The inequality between rich and poor nations in the treatment of HIVinfected people not only represents a moral scandal but has become a major economic political and social challenge that threatens world’s stability. A number of experts have assessed the obstacles to a faster access to treatment in the developing world and, for some, have advocated to favor prevention over treatment.
When highly active antiretroviral therapy (HAART) first became available in 1996, it represented the last hope for many thousands of people with a fatal disease. Compared to the threat of AIDS, side effects, as far as they were known at the time, appeared insignificant. Given the lack of alternative treatment in case of resistance the quest for primary efficacy dominated: your first chance was your only chance.
Several issues need to be considered when deciding whether to initiate therapy in a person with asymptomatic HIV infection. Concerns with delaying therapy have included: the risk of development of an AIDS defining disease; the possibility that the rate of virological failure (with its resistance-related consequences for future treatment options) is higher in those with higher viral load and/or lower CD4 count prior to therapy, and hence will increase with a delay; the possibility that there may be some irretrievable loss of immune capacity.
This session will discuss my diagnosis and the consequent evolution. Broadly this will include medical history (gastro-intestinal problems, hepatitis, etc.); virological situation today; most prominent personal fears and anxieties of starting therapy.
Although continuous HAART has resulted in a decrease in the mortality and morbidity rates associated with HIV infection in western countries, the utility of therapy is dampened by suboptimal activity, excess in toxicity, and inconvenience. Among 667 untreated patients from the Swiss HIV cohort, 126 had discontinued therapy as a consequence of treatment limitations.
Antiretroviral therapy changes the natural history of HIV infection, and this has resulted in dramatic improvements in HIV-related morbidity and mortality throughout the developed world. However, despite the current availability of 16 antiretroviral drugs approved for the treatment of HIV infection, current combination regimens have limitations.
Robert Murphy1, Alexandra Thiry, Marco Mancini2, Vadim Pokrovsky3, Willy Rozenbaum4
Atazanavir (ATV) is a potent, safe, and effective once-daily PI in phase III development. In BMS trial AI424-008, ATV demonstrated a lipid profile superior to nelfinavir (NFV) in treatment-naïve subjects. The objectives of BMS AI424-044 were to evaluate lipid profiles of subjects switched from NFV to ATV as well as ATV safety and tolerability.
Martin King, Kathryn Real, Scott Brun1Luc Perrin, Sabine Yerly2
Lopinavir (LPV), an HIV protease inhibitor, is co-formulated with ritonavir (r), which inhibits cytochrome p450 3A4, providing increased plasma levels of LPV. Long-term clinical trials of LPV/r in HIV-infected pts are ongoing.
Andrew Leigh Brown1, Simon Frost, Christopher Mathews, Douglas Richman, Susan Little2, Eric Daar3, Nicholas Hellmann4,
Effective combination therapy can reduce HIV transmission but the benefits are reduced by the selection and transmission of drug resistant strains. We analyzed treatment rates, response to antiretroviral (ARV) therapy and transmission of ARV-resistant HIV in San Diego from 1997 onwards, using an empirical epidemiological model to obtain projections of future trends.
SESSION 4:
ANTIVIRAL THERAPY IN RESOURCE POOR SETTINGS (ORGANISED BY THE INTERNATIONAL AIDS SOCIETY [IAS])
By the end of year 2001, it was estimated that 40 million people worldwide were infected with HIV. Over 80% reside in the resource-poor settings of which 28.5M are in sub-Saharan Africa. Since 1995 morbidity and mortality related to HIV-infection has been dramatically decreased in the developed world due to the use of antiretroviral drugs.
The World Health Organization (WHO) estimates that today, 6 million HIV-infected people in resource-poor settings are in immediate need of highly active antiretroviral treatment (HAART). However, only 230.000 are actually receiving the medicines and just 25.000 of them are living in sub-Saharan Africa.
Ernest Darkoh-Ampem, G Obita, D De Korte, P Mazonde
Botswana, with a relatively small population of 1.6-1.7 million, is in the unenviable situation of having the highest adult prevalence of HIV in the world (estimated 38.5% of the 15-49 age group). The Government of Botswana (GOB) therefore decided to provide anti-retroviral drugs (ARV Therapy) to all eligible citizens through the public health system to avoid human and economic losses of a devastating and unacceptable magnitude.
One of the most important clinical developments in the treatment of HIV infected patients in recent years is our understanding of the truly crucial significance adherence plays in the success of HAART. Although our initial efforts in implicating combination antiretroviral therapy focused almost entirely on the pharmacological and virological aspects of the compounds – we have now learned that drug taking behavior is perhaps the single most important element in the successful management of HIV infection.
Failure to achieve complete viral suppression by antiretroviral treatment is common in clinical practice, occurring at a high rate in many cohorts. The reasons for drug failure are multi-factorial but resistance to current medications is recognized to be an important element.
A Mocroft1, A Phillips, P Reiss, B Clotet, B Ledergerber, J Gatell, C Katlama, S Vella, N Clumeck, J D Lundgren2
The aims of this study were to determine the rate of virological rebound and factors associated with rebound among patients who initially responded to HAART by achieving undetectable levels of viraemia. Patients were followed from the date of initial undetectable viral load (<400, <200 or <50 copies/ ml), providing this occurred within 12 months of starting HAART, to the first of 2 consecutive viral loads above this level, or the date of last viral load measure.
L Bacheler1, H van Marck, T Maguire, T Van Den Bulcke, M P de Béthune, P LeCocq2
The VirtualPhenotype™. is an HIV-1 resistance analysis tool that provides a quantitative, data-driven assessment of drug susceptibility for all currently approved HIV antivirals based on viral genotype. The basis of this analysis is a large dataset (G/P dataset, currently >28,000) of HIV-1 clinical isolate genotypes and matching drug susceptibility phenotypes.
