Side effects of HIV nucleoside reverse transcriptase inhibitors

Zidovudine

Patients should be warned about the possible consequences of simultaneous use of other drugs without a doctor's prescription.

Patients should be warned that zidovudine has not been shown to prevent the risk of transmitting HIV to others through sexual contact or exposure to infected blood, and patients should continue to take appropriate precautions.

The drug Zidovudine does not cure HIV infection, and patients remain at risk of developing diseases associated with immunosuppression, including opportunistic infections and neoplasms. Although zidovudine has been shown to reduce the risk of opportunistic infections, data on the risk of neoplasms, including lymphomas, are limited.

Available data from patients treated for advanced HIV infection indicate that the risk of developing lymphoma is similar to that of untreated patients. In patients with early HIV infection receiving long-term treatment, the risk of developing lymphoma is unknown.

Pregnant women considering the use of zidovudine during pregnancy to prevent transmission of HIV to their children should be advised that in some cases transmission may occur even despite therapy.

Prevention after possible HIV infection

According to international recommendations (Center for Disease Control and Prevention - June 1998), in case of accidental contact with the blood of an HIV-infected person (for example, through an injection needle), combination therapy with zidovudine and lamivudine should be started immediately (within 1-2 hours). In case of a higher risk of infection, a drug from the group of protease inhibitors should be included in the APT regimen. Antiretroviral prophylactic treatment is recommended for 4 weeks. Controlled clinical trials of prophylactic treatment after accidental infection have not been conducted, and supporting data are limited. Despite the rapid initiation of treatment with antiretroviral drugs, the development of seroconversion cannot be ruled out.

Adverse blood reactions

In symptomatic and advanced HIV patients taking zidovudine, anemia (usually observed 6 weeks after starting zidovudine, but sometimes occurring earlier), neutropenia (usually occurring 4 weeks after starting zidovudine, but sometimes occurring earlier) can be expected to develop. ) and leukopenia (usually secondary to neutropenia). Most often, these phenomena develop when using higher doses of zidovudine (1200-1500 mg/day) and in patients with reduced bone marrow reserve before treatment, especially in the late stages of HIV infection.

Hematological parameters must be carefully monitored. For symptomatic patients with advanced HIV infection, blood tests are recommended at least every 2 weeks during the first 3 months of therapy and at least once a month thereafter. In patients with an early stage of HIV infection (with an undepleted bone marrow reserve), adverse reactions from the blood are uncommon. Depending on the patient's general condition, blood tests may be performed less frequently, for example every 1-3 months.

When the hemoglobin concentration decreases to 7.5-9.0 g/dl (4.65-5.59 mmol/l), or the number of neutrophils decreases to 0.75-1.0x109/l, the daily dose can be reduced until signs of recovery appear bone marrow; Alternatively, recovery may be accelerated by short-term (2-4 weeks) interruption of Zidovudine therapy. Bone marrow recovery is usually observed within 2 weeks, after which treatment with zidovudine can be resumed at a lower dose. In patients with severe anemia, dose adjustment does not always eliminate the need for blood transfusion.

Lactic acidosis and severe hepatomegaly with steatosis

There are reports of the development of lactic acidosis and severe hepatomegaly with steatosis, including death, due to APT with nucleoside analogues, including zidovudine, taken either alone or in combination. In most cases, these complications occur in women.

Clinical symptoms that may indicate the development of lactic acidosis include general weakness, anorexia, lack of appetite, rapid unexplained weight loss, gastrointestinal disorders (nausea, vomiting and abdominal pain), respiratory disorders (shortness of breath and tachypnea ) or neurological symptoms (including motor weakness).

Treatment with Zidovudine should be discontinued if symptomatic hyperlactatemia and metabolic acidosis/lactic acidosis, progressive hepatomegaly, or a rapid increase in aminotransferase activity develop.

