Incomplete recovery of the CD4+/CD8+ ratio is associated with the late introduction of antiretroviral therapy among people living with HIV infection

ABSTRACT Despite being subject to lower AIDS-related mortality rates and having a higher life expectancy, patients with HIV are more prone to develop non-AIDS events. A low CD4+/CD8+ ratio during antiretroviral therapy identifies people with heightened immune senescence and increased risk of mortality. In clinical practice, finding determinants of a low CD4+/CD8+ ratio may be useful for identifying patients who require close monitoring due to an increased risk of comorbidities and death. We performed a prospective study on the evolution of the CD4+/CD8+ ratio in 60 patients infected with HIV (80% males), who were subjected to two different antiretroviral regimens: early and deferred therapy. The initial CD4+/CD8+ ratio was ≤1 for 70% of the patients in both groups. Older age, CD4+ cell count at inclusion, Nadir CD8+T-cell count, and Initial CD4+/CD8+ ratio ≤ 1 were risk factors for lack of ratio recovery. In the multivariate analysis, a CD4+/CD8+ ratio > 1 at the start of the treatment was found to be a determinant factor in maintaining a CD4+/CD8+ ratio > 1. The nadir CD4+T-cell count was lower in the deferred therapy group (p=0.004), and the last CD4+/CD8+ ratio ≤1 was not associated with comorbidities. Ratio recovery was not associated with the duration of HIV infection, time without therapy, or absence of AIDS incidence. A greater improvement was observed in patients treated early (p=0.003). In contrast, the slope of increase was slower in patients who deferred treatment. In conclusion, the increase in the CD4+/CD8+ ratio occurred mostly for patients undergoing early strategy treatment and its extension did not seem to be related to previous HIV-related factors.

Resistencia transmitida de VIH-1 en pacientes sin exposición a tratamiento antirretroviral: Guatemala / Transmitted HIV-1 resistance in patients without exposure to antiretroviral treatment: Guatemala / Resistência transmitida ao HIV-1 em pacientes sem exposição ao tratamento antirretroviral: Guatemala

El objetivo del estudio fue describir los niveles de resistencia transmitida de VIH-1 en adultos atendidos en Unidades de Atención Integral de Guatemala. El estudio incluyó registros de 185 pacientes adultos VIH-1 positivo, de reciente diagnóstico sin antecedente de uso de TAR, de noviembre del 2019 a noviembre del 2020. El análisis se realizó en el software DeepChek® v2.0, para la clasificación de la resistencia se siguió el algoritmo de Stanford HIVdb (v9.4 - 07/12/2022). Se encontró 18.4% (IC 95% 13.1 - 24.7%) de resistencia general a alguna familia de ARVs. Se evidenció 15.1% (IC 95% 10.3 - 21.1%) de resistencia individual a la familia de INNTR afectando principalmente a NVP y EFV; 2.2% (IC 95% 0.6 - 5.4%) de resistencia a INTR, mayormente a FTC/3TC; y 2.7% (IC 95% 0.9 - 6.2%) de resistencia intermedia y baja los IP NFV y LPV/r. Tres casos presentaron resistencia múltiple a los INTR + INNTR. Las mutaciones más frecuentemente encontradas fueron K103N (41.2%), M184V/I (8.8%) y M46I (5.9%). La elevada resistencia transmitida del VIH-1 en pacientes atendidos en distintas Unidades de Atención Integral del VIH, demuestra la importancia de analizar periódicamente la tendencia de la resistencia en personas que no han estado expuestas a ARVs, lo cual a su vez es un marcador indirecto de presencia de resistencia adquirida en el país, datos que evidencian la necesidad de acciones e intervenciones prontas y efectivas dado su impacto en la salud pública.

The objective of this study was to describe the levels of transmitted HIV-1 resistance in patients with a recent HIV diagnosis before starting ART, treated in Comprehensive Care Units in Guatemala during the years 2019 and 2020. The study included records of 185 HIV-positive adult patients, recently diagnosed with HIV without a history of ART use. The analysis was carried out in the DeepChek® v2.0 software, the Stanford HIVdb algorithm (v9.4 - 07/12/2022) was followed to classify resistance. 18.4% (95% CI 13.1 - 24.7%) of general resistance to some family of ARVs was found. There was evidence of 15.1% (95% CI 10.3 - 21.1%) of individual resistance to the NNRTI family, mainly affecting NVP and EFV; 2.2% (95% CI 0.6 - 5.4%) resistance to INTR, mostly to FTC/3TC; and 2.7% (95% CI 0.9 - 6.2%) of intermediate and low resistance IP NFV and LPV/r. Three cases presented multiple resistance to NRTIs + NNRTIs. The most frequently found mutations were K103N (41.2%), M184V/I (8.8%) and M46I (5.9%). The high transmitted resistance of HIV-1 in patients treated in different Comprehensive HIV Care Units demonstrates the importance of periodically analyzing the trend of resistance in people who have not been exposed to ARVs, which in turn is an indirect marker. of the presence of acquired resistance in the country, data that demonstrate the need for prompt and effective actions and interventions given its impact on public health.

