Cohort profile: PRESTIGIO, an Italian prospective registry-based cohort of people with HIV-1 resistant to reverse transcriptase, protease and integrase inhibitors.

PURPOSE: The PRESTIGIO Registry was established in 2017 to collect clinical, virological and immunological monitoring data from people living with HIV (PLWH) with documented four-class drug resistance (4DR). Key research purposes include the evaluation of residual susceptibility to specific antiretrovirals and the validation of treatment and monitoring strategies in this population. PARTICIPANTS: The PRESTIGIO Registry collects annual plasma and peripheral blood mononuclear cell samples and demographic, clinical, virological, treatment and laboratory data from PLWH followed at 39 Italian clinical centres and characterised by intermediate-to-high genotypic resistance to ≥1 nucleoside reverse transcriptase inhibitors, ≥1 non-nucleoside reverse transcriptase inhibitors, ≥1 protease inhibitors, plus either intermediate-to-high genotypic resistance to ≥1 integrase strand transfer inhibitors (INSTIs) or history of virological failure to an INSTI-containing regimen. To date, 229 people have been recorded in the cohort. Most of the data are collected from the date of the first evidence of 4DR (baseline), with some prebaseline information obtained retrospectively. Samples are collected from the date of enrollment in the registry. FINDINGS TO DATE: The open-ended cohort has been used to assess (1) prognosis in terms of survival or development of AIDS-related or non-AIDS-related clinical events; (2) long-term efficacy and safety of different antiretroviral regimens and (3) virological and immunological factors predictive of clinical outcome and treatment efficacy, especially through analysis of plasma and cell samples. FUTURE PLANS: The registry can provide new knowledge on how to implement an integrated approach to study PLWH with documented resistance to the four main antiretroviral classes, a population with a limited number of individuals characterised by a high degree of frailty and complexity in therapeutic management. Given the scheduled annual updates of PLWH data, the researchers who collaborate in the registry can send study proposals at any time to the steering committee of the registry, which evaluates every 3 months whether the research studies can be conducted on data and biosamples from the registry and whether they are aimed at a better understanding of a specific health condition, the emergence of comorbidities or the effect of potential treatments or experimental drugs that may have an impact on disease progression and quality of life. Finally, the research studies should aim to be inclusive, innovative and in touch with the communities and society as a whole. TRIAL REGISTRATION NUMBER: NCT04098315.

Major Drug Resistance Mutations on Reverse Transcriptase Gene in Human Immunodeficiency Virus Type-1 in Indonesia: A Systematic Review.

PURPOSE OF REVIEW: The prevalence of HIV-1 in Indonesia is on a concerning upward trajectory, with a concurrent rise in the development of drug-resistant strains, challenging the efficacy of antiretroviral therapy (ART). Many mutations have been found in the pol gene that makes HIV resistant to ART. We aim to review the major drug resistance mutations (DRMs) of reverse transcriptase (RT) of pol gene in HIV-1 cases in Indonesia. RECENT FINDINGS: A total of eleven articles reporting DRMs in HIV-1 subjects from various regions between 2015-2020 in Indonesia are included. The prevalence of major DRMs on the RT gene in studies included varies from 3.4% to 34%. The CRF01_AE subtype stands out as the predominant variant. Notably, the prevalence of major DRMs in ART-experienced individuals is 22.1%, while ART-naïve individuals show a lower rate of 4.4%. Among the RT gene mutations, M184I/V emerges as the most prevalent (10.5%) within the nucleos(t)ide reverse transcriptase inhibitors (NRTI) group, while K103N leads among the non-NRTI (NNRTI) group, with a frequency of 6.4%. Regionally, North Sulawesi records the highest prevalence of major DRMs in the RT gene at 21.1%, whereas Riau and Central Papua exhibit the lowest rates at 3.4%. Significant variations in drug resistance mutations within the RT gene across Indonesian regions highlight the importance of closely monitoring and evaluating the effectiveness of current antiretroviral therapy (ART) regimens. Considerably, more studies are needed to understand better and overcome the emergence of DRMs on HIV-1 patients in Indonesia.