Caution should be exercised when using the drug to treat any patient (especially overweight women) with hepatomegaly, hepatitis or other known risk factors for liver damage and hepatic steatosis (including the use of certain drugs and alcohol consumption).

Patients co-infected with hepatitis C virus and treated with interferon alfa and ribavirin may be at particular risk. Patients at increased risk require special attention.

If clinical or laboratory signs of lactic acidosis with or without hepatitis appear (may manifest as hepatomegaly and steatosis even in the absence of a marked increase in transaminase activity), treatment with Zidovudine should be suspended.

Lipoatrophy

Treatment with zidovudine was accompanied by loss of subcutaneous fat. The incidence and severity of lipoatrophy are related to cumulative exposure. This loss of fat, which is most pronounced on the face, limbs and buttocks, may be only partially reversible, and improvement may not occur until several months after switching to a treatment regimen that does not contain zidovudine. During therapy with zidovudine and other drugs containing zidovudine, patients should be regularly monitored for signs of lipoatrophy, and if lipoatrophy is suspected, patients should be switched to an alternative treatment regimen if possible.

Serum lipids and blood glucose

Serum lipid and blood glucose concentrations may increase during APT. Disease control and lifestyle changes may also contribute to this process. The need to determine serum lipid and blood glucose concentrations should be considered. Lipid metabolism disorders must be treated based on their clinical manifestations.

Immune reconstitution syndrome

In HIV-infected patients with severe immunodeficiency at the time of initiation of APT, an inflammatory reaction may develop against the background of asymptomatic opportunistic infections or their residual effects, which can lead to increased symptoms or other serious consequences.

These reactions usually occur within the first few weeks or months after starting antiretroviral therapy. Typical examples are cytomegalovirus retinitis, generalized and/or focal infection caused by mycobacteria, and pneumonia caused by Pneumocystis jiroveci (P. carinii). The appearance of any symptoms of inflammation requires immediate examination and, if necessary, treatment.

Autoimmune diseases (such as Graves' disease, polymyositis, and Guillain-Barre syndrome) have also been observed in the setting of immune reconstitution, but the timing of initial manifestations varied and the disease could occur many months after the start of therapy and sometimes had an atypical course.

Concomitant viral hepatitis C

When using zidovudine as part of a treatment regimen for HIV infection, cases of exacerbation of anemia while taking ribavirin have been reported; the exact mechanism of this phenomenon remains unknown. In this regard, the simultaneous use of zidovudine with ribavirin is not recommended. If zidovudine is already included in a combination APT regimen, substitution should be considered. This is especially important for patients with a history of zidovudine-induced anemia.

Liver failure (sometimes fatal) has occurred in patients infected with HIV and hepatitis C virus who received combination APT for HIV concomitantly with interferon alfa with or without ribavirin.

Patients receiving interferon alfa with or without ribavirin and zidovudine should be monitored for treatment-related toxicities, particularly liver failure, neutropenia, and anemia. In such cases, discontinuation of use of the drug Zidovudine should be considered. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if clinical toxicity increases, including development of liver failure (eg, Child-Pugh score greater than 6) (see prescribing information for interferon alfa and ribavirin ).

Myopathy and myositis

Myopathy and myositis with pathological changes characteristic of the course of HIV infection have been associated with long-term use of zidovudine.

Combined use with drugs containing zidovudine

The drug Zidovudine should not be used in conjunction with drugs containing zidovudine as one of the components.

The drug contains sodium benzoate, which increases the risk of developing jaundice in newborns.

Side effects of HIV nucleoside reverse transcriptase inhibitors

With long-term use of HIV nucleoside reverse transcriptase inhibitors (NRTIs), they are characterized by various manifestations of toxicity [1-3].

Despite the large differences in clinical signs, lipodystrophy, lactic acidosis, hepatic steatosis and probably myopathy are due to the same underlying cause: mitochondrial (including peroxisomal) toxicity [4].