O objetivo deste estudo foi descrever os níveis de resistência transmitida ao HIV-1 em adultos tratados em Unidades de Cuidados Integrais na Guatemala. O estudo incluiu prontuários de 185 pacientes adultos HIV-1 positivos, recentemente diagnosticados sem histórico de uso de TARV, no período de novembro de 2019 a novembro de 2020. A análise foi realizada no software DeepChek® v2.0, para classificação da resistência, O algoritmo Stanford HIVdb (v9.4 - 07/12/2022) foi seguido. Foi encontrada 18.4% (IC 95% 13.1 - 24.7%) de resistência geral a alguma família de ARVs. Houve evidência de 15.1% (IC 95% 10.3 - 21.1%) de resistência individual à família de NNRTI, afetando principalmente NVP e EFV; 2.2% (IC 95% 0.6 - 5.4%) resistência ao INTR, principalmente ao FTC/3TC; e 2.7% (IC 95% 0.9 - 6.2%) de resistência intermediária e baixa ao IP NFV e LPV/r. Três casos apresentaram resistência múltipla a NRTIs + NNRTIs. As mutações mais frequentemente encontradas foram K103N (41.2%), M184V/I (8.8%) e M46I (5.9%). A elevada resistência transmitida do HIV-1 em pacientes atendidos em diferentes Unidades de Cuidados Integrados ao HIV demonstra a importância de analisar periodicamente a tendência de resistência em pessoas que não foram expostas aos ARVs, o que por sua vez é um marcador indireto da presença de ARVs adquiridos. resistência no país, dados que demonstram a necessidade de ações e intervenções rápidas e eficazes dado o seu impacto na saúde pública.

Primary drug resistance among HIV-1 patients in Hubei Province in 2020-2022 / 公共卫生与预防医学

Objective To investigate the prevalence of primary drug resistance among HIV-1 patients in Hubei Province from 2020 to 2022, and to provide corresponding basis and data support for HIV antiviral therapy (ART) in Hubei Province. Methods During 2020-2022, plasma samples of HIV-1 infected patients before ART were collected., Patients’ demographic data and baseline laboratory test data were also collected. HIV-1 pol region was amplified by in-house method for sub-type typing and drug-resistant mutation site analysis. Results The pol gene sequence was successfully amplified in 242 of 285 cases, with a success rate of 84.9%. CRF07_BC was the predominant HIV-1 sub-type, accounting for 47.11% (114/242), followed by CRF01_AE, accounting for 25.21% (61/242), sub-type B, accounting for 14.16% (35/242), and CRF55_01B, accounting for 4.13% (10/242). The primary resistance rate was 6.20% (15/242). The mutation site of nucleoside reverse transcriptase inhibitors (NRTIs) was mainly M184V, and the mutation sites of non-nucleoside reverse transcriptase inhibitors (NNRTIs) were mainly E138A/G/EG and V179E. These different mutation sites led to different degrees of drug resistance to 12 drugs. The incidence of drug resistance mutation of CRF55_01B sub-type was significantly higher than that of other sub-types. Conclusion The primary drug resistance rate of HIV-1 infected patients is at a slightly high level in Hubei Province, and close monitoring of primary drug resistance and mutation sites should be strengthened before ART, especially for CRF55_01B sub-type.

Epidemiología de infección por hepatitis B y C en personas con VIH/SIDA. Villa Clara 1986-2021 / Epidemiology of hepatitis B and C infection in people with HIV/AIDS. Villa Clara 1986-2021

Se realizó un estudio observacional descriptivo retrospectivo con el objetivo de caracterizar la infección por hepatitis B y C en pacientes seropositivos al VIH de la provincia Villa Clara, durante el período del 1 de enero de 1986 al 31 de diciembre de 2021. Esta coinfección se presentó con mayor frecuencia en pacientes adultos del sexo masculino de 60 años en adelante (22 casos, 18,48 %), seguido de pacientes con las edades 50-54 años (21, 17,64 %). Santa Clara fue el municipio de mayor prevalencia (25, 21%). Los factores de riesgo asociados fueron: la conducta sexual de riesgo (81 casos, 68,06%) y estado civil soltero (65, 54,62 %); predominó el nivel de escolaridad secundaria básica (53, 44,53 %); en la ocupación, amas de casa (42, 35,29 %) y desocupados (34, 28,57 %). En el 70,58 % de los casos, les fue diagnosticada la coinfección en el mismo año.

