Association of first-line combination antiretroviral therapy with malaria among adult HIV-infected persons in Jos, Nigeria: a pilot cross sectional study.

BACKGROUND: Malaria and human immunodeficiency virus (HIV) infection coexist in significant numbers in some geographic areas including sub-Sahara Africa (SSA). HIV-infected patients are a World Health Organization (WHO) recognized high risk group for increased malaria morbidity. Majority of HIV-infected patients undertaking treatment in SSA are on WHO recognized first-line combination antiretroviral therapy (cART). Considering the immunity-enhancing capacity of antiretroviral therapies on people living with HIV, this study aimed to explore the association between first-line combination antiretroviral therapy (cART) with malaria parasitaemia and antigenaemia in adult HIV-infected persons and to determine the predictors of malaria antigenaemia in adult persons living with HIV. METHODS: The study was conducted at the AIDS Prevention Initiative in Nigeria (APIN) Centre, Jos University Teaching Hospital, Jos, Plateau State, from August 2018 to February 2019. Epi Info statistical tool was used to determine the sample size and power of the study. The study population consisted of three groups. The first group comprised first-line cART-experienced adult HIV-seropositive subjects, the second group comprised ARV-naïve HIV-seropositive adults and the third group comprised HIV-seronegative adults. For this pilot study, 60 persons were recruited into each group via convenience sampling. Malaria rapid diagnostic test (RDT) was performed according to manufacturer's instruction for all the study participants using SD Bioline Malaria Ag P.f (HRP2/pLDH) (Standard Diagnostics, Hagal-Dong, Korea). All the study participants also had thick and thin blood film malaria microscopy. Data collected was processed and analyzed using the Stata statistical software version 15 (StataCorp, College Station, Texas). Chi square was used to test the association between malaria and first-line cART exposure. Univariate and multivariate analysis were also done to identify factors that were independently associated with malaria antigenaemia. RESULTS: A total of 180 persons participated in the study and involved 60 participants recruited in each of the three study groups. Overall, the predominant study participants were females (56.67%), traders (27.78%), secondary school leavers (43.33%) and urban dwellers (88.89%). Their mean age and standard deviation was 37.07 ± 11.53 years. Using malaria microscopy, the prevalence of malaria parasitaemia in ARV-naïve HIV-infected persons was 5% and 0% in the first-line cART-experienced HIV-infected persons as well as the HIV-negative persons. Malaria RDT result was positive in 7/60 (11.67%) of the first-line cART experienced HIV-infected participants, 6/60 (10%) of the ARV-naïve HIV-infected group and 1/60 (1.67%) of the HIV-negative group. Of the seven positive malaria RDT results in those on first-line cART, five persons were receiving zidovudine/lamivudine/nevirapine (AZT/3TC/NVP) while the remaining two were receiving tenofovir disoproxil fumarate/lamivudine/efavirenz (TDF/3TC/EFV), thus making an antigenaemia proportion of 16.67% and 6.67% respectively. Being an HIV-infected person on first-line cART (OR = 16.20, p = 0.04), having a headache (OR = 6.21, p = 0.03) and non-usage of window nets (OR = 3.74, p = 0.05) were found to be predictors of malaria antigenaemia. CONCLUSION: Malaria parasite burden in HIV-infected persons on first-line cART is lower than that observed in ARV-naïve HIV-infected persons. Our study suggests that TDF/3TC/EFV may be associated with lower malaria antigenaemia when compared with AZT/3TC/NVP and can be considered an alternative first-line antiretroviral regimen in malaria-endemic regions.

Incidence and predictors of virological failure among HIV infected children and adolescents receiving second-line antiretroviral therapy in Uganda, a retrospective study.

