Mitochondrial DNA mutations in HIV-exposed uninfected infants following the cessation of triple antiretroviral drugs.

OBJECTIVES: Mitochondrial mutations in HIV-exposed uninfected (HEU) infants after cessation of ART are rarely studied. We analysed a group of HEU newborns born to mothers with late HIV diagnosis who received three doses of ART immediately after birth. We observed mitochondrial DNA (mtDNA) mutations at different times of withdrawal. METHODS: The study was based on a clinical trial conducted from 2015 to 2020. Newborns of the intervention group who met the criteria for this study received triple antiretroviral drugs, zidovudine + lamivudine + nevirapine, within 2 h after the birth, as post-partum prophylaxis, and at 14 days were switched to zidovudine + lamivudine + lopinavir/ritonavir, which was continued until 6 weeks of age. From August to November 2019, blood samples from HEU infants were also collected after ceasing 12 months of ART, and analysed for mtDNA. RESULTS: Our study found that mtDNA mutations remained prevalent in HEU infants a few years after three ARTs were stopped immediately after birth. Among them, D-loop, ND1 and CYTB are the first three mutated regions during different withdrawal periods. This pattern of mutations is similar to, but not exactly consistent with, HIV-infected children receiving standard ART. CONCLUSIONS: Further studies are needed to determine the effects of these mutations on the development of HEU infants and whether stopping ART leads to the restoration of mitochondrial function.

Clinical Trials That Have Changed Clinical Practice and Care of Pregnant People With HIV.

Over the last 4 decades, significant advances in the care of HIV during pregnancy have successfully reduced, and nearly eliminated, the risk of perinatal HIV transmission. The baseline risk of transmission without intervention (25% to 30%) is now <1% to 2% in the United States with contemporary antepartum, intrapartum, and postnatal interventions. In this review, we discuss 3 landmark clinical trials that substantially altered obstetric practice for pregnant individuals with HIV and contributed to this extraordinary achievement: 1) the Pediatric AIDS Clinical Trials Group 076 Trial determined that antepartum and intrapartum administration of antiretroviral drug zidovudine to the pregnant individual, and postnatally to the newborn, could reduce the risk of perinatal transmission by approximately two-thirds; 2) the European Mode of Delivery Collaboration Trial demonstrated performance of a prelabor cesarean birth before rupture of membranes among pregnant people with viremia reduced the risk of perinatal transmission compared with vaginal birth; and 3) the International Maternal Pediatric Adolescent AIDS Clinical Trials Network 2010 Trial identified that dolutegravir-containing, compared with efavirenz-containing, antiretroviral regimens during pregnancy achieved a significantly higher rate of viral suppression at delivery with shorter time to viral suppression, with fewer adverse pregnancy outcomes. Collectively, these trials not only advanced obstetric practice but also advanced scientific understanding of the timing, mechanisms, and determinants of perinatal HIV transmission. For each trial, we will describe key aspects of the study protocol and outcomes, insights gleaned about the dynamics of perinatal transmission, how each study changed clinical practice, and relevant updates to current practice since the trial's publication.

The use of suboptimal antiretroviral therapy when applying for migration to Australia: a case series.

Background Australia imposes restrictions for people living with HIV (PLHIV) applying for permanent residency (PR), including spending less than AUD51,000 on medical costs over 10years. Some PLHIV opted for suboptimal and cheaper antiretroviral therapy (ART) regimens to increase their chances of receiving PR. We collated a case series to examine PLHIV on suboptimal ART because of visa issues. Methods We identified all patients applying for a PR in Australia who obtained nevirapine, efavirenz or zidovudine between July 2022 and July 2023 from the Melbourne Sexual Health Centre. Pathology results and records detailing psychological issues relating to the patients' wishes to remain on suboptimal ART were extracted from clinical records by two researchers. Results We identified six patients with a mean age of 39years migrating from Asian and European countries. Three patients used efavirenz, and three used nevirapine. All desired to remain on cheaper, suboptimal ART to stay below visa cost thresholds, which they considered to aid favourably with their application. Four displayed stress and anxiety arising from visa rejections, appeal deadlines and the lengthy visa application process. Conclusions Despite access to more effective and safer ART, we identified patients who chose to remain on cheaper ART to improve chances of obtaining an Australian visa, potentially putting their health at risk. We found significant evidence of stress and anxiety among patients. There is a need to review and revise current migration policies and laws in Australia that discriminate against PLHIV and jeopardise public health.

A Central Auditory Test reveals differences between drug treatment regimens in adults living with HIV.