Animal studies have indicated that it is possible to abort HIV infection through the use of antiretroviral agents. Moreover, studies of mother-to-child transmission suggest that a substantial proportion of the benefits of antiretroviral therapy actually reflects post-exposure prophylaxis (PEP) provided to the neonate.
Franco Maggiolo, Annapaola Callegaro, Diego Ripamonti, Giampietro Gregis, Gianpaolo Quinzan, Claudio Arici, Laura Ravasio, Fredy Suter
Well tolerated compact regimens may limit the drawbacks of HAART due to the complexity of daily dosing schedule and to the occurrence of metabolic adverse events.
Nicola Gianotti, Alessandro Soria, Laura Galli, Daniela Vacchini, Massimo Cernuschi, Adriano Lazzarin
Treatment interruption (TI) in HIV-1 infected patients with virologic failure may lead to a shift from a drug-resistant to a wild-type predominant viral population in plasma. However, long-term response to re-initiation of therapy has not been reported. The objective of this study was to assess if a long-term virologic response could be achieved in this setting.
R Murri, A Cozzi Lepri, AP Phillips, E Girardi, G Nasti, S Ferrara, MS Mura, C Mussini, E Petrelli, M Arlotti, C De Stefano, P Vigano, L Gennero, B Salassa, G Antonucci, P Narciso, S Chigiotti, T Prestileo, R Novati, R Cargnel1, A D'arminio Monforte2
Possible differences between men and women in the natural history and in the clinical management of HIV infection have been described but with conflicting results. To assess the differences between genders in the likelihood of starting antiretroviral therapy (ART), in rates of sustained discontinuations from highly active antiretroviral therapy (HAART), and to establish whether a gender difference in survival exists.
On the basis of the recent advances in the characterization of HIV-1-specific CD4 and CD8 T cell immune responses, it is clear that the type of the immune abnormalities associated with HIV-1 infection are both quantitative and qualitative.
The investigation of novel and innovative treatment approaches for long-term management of HIV-infection has intensified due to the growing number of infected individuals worldwide and the constraints of resistance, toxicity and convenience associated with lifelong therapy. Current treatment relies entirely on antiretroviral drugs targeting various stages of the life cycle of HIV, rather than on leveraging the immune system.
Susan Hopkins, Gillian Farrell, Fiona Lyons, Fiona Mulcahy, Colm Bergin
Morbidity and mortality related to HIV infection has significantly decreased due to the introduction of highly active antiretroviral therapy (HAART). However, morbidity associated with Hepatitis C (HCV) is increasingly affecting the HIV/HCV co-infected cohort.
Krishnan Bhaskaran, on behalf of CASCADE collaboration
Following the introduction of potent antiretroviral therapy in the mid-1990s, the incidence of non-Hodgkin lymphoma (NHL) did not appear to drop as dramatically as other AIDS diseases. We aimed to investigate whether the risk of NHL has changed more recently, and to assess the importance of current and nadir CD4 cell count and other prognostic factors in predicting an NHL diagnosis, thus determining whether early initiation of therapy may be warranted in certain groups.
The use of therapeutic drug monitoring (TDM) has received an increasing amount of interest during the last years. Some national guidelines (e.g. France, United Kingdom, The Netherlands) have now included TDM as part of diagnostic set up for a patient, but development of TDM in other countries still in its infancy.
Patrick Hoggard, Emma Meaden, John Tjia David Back, Saye Khoo, Phillippa Newton, Ian Williams, David Cornforth, Diane Aldam
HIV protease inhibitors (PIs) are substrates for the drug efflux transporters P-glycoprotein and multidrug resistance-associated protein. Inter-individual variation in the expression of these two transporters may therefore affect intracellular PI accumulation in vivo
Jennifer Ford, Rhiannon Meaden, Patrick Hoggard, Saye Khoo, David Back
Increased expression of the efflux transporters P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) has been suggested as a potential mechanism for decreased protease inhibitor (PI) availability at certain intracellular sites, providing sanctuary for HIV.
Jacques Grassi, François Becher, Alain Pruvost, Dimitri Schlemmer, Christophe Créminon, Henri Benech, Cécile Goujard, Jean-François Delfraissy
Nucleoside reverse transcriptase inhibitors (NRTIs) are anabolised intracellularly to their known corresponding active triphosphate (TP). This intracellular anabolism plays a critical role regarding both their efficacy and toxicity.
JA Gogtay, V Manek, VG Nayak, PV Bodhe1, A Dasgupta, V Srivatsan, G Vaidyanathan, KC Patel2
The most important factor determining virologic success in HIV therapy is patient adherence. In the last few years efforts have being made to improve adherence by the introduction of newer agents with reduced frequency of pill administration and fixed dose combination products. One such product introduced was Trizivr, which contains 3 NRTIs viz. zidovudine, lamivudine and abacavir.
HIV infection itself induces multiple metabolic abnormalities: e.g. increases in resting energy expenditure and lipolysis, while glucose metabolism is characterized by increased insulin sensitivity. Combination antiretroviral therapy including protease inhibitors for the treatment of HIV-1-infected patients has been associated with the development of a fat redistribution syndrome, which may include both central fat accumulation and peripheral fat wasting.
Whether anti-HIV drugs accelerate the atherosclerotic process and thereby enhances the risk of coronary heart disease (CHD) and stroke remains a controversial question. Drugs from all three classes may increase the plasma concentration of cholesterol, LDL-cholesterol and triglycerides.
