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Concerns about HAART (Highly Active Anti-Retroviral Therapy)

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Metabolic

HAART has many detrimental effectson the metabolism, sending cholesterol levels sky high, lipid levels in the blood and so on.

“Cushing’s syndrome, including the development of central, visceral obesity and enlargement of the dorsocervical fat pad...Here, we describe the first case of Cushing’s syndrome secondary to the co-administration of ritonavir with corticosteroid eye drops.”
Molloy A et al. Cushing's syndrome and adrenal axis suppression in a patient treated with ritonavir and corticosteroid eye drops. AIDS. 2011 Jun 19;25(10):1337-9.
http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=21659797&dopt=Abstract
“Tenofovir disoproxil fumarate (TDF) is generally considered a safe drug, well tolerated by patients and is now recommended as a first-line agent in the backbone of triple agent combination therapy (ART). Since its approval in October 2001 however, there has been a link established between its use and the incidence of proximal renal tubular dysfunction (PRTD) and Fanconi syndrome (Type 2 proximal renal tubular acidosis)…We recently performed a retrospective review of 52 patients who attended our HIV clinic between 1 September and 26 September 2009 and who were on treatment with TDF [Tenofovir] for a minimum duration of six months…Of the 30 patients who had urine analysis performed, five (16.6%) had evidence of proteinuria (with no other identifiable cause for proteinuria)…When uPCR test was performed on the same group, detection of proteinuria rose to 11 patients (36.6%)…the incidence of hypophosphataemia has been found to be around 10% in ART naive patients and this rises up to around 31% in those treated with ART…biochemical abnormalities and urinary abnormalities associated with [Tenofovir] use seem to be common”
Quinn KJ et al. Incidence of proximal renal tubular dysfunction in patients on tenofovir disoproxil fumarate. Int J STD AIDS. 2010 Feb;21(2):150-1.
“All HIV+ participants [aged 6-16 years] were infected perinatally and at baseline, 94% were receiving two or more antiretroviral drugs…Antiretroviral use was as follows: two RTIs+protease inhibitor, n=9 (14.1%), two RTI+NNRTI, n=7 (10.9%), RTI-only regimen, n=11 (17.2%), more than two RTI+protease inhibitor, n=14 (21.9%), RTIs+protease inhibitors, and NNRTI, n=14 (21.9%), other combinations, n=5 (7.8%), and none, n=4 (6.2%)…There were significant differences in the patterns of change in leg and arm fat as a percentage of total fat in the HIV-infected [and 96% drugged] versus healthy participants between baseline and the year 1 follow-up but not in changes in trunk fat percentage of total or total fat as percentage of body weight. Specifically, a greater proportion of the HIV+ group had a decrease in leg fat percentage of total in comparison to healthy participants among whom an increase in leg fat percentage of total was more common. Similarly, the pattern of change also differed for arm fat percentage of total, which was more likely to increase among HIV-infected participants, for whom an increase in arm fat percentage of total was the most common pattern seen between baseline and the 1-year follow-up, in comparison to healthy participants. Similar patterns of change in arm, leg, and trunk fat percentage of totalwere observed in the interval between baseline and year 2.”
Arpadi SM et al. Longitudinal changes in regional fat content in HIV-infected children and adolescents. AIDS. 2009 Jul 31;23(12):1501-9.
“Lipoatrophy [loss of fat] was more frequent with efavirenz than lopinavir/r when combined with stavudine or zidovudine, and less frequent when either drug was combined with tenofovir. Lipoatrophy was least frequent with the NRTI-sparing regimen, but this benefit was offset by greater cholesterol elevations and the need for lipid-lowering agents.”
Haubrich RH et al. Metabolic outcomes in a randomized trial of nucleoside, nonnucleoside and protease inhibitor-sparing regimens for initial HIV treatment. AIDS. 2009 Jun 1;23(9):1109-18.
“In a large group of vertically HIV-infected children and youth with extensive antiretroviral therapy exposure, height, weight, and total and limb fat were lower than in controls. There was a high prevalence of lipid abnormalities among those on protease inhibitors and evidence of developing insulin resistance, factors that may accelerate lifetime risk for cardiovascular disease.”
Aldrovandi GM et al. Morphologic and metabolic abnormalities in vertically HIV-infected children and youth. AIDS. 2009 Mar 27;23(6):661-72.
