CMEonHIV.com is dedicated to providing online CME presentations (slides with voiceover) on HIV/AIDS for healthcare professionals given by local and international experts to keep you up-to-date on the ongoing developments in the field.
Treatment Related Complications
Antiretroviral therapies don't come without toxicities, some of which are notorious for being the origin of lipodystrophy, metabolic abnormalities, mitochondrial depletion and bone disorders. Antiretroviral resistance represents one cause of treatment failure. It is linked to the development of quasi-species of HIV, carrying mutations that originated in HIV replication during the course of antiretroviral therapy.
"Managing HIV in Light of Cardiovascular Risks" Dr. Sharon Walmsley (biography) English - 2009-04-24 - 33 minutes
Summary : HAART is now recognized as an effective treatment for HIV, allowing the patients to live a relatively normal life. But studies have shown that although these patients suffer less from HIV/AIDS related diseases, their risk of suffering from cardiovascular diseases seems significantly higher, compared to the general population. Supporting this idea, the DAD study showed that there was an increased relative risk of heart diseases associated with protease inhibitors exposure.
Many antiretroviral drugs have been looked at, with Abacavir and Didanosine being possibly implicated. This was surprising findings for the scientific community because these drugs were not known to cause dyslipidemia, a condition that has also been related with heart diseases. Multiple studies were launched to address this issue. Some, like the DAD and the SMART studies, concluded that there effectively was a higher risk of heart diseases with Abacavir, while others, like the ALLRT study, showed the opposite. As Dr. Walmsley says, at this point in time, we are unsure as to whether or not Abacavir is a risk factor for cardiovascular diseases. Issues like confounding and drug channeling are also being raised as possible factors for these contradictory observations.
Dr. Walmsley concludes that, although we are doubtful about the associated risks with Abacavir use, every HIV patient needs a cardiovascular risk assessment. Physicians should therefore focus on advising the patient with their diet, exercise, lipid levels, smoking and other factors that we know for sure will help reduce its cumulative risk of associated diseases. Despite the rise in some non-HIV related diseases, HAART has improved the quality of life of those living with HIV and clearly has more advantages than its potential risks.
Learning objectives : After viewing this presentation, the participant will be able to discuss:
- The results from many studies looking at the association between HAART and risks for cardiovascular disease
- The correct assessment of cardiovascular risk for an HIV patient
"Pathogenesis, presentation and management of IRIS" Prof. Martyn French (biography) English - 2008-02-06 - 38 minutes
Summary : In this presentation Prof. French discusses the pathogenesis of immune reconstitution inflammatory syndrome (IRIS) and its clinical management. He describes the concept of immune restoration disease (IRD) (1) and gives several examples of immunopathogenesis.
Among the topics covered is the potential occurrence of IRD in tuberculosis (TB) patients. According to available data, it is possible to make the distinction between a TB infection and an IRD after anti-retroviral therapy (ART).
Using immune markers, Crane et al. also tried to distinguish patients with hepatitis flares from those without. These markers were found to be increased with hepatitis flares, and to correlate with ALT levels. Being able to distinguish between the two phenomena could be useful in prevention and treatment. A review by Prof. French explores these perspectives (2).
Learning objectives : After viewing this presentation the participant will be able to discuss:
- Immune reconstitution inflammatory syndrome (IRIS)
- Pathogens that may provoke IRIS
- How to treat and prevent IRIS
- Recent data in this field
"The Contribution of HAART Regimens to Liver Fibrosis Progression in HIV-Hepatitis C Co-infection" Dr. Marina Klein (biography) English - 2006-05-27 - 21 minutes
Summary : The beginning of highly active antiretroviral therapy led to an increase in end-stage liver disease. The negative effects of hepatitis C (HCV) co-infection and/or the benefits of HAART on hepatic fibrosis are still unclear and would require multiple liver biopsies to elucidate. Such a study calls for a compliance among subjects that is much too elevated. Therefore, there is a need for non-invasive methods of assessing the progression of hepatic fibrosis.
One such method is known as the aspartate aminotransferase-platelet ratio index (APRI) which is a simple equation employed to amplify the damaging effects of fibrosis on aspartate aminotransferase and platelets. This is calculated as follows:
APRI = [(AST/upper limit of normal) x 100] / Platelet count (10*9/L)
Dr. Klein presents data from her team which attempt to correlate progression of APRI with hepatic outcome in HIV infected individuals with and without HCV co-infection. Furthermore they examined the effects of HAART on the progression rate of hepatic fibrosis with specific focus on PI-based and NNRTI-based regimens.
Learning objectives : After viewing this presentation, participants will be able to discuss:
- The challenges of monitoring the progression of hepatic fibrosis;
- The association of APRI with hepatic outcome in HIV mono-infected and co-infected (HIV + HCV) individuals;
- The effects of HAART on the progression rate of hepatic fibrosis;
- Future directions of research.
