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Highly Active Anti-Retroviral Therapy
By David Crowe

June 2001

HAART is the therapy, composed of multiple anti-HIV drugs, that is prescribed to many HIV-positive people, even before they develop symptoms of AIDS (and without considering that many will never develop these symptoms). The therapy usually includes one nucleoside analog (DNA chain terminator), one protease inhibitor and either a second nucleoside analog (“nuke”) or a non-nucleoside reverse transcription inhibitor (NNRTI).

The quotes are categorized as:

Adverse Effects, in General
Adverse Effects with Nucleoside Analogs ("Nukes")
Adverse Effects with Protease Inhibitors
Adverse Effects with Other Anti-HIV Drugs
Adverse Effects, Mothers & Children
Ineffectiveness or Lack of Proof of Effectiveness, often Combined with Toxicity
Health Without Toxic Therapies
Bone Disease
AIDS Drugs disrupt Fat/Lipid Metabolism
AIDS Drugs cause Heart Disease
Liver Damage
Feedback and Comments
Adverse Effects, in General

“There was...a striking increase in [oral] warts: three-fold for patients on antiretroviral therapy and six-fold for those on HAART (p = 0.01). This pattern of oral disease in a referral clinic suggests that an increase in oral warts could be occurring as a complication of HAART.”

Greenspan D et al. Effect of highly active antiretroviral therapy on frequency of oral warts. Lancet. 2001 May 5;357:1411-2.

“We report two patients with a history of remote sarcoidosis who later in life contracted HIV infection and developed recurrent, progressive pulmonary sarcoidosis while receiving highly active antiretroviral therapy (HAART)”

Lenner R et al. Recurrent Pulmonary Sarcoidosis in HIV-Infected Patients Receiving Highly Active Antiretroviral Therapy. Chest. 2001 Mar;119(3):978-981, http://www.chestjournal.org/cgi/content/full/119/3/978.

“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.”

Lafeuillade A et al. Increased mitochondrial toxicity with ribavirin in HIV/HCV coinfection. Lancet. 2001;357(9252).

“The authors studied the occurrence of IRV [Immune Recovery Vitritis], defined as symptomatic (vision decrease and/or floaters) vitritis of 1+ or greater severity associated with inactive CMV retinitis. ...19 (63%) of 30 HAART responders [improvements in CD4 cell counts] developed IRV (26 eyes). The clinical spectrum of inflammation included vitritis, papillitis, macular edema, and epiretinal membranes. Eyes with CMV surface area >30% of the retina were at the highest risk (relative risk = 4.5) of developing IRV”

Karavellas MP et al. Immune recovery vitritis and uveitis in AIDS: clinical predictors, sequelae, and treatment outcomes. Retina. 2001;21(1):1-9.

“the severity of the HIV epidemic led to accelerated licensing of many antiretroviral agents, often with very little known about long-term safety...drug-related toxicity is being increasingly recognised because of the declining incidence of HIV-1-associated opportunistic disease...the number of possible HAART combinations is huge. Choosing between many of these combinations is, therefore, increasingly dependent upon knowledge of antiretroviral toxicities...[which includes] myopathy (zidovudine), neuropathy (stavudine, didanosine, zalcitabine; heppatic steatosis and lactic acidaemia (didanosine, stavudine, zidovudine); and possible also peripheral lipoatrophy and pancreatitis (didanosine)...drug hypersensitivity...[which] is about 100 times more common [in HIV infected people] than in the general population...a syndrome (or syndromes) of lipodystrophy...[including] peripheral fat loss (Presumed lioatrophy in the face, limbs and buttocks) and central fat accumulation (within the abdomen, breats and over the dorsocervical spine [so-called buffalo hump]...[and prevalent in] about 50% [of patients] after 12-18 months of therapy...Metabolic features significantly associated with lipdystrophy and protease-inhibitor therapy include hypertriglyceridaemia, hypercholesterolaemia, insuilin resistance...and type 2 ...diabetes mellitus. Dyslipidaemia at concentrations associated with increased cardiovascular disease occurs in about 70% of patients. These metabolic abnormalitis are more profound in those receiving protease inhibitors...Most cases of diabetes have been identified in recipients of protease inhibitors, but a causal relation has not been established...Anemia and granulocytopenia affect about 5-10% of patients who receive zidovudine...Virtually all antiretroviral medications can cause nausea, vomiting, or diarrhoea early in therapy, but these are often transient...Diarrhoea is probably most common with protease inhibitors...Most antiretroviral agents have been associated with hepatic [liver] toxicity...Most protease inhibitors seem to result in increased rates of spontaneous bleeding (burising, haemarthrosis, and rarely intracranial haemorrhage) in haemophiliacs...Combination therapy for about 4 weeks after high-risk exposure to HIV-1 [e.g. needle-stick injury] is recommended...but 25-35% of patients cannot tolerate [Zidovudine monotherapy] or triple combination therapy for 4 weeks...antiviral potency should not be sacrificed at the expense of tolerability if possible.”

Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet. 2000 Oct 21;356:1423-0.

“Inflammatory reactions involving opportunistic infections, AIDS-associated malignant conditions, and other noninfectious diseases have recently been described in patients infected with HIV-1. These conditions often appeared shortly after the introduction of HAART and were associated with pronounced reductions in plasma HIV-1 viral load and increases in CD4(+) T-lymphocyte counts [normally considered signs of success of therapy]”

DeSimone JA et al. Inflammatory Reactions in HIV-1-Infected Persons after Initiation of Highly Active Antiretroviral Therapy. Ann Int Med. 2000 Sep 19;133(6):447-454.

“The incidence of MI [Myocardial Infarction (heart attack)] in HIV infected patients increased in our cohort after the introduction of HAART”

Rickerts V et al. Incidence of myocardial infarctions in HIV-infected patients between 1983 and 1998: the frankfurt HIV-cohort study. Eur J Med Res. 2000 Aug 18;5(8):329-33.

“Previously published data on CD4 cell count changes during therapy interruptions have mainly consisted of reports on very small numbers, but there has been a tendency to observe a distinct fall in numbers. The relatively rapid early fall in CD4 cell count after interrupting therapy may correspond to the relatively rapid increase in CD4 cell count after initiating therapy, which has been ascribed to the redistribution of cells from the lymphoid tissue”

Youle M et al. (title missing). AIDS. 2000 Aug 18;14:1717-1720.

“Since the introduction of HAART there has been a dramatic decrease in HIV-related mortality. For example, at the University Hospitals of Cleveland John Carey Special Immunology Unit, the annual observed number of deaths decreased by approximately 80% between 1995 and 1998 [but later in this paper it is revealed that deaths increased from 20 in 1998 to 32 in 1999!]...There is reason to be concerned that the spectrum of morbidity and mortality in HIV disease is changing rapidly to include metabolic complications of therapies and infectious complications, such as hepatitis C. Of recent HIV-related deaths occurring in the John Carey Special Immunology Unit of University Hospitals of Cleveland (number of deaths ranging from 20 in 1998 to 32 in 1999), although OIs [Opportunistic Infections] constituted less than 25% of deaths in 1999, end-organ failures [which could well be caused by medication] constituted nearly half. Importantly, the median CD4 cell count among the patients who died in our clinic has risen, from 0/L in 1995 to 75 million/L in 1999, and about 20% of recent deaths have occurred among patients with plasma HIV RNA levels below the limit of detection.”

Lederman MM, Valdez H. Immune Restoration With Antiretroviral Therapies: Implications for Clinical Management. JAMA. 2000 Jul 12;284(2):223-8.

“I just had a dental checkup yesterday. Damn depressing.... The dentist told me all my teeth's enamel had been eaten up by the drugs; that I had so many cavities he was wondering how I could manage to eat and sleep; and that it was beyond his capacity to do anything. When I got out I was crying like a baby. We looked at the xrays. I got cavities directy in the bones. He's flabergasted by the unexpected side effects. Has anyone heard of this shit with crix [Crixivan, a protease inhibitor], 3TC [a nucleoside analog] and d4t [a second nucleoside analog] combo?”

C.M. hivthrivers support group via email. 2000 Apr 7.

“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]”

Walker UA et al. Toxicity of nucleoside-analogue reverse-transcriptase inhibitors. Lancet. 2000 Mar 25;355(9209):1096.

“We report 2 cases of neutrophil-rich ALCL [Anaplastic Large Cell Lymphoma] of T-cell lineage involving the scalp of HIV-positive men. Despite chemotherapy, both patients died within 6 months of infectious complications...Both patients were being treated with antiretroviral therapy (stavudine and lamivudine) [prior to admittance for cancer]”

Darshana NJ et al. Neutrophil-Rich anaplastic large cell lymphoma of T-cell lineage: a report of two cases arising in HIV-positive patients. Am J Clin Path. 2000;114(3):478-82, www.medscape.com/ASCP/AJCP/2000/v114.n03/ajcp1143.04.jhal/ajcp1143.04.jhal-01.html.

“One of the major barriers to effectively treating HIV is that most people do not feel sick at the time that they are offered anti-HIV medications. In fact, it is only after starting the medications that they begin to feel sick...Side effects, onset of new diseases caused by the treatment for HIV and the immense pill burden are new problems that many individuals with HIV must adapt to. The lives of many patients have become governed by their drug ‘cocktails’, which for some patients involves as many as 40 pills a day.”

Swick L. Advances in HIV treatment a mixed blessing. The Toronto Star. 1999 Sep 24.

“The incidence of diarrhea was 14.2 per 100 person-years (95% confidence interval, 13.0-15.4). Among patients with CD4 cell counts below 0.05 x 10**9/L, the probability to develop diarrhea within 1, 2, and 3 years was 48.5%, 74.3%, and 95.6%, respectively. The risk to develop diarrhea was increased among patients with severe immunodeficiency, homosexual men, and patients taking antiretroviral therapy...Diarrhea was an independent negative predictor of survival.”