“We describe a 62-year-old male who was diagnosed with HIV-1 in 2001 and died with lactic acidosis under treatment with didanosine [ddI/Videx] and stavudine [d4T/Zerit]…Lactic acidosis is a life-threatening complication of HAART. The onset is often abrupt, with uncharacteristic muscular, cardiac or hepatic symptoms. The outcome can be fatal due to liver failure and cardiac arrhythmia. Didanosine and stavudine are strong inhibitors of polymerase-gamma, which are known to induce mtDNA [mitochondrial DNA] depletion in subcutaneous adipose tissue and in liver”
Thoden J et al. Highly active antiretroviral HIV therapy-associated fatal lactic acidosis: quantitative and qualitative mitochondrial DNA lesions with mitochondrial dysfunction in multiple organs. AIDS. 2008 May 31;22(9):1093-4.
“Angiolipomas are benign [non-cancerous] tumours of adipose [fatty] tissue that have a predilection for the subcutis of the upper limbs and less commonly the trunk. These lesions typically present as tender or painful subcutaneous nodules, more often multiple than solitary…[after doing a detailed physical examination of 303 AIDS patients] We detected the presence of angiolipomas in three patients [all taking AIDS drugs and all suffering from lipodystrophy]
Blanes M et al. Angiolipomas, a rare manifestation of HIV-associated lipodystrophy. AIDS. 2008 Feb 19;22(4):552-4.
“HIV-infected women reporting no recent antiretroviral therapy had a DM [diabetes mellitus] incidence rate of 1.53/100 person-years; those reporting HAART containing a protease inhibitor (PI) had a rate of 2.50/100 person-years and those reporting non-PI-containing HAART a rate of 2.89/100 person-years.”
Tien PC et al. Antiretroviral therapy exposure and incidence of diabetes mellitus in the Women's Interagency HIV Study. AIDS. 2007 Aug 20;21(13):1739-1745.
“in immunosuppressed HIV patients with advanced disease, an effective HAART regimen can be expected to raise not only the BMI [body mass index] and CD4 lymphocyte count, but also the BP ]blood pressure]…We agree with Crane et al on the importance of monitoring BP among HIV-infected patients receiving HAART and to treat it when necessary.”
Palacios R, Santos J. Blood pressure and antiretroviral therapy. AIDS. 2007 Feb 19;21(4):529.
“The authors describe an adolescent with AIDS receiving ritonavir and inhaled fluticasone who developed Cushing’s syndrome, and review similar cases described in the literature…The patient was a female adolescent, 16 years of age, with AIDS grade C3…Her previous medical history was characterized by interstitial lymphocytic pneumonia, repeated pneumonias, chronic otitis media and bronchospasm. She has been on antiretroviral therapy since July 1996 with zidovudine and didanosine, being switched to zidovudine and estavudine after one year. She had been treated with stavudine, lamivudine and ritonavir since October 1998…After 3 months of the regular use of inhaled corticosteroids, she showed a significant improvement of the respiratory condition; however, she exhibited excessive weight gain (2.7 kg), increased appetite, fatigue, facial oedema, marked acne, stretch marks on her limbs and abdomen, hypercholesterolemia and hypertriglyceridemia. She began experiencing amenorrhea [no menstruation]…Within one month, she experienced a remarkable worsening of the symptoms described…A diagnosis of iatrogenic Cushing’s syndrome was established caused by a drug interaction between fluticasone and ritonavir, and it was decided to switch ritonavir for efavirenz, maintaining treatment with fluticasone. There was a gradual improvement of the Cushing’s syndrome symptoms within approximately 30–60 days after the discontinuation of ritonavir, with decreased oedema and stretch marks and resumed menstrual periods. Five months after the drug switch the blood cortisol level was normal.”
Pessanha TM et al. Iatrogenic Cushing's syndrome in a adolescent with AIDS on ritonavir and inhaled fluticasone. Case report and literature review. AIDS. 2007 Feb 19;21(4):529-32.
“Pancreatitis is a well-described complication of HIV [not clear that this association exists in the absence of AIDS drugs] and its therapy…A 42-year-old man diagnosed with HIV infection in 1991 presented with one day of fever and severe epigastric pain. Significant past illnesses included tuberculous lymphadenitis, cerebral toxoplasmosis, Pneumocystis carinnii pneumonia, depression, marijuana use, and alcoholism, but no previous history of pancreatitis…It is well documented that HAART, in particular protease inhibitor therapy, can cause a metabolic syndrome, the manifestations of which can include hyperlipidemia and hypertriglyceridemia. Ritonavir, more than other protease inhibitors, has been associated with marked hypertriglyceridemia and rarely hypertriglyceridemia- induced pancreatitis. To our knowledge, this is the first reported case of hypertiglyceridaemia leading to pancreatitis in the setting of tipranavir use…This case illustrates that tipranavir can be associated with the rapid development of extreme triglyceride levels, which can be associated with patient morbidity.”