"Hypersensitivity Reactions to Abacavir" Dr. Simon Mallal (biography) English - 2004-07-21 - 36 minutes
Summary : In this presentation, Dr. Simon Mallal examines hypersentivity reactions (HSR) to abacavir and discusses the emerging importance of genetic screening to susceptibility to abacavir HSR.
Dr. Mallal presents evidence in the clinical literature for suspecting a genetic predisposition. The clinical manifestations of abacavir HSR as well as its prevalence clinical trials and certain populations are discussed. The treatment of HSR is also reviewed.
Dr. Mallal presents his own research and other evidence from the literature for a benefit of screening HIV patients in certain populations for HLA-B*5701 alone and in conjuction with testing for Hsp70 hom ‘C’.
Dr. Mallal concludes his talk by proposing an immunological mechanism for HSR to abacavir based, in part, on his own data and on functional studies of the role of certain haplotypes in abacavir HSR.
Learning objectives : After viewing this presentation, participants will be able to discuss:
• The epidemiology of abacavir hypersensitivity reactions (HSR)
• The clinical manifestations of abacavir HSR
• The management of HSR
• The evidence in the literature for the value of genetic screening for abacavir HSR susceptibility
• The patient populations to which the data cannot reasonably be extrapolated at the present time
Bibliographic references : Shapiro LE, Shear NH. Mechanisms of drug reactions: the metabolic track. Semin Cutan Med Surg. 1996 Dec;15(4):217-27.
"Update on Resistance Profiles of Nucleoside Analogs" Prof. Mark Wainberg (biography) English - 2004-05-13 - 40 minutes
Summary : One of the most important considerations when selecting a treatment regimen is preventing the development of drug resistance to preserve future treatment options. In this presentation Dr. Wainberg provides a review of the resistance data obtained from various trials testing nucleoside backbone regimens.
Resistance data obtained from the CNA 30024 study (ABC vs ZDV with 3TC and EFV) showed the presence of wild-type genotype in some failing patients, as well as primary NNRTI and M184V mutations, but no ZDV mutations such as K65R and L74V. ABC QD vs ABC BID with 3TC and EFV (CNA 30021 study) showed similar resistance profiles in both ABC study arms.
The 903 trial testing TDF vs. d4T plus EFV and 3TC also showed wild-type virus in the context of virologic failure, and it was noted that the K65R mutation which confers a broad cross-resistance appeared not alone but in combination with other mutations. The ESS30009 study which compared TDF plus ABC/3TC vs EFV plus ABC/3TC showed an unexpectedly high rate of resistance in the TDF study arm with M184V and K65R mutations, again without the K65R mutation appearing alone.
Summary : Since the beginning of HAART use, there have been some well-documented benefits in terms of morbidity and mortality. In the early days of HAART there was considerable anxiety over what the long-term consequences of metabolic toxicities might be, and whether these would abrogate the benefits of HAART. Recently, however, we have been gaining a clearer understanding about these questions, notably in pathogenesis findings, and how we can circumvent these toxicities. Also there have been a number of newer drugs coming out, which incorporate drug toxicity considerations early on in drug development. Here we will focus on class-specific metabolic abnormalities, and drug-specific effects within each class. NRTIs are associated with a higher risk of lipodystrophy/SC fat wasting, and within this class there is a hierarchy of conferred risk with d4T carrying the highest risk, followed by ZDV and lastly 3TC or ABC. PI-associated abnormalities include insulin resistance, increased triglycerides, increased LDL, VLDL, sHDL, and truncal obesity, and even within this class, different drugs are being found to have varying effects. Some recent pathogenesis findings will also be presented to further validate some of these claims.
Learning objectives : The participant will learn about class- and drug-specific risks for metabolic abnormalities in HAART, and will be exposed to new data reflecting the pathogenesis of some of these abnormalities:
- Lipodystrophy/ sub-cutaneous fat wasting is predominantly associated with NRTI use, with d4T conferring the highest risk, followed by ZDV, and then 3TC and ABC.
- PI-associated abnormalities include insulin resistance, increased triglycerides, increased LDL, VLDL, sHDL, and truncal obesity
- Research now reflects the validity hypothesis that NRTI (stavudine) therapy does cause mitochondrial depletion (Nolan D et al, 4th Lipo Workshopo, San Diego, CA), and subsequent cellular and tissue toxicity (fat wasting or fat loss) over time.
- The MITOX Study showed that a switch from d4T to ABC significantly improved fat wasting. These results are supported by the Tarheel (d4T switched to ABC or ZDV) and Perth Switching (d4T and/or PI switched to Combivir/ABC) studies.
- Switch studies show that this stavudine-induced mitochondrial depletion can be improved with ZDV or ABC (Nolan D et al, 4th Lipo Workshop, San Diego, CA).