A retrospective, descriptive and observational study was carried out with the aim of characterizing hepatitis B and C infection in HIV seropositive patients in Villa Clara province from January 1, 1986 to December 31, 2021. This coinfection occurred more frequently in adult male patients, between 60 years and older (22 cases, 18.48%), followed by patients aged 50-54 years (21, 17.64%). Santa Clara was the municipality with the highest prevalence (25 cases, 21%). The associated risk factors were risky sexual behaviour (81 cases, 68.06%) and single marital status (65, 54.62%); secondary school level predominated (53, 44.53%); as well as, housewives (42, 35.29%) and unemployed people (34, 28.57%). The coinfection was diagnosed in 70.58% of the cases in the same year.

Investigation of dual anti-HIV/HSV activity of oxoquinoline-acylhydrazone derivatives by molecular docking

Abstract Someoxoquinoline-acylhydrazonederivativesshowedactivityagainst HumanImmunodeficiency Virus type 1 (HIV-1). These compounds must also be active against Herpes Simplex Virus type 1 (HSV-1) by an inhibition mechanism where they interact with the HSV-DNA-polymerase/DNA-duplex complex. There are several treatment options for HSV-1 but there is no cure for the disease, which may represent a life risk for individuals co-infected with HIV. In this work molecular docking studies were carried out in an attempt to understand the dual activity of these oxoquinoline-acyhydrazone derivatives. The compounds were docked in two possible situations: (i) in the polymerase domain of HIV-1 Reverse Transcriptase (RT) enzyme in order to verify whether the inhibition occurs similarly to the proposed mechanism for HSV-1 inhibition, where the ligand would form a complex with the enzyme and the DNA; (ii) in the allosteric site of RT in order to verify if the inhibition occur in a similar way to non-nucleoside RT inhibitors (NNRTI). The studied compounds showed higher binding affinity to the allosteric site of RT and the results indicate that the inhibition should occur in a mechanism similar to that of NNRTI, which produces an allosteric inhibition that induces structural changes in the enzymatic active site.

Ongoing HIV-1 evolution and reservoir reseeding in two elite controllers with genetically diverse peripheral proviral quasispecies

BACKGROUND Elite controllers (EC) are human immunodeficiency virus (HIV)-positive individuals who can maintain low viral loads for extended periods without antiretroviral therapy due to multifactorial and individual characteristics. Most have a small HIV-1 reservoir composed of identical proviral sequences maintained by clonal expansion of infected CD4+ T cells. However, some have a more diverse peripheral blood mononuclear cell (PBMC)-associated HIV-1 reservoir with unique sequences. OBJECTIVES To understand the turnover dynamics of the PBMC-associated viral quasispecies in ECs with relatively diverse circulating proviral reservoirs. METHODS We performed single genome amplification of the env gene at three time points during six years in two EC with high intra-host HIV DNA diversity. FINDINGS Both EC displayed quite diverse PBMCs-associated viral quasispecies (mean env diversity = 1.9-4.1%) across all time-points comprising both identical proviruses that are probably clonally expanded and unique proviruses with evidence of ongoing evolution. HIV-1 env glycosylation pattern suggests that ancestral and evolving proviruses may display different phenotypes of resistance to broadly neutralising antibodies consistent with persistent immune pressure. Evolving viruses may progressively replace the ancestral ones or may remain as minor variants in the circulating proviral population. MAIN CONCLUSIONS These findings support that the high intra-host HIV-1 diversity of some EC resulted from long-term persistence of archival proviruses combined with the continuous reservoir's reseeding and low, but measurable, viral evolution despite undetectable viremia.

HIV-1 Transmission among Injecting Drug Users is Principally Derived from Local Circulating Strains in Guangxi, China / 生物医学与环境科学（英文）

OBJECTIVE@#The mode of human immunodeficiency virus (HIV) transmission via injection drug use (IDU) still exists, and the recent shift in IDU-related transmission of HIV infection is largely unknown. The purpose of this study was to analyze the spatiotemporal sources and dynamics of HIV-1 transmission through IDU in Guangxi.@*METHODS@#We performed a molecular epidemiological investigation of infections across Guangxi from 2009 to 2019. Phylogenetic and Bayesian time-geographic analyses of HIV-1 sequences were performed to confirm the characteristics of transmission between IDUs in combination with epidemiological data.@*RESULTS@#Among the 535 subjects, CRF08_BC (57.4%), CRF01_AE (28.4%), and CRF07_BC (10.7%) were the top 3 HIV strains; 72.6% of infections were linked to other provinces in the transmission network; 93.6% of sequence-transmitted strains were locally endemic, with the rest coming from other provinces, predominantly Guangdong and Yunnan; 92.1% of the HIV transmission among people who inject drugs tended to be transmitted between HIV-positive IDUs.@*CONCLUSION@#HIV recombinants were high diversity, and circulating local strains were the transmission sources among IDUs in Guangxi. However, there were still cases of IDUs linked to other provinces. Coverage of traditional prevention strategies should be expanded, and inter-provincial collaboration between Guangxi, Yunnan, and Guangdong provinces should be strengthened.