Chapman SJ et al. Acute pancreatitis caused by tipranavir/ritonavir-induced hypertriglyceridaemia. AIDS. 2007 Feb 19;21(4):532-3.
“Hyperlactatemia [high levels of lactic acid in the blood] is prevalent in HIV-infected patients on highly active antiretroviral therapy (HAART) and may be associated with depletion of mitochondrial DNA.”
Haugaard SB et al. Glucose production, oxidation and disposal correlate with plasma lactate levels in HIV-infected patients on HAART. J Infect. 2007 Jan;54(1):89-97.
“Transient hyperphosphatasemia of infancy and early childhood is characterized by an isolated increase in serum alkaline phosphatase up to 30 times the adult upper reference limit…Here we present a case of transient hyperphosphatasemia of infancy and early childhood. This may have been triggered by the commencement of antiretroviral therapy…[The patient, a 32-year-old HIV/Hepatitis C positive hemophiliac] commenced lamivudine, didanosine and atazanavir/ritonavir on 17 February 2004. Before this, he had not taken antiretroviral therapy for 6 months. He was at the time taking acyclovir and cotrimoxazole for prophylaxis, but no other treatment changes were made. Liver enzymes had previously been normal and serum alkaline phosphatase before starting the above regimen was 135 iu/l. The patient’s CD4 cell count and HIV viral load were 10 cells/ml and more than 100,000 copies/ml, respectively. One month later, serum alkaline phosphatase had increased to approximately 10 times the upper reference limit and went on to peak at 4430 iu/l at 6 weeks. All three antiretroviral drugs were stopped…[serum analysis] showed a pattern consistent with benign transient hyperphosphatasemia of infancy and childhood. There was no history of intercurrent illness. An abdominal computed tomography scan did not show any evidence of liver disease…Over the next 4 months, the alkaline phosphatase level gradually decreased to baseline. occurring in an adult with HIV infection.”
Trower K et al. A case of transient hyperphosphatasemia of infancy and early childhood in an HIV-positive adult possibly related to atazanavir. AIDS. 2006 Jan 2;20(1):135-6.
Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med. 2005 Jan 6;352(1):48-62.
“During a 2-3 month period, 477 HIV-infected children aged >= 3 years in 30 paediatric HIV clinics were assessed at their first visit…Prevalence was 26.0% for any fat redistribution [30.7% among the majority using HAART], 8.81% for central lipohypertrophy, 7.55% for peripheral lipoatrophy and 9.64% for…more than one sign of each. Independent predictors of fat redistribution included [CDC] class C disease, female gender, ever used versus never use of protease inhibitors and of stavudine [none of 15 children not using any AIDS drugs had fat redistribution]. Increasing time since initiation of antiretroviral therapy was associated with increased severity of fat redistribution.”
Antiretroviral therapy, fat redistribution and hyperlipidaemia in HIV-infected children in Europe. AIDS. 2004 Jul 2;18(10):1443-1451.
“Gynecomastia is defined as benign enlargement of the male mammary gland [breast]…Gynecomastia in HIV-1 infection may be associated with the use of potent antiretroviral therapy (ART)…We studied the characteristics of 47 individuals [with this condition] in the Swiss HIV Cohort Study (SHCS) who received ART from 1996 to 2002 and were HIV-1 infected for a median time of 105+/-52 months…[the nucleoside analogs] stavudine and didanosine were used more frequently in patients with gynecomastia than in other patients in the SHCS [Swiss HIV Cohort Study]…Cholesterol and triglyceride levels were elevated in 38.3 and 53.2% of patients with gynecomastia, respectively. 14 patients (30%) suffered from concomitant lipodystrophy (fat accumulation). 22 of the 47 individuals (46.8%) also showed elevated liver transaminases. The endocrinological assessment revealed that 40% (8/20) had elevated luteinizing hormone levels. In 4 out of 14 patients (28.6%) testosterone concentrations were decreased.”
Strub C et al. Gynecomastia and potent antiretroviral therapy. AIDS. 2004 Jun 18;18(9):1347-9.
