, accounting for 54% (M12) and 75% (M24) of patients with detectable VLs. Among the resistant strains, 95% (M12) and 97% (M24) were resistant to lamivudine/emtricitabine, efavirenz, and/or nevirapine, the frequency of thymidine analog mutations increased from 8.1% (M12) to 14.7% (M24) and etravirine resistance increased from 13.5% (M12) to 24.5% (M24). CONCLUSIONS: Of the patients with detectable VLs at M24, 25% still did not harbor resistant virus. Preventing mutations from emerging with adherence reinforcement in patients with detectable VLs remains important beyond M24. Switching therapy early in patients with resistance to 3 TC/FTC and/or to nonnucleoside reverse transcriptase inhibitors to prevent extended resistance to nucleoside reverse transcriptase inhibitors and etravirine resistance from occurring is also a major challenge.
Assuntos
Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Mutação , Piridazinas/farmacologia , Timidina/análogos & derivados , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Estudos de Coortes , Côte d'Ivoire , Monitoramento de Medicamentos/métodos , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , HIV-1/genética , Humanos , Masculino , Nitrilas , Estudos Prospectivos , Piridazinas/administração & dosagem , Piridazinas/uso terapêutico , Pirimidinas , RNA Viral/sangue , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Timidina/farmacologia , Fatores de Tempo , Carga ViralRESUMO
OBJECTIVES: M184V in HIV-1 reverse transcriptase is among the most common mutations in patients failing antiretroviral therapy but is found only rarely in cases of transmitted drug resistance. METHODS: To investigate this apparent paradox, we developed an allele-specific real-time PCR (AS-PCR) assay to determine the transmission of M184V in newly infected individuals. RESULTS: M184V transmission may occur to a greater extent than previously thought. Persistence of M184V may commonly involve linkage to other drug resistance mutations. The presence of M184V as a single substitution in newly infected individuals was shown to wane over time, as a likely consequence of reversion and overgrowth by more fit wild-type viruses. CONCLUSIONS: The M184V mutation can be documented in newly infected individuals, and the alternative hypothesis that this substitution might impact on the ability of HIV to be transmitted is unfounded.
Assuntos
Fármacos Anti-HIV/farmacologia , Infecções por HIV/virologia , Transcriptase Reversa do HIV/genética , HIV-1/efeitos dos fármacos , HIV-1/genética , Farmacorresistência Viral , Genótipo , Infecções por HIV/tratamento farmacológico , HIV-1/enzimologia , Humanos , Dados de Sequência Molecular , Mutação , Reação em Cadeia da Polimerase em Tempo Real , Inibidores da Transcriptase Reversa/farmacologiaRESUMO
BACKGROUND: WHO recommends initiating combination antiretroviral treatment at the minimal CD4 cell threshold of 350 cells/µl. In sub-Saharan Africa, the time for a recently infected patient to reach this threshold is unclear. METHOD: We estimated the probability of reaching different CD4 cell thresholds over time in the ANRS 1220 cohort of HIV-1 seroconverters in Côte d'Ivoire. CD4 cell slopes were estimated using a mixed linear model. Probabilities of crossing the 350 and 500 cells/µl CD4 cell thresholds were estimated by the Kaplan-Meier method. RESULTS: Between 1997 and 2009, 304 recent seroconverters have been enrolled in the Primo-CI cohort (62% men, median baseline age 29 years and median time since the estimated date of seroconversion 9 months). The probability of having a first CD4 cell count below 500 cells/µl was 0.57, 0.72, 0.79 and 0.84 at study entry, 2, 4 and 6 years, respectively. For a first CD4 cell count below 350 cells/µl, these figures were 0.29, 0.40, 0.55 and 0.67. The time for 75% of patients to reach the threshold was 3.0 years for 500 cells/µl and 7.0 years for 350 cells/µl.
Assuntos
Antirretrovirais/administração & dosagem , Contagem de Linfócito CD4 , Infecções por HIV/tratamento farmacológico , Soropositividade para HIV/tratamento farmacológico , HIV-1 , Adulto , Quimioterapia Combinada , Soropositividade para HIV/diagnóstico , Humanos , MasculinoRESUMO
We have selected for resistance to etravirine (ETR) and efavirenz (EFV) in tissue culture using three subtype B, three subtype C, and two CRF02_AG clinical isolates, grown in cord blood mononuclear cells. Genotypic analysis was performed at baseline and at various weeks of selection. Phenotypic resistance in regard to ETR, EFV, and nevirapine (NVP) was evaluated at weeks 25 to 30 for all ETR-selected viruses and in viral clones that contained specific resistance mutations that were inserted by site-directed mutagenesis into pNL-4.3 and AG plasmids. The results show that ETR selected mutations at positions V90I, K101Q, E138K, V179D/E/F, Y181C, V189I, G190E, H221H/Y, and M230L and that E138K was the first of these to emerge in most instances. The time to the emergence of resistance was longer in the case of ETR (18 weeks) compared to EFV (11 weeks), and no differences in the patterns of emergent mutations could be documented between the B and non-B subtypes. Viral clones containing E138K displayed low-level phenotypic resistance to ETR (3.8-fold) and modestly impaired replication capacity (2-fold) compared to wild-type virus. ETR-selected virus showed a high degree of cross-resistance to NVP but not to EFV. We identified K101Q, E138K, V179E, V189I, G190E, and H221Y as mutations not included among the 17 currently recognized resistance-associated mutations for ETR.