OBJECTIVE: This exploratory study examined whether central auditory tests show differences between people living with HIV (PLWH) treated with two predominant antiretroviral drug therapy (ART) regimens. DESIGN: Cross-sectional. STUDY SAMPLE: 253 PLWH (mean age 39.8 years) from the Shanghai Public Health Clinical Centre, China. METHODS: The Hearing in Noise Test speech reception threshold (SRT) assessed central auditory function and the Montreal Cognitive Assessment (MoCA) assessed cognition. The relationship between ART regimen and SRT was evaluated with multivariable linear regression incorporating age, HIV duration, and peripheral hearing ability. Multivariable logistic regression was used to ascertain if SRT and ART regimen predicted MoCA impairment. RESULTS: The two predominant ART regimens differed by one drug (zidovudine or tenofovir). Participants taking the zidovudine-containing regimen had poorer SRT performance (p=.012) independent of age and hearing thresholds. MoCA scores did not differ between drug regimens, but a negative relationship was found between SRT and MoCA impairment (p=.048). CONCLUSIONS: ART regimens differed in their association with central auditory test performance likely reflecting neurocognitive changes in PLWH taking the zidovudine-containing regimen. Central auditory test performance also marginally predicted cognitive impairment, supporting further assessment of central auditory tests to detect neurocognitive deficits in PLWH.

In utero/peripartum antiretroviral therapy exposure and mental health outcomes at 8-18 years old: A longitudinal comparative study of children with perinatally acquired HIV, children perinatally HIV exposed but uninfected, and children unexposed uninfected from Uganda.

In utero/peripartum antiretroviral therapy (IPA) exposure type was examined in relationship to mental health symptoms among 577 children with perinatally acquired HIV (CPHIV), children perinatally HIV exposed but uninfected (CHEU), and children HIV unexposed uninfected (CHUU). IPA exposure was categorized for CPHIV and CHEU as none, single-dose nevirapine with or without zidovudine (sdNVP±AZT), sdNVP+AZT+lamivudine (3TC), or combination antiretroviral therapy (cART). Anxiety and depressive symptoms were reported at baseline, 6-, and 12-month follow-up per behavioral assessment system for children. Multivariable linear mixed models were used to estimate differences (b) with 95% confidence intervals (95% CI) for IPA exposure types versus CHEU without IPA exposure. Depressive and anxiety symptoms were lower in CHUU relative to CHEU and CPHIV but did not differ between CPHIV and CHEU. CHEU with sdNVP±AZT exposure had greater anxiety (b = 0.51, 95% CI: [0.06, 0.96]) and depressive symptoms (b = 0.48, 95% CI: [0.07, 0.89]) than CHEU without IPA exposure. CHEU with sdNVP+AZT+3TC exposure had higher anxiety (b = 0.0.45, 95% CI: [0.03, 0.86]) and depressive symptoms (b = 0.72, 95% CI: [0.27, 1.17]) versus CHEU without IPA exposure. Depressive and anxiety symptoms were not different for CHEU and CPHIV exposed to cART (b = 0.12-0.60, 95% CI: [-0.41, 1.30]) and CHEU and CHUU (b = -0.04 to 0.08, 95% CI: [-0.24, 0.29]) without IPA exposure. Among CHEU, peripartum sdNVP±AZT and sdNVP+AZT+3TC but not cART compared to no IPA exposure was associated with clinically important elevations in anxiety and depressive symptoms. Monitoring of mental health trajectory of HIV-affected children considering IPA is needed to inform mental health interventions. Patient Contribution: Caregivers and their dependents provided consent for participation and collaborated with study team to identify mutually convenient times for protocol implementation.

Metabolomic profiling of preterm birth in pregnant women living with HIV.