Clinical Perspective on Human Immunodeficiency Virus Care of Ukrainian War Refugees in Poland.

BACKGROUND: The Russian invasion of Ukraine forced migration for safety, protection, and assistance. Poland is the primary sheltering country for Ukrainian refugees, providing support including medical care, which resulted in the rapid ∼15% increase in the number of followed-up people with human immunodeficiency virus (HIV) (PWH) in the country. Here, we present the national experience on HIV care provided for refugees from Ukraine. METHODS: Clinical, antiretroviral, immunological, and virologic data from 955 Ukrainian PWH entering care in Poland since February 2022 were analyzed. The dataset included both antiretroviral-treated (n = 851) and newly diagnosed (n = 104) patients. In 76 cases, protease/reverse transcriptase/integrase sequencing was performed to identify drug resistance and subtype. RESULTS: Most (70.05%) of the patients were female, with a predominance of heterosexual (70.3%) transmissions. Anti-hepatitis C antibody and hepatitis B antigen were present in 28.7% and 2.9% of the patients, respectively. A history of tuberculosis was reported in 10.1% of cases. Among previously treated patients, the viral suppression rate was 89.6%; 77.3% of newly HIV diagnosed cases were diagnosed late (with lymphocyte CD4 count <350 cells/µL or AIDS). The A6 variant was observed in 89.0% of sequences. Transmitted mutations in the reverse transcriptase were found in 15.4% treatment-naive cases. Two patients with treatment failure exhibited multiclass drug resistance. CONCLUSIONS: Migration from Ukraine influences the characteristics of HIV epidemics in Europe, with an increase in the proportion of women and hepatitis C coinfected patients. Antiretroviral treatment efficacy among previously treated refugees was high, with new HIV cases frequently diagnosed late. The A6 subtype was the most common variant.

Resistant mutations within the hepatitis B virus reverse transcriptase sequence in treatment failure patients with chronic HBV infection in Vietnam.

OBJECTIVES: We conducted this study to describe whether mutations in the gene coding for the enzyme reverse transcriptase (RT) were related to drugs used in the treatment of hepatitis B in Vietnam. METHODS: Patients receiving antiretroviral therapy with evidence of treatment failure were included in the study. The RT fragment was cloned using the polymerase chain reaction technique after being extracted from patients' blood samples. The nucleotide sequences were analysed using Sanger method. The HBV drug resistance database contains mutations associated to resistance to existing HBV therapies. Medical records were accessed to collect information on patient parameters, such as treatment, viral load, biochemistry, and blood count. RESULTS: Resistance mutations to lamivudine, telbivudine, and entecavir were found in the highest proportion (75-91.7%) of HBV samples from patients who had failed antiretroviral therapy. Only 20.8% of HBV strains had mutations exhibiting adefovir resistance, while none had mutations conferring tenofovir resistance. M204I/V, L180M, and L80I are frequent variants linked with resistance to lamivudine, telbivudine, and entecavir. In contrast, the A181L/T/V mutation was detected predominantly in tenofovir-resistant HBV strains. Following the drug resistance mutation test, patients achieved the greatest virological response after 24 weeks of therapy with tenofovir and entecavir at a daily dose of one tablet. CONCLUSION: Lamivudine, telbivudine, and entecavir were all highly resistant to the RT enzyme modifications in 24 treatment failure patients, with M204I/V, L180M, and L80I being the most prevalent mutations. Tenofovir resistance mutations have not been found in Vietnam.

A Concise Analytical Profile of Efavirenz: Analytical Methodologies.

