Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The appearance in the clinic of two to three new antiretroviral agents yearly since 1995 has permitted unprecedented advances in HIV treatment. This remarkable pace of drug development is a testimony to an extraordinary international effort involving scientists, clinicians, governments, community activists and industry dedicated to the rapid and safe development of novel therapies. New drugs present the opportunity to improve HIV therapy. They also create an enormous challenge to the clinician, who must constantly assimilate data on new drugs and incorporate this information into practical management strategies. Combination therapy has proven the most effective approach to treat HIV disease. The profound and sustained viral suppression achievable with combinations such as indinavir (IDV), lamivudine (3TC) and zidovudine (ZDV) have resulted in a dramatic shift in HIV treatment paradigms over the last year. The full potential of combination therapy with available drugs has yet to be realized as only a limited number of the possible combinations incorporating new drugs have been fully tested. Even drugs available for many years may have untapped potential. Didanosine (ddI) and stavudine (d4T), once thought to be contraindicated in combination because of their overlapping peripheral neuropathy toxicity, have proven well tolerated and effective. Combination therapy can increase antiviral suppression, prevent drug resistance, optimize drug exposure and simplify dosing, but it can also result in pharmacologic antagonism, subtherapeutic drug concentrations and unexpected toxicities. Clinical studies have confirmed in vitro studies showing pharmacologic antagonism for the combination of ZDV and d4T. Combining protease inhibitors with each other or with non-nucleoside reverse transcriptase inhibitors is complicated by effects both classes of drugs have on drug metabolism and clearance. These observations underline the importance of carefully conducted clinical studies to characterize safety, pharmacokinetics and efficacy of combination therapies. In this review, we will first summarize the clinical profile of new drugs which either became commercially available last year [nelfinavir, nevirapine, delavirdine (DLV)] or are in the late stages of clinical development (DMP-266, abacavir and 141W94). Later we will summarize new data on nucleoside, protease inhibitor and non-nucleoside reverse transcriptase combination regimens. Finally, we will briefly mention new drugs in early stages of development.
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PMID:New antiretrovirals and new combinations. 963 99

In HIV/AIDS illness the reverse transcriptase and protease enzymes of human immunodeficiency virus (HIV) are currently the agents of antiretroviral therapy. Nucleoside analogues were the first group of drugs which exerted antiviral activity in humans. More recently protease inhibitors have provided new approaches in the treatment of HIV-infection and AIDS. Impressive clinical results have been obtained with combined therapies of three antiretroviral drugs, including one protease inhibitor. It is worth to mention that apart from the above, many new compounds are under development, including the vaccine against HIV.
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PMID:[HIV protease inhibitors (new possibilities in the treatment of HIV infection and AIDS)]. 965 65

Infection with HIV leads to AIDS and death in about 90% of patients within ten years. The first generation of anti-HIV drugs inhibited the viral enzyme reverse transcriptase (RT); but long-term studies have revealed side-effects and a high rate of emergence of drug-resistant HIV mutants. The more recent combination of two anti-RT drugs and a protease inhibitor appears to be more promising: approximately 75% of AIDS patients benefit. However, increasing numbers of treatment failures from toxicity and drug-resistant mutants are emerging. Passive immunotherapy (PIT) is a non-toxic form of treatment based on the neutralization of HIV with antibody-rich plasma from healthy HIV-positive individuals. Studies show it can benefit AIDS patients. Here, we suggest that, in combination with anti-HIV drugs, PIT could reduce some of the toxicity of the latter and limit the emergence of drug-resistant HIV strains. In addition, regular plasma donation seems to be beneficial to the donors.
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PMID:How to prolong the effects of combination therapy for HIV. 967 42

As many factors may be involved in therapeutic response to triple therapy with protease inhibitor (PI), the aim of this study was to determine the influence of epidemiological factors (sex, risk factors), clinical status (previous number of AIDS defining events), immunological status (baseline CD4 T cells count), virological factor (baseline viral load), previous antiretroviral therapy and duration of AZT therapy (> or < 6 months), number of prescribed reverse transcriptase inhibitors (RTI), therapeutic strategy (switch to different RTI or only addition of PI) and compliance, on early virological response (M2-M3) after initiation of triple therapy with PI. These results concerned 167 patients treated with triple therapy including PI. A viral load response was defined in three types: complete response (undetectable: < 500 copies/ml) for 100 patients; partial response (significant decrease: > 0.5 log from baseline) for 30 patients and no response for 37 patients. Only two parameters were associated of good virological response: no previous antiretroviral therapy (p < 0.001) and good compliance (p < 0.001). No significant difference was observed between patients with no prior therapy and pretreated patients, in terms of median baseline CD4 count and observance. The baseline median viral load was higher in naive patients despite a better response. In pretreated patients, the type of response appeared to be dependent on the duration of AZT treatment (p = 0.06) and good compliance (p = 0.06). Among the 100 patients with initial complete response, only 23/81 were still undetectable after a median of 13 months of therapy.
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PMID:[Factors predictive of early virologic response after a first treatment with an protease inhibitor in the course of HIV infection]. 973 2