BACKGROUND: In Uganda, 20% (19,073/94,579) of children and adolescents (0-19 years) living with HIV (CALHIV) were receiving second-line antiretroviral therapy (ART) by the end of March 2020. Data on incidence and predictors of virological failure among these CALHIV on second-line ART is limited. Lack of this information and limited access to HIV drug resistance testing prevents early identification of CALHIV at risk of virological failure on second-line ART. The aim of this study was to determine the incidence and predictors of virological failure among CALHIV on second-line ART in Uganda. METHODOLOGY: This was a retrospective cohort study of all CALHIV aged 0-19 years who were switched to second-line ART regimen between June 2010 and June 2019 at the Baylor Uganda Centre of Excellence clinic. Data was analysed using STATA 14. Cumulative incidence curves were used to assess incidence of virological failure. Factors associated with virological failure were identified using sub-distributional hazard regression analysis for competing risks considering death, transfer out and loss to follow-up as competing risks. RESULTS: Of 1104 CALHIV, 53% were male. At switch to Protease Inhibitor (PI) based second-line ART, majority (47.7%) were aged 5 - 9 years,56.2% had no/mild immune suppression for age while 77% had viral load copies < 100,000 copies/mL. The incidence of virological failure on second-line ART regimen among CALHIV was 3.9 per 100 person-years (PY) with a 10-year cumulative incidence rate of 32%. Factors significantly associated with virological failure were age 10 - 19 years (HR 3.2, 95% 1.6 - 6.2, p < 0.01) and HIV viral load count > 100,000 copies/mL (HR 2.2, 95% CI 1.5 - 3.1), p < 0.01) prior to second-line ART switch. CONCLUSION: Treatment outcomes for children and adolescents on second-line ART are favourable with one third of them developing virological failure at 10 years of follow up. Adolescent age group and high HIV viral load at the start of second-line ART were significantly associated with virological failure on second-line ART. There is need to determine optimal strategies to improve ART treatment outcomes among adolescents with high viral load counts at second-line ART switch.

The viral load monitoring cascade in HIV treatment programmes in sub-Saharan Africa: a systematic review.

BACKGROUND: The United Nations' 95-95-95 (95% of people with HIV being aware of their diagnosis, 95% of those aware of their diagnosis being on treatment and 95% achieving viral suppression) target aims to reduce morbidity and mortality of HIV. However, with 60% of new HIV infections occurring in sub-Saharan Africa (SSA), achieving this target in the region is challenging. Viral load (VL) monitoring is the gold-standard approach of assessing treatment efficacy, and its implementation into national health systems is a global health priority if elimination of HIV as a public health threat is to be achieved by 2030. This systematic review aims to investigate VL monitoring outcomes in SSA, and to identify gaps and possible interventions to help nations meet their 2030 targets. METHODS: A literature search of three electronic platforms (MEDLINE, EMBASE and Global Health) was undertaken from 1 January to 9 August 2024 to identify studies published in English and conducted in SSA. The primary outcome was the proportion of people living with HIV (PLHIV) on antiretroviral therapy (ART) with routine VL monitoring at the recommended time points (initially, 6 months, 12 months and annually). Secondary outcomes reported proportions of PLHIV who received routine VL monitoring who went on to complete the cascade of care after identified virological failure [enhanced adherence counselling (EAC), switch to second-line ART, and finally viral suppression]. RESULTS: The initial search identified 342 papers, of which 35 studies were included for narrative synthesis. Included studies reported on findings from 14 African countries and demonstrated extensive variation in rates of VL monitoring (range: 24.3-99.7%, mean: 63.8%). Results were more unfavourable in the latter steps of the viral load monitoring cascade, with a range of 0-88%, and a switch to second-line ART mean of 42% (range: 4.4-93%). Studies with additional support, and those with community-based models of care, had higher rates of VL testing and viral suppression. CONCLUSIONS: VL monitoring and management of virological failure are suboptimal in many SSA countries due to individual and health system-related challenges. Health system strengthening is vital to ensure the sustainability of HIV treatment programmes and the achievement of 95-95-95 targets by 2030.

Peripheral neuropathy and associated factors among children living with HIV on antiretroviral therapy in Gamo zone, Southern Ethiopia: an institution-based cross-sectional study.

BACKGROUND: Peripheral neuropathy (PN) is a common neurological complication of HIV (Human Immunodeficiency Virus) that can significantly affect patients' quality of life. In Ethiopia, children living with HIV are at an increased risk of developing peripheral neuropathy due to comorbidities such as anemia, tuberculosis, malnutrition, and poor socio-economic status. Our study aims to evaluate the prevalence of peripheral neuropathy among children living with HIV in Ethiopia using a simple clinical screening tool. METHODS: A health institution-based cross-sectional study was conducted among 148 children aged 5 to 18 years living with HIV who are receiving treatment at the antiretroviral therapy (ART) clinic of the randomly selected public health institutions in the Gamo zone. An interview and neurologic examination were conducted. A binary logistic regression model was used to identify factors associated with the outcome variable. Variables with p-value < 0.25 in the bi-variable logistic regression analysis were entered and checked for association in a multivariable logistic regression model. The level of statistical significance was declared at the p-value < 0.05. RESULT: In this study, 148 children participated, making a response rate of 97.5%. The mean ± standard deviation (SD) age of the respondents was 15.03 ± 2.99 years, and 81(54.7%) were male. The magnitude of PN was 20.9% (31/148). Children in the age category of 15-18 (adjusted odds ratio (AOR) = 1.88, 95%CI; 1.24-4.60), low BMI for age (AOR = 1.66, 95%CI; 1.12-4.15), last exposure to isoniazid within 1 year (AOR = 2.31, 95%CI; 1.12-8.53). Longer duration of HIV illness (AOR = 2.17, 95%CI; 1.54-4.64), and past tuberculosis (TB) treatment (AOR = 2.11, 95%CI; 1.08-7.48) were significantly associated factors with peripheral neuropathy. CONCLUSION: Our analysis revealed that being in the age category of 15-18 years, low BMI for age, Isoniazid exposure, longer Duration of HIV illness, and past TB treatment were significantly associated with peripheral neuropathy in children living with HIV. These disease-related factors may contribute to the development and progression of peripheral neuropathy in this population. CLINICAL TRIAL NUMBER: Not applicable.