Lipodystrophy (LD; peripheral lipoatrophy, central fat accumulation, and lipomatosis) is a common, disfiguring but ill-defined problem in HIV-infected patients receiving antiretroviral therapy that is associated with sub-optimal antiretroviral adherence.
In Europe, it is estimated that approximately 30% of HIV-infected individuals are coinfected with HCV. HCV coinfection is even higher (50% to 90%) among high risk groups such as intravenous drug users and hemophiliacs.
Hepatitis B virus (HBV) infection is common in HIV-positive individuals, due to shared routes of transmission of both viruses. Chronic HBV infection (as defined by positivity for serum HBsAg) affects overall 8% of HIV-positive persons in western countries. As HBV causes liver damage through an immune-mediated mechanism, the immunodeficiency produced by HIV is associated with a reduction in aminotransferase levels despite an enhancement in HBV replication.
Vaccination is an excellent and easy way to protect individuals against a variety of infectious diseases. Whether vaccination is beneficial for the individual depends on the incidence of the relevant disease, the rate of protection induced by the vaccine and the potential side effects of the vaccination.
Advances in the management of HIV in pregnancy have lead to large reductions in the mother-to-child transmission (MTCT) rate in countries where these interventions are accessible. Clinical trials and a number of observational studies have shown that overall rates can be reduced to below 2%.
Tolerance of perinatal antiretroviral prophylaxis remains to be assessed on a large scale and in the long term. The possibility of mitochondrial toxicity remains contested.
In England, recent increases in the rates of sexually transmitted infections (STI), coupled with the emerging outbreaks of infectious syphilis, have drawn attention to the need for improving the sexual health of HIVpositive individuals.
C Pradier, E Fontas1, C Sabin2, N Friis-Møller, JD Lundgren for the D:A:D study group3, R Weber4, P Reiss5, A d'Arminio Monforte6, O Kirk7, R Thiebaut8, L Morfeldt9, G Calvo10, M Law11, G Bartsch12, S De Wit13
To compare the impact of the various individual PIs and PI combinations on dyslipidaemia. Baseline risk factors for the development of cardiovascular disease (CVD) were collected on 17,852 HIV-patients from Europe, USA and Australia, enrolled in DAD, a prospective cohort study assessing risk of CVD, established in year 2000.
Luis Caldeira1, Celia Carvalho1, Emilia Valadas1, Luis Tavares1, Alexandra Zagalo e Melo1, Alvaro Pereira1, Nelson Duarte1, Alice Ribeiro1, Nidia Garrido1, Patricia Pacheco1, Francisco Antunes1, João Cruz2, Pedro Aguiar3
Antiretroviral compounds from the NNRTI group have been associated with the occurrence of hepatic toxicity. However, large studies evaluating the comparative incidence of liver toxicity of nevirapine and efavirenz, especially in the subset of patients with HBV and/or HCV co-infection, are scarce and contraditory.
Graeme Moyle1, Eric Daar2, Joseph Gertner3, Donald Kotler4, Jean-Claude Melchior5, Fanny O'brien3, Elisabeth Svanberg6
Wasting with lean body mass (LBM) loss is a major complication in AIDS. Although prevalence has fallen, wasting remains a chronic debilitating, life-threatening condition.
Recent years have seen an increased risk of bone problems emerge as a potential long-term problem for HIV-infected individuals. Two issues in particular seem to be relevant and different: an apparent increased rate of osteonecrosis and an apparent increased risk of developing osteopenia and osteoporosis.
NRTIs act as false nucleoside substrates for Polymerase-g, which mediates mitochondrial DNA synthesis, and this may result in NRTI-related DNA depletion and clinical manifestations of mitochondrial dysfunction.
Experts in drug safety monitoring from the academic, government, and industry sectors held a workshop with research clinicians specializing in HIV in April of this year to review the relevance of ‘standard’ monitoring procedures for long-term drug safety to HIV.
S López, Ò Miró, F Cardellach, A Beato, J Casademont1, M Garcia, E Martínez, A Milinkovic, Jl Blanco2, A Soler, E Pedrol3
Nucleoside reverse transcriptase inhibitors (NRTIs) are being increasingly associated with mitochondrial (MT) toxicity. We aimed to assess MT content and function in peripheral blood mononuclear cells (PBMCs) of HIV-infected patients previous to the development of clinically evident body fat changes.
Ò Miró, S López, E Martínez, F Cardellach, J Casademont, J M Gatell1, E Pedrol, A Soler2, B Rodríguez-Santiago, V Nunes3
To simultaneously evaluate mitochondrial DNA (mtDNA) content and mitochondrial respiratory chain (MRC) function in peripheral lymphocytes of HIV-infected patients who had developed lipodystrophy (LD) while on highly active antiretroviral therapy (HAART).
Anna-Maria Bauer, Johannes Bogner, Sophia Horster, Mirjam Schunk, Thomas Sternfeld, Frank-D Goebel
Prognosis of lactic acid (LA) increase is still uncertain. While asymptomatic elevation is thought to be of little significance, lactic acidosis still has a high mortality. Our objective was to determine kinetics of LA in order to test whether the metabolic capacity of lactate degradation is influenced by HAART and baseline LA levels.
Joep Lange1, A Lazzarin2, B Clotet3, D Cooper4, J Reynes5, K Arasteh6, M Nelson7, C Katlama8, H-J Stellbrink9, J-F Delfraissy10, J Chung, M Salgo, on Behalf of The TORO 2 Study Group11, R Demasi, J Delehanty12
Enfuvirtide (T-20; ENF) is the first in a new class of HIV antiretrovirals, the fusion inhibitors, which targets HIV gp41 and blocks the virus from entering the host cells. The phase III study TORO 2 (T-20 vs Optimized Regimen Only) was conducted in Europe and Australia. Patients with ≥ 3 months prior experience with three classes of ARVs, and HIV-1 RNA ≥ 5,000 copies/mL selected an optimized background (OB) regimen of three to five ARVs based on prior history and BL genotypic and phenotypic viral resistance.