Analysis of HIV-1 subtypes and pretreatment drug resistance in newly reported HIV/AIDS cases in Hangzhou, 2020-2022 / 中华微生物学和免疫学杂志

Objective:To analyze the HIV-1 subtypes and drug resistance among newly reported HIV/AIDS cases before antiretroviral therapy (ART) in Hangzhou.Methods:Blood samples were collected from newly diagnosed HIV-1/AIDS cases not receiving ART in Hangzhou from 2020 to 2022. HIV-1 pol gene was amplified and then sequenced. A phylogenetic tree was construct using MEGA7.0 software to analyse the HIV-1 subtypes, The sequences were submitted to the Stanford University drug resistance database to identify drug resistance mutation sites and drug sensitivity. Results:A total of 2 700 sequences were obtained. Twelve subtypes were identified, and the predominant subtypes were CRF07_BC (46.8%, 1 263/2 700) and CRF01_AE (34.6%, 933/2 700). The overall drug resistance rate before ART was 8.1% (220/2 700) and the resistance rates to protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) were 2.8% (75/2 700), 1.3% (36/2 700) and 4.4% (119/2 700), respectively. Among the 220 drug-resistant cases, mutations conferring resistance to PIs (Q58E), NRTIs (M184V/I) and NNRTIs (K103N/S and E138A/G/K/Q) were detected in 47 (21.4%), 13 (5.9%), 42 (19.1%) and 41 (18.6%) patients, respectively.Conclusions:HIV-1 genotypes were highly complex in newly reported HIV/AIDS cases in Hangzhou from 2020 to 2022. There were cases showing moderate or high resistance to backbone drugs before ART, indicating that HIV-1 monitoring should be strengthened to avoid treatment failure and reduce the spread of drug-resistant strains.

Characteristics of HIV-1 CRF01_AE molecular network in Yunnan Province / 中华微生物学和免疫学杂志

Objective:To investigate the molecular network of HIV-1 CRF01_AE in Yunnan Province and the factors influencing it.Methods:Demographic data and plasma samples of HIV/AIDS patients in Yunnan drug resistance monitoring database from 2018 to 2021 were collected. HIV-1 pol gene fragments (protease and reverse transcriptase region) were amplified using RT-PCR and then sequenced. The optimal gene distance was selected and a molecular network was constructed based on the sequences of CRF01_AE genotype. Results:In this study, a total of 967 sequences of CRF01_AE genotype were obtained by sequencing. At the optimal gene distance threshold of 1.75%, a total of 320 sequences were involved in the network with a rate of 33.1%, and 84 clusters were identified. In the regional distribution, one cluster dominated by multiple regions, one cluster dominated by Zhaotong, one cluster dominated by Honghe and five clusters dominated by Wenshan were formed in the network. In the network, 75.8% of heterosexual men were connected with other heterosexual men and 54.1% were connected with heterosexual women. There was potential transmission among 66.7% of men who have sex with men (MSM). HIV/AIDS patients in Chuxiong, Dali, Dehong, Honghe, Lincang, Pu′er, Wenshan, Yuxi and Zhaotong were more likely to be involved in the network that those in Kunming. People who were 50 years old and above were more likely to be involved in the network than those less than 25 years old. Factors influencing HIV/AIDS patients with HIV-1 CRF01_AE infection to become high-risk transmitters in Yunnan were not found and further study on this subject was needed.Conclusions:HIV-1 CRF01_AE strains had spread actively in different regions of Yunnan Province and the transmission network was complex. Dynamic monitoring of CRF01_AE strains should be strengthened and a precise intervention for high-risk transmitters should be performed to reduce new infections.

Development of fluorine-substituted NH2-biphenyl-diarylpyrimidines as highly potent non-nucleoside reverse transcriptase inhibitors: Boosting the safety and metabolic stability

Our recent studies for nonnucleoside reverse transcriptase inhibitors identified a highly potent compound JK-4b against WT HIV-1 (EC50 = 1.0 nmol/L), but the poor metabolic stability in human liver microsomes (t 1/2 = 14.6 min) and insufficient selectivity (SI = 2059) with high cytotoxicity (CC50 = 2.08 μmol/L) remained major issues associated with JK-4b. The present efforts were devoted to the introduction of fluorine into the biphenyl ring of JK-4b, leading to the discovery of a novel series of fluorine-substituted NH2-biphenyl-diarylpyrimidines with noticeable inhibitory activity toward WT HIV-1 strain (EC50 = 1.8-349 nmol/L). The best compound 5t in this collection (EC50 = 1.8 nmol/L, CC50 = 117 μmol/L) was 32-fold in selectivity (SI = 66,443) compared to JK-4b and showed remarkable potency toward clinically multiple mutant strains, such as L100I, K103N, E138K, and Y181C. The metabolic stability of 5t was also significantly improved (t 1/2 = 74.52 min), approximately 5-fold higher than JK-4b in human liver microsomes (t 1/2 = 14.6 min). Also, 5t possessed good stability in both human and monkey plasma. No significant in vitro inhibition effect toward CYP enzyme and hERG was observed. The single-dose acute toxicity test did not induce mice death or obvious pathological damage. These findings pave the way for further development of 5t as a drug candidate.