- The risk of hyperlactatemia was found to be higher with d4T or ddI use compared to ABC use (John M. Curr Opin Inf Dis. 2002; 15:23-29).
- Certain host susceptibility factors exist predisposing to lipoatrophy, e.g. gender, race, and a TNF alpha polymorphism, TNF alpha G238A.
- NFV is associated with higher rates of hypercholesterolemia and hypertriglyceridemia compared to ABC, and NFV seems to have a synergistic effect with d4T in raising triglycerides (Kumar P et al. 9th CROI. 2002:abstract 33).
- The D:A:D Study showed that there was a 27% increased rate of MI per year over the first 7 years of HAART therapy.
- Switch studies from PI to NVP or ABC show favourable metabolic/insulin sensitivity and/or virologic effects, whereas an improvement in fat wasting was only seen in the switch from an NNRTI or PI-based regimen to Trizivir (TRIZAL Study).
Bibliographic references : John M, Mallal S. 2002. Hyperlactatemia Syndromes in People with HIV Infection. Curr Opin Infect Dis.15(1):23-9
"Dyslipidemias and Highly Active Anti-viral Therapy (HAART)" Dr. Greg Bondy (biography) English - 2003-03-30 - 32 minutes
Summary : Advances in anti-viral therapy have revolutionized the treatment of patients with HIV. These patients have a much greater life expectancy with a good quality of life. Unexpectedly, highly active anti-viral therapy (HAART) has induced a number of metabolic problems and this side effect of HIV therapy has been called the HIV metabloc syndrome. This syndrome is characterized by alterations in body fat distribution, dyslidipidemias, insulin resitance and most recently accelerated bone loss. Features of the dyslipidemia seen in this syndrome include severe hypertriglyceridemia, low HDL cholesterol and an elevation in the LDL cholesterol. This dyslipidemia pattern is extremely atherogenic and coupled with other factors present in HIV patients such as insulin resitance and vascular inflammation places these patients at increased risk for developing premature cardiovascular disease. Re-assuredly, the Veterans Affair HIV study (NEJM 348:702, 2003) showed that HAART therapy did not lead to increased rates of cardiovascular disease. This study is limited by the short mean duration of exposure of patients to HAART and the relatively young age of the cohort studied (< 10% greater than age 55). It remains to be determined if long-term treatment with HAART will lead to increase rates of vascular disease.
This presentation will review the assessment and treatment of the dyslipidemias associated with HAART therapy. Cardiovascular risk assessment included the use of traditional risk factors in Framingham tables and the utility of surrogate markers of cardiovascular disease such as apo B, C-reactive protein and B-mode carotid ultrasound. Treatment paradigms used at the St. Paul`s IDC HIV metabolic clinic were outlined and included ongoing studies examining the effectiveness of dietary and pharmacological treatment of patients with the HIV metabolic syndrome.
"Differences Among HIV Subtypes in Regard to Drug Resistance" Prof. Mark Wainberg (biography) English - 2003-03-30 - 29 minutes
Summary : HIV Drug resistance: Novel Mutational profiles in Non-Subtype B Infections
Despite the predominance and rising expansion of HIV-1 non-B infections (class A through J) worldwide, there is limited information on the effects of subtype genomic diversity on viral responses to antiretroviral therapy and on the development of resistance to these drugs. Non-B subtypes differ by 10-20% in the reverse transcriptase (RT) and protease (PR) genes, in addition to 30-40% sequence divergence in viral envelope genes. Indeed, recent studies have identified novel mutations in non-B clades that are not presently identified by current genotypic testing and virtual phenotypic algorithms. Moreover, differences in rates of replication, referred to as viral fitness, may have a considerable impact on both drug and development of resistance. An example is a previously unrecognized V106M mutation that is selected by efavirenz (EFV) among the clade C but not the clade B viruses. This is due to the fact that subtype C variants contain a valine codon 106 polymorphism (GTG) that facilitates a V106M transition (GTG ATG) after selection with EFV. In contrast, subtype, B viruses encode, V through a GTA codon at position 106 that is most likely to mutate to GCA (A), which encodes resistance to nevirapine (NVP). Moreover, the V106M but not the V106A substitution confers broad cross-resistance to all currently approved NNRTIs.
We have also compared the evolutionary potential of wild-type and M184V-containing variants of HIV-1 under conditions of selective drug pressure. To assess the effect of the M184V substitution on the development of resistance-associated mutations, we grew viruses of either subtype B or C origin, containing M184V or not, in the presence of amprenavir (APV) and efavirenz (EFV) in peripheral blood mononuclear cells (PBMCs). In all our selections, subtype C viruses showed a replicative advantage compared to subtype B viruses. For both subtypes B and C, we found a 5 to 7 week lag in development of phenotypic resistance to either APV or EFV in the M184V-containing viruses compared to their wild-type (WT) counterparts. Genotypic analysis revealed some differences in the resistance-conferring mutations in the different subtypes, and the appearance of these mutations was also delayed in the M184V-containing variants compared to viruses not containing M184V. These genotypic data are in agreement with previous studies showing that M184V does not limit the evolutionary potential of HIV. However M184V can influence the types of resistance-conferring mutations that arise in tissue culture selection for both subtype B and C viruses as well as the rapidity of accumulation of relevant resistance-conferring mutations.