Mitochondrial toxicity, to one degree or another, is inherent in all NRTIs, but for each of the drugs it has a different nature and, therefore, tissue specificity, and also differs greatly in the rate of development and degree of toxicity.

Several main mechanisms of mitochondrial toxicity can be identified [5]:

• direct inhibition of mitochondrial DNA polymerase;
• influence on the Krebs cycle and β-oxidation of fatty acids;
• influence on the efficiency of carnitine-dependent transport of fatty acids across the mitochondrial membrane;
• possible influence on AMP-activated protein kinase, which controls the energy balance of the cell.

Currently, direct inhibition of mitochondrial DNA polymerase has been studied in detail. It is characteristic of zalcitabine , didanosine , stavudine and, to a much lesser extent, lamivudine . These drugs, or rather their triphosphorylated forms, terminate the synthesis of mitochondrial DNA and inhibit excision repair of defects that arise in its structure [6-9]. As a result, the number of mitochondria in cells decreases, while the DNA mutates, deletions and large insertions almost completely disrupt the expression of mitochondrial genes. Therapy for 6-12 months leads to acidosis in almost 70% of patients (zalcitabine, didanosine); after 18-24 months, lipodystrophy develops in almost 50% of cases (stavudine) [10-12]. The toxic effect caused by this process is independent of the tissue and can only be eliminated by drug withdrawal. Restoration of normally functioning mitochondria takes months and years [10,13]. Apparently, this is why the proportion of patients treated with zalcitabine , didanosine and stavudine is constantly decreasing.

Zidovudine, abacavir and tenofovir practically do not cause either suppression of mitochondrial DNA synthesis or suppression of the repair function of mitochondrial DNA polymerase, however, they can be involved in other mechanisms of mitochondrial activity [14,15].

The use of tenofovir causes the following complications, which may be associated with mitochondrial dysfunction:

1. Fatty liver , ultimately – steatosis . The developers of tenofovir do not recommend its use in patients with fatty liver disease, noting fatal outcomes when used as part of antiretroviral therapy [16].
2. Mitochondria in the liver and adipocytes begin to actively process sugars and synthesize fatty acids, which leads to lactic acidosis . The developers of tenofovir also do not recommend its use in cases of lactic acidosis [16].

Abacavir , like tenofovir, is an analog of purine nucleosides, which is probably why it is characterized by similar manifestations of mitochondrial toxicity [17].

zidovudine therapy causes complications, some of which are of the opposite nature:

1. There is an inhibition of brown fat cells located in muscle tissue and adipocytes in the subcutaneous layer, which leads, in contrast to the effect of tenofovir, to lipodystrophy . However, fat accumulates in the visceral organs and the nape of the neck, and a “bull’s hump” is formed [18].
2. As fatty acid reserves in muscle tissue and the subcutaneous layer are depleted, a switch occurs to mitochondria consuming sugars in muscle cells, which leads to myopathy and, in acute form, lactic acidosis [18].

The molecular mechanisms underlying the stimulation of obesity with the use of purine derivatives and, conversely, lipodystrophy with therapy with thymidine analogues can ultimately be reduced to the inhibition or activation of the Krebs cycle and β-oxidation of fatty acids - the main mechanisms leading to the synthesis of ATP (see Appendix ).

Thus, it can be stated that abacavir, zidovudine and tenofovir , unlike other NRTIs, have virtually no inhibitory effect on mitochondrial DNA polymerase, however, they are involved in various mechanisms of mitochondrial activity, more precisely in the processes of fatty acid metabolism, which leads to distortion of these mechanisms , and ultimately to toxic effects. In addition to mitochondrial toxicity, other toxic effects occur.

Thus, the use of abacavir causes hypersensitivity (up to 10% of cases), which usually manifests itself in the form of fever (fever), rash, gastrointestinal disorders (nausea, vomiting, diarrhea or abdominal pain), general malaise, including fatigue, and respiratory manifestations (pharyngitis, shortness of breath, cough, etc.). In some cases, hypersensitivity is fatal. In addition, the development of lymphopenia is observed. Patients who are carriers of the histocompatibility gene variant HLA-B*5701 are not recommended to use abacavir. Abacavir is also not recommended for children under 3 months of age [17].