Incidence of loss to follow-up and its predictors among HIV-infected under-five children after initiation of antiretroviral therapy in West Amhara Comprehensive Specialized Referral Hospitals, Northwest Ethiopia: a multicenter retrospective follow-up study.

BACKGROUND: Loss to follow-up (LTFU) among under-five children from HIV care profoundly affects the treatment outcomes of this vulnerable population. It is a major factor that negatively affects the benefits of antiretroviral therapy (ART). Current information about LTFU among HIV-positive under-five children on ART is essential for effective treatments. To far, nevertheless, limited research has been done in Ethiopia to address this issue. Thus, this study aimed to assess the incidence and predictors of LTFU among HIV-infected under-five children receiving ART in West Amhara Comprehensive Specialized Referral Hospitals. METHODS: A multicenter institution-based retrospective follow-up study was conducted among 435 HIV-infected under-five children on ART selected by simple random sampling from January 1, 2010 to December 31, 2019, and data were collected between December 1, 2021, and January 31, 2022. A standardized data extraction tool adapted from the ART entry and follow-up forms was used. The event of interest for this study was LTFU, whereas the absence of LTFU was censored. Before being transferred to STATA version 14 for analysis, the data were entered into Epi-Data version 3.1. The Kaplan‒Meier curve was used to estimate an individual's survival-free probability at each specific point in time. The Cox proportional hazards model was used to identify predictors of LTFU. RESULTS: Among the 420 records included in the final analysis, 30 (7.14%) of the individuals were LTFUs. The incidence rate of LTFU was 3.4 per 1000 person-months of observation (95% CI: 2.43-4.87). The survival probabilities of children after 12, 24, 36, and 48 months were 0.97, 0.92, 0.88, and 0.77, respectively. The independent predictors of LTFU were HIV infection in under-five children who lived in rural areas (AHR = 3.64; 95% CI: 1.41, 9.37), poor adherence to ART (AHR = 4.37; 95% CI: 1.59, 12.02), not receiving cotrimoxazole preventive therapy (AHR = 3.75; 95% CI: 1.39, 10.08), not receiving isoniazid prophylaxis (AHR = 3.4; 95% CI: 1.29, 9.01), and having a severe WHO clinical stage (AHR = 5.43; 95% CI: 1.38, 11.43). CONCLUSION AND RECOMMENDATION: The incidence of loss to follow-up was high, especially in the first two years after ART initiation. The risk of LTFU was greater for those who were rural residents, had poor adherence, lacked cotrimoxazole preventive therapy, not given isoniazid prophylaxis, and presented with WHO clinical stages III and IV. Therefore, clinicians should emphasize for cotrimoxazole preventive therapy and isoniazid prophylaxis, for those living in rural areas, who present with poor adherence and WHO clinical stages III and IV.

Burden of metabolic syndrome in the global adult HIV-infected population: a systematic review and meta-analysis.