"Learning to Live With ART - Managing Long-Term Tolerability" Dr. Mina John (biography) English - 2002-12-10 - 74 minutes
Summary : In the past 6 years or so there has been a widespread uptake of highly active antiretroviral therapy (HAART). Whilst that has brought a number of well-documented benefits, there's also been a number of chronic toxicities that have emerged in this time, notably a collection of morphologic and metabolic abnormalities, in particular, a slow, progresive form of subcutaneous fat wasting as well as a triad of metabolic abnormalities. To add to the entity of lactic acidosis and hepatic steatosis, we now know that there's a spectrum of clinical disorders associated with chronic elevations of blood lactate. Of course we still also have to deal with peripheral neuropathy, and drug hypersensitivity reactions. These problems have lately been driving our opinions on how to use HAART, for example using later treatments rather than earlier ones, using structured treatment interruptions (STIs) rather than chronic viral suppression, and so on. This presentation will show new data, in particular the pathogenesis studies which are coming out, showing what the pathological correlates of these clinical syndromes might be: for example, mitochondrial DNA depletion in tissues that might be relevant for fat wasting, for hyperlactatemia and for neuropathy, and endothelial dysfunction reflecting the vascular risk associated with these metabolic changes.. as well as host factors that might be important. All of this new information might help us as clinicians to face this challenge.
Learning objectives : The participant will be able to review newer data focusing on the pathology of clinical toxicity syndromes associated with HAART, for example conditions such as mitochondrial DNA depletion, fat wasting, hyperlactatemia, endothelial dysfunction, as well as host factors. These data will be discussed in an attempt to better understand how to use the current antiretroviral therapies available.
Bibliographic references : Hyperlactatemia syndromes in people with HIV infection.
John M, Mallal S.
Centre for Clinical Immunology, North Block Level 2, Royal Perth Hospital, Wellington Street, Perth, WA 6000, Australia. Mina.John@health.wa.gov.au
Hyperlactatemia associated with use of nucleoside analogue reverse transcriptase inhibitors (NRTIs) is not a single entity but a spectrum of abnormalities. The spectrum reflects varying degrees of derangement in systemic homeostasis in the face of primary drug effects on lactate load. Lactic acidosis, characterized by metabolic acidosis, blood lactate above 5 mmol/l, hepatic steatosis and high mortality, represents the extreme end of this spectrum where there is complete decompensation. Partially compensated states of lactate excess have now been described, ranging from less fulminant symptomatic hyperlactatemia with hepatic steatosis to chronic or intermittent low-grade hyperlactatemia without acidosis, steatosis or any symptoms. At a population level, average venous lactate concentrations do rise following treatment with NRTIs but stabilize long term in the majority of cases. The average increase in systemic lactate turnover that is required to maintain such compensated blood levels is not known and research into this may provide insights into the extent of incipient mitochondrial toxicity associated with chronic NRTI use. At a tissue-specific level, it is not known which tissues or organs (liver, fat, other) are the predominant contributors to an increase in systemic lactate load, nor whether the primary defect is one of increased production, decreased elimination or both.
Curr Opin Infect Dis 2002 Feb;15(1):23-9
"HAART as a potential risk factor for cardiovascular disease" Dr. Jens Lundgren (biography) English - 2002-11-17 - 27 minutes
"Prospective study of hyperlipidemia in ART-naïve subjects taking Combivir/abacavir (COM/ABC) vs. Combivir/nelfinavir (COM/NFV) vs. stavudine/lamivudine/nelfinavir (d4T/3TC/NFV): 48 week data" Dr. Princy N. Kumar (biography) English - 2002-04-26 - 37 minutes
Summary : Combination ARV regimens have been effective in suppressing viral loads, but are associated with long-term toxicities in some patients. The effect that PI- and non-PI-based regimens have on the development of hyperlipidemia, including lipodystrophy, is not fully known.
Gender-related differences in the development of HAART-associated
lipodystrophies are also unclear. In this talk, Dr Kumar presents 48-week data evaluating the development of hyperlipidemia as a component of the Fat Redistribution (FR) syndrome in ARV naïve subjects treated with a triple nucleoside regimen compared to two separate three-drug regimens each containing two nucleosides and a protease inhibitor. The study also takes into account gender differences.
Learning objectives : To evaluate the development of hyperlipidemia as a component of the Fat Redistribution (FR) Syndrome in antiretroviral-na?ve subjects treated with a triple nucleoside regimen compared to two separate three-drug regimens each containing two nucleosides and a protease inhibitor.