Design, synthesis and biological activity of DB02 amino acid derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors / 药学学报

To improve the stability of amino acid ester derivatives of DB02, a series of 24 amide derivatives of DB02 amino acids as non-nucleoside HIV-1 reverse transcriptase inhibitor were designed and synthesized based on bioisosterism by replacing amino acid ester scaffold with more stable amide bond. The anti-HIV-1 activity of these compounds was evaluated by MTT assay and counting the number of syncytia. Most of the target compounds showed a potential anti-HIV-1 activity, among which compounds 2d, 2i, 2l, 2s, and 2w had better antiviral effect than lead compound DB02, with a therapeutic index > 1 000.00. Finally, the structure-activity relationship of these compounds was discussed, which provided new ideas for the further development of DB02 derivatives.

Picomolar inhibitor of reverse transcriptase featuring significantly improved metabolic stability

Considering the undesirable metabolic stability of our recently identified NNRTI 5 (t1/2 = 96 min) in human liver microsomes, we directed our efforts to improve its metabolic stability by introducing a new favorable hydroxymethyl side chain to the C-5 position of pyrimidine. This strategy provided a series of novel methylol-biphenyl-diarylpyrimidines with excellent anti-HIV-1 activity. The best compound 9g was endowed with remarkably improved metabolic stability in human liver microsomes (t1/2 = 2754 min), which was about 29-fold longer than that of 5 (t1/2 = 96 min). This compound conferred picomolar inhibition of WT HIV-1 (EC50 = 0.9 nmol/L) and low nanomolar activity against five clinically drug-resistant mutant strains. It maintained particularly low cytotoxicity (CC50 = 264 μmol/L) and good selectivity (SI = 256,438). Molecular docking studies revealed that compound 9g exhibited a more stable conformation than 5 due to the newly constructed hydrogen bond of the hydroxymethyl group with E138. Also, compound 9g was characterized by good safety profiles. It displayed no apparent inhibition of CYP enzymes and hERG. The acute toxicity assay did not cause death and pathological damage in mice at a single dose of 2 g/kg. These findings paved the way for the discovery and development of new-generation anti-HIV-1 drugs.

Discovery of novel sulfonamide substituted indolylarylsulfones as potent HIV-1 inhibitors with better safety profiles

Indolylarylsulfones (IASs) are classical HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a unique scaffold and possess potent antiviral activity. To address the high cytotoxicity and improve safety profiles of IASs, we introduced various sulfonamide groups linked by alkyl diamine chain to explore the entrance channel of non-nucleoside inhibitors binding pocket. 48 compounds were designed and synthesized to evaluate their anti-HIV-1 activities and reverse transcriptase inhibition activities. Especially, compound R10L4 was endowed with significant inhibitory activity towards wild-type HIV-1 (EC50(WT) = 0.007 μmol/L, SI = 30,930) as well as a panel of single-mutant strains exemplified by L100I (EC50 = 0.017 μmol/L, SI = 13,055), E138K (EC50 = 0.017 μmol/L, SI = 13,123) and Y181C (EC50 = 0.045 μmol/L, SI = 4753) which were superior to Nevirapine and Etravirine. Notably, R10L4 was characterized with significantly reduced cytotoxicity (CC50 = 216.51 μmol/L) and showed no remarkable in vivo toxic effects (acute and subacute toxicity). Moreover, the computer-based docking study was also employed to characterize the binding mode between R10L4 and HIV-1 RT. Additionally, R10L4 presented an acceptable pharmacokinetic profile. Collectively, these results deliver precious insights for next optimization and indicate that the sulfonamide IAS derivatives are promising NNRTIs for further development.

Expression of TIGIT, PD-1 and HLA-DR/CD38 markers on CD8-T cells of children and adolescents infected with HIV and uninfected controls

ABSTRACT Immune exhaustion and senescence are scarcely studied in HIV-pediatric patients. We studied the circulatory CD8 T cells activation/exhaustion and senescent phenotype of children and adolescents vertically infected with HIV or uninfected controls based on the expression of human leukocyte antigen (HLA-DR), CD38, T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT), programmed death 1 (PD-1) and CD57 by flow cytometry, during approximately one year. Eleven HIV-infected (HI) and nine HIV-uninfected (HU) children/adolescents who received two doses or one dose of meningococcal C conjugate vaccine (MenC), respectively, were involved in this study. Blood samples were collected before the immunization (T0), 1-2 months after the first dose (T1), and 1-2 months after the second dose (T2), which was administered approximately one year after the first one. HI patients not receiving combined antiretroviral therapy (cART) showed a higher frequency of CD8 T cells TIGIT+, PD-1+ or CD57+, as well as a higher frequency of CD8 T cells co-expressing CD38/HLA-DR/TIGIT or CD38/HLA-DR/PD-1 when compared to HI treated or HU individuals, at all times that they were assessed. CD8 T cells co-expressing CD38/DR/TIGIT were inversely correlated with the CD4/CD8 ratio but positively associated with viral load. The co-expression of CD38/DR/TIGIT or CD38/DR/PD-1 on CD8 T cells was also inversely associated with the CD4 T cells expressing co-stimulatory molecules CD127/CD28. The results showed a higher expression of exhaustion/senescence markers on CD8 T cells of untreated HI children/adolescents and its correlations with viral load.