BACKGROUND: Preterm birth is a leading cause of death in children under the age of five. The risk of preterm birth is increased by maternal HIV infection as well as by certain antiretroviral regimens, leading to a disproportionate burden on low- and medium-income settings where HIV is most prevalent. Despite decades of research, the mechanisms underlying spontaneous preterm birth, particularly in resource limited areas with high HIV infection rates, are still poorly understood and accurate prediction and therapeutic intervention remain elusive. OBJECTIVES: Metabolomics was utilized to identify profiles of preterm birth among pregnant women living with HIV on two different antiretroviral therapy (ART) regimens. METHODS: This pilot study comprised 100 mother-infant dyads prior to antiretroviral initiation, on zidovudine monotherapy or on protease inhibitor-based antiretroviral therapy. Pregnancies that resulted in preterm births were matched 1:1 with controls by gestational age at time of sample collection. Maternal plasma and blood spots at 23-35 weeks gestation and infant dried blood spots at birth, were assayed using an untargeted metabolomics method. Linear regression and random forests classification models were used to identify shared and treatment-specific markers of preterm birth. RESULTS: Classification models for preterm birth achieved accuracies of 95.5%, 95.7%, and 80.7% in the untreated, zidovudine monotherapy, and protease inhibitor-based treatment groups, respectively. Urate, methionine sulfone, cortisone, and 17α-hydroxypregnanolone glucuronide were identified as shared markers of preterm birth. Other compounds including hippurate and N-acetyl-1-methylhistidine were found to be significantly altered in a treatment-specific context. CONCLUSION: This study identified previously known as well as novel metabolomic features of preterm birth in pregnant women living with HIV. Validation of these models in a larger, independent cohort is necessary to ascertain whether they can be utilized to predict preterm birth during a stage of gestation that allows for therapeutic intervention or more effective resource allocation.

Zidovudine and Interferon Alfa based regimens for the treatment of adult T-cell leukemia/lymphoma (ATLL): a systematic review and meta-analysis.

BACKGROUND: ATLL (Adult T-Cell Leukemia/Lymphoma) is an aggressive hematological malignancy. This T-cell non-Hodgkin lymphoma, caused by the human T-cell leukemia virus type 1 (HTLV-1), is challenging to treat. There is no known treatment for ATLL as of yet. However, it is recommended to use Zidovudine and Interferon Alfa-based regimens (AZT/IFN), chemotherapy, and stem cell transplant. This study aims to review the outcome of patients with different subtypes of ATLL treated with Zidovudine and Interferon Alfa-based regimens. METHODS: A systematic search was carried out for articles evaluating outcomes of ATLL treatment by AZT/IFN agents on human subjects from January 1, 2004, until July 1, 2022. Researchers assessed all studies regarding the topic, followed by extracting the data. A random-effects model was used in the meta-analyses. RESULTS: We obtained fifteen articles on the AZT/IFN treatment of 1101 ATLL patients. The response rate of the AZT/IFN regimen yielded an OR of 67% [95% CI: 0.50; 0.80], a CR of 33% [95% CI: 0.24; 0.44], and a PR of 31% [95% CI: 0.24; 0.39] among individuals who received this regimen at any point during their treatment. Our subgroup analyses' findings demonstrated that patients who received front-line and combined AZT/IFN therapy responded better than those who received AZT/IFN alone. It is significant to note that patients with indolent subtypes of disease had considerably higher response rates than individuals with aggressive disease. CONCLUSION: IFN/AZT combined with chemotherapy regimens is an effective treatment for ATLL patients, and its use in the early stages of the disease may result in a greater response rate.

Lower Insulin Sensitivity in Newborns With In Utero HIV and Antiretroviral Exposure Who Are Uninfected in Botswana.

BACKGROUND: Few data exist on early-life metabolic perturbations in newborns with perinatal HIV and antiretroviral (ARV) exposure but uninfected (HEU) compared to those perinatally HIV unexposed and uninfected (HUU). METHODS: We enrolled pregnant persons with HIV (PWH) receiving tenofovir (TDF)/emtricitabine or lamivudine (XTC) plus dolutegravir (DTG) or efavirenz (EFV), and pregnant individuals without HIV, as well as their liveborn infants. Newborns were randomized to receive either zidovudine (AZT) or nevirapine (NVP) postnatal prophylaxis. Preprandial homeostasis model assessment for insulin resistance (HOMA-IR) was assessed at birth and 1 month. Linear mixed models were fit to assess the association between in utero HIV/ARV exposure and average HOMA-IR from birth to 1 month, adjusting for confounders. RESULTS: Of 450 newborns, 306 were HEU. HOMA-IR was higher in newborns HEU versus HUU after adjusting for confounders (mean difference of 0.068 in log HOMA-IR, P = .037). Among newborns HEU, HOMA-IR was not significantly different between TDF/XTC/DTG versus TDF/XTC/EFV in utero ARV exposure and between AZT versus NVP newborn postnatal prophylaxis arms. CONCLUSIONS: Newborns HEU versus HUU had lower insulin sensitivity at birth and at 1 month of life, raising potential concern for obesity and other metabolic perturbations later in life for newborns HEU. CLINICAL TRIALS REGISTRATION: NCT03088410.

Antiretroviral drug switches to zidovudine-based regimens and loss to follow-up during the first COVID-19 lockdown in Bali, Indonesia.