D Schürmann1, J Gathe2, I Sanne3, R Wood4 on behalf of the SOLO Study Team
GW433908 (908) is a new protease inhibitor, with a well characterised distinct resistance profile, and the potential for once daily dosing (QD) when combined with low dose ritonavir (RTV). SOLO is a randomised, open-label study in ART-naïve subjects comparing the efficacy and safety of 908/RTV QD vs nelfinavir (NFV) BID over 48 weeks.
Ulrik Bak Dragsted1, J Gerstoft2, M Youle2, A Duran2, D TJayaweera2, A Rieger2,J NBruun2, A Castagna2, SWalmsley2, Z Fox2, A Hill2, J D Lundgren1,2
Few comparative data exists on the efficacy and safety of ritonavir(r)-boosted protease inhibitor regimens in the average HIV-1 infected population seen in out-patients’ clinics.
Anton Pozniak1, Schlomo Staszewski2, Joel Gallant3, Jamal Suleiman4, Edwin DeJesus5, Adriano Lazzarin6, San Tran, Biao Lu, Andrew Cheng, Dion Coakley7
TDF is a single tablet, once daily nucleotide analogue reverse transcriptase inhibitor with potent activity against wild-type and nucleoside resistant HIV. Prior studies have demonstrated significant and sustained anti- HIV activity when TDF was added to stable background ART in treatmentexperienced patients.
Ana Barrios, Teresa García-Benayas, Carmen De Mendoza1, Miriam Garrote, Luz Martín-Carbonero, Angélica Corral, Vincent Soriano1, Pere Domingo2, M José Galindo3, Juan Gálvez4, Vicente Estrada5, David Dalmau6, Víctor Asensi7
Tenofovir disoproxil fumarate (TDF), the first approved nucleotide analog (NtRTI), has shown a potent antiviral effect (mean reduction in plasma HIVRNA of 0.6 logs in pretreated patients) in clinical trials. TDF potency seems to be compromised when nucleoside-associated mutations (NAMs) are present, particularly 41L and/or 210W.
B Kearney, S Liaw, K Yale, S Hayashi, H Namini, J Wolf, D Coakley, J Flaherty
Tenofovir is eliminated by the kidney by both glomerular filtration and active tubular secretion. The pharmacokinetics (PK) of tenofovir are expected to be altered in subjects with clinically significant renal insufficiency.
Kit Simpson, E Chumney1, Michelle Luo, Barry Bernstein, Eugene Sun, Talat Ashraf2
Selecting the optimal treatment regimen for antiretroviral (ARV)-naïve patients may be difficult, given the concern about the antiviral activity, the development of drug resistance and the increase in drug costs. This study was undertaken to evaluate the costs and effectiveness of using lopinavir/ritonavir (LVP/r) vs. nelfinavir (NFV) as the first HAART regimen in treating HIV patients, based on the results from the recently published clinical trial ABTM98- 863.
D Bánhegyi, Z Gerlei, J Szlávik, Z Jánosi, E Ujhelyi
The ABT-378/r European Early Access Program was initiated in Hungary in November 2000 and between this date and December 2001 22 patients (pts), heavily pretreated with antiretrovirals (ARs) limited treatments options with viral failure were included.
Beatriz Díaz, Luz Martín-Carbonero, Carmen de Mendoza, Vicenç Soriano1, Pere Domingo2, María de los Angeles Lozano, María Jesús Téllez3, Jose Carmena4, Jose Sanz-Moreno5, María Leyes6
The aim of this research is to study treatment with Lopinavir in patients outside clinical trials and having failed on drugs from all classes.
J L Andrade Neto1, A Soto2, E Sprinz3, S Green4, M P Luo, R Rode, R L Tressler for the M00-267 Study Group5
A significant number of virologically stable, HIV-infected subjects experience mild-to-moderate side effects (SEs) related to the NNRTI or PI in their antiretroviral (ARV) regimen. Lopinavir/ritonavir (LPV/r) is generally well tolerated, and has demonstrated durable virologic suppression. However, it is unclear whether substituting LPV/r for the NNRTI/PI will alleviate the SEs and improve quality of life (QOL).
Mona Loutfy1, Courtney Thompson, Colin Kovacs, Anita Rachlis, Sharon Walmsley2, John Goodhew, Gary Rubin3
Current research efforts are focused on simplifying drug regimens to improve adherence and quality of life. Simplification strategies have included replacing the protease inhibitor (PI) component with lopinavir/ritonavir (LPV/r). We previously noted that such patients (pts) had an increase in their CD4c cell count. The purpose of the present study is to determine whether the CD4c increase was related to the LPV/r or was it a function of a pts’ improving immune status prior to the switch.
Michelle Luo, Robert Boggs, Barry Bernstein, Eugene Sun, Talat Ashraf
The ABT-M98-863 trial (double blinded, randomized) compared clinical outcomes of lopinavir/ritonavir (LVP/r) vs nelfinavir (NFV) plus d4T/3TC in 653 antiretroviral (ARV) naïve subjects.
Alan Landay1, John Spritzler2, Harold Kessler1, Donna Mildvan3, Minya Pu2, Lawrence Fox4, Daniel Kuritzkes5, Michael Lederman6
There still is substantial controversy in the field as to whether PI containing regimens offer a selective advantage over NRTI containing regimens regarding their level of functional immune reconstitution.