Weber R et al. Enteric Infections and Diarrhea in Human Immunodeficiency Virus-Infected Persons. Arch Intern Med. 1999 Jul 12;159:1473-80.

“HAART use had an independent effect on REE [Resting Energy Expenditure]...Compared with the subjects who were not on HAART, the adjusted REE was 339 kJ/day higher in the patients receiving HAART.”

Shevitz AH et al. Elevated resting energy expenditure among HIV-seropositive persons receiving highly active antiretroviral therapy . AIDS. 1999 Jul 30;13(11):1351-7.

“...we examined 304 anti-retroviral-experienced patients who were placed on HAART for a period of 18 months. The baseline CD4 count was 385x10(6)/1 and HIV RNA level was 3.2 log[10] copies/ml. At baseline, 39 percent were classified as asymptomatic, 33 percent were symptomatic, and 28 percent had an AIDS defining illness. The HAART regimens included 3-5 anti-retroviral agents at least one of which was a protease inhibitor...After 18 months, 14 percent of the population remained asymptomatic, 10 percent of which had an undetectable viral load. 39 percent were symptomatic and 47 percent of the population had an AIDS defining illness. The average CD4 count after 18 months on HAART was 301.79x10(6)/1 and HIV RNA level of 3.2 log[10] copies/ml. [i.e. HAART did not prevent progression, reduced CD4 counts and did not affect HIV RNA levels]”

Ramirez CM, Gottlieb MS. Long-Term Highly Active Anti-Retroviral Therapy in an Anti-Retroviral Experienced Population. AIDS Weekly Plus. 1999 Jun 28.

“In the era of HAART (highly active antiretroviral therapy), we're seeing less of the common oral lesions but an increase in oral warts caused by the human papillomavirus...We do not understand why this is happening.”

Greenspan et al. Abstract #704: Emergence of Oral Warts in the HAART Era. 6th Conference on Retroviruses and Opportunistic Infections. 1999 Feb.

“The use of antiretrovirals and PCP prophylaxis before AIDS were associated with a significantly poorer survival after AIDS [median of 16 months before death with antiretrovirals, 25 months without].”

van Benthem BHB et al. Is AIDS a floating point between HIV seroconversion and death? Insights from the Tricontinental Seroconverter Study. AIDS. 1998 Jun 18;12(9):1039-1045.

“ Of 5,574 SCKP members identified with HIV infection, 429 (7.7%) were diagnosed with a malignancy between 1991 and 1995, of which 57 (13.3%) were non AIDS defining (NAD). Although cohort member census declined slightly in successive study years, the number of NAD malignancies diagnosed tended to increase over time, with six, eight, 13, 15, and 15 such neoplasms occurring in 1991-1995, respectively. The most frequent NAD cancers included anorectal (14); Hodgkin's disease (9); lung/intrathoracic cancer (9); and melanoma (8). Less frequently seen malignancies included leukemias (2); testicular seminoma (2); prostate cancer (2); urinary tract cancer (ureters) (1); vaginal cancer (1); multiple myeloma (1); and "other and unspecified" malignancies (3). [the possibility that non-AIDS cancers are caused by the therapy was apparently not considered by the authors]”

Speck CE et al. Non AIDS defining malignancies among 5,574 HIV seropositive members of a larger managed care-based cohort. 2nd National AIDS Malignancy Conference. 1998 Apr;12.

“The faster disease progression and the higher speed of CD4 cell decline at early stages in the patients with recently acquired HIV infection suggest changes in the clinical course of HIV infection. [apparently the possibility that drug treatments could be causing this was not considered.]”

Sinicco A et al. Is the clinical course of HIV-1 changing? Cohort study. BMJ. 1997 Apr 26;314:1232-1237.

“Overall rates [of adverse drug reactions] ranged from 16.2 to 37.0 events for 100 person-years of follow-up on [Zidovudine, Didanosine, Zalcitabine, Cotrimoxazole, Dapsone]. For all of these drugs except dapsone, there was an increasing risk of adverse events as the CD4+ count declines.”

Moore RD et al. Adverse events from the drug therapy for human immunodeficiency virus disease. American Journal of Medicine (JAMA?). 1996 Jul;101:34-40.

“The precise duration of HIV suppression [low viral load] necessary to result in measurable clinical benefit still needs to be clearly defined [and there is no guarantee that people taking these drugs can withstand the toxic side effects long enough for the clinical benefits to materialize]”

Saag MS et al. HIV Viral load markers in clinical practice. Nature Medicine. 1996;2(6):625-9.

Adverse Effects with Nucleoside Analogs ("Nukes")

Also see information specifically related to AZT.

“Pancreatitis occurs with a frequency of 1 to 7% with the currently recommended doses of didanosine...Our analysis demonstrated that the use of hydroxyurea was associated with an adjusted four-fold increase in the risk of pancreatitis compared with patients on didanosine alone...There was one fatal case in a patient on didanosine + stavudine + hydroxyurea”

Moore RD et al. Incidence of pancreatitis in HIV-infected patients receiving nucleoside reverse transcriptase inhibitor drugs. AIDS. 2001 Mar 30;15(5):617-20.

“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 or pancreas may be damaged. Severe lactic acidosis is an infrequent, but well-described complication of the class of HIV drugs known as nucleoside analogues. Pancreatitis is also a well-described complication of Videx and Zerit.

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/Bristol Myers Squibb issues caution for HIV combination therapy with Zerit and Videx in pregnant women. FDA Talk Paper. 2001 Jan 5.

“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. Clinical symptoms included abnormal fatigue, tachycardia [abnormally rapid heart beat], abdominal pain, weight loss, peripheral neuropathy [surface nerve damage], and more specifically exercise-induced dyspnoea [shortness of breath] occurring despite effective antiretroviral treatment [note: effectiveness is defined by elevated CD4 cell counts/reduced viral load not improved health]. FRT [functional respiratory tests] showed a metabolic deviation towards anaerobiosis with a high lactate/ pyruvate ratio. Ultrastructural mitochondrial abnormalities were seen in all four patients for whom this was examined. There was a marked decrease in complex IV activity in muscle biopsies from four of five patients, consistent with a mitochondrial dysfunction...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.”

Gerard Y et al. Symptomatic hyperlactataemia: an emerging complication of antiretroviral therapy. AIDS. 2000 Dec 1;14(17):2723-30.

“An uncommon but life-threatening syndrome of severe hepatic steatosis and 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 hepatic steatosis and lactic acidosis. We report on four patients who developed this syndrome while receiving an antiretroviral regimen containing stavudine.”

Miller KD et al. Lactic Acidosis and Hepatic Steatosis Associated with Use of Stavudine: Report of Four Cases. Ann Int Med. 2000 Aug 1;133(3):192-6.

“Glaxo Wellcome on Sunday played down renewed fears about its Ziagen [Abacavir, a nucleoside analog] HIV treatment and said it planned to proceed with this year's European launch of Trizivir, its new Aids drug, which contains Ziagen...Glaxo...yesterday confirmed patients had died as a result of "hypersensitive" reactions since Ziagen was launched in the US and Europe last year. There are as yet no reliable figures on the number of fatalities from the treatment but Glaxo admitted that about 4 per cent of patients had displayed symptoms such as fever and vomiting. It put the negative response to the drug at about two people in every 10,000 patients, which is 10 times higher than the figures for other drugs generally. The company said: "This is a very potent drug and clinical trials have indeed shown that it has a potential for side effects and patients have died from using it."”

Kibazo J. Glaxo plays down Ziagen fear. Financial Times. 2000 Aug 21.

“Bristol-Myers Squibb Co., the No. 1 maker of cancer drugs, has strengthened the warning on its HIV drug Videx after four patients, who were taking Videx and another top-selling AIDS drug, died of pancreatitis.”

Bloomberg. 1999 Nov 19.

“The antiretroviral drugs currently licensed in the United Kingdom [June 1996] are zidovudine (azidothymidine [AZT]), zalcitabine (ddC) and didanosine (ddI). All three are nucleoside analogues...All are very toxic. Suppression of bone marrow elements can occur with any of the three, as can peripheral neuropathy [nerve damage].”

Ellis CJ, Leung D. Adverse drug reactions in patients with HIV infection. Adverse Drug Reaction Bulletin. 1996 Jun;178:675-8.

Adverse Effects with Protease Inhibitors

“Indinavir is a protease inhibitor used for treating HIV-1. The drug is lithogenic and was thought to cause a 3% incidence of kidney stones...Our cohort study of the prevalence of indinavir nephrolitihiasis [kidney stone formation] included 155 patients with HIV for 5,732 patient-weeks...At 78 weeks 43.2% of patients had stones...The clinical prevalence of indinavir nephrolithiasis is much greater than initially reported.”

Saltel E et al. Increased prevalence and analysis of risk factors for Indinavir nephrolithiasis. J Urol. 2000 Dec;164:1895-7.

“This study demonstrates a higher than expected prevalence of premature carotid vessel lesions in the patient group treated with PI [Protease Inhibitors] for at least 12 months with respect to a patient cohort previously untreated with these drugs, thus confirming preliminary observations...The overwhelming difference between the percentage of acquired lesions reported for healthy individuals (6.7%) and our two seropositive groups including the PI-naive (14.9%) and PI-experienced (52.7%) patients indicates that HIV-1-positive patients have a much higher risk of endothelial damage which becomes quite remarkable in the case of the patients treated with PI-containing regimens for prolonged periods of time.”

Maggi P et al. Premature lesions of the carotid vessels in HIV-1-infected patients treated with protease inhibitors. AIDS. 2000 Nov 10;14:F123-8.

“Osteopenia and osteoporosis are unique metabolic complications associated with protease inhibitor-containing potent antiretroviral regimens, that appear to be independent of adipose tissue maldistribution.”

Tebas P et al. Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. AIDS. 2000 Mar 10;14(4):F63-7.

