BACKGROUND: The HIV drugs lopinavir and ritonavir have recently been reported to cause transient adrenal insufficiency in preterm newborns. We, therefore, considered HIV drugs as a cause of transiently elevated 17-hydroxyprogesterone (17OHP) levels in a neonatal screening test for congenital adrenal hyperplasia in a preterm girl exposed to zidovudine, efavirenz, tenofovir, and emtricitabine. OBJECTIVE: So far, HIV drugs have not been tested for their effect on steroidogenesis and the steroidogenic enzyme activity of CYP21A2 specifically in an in vitro system. METHODS: We tested the effect of efavirenz, tenofovir, emtricitabine, and zidovudine on steroidogenesis of human adrenal H295R cells. Cells were treated with the drugs at different concentrations including concentrations in therapeutic use. The effect on CYP21A2 activity was assessed by testing the conversion of radiolabeled 17OHP to 11-deoxycortisol. Cell viability was tested by an MTT assay. In addition, recombinant human CYP21A2 protein was used to assess direct drug effects on CYP21A2 activity. RESULTS: We observed significantly decreased CYP21A2 activity in both in vitro testing systems after treatment with efavirenz at therapeutic concentrations. Moreover, efavirenz affected cell viability. By contrast, the other test drugs did not affect steroidogenesis. Follow-up of our patient revealed elevated 17OHP and androgen levels during the first weeks of life, but values normalized spontaneously. Genetic testing for CYP21A2 mutations was negative. Thus, it remains unsettled whether the transient 17OHP elevation in this baby was due to a drug effect. CONCLUSION: The HIV drug efavirenz inhibits CYP21A2 activity in vitro through direct interaction with enzyme catalysis at therapeutic concentrations. This may have clinical implications for HIV treatment in children and adults. However, so far, clinical data are scarce, and further studies are needed to be able to draw clinical conclusions.

• MeSH
• Benzoxazines * administration & dosage   adverse effects   MeSH
• Cell Line MeSH
• Adult MeSH
• HIV Infections drug therapy   MeSH
• Pregnancy Complications, Infectious drug therapy   MeSH
• Reverse Transcriptase Inhibitors * administration & dosage   adverse effects   MeSH
• Adrenal Hyperplasia, Congenital * chemically induced   enzymology   MeSH
• Humans MeSH
• Infant, Newborn MeSH
• Premature Birth * chemically induced   enzymology   MeSH
• Steroid 21-Hydroxylase antagonists & inhibitors   metabolism   MeSH
• Pregnancy MeSH
• Prenatal Exposure Delayed Effects * chemically induced   enzymology   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Infant, Newborn MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH

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• MeSH
• Algorithms MeSH
• Anti-Retroviral Agents * administration & dosage   adverse effects   therapeutic use   MeSH
• Adult MeSH
• Dyslipidemias complications   MeSH
• Drug Combinations MeSH
• HIV Infections * diagnosis   drug therapy   MeSH
• Pregnancy Complications, Infectious MeSH
• HIV Fusion Inhibitors administration & dosage   adverse effects   MeSH
• HIV Integrase Inhibitors administration & dosage   adverse effects   MeSH
• HIV Protease Inhibitors administration & dosage   adverse effects   MeSH
• Reverse Transcriptase Inhibitors administration & dosage   adverse effects   MeSH
• Drug Therapy, Combination methods   MeSH
• Anti-HIV Agents administration & dosage   adverse effects   MeSH
• Humans MeSH
• Kidney Diseases complications   MeSH
• Post-Exposure Prophylaxis * methods   MeSH
• Pregnancy MeSH
• Viremia diagnosis   MeSH
• Hepatitis, Viral, Human complications   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Pregnancy MeSH
• Publication type
• Practice Guideline MeSH