Bibliographic references : Murphy EL, Collier AC, Kalish LA, Assmann SF, Para MF, Flanigan TP, Kumar PN, Mintz L, Wallach FR, Nemo GJ; Highly active antiretroviral therapy decreases mortality and morbidity in patients with advanced HIV disease. Ann Intern Med 2001 Jul 3;135(1):17-26
"Mitochondrial Toxicity in the era of HAART" Dr. Julio Montaner (biography) English - 2002-04-26 - 23 minutes
Summary : Nucleoside analogues can induce mitochodrial toxicity through the inhibition of the human DNA polymerase gamma enzyme. This can lead to a wide range of clinical toxicities, from asymptomatic hyperlactaemia to death. We have recently developed an assay that can monitor changes in mitochondrial DNA(mtDNA) levels in peripheral blood cells. Using this assay, we have characterized changes in mtDNA relative to nuclear DNA (nDNA) in peripheral blood cells of patients with symptomatic nucleoside induced hyperlactataemia. Total DNA was extracted from blood cells derived from buffycoast. A nuclear gene and a mitochondrial gene were quantified by real-time PCR. Three groups of patients were assayed: i)HIV uninfected controls (N=24), ii) HIV infected asymptomatic and antiretroviral naïve (N=47), iii) HIV infected taking antiretroviral with symptomatic hyperlactataemia (N=8). The latter patients were studied longitudinally before, during and after antiretroviral interruption. Selected patients re-introduced antiretroviral therapy with d4T-sparing regimens. The decline in mtDNA preceded the increase in venous lactate levels.
More recentlys, we have evaluated the changes in mtDNA/nDNA in relation to various selected antiretroviral drug regimens in a population setting. To this end, we recently completed a cross-sectional study on a non-random sample of participant within the BC CFE Drug Treatment Program. Eligible patients had continuously received saquinavir plus ritonavir with either nevirapine (N=20), laminadine (N=15), stavudine (d4T)(N=53) or lamivudine plus d4T (N=69), for 4 to 30 months. Participants were included if a buffycoat sample collected between Aug 1998-Sept 2001 was available for testing. The mtDNA/nDNA ratio was measured using real-time PCR on the last sample collected during the observation period. We found that d4T-sparing regimens were associated with a higher median mtDNA/nDNA ratio than d4T-containing regimens (p=0.016). Furthermore, the mtDNA/nDNA ratio were skewed toward lower values for the d4T-containing regimens but normally distributed for the d4T-sparing ones. Of note, this was despite the fact that study patients had received d4T-containing regimens for a shorter median time than patients taking d4T-sparing regimens (13 vs. 25 months, p=0.002).
In conclusion, these results demonstrate that mtDNA levels are significantly decreased among patients who develop symptomatic, nucleoside related hyperlactataemia, an effect that was reversed upon therapy discontinuation. Furthermore, we demonstrated that mtDNA/nDNA ratios are statically significantly lower in d4T-containing regimens then in selected d4T-sparing regimens in a population setting. Of note, the latter results represent a conservative estimate of the magnitude of the effect of d4T-containing regimens on mtDNA/nDNA, due to a survivor bias effect in the d4T-containing cohort.
Learning objectives : The viewer will gain insights into the rapidly evolving field of mitochondrail toxicity research.
Random venous lactic acid (RVLA) as a monitoring tool.
Introduction to the mitochondrial DNA assay.
Mitochondrial toxicity is often associated with NRTI use.
Hyperlactemia is more often associated with d4T and HU, possibly other NRTIs.
Significance of lactic acidsis (LA) in HAART-treated patients.
"Emerging data regarding the effect of antiretroviral therapy on lipid profiles" Dr. Peter Reiss (biography) English - 2002-04-26 - 30 minutes
Summary : Access to combination antiretroviral therapy in industrialized countries has resulted in unprecedented reductions in HIV-associated morbidity and mortality. However, follow up of patients in clinical trials and observational cohorts has revealed a high rate of adverse events associated with current treatment regimens. A significant proportion of patients change their treatment regimen because of drug intolerance and/or toxicity within the first year of initiating treatment.
A common adverse effect, which occurs in at least 50% of patients, is the “lipodystrophy syndrome”. This syndrome is characterized by a disruption of normal fat and glucose metabolism resulting in hyperlipidaemia; glucose intolerance due to insulin resistance; and noticeable changes in body appearance as a result of an abnormal distribution of body fat. Subcutaneous fat is lost in the peripheral parts of the body (arms, legs, face, buttocks), while fat accumulation occurs in other parts (inside the abdominal cavity, dorsocervical, breasts). Although initially it was assumed that these changes were solely associated with use of protease inhibitors (PI), it is now clear that other classes of antiretroviral drugs, particularly the nucleoside analogue reverse transcriptase inhibitors (nNRTI), play a role. Host genetic factors and possibly HIV itself or the immune response against the virus may also contribute. Although certain components of the lipodystrophy syndrome are understood, the comprehensive pathogenesis of the syndrome remains unresolved. As a result, there is a paucity of therapeutic options to reverse the syndrome once it has developed. There is a growing concern that the syndrome, or at least certain of its components such as hyperlipidaemia, may be associated with an increased risk of developing premature atheriosclerosis and cardiovascular disease.