OBJECTIVES: International lockdowns during the COVID-19 pandemic impacted antiretroviral drug supplies in Indonesia. We assessed the impact of antiretroviral treatment (ART) provision and being lost to follow-up (LTFU) on people living with HIV, attending a key population-focused HIV clinic in Denpasar, Bali. METHODS: This was a retrospective note review of anonymized data from adult Indonesian patients living with HIV. We collected demographic data and information on being LTFU, and assessed the numbers of patients impacted by ART switches from fixed-dose combination (FDC) tenofovir/lamivudine/efavirenz to multi-pill zidovudine-based regimens, during the first international lockdown from March 2020. RESULTS: Records of 260 Indonesian adult patients registered for HIV care and prescribed ART were reviewed; 240 (92.3%) were men, and 90% were men who have sex with men. Between 13 March and 28 May 2020, 214 (87%) out of 247 patients (previously diagnosed with HIV) had to switch to individual, multi-pill zidovudine-based regimens from their FDC. The switch lasted a mean of 35 days (range 10-85). Twenty-five patients (10%) were LTFU; patients who switched were more likely to remain in care. Data on viral load status and toxicity are lacking as laboratory testing requires self-payment. CONCLUSIONS: The majority of patients living with HIV had no choice but to switch to multi-pill, zidovudine-based regimens. Despite significant efforts to minimize the impact of lockdown on care, 10% of patients were LTFU. Patients switching ART required greater clinic attention and support, improving retention. Complete national data are needed to understand the impact of ART stockouts on virological suppression and drug resistance throughout Indonesia.

Maternal and infant renal safety following tenofovir disoproxil fumarate exposure during pregnancy in a randomized control trial.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) in combination with other antiretroviral (ARV) drugs has been in clinical use for HIV treatment since its approval in 2001. Although the effectiveness of TDF in preventing perinatal HIV infection is well established, information about renal safety during pregnancy is still limited. TRIAL DESIGN: The IMPAACT PROMISE study was an open-label, strategy trial that randomized pregnant women to one of three arms: TDF based antiretroviral therapy (ART), zidovudine (ZDV) based ART, and ZDV alone (standard of care at start of enrollment). The P1084s substudy was a nested, comparative study of renal outcomes in women and their infants. METHODS: PROMISE participants (n = 3543) were assessed for renal dysfunction using calculated creatinine clearance (CrCl) at study entry (> 14 weeks gestation), delivery, and postpartum weeks 6, 26, and 74. Of these women, 479 were enrolled in the P1084s substudy that also assessed maternal calcium and phosphate as well as infant calculated CrCl, calcium, and phosphate at birth. RESULTS: Among the 1338 women who could be randomized to TDF, less than 1% had a baseline calculated CrCl below 80 mL/min. The mean (standard deviation) maternal calculated CrCl at delivery in the TDF-ART arm [147.0 mL/min (51.4)] was lower than the ZDV-ART [155.0 mL/min (43.3); primary comparison] and the ZDV Alone [158.5 mL/min (45.0)] arms; the mean differences (95% confidence interval) were - 8.0 mL/min (- 14.5, - 1.5) and - 11.5 mL/min (- 18.0, - 4.9), respectively. The TDF-ART arm had lower mean maternal phosphate at delivery compared with the ZDV-ART [- 0.14 mg/dL (- 0.28, - 0.01)] and the ZDV Alone [- 0.17 mg/dL (- 0.31, - 0.02)] arms, and a greater percentage of maternal hypophosphatemia at delivery (4.23%) compared with the ZDV-ART (1.38%) and the ZDV Alone (1.46%) arms. Maternal calcium was similar between arms. In infants, mean calculated CrCl, calcium, and phosphate at birth were similar between arms (all CIs included 0). CONCLUSIONS: Although mean maternal calculated CrCl at Delivery was lower in the TDF-ART arm, the difference between arms is unlikely to be clinically significant. During pregnancy, the TDF-ART regimen had no observed safety concerns for maternal or infant renal function. TRIAL REGISTRATION: NCT01061151 on 10/02/2010 for PROMISE (1077BF). NCT01066858 on 10/02/2010 for P1084s.

Factors associated with viral suppression and rebound among adult HIV patients on treatment: a retrospective study in Ghana.