“14 patients (14.6%), only one of whom being antiretroviral naive, experienced prolong side-effects, mainly lipodystrophy”
Piroth L et al. Clinical, immunological and virological evolution in patients with CD4 T-cell count above 500/cubic mm: is there a benefit to treat with highly active antiretroviral therapy (HAART)?. Eur J Epidemiol. 2004;19(6):597-604.
“Claims that Efavirenz has the opposite effect of PI's and is good for your cholesterol levels!”
Negredo E et al. Efavirenz induces a striking and generalized increase of HDL-cholesterol in HIV-infected patients. AIDS. 2004 Apr 12;18(5):819-821.
“A dose of 400 mg lopinavir/100 mg ritonavir was given twice a day to 10 HIV-negative[!] men…On lopinavir/ritonavir, there was an increase in fasting triglyceride, free fatty acid [FFA], and VLDL [very low density lipoprotein] cholesterol levels”
Lee GA et al. The metabolic effects of lopinavir/ritonavir in HIV-negative men. AIDS. 2004 Mar 5;18(4):641-9.
“Among 743 HIV-infected patients, a 6-month case-control study disclosed a 35.9% rate of hyperlactatemia [high blood lactic acid levels] in those with a longer duration of anti-HIV therapy…After the introduction of HAART, abnormalities involving glucose and lipid metabolism, muscle, nerges, and bone became apparent and were probably related to NA[nucleoside analog]-associated mitochondrial damage”
Manfredi R et al. Frequency, risk factors and features of hyperlactatemia in a large number of patients undergoing antiretroviral therapy. AIDS. 2003 Sep 26;17(14):2131-3.
“Diabetes mellitus was diagnosed in 16 out of 1011 HIV-positive patients over a median follow-up of 289 days”
Brambilla AM et al. Stavudine or indinavir-containing regimens are associated with an increased risk of diabetes mellitus in HIV-infected individuals. AIDS. 2003 Sep 5;17(13):1993-5.
“Many patients now initiate treatment with an NNRTI, and these regimens, like PI-containing regimens, can result in lipid abnormalities. Data are required to demonstrate whether switch maintenance from an NNRTI-containing regimen to a triple nucleoside regimen can similarly improve the lipid profile while maintaining virological control.”
Katlama C et al. Comparison of metabolic abnormalities 48 weeks after switching from highly active antiretroviral therapy containing a non-nucleoside reverse transcriptase inhibitor to Trizivir versus continued highly active antiretroviral therapy. AIDS. 2003 Aug 15;17(12):1855-6.
“NRTI [nucleoside reverse transcriptase inhibitor] treatment was associated with reduced adipocyte [fat cell] mtDNA [mitochondria] copies/cell, representing mean mtDNA depletion in NRTI treated individuals of 77.7% compared with the mean value for the HIV-infected control group…NRTI therapy is associated with mtDNA depletion and mitochondrial proliferation in adipocytes, consistent with the hypothesis that NRTI-induced mtDNA depletion contributes to the pathogenesis of subcutaneous fat wasting.”
Nolan D et al. Mitochondrial DNA depletion and morphologic changes in adipocytes associated with nucleoside reverse transcriptase inhibitor therapy. AIDS. 2003 Jun 13;17(9):1329-38.
“There were increases in limb fat, central abdominal fat and lean mass over the initial 24 weeks of [anti-retroviral] therapy followed by a selective, progressive loss of limb fat from week 24. There was a median 13.6% loss of limb fat per year from week 24 onwards…In multivariate analysis, treatment with stavudine was the strongest independent factor associated with rate of limb fat loss. Hypercholesterolaemia [high blood cholesterol] developed early in treatment, whereas hypertriglyceridaemia [high levels of triglycerides], hyperinsulinaemia [high insulin] and decreased bone mineral density developed later. The largest changes in CD4 cell counts and HIV viral load, seen early into treatment, were associated with gain rather than loss of fat…treatment with antiretrovirals results in progressive, selective loss of limb fat. Loss of limb fat occurred after the period of most intense immune restoration, making an immune aetiology unlikely.”
Mallon PW et al. Prospective evaluation of the effects of antiretroviral therapy on body composition in HIV-1-infected men starting therapy. AIDS. 2003 May 2;17(7):971-9.
“During the study period, mean HAART exposure increased from 39.3 to 50.9 months and the number of HIV-infected children with clinical lipodystrophy (LD) increased from 6 to 8, whereas mean BMI, CD4 percentage, and percentage of HIV-infected children with HIV RNA <50 copies/mL did not change.”