Tenofovir promotes the removal of calcium from bone tissue, which leads to osteoporosis. Calcium-related osteopenia and pre- and postnatal toxicities have also been associated with tenofovir use. Apparently, therefore, it is not indicated for persons under 18 years of age (FDA), and pregnant women can be prescribed only in cases of extreme necessity [16]. The main side effect of tenofovir therapy is nephrotoxicity, which is associated with irreversible changes in the cells of the proximal renal tubules [19].

Zidovudine by inhibition of hematopoiesis, which is primarily manifested in the development of anemia and neutropenia [20]. It should be noted here that the use of phosphazide , which is a long-acting prodrug of zidovudine, can significantly reduce the development of anemia and other manifestations of hemotoxicity [21,22].

In general phosphazide is a less toxic drug than zidovudine [22,23]. Moreover, it is indicated for patients who have developed intolerance to zidovudine [24]. It is recommended for pregnant women and children, as well as for patients with liver disease [25-27]. There is evidence of successful treatment of combined infections (HIV + hepatitis C, HIV + tuberculosis) using phosphazide [28-30]. Finally, a significantly lower (several times) maximum concentration of azidothymidine in blood plasma when taking phosphazide compared to zidovudine can reduce the manifestations of mitochondrial toxicity [1] [31]. This may be why therapy using phosphazide, as a rule, is not accompanied by side effects characteristic of other antiretroviral drugs: vomiting, headaches, diarrhea, myalgia, anemia, thrombocytopenia and neutropenia [31].

Thus, abacavir, zidovudine, tenofovir and phosphazide have different toxic effects, which makes it possible to recommend their use for different groups of patients (see Table 1 and Table 2).

Tenofovir appears to selectively inhibit the hepatic form of AMPK [2], which leads to suppression of β-oxidation of fatty acids and increased cholesterol synthesis. In this case, mitochondria more intensively begin to process glucose and polysaccharides for the synthesis of ATP, which leads to obesity, including fatty liver (steatosis), as well as lactic acidosis. It is likely that tenofovir may also have an inhibitory effect on the Krebs cycle and β-oxidation of fatty acids, acting as a competitive inhibitor in a variety of enzymatic processes involving ADP, ATP and NAD. The exact mechanism of these processes is not known, but their result is the accumulation of fat throughout the body.

Zidovudine, on the contrary, leads to activation of the Krebs cycle and β-oxidation of fatty acids in mitochondria. This is probably due to the formation of 2-methylmalonate and β-aminoisobutyric acid (BAIBA), products of intracellular thymine processing. BAIBA [4-7] activates the expression of the hepatic isomer of carnitine palmitoyl transferase I (CPT I) [8], which leads to increased carnitine-dependent fatty acid transport in liver cells (hepatocytes) and white adipocyte cells, but not in muscle cells .

Malonate (derived from uracil by the same enzymes as methyl malonate from thymine) is an active inhibitor of the Krebs cycle, respiratory β-oxidation of fatty acids (inhibiting the activity of succinate dehydrogenase in both processes) and, in the form of malonyl-CoA, a participant in the initial and final stages of the β-oxidation cycle fatty acids [9]. The role of methyl malonate in this process apparently boils down to competition with malonate, which leads to activation of the Krebs cycle. At the same time, the efficiency of β-oxidation in muscle cells increases until fat reserves in brown and subcutaneous adipocytes are completely exhausted, which leads to a switch to the consumption of sugars with the occurrence of myalgia, myopathy and lactic acidosis [3]. Unlike abacavir and tenofovir, zidovudine does not cause fat accumulation in muscle tissue, much less in the liver, where fatty acid consumption is greatly increased due to the stimulation of CPT I under the influence of BAIBA.