BACKGROUND: Viral suppression remains the most desired outcome in the management of patients with Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS) and this can be achieved by an effective Antiretroviral Therapy (ART). However, some patients who achieve viral suppression may experience viral rebound with dire consequence. We evaluated viral suppression and rebound and their associated factors among adult patients on ART in Kumasi, Ghana. METHODS: This hospital-based retrospective study was conducted at the Komfo Anokye Teaching Hospital in Ghana. We reviewed the medical records of 720 HIV patients on ART. Statistical analyses were performed using SPSS Version 26.0 and GraphPad prism version 8.0. p < 0.05 was considered statistically significant. RESULTS: Proportions of patients with viral suppression and viral rebound were 76.1% and 21.0% respectively. Being diagnosed at WHO stage I [aOR = 11.40, 95% CI (3.54-36.74), p < 0.0001], having good adherence to ART [aOR = 5.09, 95% CI (2.67-9.73), p < 0.0001], taking Nevirapine-based regimen [aOR = 4.66, 95% CI (1.20-18.04), p = 0.0260] and increasing duration of treatment (p < 0.0001) were independently associated with higher odds of viral suppression. However, being diagnosed at WHO stage II (aOR = 7.39, 95% CI 2.67-20.51; p < 0.0001) and stage III (aOR = 8.62, 95% CI 3.16-23.50; p < 0.0001), having poor adherence (aOR = 175.48, 95% CI 44.30-695.07; p < 0.0001), recording baseline suppression value of 20-49 copies/mL (aOR = 6.43, 95% CI 2.72-15.17; p < 0.0001) and being treated with Zidovudine/Lamivudine/Efavirenz (aOR = 6.49, 95% CI 1.85-22.79; p = 0.004) and Zidovudine/Lamivudine/Nevirapine (aOR = 18.68, 95% CI 1.58-220.90; p = 0.02) were independently associated with higher odds of viral rebound. CONCLUSION: Approximately 76% viral suppression rate among HIV patients on ART in Kumasi falls below the WHO 95% target by the year 2030. Choice of ART combination, drug adherence, WHO clinical staging and baseline viral load are factors associated with suppression or rebound. These clinical characteristics of HIV patients must be monitored concurrently with the viral load.

Patient and health facility attributes associated with retention and virologic suppression in private for-profit health facilities in Nigeria.

BACKGROUND: In Nigeria, private for-profit health facilities present an opportunity to achieve the UNAIDS 95-95-95 HIV targets because of their reach and patronage. However, little is known about determinants of outcomes in these facilities. This study describes patient outcomes and the patient and health facility characteristics associated with these outcomes in adults receiving HIV treatment in private facilities in the Federal Capital Territory (FCT), Benue and Nasarawa states in north-central Nigeria. METHODS: A retrospective longitudinal analysis of program data collected between 2013 and 2019 was done. Patient attributes and outcomes were compared across the two states and FCT. Incidence rates were determined for all cause exit, mortality and loss to follow up (LTFU). Cox proportional hazard models were used to identify associations between patient and facility attributes and these outcomes. Bivariate and multivariate logistic regression models were used to determine the factors associated with viral suppression among the study participants. RESULTS: Of the 22,010 study subjects, 42.7%, 22.2% and 35.1%, respectively, were in Benue, FCT and Nasarawa. Almost a third (31.8%) had received antiretroviral treatment (ART) for less than a year at censoring. Incidence rates for all-cause exit, mortality and loss to follow up (LTFU) were 17.2 (95% CI 16.8, 17.5), 2.1 (95% CI 2.0, 2.2), and 11.2 (95% CI 10.8, 11.8) per 100 person years respectively. Males had higher risks of death (HR = 1.47, 95% CI 1.25-1.73), and LTFU (HR = 1.08, 95% CI 1.00-1.16). Age at ART start showed a dose-response association with both mortality and LTFU. Care at model facilities (OR = 2.16, p < 0.001), Zidovudine (AZT)-based regimens (OR = 2.00, p < 0.001), and lowest quartile baseline CD4 + count (OR = 2.40, p < 0.001) were associated with regimen switch. 75.6% of subjects were viral suppressed. Male gender (OR = 0.84, p = 0.025); AZT-based regimen (OR = 0.72, p < 0.001), age in the bottom quartile (OR = 0.71, p = 0.002) were associated with virally suppression. CONCLUSION: Private for-profit facilities are a major provider of HIV and other health services in Nigeria. With appropriate technical support and engagement, they can help accelerate efforts to achieve epidemic control of HIV in Nigeria, and contribute to achievement of UNAIDS 95-95-95 target by 2030.

Mother-to-Child HIV Transmission among Pregnant Women in a City with the Highest Rates of HIV in Brazil.