Vigano A et al. Increased lipodystrophy is associated with increased exposure to highly active antiretroviral therapy in HIV-infected children. J Acquir Immune Defic Syndr. 2003 Apr 15;32(5):482-9.
“HIV-associated lipodystrophy [fat redistribution] is frequently found in HIV-infected individuals on antiretroviral treatment. Although antiretroviral treatment has been identified as a risk factor, it is not known if HIV infection is a prerequisite for the development of the lipodystrophy syndrome or if lipodystrophy can be considered a genuine adverse event of antiretroviral treatment. Data from HIV-seronegative individuals treated with antiretroviral drugs are only available from phase 1 monotherapy trials or anecdotally from patients with postexposure prophylaxis…we report the case of a 32-year-old male HIV-seronegative patient who twice received antiretroviral postexposure prophylaxis after having repeated high-risk sexual contacts with an HIV-infected partner. Postexposure prophylaxis consisted of two 3-week courses of stavudine 40 mg twice a day, lamivudine 150 mg twice a day, and efavirenz 300 mg twice a day. Treatment episodes were 10 weeks apart. The patient reported no change in physical activity or diet during or after this period. The patient has remained HIV seronegative now for 4 months after the last exposure. Within 6 weeks after the second course of postexposure prophylaxis he developed a rapid increase in abdominal girth, associated with bloating and loss of appetite…The clinical picture resembles the ‘protease paunch’ first described by Miller et al. Computed tomography…showed visceral and subcutaneous fat accumulation…The abdominal fat accumulation has persisted now for 4 months after the last exposure to antiretroviral drugs. To our knowledge this is the first case report on the development of visceral lipohypertrophy in an HIV-seronegative patient after exposure to antiretroviral combination therapy. Although the patient did not develop metabolic abnormalities, or peripheral lipoatrophy, this case report may be a limited proof of principle that the alterations in adipose tissue are caused by antiretroviral combination therapy rather than HIV infection itself.”
Mauss S et al. Rapid development of central adiposity after postexposure prophylaxis with antiretroviral drugs: a proof of principle?. AIDS. 2003 Apr 11;17(6):944-5.
“A syndrome characterized by hypertriglyceridaemia, hypercholesterolaemia, hyperinsulinaemia, and lipodystrophy has been found to be associated with highly active antiretroviral treatment (HAART) including protease inhibitors…Indinavir inhibits important effector genes of the SREBP-1c pathway, explaining major HAART-related adverse effects.”
Miserez AR, Muller PY, Spaniol V. Indinavir inhibits sterol-regulatory element-binding protein-1c-dependent lipoprotein lipase and fatty acid synthase gene activations. AIDS. 2002 Aug 16;16(12):1587-94.
“Patients enrolled in a province[of British Columbia]-wide HIV/AIDS treatment program reported annually on the occurrence of lipoatrophy [fat loss], lipohypertrophy [abnormal fat gain], and elevated triglyceride and cholesterol levels…745 [participants] were available at follow-up, among whom incidence was 27% for lipoatrophy, 21% for lipohypertrophy, and 10% and 16% for increased triglyceride and cholesterol levels, respectively…incident lipoatrophy was associated with duration of stavudine (per quarter) and having been diagnosed with AIDS [which increases the likelihood and intensity of exposure to antiretroviral drugs]. Lipohypertrophy risk increased with use of protease inhibitor and stavudine. Incident cholesterol or triglyceride abnormalities were associated with protease inhibitor use and duration of ritonavir [a Protease Inhibitor] (per quarter).”
Heath KV et al. Antiretroviral treatment patterns and incident HIV-associated morphologic and lipid abnormalities in a population-based cohort. J Acquir Immune Defic Syndr. 2002 Aug 1;30(4):440-7.