Currently available PI-containing regimens are associated with elevations in LDL-cholesterol and triglycerides, which are presumed to be deleterious to the patient. However, several studies have shown remarkable rises in HDL-cholesterol plasma levels in patients taking nevirapine-containing regimens, either as a 1st line regimen or to replace the PI component of a regimen. These increases in HDL-cholesterol plasma levels greatly surpass those observed with statins. Similar findings have been reported for efavirenz. The mechanism by which nNRTIs induce rises in HDL-cholesterol plasma levels remains to be elucidated. These lipid profiles, however, are in marked contrast to those associated with the use of PIs and would be expected to result in a reduced risk of (premature) atherosclerosis.
Learning objectives : The participant will be able to distinguish the effects of different kinds of antiretroviral therapy (ART) on the patient's lipid profile, e.g., the effects of NNRTIs versus PIs.
Conclusions of the FRAM and DAD studies.
"Mitochondrial Toxicity" Dr. Marianne Harris (biography) English - 2002-04-15 - 33 minutes
Summary : Nucleoside analogues compete with nucleosides, the natural substrate of human DNA polymerase gamma, which is the only enzyme responsible for the synthesis of mitochondrial DNA (mtDNA). The inhibition of this enzyme leads to depletion of mtDNA and thus of the proteins it encodes, including those involved in oxidative phosphorylation, resulting in impaired cellular energy production. This is the putative mechanism of several known toxicities of nucleoside analogues: myopathy, cardiomyopathy, peripheral neuropathy, pancreatitis, hepatic steatosis and lactic acidosis. In fact, it has been hypothesized that mitochondrial toxicity plays a role in virtually all nucleoside-related toxicities, including bone marrow suppression and lipodystrophy.
The most potentially serious of the nucleoside-related side effects attributed to mitochondrial toxicity is acute lactic acidosis with hepatic steatosis, which is often fatal. Milder increases in lactate levels have been observed chronically in approximately 10-20% of HIV patients receiving nucleoside analogues, and may be accompanied by symptoms such as fatigue, weakness, and weight loss. Chronic hyperlactataemia is seen more often in association with d4T and hydroxyurea; however, the relationship of this clinical syndrome to the fulminant form of lactic acidosis is unclear. The laboratory of the B.C. Centre for Excellence in HIV/AIDS (B.C. CfE) has recently developed an assay to measure the ratio of mitochondrial DNA (mtDNA) to nuclear DNA (nDNA) in peripheral blood cells. This assay was applied to three groups of patients: I) HIV uninfected controls (N=24), II) HIV infected asymptomatic, antiretroviral naive (N=47), and III) HIV infected taking antiretrovirals with symptomatic hyperlactataemia (N=8). The latter patients were studied longitudinally before, during and after interruption of antiretroviral therapy. Symptomatic hyperlactataemia was associated with markedly low mtDNA/nDNA ratios, on average 69% lower than HIV uninfected controls and 45% lower than HIV infected asymptomatic/antiretroviral naive controls. The decline in mtDNA preceded the increase in venous lactate levels. A significant increase in mtDNA/nDNA ratio was observed following discontinuation of antiretroviral therapy. The mtDNA/nDNA ratio remained stable in patients who re-introduced antiretroviral therapy with d4T-sparing regimens.
In order to evaluate differences in mtDNA/nDNA in relation to specific antiretroviral drug regimens, a cross-sectional study was performed using a non-random sample of B.C. CFE Drug Treatment Program participants. Eligible patients had continuously received saquinavir plus ritonavir with either nevirapine (N=20), 3TC (N=15), d4T (N=53) or 3TC plus d4T (N=69), for 4 -30 months. The mtDNA/nDNA ratio was measured from the last buffycoat sample collected between August 1998 and September 2001. Median mtDNA/nDNA ratios were significantly lower in patients receiving d4T- containing regimens than in those receiving d4T- sparing regimens, despite the fact that the median duration of the d4T-containing regimens was shorter than that of the d4T-sparing regimens (13 vs. 25 months, p=0.002).
In summary, mtDNA/nDNA ratios are significantly decreased in patients who develop symptomatic, nucleoside-related hyperlactataemia, and increase when antiretroviral therapy is interrupted. Furthermore, in a cross-sectional study, mtDNA/nDNA ratios are significantly lower in patients receiving d4T-containing regimens than in those receiving selected d4T-sparing regimens. This assay is being evaluated as a tool to monitor mitochondrial toxicity in HIV infected patients receiving nucleoside analogue-based antiretroviral therapy.