“Further study is needed to characterize the association between indinavir and thrombosis [2.4 times the risk of blood clots inside blood vessels]”

Sullivan PS et al. Epidemiology of thrombosis in HIV-infected individuals. AIDS. 2000 Feb 18;14(3):321-4.

“Use of HIV-1 protease inhibitors is associated with endothelial dysfunction. The metabolic and phenotypic changes observed with these medications may predispose to atherosclerosis and increased vascular risk.”

Sosman JM et al. Endothelial Dysfunction Is Associated with the Use of Human Immunodeficiency Virus-1 Protease Inhibitors. 7th Conference on Retroviruses and Opportunistic Infections. 2000 Jan 30.

“It has previously been suggested that the metabolic and fat distribution abnormalities are a result of chronic HIV infection itself. Our results support those of others who have suggested that hyperlipidemia in the setting of HAART is a drug effect that reverses with drug withdrawal”

Hatano H et al. Metabolic and anthropometric consequences of interruption of highly active antiretroviral therapy. AIDS. 2000;14:1935-42.

“Dr. Klein and her colleagues at the University of Wisconsin Medical School in Madison are conducting an ongoing pilot study with 21 HIV-infected patients who have received protease inhibitor therapy for more than 6 months and 7 HIV-infected controls...Flow-mediated vasodilation was impaired in all of the patients receiving protease inhibitors, but in none of the controls...These preliminary observations suggest that protease inhibitor use is associated with endothelial dysfunction, which may ...predispose to atherosclerosis and increased vascular risk.”

Reuters Health. 1999 Nov 9.

“We describe four men with HIV infection who sustained myocardial infarction (two of which were fatal) after 24 to 29 months of protease inhibitor therapy...Thus, AIDS, a fatal illness that is routinely and effectively managed with protease inhibitors, now seems to be presenting with potentially serious new risks associated with that therapy.”

Flynn TE, Bricker LA. Myocardial Infarction in HIV-Infected Men Receiving Protease Inhibitors. Ann Int Med. 1999 Oct 5.

“British investigators have added two new cases to the growing list of reports of disfiguring striae [stretch-marks] in HIV-infected patients using protease inhibitors. "In both cases, the appearance of striae occurred within 3 months after the patient began treatment with the protease inhibitor indinavir," Dr. Amrit Darvay, now at St. Thomas’ Hospital in London, UK, and colleagues at Ealing Hospital report in the September issue of the Journal of the American Academy of Dermatology.”

Reuters Health. 1999 Oct 4.

“Higher plasma levels of ritonavir are significantly associated with an increased risk of neurological or gastrointestinal side effects, Italian investigators report in [AIDS 1999; 13:2083-9]”

Reuters Health. 1999 Oct 18.

“Adverse reactions to protease inhibitors occurred in 29% of the cohort...patients taking ritonavir were at increased risk for adverse drug reactions [particularly gastrointestinal disturbances]”

Lucas G et al. Highly Active Antiretroviral Therapy in a Large Urban Clinic: Risk Factors for Virologic Failure and Adverse Drug Reactions. Ann Int Med. 1999 Jul 24;131:81-7.

“Hyperlipidaemia at degrees associated with cardiovascular morbidity occurred in 74% of protease-inhibitor recipients. Our cut-offs may be conservative because cholesterol concentrations above 5.0 mmol/L and triglyceride concentrations above 1.6 mmol/L have been identified as clinically significant.”

Carr A et al. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet. 1999 Jun 19;353(9170):2093-9.

“71% of the protease inhibitor-treated patients had hyperlipidemia compared with only 24% of the protease inhibitor-naive patients. Among the protease inhibitor-treated patients, 44% had isolated hypertriglyceridemia, 7% had type V hyperlipidemia, 37% had type IV hyperlipidemia, 36% had type IIb hyperlipidemia, and 18% had isolated hypercholesterolemia.”

Behrens G et al. AIDS. 1999;13:F63-70.

“Despite biological plausibility, studies of protease inhibitors which evaluate survival benefit have not yet been carried out. The post-1996 AIDS conference hype that 'combination therapy including a protease inhibitor will make HIV a chronic, manageable disease just like diabetes' came back to haunt us.”

Carr A, Cooper DA. Gap between biology and reality in AIDS. Lancet. 1998 Dec 19;352(S5):16.

“Protease inhibitors can be associated with a non-ketosis-prone hyperglycaemia that occurs 1-7 months after starting treatment”

Dube MP et al. Protease inhibitor-associated hyperglycaemia. Lancet. 1997 Sep;350:713-4.

Adverse Effects with Other Anti-HIV Drugs

“myelosuppression [deficiency of white blood cell production] and neutropenia [deficiency of one type of white blood cells responsible for clearing bacteria and cellular debris] may result from any one of several medications commonly used in HIV-infected patients [including nucleoside analogs AZT, 3TC, ddI, ddC and d4T as well as anti-PCP therapies Trimethoprim, Pyrimethamine and Pentamidine]”

Levine AM. Anemia, Neutropenia, and Thrombocytopenia: Pathogenesis and Evolving Treatment Options in HIV-Infected Patients. Medscape. 2001 May 23.

“Adverse Events in the Lamivudine-Zidovudine Group: 124 adverse events were re-ported in 99 [pregnant] women. Most of these events were [judged to be] related to documented pregnancy- related or postpartum complications [but without a placebo-control group, this cannot be verified]. 2 women discontinued study drugs because of elevation of transaminase levels...Hemoglobin levels of less than 8 g/dL occurred in 29 women, half of whom had a known cause of anemia not related to study drugs. There were no cases of lactic acidosis. 38 adverse events were reported related to fetal well-being in 37 pregnancies”

Madelbrot L et al. Lamivudine-Zidovudine Combination for Prevention of Maternal-Infant Transmission of HIV-1. JAMA. 2001 Apr 25;285(16):2083-93.

“In 516 patient-years of observation, 2 patients experienced severe fulminant lactic acidosis (lactate >5 mmol/l) and hepatic steatosis attributable to nucleoside analogue reverse transcriptase inhibitors (NRTI). A further 5 patients with lesser elevations of lactate (2.8-4.1 mmol/l) but with symptoms of nausea or abdominal discomfort and evidence of hepatic steatosis had NRTI therapy revised, with relief of symptoms and a fall in lactate levels. Most remaining patients on highly active antiretroviral therapy (HAART) had mild, chronic, asymptomatic hyperlactatemia”

John M et al. Chronic hyperlactatemia in HIV-infected patients taking antiretroviral therapy. AIDS. 2001 Apr 13;15(6):717-723.

“FDA received reports of 22 cases of serious adverse events related to NVP [Nevirapine/Viramune] taken for PEP from March 1997 through September 2000. These 22 events included hepatotoxicity (12), skin reaction (14), and rhabdomyolysis (one); four cases involved both hepatotoxicity and skin reaction, and one case involved both rhabdomyolysis and skin reaction. ”

CDC. Serious adverse events attirbuted to Nevirapine regimens for postexposure prophylaxis after HIV exposures - worldwide 1997-2000. MMWR. 2001 Jan 5;49(51):1153-6.

“In January 1998 a 26 year old man who was HIV positive started taking stavudine..., didanosine..., and nevirapine...because of a falling CD4 count (250x10^6/l), high viral load (81,747 copies/ml), and symptoms related to HIV. He was receiving no other treatment. He had no additional risk factors for pancreatitis. Response to treatment was good: the viral load decreased to undetectable levels, the CD4 count increased to 470x10^6/l, and the symptoms improved, enabling the patient to resume full time employment. In June 1999 the viral load increased to 1390 copies/ml despite the patient's adherence to treatment, so treatment was intensified with hydroxyurea 500mg twice daily (Hydrea, Bristol-Myers Squibb). The viral load decreased to 237 copies/ml. The patient began to experience malaise and pain in the upper abdomen. This was attributed to the hydroxyurea, which was stopped after 42 days. The symptoms worsened, and three weeks later he was admitted to hospital with severe pain, vomiting, fever, tenderness of the upper abdomen, and guarding...Computed tomography showed changes consistent with pancreatitis. All drugs were stopped. The patient made an uneventful recovery with conservative treatment. He is no longer taking antiretroviral drugs”

Longhurst HJ, Pinching AJ. Pancreatitis associated with hydroxyurea in combination with didanosine. BMJ. 2001 Jan 13;322:81, http://bmj.com/cgi/content/full/322/7278/81 .

“A severe hypersensitivity reaction is a known complication of nevirapine and can present as a fulminant hepatitis or as a systemic syndrome with predominant cutaneous manifestations referred to as hypersensitivity syndrome (HSS) or drug rash with eosinophilia and systemic symptoms. We report a case of a severe systemic reaction with rash in a health care worker shortly after administration of a nevirapine-containing PEP [post-exposure prophylaxis] regimen...In light of the increased reports of severe hypersensitivity reactions to nevirapine, we suggest that this agent not be used for PEP until the incidence and full spectrum of nevirapine toxicity is clear, particularly if the risk of HIV seroconversion following a needlestick (0.3%) is equal to or less than the risk of this life-threatening complication.”

Johnson S, Baraboutis JG. Adverse Effects Associated With Use of Nevirapine in HIV Postexposure Prophylaxis for 2 Health Care Workers [first case]. JAMA. 2000 Dec 6.

“We report a case of sarcoidosis beginning after 2 months of interleukin-2 (IL-2) therapy in a patient with HIV who had undectable plasmatic viral load under HAART and we discuss possible mechanisms...IL-2 [Interleukin-2] plays a pivotal role in the pathology of sarcoidosis [formation of nodules in the lungs, liver, lymph nodes and salivary glands].”

Blanche P et al. Sarcoidosis in a patient with acquired immunodeficiency syndrome treated with Interleukin-2. Clin Infect Dis. 2000 Dec;31:1493-4, http://www.journals.uchicago.edu/CID/journal/issues/v31n6/000025/brief/000025.abstract.html.