BACKGROUND: Metabolic syndrome (MetS) elevates the risk of heart disease and stroke. In recent decades, the escalating prevalence of MetS among people living with HIV/AIDS (PLWHA) has garnered global attention. Despite MetS development being associated with both traditional and HIV-related factors, evidence from prior studies has shown variability across geographical regions. This study aimed to conduct a systematic review and meta-analysis of MetS burdens in adult PLWHA at the regional and global levels, focusing on the common effect size of HIV infection and antiretroviral therapy (ART) on MetS. METHODS: This review followed the PRISMA 2020 guidelines. A comprehensive search and review of original articles related to MetS and HIV published in peer-reviewed journals between January 2000 and December 2023 were conducted. A random effects model was used to calculate the pooled prevalence/incidence of MetS and the common effect size of HIV infection and ART exposure on MetS. RESULTS: A total of 102 studies from five continents comprising 78,700 HIV-infected participants were included. The overall pooled prevalence of MetS was 25.3%, 25.6% for PLWHA on ART, and 18.5% for those not receiving treatment. The pooled incidence of MetS, calculated from five studies, was 9.19 per 100 person-years. The highest pooled prevalence of MetS was observed in the Americas (30.4%), followed by the Southeast Asia/Western Pacific regions (26.7%). HIV-infected individuals had 1.6 times greater odds of having MetS than non-HIV-infected individuals did (pooled OR = 1.604; 95% CI 1.154-2.230), and ART exposure had 1.5 times greater odds of having MetS than nontreatment had (pooled OR = 1.504; 95% CI 1.217-1.859). CONCLUSIONS: HIV infection and ART exposure contribute significantly to the increased burden of MetS. Regions with a high burden of HIV and MetS should prioritize awareness and integrated care plans for major noncommunicable diseases (NCDs), such as heart disease and stroke. The implementation of integrated care for HIV/AIDS patients and NCDs is essential for addressing the high burden of multimorbidity in PLWHA. REGISTRATION NUMBER: INPLASY202290018.

Predictors of Adherence to Antiretroviral Therapy among People Living with HIV in Northern Egypt.

Background: Adherence to medications is a crucial factor in achieving the best therapeutic outcomes for patients who have human immunodeficiency virus (HIV). Little is known about the rate and predictors of adherence to antiretroviral therapy (ART) in Egypt. Objectives: To assess the degree of adherence to ART among people living with HIV/AIDS (PLWHA) in Egypt and to explore the predictors of non-adherence. Methods: A cross-sectional study was conducted from January 2021 to December 2021 on 785 PLWHA attending an ART clinic at the main fever hospital in Alexandria, Egypt. Data collection was done using an interviewing questionnaire and pharmacy database records. Multivariate logistic regression analysis was done to identify the predictors of adherence to ART. Results: The overall adherence rate to ART among the study subjects was 66.7%. Female sex (Adjusted Odds Ratio [95% CI]: 1.73 [1.01-2.96]), intravenous drug use (AOR [95% CI]: 2.87 [1.27-6.49]), fair satisfaction with the health service at ART clinics (OR [95% CI]: 1.86 [1.27-2.73]) appeared as independent predictors of poor adherence. Conclusion: The degree of adherence to ART among PLWHA in Egypt is noticeably high, although it was influenced by several patient-, healthcare-, and community-related factors. This work provides an accurate, standardized tool to measure adherence and identify factors that contribute to non-adherence.

The severity of distal sensory polyneuropathy increasing with HIV/AIDS stage.

Distal sensory polyneuropathy (DSP) is the most common neurological problem in HIV/AIDS Patients. It represents a complex symptom that occurs because of peripheral nerve damage related to advanced HIV disease and in association with the use of antiretroviral therapy. DSP is a frequent symptom in which the specific pathophysiology is not well understood. Recently, mitochondrial toxicity and antiretroviral toxic neuropathies have been more identified as a possible etiology of DSP. This study's objective was to determine factors associated with DSP severity in HIV/AIDS patients. This cross-sectional study was followed by 50 HIV/AIDS outpatients at some hospitals in Makassar, Indonesia who met the inclusion criteria. DSP is diagnosed using non-invasive screening tools subjective peripheral neuropathy screen (SPNS) which can determine the severity of DSP in advance. Some factors were analyzed by using Pearson's chi-square test and Spearman's correlation test. Forty-three participants (86%) had diagnosed DSP which is mostly moderate in severity (48%). Statistical analysis showed significant correlation between HIV/AIDS Stage and DSP severity (p=0.032) meanwhile CD4 count, antiretroviral, body mass index (BMI), and hemoglobin level have no significant correlation to DSP severity. In conclusion, HIV/AIDS stage and DSP severity correlate where the later the stage the more severe DSP.

Clinico-epidemiological characteristics of adolescents and young adults living with HIV in Ghana.