(Marianne Harris, Julio Montaner, Helene Côté, St. Paul's Hospital AIDS Research Program, Vancouver, B.C.)
"Interactions Among Drugs for HIV and Opportunistic Infections" Dr. Keith Gallicano (biography) English - 2002-04-15 - 30 minutes
Summary : Drug interactions are an important factor in the management and treatment of patients infected with HIV. In addition to their antiretroviral medications, patients may receive drugs for supportive care, opportunistic infections, and immunomodulation, as well as alternative medications obtained outside of their primary provider. Thus, interactions among these agents are often unavoidable. Most of these interactions are metabolic in nature as a result of alterations of cytochrome P450 (CYP) isoenzymes. All of the non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors are metabolized by CYP isoenzymes, and several are inhibitors and/or inducers of CYP. The nucleoside reverse transcriptase inhibitors (NRTI) are primarily eliminated by the kidneys and are not involved in CYP-mediated interactions. The role of membrane proteins that mediate the transcellular transport of drugs is now recognized in clinically significant interactions in infectious diseases. Inhibition and induction of membrane transporters such as P-glycoprotein (P-gp) and multiple-drug resistance-associated protein (MRP) that bind drugs can produce beneficial and detrimental interactions at sites where these transporters are located. For example, penetration of antiretroviral agents into HIV-1 reservoirs such as the central nervous system and male genital tract is important to control HIV penetration and evolution within these sites. Several protease inhibitors are substrates for and inhibitors or inducers of P-gp. Drugs such as ketoconazole increase exposure of ritonavir and saquinavir in cerebrospinal fluid by inhibiting CYP and P-gp at the blood-cerebrospinal fluid barrier. Both CYP and P-pg can present a barrier to the absorption of orally administered drugs and have a considerable effect on drug interactions. Drug interactions are often complex, time-dependent, and multidirectional. In HIV disease, interactions are complicated by their bi- or multi-directional nature, particularly when metabolic inhibitors, such as the protease inhibitors, and inducers, such as the rifamycins, are administered concurrently. Devising suitable dosing regimens for rifabutin in the presences of NNRTI and protease inhibitors has been challenging, especially for antiviral regimens that include ritonavir and lopinavir. Some agents such as ritonavir and some herbal products such as garlic are capable of acting as inhibitors during their initial dosing and as inducers during their extended therapy, which can question the relevance of single or acute dosing studies to multiple dosing conditions. This presentation will review clinically important beneficial and detrimental pharmacokinetic drug interactions in HIV therapy that occur between antiretroviral agents and other medications, and highlight the concerns that physicians have had from estimating the magnitude of drug interactions when inhibitors and inducers are given together, such as in the treatment and prevention of tuberculosis in HIV, or when the interacting drug has time dependent pharmacokinetics.
"Lipodistrophy and Related Issues" Dr. Stephano Vella (biography) English - 2002-04-15 - 25 minutes
Summary : The major metabolic abnormalities that complicate the management of HIV infection include serum lipid abnormalities, body fat maldistribution, dysregulation of glucose metabolism, lactic acidemia, and reduced bone mineral density. It has not been determined whether these observed changes are all components of a single syndrome related to HIV treatment or whether they have different etiologies. Concern has been expressed about long-term cardiovascular morbidity in subjects who experience increases in atherogenic serum lipids, insulin resistance/dysglycemia, and body fat redistribution, but at present this risk is undefined.
From a pathogenetic point of view, if these conditions are part of a single syndrome or represent distinct syndromes, and whether the etiology is unique or multifactorial remain unanswered questions. Predictors of fat redistribution syndromes are numerous and may include: age > 40 years, longer time since HIV diagnosis, longer time since nadir CD4+, NRTI use > 6 months, protease inhibitor use > 2 years, nadir CD4%, Body Mass Index loss > 1.0 kg/m2. Overall, etiology remains unknown; and appears to be multifactorial and influenced by ARV use and host factors.
Morphologic changes include both fat accumulation (lipohypertrophy: dorsocervical fat, visceral adiposity, breast enlargement) and fat loss (lipoatrophy: facial fat loss, subcutaneous fat loss of extremities). Morphologic changes have a substantial impact on quality of life Management approaches are largely empirical. Only few of them are based on short term controlled studies: antiretroviral therapy switches, exercise and diet, anabolic steroids, recombinant human growth hormone (rhGH), testosterone, metformin, tiazolidinediones and plastic surgery.
Lipid abnormalities are also frequent and varies by drug (even within the same class). Recommended initial evaluations includes baseline and fasting cholesterol (total, HDL, LDL, triglycerides) and the assessment of cardiovascular risk and lifestyle factors (family history, exercise, diabetes, smoking, obesity, alcohol use, comorbidities such as pancreatitis).