S Staszewski, B Dauer, P Gute, A Carlebach, A Haberl, S Klauke, M Mösch1, A N Phillips2
Based on data from controlled clinical trials, there is some concern about the activity of abacavir/zidovudine/lamivudine (ABC/AZT/3TC) in therapynaïve patients with a baseline viral load greater than 100,000 copies/ml.
Nelfinavir (NFV) and indinavir (IDV) are the most prescribed PIs. IDV combined with ritonavir (RTV) 100 mg bid is usually prescribed at the dose of 800 mg bid but recent pharmacokinetic data have shown that IDV 400 mg bid presents a good PK profile and provides a better tolerance.
The purpose of this study was 1) to follow changing trends in starting antiretroviral therapy (ART) between 1995 and 2001, 2) to evaluate sustainability of the initial ART over time, 3) to determine reasons for stopping/changing initial ART and 4) to compare PI- vs NNRTI-based therapy.
R A Seaton, R Fox, N Bodasing, S Peters, Y Gourlay
There are few data describing the use of co-formulated zidovudine, lamivudine and abacavir (Trizivir) in patients with AIDS. There has been concern that such therapy may be sub-optimal for patients with advanced disease.
To relate the outcome of our treatment model to outstanding problems in treated and treatment naïve patients and as a basis for discussion on allocation of resources for further improvement.
To determine the efficacy and tolerance of saquinavir (SQV) 3,600mg/d plus two nucleoside analogues in the treatment of naïve HIV-positive patients at 24 months.
To determine the efficacy and tolerance of saquinavir 1,800mg/d for intensifying the response of two nucleoside analogues in the treatment of non-naïve HIV-positive patients at four years.
George Chrysos, Androula Pastelli, Anastasios Visvikis, Stamatina Anagnostopoulou, George Lepeniotis, Panagiota Spyropoulou, Maria Dimou, Maria Papanocolaou
Highly Active AntiRetroviral Therapy (HAART) has dramatically reduced morbidity and mortality in HIV infected patients. However, with increasing concerns about toxicity and adherence, structured treatment interruption (STI) trials are not uncommon since STI may boost anti-HIV specific immunity.
A 49-year-old Zairian woman presented with a seven day history of headache, fever, lower back pain and general malaise 14 days after stopping her antiretrovirals (indinavir 800mg bd, ritonavir 100mg bd, lamivudine 150mg bd, zidovudine 300mg bd) at the start of a drug holiday.
Jan Gerstoft1, Ulrik Bak Dragsted2, Pedro Cahn3, Antonella Castagna4, Adriana Duran5, Andrew Hill6, Court Pedersen7, Barry Peters8, Pietro Vernazza9, Mike Youle10, Jens D. Lundgren on behalf of the MaxCmin1 Trial Group 2
Previous studies have claimed superiority of a ritonavir (r)-boosted protease inhibitor (PI) regimen. However, only a head-to-head comparison - of which this is the first - can reliably assess possible differences in r-boosted PI regimens.
Jean-Guy Baril1, Benoit Trottier2, Roger Leblanc3, Jim Lin4
Limited experience exists for once daily SQV 1600 mg plus RTV 100 or 200 mg (SQVr QD) based regimen as switch therapy especially in patients who have prior antiretroviral therapy (ART) failure.
Remko Van Leeuwen, on behalf of the 2NN Study Group
Nevirapine (NVP) and efavirenz (EFV) are non- nucleoside reverse transcriptase inhibitors (NNRTIs) that have demonstrated potency, safety, and convenience in separate clinical trials. As a result, they are frequently used as the basis of highly active antiretroviral therapy (HAART) for management of treatment-naïve patients.
Jean-Francois Delfraissy1, Antonio Rivero2, Alexey Yakovlev3, Kathleen Squires4, Alexandra Thiry, Michael Giordano, for the AI424-034 International Study Team5
Atazanavir (ATV) is a potent, safe, once-daily PI that has a distinct resistance profile, rapidly suppresses HIV RNA, increases CD4 cells, and provides superior lipid profile to other PIs. Efavirenz (EFV), a potent, once-daily NNRTI, is a standard of care in antiretroviral (ARV)-naïve patients.
A Holmes, F McGlynn, L McCullagh, S Hopkins, F Mulcahy
Treatment simplification to AZT/ 3TC/ ABC has been shown to maintain efficacy and improve metabolic parameters in several trials. Lower pill burden is postulated to increase the likelihood of adherence.
Franco Maggiolo, Claudio Arici, Laura Ravasio, Annapaola Callegaro, Giampietro Gregis, Gianpaolo Quinzan, Diego Ripamonti, Fredy Suter
Well tolerated compact regimens are required to overcome the drawbacks of HAART and its limits due to the complexity of daily dosing schedule and to the occurrence of metabolic adverse events.
Alain Lafeuillade, Patrick Philibert, Philippe Halfon, Gisele Philip, Veronique Lambry, Patricia Jolly, Marie Emmanuelle Mars-Kallee
Triple drug therapy containing either a PI or 3 NRTIs is recognized as the standard of care for HIV-1 infection. Although similar rates of undetectable viremia are obtained with these 2 regimens in naïve patients, it is not well known what are the differences in potency in terms of residual HIV-1 replication when plasma viral load is controlled.
Enfuvirtide (ENF, T-20), a HIV-1 fusion inhibitor, added to optimized background (OB) regimen provides additional viral suppression compared to OB alone in highly antiretroviral-experienced patients.1 A Markov model was developed to predict the relative clinical prognoses of patients receiving ENF + OB or OB alone from changes in virological and immunological response found in a Phase III trial (TORO 1; T-20 vs. Optimized Regimen Only).