Non-nucleoside reverse transcriptase inhibitors are the prime members of antiretroviral therapy that are presently employed for the management of the human immunodeficiency virus. It uses an enzyme i.e., reverse transcriptase to convert its ribonucleic acid into reverse transcription; these agents impede the function of reverse transcriptase and reverse transcription counter human immunodeficiency virus from replicating. Efavirenz is the first-generation non-nucleoside reverse transcriptase inhibitor agent. Similar to the other non-nucleoside reverse transcriptase inhibitor agents; it is prescribed with other inhibitors in combination for regimens antiretroviral therapy. To enhance survival and avoid aggressive infections in patients affected with human immunodeficiency virus infection, adequate antiretroviral therapy is the most significant treatment. Accordingly, the development and validation of such therapeutic agents are challenging work for the analysts. Therefore, the proposed review integrally addresses the analytical reports of efavirenz recorded in the literature databases like Scopus, Web of Science, Google Scholar, Pub-Med, and through many other sources. It has been remarked that for the development of efavirenz many analytical techniques were used for addressing the qualitative and quantitative estimation of efavirenz from various pharmaceutical and biological matrices. This review plan to review the stereochemistry, mechanism of action, resistance, pharmacokinetics, pharmacodynamics, safety and adverse reaction, and various analytical approaches assessed for the same. The hyphenated and chromatographic techniques are frequently used for analysis of cited drug.

[Analysis of risk factors for drug resistant mutations in the reverse transcriptase region in chronic hepatitis B virus-infected patients].

Objective: To analyze the risk factors that may affect the mutations in the reverse transcriptase region in chronic hepatitis B virus-infected patients. Methods: 678 hospitalized cases with chronic HBV infection who underwent HBV RT testing at Tianjin Second People's Hospital from January 1, 2016 to December 31, 2016 were collected retrospectively. Among them, 417 cases were diagnosed with chronic hepatitis B, 219 cases with liver cirrhosis and 42 cases with primary liver cancer. There were 268 cases of non-use of any antiviral therapy, 138 cases of discontinuation of antiviral drugs for 6 months or more, and 272 cases of continuous antiviral therapy. HBV genotyping and RT region mutation sites were detected by direct sequencing. The risk factors that may affect the drug resistant mutation in the HBV RT mutation, including age, genotype, antiviral drug selection and medication time, hepatitis B virus infection, and biochemical markers were analyzed by univariate analysis to screen out independent risk factors. Results: Among 678 HBV-infected cases, 290 cases (42.8%) were detected with RT-region mutation. Among them, the pre-existing drug resistant rate was 6.72%, and the drug resistant mutation rate was 23.19% in treated patients. The drug resistant mutation rate of patients with continuous antiviral therapy was 66.18%. Gene mutations highest rate for 1 ~ 5 years was 27.14% in chronic HBV patients treated with antiviral therapy. Logistic regression analysis of the factors that had led to HBV mutation showed that old age, the selection of nucleoside drugs at the beginning of treatment and medication time were the main factors affecting HBV RT mutations. Conclusion: Abnormal ALT level, HBV genotype, HBV DNA quantitative level are the main factors influencing non-drug resistant mutations. Age over 60 years old, and long-term use of low-barrier nucleoside drugs are high-risk groups for HBV resistant. Therefore, HBV resistant monitoring should be strengthened.

[Study of the specific toxic effects of the substance 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil, the original non-nucleoside inhibitor of human immunodeficiency virus type 1 (Retroviridae; Orthoretrovirinae; Lentivirus: Human immunodeficiency virus 1) reverse transcriptase].

INTRODUCTION: Combination antiretroviral therapy is currently the main component of treatment for human immunodeficiency virus (HIV) infected patients. At the same time, the high mutational potential of the virus and the frequency of side effects of existing drugs dictate the need for the development and preclinical study of new, more effective and safer compounds.The aim of the study is to evaluate the specific types of toxicity of a new non-nucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RNA-dependent DNA revertase) (NNRTI) based on the substance 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil, a benzophenone derivative. MATERIAL AND METHODS: The study investigated reproductive toxicity, embryotoxicity, immunotoxicity, genotoxic (in micronucleus test in and comet assay) and allergenic properties of the test itemcompound. It was tested on three species of animals in two doses: the estimated therapeutic dose (1 TD) and its tenfold equivalent (10 TD). Taking into account the metabolic coefficients, the doses for rats (Rattus) were 9 and 90 mg/kg, for mice (Mus musculus), 21 and 210 mg/kg, and for guinea pigs (Cavia porcellus), 8 and 80 mg/kg, respectively. RESULTS AND DISCUSSION: According to the obtained results, a favorable safety profile of the tested compound was established. Negative effects on the immune system, reproductive function, the body of pregnant animals and the fetus were not observed, as well as the compound did not have genotoxic and allergenic properties. CONCLUSION: These data allows to consider the studied compound as a promising therapeutic candidate for the treatment of HIV-1 infection.

