|HIV drugs||AZT/PIs||Side effects||Hyperlactatemia|
|DOCTORS WARNED OF HIV DRUG RISKS IN PREGNANCY|| ||Reuters
| ||Doctors throughout Europe are being warned of a potentially fatal side effect if pregnant women infected with HIV take Bristol-Myers Squibb's AIDS drugs Zerit (stavudine) and Videx (didanosine). In a public statement, the European Medicines Evaluation Agency (EMEA) said seven cases of lactic acidosis--three of them fatal--had been reported worldwide in pregnant women taking the two drugs in combination.|
| ||Reuters, London 1 February 2001||2001|
|Lactic Acidosis and Hepatic Steatosis Associated with Use of Stavudine: Report of Four Cases.|| ||Miller KD et al.
| ||“An uncommon but life-threatening syndrome of severe lactic acidosis ... among patients infected with HIV-1 was first described in the early 1990s. By early 1994, at least 40 such cases had been reported to regulatory authorities, and an association with use of zidovudine and didanosine was established. An underlying mechanism involving impaired replication of mitochondrial DNA was proposed. Although stavudine (Zerit, Bristol-Myers Squibb, Princeton, New Jersey) is the second most widely prescribed antiretroviral nucleoside analogue, it has rarely been associated with the syndrome of severe ... lactic acidosis. We report on four patients who developed this syndrome while receiving an antiretroviral regimen containing stavudine.”|
| ||Ann Int Med. 2000 Aug 1;133(3):192-6.||2000|
|Symptomatic hyperlactataemia: an emerging complication of antiretroviral therapy.|| ||Gerard Y et al.
| ||“Fourteen HIV-infected adults treated with antiretroviral drugs were identified with symptomatic hyperlactataemia [elevated lactic acid levels that can result in fatal lactic acidosis] during a 2-year period follow-up study. The incidence of hyperlactataemia was 0.8% per year but reached 1.2% if only patients treated with a regimen including stavudine were considered...One patient developed severe lactic acidosis...and died. Another was lost to follow-up. Among the remaining 12 patients, nucleoside analogue therapy was stopped in 10, as clinical improvement was combined with a decrease in lactate levels...The improvements observed in the next few weeks after drug withdrawal or modification suggest that antiretroviral drugs are responsible for the occurrence of symptomatic hyperlactataemia. Furthermore, symptomatic hyperlactataemia has never been diagnosed in naive untreated HIV-infected subjects followed up in our unit...Stavudine [d4T/Zerit] was strikingly involved in treating all these hyperlactataemic patients.”|
| ||AIDS. 2000 Dec 1;14(17):2723-30.||2000|
|7 principal factors for heart failure|| ||Tsuyuki et al.
| ||“Bristol Myers Squibb (BMS) has chosen to inform doctors of rapidly ascending muscular weakness as new symptom of nucleoside-related lactic acidosis and hyperlactataemia...A review by the EMEA of nucleoside analogue-related LA [lactic acidosis] and HL [hyperlactataemia] has highlighted seven cases of rapidly ascending muscular weakness, similar to that symptoms seen with Guillain-Barré Syndrome, and a further seven cases of muscular weakness or pain which preceded the development of LA and HL...Early symptoms of LA and HL include nausea, vomiting, diarrhoea, rapid and deep breathing, stomach cramp, myalgia [muscle pain] and parasthesia [numbness]. Ascending neuromuscular weakness should now be added to this list...All nucleoside analogues have been associated with symptoms of LA and HA...Severe lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure, renal failure, or motor paralysis.”|
| ||Arch Int Med. 2001 Oct 22.||2001|
|Severe transient neonatal lactic acidosis during prophylactic zidovudine treatment|| ||Scalfaro P, Chesaux J J, Buchwalder P A, Biollaz J and Micheli J L
| ||Zidovudine (ZDV) treatment during pregnancy, delivery and the postnatal period is effective in reducing the maternal-infant transmission of the human immunodeficiency virus. Reported adverse effects in the neonate during this longterm treatment are bone marrow suppression and elevation in aspartate aminotransferase activity. We report a case of severe ZDV-associated lactic acidosis in a neonate, which resolved rapidly following discontinuation of ZDV. The mechanisms leading to this side effect are poorly understood.|
| ||Intensive Care Med. 1998, 24 247–250||1998|
|FDA/Bristol Myers Squibb issues caution for HIV combination therapy with Zerit and Videx in pregnant women|| ||FDA
| ||“FDA and Bristol Myers Squibb are warning health care professionals that pregnant women may be at increased risk of fatal lactic acidosis when prescribed the combination of the HIV drugs stavudine (Zerit) and didanosine (Videx or Videx EC) with other antiretroviral agents. Lactic acidosis occurs when cells of the body are unable to convert food into usable energy. As a result, excess acid accumulates in the body and vital organs such as the liver ... may be damaged. Severe lactic acidosis is an infrequent, but well-described complication of the class of HIV drugs known as nucleoside analogues... This new warning follows three reported cases of fatal lactic acidosis, with or without pancreatitis, that occurred in pregnant women taking Zerit and Videx in combination with other drugs used to treat HIV.”|
| ||FDA Talk Paper. 2001 Jan 5.||2001|
|Increased mitochondrial toxicity with ribavirin in HIV/HCV coinfection.|| ||Lafeuillade A et al.
| ||“In two of 15 patients coinfected with HIV and hepatitis C virus who received interferon- plus ribavirin in addition to HAART, we observed multiorgan dysfunction and lactic acidaemia. As ribavirin is a nucleoside analogue, an increased risk of mitochondrial toxicity can be induced in HIV-infected patients already treated with nucleoside analogues, leading to clinical deterioration in some cases.”|
| ||Lancet. 2001;357(9252).||2001|
|Toxicity of nucleoside-analogue reverse-transcriptase inhibitors.|| ||Walker UA et al.
| ||“NRTIs [Nucleosid Reverse Transcriptase Inhibitors] do inhibit mitochondrial DNA synthesis but many also interfere with mitochondrial RNA formation. Although base excision repair operates in mitochondrial DNA, no repair mechanisms have been established for mitochondrial RNA. [Note that mitochondria are the energy producers present in all living human cells]”|
| ||Lancet. 2000 Mar 25;355(9209):1096.||2000|
|Reuters 13 March 2002|| ||McKinney Merritt
| ||The power plants of cells, mitochondria create the energy that cells need to function normally. But a class of anti-HIV drugs called nucleoside analogues, which include medications like AZT, can interfere with the ability of mitochondria to produce energy. It is unclear at this time how frequently mitochondrial toxicity is at the bottom of some of the side effects that we currently see in the clinic among patients on antiretroviral therapy, Montaner told Reuters Health. But it is "quite clear," he said, that severe mitochondrial toxicity is to blame for rare, but sometimes fatal, severe cases of a condition called lactic acidosis. (The New England Journal of Medicine 2002;346:811-820)|
| ||TEST DETECTS ANTI-HIV DRUGS' EFFECTS ON CELLS||2002|