Giuseppina Liuzzi, Mauro Zaccarelli, Simone Topino, Alessandra Amendola, Daniela Zinzi, Mariarosaria Capobianchi, Pasquale Narciso, Carlo Federico Perno, Andrea Antinori1
The efficacy of sexual transmission of HIV primarily depends by the concentration of infectious virus in semen. In order to evaluate the effectiveness of a widely used antiretroviral regimen in reducing HIV viral load in male seminal fluid, we quantified HIV-RNA in semen of HIV patients in treatment with a combination regimen including two nucleoside reverse transcriptase inhibitors and efavirenz (EFV).
C Sabin, C J Smith, M Youle, F Lampe, M A Johnson, A N Phillips
Although albumin is a strong predictor of mortality over both the short and long-term [1,2], little is known about the factors associated with albumin levels or how levels change in those on HAART. The aim of this study was to describe albumin levels in 101 patients who started HAART (n=23) or switched a PI or NNRTI (n=78) between October 2000 and June 2001.
George Perez, Rodger Macarthur, John Baxter, Chris Mullin, Barry Schmetter, James Neaton, Sharon Walmsley
This study was designed to compare the long-term clinical efficacy and toxicity of nelfinavir (NFV) or ritonavir (RTV) in patients with CD4+ cells below 200/mm.
To describe the survival of patients with HIV in Edinburgh following the introduction of highly active antiretroviral therapy (HAART). Method Analysis of prospectively collected data from an ongoing observational cohort.
Rosario Palacios, Josefa Ruiz, Mercedes González, Manuel Márquez
To analyse the evolutive features of a cohort of patients with a late stage of HIV infection diagnosed in the HAART era and to study the efficacy of HAART, associated complications and healthcare resource utilization.
Shlomo Maayan, Tania Goslitzer, Ran Nirpaz, Michelle Haouzi1, Klaris Riesenberg, Michael Alkan, Fransic Schlaeffer2, Hewott Nagusa3
To compare the response to HAART in 2 groups of Ethiopian immigrant patients infected by HIV-C and followed at two clinics in Israel, and in one group of non-Ethiopian, non-immigrant patients, infected by HIV non-C. To assess lipid derangements in the study groups.
This study was conducted to assess the experience of twice daily injections of enfuvirtide in patients in two ongoing multinational Phase III trials (TORO 1 and TORO 2) at 24 weeks.
Nuria Camino, Rosa De Julián, Pablo Barreiro, Vicente Soriano, Juan González-Lahoz1
The potency, good tolerance and simple administration of NNRTIs makes them suitable for second-line drugs after PI therapy. The NNRTIs have been proved to add efficacy to rescue interventions, and to sustain treatment success in simplification strategies. In this context, little is known on the comparative performance of the two available NNRTIs (NVP and EFV).
Brian Conway, Salima Jutha, Michelle Jones, Jennie Prasad, Amanda Roze Des Ordons, Robert Reynolds, John Farley1, Nadine Smith, Annabel Mead, Stanely De Vlaming2
DLV is a non-nucleoside reverse transcriptase inhibitor (NNRTI) whose specific role in therapy remains undefined. The fact that it is an inhibitor of CYP3A4 and CYP2D6 may make it useful to increase the concentration of protease inhibitors (PIs) in combinations to be prescribed to previously treated patients and to avoid the need to increase methadone (MET) doses in IVDUs receiving HAART.
There is concern that long-term benefits of HAART can be threatened by incomplete control of HIV viraemia caused by drug resistance of HIV, adverse effects and poor adherence. Our aim was to find out how plasma viral loads evolved over time among our patients on HAART.
S Das1, A Joseph2, V Harindra, M Browning3, K Yoganathan, J Tobin4, A Wade, P S Allan5
Nevirapine, a non-nucleoside analogue, has demonstrated suppression of Human immunodeficiency virus (HIV) replication alone and in combination therapy. However, the durable suppression of HIV with nevirapine when used along with other nucleosides in HIV-infected patients needs further evaluation.
Highly active antiretroviral therapy with a protease inhibitor (PI) is widely used. Due to metabolic side effects and impaired adherence caused by high pill burden, there is a desire to switch to a PI-free regimen. The aim of the study was to assess the virological and immunological status of HIV-1 infected adult out-patients during one year of HAART including nevirapine (NVP).
Giorgio Gatti, Cleta Raffaella De Pascalis, Andrea De Luca, Antonio Di Biagio, Patrizia Zucchi, Renato Maserati, Laura Trentini, Stefano Bonora, Paola Meraviglia, Dante Bassetti1
The study objectives were to evaluate (a) possible predictors of virologic and immunologic outcome and (b) the relationship between virologic and immunologic outcome in deep-salvage HIV-positive patients receiving an amprenavir (APV)-containing regimen.
R Bucciardi, V Fragola1, R L Goodall2, B Conway, D Churchill, A Mijch, A Orani, M Schechter, J Weber, on behalf of the INITIO Co-ordinating Committee3
INITIO is a large randomised trial in progress, designed to evaluate three different therapeutic strategies using combinations of the three classes of anti-retroviral drugs. 913 antiretroviral therapy (ART) naïve individuals from 17 countries have been enrolled, of whom 148 individuals from 5 countries (Australia, Brazil, Canada, Italy, UK) are participating in a Quality of Life (QoL) substudy.
Jean-Michel Livrozet1, Nora Berra, Jean-Louis Touraine2, Isabelle Ravaux3, Lise Cuzin4, Elisabeth Bouvet5, Jean-Pierre Stahl6, David Rey7, Bruno Hoen8, Renato Fiore9, Elisabeth Rouveix10 Jean-Pierre Bru11 Pascal Chavanet12
Post Exposure Prophylaxis (PEP), using two nucleoside reverse transcriptase inhibitors (NRTIs) and one protease inhibitor (PI), is recommended in France since 1998, but side effects adversely affect adherence.