“the potential benefit gained from an increase in the number of CD4 cells needs to be balanced against the toxic effects of the treatment. In the study by Davey et al, 54% of the patients receiving IL-2 [Interleukin-2] with HAART had serious adverse effects compared with 16% of patients receiving HAART alone. Studies demonstrating a clinical benefit from IL-2 therapy are needed before it is adopted as a complementary option in conjunction with antiretroviral therapy.”

Blankson J, Siliciano RF. Interleukin 2 Treatment for HIV Infection. JAMA. 2000 Jul 12;284(2):236-238.

“IL-2 [Interleukin-2] recipients experienced more adverse events than recipients of ART [standard antiretroviral therapy, not including IL-2] alone. The most common toxic effects experienced by IL-2-treated patients were constitutional symptoms of fever, fatigue, and myalgias of varying severity. Per protocol-defined guidelines, mild-to-moderate symptoms were managed by scheduled administration of alternating acetaminophen and ibuprofen, oral hydration, oral narcotics to control rigors, and rest. More serious or sustained symptoms were managed by omitting a scheduled dose, dosage reduction, or both, as required. Despite these measures, serious (at least grade 3) adverse events occurred in 20 (54%) of 37 evaluable IL-2 recipients and 7 (16%) of 43 ART recipients.”

Davey RT Jr et al. Immunologic and Virologic Effects of Subcutaneous Interleukin 2 in Combination With Antiretroviral Therapy: A Randomized Controlled Trial. JAMA. 2000 Jul 12;284(2):183-189.

“Physicians describe in [Clin Infect Dis 1999;29:692-693] two cases of myelosuppression that occurred in HIV-infected patients while on hydroxyurea. Both cases required prolonged platelet or red blood cell transfusions after hydroxyurea was discontinued…Although data on hydroxyurea for HIV therapy are incomplete, the use of this drug is on the rise…”

Reuters Health. 1999 Oct 18.

“This study was conducted to determine the likelihood of the development of a new ocular inflammatory syndrome (immune recovery vitritis, IRV), which causes vision loss in AIDS patients with cytomegalovirus (CMV) retinitis, who respond to HAART. We followed 30 HAART-responders with CD4 cell counts of >=60 cells/mm3. Patients were diagnosed with IRV if they developed symptomatic vitritis of >=1+ severity associated with inactive CMV retinitis. Symptomatic IRV developed in 19 (63%) of 30 patients”

Karavellas MP et al. Incidence of immune recovery vitritis in cytomegalovirus retinitis patients following institution of successful highly active antiretroviral therapy. JID. 1999 Mar;179(3):697-700.

“Among severely ill patients, mortality was 3-fold higher when corticosteroids were given according to CDC guidelines. Our findings suggest that that the utility of adjunctive corticosteroids in severe PCP needs to be revisited.”

McIlraith T et al. Corticosteroid Utilization and Outcomes in HIV Associated Pneumocystis carinii Pneumonia: Three-fold Higher Mortality Among Severely Ill Patients When Corticosteroids Given by CDC Guidelines. 6th Conf on Retroviruses and Opportunistic Infections. 1999.

“We report on the occurrence of autoimmune hyperthyroidism in three patients with AIDS after 16-22 months of taking highly active antiretroviral therapy (HAART). A woman aged 41 years with AIDS presented with preogressive weight loss, asthenia, tachycardia, tremor and swollen eyelids. She had been taking indinavir, stavudine and lamivudine for 19 months...A male aged 42 years with AIDS presented with preogressive weight loss, tremor,, and tachycardia....The patient had been on indinavir, stavudine, and lamivudine for 16 months...A man aged 36 years with AIDS was started on ritonavir, stavudine and lamivudine in April, 1996. In february, 1998, he presented with progressive weight loss, tremor, and hypertension...Although the number is small and the onset of hyperthyoidism could be coincidental to AIDS, autoimmunity probably relates to incomplete or unbalanced immune restoration under HAART [or direct toxic effects of these medications?]”

Gilquin J et al. Delayed occurrence of Graves' disease after immune restoration with HAART. Lancet. 1998 Dec 12;352:1907-8.

Adverse Effects, Mothers & Children

“A total of 397 adverse events, 180 biological (ie, involving hematologic or blood chemistry alterations) and 217 clinical in nature, were reported among 238 of the 452 children in the lamivudine[3TC]- zidovudine[AZT] cohort. Altogether, 151 hematologic adverse events, defined as moderate to severe according to the age-adjusted ACTG classification,17 occurred during exposure to study drugs. These mostly consisted of neutropenia (81 cases) or anemia (68 cases), leading to blood transfusion because of clinical symptoms in 9 infants (5 had mild symptoms (pallor or tachycardia) and 4 had severe symptoms (cardiac insufficiency or dyspnea)) and to premature treatment discontinuation for 19 children. Of the children with hematologic...Liver abnormalities without proven cause were recorded in 6 children ...Of the 217 clinical adverse events reported among children, most were [judged to be] due to a known cause unrelated to study drugs [but without a true control, this is impossible to say with assurance]... 16 children (4%) had major birth defects, including 4 cardiac malformation cases, 4 cases of polydactyly, 3 talipes cases, and 1 case each of congenital diaphragmatic hernia, hydronephrosis, imperforate anus, genu recurvatum with a suburethral cyst, and hypospadia. 1 child each had Down syndrome, Ito nevus, and sickle cell anemia...Neurologic signs/symptoms were reported in 12 children who did not have HIV infection and had no other known infectious or genetic disease.”

Madelbrot L et al. Lamivudine-Zidovudine Combination for Prevention of Maternal-Infant Transmission of HIV-1. JAMA. 2001 Apr 25;285(16):2083-93.

“[A news article stated that, in this oral abstract]…two cases of acute lactic acidosis in the third trimester of pregnancy were reported. In one case, a pregnant woman who had been treated with Videx (didanosine, ddI), Zerit (stavudine, d4T) and Viramune for three years and had a CD4+ cell count of 450 cells/mm3 and a viral load less than 50 copies/mL, presented in the 37th week of pregnancy with acute lactic acidosis, which resulted in fetal death. In the second case, a pregnant woman treated with the Videx, Zerit and Viramune, and with a CD4+ cell count of 650 cells/mm3 and a viral load less than 50 copies/mL for 2 years, presented in her 33rd week of pregnancy with acute lactic acidosis and pancreatitis.”

Sarner, Fakoya A. Acute onset lactic acidosis and pancreatitis in the third trimester of pregnancy as a result of antiretroviral medication. 7th Annual Conference of the British HIV Association. April 2001. Oral Abstract 020.. 2001 April;Abstract 23.

“[A news article on this oral abstract] reported three cases of unexplained neonatal lactic acidosis and hypoglycemia, either alone or in combination, in non-HIV-infected infants exposed perinatally to Retrovir (zidovudine, AZT), Epivir (lamivudine, 3TC) and Viramune (nevirapine). At birth, two of the three infants had severe acidosis, with a pH less than 7.1, and the third infant, as well as one of the 2 infants with lactic acidosis, had severe and persistent hypoglycemia.”

Foster CJ et al. Lactic acidosis and hypoglycaemia in three neonates exposed to HAART in utero. 7th Annual Conference of the British HIV Association. April 2001. Oral Abstract 020.. 2001 April;Abstract 20.

“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)...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...Lactic acidosis occurs when the body's cells are unable to convert food into usable energy. The condition causes excess acid to accumulate in the body, potentially damaging vital organs such as the liver and pancreas...the EMEA pointed out that lactic acidosis is a known side effect of the class of HIV drugs called nucleoside reverse transcriptase inhibitors (NRTIs). The use of this class of drugs is not recommended during pregnancy unless the potential benefit clearly outweighs the potential risks [note that AZT is a drug in this class that is heavily promoted for use during pregnancy].”

Doctors warned of HIV drug risks in pregnancy. Reuters Health. 2001 Feb 1.

“Two popular HIV drugs may cause birth defects and should be avoided by pregnant women until more is known about their effects, German researchers said on [September 28, 1999]. They found the two drugs, both members of a class known as protease inhibitors, caused abnormal eye development in baby rats. Kai Riecke and colleagues at Freie Universitat Berlin gave the two drugs, Merck's indinavir, known as Crixivan, and Abbott Laboratories' Norvir, or ritonavir, to pregnant rats. They had to stop the ritonavir after a week because it made the rats sick. The rats stayed on the indinavir for the full terms of their pregnancies. Seven of the 236 baby rats exposed to indinavir in the womb were born missing one eye, and two of the 113 baby rats exposed to ritonavir had a missing eye, Riecke's team reported. Fur and teeth also developed later than normal in some of them, they said.”

Reuters. 1999 Sep 28.

“There were five serious adverse events including two deaths in the infants in cohort 1 [out of 8!]. Only one of the five serious adverse events was thought by the investigators to be possibly, but not likely study drug related [but, without a control group, it is possible that all adverse events were related]...In cohort 2 there were seven serious adverse events [out of 13], including two infant deaths, although none were related to the study drug”

Musoke P et al. A phase I/II study of the safety and pharmacokinetics of nevirapine in HIV-1-infected pregnant Ugandan women and their neonates (HIVNET 006). AIDS. 1999 Mar 11;13(4):479-86.

“11 [of 90] children had been withdrawn from study for disease progression [in other words, it didn't work for them] and 10 because of possible lamivudine-related toxicity, and 6 had died...In summary, this study confirms that lamivudine can be safely given to children with HIV infection and that it has a favorable pharmacokinetic profile and evidence of antiretroviral activity”

Lewis LL et al. Lamivudine in children with human immunodeficiency virus infection: a phase I/II study. JID. 1996;174:16-25.