“an increasing number of complications associated with [new antiretroviral drugs, particularly protease inhibitors] have been recognized. Recently, the appearance of subcutaneous lipomas [fatty tumors] and angiolipomas shortly after starting treatment with antiretroviral therapy, including indinavir, has been described. We would like to report on one HIV-positive patient who presented with eruptive angiolipomas, probably induced by saquinavir. A 49-year-old woman, HIV-positive since 1993, presented at our department in March 1999. She referred to the appearance, 5 years before, of a subcutaneous nodule on the right thigh, and a new nodule on the left thigh the following year. Since then, the lesions have remained stable. Eight months before the consultation, she had noticed the relatively sudden appearance of six more slightly tender nodules on the right hip and both thighs, and a simultaneous increase in the size of the previous lesions. These changes coincided with a progressive body fat redistribution. The patient had been treated since 1996 with zidovudine [AZT], zalcitabine and didanosine. Because of the inefficacy of the therapy, a new regimen with stavudine (30 mg twice a day), lamivudine (150 mg twice a day) and the protease inhibitor saquinavir (600 mg every 8 h) was started 3 months before the previously mentioned changes in the nodules and the subcutaneous fat. On examination, eight firm, well-circumscribed, rounded nodules, 2–3 cm in diameter, were found on both thighs and on the right hip. They were movable against the overlying skin. Besides that, a loss of buccal fat pads, a wasting of the buttocks, an accumulation of fat in the dorsocervical region, an increased abdominal girth, and hypertrophy of the breasts were observed…Haematological, biochemical and hormonal studies revealed a discrete low haemoglobin level [common with AZT and related drugs], and an increase in total cholesterol”
Daubén E et al. Eruptive angiolipomas associated with antiretroviral therapy. AIDS. 2002;16(5):805.
“We studied the effects of protease inhibitor (PI)-containing highly active antiretroviral therapy (HAART) on metabolic and hemostatic parameters in 363 HIV-infected individuals, of whom 266 were receiving PI-containing HAART and 97 were treatment naive…The levels of insulin, triglycerides, cholesterol, and low-density lipoprotein cholesterol; visceral adipose tissue area; low-density lipoprotein/high-density lipoprotein ratio; and visceral adipose tissue/subcutaneous adipose tissue area ratio were significantly increased in patients receiving PI-containing HAART …The levels of PAI-1 [plasminogen activator inhibitor type 1] and fibrinogen [blood coagulating protein] were significantly higher in patients receiving PI-containing HAART…These findings suggest that patients receiving PI-containing HAART have decreased fibrinolysis and increased coagulability, which may thus represent additional risk factors for cardiovascular disease”
Koppel K et al. Hypofibrinolytic State in HIV-1 Infected Patients Treated With Protease Inhibitor Containing Highly Active Antiretroviral Therapy. J Acquir Immune Defic Syndr. 2002;29:441-9.
“The HIV-1-infected group consisted of 26 patients treated with both protease inhibitors and NRTIs [Nucleoside Reverse Transcriptase Inhibitors, such as AZT] who had developed peripheral lipoatrophy [abnormal fat loss]…The disposition and size of adipocytes was relatively homogeneous in control fat, whereas fat from HIV-1 patients contained clusters of small adipocytes [fat cells], together with normal-sized adipocytes…In conclusion, we found profound alteration of some transcription factors and adipocyte markers in HIV-1- infected patients on antiretroviral therapy, which strongly suggests that adipocyte differentiation is markedly abnormal.”
Bastard JP et al. Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differentiation and insulin resistance. Lancet. 2002 Mar 23;359(9311):1026-31.
“Symptomatic hyperlactatemia [elevated lactic acid levels] was associated with marked reductions in the ratios of mitochondrial to nuclear DNA, which, during therapy, averaged 68% lower than those of non–HIV-infected controls and 43% lower than those of HIV-infected asymptomatic patients never treated with antiretroviral drugs. After the discontinuation of antiretroviral therapy, there was a statistically significant increase in the ratio of mitochondrial to nuclear DNA. In the patients followed longitudinally [for a period of time], the decline in mitochondrial DNA preceded the increase in venous lactate levels. Conclusions: Mitochondrial DNA levels are significantly decreased in patients with symptomatic, nucleoside- related hyperlactatemia, an effect that resolves on the discontinuation of therapy.”
Cote HCF et al. Changes in Mitochondrial DNA as a Marker of Nucleoside Toxicity in HIV-Infected Patients. N Engl J Med. 2002 Mar 14;346(11):811-820.
http://content.nejm.org/cgi/content/full/346/11/811
“during 1995-2000, we identified an increasing number of cases of the symptomatic lactic acidosis syndrome [elevated lactic acid levels, first presenting as nausea, vomiting or abdominal pain, and sometimes leading to liver or pancreas failure] in patients infected with HIV who had been treated with antiretrovirals, which suggests enhanced physician recognition and/or cumulative toxicities. We found concurrent chemical pancreatitis [pancreas inflammation] in 6 patients and identified a clinical syndrome similar to lipoatrophy [fat wasting] that occurred as an early component of symptomatic hyperlactatemia…Early recognition and discontinuation of antiretroviral therapies are probably essential to recovery.”