Reverse transcriptase and protease inhibitors mutational viral load in HIV infected pregnant women with transmitted drug resistance in Argentina.

OBJECTIVE: Argentina has reported high levels of transmitted drug resistance (TDR), in HIV-infected pregnant women by population sequencing. We aimed to describe, in patients with TDR, the percentage of quasispecies harboring resistance mutations (RAMs) and mutational load (ML). METHODS: Retrospective study in a cohort of 40 naïve HIV-infected pregnant women, whose pretreatment samples had been genotyped by TRUGENE (period 2008-2014). Samples were re-sequenced with Ultra-deep Sequencing and ML was calculated considering baseline HIV-1 RNA load multiplied by the frequency of quasispecies harboring RAMs. RESULTS: TDR for NNRTIs, NRTIs and PIs was 17.5% (n=7 patients), 10% (n=4), 12.5% (n=5) respectively. Predominant NNRTI RAMs were K103N (n=4; 10%) and G190A/E/S (n=3; 7.5%). For NNRTIs, 78% of RAMs were present in >93.5% of viral population and ML was >1000 copies/mL (c/mL) for 89%, with a median (IQR) of 8330 c/ml (7738-29796). The following NRTI RAMs were described (per patient: % of quasispecies, ML): T215I (99.7%, 11014 c/ml); D67G (1.28%, 502 c/mL); M41L (79.8%, 88578 c/mL) and M184I (1.02%, 173 c/mL). Most frequent PI-RAMs were I85V, M46I, I50V and L90M (n=2, 5% each). For PIs, quasispecies with RAMs were <2.3% of viral population and ML was <350 c/mL for 77.8% of them. CONCLUSIONS: NNRTI-RAMs are predominant within the viral population, usually exceeding the threshold of 1000 c/mL, indicating potential higher risk of perinatal transmission. Conversely, PI mutations appear mostly as minority variants, with potential lower risk of transmission. Among NRTI, quasispecies harboring RAMs and ML values were variable.

Very high baseline HIV viremia impairs efficacy of non-nucleoside reverse transcriptase inhibitor-based ART: a long-term observation in treatment-naïve patients.

BACKGROUND: It is not completely clear whether a very high pre-therapy viral load (≥ 500 000 copies/ml) can impair the virological response. The aim of this study was to examine the influence of very high baseline HIV-RNA levels on long-term virological responses under one type of regimen. METHODS: A retrospective study was performed based on data from two multicenter cohorts in China from January to November 2009, and from May 2013 to December 2015. Untreated HIV infected adults between 18 and 65 years old were recruited before receiving non-nucleoside reverse transcriptase inhibitor-based regimen. All patients had baseline HIV-RNA levels over 500 copies/ml, good adherence, and were followed for at least 24 weeks. Virological suppression was defined as the first HIV-RNA < 50 copies/ml. Virological failure was defined as any of incomplete viral suppression (HIV-RNA ≥ 200 copies/ml without virological suppression within 24 weeks of treatment) and viral rebound (confirmed HIV-RNA level ≥ 50 copies/ml after virological suppression). Chi-square test, Kaplan-Meier analysis, Cox proportional hazards model and Logistic regression were used to compare virological response between each pretreated viral load stratum. RESULTS: A total of 758 treatment-naïve HIV patients in China were enlisted. Median follow-up time (IQR) was 144 (108-276) weeks. By week 48, rates of virological suppression in three groups (< 100 000, 100 000-500 000 and ≥ 500 000 copies/ml) were 94.1, 85.0, and 63.8%, respectively (P < 0.001). Very high baseline HIV viremia over 500 000 copies/ml were found to be associated with delayed virological suppression (≥ 500 000 vs <  100 000, adjusted relative hazard = 0.455, 95% CI: 0.32-0.65; P < 0.001) as well as incomplete viral suppression (≥ 500 000 vs < 100 000, adjusted odds ratio [aOR] = 6.084, 95% CI: 2.761-13.407; P < 0.001) and viral rebound (≥ 50 000 vs < 100 000, aOR = 3.671, 95% CI: 1.009-13.355, P = 0.048). CONCLUSIONS: Very high levels of pre-treatment HIV-RNA were related with delayed efficacy of NNRTI-based ART and increased risk of treatment failure. More potent initial regimens should be considered for those with this clinical character.