OBJECTIVE: Most of the HIV pediatric infections are acquired through mother-to-child transmission (MTCT). Porto Alegre is a state capital of Brazil that had a HIV MTCT rate of 4.1% in 2013 and the highest rate of HIV-infected pregnant women in the country during 2018. Zidovudine and nevirapine have been used in Brazil for high-risk newborns since 2012. The aim of the study was to investigate HIV MTCT rate and the factors associated with HIV transmission at a hospital that is a reference center for HIV-infected mothers in Porto Alegre, after the introduction of this policy. STUDY DESIGN: This retrospective cohort study included all HIV-exposed infants born between February 2013 and December 2016 at the Hospital de Clínicas de Porto Alegre. Student's t-test or Fisher's exact test was used to compare variables between HIV-infected and uninfected groups of newborns. Poisson's regression with robust variance was used to determine the factors associated with HIV MTCT. RESULTS: A total of 375 newborns were exposed to HIV, with an outpatient loss of 14.4% (n = 54). The HIV MTCT rate was 2.18% (n = 7), with four infected during the intrauterine period. The risk factors for MTCT were no prenatal care (relative risk [RR] = 9.4; 95% confidence interval [CI]: 2.0-44.3), late maternal HIV diagnosis in the peripartum period (RR = 16.3; 95% CI: 3.6-73.0), syphilis infection during pregnancy (RR = 9.3; 95% CI: 2.1-40.3), maternal viral load >1,000 copies/mL in the third trimester or peripartum period (RR = 9.5; 95% CI: 1.7-50.5), and lack of or inappropriate antiretroviral therapy during pregnancy (RR = 8.2; 95% CI: 1.6-41.4). CONCLUSION: MTCT rate was 2.18%. With the institution of two-drug prophylaxis for high-risk newborns, persistent cases HIV MTCT were predominantly found among women with absence of antenatal care, late HIV diagnosis, syphilis coinfection, high viral load, and inadequate ARV therapy during pregnancy. Although zidovudine and nevirapine were administered postnatally to high-risk newborns, this regimen could not prevent transplacental transmission. KEY POINTS: · Most of the HIV pediatric infections are acquired through mother-to-child transmission.. · The study investigated HIV MTCT rate and the factors associated with HIV transmission in Brazil.. · HIV MTCT rate was 2.18% and most of them were infected during the intrauterine period..

The Use of Zidovudine Pharmacophore in Multi-Target-Directed Ligands for AIDS Therapy.

The concept of polypharmacology embraces multiple drugs combined in a therapeutic regimen (drug combination or cocktail), fixed dose combinations (FDCs), and a single drug that binds to different targets (multi-target drug). A polypharmacology approach is widely applied in the treatment of acquired immunodeficiency syndrome (AIDS), providing life-saving therapies for millions of people living with HIV. Despite the success in viral load suppression and patient survival of combined antiretroviral therapy (cART), the development of new drugs has become imperative, owing to the emergence of resistant strains and poor adherence to cART. 3'-azido-2',3'-dideoxythymidine, also known as azidothymidine or zidovudine (AZT), is a widely applied starting scaffold in the search for new compounds, due to its good antiretroviral activity. Through the medicinal chemistry tool of molecular hybridization, AZT has been included in the structure of several compounds allowing for the development of multi-target-directed ligands (MTDLs) as antiretrovirals. This review aims to systematically explore and critically discuss AZT-based compounds as potential MTDLs for the treatment of AIDS. The review findings allowed us to conclude that: (i) AZT hybrids are still worth exploring, as they may provide highly active compounds targeting different steps of the HIV-1 replication cycle; (ii) AZT is a good starting point for the preparation of co-drugs with enhanced cell permeability.

Virologic Response Following a Switch to Dolutegravir-based Regimen in People Living with HIV/AIDS at a Tertiary Care Center in Nepal.

Background The dolutegravir-based antiretroviral regimen is the preferred first-line regimen for the management of people living with human immunodeficiency virus in Nepal recently. It is considered safe to transition to a dolutegravir-based regimen for children and adults on Nevirapine and Efavirenz-based regimens. Objective To determine the virologic response following the transition to a Dolutegravir-based regimen in people living with human immunodeficiency virus previously taking Nevirapine and Efavirenz-based regimen. Method This is a retrospective cohort study including people living with human immunodeficiency virus/ acquired immunodeficiency syndrome (HIV/AIDS) who were transitioned to Tenofovir/Lamivudine/Dolutegravir previously on other antiretroviral therapy regimens for at least 6 months and who had their viral load test done before transition. The medical records of patients were reviewed from records available at the antiretroviral therapy clinic of Dhulikhel Hospital. The viral load done at least 3 months after switching to the Dolutegravir-based regimen was recorded. Descriptive analysis of socio-demographic and clinical characteristics data was done. Result Fifty-seven people living with human immunodeficiency virus/ acquired immunodeficiency syndrome who transitioned to a Dolutegravir-based regimen previously on other antiretroviral therapy regimens for at least 6 months were included in this study. Tenofovir/Lamivudine/Efavirenz (47.4%), Zidovudine/ Lamivudine/Nevirapine (22.8%) and Zidovudine/Lamivudine/Efavirenz (17.5%) were the most common antiretroviral regimens before transition. The majority of the patients (86%) had suppressed viral load of fewer than 40 copies/mL before the switch. Following the transition, 96.5% of the patients had suppressed viral load of fewer than 40 copies/mL. Conclusion Dolutegravir-based antiretroviral regimen led to untransmittable viral load following a switch from Nevirapine and Efavirenz-based regimen.