Coghlan ME et al. Symptomatic lactic acidosis in hospitalized antiretroviral-treated patients with human immunodeficiency virus infection: a report of 12 cases. Clin Infect Dis. 2001 Dec 1;33(11):1914-21.
“Trunk fat was greater in men and women and leg fat was lower in men and women receiving HAART than in those not. This corresponded to a greater percentage of total fat mass located in the trunk. Lean mass was also greater with longer duration of HAART in men. In men receiving HAART, total and regional bone mineral content were less than in the men not receiving HAART. These effects increased with longer duration of HAART. Protease inhibitors were associated with the largest differences in regional fat…[Conclusions] HAART is associated with redistribution of fat mass from the legs to the trunk, despite no significant differences in total fat mass or weight. In men, HAART is also associated with a reduction in bone mineral content, suggesting that HAART increases the risk of central obesity and osteoporosis.”
McDermott AY et al. Effect of highly active antiretroviral therapy on fat, lean, and bone mass in HIV-seropositive men and women. Am J Clin Nutr. 2001 Nov;74(5):679-86.
“PI [Protease Inhibitor]-treated patients with lipodystrophy were significantly less insulin sensitive than PI-treated patients and PI-naive patients without any changes in fat distribution…Visceral adipose [fat] tissue area and other measures of central adiposity correlated strongly with metabolic disturbances as did the percent of total body fat present in the extremities; visceral adipose tissue was an independent predictor of insulin sensitivity and high density lipoprotein cholesterol levels. REE [Resting Energy Expenditure] per kg lean body mass was significantly higher in the group with lipodystrophy compared to the groups without lipodystrophy, and SI [Insulin Sensitivity] was strongly correlated with and was an independent predictor of REE in this population. [Note that PI-treated patients with lipodystrophy had been HIV-positive longer, and taking PI’s longer than those without]
Kosmiski, LA et al. Fat distribution and metabolic changes are strongly correlated and energy expenditure is increased in the HIV lipodystrophy syndrome. . AIDS. 2001 Oct 19;15(15):1993-2000.
“Some 51 patients (29%) developed lipodystrophic syndrome after a mean 20.0 months on HAART: 16 were classified as pure lipoatrophy [loss of fat tissue], 5 as pure truncal fat accumulation, and 30 as a mixed syndrome...Four patients...developed diabetes mellitus that required insulin therapy. One of them, who was also a heavy smoker, also had myocardial infarction in the setting of major hypertriglyceridemia. All of these events occurred in the 3 months after the clinical diagnosis of lipodystrophic syndrome...Length of treatment with HAART was significantly associated with lipoatrophy...Blood lipid levels rose significantly [in all patients] in comparison with pre-HAART values”
Viard J-P et al. Lipodystrophic syndromes and hyperlipidemia in a cohort of HIV-1-infected patients receiving triple combination antiretroviral therapy with a protease inhibitor. J Acquir Immune Defic Syndr. 2001 Aug 15;27(5):443-9.
http://www.jaids.com/pt/re/jaids/fulltext.00126334-200108150-00004.htm;jsessionid=F5Wfn7DgBss2Wp9yQ0bTy5FLyJYy87Sy1ljBXdYy1QXppPl0yhxB!-1040256789!-949856144!8091!-1
“The incidence of any lipodystrophy [generally accumulations of fat in the abdomen and/or loss of fat in the face or limbs] was 11.7 per 100 person-years...By 24 months after starting HAART, 23% of the patients were estimated to have any liopdystrophy...Each 6 months of additional exposure to HAART was associated with a 57% increased risk of lipodystrophy...the risk of any lipodystrophy was related to the exposure to HAART in general but not with 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.
“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 4;15(7):F11-18.
“Of 1035 participants, 50% appeared to have probable lipodystrophy [fat redistribution], with 36% reporting peripheral wasting, 33% abdominal weight gain, 6% buffalo hump, and 10 and 12% increased triglyceride or cholesterol levels, respectively…Lipodystrophy was associated with…having ever used protease inhibitors (PI), and duration of stavudine treatment…the inordinately high prevalence of both lipodystrophy syndrome and its component symptoms identified through self-report within a large observational, population-based treatment programme by individuals representing a broad spectrum of those living with HIV/AIDS and utilizing a wide variety of antiretroviral regimens is of grave concern. Most pressing are the implications regarding PI and nucleoside analogues, drugs widely prescribed both as first-line agents and throughout the course of the disease…Morphological abnormalities can be disfiguring and often frightening, as they may be experienced as one of the first overt physical manifestations related to HIV disease [i.e. people are healthy until they start experiencing the side effects of drugs for a condition that has not yet done them any harm].”