The use of combinations of anti-human immunodeficiency virus (anti-HIV) agents targeted to different molecular targets will most likely result in increased viral suppression and may also delay or prevent the emergence of resistant HIV strains. The purpose of the present study was to develop information on the in vitro anti-HIV activities of combinations of the reverse transcriptase inhibitor 1592U89 and the protease inhibitor 141W94 to help guide the choice of dosages in clinical trials. Triplicate in vitro dose-response matrices were prepared with MT-2 cells infected with HIV type 1 (HIV-1) strain IIIB. In order to account for the effects of protein binding, tissue culture medium with 10% fetal bovine serum was supplemented with the human serum proteins alpha1 acid glycoprotein (1 mg/ml) and albumin (40 mg/ml). The three-dimensional drug interaction surface for 1592U89 and 141W94 was constructed with the program MacSynergy II. As analyzed relative to a Bliss Independence null reference model, this combination was synergistic, with volumes of synergy exceeding 100 (99% confidence). Analysis of the data set with a fully parametric form of an equation for the quantitation of drug interaction developed by Greco et al. (W. R. Greco, G. Bravo, and J. C. Parsons, Pharmacol. Rev. 47:331-385, 1995) resulted in an interaction term statistically significantly greater than 0.0, indicating true synergy. Both methods concur that this combination is significantly synergistic. These data, with favorable findings from phase I/II trials for each drug alone, suggest that the combination of 1592U89 plus 141W94 should be further evaluated in clinical trials.
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PMID:Nucleoside analog 1592U89 and human immunodeficiency virus protease inhibitor 141W94 are synergistic in vitro. 973 27

The interleukin-2 (IL-2)/IL-2 receptor (IL-2R) system is the main regulatory determinant of T cell reactivity. Although it is well known that IL-2 secretion is impaired during HIV infection, up to now IL-2R expression has not been extensively studied in HIV-infected patients despite the use of IL-2 in clinical therapy trials. We show here that IL-2R expression in HIV patients with high viral load (group 1 in the study) is greatly enhanced on B lymphocytes, CD8 T lymphocytes, and monocytes, but not on CD4 T lymphocytes, compared with noninfected individuals. Paradoxically, this modified IL-2R expression does not lead to increased IL-2 responsiveness, except for B lymphocytes. In patients receiving triple combination therapy (TCT, two reverse transcriptase inhibitors and one protease inhibitor) that has triggered a drastic reduction in plasma viral load and an increase in CD4 counts (group 2 patients), IL-2R expression is significantly lower than in group 1 patients. Moreover, cells involved in cellular immunity and CD4 T lymphocytes have the capacity to respond to IL-2 after TCT. These results allow us to anticipate a beneficial role of IL-2 immunotherapy in combination with TCT.
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PMID:Regulatory dysfunction of the interleukin-2 receptor during HIV infection and the impact of triple combination therapy. 973 39

High-density oligonucleotide arrays were used to determine the sequence of the protease (PR) and reverse transcriptase (RT) genes of human immunodeficiency virus type 1 isolates from 35 patients in whom combination therapy that included a protease inhibitor had failed. Isolates had a median of three PR mutations (range, none to six). Three isolates had no known resistance mutations in PR. Twelve isolates (34%) had two or fewer resistance mutations in PR. The most commonly observed PR mutations were L10I, V82A/T/F, and L90M. No mutations were observed at codons 30 or 48. Mutations at RT codons 215 and 184 were observed in the majority of isolates. These data suggest that therapy can fail in some patients with relatively few PR resistance mutations. Clinical failure in the absence of resistance mutations implies inadequate drug exposure due to pharmacologic factors or suboptimal patient adherence to drug therapy.
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PMID:Resistance mutations in protease and reverse transcriptase genes of human immunodeficiency virus type 1 isolates from patients with combination antiretroviral therapy failure. 1039 85