Introduction: sub-Saharan Africa is experiencing a boom in the number of adolescents and young adults living with HIV (AYALHIV). Existing HIV intervention programs are mainly for children and adults living with HIV, with little attention paid to AYALHIV. Characterizing this population is necessary for planning, and designing, AYALHIV-centered HIV intervention programs. Methods: a retrospective single-center, hospital-based chart review was conducted at the largest HIV clinic in Ghana. We examined routinely collected data for AYALHIV (aged 10-24 years) on antiretroviral therapy (ART) for at least 1 year and in active care from 1st January to 31st December 2019. Data was collected using a structured data extraction form. The Chi-square and the Student´s t-test were used to compare characteristics between adolescents and young adults. Results: of 252 AYALHIV, 68% (172/252) were adolescents with a median age of 17 years (IQR 13-19); 32% were young adults with a median age of 22 years (IQR: 20-24). Most (56.7% (143/252)) AYALHIV were female. Almost 40% were orphans. Eighty-six percent of AYALHIV had HIV type I infection. The commonest mode of HIV acquisition among adolescents was vertical transmission (70.5%) and that among young adults was via unprotected sex (31.3%). Eighty-eight percent (88%) of AYALHIV were on non-nucleoside reverse transcriptase inhibitors-based regimen. The viral suppression rate among AYALHIV was 78%. Conclusion: the study shows there is a growing population of AYALHIV most of which are adolescents. About two-fifths were orphans. Policymakers and HIV programs should ensure AYALHIV-centred interventions are developed for this vulnerable population.

A Case Report of Lenacapavir Use in a Patient with Multidrug-Resistant HIV: The First Experience in Asia.

Lenacapavir is a novel, first-in-class, capsid inhibitor, which has been approved as an adjunctive therapy for multidrug-resistant human immunodeficiency virus (HIV)-1 virus in combination with optimized background regimen (OBR). Lenacapavir has demonstrated a significant decrease in viral load and high rate of virologic suppression in patients with multidrug-resistant HIV-1 infection with limited treatment options. Here, we report a case of 43-year-old male who was diagnosed with HIV-1 infection in 2005 but failed to achieve viral suppression due to multiclass resistance. After lenacapavir use with OBR, viral suppression was achieved, and recovery of CD4+ T-cell count was observed for 8 months. This case report shows the first lenacapavir experience in Asia in a heavily treatment-experienced HIV patient with limited treatment options.

Hodgkin's Lymphoma after Initiation of Antiretroviral Therapy in a Patient from India.

SUMMARY: Malignancies in human immunodeficiency virus (HIV) positive individuals have a larger role in morbidity and mortality. Appropriate clinical acumen is required for a clinician to anticipate the occurrence of lymphoma after starting antiretroviral therapy, especially in patients with CD4 <100 cells/mm3. Here is a 30-year-old man with weight loss and appetite, found to be retroviral disease positive status with low CD 4 counts. He was started on antiretroviral treatment, and following that, he developed Hodgkin's lymphoma of mixed cellularity. He is planned for an ABVD regimen and received one cycle of the same without any complications. To our knowledge, we are reporting the first case of an HIV patient with a mixed cellularity form of classical Hodgkin's lymphoma from India.

Feasibility and assessment of a comprehensive emergency department-based intervention for patients at risk of HIV.

Behavioral factors increase the risk of contracting HIV. A comprehensive prevention services (CPS) intervention includes risk assessment and referral for those with confirmed risk. This project sought to assess the feasibility of an emergency department (ED)-based CPS program. A prospective cross-sectional assessment was conducted from October, 2021 through May, 2023, at a single ED in Birmingham, Alabama. Either of two screening methods were subjected to HIV negative adults: 1) manual chief complaint review or 2) objective electronic medical record (EMR) query. Manual and EMR screening methods considered sexually transmitted infections (STIs) or a positive urine drug test (to observe for commonly injectable drugs) within 12 months of current ED visit. Identified patients were approached in the ED (manual review) or via phone (EMR alert). Persons confirmed at risk for HIV following engagement questionnaire completion were made aware of their risk and offered referral to local CPS clinics. Primary outcome was CPS linkage. Descriptive analysis was performed. Of 184 patients approached, 147 agreed to engagement (79.9%), 117 in-person and 30 via phone; 125 (85.1%) were confirmed at risk for HIV; majority were white (66.4%), male (63.2%), between the ages of 30 and 49 (64.8%), uninsured (78.4%), and without a primary care provider (93.6%). Sexual behavior was identified as a recent (within six months) risk factor in 97 (77.6%) patients. Injection drug use was identified as a recent (within six months) risk factor in 71 (56.8%) patients. Fifty-four (43.2%) expressed interest in obtaining CPS follow-up. To-date, ten patients (18.5%) have connected with a CPS counsellor via phone and five (9.3%) have had a subsequent follow-up appointment to discuss CPS with a medical provider. Thirty at-risk patients (24.0%) received ED-initiated buprenorphine/naloxone. Targeted screening tools can aid in the identification of persons at risk for HIV in the ED; further, subsequent engagement and CPS implementation amongst this cohort is feasible. CPS clinic linkage may be challenging however, a CPS definition inclusive of ED-initiated medication for opioid use disorder, may offer opportunity for increased uptake.