Heath KV et al. Lipodystrophy-associated morphological, cholesterol and triglyceride abnormalities in a population-based HIV/AIDS treatment database. AIDS. 2001 Jan 26;15(2):231-9.
“71 patients (49 men and 22 women) with HIV infection who reported recent changes in body fat distribution...7 (10%) case patients were PI [Protease Inhibitor] naive [had never taken this class of drugs], 50 (70%) were currently receiving a PI, and 14 (20%) had a history of previous PI exposure”
Hadigan C et al. Metabolic Abnormalities and Cardiovascular Disease Risk Factors in Adults with Human Immunodeficiency Virus Infection and Lipodystrophy. Clin Infect Dis. 2001 Jan;32(1):130-9.
“83 of the participants [HIV-positive Australians] were taking antiretroviral therapy [ART]. 17 were antiretroviral naive. Of the 83 subjects on [ART], 69 were on a regimen including at least one PI [Protease Inhibitor]…44 subjects, all taking [ART], reported FRS [Fat Redistribution Syndrome]. In all but two cases the morphological changes were accompanied by at least one biochemical abnormality in the serum metabolic parameters measured. The prevalence of FRS was 59% in those receiving [ART] including a PI, 21% in those…who were PI naive and 0% in untreated cases.”
Batterham MJ, Garsia R, Greenop PA. Dietary intake, serum lipids, insulin resistance and body composition in the era of highly active antiretroviral therapy `Diet FRS Study'. AIDS. 2000 Aug 18;14(12):1839-43.
“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.
“Results: The cumulative incidence of new-onset hyperglycemia, hypercholesterolemia, hypertriglyceridemia, and lipodystrophy was 5%, 24%, 19%, and 13%, respectively. Most of these events occurred after initiation of PI [Protease Inhibitor] therapy. Protease inhibitors were independently associated with hyperglycemia, hypercholesterolemia, hypertriglyceridemia, and lipodystrophy. Anabolic steroids and psychotropic medications were also associated with lipodystrophy. Inclusion of potential intermediate variables (eg, virological suppression and increase in body weight) did not reduce the magnitude of the association with PIs…[statistically] controlling for surrogate markers did not abolish the strong association between PIs and increase in serum lipid levels.”
Tsiodras S et al. Effects of Protease Inhibitors on Hyperglycemia, Hyperlipidemia, and Lipodystrophy. Arch Intern Med. 2000 Jul 10;160(13):2050-6.
“At present, HIV-associated lipodystrophy 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 nucleoside reverse transcriptase 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.
“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. J Biol Chem. 2000 May 9
“Fourteen patients receiving combination NRTI [nucleoside analog] therapy but having never been treated with a protease inhibitor [the drugs usually associated with lipodystrophy (LD/fat redistribution) presented with clinical features consistent with LD syndrome and most were found to have lactic acidaemia and liver dysfunction…Ten cases ceased therapy. One case…died after 3 months of progressive encephalopathy and wasting. The other nine cases were followed for an average of 4 months. Fatigue and nausea generally improved but four cases remained symptomatic. Weight gain was limited and only two cases reached their pre-therapy weight…Lactic acidaemia [high levels of lactic acid in the blood] resolved in seven cases in a mean time period of 3 months after ceasing therapy; anion gap and liver enzymes also fell…[our conclusion is] NRTI therapy can cause a partially reversible syndrome of subacute onset fatigue, nausea, peripheral lipoatrophy [fat wasting], abdominal distension [swelling], lactic acidaemia and hepatic dysfunction [liver damage]…Both NRTI therapy and protease inhibitor therapy appear to be associated with the physical feature of LD syndrome”]
Carr A et al. A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction associated with HIV nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy syndrome. AIDS. 2000 Feb 18;14(3):F25-32.
“Lactic acidosis…including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including Ziagen and other antiretrovirals”
Important Drug Warning: Fatal Hypersensitivity Reactions, Respiratory Symptoms, and Ziagen (abacavir sulfate). Glaxo Wellcome. 2000 Jan
“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.

Courtesy Alberta Reappraising AIDS Society, August 10, 2011.

© Copyright August 10, 2011 by Rethinking AIDS.