Cíl: Srovnat chronické účinky antiretrovirotické léčby (lamivudin, stavudin, delavirdin, nelfinavir, amprenaviru a kombinace lopinaviru/ritonaviru) u březích potkanů albínů. Typ studie: Review. Název a sídlo pracoviště: Gynekologicko-porodnická klinika, Federal University of S?o Paulo (UNIFESP), Sao Paulo, SP, Brazílie. Metodika: Retrospektivní srovnávací studie se zabývala 18 skupinami po 10 březích samičkách potkanů, které byly téměř tři měsíce staré a vážily 200 gramů. Každé z nich byla denně aplikována léčba pomocí žaludeční sondy, zatímco kontrolní skupině byl aplikován 1 ml destilované vody. Studijní skupiny obdržely lamivudin (5, 15 a 45 mg/kg/den); stavudin (na 1, 3 a 9 mg/kg/den); nelfinavir (40, 120 a 360 mg/kg/den); amprenavir (na 46, 138 a 414 mg/kg/den); lopinavir/ritonavir (12.8/3.2, a 38.4/9.6 115/28.8 mg/kg/den) a delavirdin (20 a 60 mg/kg/den). To představuje jedno-, troj- a devítinásobek terapeutické dávky pro člověka, s výjimkou posledního léku, kde nebyla nejvyšší dávka podána. Byla hodnocena hmotnost samice, plodu a placenty, počet implantací a reabsorpcí, hlavní zevní malformace plodu a odumření samice nebo plodu. Pro statistické zpracování byly použity test Kruskalův-Wallisův a χ2 test. Výsledky: U všech tří dávek stavudin zvyšoval hmotnost samice (p = 0,001), zatímco lamivudin při trojnásobné a devítinásobné dávce hmotnost snižoval (p < 0,001). Amprenavir u všech dávek, a lopinavir//ritonavir u troj- a devítinásobné dávky zvyšoval úmrtnost samic (p < 0,001). Z hlediska plodů nebylo žádné z antiretrovirotik škodlivé, pokud jde o implantaci, reabsorpci, teratogenitu a úmrtnost (p > 0,05). Stavudin při všech dávkách snižoval hmotnost mláďat(p < 0,001); Nicméně lamivudin u trojnásobné, delavirdin u trojnásobné a amprenavir u trojnásobné dávky hmotnost mláďat zvyšoval (p < 0,001). Závěr: U březích samic jsme pozorovali letální toxicitu u krys, kterým byl aplikován amprenavir a ritonavir/lopinavir; hmotnost krys se měnila při užití lamivudinu a stavudinu . U plodů byly pozorovány nežádoucí účinky v souvislosti s hmotností mláďat u stavudinu, lamivudinu, amprenaviru a delavirdinu..

Objective: To compare the chronic effects of antiretrovirals (lamivudine, stavudine, delavirdine, nelfinavir, amprenavir and an association of lopinavir/ritonavir) on albino pregnant rats. Design: Review. Setting: Department of Obstetrics, Federal University of S?o Paulo (UNIFESP), S?o Paulo, SP, Brazil. Methods: This was a comparative retrospective study formed by 18 groups of 10 pregnant rats each, which were nearly three months of age and weighed 200 g. All of them were medicated every day using a stomach probe, while the control group was given 1 mL of distilled water. The study groups received lamivudine (at 5, 15 and 45 mg/kg/day); stavudine (at 1, 3 and 9 mg/kg/day); nelfinavir (at 40, 120 and 360 mg/kg/day); amprenavir (at 46, 138 and 414 mg/kg/day); lopinavir/ritonavir (at 12.8/3.2, 38.4/9.6 and 115/28.8 mg/kg/day) and delavirdine (at 20 and 60 mg/kg/day). These represented 1, 3 and 9 times the human therapeutic dose, except for the last drug, for which the 9-times dose was not used. Maternal, litter and placental weights, implantation and reabsorption numbers, major external fetal malformations and fetal and maternal deaths were evaluated. The Kruskal-Wallis test was used to compare quantitative variables and the chi-square test was used to compare qualitative variables. Results: At all three doses, stavudine increased the maternal weight (p=0.001), while lamivudine at 3- and 9-times doses reduced it (p<0.001). Amprenavir at all of the doses, and lopinavir/ritonavir at 3- and 9-times doses, caused higher rates of maternal death (p<0.001). Regarding the fetuses, none of the antiretroviral drugs studied were harmful with regard to implantation, reabsorption, teratogenity and mortality (p>0.05). Stavudine at all doses reduced the litter weights (p<0.001); however, lamivudine at the usual and 3-times doses, delavirdine at 3-times dose, and amprenavir at 3-times dose increased the litter weight (p<0.001). Conclusion: In the maternal compartment, we observed lethal toxicity in the pregnant rats that received amprenavir and ritonavir/lopinavir; and maternal weight change with lamivudine and stavudine. In the fetal compartment, adverse effects were observed in relation to litter weight from stavudine, lamivudine, delavirdine and amprenavir. Keywords: pregnant rats, antiretroviral drugs, teratology, biological assay