Suppression of HIV in the first 12 months of antiretroviral therapy: a comparative analysis of dolutegravir- and efavirenz-based regimens

ABSTRACT Objective To compare viral suppression in treatment-naïve adults starting antiretroviral therapy with dolutegravir (50mg)- and efavirenz (600mg)-based regimens. Methods We analyzed secondary data from Brazilian health information systems of people living with human immunodeficiency virus who started antiretroviral therapy between 2015 and 2017 in Minas Gerais, Brazil. The outcome was viral suppression, defined as the achievement of the first viral load <50 copies/mL within 12 months after initiating antiretroviral therapy. This outcome was also compared with viral load <1,000 copies/mL and analyzed in two scenarios: intention-to-treat versus per-protocol. Time to viral suppression and adjusted odds ratio accompanied by 95% confidence intervals were estimated. Results Of the 2,599 participants enrolled, 77.5% were men, and the median age was 34 years. In the intention-to-treat analysis, viral suppression was 58.1% for efavirenz and 76.7% for dolutegravir. People living with HIV on dolutegravir-based regimen were more likely to achieve viral suppression (aOR: 2.44; 95%CI: 2.01-2.95) and had a shorter median time to viral suppression (p<0.0001). Antiretroviral therapy initiation within <120 days, baseline CD4⁺T-cells ≥200 cells/mm3, and viral load <100,000 copies/mL had higher odds of viral suppression. According to the per-protocol analysis, viral suppression ≥90% was observed by considering viral load <1,000 copies/mL. Conclusion Our study demonstrated that viral suppression improved after introducing dolutegravir, although the proportion of patients with viral load <50 copies/mL was lower than expected. Improved access to routine viral load examinations and continuous surveillance of the effectiveness of antiretroviral therapy should be considered.

Conserved multiepitope vaccine constructs: A potent HIV-1 therapeutic vaccine in clinical trials

Abstract Despite the success of Antiretroviral Therapy (ART) in preventing HIV-1-associated clinical progression to AIDS, it is unable to eliminate the viral reservoirs and eradicate the HIV-1 infection. Therapeutic vaccination is an alternative approach to alter the HIV-1 infection course. It can induce effective HIV-1-specific immunity to control viremia and eliminate the need for lifelong ART. Immunological data from spontaneous HIV-1 controllers have shown that cross-reactive T-cell responses are the key immune mechanism in HIV-1 control. Directing these responses toward preferred HIV-1 epitopes is a promising strategy in therapeutic vaccine settings. Designing novel immunogens based on the HIV-1 conserved regions containing a wide range of critical T- and B-cell epitopes of the main viral antigens (conserved multiepitope approaches) supplies broad coverage of global diversity in HIV-1 strains and Human Leukocyte Antigen (HLA) alleles. It can also prevent immune induction to undesirable decoy epitopes theoretically. The efficacy of different novel HIV-1 immunogens based on the conserved and/or functional protective site of HIV-1 proteome has been evaluated in multiple clinical trials. Most of these immunogens were generally safe and able to induce potent HIV-1-specific immunity. However, despite these findings, several candidates have demonstrated limited efficacy in viral replication control. In this study, we used the PubMed and ClinicalTrial.gov databases to review the rationale of designing curative HIV-1 vaccine immunogens based on the conserved favorable site of the virus. Most of these studies evaluate the efficacy of vaccine candidates in combination with other therapeutics and/or with new formulations and immunization protocols. This review briefly describes the design of conserved multiepitope constructs and outlines the results of these vaccine candidates in the recent clinical pipeline.

Lamivudine-based two-drug regimens with dolutegravir or protease inhibitor: Virological suppression in spite of previous therapy failure or renal dysfunction