Jean-Marie Ragnaud1, Benedicte Delmas2, Herve Gallais3, Dominique Peyramond4, Henri Laurichesse5, Pierre Dellamonica6, Jean-Luc Pellegrin7, Thierry Allegre8, Nathalie Audebert9, Jacques Reynes10 on behalf of InfectioSud group
To evaluate efficacy and safety of switch to Trizivir (TZV) at week 24 in HIV-1 infected patients (pts) initially treated with a quadruple therapy.
Louis Lupo, Jen-Fue Maa, Christopher Dezii, Deena Said, Laura Bessen, Sally Hodder1
Racial differences in the efficacy of drug therapy have recently been described. This post-hoc subgroup analysis investigates time to virologic and treatment failure among various racial groups in a multinational clinical trial.
To evaluate the efficacy, immunological outcome and safety of an amprenavir/ritonavir containing regimen in PI-pre-treated patients in routine clinical practise.
Pompeyo Viciana1, Rogelio Perez2, José Hernández Quero3, Jose Juan Hernández Burruezo4, Pablo Labarga5, Antonio Vergara6. and the NNIP Study Group
NNRTI therapy is currently used very frequently, however there is no information from clinical trials that describe how these treatments can be salvaged. The objective of this study was to obtain information about the NNRTI salvage with PI’s (nelfinavir 1.250 mg bid in PI naïve patients failing NNRTI and saquinavir/ritonavir 1.000/100 bid in PI experienced patients failing NNRTI).
Andrew Owen, Patrick Hoggard, Saye Khoo, Anthony Hart, David Back1, Patrick Bray, Stephen Ward2
The need for low cost alternatives in HIV therapy has led us to examine the antiviral potential of a range of antimalarial agents. Chloroquine (CO) has recently been shown to have in-vitro activity against HIV at clinically achievable concentrations, possibly by a post-integrational mechanism.
Juultje van den Berg1, E Hak2, I M Hoepelman, C A Boucher, M M E Schneider3
It has been suggested that HIV-infected patients from resource-poor (non-European) countries have a higher risk of treatment failure than their European counterparts. We compared early and late phase failure to highly active antiretroviral therapy (HAART) in both groups.
Roberto Manfredi, Leonardo Calza, Francesco Chiodo1
The immigration towards Italy is a recent phenomenon, but it brought to our attention patients (p) coming from areas which are highly endemic for HIV infection, or were exposed to HIV after their arrival in our country, due to the poor economic, social, and healthcare conditions of novel immigrants.
Roberto Manfredi, Leonardo Calza, Francesco Chiodo1
Saquinavir hard-gel was never assessed as a part of a de-intensification therapy in patients who had a prolonged favourable response to protease inhibitor-containing potent HAART. We present a prospective survey of saquinavir hard gel-naïve patients who resorted to saquinavir hard-gel plus two nucleoside analogues after interrupting indinavir-, ritonavir-, or nelfinavir-based HAART which achieved a viremia below 50 copies/mL since 3-6 months, and refused other HAART regimens.
Roberto Manfredi, Antonio Gramegna, Ginevra Marinacci, Leonardo Calza, Lorenza Fortunato, Marina Tadolini, Gabriela Salvucci, Simona Varani, Francesco Chiodo, Franco Bocchi1
In order to analyze the features of patient population referring to the day hospital service of our infectious diseases division, all hospitalizations carried out from the year 2000 to the first six months of the year 2002 have been assessed according to discharge diagnosis, days of hospitalization, diagnosis-related group (DRG) score, and mean number of admissions per patient.
Roberto Manfredi, Leonardo Calza, Francesco Chiodo1
The emergence of resistance, problems related to patients’ adherence, and short- and long-term toxicity, represent the most relevant causes of antiretroviral therapy failure. In patients who received a long-term prior anti-HIV treatment, a combination between multiple genotypic resistances and severe drug intolerance may make extremely difficult the selection of a combination antiretroviral regimen which is expected to be concurrently effective and safe.
Roberto Manfredi, Leonardo Calza, Francesco Chiodo
Aim of our survey is to compare the healthcare resource consumption (including the progressively increasing administration of HAART, and the use of other prescription drugs and therapies for HIV disease management), with the trend of the major end-points of HIV disease progression (AIDS notification and mortality index), in a nine-year-long monitoring of our cohort of around 1000 patients, in order to give an estimate of the balance between economic features and evolution of clinical care of HIV disease.
Y R Sitdykova, A V Kravchenko, V V Beliaeva, V V Serebrovskaya, A G Gurgenov, A Y Pronin, V V Pokrovsky1
To evaluate safety and efficacy of regimen with saquinavir SGC (FTV, Fortovase), ritonavir (RTV, Norvir), didanosine (ddI, Videx) and phosphazid (Nicavir, monophosphanat of AZT) in HIV-infected treatment naïve patients.
Robert Jablonka, Stefan Esser, Maija Koppermann, Johanna Huczalla, Manfred Goos1
To evaluate the efficacy and tolerability of RTV-boosted APV-based salvage regimens in heavily pretreated patients after virological, immunological or clinical failure of previous antiretroviral therapy (pART).
Sorin Petrea, George Jugulete, Mariana Mardarescu, Monica Luminos1
There are over 4,000 children living with HIV/AIDS according to the Romanian Public Health Ministry. In our clinic we have registered over 900 HIVinfected children, 90 % are treated with antiretroviral therapy (ARV). Approximate 80% of HIV-infected children have HAART.