Table 1

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*Recommendations are based on NRTIs that cause little or no direct inhibition of mitochondrial DNA polymerase.

**Before prescribing abacavir-containing therapy, patients must be analyzed for the presence of the histocompatibility gene variant HLA-B*5701. In cases of a positive result, the use of abacavir is unacceptable.

table 2

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*Recommendations are based on NRTIs that cause little or no direct inhibition of mitochondrial DNA polymerase.

**Before prescribing abacavir-containing therapy, patients must be analyzed for the presence of the histocompatibility gene variant HLA-B*5701. In cases of a positive result, the use of abacavir is unacceptable.

1. Dieterich DT // Long-term complications of nucleoside reverse transcriptase inhibitor therapy // AIDS Read., 2003, v. 13(4), p. 176-184, 187.

2. Brinkman K., Smeitink JA, Romijn JA, et al. // Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy // Lancet, 1999, v. 354(9184), p. 1112-1115.

3.Troll JG // Approach to dyslipidemia, lipodystrophy, and cardiovascular risk in patients with HIV infection // Curr. Atheroscler. Rep., 2011, v. 13(1), p. 51-56.

4. Mallon, P. W., Unemori P., Sedwell R., et al. // In vivo, nucleoside reverse-transcriptase inhibitors alter expression of both mitochondrial and lipid metabolism genes in the absence of depletion of mitochondrial DNA // J. Infect. Dis., 2005, v. 191(10), p. 1686-1696.

5. Viengchareun S., Caron M., Auclair M., et al. // Mitochondrial toxicity of indinavir, stavudine and zidovudine involves multiple cellular targets in white and brown adipocytes // Antivir. Ther., 2007, v. 12(6), p. 919-929.

6. Levis W. // Pharmacogenomics, toxicogenomics, and DNA polymerase gamma // J. Infect. Dis., 2007, v. 195(10), p. 1399-1401.

7. Lim SE, Copeland WC // Differential incorporation and removal of antiviral deoxynucleotides by human DNA polymerase gamma // J. Biol. Chem., 2001, v. 276(26), p. 23616-23623.

8. Johnson AA, Ray AS, Hanes J., et al. // Toxicity of antiviral nucleoside analogs and the human mitochondrial DNA polymerase // J. Biol. Chem., 2001, v. 276(44), p. 40847-40857.

9. Moyle G. // Mitochondrial toxicity: myths and facts // J. HIV Ther., 2004, v. 9(2) p. 45-47.

10. McComsey GA, Paulsen DM, Lonergan JT, et al. // Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine with abacavir or zidovudine // AIDS, 2005, v. 19(1), p. 15-23.

11. van Vonderen MG, van Agtmael MA, Hassink EA, et al. // Zidovudine/lamivudine for HIV-1 infection contributes to limb fat loss // PLoS One, 2009, v. 4(5), e5647.

12. Kaul S, Dandekar KA, Schilling BE, et al. // Toxicokinetics of 2′,3′-didehydro-3′-deoxythymidine, stavudine (D4T) // Drug Metab. Dispos., 1999, v. 27(1), p. 1-12.

13. Martin A., Smith DE, Carr A., ​​et al. // Reversibility of lipoatrophy in HIV-infected patients 2 years after switching from a thymidine analogue to abacavir: the MITOX Extension Study // AIDS, 2004, v. 18(7), p. 1029-1036.

14. Lund KC, Wallace KB // Direct, DNA pol-gamma-independent effects of nucleoside reverse transcriptase inhibitors on mitochondrial bioenergetics // Cardiovasc. Toxicol., 2004, v. 4(3), p. 217-228.

15. Note R., Maisonneuve C., Lettéron P., et al. // Mitochondrial and metabolic effects of nucleoside reverse transcriptase inhibitors (NRTIs) in mice receiving one of five single- and three dual-NRTI treatments // Antimicrob. Agents Chemother., 2003, v. 47(11), p. 3384-3392.

