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HIV/AIDS
Published in Patricia G. Melloy, Viruses and Society, 2023
Nucleoside/nucleotide analogs are drugs that are competitive inhibitors of the reverse transcriptase that is needed to copy the HIV genome. One of the most famous drugs in this category is AZT (Ojikutu 2008b; Lostroh 2019). AZT can be used to reduce the chance of mother-to-child transmission of HIV, which can occur in utero, during birth, or just after birth (Ojikutu 2008b). Other categories of drugs include non-nucleoside inhibitors of reverse transcriptase, drugs that block fusion of the virus with the cell, and drugs that block the integration of the genome into the host’s cellular genome, among others. One can look at every stage of the HIV life cycle as a possible point of attack for an antiretroviral drug (Lostroh 2019; Gulick and Flexner 2019). Another important class of anti-HIV drugs are the protease inhibitors that block the viral enzyme called a protease that is needed for the maturing of the virus. Protease inhibitors were developed through “rational drug design,” meaning that the crystal structure of the protease was resolved, and then a drug was designed to block it, rather than testing an existing compound for its effectiveness against the virus (Lostroh 2019).
The Viruses
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
Despite the difficulty of the problem some effective antiviral drugs have been developed against herpesviruses and retroviruses. The nucleoside analogue acycloguanosine (Acyclovir) is activated by phosphorylation via thymidine kinase, a herpesvirus encoded enzyme. The phosphorylated analogue acts then to inhibit the activity of the virus-encoded polymerase. Nucleoside and nonnucleoside inhibitors have been developed against retroviral infections as a result of the massive efforts developed in response to the AIDS epidemic (see below). Nucleoside analogues such as azidothymidine (AZT) selectively inhibit reverse transcriptase (RT) and thereby inhibit the replication of the retroviruses including HIV. A variety of nucleoside analogs have been produced to combat HIV infections (e.g., ddl, didanosine). The need for additional antiviral drugs against HIV has been driven, in part, by the ability of retroviruses like HIV to mutate and become resistant to the effects of drugs that have been developed. The introduction of protease inhibitors like nelfinavir has provided additional types of drugs active against HIV infection. These drugs in combination with RT inhibitors have provided new hope in the battle against AIDS. However, before long-term success against HIV is achieved elimination of sites of latent virus production and continued development of drugs against resistant strains will be required.
HIV and AIDS
Published in Rae-Ellen W. Kavey, Allison B. Kavey, Viral Pandemics, 2020
Rae-Ellen W. Kavey, Allison B. Kavey
In 1994, the discovery that AZT treatment of the mother and baby at the time of delivery effectively blocked HIV infection in 70% of cases was a tremendous advance, but one that was initially largely unavailable outside of industrialized countries.155 Controversy arose about the ethics of prophylactic research trials to prevent maternal–fetal transmission of HIV in the less-developed world, centered around the need for placebo-controlled trials, the virtual impossibility of true informed consent, failure to provide an intervention of known efficacy and potential subject exploitation.199–202 While this discussion was still ongoing, the CDC reported that a short course of oral AZT given late in pregnancy and during delivery with no infant dose had been proven effective in reducing perinatal HIV transmission in a placebo-controlled study in Thailand.203 Confirmation that sound evidence had shown there was an available, effective and relatively easy to implement intervention appeared to resolve the ethical controversy. Ultimately, subsequent studies showed that when HIV(+) mothers received combination ART and avoided breastfeeding, the rate of perinatal HIV transmission was reduced to less than 2%.158 Breastfeeding was addressed by considering the balance of factors – in a developing country, breastfeeding was almost always the better choice for nutrition and safety reasons and often the only choice because of economic and practical constraints.