“Thirty-five of 37 subjects experienced serious clinical adverse events, including infection (33 subjects), lymphadenopathy (19 subjects), hepatosplenomegaly (15 subjects), chills and fever (12 subjects), and development of an AIDS-defining condition (four subjects)...Clinical adverse events of lesser severity that were reported by more than 20% of subjects included rhinitis (76%), cough (70%), diarrhea (68%), rash (62%), nausea and vomiting (51%), abdominal pain (43%), anorexia (41%), respiratory disorder (38%), headache (35%), pharyngitis (32%), pruritis (30%), pain (22%), peripheral neurologic symptoms (22%), and nervousness (22%)”

Kline MW et al. A phase I/II evaluation of Stavudine (d4T) in children with human immunodeficiency virus infection. Pediatrics. 1995;96:247-52.

“Transfusion was required in 14 patients because of low levels of hemoglobin. Dose-limiting neutropenia occurred in most patients who received doses of 1.4 mg per kilogram per hour or more...The major limitation of the therapy was hematologic toxicity--a decrease in both the hemoglobin concentration and the white-cell count...Regardless of the starting dose, nearly all patients had a transient drop in their neutrophil counts within 10 days of the initiation of AZT therapy...In three of the five children who died, evidence of a response to AZT, particularly neurodevelopmental improvement, was present at the time of death [i.e. the children were getting better, only they died first]”

Pizzo PA et al. Effect of continuous intravenous infusion of zidovudine (AZT) in children with symptomatic HIV infection. NEJM. 1988;319:889-96.

Ineffectiveness or Lack of Proof of Effectiveness, often Combined with Toxicity

“The drugs are imperfect: Experts say they only extend life, on average, 1.8 years for people with AIDS, and have many severe side effects. Some people live longer, others shorter, on the drugs. About 10 percent of AIDS deaths now are due to protease inhibitor-induced heart disease...Half the people who try the medications do not respond to them and the side effects, such increased cholesterol levels and diabetes, may be so severe that the risk of taking the drug outweighs their benefits.”

Eisner R. AIDS Medications Extend Lives But Side Effects Are a Se. ABC News. 2001 Jun 4, http://abcnews.go.com/sections/living/DailyNews/aids010604.html.

“Of some concern, however, is the observation that despite increased pharmaceutical usage, the total mortality has not decreased since the first quarter of FY1997. Furthermore, we found an upward tendency of per-patient costs over the last 12 months of this study...The virological failure of up to 60% of treatment-experienced patients and the increased recognition of the toxicities of antiretroviral therapy suggests that substantial additional medical costs may eventually accrue in the care of these patients”

Goetz MB et al. Effect of highly active antiretroviral therapy on outcomes in Veterans Affairs Medical Centers. AIDS. 2001 Mar 9;15(4):530-2.

“One of the first studies to look at the success of HIV treatment in inner-city patients from the time of diagnosis reveals a dire situation, a doctor working in Atlanta, Georgia, said here on Tuesday at the 8th Conference on Retroviruses and Opportunistic Infections. His study found that only 1 in 10 patients newly diagnosed with HIV achieved a reduction in virus in blood to ''undetectable'' levels--a major goal of treatment...One year after being diagnosed, 24 patients (18%) had died, del Rio reported. Of the 103 eligible to attend an outpatient clinic, the majority discontinued treatment after a few months. Only 55 patients (53%) ever went to the outpatient clinic and 40% of these dropped out within 1 year. Of the 55 patients seen at the outpatient clinic, 30 were prescribed antiretroviral therapy. One year from diagnosis, only 23 were still on therapy and 12 (of the original 135 patients) had undetectable levels of virus in their blood. ”

In U.S. cities, successful HIV treatment rare. Reuters. 2001 Feb 7.

“Five patients with plasma HIV-1-RNA levels of less than 500 copies/ml for at least 3 months and less than 50 copies/ml at the time of sampling were initially selected, followed by an additional five patients with viral loads of less than 50 copies/ml for 3 months or more...Virus was recovered from monocytes of five patients. Sequencing of the recovered viruses did not reveal multiple drug resistance, and was consistent with a non-syncytium-inducing/CCR5 phenotype. Proviral DNA was detectable in monocytes from all subjects, and unintegrated HIV-1 DNA and MS RNA was found in four out of five populations examined.”

Sonza S et al. Monocytes harbour replication-competent, non-latent HIV-1 in patients on highly active antiretroviral therapy. AIDS. 2001 Jan 5;15:17-22.

“In a cohort of 1,047 human immunodeficiency virus type 1-infected patients started on protease inhibitors (PIs), the incidence of severe hepatic cytolysis (alanine aminotransferase concentration five times or more above the upper limit of the normal level>=5N) was 5% patient-years after a mean follow-up of 5 months.”

Savs M et al. Hepatitis B or Hepatitis C Virus Infection Is a Risk Factor for Severe Hepatic Cytolysis after Initiation of a Protease Inhibitor-Containing Antiretroviral Regimen in Human Immunodeficiency Virus-Infected Patients. Antimicrobial Agents and Chemotherapy. 2000 Dec;44(12):3451-5, http://aac.asm.org/cgi/content/abstract/44/12/3451.

“Clinicians are now realizing that the existing therapies are no longer long-term therapies, they start to give out sometimes within two years. In addition, the drugs are having severe side effects, including osteoporosis and cardiac problems.”

Rose S. AIDS toll on the rise. Provincetown Banner. 2000 Sep 21.

“All AIDS diagnoses from 1992-1998 notified to the Victorian State [Australia] AIDS Registry were included. Subjects were grouped as individuals diagnosed with AIDS within 8 weeks of a first positive HIV test (late presenters), or individuals for whom there was more than 8 weeks between AIDS diagnosis and first positive HIV test (non-late presenters) [this group is more likely to have taken anti-HIV drugs]. Of 1021 AIDS diagnoses notified, 24% were late presenters...Late presenters survived longer following AIDS diagnosis (P <0.0001).”

Hocking JS et al. Late presentation of HIV infection associated with prolonged survival following AIDS diagnosis-characteristics of individuals. International Journal of STD & AIDS. 2000 Aug; 11(8):503-50.

“There's no hope for a cure for AIDS with current drugs, the head of the National Institute of Allergy and Infectious Diseases (NIAID) said at the 13th International AIDS Conference. ''Eradication is not possible,'' Anthony Fauci said.”

Smith M. Current drugs no match for AIDS epidemic: Fauci. Biotechnology Newswatch. 2000 Jul 17;1.

“We found that prolonged treatment of late-stage HIV-1-infected patients with a protease inhibitor and two nucleoside reverse transcriptase inhibitors failed to restore sustained, high levels of HIV-1-specific, HLA class I-restricted, cytotoxic-T-lymphocyte precursors and gamma interferon (IFN-gamma) production by CD8+ T cells...These effects of combination therapy were not unique to HIV-1 specific T-cell responses, since similar effects were noted for CD8+ T cells specific for the cytomegalovirus p65 matrix protein.”

Rinaldo CR et al. Anti-Human Immunodeficiency Virus Type 1Ê(HIV-1) CD8+ T-Lymphocyte Reactivity during Combination Antiretroviral Therapy in HIV-1-Infected Patients with Advanced Immunodeficiency . J Virol. 2000 May;74(9):4127-38.

“We studied the HIV aspartyl PIs [Protease Inhibitors] indinavir, ritonavir, nelfinavir and saquinavir, at clinically achievable concentrations, for their ability to inhibit P. carinii [causative factor of AIDS-defining pneumonia PCP]...We found a partial, dose-dependent antipneumocystis effect [i.e. perhaps the benefits of this therapy that are sometimes found are because they directly target PCP, and not HIV]”

Atzori C et al. In Vitro Activity of Human Immunodeficiency Virus Protease Inhibitors against Pneumocystis carinii. JID. 2000 May;181:1629-34.

“Amanda Mocroft (Royal Free Centre for HIV Medicine, London, UK) reported that rates of treatment failure in the EuroSIDA cohort were 50%, 70%, and 80% after first, second, and third courses, respectively. Results from several trials confirmed the poor response (about 30%) to salvage regimens in patients who had already taken a protease inhibitor. Previous use of non-nucleoside reverse-transcriptase inhibitors lowered the response rate further (to about 15%)...Over the past year, the development of several promising drugs has been put on hold or stopped because of toxicity, unfavourable pharmacokinetics, and inadequate potency”

Montaner J et al. Salvage therapy for HIV-1 infection - the challenge grows. LanceT. 2000 Apr 22;335.

“current potent regimens do not completely inhibit HIV replication in most patients...resistance develops during ongoing HIV replication in the presence of anti-HIV drugs...in most patients...Although it may seeem reasonable to believe that use of potent therapy could delay or prevent the evolution of more virulent strains of the virus, few data support that argument...cure with current potent therapy may be possible after 10 years of therapy, 60 to 115 years of therapy, or never [depending on the research cited]...it is safe to conclude that a cure is extremely unlikely with the current approach to treatment...There is growing concern about the long-term toxicity and adverse effects of therapy, including liver damage and mitochondrial toxicity caused by nucleosides, the most studied anti-HIV drugs. After drugs are approved, fewer organized efforts are made to monitor them for long-term toxicities...the quest for HIV treatemtn is fueled by the expensive, technologically oriented approach used in wealthy countries. Current research is not directed toward simple long-term survival...The fastest-growing treatment category in my clinic [Regions Hospital, Minnesota] is no treatment or delayed treatment.”

Henry K. The case for more cautious, pateint-focused antiretroviral therapy. Ann Int Med. 2000 Feb 15;132(4):306-311.

“The existence of a reservoir of resting CD4+ T cells harboring latent replication-competent HIV has been demonstrated in patients on prolonged highly active antiretroviral therapy (HAART). Latently infected tissue macrophages may constitute a second HIV reservoir...These results demonstrate the long-term persistence of infectious virus in cells of the monocyte-macrophage lineage in patients receiving HAART.”