• MeSH
• Anti-Retroviral Agents * administration & dosage   classification   therapeutic use   MeSH
• HIV Infections * drug therapy   MeSH
• HIV Protease Inhibitors administration & dosage   classification   adverse effects   therapeutic use   MeSH
• Reverse Transcriptase Inhibitors administration & dosage   classification   adverse effects   therapeutic use   MeSH
• Anti-HIV Agents administration & dosage   classification   adverse effects   therapeutic use   MeSH
• Disease Models, Animal * MeSH
• Fetus drug effects   MeSH
• Rats, Wistar MeSH
• Retrospective Studies MeSH
• Statistics as Topic MeSH
• Pregnancy MeSH
• Body Weight drug effects   MeSH
• Teratology MeSH
• Animals MeSH
• Check Tag
• Pregnancy MeSH
• Animals MeSH

Od druhé poloviny devadesátých let minulého století je hlavní léčebnou strategií HIV infekce tzv. kombinovaná antiretrovirová terapie. Jednou z tradičně používaných lékových skupin jsou inhibitory reverzní transkriptázy. Etravirin je zástupcem druhé generace nenukleosidových inhibitorů reverzní transkriptázy (NNRTI). Vzhledem k nutnosti kombinovat léky z různých terapeutických skupin, je každý nový léčebný přípravek možnou alternativou v případě nesnášenlivosti nebo neúčinnosti předchozí terapie. Etravirin je obecně charakterizován dobrou účinností, menším rizikem vzniku nežádoucích účinků a vyšší odolností proti vzniku rezistence v porovnání se zástupci první generace NNRTI.

Since the mid-nineties of the last century, combination antiretroviral therapy has been the main treatment strategy for HIV. Reverse transcriptase inhibitors are among the traditionally used drug classes. Etravirine is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI). Due to the need to combine drugs from different classes, each newly approved medicinal product is an option for patients with resistance or intolerance to previous therapy. Etravirine is generally characterized by high efficacy, a low risk of side effects and a higher resistance barrier in comparison with first-generation NNRTIs.

• MeSH
• Administration, Oral MeSH
• HIV Infections * drug therapy   MeSH
• HIV-1 drug effects   MeSH
• Reverse Transcriptase Inhibitors * pharmacology   adverse effects   therapeutic use   MeSH
• Anti-HIV Agents pharmacology   adverse effects   therapeutic use   MeSH
• Humans MeSH
• Pyridazines * pharmacology   adverse effects   therapeutic use   MeSH
• Antiretroviral Therapy, Highly Active MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

• Keywords
• antiretrovirová léčba,
• MeSH
• Antiviral Agents * MeSH
• HIV Infections * diagnosis   etiology   drug therapy   prevention & control   MeSH
• HIV Reverse Transcriptase biosynthesis   drug effects   MeSH
• Protease Inhibitors administration & dosage   adverse effects   therapeutic use   MeSH
• Reverse Transcriptase Inhibitors administration & dosage   adverse effects   therapeutic use   MeSH
• Clinical Trials as Topic MeSH
• Contraceptive Agents, Female administration & dosage   MeSH
• Humans MeSH
• Drug-Related Side Effects and Adverse Reactions metabolism   MeSH
• Socioeconomic Factors MeSH
• Pregnancy drug effects   MeSH
• Women MeSH
• Check Tag
• Humans MeSH
• Pregnancy drug effects   MeSH
• Female * MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