Safety and Efficacy of Starting Antiretroviral Therapy in the First Week of Life.

BACKGROUND: Early antiretroviral therapy (ART) is recommended for infants with human immunodeficiency virus (HIV) infection. However, few antiretroviral options are available for neonates. METHODS: The Early Infant Treatment Study in Botswana tested HIV-exposed infants within 96 hours of birth, and HIV-infected infants started nevirapine (NVP) 6 mg/kg twice daily, zidovudine (ZDV), and lamivudine (3TC) at age < 7 days. NVP trough concentrations were tested at 1 and 2 weeks. NVP was switched to ritonavir-boosted lopinavir (LPV/r) at week 2, 3, 4, or 5 according to delivery gestational age. RESULTS: Forty HIV-infected infants started ART at median age 2 days (range, 1-5 days). NVP trough concentrations were highly variable and below therapeutic target (3000 ng/mL) for 50% of 2-week measurements; concentrations did not correlate with viral decline at weeks 2, 4, or 12. Two deaths unrelated to ART occurred through 24 weeks. Only 1 unscheduled treatment modification was required. Within 4 weeks of transition to LPV/r, 9 (22.5%) had transient HIV RNA increases, likely due to poor LPV/r palatability. At 12 weeks, 22 (55%) of 40 were <40 copies/mL (93% <400 copies/mL); by 24 weeks, 27 of 38 (71%) were < 40 copies/mL (84% < 400 copies/mL). HIV-1 RNA response at 12 and 24 weeks did not differ by baseline HIV RNA or other factors. CONCLUSIONS: NVP/ZDV/3TC started in the first week of life was safe and effective, even when trough NVP levels were below target. Transient viral increases occurred following transition to LPV/r, but by 12 and 24 weeks most children achieved and maintained viral suppression. CLINICAL TRIALS REGISTRATION: NCT02369406.

Birth Outcomes for Pregnant Women with HIV Using Tenofovir-Emtricitabine.

BACKGROUND: In a previous trial of antiretroviral therapy (ART) involving pregnant women with human immunodeficiency virus (HIV) infection, those randomly assigned to receive tenofovir, emtricitabine, and ritonavir-boosted lopinavir (TDF-FTC-LPV/r) had infants at greater risk for very premature birth and death within 14 days after delivery than those assigned to receive zidovudine, lamivudine, and ritonavir-boosted lopinavir (ZDV-3TC-LPV/r). METHODS: Using data from two U.S.-based cohort studies, we compared the risk of adverse birth outcomes among infants with in utero exposure to ZDV-3TC-LPV/r, TDF-FTC-LPV/r, or TDF-FTC with ritonavir-boosted atazanavir (ATV/r). We evaluated the risk of preterm birth (<37 completed weeks of gestation), very preterm birth (<34 completed weeks), low birth weight (<2500 g), and very low birth weight (<1500 g). Risk ratios with 95% confidence intervals were estimated with the use of modified Poisson models to adjust for confounding. RESULTS: There were 4646 birth outcomes. Few infants or fetuses were exposed to TDF-FTC-LPV/r (128 [2.8%]) as the initial ART regimen during gestation, in contrast with TDF-FTC-ATV/r (539 [11.6%]) and ZDV-3TC-LPV/r (954 [20.5%]). As compared with women receiving ZDV-3TC-LPV/r, women receiving TDF-FTC-LPV/r had a similar risk of preterm birth (risk ratio, 0.90; 95% confidence interval [CI], 0.60 to 1.33) and low birth weight (risk ratio, 1.13; 95% CI, 0.78 to 1.64). As compared to women receiving TDF-FTC-ATV/r, women receiving TDF-FTC-LPV/r had a similar or slightly higher risk of preterm birth (risk ratio, 1.14; 95% CI, 0.75 to 1.72) and low birth weight (risk ratio, 1.45; 95% CI, 0.96 to 2.17). There were no significant differences between regimens in the risk of very preterm birth or very low birth weight. CONCLUSIONS: The risk of adverse birth outcomes was not higher with TDF-FTC-LPV/r than with ZDV-3TC-LPV/r or TDF-FTC-ATV/r among HIV-infected women and their infants in the United States, although power was limited for some comparisons. (Funded by the National Institutes of Health and others.).