Lambotte O et al. Detection of infectious HIV in circulating monocytes from patients on prolonged highly active antiretroviral therapy. JAIDS. 2000 Feb 1;23(2):114-9.

“These data suggest that a large pool of infectious virus is established soon after infection and that initiation of antiretroviral therapy when symptoms of primary HIV infection are recognized is unlikely to prevent substantial accumulation of virus in the FDC network...The FDC pool of virus is established by the time symptoms associated with primary HIV infection are recognized, based on these data. We observed 7-8 log10 copies of HIV-1 RNA/g of LT sampled within a few days of symptom onset, similar to levels associated with late-stage disease. The fact that this tissue was both axillary and from patients with rectal exposure illustrates the speed at which systemic dissemination occurs after mucosal transmission...This finding was a surprise to us, because it has been reported that accumulation of virus into this pool is gradual. These discrepant results may represent a sampling error, because the number of patients reported by Pantaleo et al. and by us is relatively small...Collectively, these findings on the early accumulation of virus into the FDC pool make it unlikely that antiretroviral therapy initiated as soon as symptoms are recognized will necessarily prevent deposition of large enough quantities of virus in the FDC pool or the FDC network.”

Shacker T et al. Rapid Accumulation of Human Immunodeficiency Virus (HIV) in Lymphatic Tissue Reservoirs during Acute and Early HIV Infection: Implications for Timing of Antiretroviral Therapy. JID. 2000 Jan;181(1):354-7.

“Results: Indinavir resistance was not detected in the 9 subjects with viral rebound during indinavir monotherapy or in the 17 subjects with rebound during triple-drug therapy, despite plasma HIV RNA levels ranging from 102 to 105 copies/mL. In contrast, lamivudine resistance was detected by phenotypic assay in rebound isolates from 14 of 17 subjects receiving triple-drug therapy, and genotypic analyses showed changes at codon 184 of reverse transcriptase in these 14 isolates. Mean random plasma indinavir concentrations in the 2 groups with rebound were similar to those of a control group with sustained viral suppression, although levels below 50 ng/mL were more frequent in the triple-drug group than in the control group (P = .03). ”

Havlir DV et al. Drug Susceptibility in HIV Infection After Viral Rebound in Patients Receiving Indinavir-Containing Regimens. JAMA. 2000 Jan 12;283(2):229-234.

“Our results show that immune responses are potent in antiretroviral-naive but significantly reduced in HAART-treated patients with undetectable viraemia (< 500 copies/ml)...T-cell proliferation to HIV-specific and HIV-unrelated antigens is potent in antiretroviral-naive but suppressed in HAART-treated individuals”

Clerici M et al. Different immunologic profiles characterize HIV infection in highly active antiretroviral therapy-treated and antiretroviral-naive patients with undetectable viraemia. AIDS. 2000 Jan 28;14:109-116.

“During 7007 person-years of follow-up 2285 (69%) patients started HAART and 318 (10%) developed a new AIDS event. In multivariable analysis controlling for CD4 cell count, viral load and disease stage at baseline, the probability of starting HAART was lower in injection drug users compared with men who have sex with men, hazard ratio 0.63 (95% confidence intervals 0.56-0.70) and in patients with minimum schooling compared with those with vocational training, hazard ratio 0.82 (0.75-0.91). The risk of progression to AIDS was similar among men and women, patients with a history of injecting drug use, and patients with lower educational attainment in both univariable and multivariable analysis. CONCLUSION: HIV-infected injecting drug users and those with lower levels of educational attainment start HAART later than other patient groups. The deferred initiation of therapy in these patients does not, however, appear to translate into an increased risk of clinical disease progression. This observation has important implications for treatment policy and the design of future clinical trials. ”

Junghans C et al. Uniform risk of clinical progression despite differences in utilization of highly active antiretroviral therapy:Swiss HIV Cohort Study. AIDS. 1999 Dec 24;13(18):2547-54.

“This finding raises the possibility that there may be other tissue reservoirs of HIV that contribute to early plasma viral rebound following discontinuation of HAART in infected patients.”

Chun T et al. Re-emergence of HIV after stopping therapy. Nature. 1999 Oct 28;401:874-5.

“Infection was propagated not only in activated and proliferating T cells but also, surprisingly, in resting T cells. The infected proliferating cells correspond to the short-lived population that produces the bulk of HIV-1. Most of the HIV-1-infected resting T cells persisted after antiretroviral therapy.”

Zhang Z-Q et al. Sexual Transmission and Propagation of SIV and HIV in Resting and Activated CD4+ T Cells. Science. 1999 Nov 12;286(5443):1353-7.

“"This virus is a really smart actor," said Dr. Ann Collier, director of the AIDS Clinical Trial Unit at Harborview's Madison Clinic. Collier said about one-third of patients are resistant to the drugs within six months of starting treatment, and the proportion increases over time. Patients are often switched to new combinations of drugs, but their conditions often gradually deteriorate, she said.”

The Seattle Times. 1999 Nov 10;B1.

“our data demonstrate that indinavir and ritonavir [both protease inhibitors (PI)], two major components of HAART regimens, have direct anticandidal effects in vitro and in vivo...Thus, we are tempted to speculate that this novel effect of PI on Candida virulence might concur with and possibly also favor immunoreconstitution in explaining the unprecedented beneficial activity of HAART on candidiassis in persons with AIDS [i.e. these drugs may have beneficial effects due to their activity on this fungal infection, and not from their activity against HIV]”

Cassone A et al. In vitro and in vivo anticandidal activity of Human Immunodeficiency Virus protease inhibitors. JID. 1999 Aug;180:448-53.

“According to the study, [published in 7/20/99 Annals of Internal Medicine] 37 percent of the Johns Hopkins patients getting the cocktail treatment had undetectable HIV levels one year after starting therapy. Only 23 percent suppressed the virus in all three time periods studied - 1-90 days, 3-7 months and 7-14 months. Clinical trials using similar drugs show suppression rates twice as high as those numbers.”

Loviglio J. Study looks at HIV ‘Cocktail’. Associated Press. 1999 July 19.

“the proportion of patients who experience virologic suppression during HAART in the clinic setting was substantially lower than that in clinical trials...only 23% experienced viral suppression in all three time periods”

Lucas G et al. Highly Active Antiretroviral Therapy in a Large Urban Clinic: Risk Factors for Virologic Failure and Adverse Drug Reactions. Ann Int Med. 1999 Jul 24;131:81-7.

“As the ADARC group suggested, immediate attention should focus on the reasons why three- and four-drug potent anti-retroviral therapy does not completely suppress virus replication. Based on their data, it is unlikely that anatomical sanctuaries are protecting cells from drugs; instead, the positive cells seem to be readily circulating through the body, as suggested by the presence of many of the HIV-expressing cells in lymphoid sinuses.”

Saag MS, Kilby JM. HIV-1 and HAART: A time to cure, a time to kill. Nature Medicine. 1999 June;5(6):609-11.

“our findings suggest that 48 weeks of HAART does not significantly reduce the integrated HIV-1 proviral DNA load in the latently infected CD4 T cell reservoir”

Ibanez A et al. Quantification of integrated and total HIV-1 DNA after long-term highly active antiretroviral therapy in HIV-1-infected patients. AIDS. 1999 Jun 18;13(9):1045-9.

“The results obtained for patients with a broad range of plasma viral loads before and after antiretroviral therapy reveal a constant mean viral (v)RNA copy number (3.6 log10 copies) per infected cell, regardless of plasma virus load or treatment status.”

Hockett RD et al. Constant Mean Viral Copy Number per Infected Cell in Tissues Regardless of High, Low, or Undetectable Plasma HIV RNA. Journal of Experimental Medicine. 1999 May 17;189(10):1545-54.

“The researchers concluded that, while combination antiretroviral therapies effectively suppress HIV-1 replication in some patients, the benefit to others may not be as great. Considering the half-life of latently infected CD4 lymphocytes, researchers conclude that efficacious antiretroviral therapy may take years to eliminate such sources of HIV-1...The continued replication of HIV-1 in two patients seems to be due to the presence of drug-sensitive viruses within lymphoid tissues. We are unable, however, to explain why drug-sensitive HIV-1 is capable of replicating at low levels during treatment with three or four drugs. But it is essential to the therapeutic effort that the answer, be it pharmacokinetic or cellular in nature, be obtained promptly.”

Zhang L et al. Quantifying Residual HIV-1 Replication in Patients Receiving Combination Antiretroviral Therapy. NEJM. 1999 May 27;340(21):1605-13.

“Potent antiretroviral therapy seems unable to eradicate latent HIV-1 reservoirs in CD4+ T cells.”

Furtado M et al. Persistence of HIV-1 Transcription in Peripheral-Blood Mononuclear Cells in Patients Receiving Potent Antiretroviral Therapy. NEJM. 1999 May 27;340(21):1614.

“As the evanescent blush of success with so-called highly active antiretroviral therapy (HAART) regimens begins to recede into the darkness, we have increasingly come to appreciate the importance of the host immune response. As with pharmacotherapy of other infectious diseases, the drugs are not very effective without substantial help from the immune system. [note that AZT, by damaging or destroying bone marrow, damages the immune system]”

O’Brien WA. The most potent antiretroviral weapon - cellular immunity. 6th Conference on Retroviruses and Opportunistic Infections. 1999 Feb 2.

“In 3 of the 5 patients, the percentage of productively infected cells increased while on therapy”

Patterson BK et al. Monitoring HIV-1 treatment in immune-cell subsets with ultrasensitive fluorescence-in-situ hybridisation. Lancet. 1999 Jan 16;353(9148):211-2.

“The main kinetic difference in the HAART [ritonavir/saquinavar plus one or more nucleoside analogs] group was therefore higher production rates of circulating T cells and shorter (not longer) half lives…This analysis confirms that the rate of removal of CD4+ T cells is indeed elevated and the half-life is indeed shortened in the HAART group”

Hellerstein M et al. Directly measured kinetics of circulating T lymphocytes in normal and HIV-1 infected humans. Nat Med. 1999 Jan;5(1):83-9.