Abstract Background Two-Drug Regimens (2DR) have proven effective in clinical trials but real-world data, especially in resource-limited settings, is limited. Objectives To evaluate viral suppression of lamivudine-based 2DR, with dolutegravir or ritonavir-boosted protease inhibitor (lopinavir/r, atazanavir/r or darunavir/r), among all cases regardless of selection criteria. Patients and methods A retrospective study, conducted in an HIV clinic in the metropolitan area of São Paulo, Brazil. Per-protocol failure was defined as viremia above 200 copies/mL at outcome. Intention-To-Treat-Exposed (ITT-E) failure was considered for those who initiated 2DR but subsequently had either (i) Delay over 30 days in Antiretroviral Treatment (ART) dispensation, (ii) ART changed or (iii) Viremia > 200 copies/mL in the last observation using 2DR. Results Out of 278 patients initiating 2DR, 99.6% had viremia below 200 copies/mL at last observation, 97.8% below 50 copies/mL. Lamivudine resistance, either documented (M184V) or presumed (viremia > 200 copies/mL over a month using 3TC) was present in 11% of cases that showed lower suppression rates (97%), but with no significant hazard ratio to fail per ITT-E (1.24, p= 0.78). Decreased kidney function, present in 18 cases, showed of 4.69 hazard ratio (p= 0.02) per ITT-E for failure (3/18). As per protocol analysis, three failures occurred, none with renal dysfunction. Conclusions The 2DR is feasible, with robust suppression rates, even when 3TC resistance or renal dysfunction is present, and close monitoring of these cases may guarantee long-term suppression.

Manifestaciones bucales en pacientes con SIDA bajo terapia antirretroviral en un hospital en Perú / Oral manifestations in AIDS patients receiving antiretroviral therapy in a referral hospital in Peru

Resumen Objetivo: Determinar la prevalencia de las manifestaciones bucales, en pacientes con SIDA bajo terapia antirretroviral en un Hospital Referencial en Perú. Materiales y métodos: Estudio prospectivo, no experimental, transversal y cuantitativo. Se contó con una población de 380 y una muestra de 191 pacientes, que cumplieron los criterios de selección. El instrumento utilizado fue una ficha de recolección de datos adaptada, que consta de dos partes, en una los datos personales y en otra las manifestaciones bucales más frecuentes. Resultados: La prevalencia de las manifestaciones bucales en pacientes con SIDA bajo terapia antirretroviral en un 59.50%, siendo la candidiasis oral la más frecuente con un 35.5%; El predominio de estas manifestaciones bucales es mayor en el género masculino con un 67% y en el rango de edades entre 18-25 años en un 57%. Conclusiones: Existe alta prevalencia de manifestaciones bucales en pacientes con SIDA bajo terapia antirretroviral, siendo la más frecuente la candidiasis oral, en el género masculino y en menores de 25 años.

Abstract Objective: TodeterminetheprevalenceoforalmanifestationsinAIDS patients, under antiretroviral therapy in a referral hospital in Perú. Materials and methods: A prospective, not experimental, cross - sectional and quantitative study. There was a population consisting of 380 and a sample of 191 patients who met the selection criteria. The instrument was an adapted data collection form that consist of two parts, in one the personal data and in another the most frequent oral manifestations. Results: The prevalence of oral manifestations in AIDS patients under antiretroviral therapy in 59.50% with oral candidiasis being the most frequent with 35.5%, the prevalence of oral manifestations is higher in male gender with a 67% and in the age range between 18-25 years old in a 57%. Conclusions: There is a high prevalence of oral manifestations in patients with AIDS under antiretroviral therapy, the most frequent being oral candidiasis in males and in those under 25 years old.

Alteraciones en la producción de citosinas en respuesta a Toxoplasma gondii aparecen desde las etapas tempranas en pacientes co-infectados con VIH-1 / Alterations in the production of cytokines in response to Toxoplasma gondii appear from early stages in patients co-infected with HIV-1

Resumen Tanto el Virus de Inmunodeficiencia Humana-1 (VIH-1), como el protozoo Toxoplasma gondii son capaces de infectar al ser humano e invadir su sistema nervioso central (SNC). En individuos inmunocompetentes T. gondii causa infecciones crónicas, generalmente asintomáticas; sin embargo, la inmunodeficiencia asociada a etapas avanzadas de la infección por VIH-1, se relaciona con la pérdida del control de la infección parasitaria latente y enfermedades graves a nivel del SNC, como encefalitis toxoplásmica. Este trabajo tuvo como objetivo evaluar la evolución de la respuesta inmunitaria contra T. gondii en pacientes co-infectados con VIH-1, en distintas etapas de la infección viral. La respuesta contra T. gondii se evaluó a través de la producción in vitro de citosinas en respuesta a antígenos parasitarios, en individuos con serología positiva para VIH-1 y negativa para T. gondii (P1), positiva para VIH-1 y T. gondii (P2), negativa para VIH-1 y T. gondii (C1) y negativa para VIH-1 y positiva para T. gondii (C2). Los pacientes (P1 y P2) se agruparon en tempranos/asintomáticos (P1A, P2A) o tardíos/sintomáticos (P1B/C, P2B/C) de acuerdo a su recuento de linfocitos T CD4+ en sangre periférica (>350 o <350 células/μL, respectivamente). La infección por VIH-1, desde etapas tempranas, se asoció con una producción de IL-2, TNF-α e IFN-γ en respuesta a T. gondii significativamente menor. Estos defectos pueden entorpecer la respuesta anti-T. gondii en pacientes co-infectados, aumentando la posibilidad de reactivación de las infecciones latentes, lo que representa un riesgo para la integridad y funcionalidad del SNC.