16. https://www.gilead.com/pdf/viread_pi.pdf

17. https://us.gsk.com/products/assets/us_ziagen.pdf

18. https://us.gsk.com/products/assets/us_retrovir.pdf

19. Rodríguez-Nóvoa S., Labarga P., Soriano V., et al. // Predictors of kidney tubular dysfunction in HIV-infected patients treated with tenofovir: a pharmacogenetic study // Clin. Infect. Dis., 2009, v. 48(11), e108-e116.

20. Kakuda TN // Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity // Clin. Ther., 2000, v. 22(6), p. 685-708.

21. Ivanova E., Vorobeva N. // Efficacy and safety of hematological of phosphazide of highly active antiretroviral therapy for HIV-infected patients: 48 weeks of treatment // Program abstracts Euromedica, Hannover, 2011, p. 68-69.

22. Kravchenko A.V. // Use of Nikavir as part of antiretroviral therapy // Medical Department, 2004, No. 2(10), p. 90-92, 166-172.

23. Galegov G.A. // Nikavir (phosphazide) - an antiretroviral drug: anti-HIV activity, toxicology, pharmacokinetics and some prospects for clinical use // Antibiotics and Chemotherapy, 2004, v. 49(7), p. 3-8.

24. Yurin O., Kravtchenko A., Afonina L., et al. // Treatment of the patients with intolerance to AZT by phosphazid // 5 International Congress on drug therapy in HIV-infection, Glasgow, UK, 2000, v. 14, Suppl. 4, Abstr. P13.

25. Ivanova E.S., Shmagel N.G., Vorobyova N.N. // Nikavir in schemes for chemoprophylaxis of vertical transmission of HIV infection // Questions of Virology, 2010, v. 55(2), p. 31-34.

26. Ivanova E.S., Vorobyova N.N. // Nikavir in perinatal chemoprophylaxis // Materials of the IV (XIII) International Scientific Conference “Oncology - XXI Century”, Ho Chi Minh City, Vietnam, 2009, p. 88-91.

27. Kravchenko AV, Gankina NY // Efficiency and safety of phosphazide in circuit oh HAART in HIV-infected treatment-naïve patient // 8 International Congress on drug therapy in HIV-infection, Glasgow, UK, 2006, Abstr. P395.

28. Gankina N.Yu., Kravchenko A.V., Kuimova U.A., et al. // Nucleoside inhibitors in antiretroviral therapy regimens for co-infection of HIV and chronic hepatitis C // Infectious Diseases, 2010, v. 8( 1), p. 14-18.

29. Kuimova U.A., Kravchenko A.V., Gankina N.Yu. and others // Frequency of hematological disorders in the treatment of chronic hepatitis C in patients with HIV infection receiving ART // Collection of abstracts of the III Conference on HIV/AIDS in Eastern Europe and Central Asia, Moscow, 2009, vol. 1, p. 24-25.

30. Panteleev A.M., Goliusova M.Yu., Kabanova V.I. // Results of the use of phosphazide (Nikavir) in patients with HIV infection and tuberculosis // HIV infection and immunosuppression, 2010, v. 2(2), p. 75-79.

31. Khandazhinskaya A., Matyugina E., Shirokova E. // Anti-HIV therapy with AZT prodrugs: AZT phosphonate derivatives, current state and prospects // Expert Opin. Drug Metab. Toxicol., 2010, v. 6(6), p. 701-714.

[1] Despite more than ten years of use of phosphazide in clinical practice, there is no data on the development of lipodystrophy, myopathy and lactic acidosis with its use.

[2] It is known that metformin (an antidiabetic drug) activates AMPK, reduces blood glucose concentrations by inhibiting glucose production (gluconeogenesis) in the liver and increases fatty acid oxidation [10], which indirectly confirms the inhibition of AMPK by tenofovir.

[3] These side effects that occur with zidovudine therapy can be compensated for by regular use of uracil [11-13].