Changing cost of English HIV service provision 1996-1997. NPMS Steering Group. National Prospective Monitoring System.

The objectives of this study were to provide individual and population-based unit cost estimates of HIV treatment and care by stage of HIV infection for adults in England and estimate the financial impact of the use of combination antiretroviral therapy. Individual unit cost estimates were calculated, based on 1997 activity data, and linked to the number of diagnosed HIV-infected individuals using statutory medical services by clinical stage of HIV infection in England during 1997 to obtain population-based cost estimates; these were compared with 1996 estimates. Most clinical guidelines now recommend the use of 3 antiretroviral agents, but cost estimates for mono and dual therapy were included as baseline estimates. Baseline costs for treating AIDS patients with zidovudine (AZT) monotherapy were estimated at pound sterling 16,830 (95% CI 14,633-18,985) per patient-year which was substantially lower than the 1996 estimate; costs for asymptomatic individuals and people with symptomatic non-AIDS were pound sterling 4450 (95% CI 3521-5612) and pound sterling 7289 (95% CI 6169-8386) per respective patient-year which did not differ substantially from 1996. The total annual population cost estimate for HIV service provision amounted to pound sterling 128 million (95% CI pound sterling 109m to pound sterling 147m), if all patients with HIV disease were treated with AZT monotherapy only. For all eligible patients to be treated with 2 nucleoside reverse transcriptase inhibitors (NRTI) (AZT and didanosine (ddI) or zalcitabine (ddC)), cost estimates amounted to pound sterling 161m (95% CI pound sterling 141m to pound sterling 181m), while for triple therapy, annual estimated expenditure amounted to pound sterling 185m (95% CI pound sterling 165m to pound sterling 206m) when a non-nucleoside reverse transcriptase inhibitor (NNRTI) (nevirapine) was included or pound sterling 205m (95% CI pound sterling 186m to pound sterling 235m) when a protease inhibitor was included. Compared with 1996 population-based cost estimates, the estimates for monotherapy decreased by 14%, by 11% for dual therapy, by 10% for triple therapy which included a NNRTI and by 9% if a protease inhibitor was used as part of a triple therapy regimen. Similarly, compared with 1996 estimates, the proportion of total costs attributable to treating asymptomatic individuals increased by 5% and 2-3% for people with symptomatic non-AIDS, while the proportion attributable for treating people with AIDS decreased by 8-9%.

Update on clinical trials of combination therapies for HIV infection.

AIDS: A list is provided of open trials of combination therapies underway at sites of the AIDS Clinical Trials Group (ACTG) and the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA). Most trials are open to new patients or are expected to open shortly.^ieng

The treatment of HIV infection. Azidothymidine (AZT) and other new antiviral drugs.

The first phase in the history of the chemotherapy of infection by HIV has been completed. An effective compound, AZT, has been identified that prolongs life and reduces morbidity. The next phase will be to determine the most effective and least toxic regimens of AZT and the patient populations who will most benefit. This phase will also involve the identification and evaluation of additional drugs. The most compassionate way to evaluate these drugs will be expeditious and systematic study rather than ad hoc administration and anecdotal observation. Advances in the chemotherapy of HIV infection are urgently needed. These advances will require new compounds, and because of probable drug toxicity, especially for chronic suppressive therapy, investigation must include examination of regimens that involve drug cycling and combinations.