“our analysis shows that San Francisco would have experienced a significant decline in AIDS cases, due to the decrease in HIV seroconversions, even if combination antiretroviral therapy had not been developed...the treatment [AZT] benefit is temporary and confers no long-term survival advantage”

Lemp GF et al. Projected incidence of AIDS in San Francisco: the peak and decline of the epidemic. JAIDS. 1997 Nov;1;16(3):182-189.

“Decreases in concentrations of and detection of seminal HIV in men taking zidovudine or newer antiretroviral drugs have been observed in some [2 referenced], but not all studies [4 referenced]. Antiretroviral therapy apparently does not affect the detection of HIV in cervicovaginal specimens”

Royce RA et al. Sexual transmission of HIV. NEJM. 1997 Apr 10;336(15):1072-8.

“The median prolongation of survival associated with changing therapy was, at best, 3 to 6 months...Mortality within [3.5-4.9 years, depending on starting CD4 cell counts] was 100%, regardless of treatment group or landmark...Overall long-term survival [in a study comparing AZT monotherapy with various combination therapies] was grim, even among patients who changed therapy; this finding indicates the continued need for newer, more active antiretroviral regimens. The small effect of changing ther”

Graham NMH et al. Survival in HIV-infected patients who have received zidovudine: comparison of combination therapy with sequential monotherapy and continued zidovudine monotherapy. Ann Int Med. 1996;124:1031-8.

“The survival of patients in group B [symptomatic at time of HIV diagnosis] after the onset of AIDS was significantly longer than that of patients in group A [asymptomatic at the time of diagnosis] as determined by Kaplan-Meier log rank analysis (P = 0.0026) [i.e. does exposure to antiviral therapy earlier make AIDS worse?]”

Poznansky MC et al. HIV positive patients first presenting with an AIDS defining illness: characteristics and survival. BMJ. 1995 Jul 15;311(6998):156-8.

Health Without Toxic Therapies

“Vitamin B12 treatment led to an increase in the number of lymphocytes, including CD8+ cells, not only in [Vit. B12 deficient] patients but also in control subjects, and to a significant increase of NK cell activity in patients”

Tamura J et al. Immunomodulation by vitamin B12: augmentation of CD8+ T lymphocytes and natural killer (NK) cell activity in vitamin B12-deficient patients by methyl-B12 treatment. Clinical and Experimental Immunology. 1999 Apr;116:28-32.

“we estimate that between 21 and 40% (95% confidence interval) [of healthy, HIV+ people not using antiretroviral drugs] will be free from clinical AIDS 12 years from seroconversion and between 10 and 17%…20 years from seroconversion.”

Munoz A et al. The incubation period of AIDS. AIDS. 1997;Vol 11 (suppl A):S69-76.

“LTNPs [Long-term non-progressors] were defined as having documented HIV-1 infection for >7 years, CD4 cell counts of >600 cells/cubic mm, and no symptoms related to HIV-1 infection. With the exception of [two of nineteen] patients, no patients had ever received antiretroviral therapy.”

Montefiori DC et al. Neutralizing and infection-enhancing antibody responses to HIV type-1 in long-term nonprogressors. JID. 1996;173:60-67.

“we have three reasons to question the administration of combination therapy (also known as highly activated antiviral therapy, or HAART: -- The drugs do not eliminate virus-infected cells and thus cannot "cure." -- Long-term use of antiviral therapy, which can be toxic, may also lead to the emergence of resistant viruses. -- There is no evidence that early treatment has made a difference in overall disease progression. ”

Levy JA et al. The Big Question Now in Anti-HIV Therapy - When?. San Francisco Chronicle, http://www.sfgate.com/cgi-bin/article.cgi?file=/chronicle/archive/2001/02/23/ED200718.DTL/ul>

Bone Disease

“Prior to the introduction of long-term highly active antiretroviral therapy, healthy HIV-infected adults generally had normal bone mineral density that was stable over time...The present study has confirmed previous studies that found osteopenia [loss of bone mass] to be common in HIV-infected adult males receiving antiretroviral therapy even after adjustment for age. This osteopenia may result from mitochondrial toxicity of nucleoside analogues [which also may be the cause of excessive, sometimes fatal, levels of lactic acid]”

Carr A et al. Osteopenia in HIV-infected men: association with asymptomatic lactic acidemia and lower weight pre-antiretroviral therapy. AIDS. 2001 Apr 13;15(6):703-709.

“We describe 5 patients whose symptoms of osteonecrosis [bone disintegration] developed with viral suppression and improvement in CD4 lymphocyte counts as a result of antiretroviral therapy. In addition, we review previously reported cases...We conclude that osteonecrosis is an emerging manifestation of HIV infection and that it may be either a consequence of immunologic and virologic improvement resulting from antiretroviral therapy or a complication caused by the drugs themselves. ”

Monier P, McKown K, Bronze MS. Osteonecrosis Complicating Highly Active Antiretroviral Therapy in Patients Infected with Human Immunodeficiency Virus. Clin Inf Dis. 2000 Dec;31:1488-92.

“Osteopenia and osteoporosis are unique metabolic complications associated with protease inhibitor-containing potent antiretroviral regimens, that appear to be independent of adipose tissue maldistribution.”

Tebas P et al. Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. AIDS. 2000 Mar 10;14(4):F63-7.

“We report on six patients (out of a cohort of 508 HIV-infected patients, including 280 on triple antiretroviral treatment) who were diagnosed with bilateral avascular necrosis of the femoral head, all between 1998 and January 2000...Four of the six patients had to undergo hip replacement surgery (bilateral in three cases). Of note was the fact that no case of osteonecrosis had been diagnosed in our cohort between 1992 and 1998. As shown in Table 1, all six patients had long exposure to antiretroviral treatments, including protease inhibitors; five out of six had signs of fat redistribution. When on therapy including a protease inhibitor, all patients had an elevated level of plasma triglycerides or cholesterol, and three had developed diabetes linked to insulin resistance...osteonecrosis may be more frequent in HIV-infected individuals, and two cases have already been reported in patients on highly active antiretroviral therapy In our cohort, osteonecrosis involved 2% of all treated patients and approximately 10% of patients had clinical features of lipodystrophy. ”

RoudiŽre L et al. Osteonecrosis of the hip, lipodystrophy and antiretroviral treatment. AIDS. 2000;14(13):2056.

AIDS Drugs disrupt Fat/Lipid Metabolism

HAART therapy seriously affects human metabolism. Outward signs are serious fat redistribution - wasting in some parts of the body (such as the arms) and lumps of fat forming elsewhere (such as on the back of the neck). These outward symptoms are, however, not as serious as the metabolic changes that can cause heart disease, extremely high cholesterol levels, diabetes and other potentially fatal illnesses.

“Indinavir 800 mg twice daily was given to 10 HIV-seronegative healthy men...Fasting glucose insulin concentrations, insulin : glucose ratio and insulin resistance index by homeostasis model assessment all increased significantly. During OGTT [Oral Glucose Tolerance Test], 2 hour glucose and insulin levels also increased significantly. Insulin-mediated glucose disposal decreased significantly. ”

Noor MA et al. Metabolic effects of indinavir in healthy HIV-seronegative men. AIDS. 2001 May;15(7):F11-18.

“Clinical research on lipodystrophy has usually rested on the idea that it was merely a complex adverse event related to individual antiretroviral agents or families of drugs...Our study suggests that the risk of lipodystrophy is mainly related to the total exposure to HAART and only to a lesser degree to specific antiretroviral drugs.”

Martinez E et al. Risk of lipodystrophy in HIV-1 infected patients treated with protease inhibitors: a prospective cohort study. Lancet. 2001;357(9256):592-8.

“Our study reports an independent association between PI [protease inhibitors] use and hyperlipidemia, hyperglycemia, and lipodystrophy, on the basis of a 5-year cohort study that encompassed the pre-PI and post-PI therapeutic eras. Although these metabolic changes were occasionally observed in patients not exposed to PIs, they were much more frequent after initiation of PI therapy. Although it appears that the metabolic effects are not serious enough to warrant discontinuation of PI therapy, this decision should be left with the patients and their primary health care providers. Future studies of PI-treated patients are warranted to further address the clinical implications of these metabolic effects and examine their pathogenesis.”

Tsiodras S et al. Effects of Protease Inhibitors on Hyperglycemia, Hyperlipidemia, and Lipodystrophy. Arch Intern Med. 2000 Jul 10;160(13):2050-6, archinte.ama-assn.org/issues/v160n13/full/ioi90558.html.

“Retroviral protease inhibitors used as therapy for HIV-1 infection have been causally associated with serious metabolic side effects, including peripheral lipodystrophy, hyperlipidemia, insulin resistance, and in some cases, overt type 2 diabetes...We demonstrate that the HIV protease inhibitor, indinavir, dramatically inhibits insulin-stimulated glucose uptake in 3T3-L1 adipocytes in a dose-dependent manner...Similar effects on glucose transport were observed for other HIV protease inhibitors. We conclude that HIV protease inhibitors as a class are capable of selectively inhibiting the transport function of Glut4 and that this effect may be responsible for a major iatrogenic complication frequently observed in HIV patients [insulin resistance].”

Murata H, Hruz PW, Mueckler M. The Mechanism of Insulin Resistance Caused by HIV Protease Inhibitor Therapy. JBC. 2000 May 9.

“At present, HIV-associated liposystrophy is regarded by many investigators as a complication of antiretroviral therapy, in general, in combination with a variety of additional risk factors, and is not to be associated with any particular class of drugs...[even though]...treatment with dual nucleoside reverse transcriptase inhibitors appears to be associated with a lower prevalence of HIV-associated lipodystrophy as compared with triple-drug regimens including an HIV-protease inhibitor [which is perhaps why the syndrome was first called ‘Crix belly’, named after Crixivan, a protease inhibitor]”

Mauss S. HIV-associated lipodystrophy syndrome. AIDS. 2000;14(suppl 3):S197-207.