The time to offer treatments for COVID-19
Published in Expert Opinion on Investigational Drugs, 2021
Binh T. Ngo, Paul Marik, Pierre Kory, Leland Shapiro, Raphael Thomadsen, Jose Iglesias, Stephen Ditmore, Marc Rendell, Joseph Varon, Michael Dubé, Neha Nanda, Gino In, Daniel Arkfeld, Preet Chaudhary, Vito M. Campese, Diana L. Hanna, David E. Sawcer, Glenn Ehresmann, David Peng, Miroslaw Smogorewski, April Armstrong, Rajkumar Dasgupta, Fred Sattler, Denise Brennan-Rieder, Cristina Mussini, Oriol Mitja, Vicente Soriano, Nicolas Peschanski, Gilles Hayem, Marco Confalonieri, Maria Carmela Piccirillo, Antonio Lobo-Ferreira, Iraldo Bello Rivero, Mika Turkia, Eivind H. Vinjevoll, Daniel Griffin, Ivan Fn Hung
We should remember that the greatest success in fighting a pandemic occurred over the past two decades in the battle against the HIV which causes AIDS. AIDS was first recognized in 1981 in the MSM (men who have sex with men) community [144]. The disease was considered a death sentence. There was widespread fear because there was no treatment, and projections of infection escalated into the millions. The first AIDS remedy was azidothymidine (AZT), synthesized in 1964 in the hope that it would combat cancer. Twenty years later Dr. Samuel Broder, head of the National Cancer Institute, showed that the drug had activity against the HIV virus in vitro [145]. Burroughs Wellcome launched a rapidly conceived trial with just 300 patients. They stopped the trial in 16 weeks claiming that more patients survived on AZT. The FDA came under enormous pressure from AIDS activists to make the drug available, and it was approved on 19 March 1987, with only that one trial. It had taken 20 months for the FDA to give approval to release the drug. To this day, the design and results of the trial remain controversial.
Assessment of complex genomic alterations induced by AZT, 3TC, and the combination AZT +3TC
Published in Drug and Chemical Toxicology, 2020
Allyne Cristina Grando, Nilza Nascimento Guimarães, Ana Paula de Souza, Mauricio Lehmann, Kênya Silva Cunha, Rafael Rodrigues Dihl
The comparisons of MNi and NPBs frequencies for individual treatments of AZT and 3TC with their respective combined treatments and the result of the CI are shown in Figures 3 and 4. Considering the results observed for the combination 3TC + AZT and of 3TC and AZT administered as separate drugs, a statistically significant increase in MNi frequency was observed in cells exposed to all concentrations of the combination, compared with 3TC alone. However, no such significant statistical difference was observed between combinations and AZT alone. Considering the induction of NPBs, a statistically significant reduction was observed after exposure of cells to high concentrations of the combination AZT +3TC, compared to AZT prescribed alone. No significant difference was observed between 3TC alone and the combination 3TC + AZT. Thus, it is possible to conclude that the combination 3TC + AZT had antagonistic effect on all the statistically significant concentrations evaluated.
Maternal and child health outcomes in rural South African mothers living with and without HIV
Published in AIDS Care, 2020
Karl W. le Roux, Joan Christodoulou, Emily C. Davis, Linnea Stansert Katzen, Elaine Dippenaar, Mark Tomlinson, Mary Jane Rotheram-Borus
Vertical HIV transmission prevention tasks for mothers living with HIV: All of the mothers living with HIV reported taking either full antiretroviral therapy (ART) (57%) or AZT (43%) during pregnancy as per the “Option A” vertical HIV transmission prevention protocol. At two years post-birth, 73% of mothers living with HIV were on ART – the rest either did not qualify for treatment or had defaulted. The majority of mothers living with HIV received NVP for their child at birth (93%), however only about half of HIV-exposed children who had their RtHC available (55%; 48/87) had an HIV test and the results written in to the card by 6 months post-birth. By 12 months, 89% of mothers living with HIV who were interviewed said their children had had a PCR test but only half of them had the results written in their RtHC (40/81; 49%). By 24 months, 61% (88/145) of mothers living with HIV had children with an HIV PCR result written in their RtHC, while no result could be found for 21% (31/145).