Mapping Transmission Dynamics and Drug Resistance Surveillance in the Cyprus HIV-1 Epidemic (2017-2021).

The human immunodeficiency virus type 1 (HIV-1) epidemic has been a major public health threat on a global scale since the early 1980s. Despite the introduction of combination antiretroviral therapy (cART), the incidence of new HIV-1 infections continues to rise in some regions around the world. Thus, with the continuous transmission of HIV-1 and the lack of a cure, it is imperative for molecular epidemiological studies to be performed, to monitor the infection and ultimately be able to control the spread of this virus. This work provides a comprehensive molecular epidemiological analysis of the HIV-1 infection in Cyprus, through examining 305 HIV-1 sequences collected between 9 March 2017 and 14 October 2021. Employing advanced statistical and bioinformatic techniques, the research delved deeply into understanding the transmission dynamics of the HIV-1 epidemic in Cyprus, as well as the monitoring of HIV-1's genetic diversity and the surveillance of transmitted drug resistance. The characterization of Cyprus's HIV-1 epidemic revealed a diverse landscape, comprising 21 HIV-1 group M pure subtypes and circulating recombinant forms (CRFs), alongside numerous uncharacterized recombinant strains. Subtypes A1 and B emerged as the most prevalent strains, followed by CRF02_AG. The findings of this study also revealed high levels of transmitted drug resistance (TDR) patterns, raising concerns for the efficacy of cART. The demographic profiles of individuals involved in HIV-1 transmission underscored the disproportionate burden borne by young to middle-aged Cypriot males, particularly those in the MSM community, who reported contracting the virus in Cyprus. An assessment of the spatiotemporal evolutionary dynamics illustrated the global interconnectedness of HIV-1 transmission networks, implicating five continents in the dissemination of strains within Cyprus: Europe, Africa, Asia, North America, and Oceania. Overall, this study advances the comprehension of the HIV-1 epidemic in Cyprus and highlights the importance of understanding HIV-1's transmission dynamics through continuous surveillance efforts. Furthermore, this work emphasizes the critical role of state-of-the-art bioinformatics analyses in addressing the challenges posed by HIV-1 transmission globally, laying the groundwork for public health interventions aimed at curbing its spread and improving patient outcomes.

Next-Generation Sequencing Reveals a High Frequency of HIV-1 Minority Variants and an Expanded Drug Resistance Profile among Individuals on First-Line ART.

We assessed the performance and clinical relevance of Illumina MiSeq next-generation sequencing (NGS) for HIV-1 genotyping compared with Sanger sequencing (SS). We analyzed 167 participants, 45 with virologic failure (VL ≥ 1000 copies/mL), i.e., cases, and 122 time-matched participants with virologic suppression (VL < 1000 copies/mL), i.e., controls, 12 months post-ART initiation. Major surveillance drug resistance mutations (SDRMs) detected by SS were all detectable by NGS. Among cases at 12 months, SS identified SDRMs in 32/45 (71.1%) while NGS identified SDRMs among 35/45 (77.8%), increasing the number of cases with SDRMs by 3/45 (6.7%). Participants identified with, and proportions of major SDRMs increased when NGS was used. NGS vs. SS at endpoint revealed for NNRTIs: 36/45 vs. 33/45; Y181C: 26/45 vs. 24/45; K103N: 9/45 vs. 6/45 participants with SDRMs, respectively. At baseline, NGS revealed major SDRMs in 9/45 (20%) cases without SDRMs by SS. Participant MBL/043, among the nine, the following major SDRMs existed: L90M to PIs, K65R and M184V to NRTIs, and Y181C and K103N to NNRTIs. The SDRMs among the nine increased SDRMs to NRTIs, NNRTIs, and PIs. Only 43/122 (25.7%) of participants had pre-treatment minority SDRMs. Also, 24.4% of the cases vs. 26.2 of controls had minority SDRMs (p = 0.802); minority SDRMs were not associated with virologic failure. NGS agreed with SS in HIV-1 genotyping but detected additional major SDRMs and identified more participants harboring major SDRMs, expanding the HIV DRM profile of this cohort. NGS could improve HIV genotyping to guide treatment decisions for enhancing ART efficacy, a cardinal pre-requisite in the pursuit of the UNAIDS 95-95-95 targets.

A Comparison of Sanger Sequencing and Amplicon-Based Next Generation Sequencing Approaches for the Detection of HIV-1 Drug Resistance Mutations.