Abstract Both HIV-1 and Toxoplasma gondii are able to invade central nervous system and affect its functionality. Advanced HIV-1 infection has been associated with defects in immune response to T. gondii, leading to reactivation of latent infections and the appearing of toxoplasmic encephalitis. This study evaluated changes in the immune response to T. gondii in different stages of HIV infection. Immune response to T. gondii was assessed studying cytokine production in response to parasite antigens in HIV-1-infected/T. gondii-noninfected (P1), HIV-1/T. gondii co-infected (P2), HIV-1-non-infected/T. gondiinon-infected (C1) and HIV-1-non-infected/T. gondii-infected (C2) individuals. Patients (P1 and P2) were divided in early/asymptomatic (P1A, P2A) or late/symptomatic (P1B/C, P2B/C) according to peripheral blood CD4+ T lymphocyte counts (>350 or <350/μL, respectively). The HIV-1 infection, from early/asymptomatic stages, was associated with significant lower production of IL-2, TNF-α and IFN-γ in response to T. gondii, when P2 patients were compared with C2 controls. These early defects may impair anti-parasitic response in co-infected patients, allowing to reactivation of parasitic latent infection, enhancing the risk of CNS damage and impairment of neurocognitive functions.

Expresión de los componentes del inflamasoma y su relación con los marcadores de riesgo cardiovascular en personas con infección por HIV-1 / Expression of the inflammasome components and its relationship with cardiovascular risk markers in people living with HIV-1

Introducción. La infección por el HIV-1 induce un estado de inflamación crónico en el que participan los inflamasomas. El incremento de los parámetros inflamatorios es mayor en individuos con replicación viral activa que en aquellos con control de la replicación viral. Este proceso desencadena alteraciones metabólicas relacionadas con cambios en el perfil lipídico, lo cual podría incrementar el riesgo de eventos cardiovasculares, incluso en pacientes con terapia antirretroviral. Objetivo. Establecer si existe correlación entre la expresión de los componentes de los inflamasomas y los marcadores de riesgo cardiovascular en individuos con control de la replicación viral y en aquellos con replicación viral activa con terapia antirretroviral o sin ella. Materiales y métodos. Se estudiaron 13 individuos con control de la replicación viral y 40 con replicación viral activa (19 sin terapia antirretroviral y 31 con terapia). Se evaluaron los marcadores clásicos de riesgo cardiovascular y se cuantificó mediante RT-PCR la expresión de los componentes de los inflamasomas (NLRP1, NLRP3, NLRC4, AIM2, ASC, IL-1ß, IL-18 y caspasa-1), TLR2, TLR4, TGF-ß e IL-10. Resultados. Se observó que los pacientes con replicación viral activa y con terapia antirretroviral presentaron un incremento en la expresión de TLR2, TLR4 e IL-18, comparados con los controladores del HIV-1. Además, mostraron grandes valores de triglicéridos y lipoproteína de muy baja densidad (Very Low Density Lipopretein, VLDL), lo que se correlaciona positivamente con la expresión de los componentes de los inflamasomas NLRP1, NLRP3, NLRC4, AIM2, ASC y caspasa-1. Conclusión. El aumento en la expresión de los componentes de los inflamasomas en los individuos con replicación viral activa y con terapia antirretroviral se correlacionó con las concentraciones de triglicéridos y VLDL, lo que sugiere el papel de la activación inmunitaria y la terapia antirretroviral en el riesgo cardiovascular.

Introduction: HIV-1 infection induces a chronic inflammatory state in which inflammasomes participate. The increase in inflammatory parameters is higher in individuals with active viral replication (progressors) than in those with viral control (HIV-1 controllers). This process triggers metabolic alterations related to changes in the lipid profile, which could increase the risk of cardiovascular events, even in patients with antiretroviral therapy. Objective: To establish whether there was a correlation between the expression of inflammasome components and cardiovascular risk markers in HIV-1 controllers and progressors with or without antiretroviral therapy. Materials and methods: We studied 13 HIV-1 controllers and 40 progressors (19 without antiretroviral therapy and 31 with therapy) and evaluated in them classic markers of cardiovascular risk. Using RT-PCR we quantified the expression of inflammasome components (NLRP1, NLRP3, NLRC4, AIM2, ASC, IL-1ß, IL-18, and caspase-1), TLR2, TLR4, TGF-ß, and IL-10. Results: Progressors with antiretroviral therapy had an increased expression of TLR2, TLR4, and IL-18 compared to HIV-1 controllers. They also showed high levels of triglycerides and VLDL, which positively correlated with the expression of the inflammasome components NLRP1, NLRP3, NLRC4, AIM2, ASC, and caspase-1. Conclusion: Progressors receiving antiretroviral therapy exhibited an increased expression of the inflammasome components, which correlated with the levels of triglycerides and VLDL. This supports the role of inflammation in cardiovascular risk during HIV-1 infection.