“Much attention has been paid to the lipodystrophic syndrome observed in HIV-infected patients receiving antiretroviral treatment. Antiretroviral drugs probably play a crucial role in its pathogenesis: in addition to a possible interference of protease inhibitors with lipid metabolism, it has been hypothesized that the mitochondrial toxicity of nucleosidic reverse transcrip- tase inhibitors could also be involved”

Zylberberg H et al. Is there a relationship between hepatitis C virus infection and antiretroviral-associated lipoatrophy?. AIDS. 2000;14(13):2055.

“Highly active antiretroviral therapy (HAART) can induce a characteristic lipodystrophy syndrome of peripheral fat wasting and central adiposity. HIV-1 protease inhibitors are generally believed to be the causal agents, although the syndrome has also been observed with protease-inhibitor-sparing regimens. Here, we postulate that the mitochondrial toxicity of the nucleoside-analogue reverse-transcriptase inhibitors plays an essential part in the development of this lipodystrophy, similar to the role of mitochondrial defects in the development of multiple symmetrical lipomatosis. ”

Brinkman K et al. Mitochondrial toxicity induced by nucleoside-analogue reverse transcriptase inhibitors is a key in the pathogenesis of antiretroviral-related lipodystrophy. Lancet. 1999 Sep 25;354:1112-15.

“Human immunodeficiency virus (HIV) -1 infection, or its treatment with protease inhibitors, may be associated with abnormal fat deposition. One or more of several areas may be affected, including the dorsal-cervical fat pad (‘buffalo hump’), abdominal region (‘protease paunch’, ‘crixbelly’), breasts or as a generalized lipomatosis. Fat accumulation is most common in the dorsal cervical and the abdominal areas...The present study describes an HIV-1-infected man who developed a very large buffalo hump after treatment with indinavir who was successfully treated using tumescent suction-assisted lipectomy.”

Peters W, Phillips A. Buffalo hump and HIV-1 infection: Current concepts and treatment of a patient with the use of suction-assisted lipectomy. Can J Plast Surg. 1999;7(3):129-31.

AIDS Drugs cause Heart Disease

HAART therapy has been associated with an increase in heart disease (no pun intended). This is apparently related to the mechanism that also causes fat redistribution and other problems.

“Dr. Egger estimates that the more severe forms of lipodystrophy that develop as a result of highly active antiretroviral therapy (HAART) can increase the risk of coronary artery disease by three to four times.”

Mitchell D. Commentary on Welsh study of cardiovascular disease in HIV-infected people. Reuters Health. 2000 Sep 21.

“A significant number of the HAART patients had very high levels of Lp(a) and various combinations of increased lipid values associated with considerably increased risk for CHD [coronary heart disease]. The elevation of Lp(a) did not relate to any other clinical or laboratory parameter than to LDL-cholesterol. ”

Koppel K et al. Serum lipid levels associated with increased risk for cardiovascular disease is associated with highly active antiretroviral therapy (HAART) in HIV-1 infection. International Journal of STD & AIDS. 2000 Aug;11:451--455.

“highly active antiretroviral therapy, which includes two nucleoside reverse-transcriptase inhibitors and a protease inhibitor, has been associated with an increased risk of potential cardiovascular complications that was related to the length of protease-inhibitor treatment and the type of protease inhibitor used. In approximately 60 percent of patients who were treated with this type of therapy, complications such as lipodystrophy, insulin resistance, and high cholesterol and triglyceride levels developed. In 10 to 20 percent of patients these complications were severe. There is also anecdotal information suggesting that the risk of angina and myocardial infarction is increased with high active antiretroviral therapy.”

Lipshultz SE. Dilated Cardiomyopathy in HIV-Infected Patients. NEJM. 1998;339(16):1153-5.

Liver Damage

HAART therapy can cause serious or even fatal liver damage.

“The antiretroviral drugs used to fight H.I.V., particularly the protease inhibitors, place a great strain on the liver, the organ whose function it is to metabolize them...When Brian Klein of San Francisco found out that he was HIV-positive in 1996, he immediately started on a three-drug regimen that included a protease inhibitor. "Within two weeks I got extremely sick," he recalled. "I became jaundiced. I lost 15 pounds. They did some tests, and, lo and behold, I had hepatitis C [or liver damage from the protease inhibitors generated auto-antibodies misidentified as from Hepatitis C]. They pulled me off the medications because this was all new at the time and they didn't know what to do." ”

Tuller D. Hepatitis C poses new threat to many with AIDS. NY Times. 2001 May 1.

“Acute hepatitis with lactic acidosis is a life-threatening but [sometimes] reversible toxic effect on mitochondria of HIV-1 nucleoside-analogue treatment [later this letter notes that 80% of patients with lactate greater than 10 mmol/L die]. We report fatal portal hypertension, liver failure, and persistent mitochondrial dysfunction in a man aged 65 years with HIV-1 infection who had recovered from nucleoside-analogue-induced acute hepatitis and lactic acidaemia more than 18 months previously. We believe that symptom-free patients who receive nucleoside-analogue therapy should have hepatic [liver] function constantly monitored, especially those with past or present lactic acidaemia. ”

Carr A et al. Fatal portal hypertension, liver failure, and mitochondrial dysfunction after HIV-1 nucleoside analogue-induced hepatitis and lactic acidaemia. Lancet. 2001 May 5;357:1412.

“A comprehensive retrospective review of more than 10,000 adult AIDS patients participating in 21 different AIDS Clinical Trials Group (ACTG) studies [confirms]... that antiretroviral therapy is associated with a high rate of severe hepatotoxicity [liver damage], regardless of drug class or combination. Dr. Chung of Massachusetts General Hospital in Boston presented the findings to the Digestive Disease Week annual meeting...The researchers evaluated data for AIDS patients, enrolled in ACTG studies between 1991 and 2000. The subjects were taking a variety of drug combinations including one or more nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs)...Overall, 10% of patients developed grade 3 and 4 hepatotoxicity and 23% of them had to discontinue therapy permanently. According to the data, 2.5% of all deaths in the study period were liver related. NNRTI[non-nucleoside reverse-transcriptase inhibitors]-containing regimens, especially those including nevirapine and efavirenz, were particularly hard on the liver, with high rates of discontinuation.”

High Rate of Severe Liver Toxicity Associated With Antiretroviral Therapy. Reuters Health. 2001 May 23.

“ In 1998-1999, 11 (50%) of 22 deaths were due to end-stage liver disease, compared with 3 (11.5%) of 26 in 1991 and 5 (13.9%) of 36 in 1996 (P = .003). In 1998-1999, 55% of patients had nondetectable plasma HIV RNA levels and/or CD4 cell counts of >200 cells/mm3 within the year before death. Most of the patients that were tested had detectable antibodies to hepatitis C virus (75% of patients who died in 1991, 57.7% who died in 1996, and 93.8% who died in 1998-1999; P = NS). In 1998-1999, 7 patients (31.8%) discontinued antiretroviral therapy because of hepatotoxicity, compared with 0 in 1991 and 2 (5.6%) in 1996. End-stage liver disease is now the leading cause of death in our hospitalized HIV-seropositive population.”

McGovern B et al. Increasing Mortality Due to End-Stage Liver Disease in Patients with Human Immunodeficiency Virus Infection. Clin Infect Dis. 2001 Feb 1;32:492-497, http://www.journals.uchicago.edu/CID/journal/issues/v32n3/000297/brief/000297.abstract.html.

“While the risk of transmission of HIV via a needlestick is approximately 0.3%, the risk of serious adverse effects of these preventive strategies remains undefined. We report a case of a health care worker who experienced serious morbidity from PEP [post-exposure prophylaxis]...A 43-year-old female, African American phlebotomist sustained a needlestick injury after drawing blood from an HIV- and hepatitis C virus (HCV) infected patient. She received PEP with zidovudine, lamivudine, and nevirapine. Triple therapy including nevirapine was selected based on the source patient's advanced disease, antiretroviral treatment history, and severity of the exposure...The patient required an orthotopic liver transplant 35 days following initiation of PEP. Pathology of the native liver showed confluent hepatic necrosis...We think that this patient had a severe hypersensitivity reaction to nevirapine that resulted in hepatic failure...This case raises the question of whether the safety profile of nevirapine warrants its use as a prophylactic medication in health care workers who are exposed to HIV when the risk of transmission is low.”

Sha BE, Proia LA, Kessler HA. Adverse Effects Associated With Use of Nevirapine in HIV Postexposure Prophylaxis for 2 Health Care Workers [second case]. JAMA. 2000 Dec 6.

“Liver disease has become the leading cause of death among HIV patients at a Massachusetts hospital, a report issued on Friday...[by] Dr. Barbara McGovern, a professor at Tufts University School of Medicine and a member of staff at Lemuel Shattuck Hospital in Jamaica Plains, Mass. The findings were reported on Friday at the annual meeting of the Infectious Diseases Society of America in Philadelphia. McGovern said HIV patients who take a powerful combination of AIDS drugs called highly active antiretroviral therapy (HAART) were at particular risk because of the drug's potential toxicity to the liver. One-third of HIV patients with underlying liver disease at Lemuel Shattuck have had to stop taking HAART.”

Liver disease raises questions for AIDS patients. Reuters. 1999 Nov 19.

“hepatotoxicity is frequently seen in patients under HAART, and can force the withdrawal of antiviral treatment in a significant proportion of patients, occasionally resulting in fatal outcome”

Rodriguez-Rosado R et al. Hepatotoxicity after introduction of highly active antiretroviral therapy. AIDS. 1998 Jul 9;12(10):1256.


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