In utero and peripartum antiretroviral exposure as predictor of cognition in 6- to 10-year-old HIV-exposed Ugandan children - a prospective cohort study.

OBJECTIVES: To quantify association between in utero/peripartum antiretroviral (IPA) exposure and cognition, i.e. executive function (EF) and socioemotional adjustment (SEA), in school-aged Ugandan children who were perinatally HIV-infected (CPHIV, n = 100) and children who were HIV-exposed but uninfected (CHEU, n = 101). METHODS: Children were enrolled at age 6-10 years and followed for 12 months from March 2017 to December 2018. Caregiver-reported child EF and SEA competencies were assessed using validated questionnaires at baseline, 6 and 12 months. IPA type - combination antiretroviral therapy (cART), intrapartum single-dose nevirapine ± zidovudine (sdNVP ± ZDV), nevirapine + zidovudine + lamivudine (sdNVP + ZDV + 3TC) - or no IPA (reference) was verified via medical records. IPA-related standardized mean differences (SMDs) with corresponding 95% confidence intervals (CIs) in cognitive competencies were estimated from regression models with adjustment for caregiver sociodemographic and contextual factors. Models were fitted separately for CPHIV and CHEU. RESULTS: Among CPHIV children, cART (SMD = -0.82, 95% CI: -1.37 to -0.28) and sdNVP ± ZDV (SMD = -0.41, 95% CI: -0.81 to -0.00) vs. no IPA predicted lower executive dysfunction over 12 months. Intrapartum sdNVP + ZDV + 3TC vs. no IPA predicted executive dysfunction (SMD = 0.80, 95% CI: 0.30-1.31), SEA problems (SMD = 0.63-0.76, 95% CI: 0.00-1.24) and lower adaptive skills (SMD = -0.36, 95% CI: -0.75-0.02) over 12 months among CHEU. Further adjustment for contextual factors attenuated associations, although most remained of moderate clinical importance (|SMD| > 0.33). CONCLUSIONS: Among CPHIV children, cART and sdNVP ± ZDV IPA exposure predicted, on average, lower executive dysfunction 6-10 years later. However, peripartum sdNVP + ZDV + 3TC predicted executive and SEA dysfunction among CHEU 6-10 years later. These data underscore the need for more research into long-term effects of in utero ART to inform development of appropriate interventions so as to mitigate cognitive sequelae.

Antiretroviral Prophylaxis: A Digestive Complication to Know.

ABSTRACT: An 8-year-old child experienced abdominal pain and melena due to duodenal and ileal ulcerations throughout antiretroviral prophylactic treatment after a needlestick injury. Mild to moderate adverse effects often occur with lamivudine and zidovudine, but more severe adverse effects such as intestinal ulcers resulting in melena after a prophylactic antiretroviral treatment may question the safety of the current guidelines.

Nationwide Study of Drug Resistance Mutations in HIV-1 Infected Individuals under Antiretroviral Therapy in Brazil.

The success of antiretroviral treatment (ART) is threatened by the emergence of drug resistance mutations (DRM). Since Brazil presents the largest number of people living with HIV (PLWH) in South America we aimed at understanding the dynamics of DRM in this country. We analyzed a total of 20,226 HIV-1 sequences collected from PLWH undergoing ART between 2008-2017. Results show a mild decline of DRM over the years but an increase of the K65R reverse transcriptase mutation from 2.23% to 12.11%. This increase gradually occurred following alterations in the ART regimens replacing zidovudine (AZT) with tenofovir (TDF). PLWH harboring the K65R had significantly higher viral loads than those without this mutation (p < 0.001). Among the two most prevalent HIV-1 subtypes (B and C) there was a significant (p < 0.001) association of K65R with subtype C (11.26%) when compared with subtype B (9.27%). Nonetheless, evidence for K65R transmission in Brazil was found both for C and B subtypes. Additionally, artificial neural network-based immunoinformatic predictions suggest that K65R could enhance viral recognition by HLA-B27 that has relatively low prevalence in the Brazilian population. Overall, the results suggest that tenofovir-based regimens need to be carefully monitored particularly in settings with subtype C and specific HLA profiles.