Dyslipidemia management approaches include the assessment of cardiovascular risk followed by dietary and lifestyle changes and, possibly, using lipid-lowering agents (statins, fibrates). The impact of the mofication of antiretroviral therapy is still under investigation, despite some short term favourable trial results (e.g. substitute NNRTIs for PIs or substitute abacavir for PIs). In conclusion, initial management approach should be lifestyle modification (diet, exercise). Lipid-lowering agents can be added as necessary (but beware of drug-drug interactions and toxicities). Switching to non-PI regimens may be most effective for triglyceride elevations, but long-term efficacy is unclear. Finally, cardiovascular sequelae are minimal short-term; but long-term outcome is unknown.
"Multiple Failure" Dr. Julio Montaner (biography) English - 2002-04-14 - 53 minutes
Summary : Triple drug therapy has led to a dramatic decrease in morbidity and mortality associated with infection by the Human Immunodeficiency Virus (HIV). Despite this, we continue to see substantial rates of virological failure. Given our understanding of the physiopathology of HIV disease, it is clear that this will lead to eventual CD4 decline and disease progression over a period of months to years. Every effort should therefore be made to try to abort this sequence of events. Rates of treatment failure are anywhere between 10-50% at one year after initiation of the first course of triple drug therapy.
It is now clear that rates of failure accelerate with successive rounds of treatment. The issue is aggravated by the presence of co-morbidities, such as HCV. Furthermore, the pre-existence of HIV resistance to antiretroviral therapies whether through primary resistance or acquired resistance, in the case of pre-treated patients, further aggravates this issue. Over recent years, we have become aware of the contribution of resistance testing to optimize the selection of antiretroviral agents. This is particularly useful in second and third line therapy. Unfortunately, the role of resistance testing is limited in patients with multiple failures because of the relatively limited menu of options available in terms of alternative drugs. More recently, we have been able to incorporate pharmacokinetic measurements to the evaluation of multiple drug rescue therapy. When taken together, pharmacokinetic profiles in combination with resistance testing allow for better characterization of the potential contribution of the given agent. While these concepts are certainly contributing greatly to the management of one and two class failures, things become increasingly difficult as patients present with three class failure and with high levels of resistance to all agents. Multiple drug rescue therapy has evolved as an important interim measure to prevent disease progression as well as further evolution of resistance. MDRT regimens have evolved over the last several years becoming more acceptable and better tolerater. Fortunately, new agents are coming to the front to assist in this task. Among them, T20, tenofovir, tipranavir, and the TMC line of compounds appear to be highly promising in this regard. As in other settings, physician experience and patient's adherence should be regarded as critically important in optimizing therapeutic response.
"Relating Resistance to Clinical Response" Dr. Veronica Miller (biography) English - 2002-03-08 - 50 minutes
Learning objectives : Further to this presentation, the participant should be capable to:
- Have a better understanding of the transmission of resistant HIV;
- Apply the interpretation of probation of the tests of resistance to the clinical treatment;
- Foresee a clinical answer based on the result of the test of resistance.
"A prospective study of body fat redistribution and Metabolic abnormalities in patient initiating HAART" Dr. Sharon Walmsley (biography) English - 2001-06-02 - 20 minutes
"Antiretrovirals And Hepatoxicity" Dr. Marianne Harris (biography) English - 2001-06-01 - 25 minutes
"Optimizing antiretroviral therapy-resistance and sequencing" Prof. Mark Wainberg (biography) English - 2001-06-01 - 45 minutes
"Nevirapine Related Hepatic Toxicity (A comprehensive safety analysys)" Dr. Julio Montaner (biography) English - 2001-06-01 - 25 minutes
"Update on HIV-1 Drug Resistance" Dr. Daniel R. Kuritzkes (biography) English - 2001-03-16 - 62 minutes
"Virological Failure on First-Line Antiretroviral Regimen: From Mechanisms to Clinical Implications" Pr. François Raffi (biography) English - 2000-06-19 - 45 minutes
"Mitochondrial Toxicity And HIV Therapy" Dr. Kees Brinkman (biography) English - 2000-04-28 - 105 minutes
"Benefits of Maintaining the M184V Mutation in Clinical Therapy of HIV Disease" Prof. Mark Wainberg (biography) English - 2000-04-27 - 41 minutes
"The Use of HIV Resistance Testing in Newly-Infected Individuals" Dr. Marty Markowitz (biography) English - 2000-04-27 - 33 minutes
"Mitochondrial Toxicity And HIV Therapy" Dr. Alex White (biography) English - 2000-04-03 - 59 minutes
USER ACKNOWLEDGES AND AGREES THAT ALL DECISIONS MADE WITH THE ASSISTANCE OR USE OF THE SOFTWARE AND/OR THE WEBSITE AND/OR BASED ON CONTENT FOUND HEREIN WILL BE EXCLUSIVELY THE RESPONSIBILITY OF THE USER.