Recent advances in the chemotherapeutic agents against HIV enabled us to conduct combination therapies using two nucleoside reverse transcriptase inhibitors and a protease inhibitor. The three-drug combination chemotherapies have been shown to be very potent in inhibiting HIV replication; they markedly suppress plasma HIV-RNA levels, elevate CD4 counts, reduce opportunistic infections and prolong survival of the patients. Early and hard treatment is now recommended. Among opportunistic infections in patients with HIV infection/AIDS, most frequent are respiratory tract infections including Pneumocystis carinii pneumonia, bacterial pneumonia, pulmonary tuberculosis, CMV pneumonia and fungus infections. Sensitivity and specificity of PCR method to detect Pneumocystis carinii are much better than the conventional Grocott stain of sputa. Early diagnosis of tuberculosis and atypical mycobacteriosis became possible using PCR and other molecular technology. Multi-drug resistant tuberculosis is fortunately rare among Japanese HIV-positive patients. Early and correct diagnosis of opportunistic infections markedly improves the prognosis of the patients.
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PMID:[HIV Infection/AIDS and respiratory tract infections in Japan]. 979 9

Combinations of anti-human immunodeficiency virus (HIV) drugs, including reverse transcriptase inhibitors and protease inhibitors, have proven immensely potent in the therapy of acquired immune deficiency syndrome (AIDS). To determine whether HIV integrase is a suitable target for combination therapy, the ability of an HIV integrase inhibitor, L-chicoric acid, to work in combination with a protease inhibitor and Zidovudine was tested in vitro. The addition of L-chicoric acid to either Zidovudine or protease inhibitor improved upon the observed anti-HIV activity of either compound alone. When all three drugs were combined, the anti-HIV activity was substantially better than either of the three compounds alone or any combination of two inhibitors. Doses of both Zidovudine and protease inhibitor could be reduced by more than 33% for an equivalent anti-HIV effect if L-chicoric acid was added. The improved anti-HIV activity was observed with a tissue culture adapted strain of HIV (HIV(LAI)) and with limited passage clinical isolates of HIV (HIV(R19) and HIV(R45)). These data demonstrate that a first generation HIV integrase inhibitor, L-chicoric acid, is at least additive in combination with existing multi-drug regimens and suggest that HIV integrase will be an excellent target for combination therapy of HIV infection.
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PMID:L-chicoric acid, an inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase, improves on the in vitro anti-HIV-1 effect of Zidovudine plus a protease inhibitor (AG1350). 980 87

These guidelines update previous CDC recommendations for the diagnosis, treatment, and prevention of tuberculosis (TB) among adults and children coinfected with human immunodeficiency virus (HIV) in the United States. The most notable changes in these guidelines reflect both the findings of clinical trials that evaluated new drug regimens for treating and preventing TB among HIV-infected persons and recent advances in the use of antiretroviral therapy. In September 1997, when CDC convened a meeting of expert consultants to discuss current information about HIV-related TB, special emphasis was given to issues related to coadministration of TB therapy and antiretroviral therapy and how to translate this information into management guidelines. Thus, these guidelines are based on the following scientific principles: * Early diagnosis and effective treatment of TB among HIV-infected patients are critical for curing TB, minimizing the negative effects of TB on the course of HIV, and interrupting the transmission of Mycobacterium tuberculosis to other persons in the community. * All HIV-infected persons at risk for infection with M. tubercu losis must be carefully evaluated and, if indicated, administered therapy to prevent the progression of latent infection to active TB disease and avoid the complications associated with HIV-related TB. * All HIV-infected patients undergoing treatment for TB should be evaluated for antiretroviral therapy, because most patients with HIV-related TB are candidates for concurrent administration of antituberculosis and antiretroviral drug therapies. However, the use of rifampin with protease inhibitors or nonnucleoside reverse transcriptase inhibitors is contraindicated. Ideally, the management of TB among HIV-infected patients taking antiretroviral drugs requires a) directly observed therapy, b) availability of experienced and coordinated TB/HIV care givers, and in most situations, c) use of a TB treatment regimen that includes rifabutin instead of rifampin. Because alternatives to the use of rifampin for antituberculosis treatment are now available, the previously recommended practice of stopping protease inhibitor therapy to allow the use of rifampin for TB treatment is no longer recommended for patients with HIV-related TB. The use of rifabutin-containing antituberculosis regimens should always include an assessment of the patient's response to treatment to decide the appropriate duration of therapy (i.e., 6 months or 9 months). Physicians and patients also should be aware that paradoxical reactions might occur during the course of TB treatment when antiretroviral therapy restores immune function. Adding to CDC's current recommendations for administering isoniazid preventive therapy to HIV-infected persons with positive tuberculin skin tests and to HIV-infected persons who were exposed to patients with infectious TB, this report also describes in detail the use of new shortcourse (i.e., 2 months) multidrug regimens (e.g., a rifamycin, such as rifampin or rifabutin, combined with pyrazinamide) to prevent TB in persons with HIV infection. A continuing education component for U.S. physicians and nurses is included.
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PMID:Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. Centers for Disease Control and Prevention. 980 43


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