BACKGROUND: Next-generation sequencing (NGS) kits are needed to finalise the transition from Sanger sequencing to NGS in HIV-1 genotypic drug resistance testing. MATERIALS AND METHODS: We compared a homemade NGS amplicon-based protocol and the AD4SEQ HIV-1 Solution v2 (AD4SEQ) NGS kit from Arrow Diagnostics for identifying resistance-associated mutations (RAMs) above the 5% threshold in 28 plasma samples where Sanger sequencing previously detected at least one RAM. RESULTS: The samples had a median 4.8 log [IQR 4.4-5.2] HIV-1 RNA copies/mL and were mostly subtype B (61%) and CRF02_AG (14%). Homemade NGS had a lower rate of samples with low-coverage regions (2/28) compared with AD4SEQ (13/28) (p < 0.001). Homemade NGS and AD4SEQ identified additional mutations with respect to Sanger sequencing in 13/28 and 9/28 samples, respectively. However, there were two and eight cases where mutations detected by Sanger sequencing were missed by homemade NGS and AD4SEQ-SmartVir, respectively. The discrepancies between NGS and Sanger sequencing resulted in a few minor differences in drug susceptibility interpretation, mostly for NNRTIs. CONCLUSIONS: Both the NGS systems identified additional mutations with respect to Sanger sequencing, and the agreement between them was fair. However, AD4SEQ should benefit from technical adjustments allowing higher sequence coverage.

Comparative Effects of Efavirenz and Dolutegravir on Metabolomic and Inflammatory Profiles, and Platelet Activation of People Living with HIV: A Pilot Study.

Antiretroviral therapy (ART) has reduced the mortality and morbidity associated with HIV. However, irrespective of treatment, people living with HIV remain at a higher risk of developing non-AIDS-associated diseases. In 2019, the World Health Organization recommended the transition from efavirenz (EFV)- to dolutegravir (DTG)-based ART. Data on the impact of this transition are still limited. The current study therefore investigated the metabolic profiles, cytokine inflammatory responses, and platelet activation before and after the treatment transition. Plasma samples from nine virally suppressed adults living with HIV and sixteen healthy, HIV-uninfected individuals residing in Gauteng, South Africa were compared. Metabolite and cytokine profiles, and markers associated with platelet activation, were investigated with untargeted proton magnetic resonance metabolomics, multiplex suspension bead array immunoassays, and sandwich enzyme-linked immunosorbent assays, respectively. In those individuals with normal C-reactive protein levels, the transition to a DTG-based ART regimen resulted in decreased concentrations of acetoacetic acid, creatinine, adenosine monophosphate, 1,7-dimethylxanthine, glycolic acid, 3-hydroxybutyric acid, urea, and lysine. Moreover, increased levels of formic acid, glucose, lactic acid, myo-inositol, valine, glycolic acid, and 3-hydroxybutyric acid were observed. Notably, levels of interleukin-6, platelet-derived growth factor-BB, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, soluble cluster of differentiation 40 ligand, as well as regulated on activation, normal T-cell expressed and secreted (RANTES) reached levels close to those observed in the healthy control participants. The elevated concentration of macrophage inflammatory protein-1 alpha was the only marker indicative of elevated levels of inflammation associated with DTG-based treatment. The transition from EFV- to DTG-based regimens therefore appears to be of potential benefit with metabolic and inflammatory markers, as well as those associated with cardiovascular disease and other chronic non-AIDS-related diseases, reaching levels similar to those observed in individuals not living with HIV.

New Therapies and Strategies to Curb HIV Infections with a Focus on Macrophages and Reservoirs.

More than 80 million people worldwide have been infected with the human immunodeficiency virus (HIV). There are now approximately 39 million individuals living with HIV/acquired immunodeficiency syndrome (AIDS). Although treatments against HIV infection are available, AIDS remains a serious disease. Combination antiretroviral therapy (cART), also known as highly active antiretroviral therapy (HAART), consists of treatment with a combination of several antiretroviral drugs that block multiple stages in the virus replication cycle. However, the increasing usage of cART is inevitably associated with the emergence of HIV drug resistance. In addition, the development of persistent cellular reservoirs of latent HIV is a critical obstacle to viral eradication since viral rebound takes place once anti-retroviral therapy (ART) is interrupted. Thus, several efforts are being applied to new generations of drugs, vaccines and new types of cART. In this review, we summarize the antiviral therapies used for the treatment of HIV/AIDS, both as individual agents and as combination therapies, and highlight the role of both macrophages and HIV cellular reservoirs and the most recent clinical studies related to this disease.

K103N, V106M and Y188L Significantly Reduce HIV-1 Subtype C Phenotypic Susceptibility to Doravirine.