• MeSH
• Acquired Immunodeficiency Syndrome epidemiology   drug therapy   MeSH
• Anti-Retroviral Agents administration & dosage   economics   MeSH
• HIV Infections epidemiology   drug therapy   MeSH
• Reverse Transcriptase Inhibitors economics   adverse effects   therapeutic use   MeSH
• Humans MeSH
• Viral Vaccines MeSH
• Check Tag
• Humans MeSH

• Keywords
• raltegravir, bocaprevir,
• MeSH
• Fibrosis MeSH
• Hepatitis C MeSH
• Protease Inhibitors MeSH
• Reverse Transcriptase Inhibitors adverse effects   MeSH
• Clinical Trials as Topic MeSH
• Congresses as Topic MeSH
• Middle Aged MeSH
• Humans MeSH
• Proline analogs & derivatives   administration & dosage   adverse effects   MeSH
• Pyrrolidinones therapeutic use   MeSH
• Treatment Outcome MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH

• MeSH
• Anti-Retroviral Agents therapeutic use   MeSH
• Long-Term Care methods   MeSH
• HIV Infections drug therapy   MeSH
• Reverse Transcriptase Inhibitors adverse effects   therapeutic use   MeSH
• Humans MeSH
• Antiretroviral Therapy, Highly Active methods   MeSH
• Check Tag
• Humans MeSH

• MeSH
• Anti-Retroviral Agents adverse effects   MeSH
• Myocardial Infarction drug therapy   MeSH
• Reverse Transcriptase Inhibitors adverse effects   therapeutic use   MeSH
• Humans MeSH
• Check Tag
• Humans MeSH

Zavedení antiretrovirové terapie do klinické praxe přineslo výrazné zkvalitnění a prodloužení délky života osob s HIV infekcí. V současné době jsou v klinickém užívání léky ze 4 různých skupin a řada dalších nadějných přípravků je v různém stádiu klinického výzkumu. Zásadními problémy současné antiretrovirové terapie je jednak častý výskyt závažných nežádoucích účinků a také poměrně snadný vznik rezistence. Základní podmínkou úspěchu antiretrovirové terapie je dobrá spolupráce lékaře a pacienta, založená na bedlivém sledování rozvoje nežádoucích účinků lékařem a maximální adherencí k terapii ze strany pacienta. Od vývoje nových antiretrovirových léku jsou očekávány přípravky méně toxické, odolnější ke vzniku rezistence a v neposlední řadě také levnější, protože pro vysokou cenu těchto léků má k antiretrovirové terapii v současné době přístup ve světě pouze asi 25 % všech lidí, kteří by tuto léčbu potřebovali.

The introduction of antiretroviral therapy to clinical practice has assured a significant improvement in the quality of life for people living with HIV infection, and has substantially prolonged their life expectancy. At present there are four classes of antiviral drugs in clinical use and several new promising molecules are in various stages of clinical research and development. The major problems with current antiretroviral therapy are the occurrence of serious side-effects and a relatively quick development of resistance. Good cooperation between the patient and the physician is essential for the success of antiretroviral therapy. This success is based primarily on careful monitoring of side-effects by the physician and maximum adherence by the patient. The new antiretroviral drugs under development are thus expected to háve lower toxicity and lower sensitivity to the development of viral resistance. The new drugs should be also cheaper because, due to the high costs of the antiretroviral drugs that are currently being ušed, only about 25 % of all people indicated for treatment worldwide have access to therapy.

• MeSH
• HIV Infections diagnosis   drug therapy   physiopathology   MeSH
• HIV Fusion Inhibitors classification   adverse effects   therapeutic use   MeSH
• HIV Integrase Inhibitors classification   adverse effects   therapeutic use   MeSH
• HIV Protease Inhibitors classification   adverse effects   therapeutic use   MeSH
• Reverse Transcriptase Inhibitors classification   adverse effects   therapeutic use   MeSH
• Drug Therapy, Combination MeSH
• Drug Resistance, Viral MeSH
• Zidovudine adverse effects   therapeutic use   MeSH
• Publication type
• Review MeSH