Doravirine (DOR) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with efficacy against some NNRTI-resistant mutants. Although DOR resistance mutations are established for HIV-1 subtype B, it is less clear for non-B subtypes. This study investigated prevalent NNRTI resistance mutations on DOR susceptibility in HIV-1 subtype C. Prevalent drug resistance mutations were identified from a South African genotypic drug resistance testing database. Mutations, single or in combination, were introduced into replication-defective pseudoviruses and assessed for DOR susceptibility in vitro. The single V106M and Y188L mutations caused high-level resistance while others did not significantly impact DOR susceptibility. We observed an agreement between our in vitro and the Stanford HIVdb predicted susceptibilities. However, the F227L mutation was predicted to cause high-level DOR resistance but was susceptible in vitro. Combinations of mutations containing K103N, V106M or Y188L caused high-level resistance, in agreement with the predictions. These mutations are frequently observed in patients failing efavirenz- or nevirapine-based first-line regimens. However, they are also observed in those failing a protease inhibitor-based second-line regimen, as we have observed in our database. Genotypic drug resistance testing is therefore vital prior to the initiation of DOR-based treatment for those previously exposed to efavirenz or nevirapine.

Putting a Kink in HIV-1 Particle Infectivity: Rocaglamide Inhibits HIV-1 Replication by Altering Gag-Genomic RNA Interaction.

Our examination of RNA helicases for effects on HIV-1 protein production and particle assembly identified Rocaglamide (RocA), a known modulator of eIF4A1 function, as an inhibitor of HIV-1 replication in primary CD4+ T cells and three cell systems. HIV-1 attenuation by low-nM RocA doses was associated with reduced viral particle formation without a marked decrease in Gag production. Rather, the co-localization of Gag and HIV-1 genomic RNA (gRNA) assemblies was impaired by RocA treatment in a reversible fashion. Ribonucleoprotein (RNP) immunoprecipitation studies recapitulated the loss of Gag-gRNA assemblies upon RocA treatment. Parallel biophysical studies determined that neither RocA nor eIF4A1 independently affected the ability of Gag to interact with viral RNA, but together, they distorted the structure of the HIV-1 RNP visualized by electron microscopy. Taken together, several lines of evidence indicate that RocA induces stable binding of eIF4A1 onto the viral RNA genome in a manner that interferes with the ordered assembly of Gag along Gag-gRNA assemblies required to generate infectious virions.

Virologic suppression rate and associated factors for third-line HIV treatment in Addis Ababa, Ethiopia.

BACKGROUND: HIV/AIDS has left a profound impact, leading to significant mortality, morbidity, economic strain, and disability on a global scale. The introduction of antiretroviral therapy (ART) has played a pivotal role in mitigating the economic burden of HIV and enhancing overall productivity. However, the emergence of virological failure presents a critical contemporary challenge within global health, reflecting the complexity of effectively managing HIV treatment outcomes in the 21st century. METHODS: An institutional based, cross-sectional study was conducted. Data were collected using a pretested, structured checklist. Data were edited and cleaned using Microsoft Excel 2016 and analyzed using SPSS version 25. Baseline demographic and clinical data were summarized using descriptive statistics. Multiple logistic regression analysis was run to identify association between dependent and independent variables, by computing odds ratio and 95% confidence interval. A p-value < 0.05 was considered significant. RESULTS: The study delved into the health profile of 117 individuals who were receiving treatment with a third-line antiretroviral therapy (ART) regimen. The findings revealed that the median age of the participants stood at 44 (IQR = ± 17) years and male accounted 53%. The median duration of after HIV diagnosis was found to be 14.25 (± IQR = 5.71) years. Overall virological suppression after third line ART was 76.9% at 6 months. Following adjustment with multiple variable logistic regression, good adherence to medication showed statistical significance in achieving virologic suppression (AOR = 8.48(95% CI: 2.3-30.8), p = 0.001). In contrast, the absence of a change in the second line regimen (AOR = 3.0(95% CI: 0.36-24.8), p = 0.31) and receiving second-line medication for less than three years (AOR = 1.07(95% CI: 0.39-2.95), p = 0.89), and baseline viral load above 100,000 (AOR = 1.74(0.64-2.95), p = 0.27) shows statistically non-significant association with virologic suppression. CLINICAL TRIAL NUMBER: Not applicable. CONCLUSION: This multicenter study provides strong evidence on virological suppression following the use of third-line antiretroviral therapy drugs in Ethiopia. The results of the study indicate rate of Virological suppression after starting third-line ART drugs is significantly linked to good adherence.