To assess the effectiveness of palliative paediatric care and counselling using a holistic approach to improve the quality of life of HIV-infected and affected children.
G Jugulete, M Dragan, M Mardarescu, M Luminos, S Petrea1
There are over 10,000 HIV-infected children registered on Romanian Public Health Ministery. In our clinic we have registred over 950 HIV-infected children, 90% are treated with antiretroviral therapy (ARV). Approximate 80% from HIV-infected children have HAART.
Hermione Lyall, Stephen Head1, Sarah Gibbons, Saye Khoo2
There were 11(21%) low KAL levels, including 4 undetectable, median - 431 ng/ml (172-1,382). 28(53%) levels were in the acceptable range, median – 8,168 ng/ml (1,762-12,991). There were 14 (26%) high levels median – 16,765 ng/ml (pre dose 12,427 - 42,255). Non-adherence was contributory in 7/8 children who ever had low/undetectable levels, the eighth child was a three month old infant commenced on an initial low dose of KAL. At last visit 4/8 of this group of children had VL < 50, and 7/8 had subsequent acceptable KAL levels. Five children always had levels within the acceptable range, at last visit 2 had VL <50, 2 had VL still declining (60 & 212 copies / ml) and one had virological failure. Seven children had at least one high KAL level, at last visit 6/7 had VL <50, and one had virological failure. A possible relationship between high KAL levels and maximal lipid levels is under further study. In this small cohort, measurement of KAL levels
identified non-adherence early enough for intervention, however there were a worrying number of high levels.
Hermione Lyall1, Stephen Head, Sarah Gibbons, Saye Khoo2
Measurement of EFV levels in this small cohort of children has been helpful in assessment of adherence and drug metabolism. Larger studies are required to determine the additional effect of therapeutic drug monitoring in children.
Although median changes over time were relatively small in this cohort of children on KAL, a worrying number of elevated levels occurred. This is of concern for the longterm cardiovascular health of these children. Median change in Cholesterol (mmols), Triglyceride (mmols) and Chol/HDL ratios from baseline.
Pieter Fraaij1, Alina Bergshoeff2, Jennifer Ndagijimana3, Annemarie Van Rossum1, Nico Hartwig1, David Burger2, Ronald De Groot1, Horst Schroten3, Tim Niehues3
1) Dual therapy with EFV and LPV/r results in optimal viral suppression in children who were pretreated with NRTIs. 2) CD4+ T-cell counts show a tendency to increase after previous suboptimal suppression of the virus. 3) Side effects included a rash and elevated serum cholesterol levels.
HAART was introduced in Poland in 1997. Since then the following drugs are available: NRTI - ZDV, 3TC, ddI, d4T, tenofovir (since 2002), PI - NFV, RTV, IDV, LPV/RTV, NNRTI – NVP, EFV. Since 2001 the recommendations for HIV-infected children include 2 NRTIs and 1 protease inhibitor or 1 non-NRTIs.
The purpose of the study was the assessment of clinical, immune, virological status of children with AIDS who were treated using therapy Highly Active Antiretroviral Therapy (HAART). Twenty-five patients were studied with AIDS (C1-C3 category), who had been treated before with antiretroviral agents.
Dominik Dunsch, Richard Linde, Ziju Elanjikal, Wolfhart Kreuz, Thomas Klingebiel1, Caroline Faul-Burbes2, Anette Haberl3,
Our results show, that in all cases of premature craniosynostosis COV during pregnancy was given and therafter newborns were treated with AZT according to ACTG076. We suspect that the incidence of premature craniosynostosis in HIV-exposed children might be higher than in normal population. In order to prove this hypothesis further investigations on premature craniosynostosis and HIV-exposition are neccessary.
Roberto Manfredi, Leonardo Calza, Francesco Chiodo1
The emerging of extensive multi-drug antiretroviral resistance represents a growing phenomenon also among children with vertical HIV disease, especially when HIV infection has been treated since birth, and suboptimal regimens have been administered for a long time, waiting for the availability and/or the registration of potent HAART regimens.
Adriana Ammassari, Alessandro Cozzi-Lepri, Maria Paola Trotta, Anna Cappelletti, Sara Melzi, Patrizio De Longis, Mauro Zaccarelli, Vincenzo Vullo, Rita Murri, Paola Piano, Sergio Lo Caputo, Salvatore Nappa, Francesco Baldelli, Antonella D’Arminio Monforte, Andrea Antinori, Massimo Galli
Better HAART adherence is associated with a higher risk of faster subsequent development of ATA. Patient-perceived fat accumulation but not prior clinical diagnosis of ATA seems to negatively affect medication intake.
CT patients have a greater understanding of HIV infection and ART compared to NCT. Virological outcome one year post commencement of antiretroviral therapy was significantly better in those in CT, however there was no significant difference in CD4 counts at one year. Further sub-analysis to elucidate reasons for failure in each group need to be performed.
Aisling O’Hagan, C Bergin, F Mulcahy, C Merry, L McCullagh1
Prescription charts for all outpatient, in patient and day-ward HIV patients are reviewed daily by specialist pharmacists, to help ensure safe, cost effective and appropriate prescribing. The aim of this prospective study was to record all pharmacy interventions made in a two-week period in July 2002 and to obtain qualitative data for teaching, peer review and audit purposes.
Maria Paola Trotta, Pasquale Noto, Andrea Antinori1, Adriana Ammassari, Rita Murri2, Alessandro Cozzi-Lepri3, Cristina Minardi4, Giancarlo Orofino5, Luigina Tacconi6, Francesco Alberici7, Guglielmo Nasti8, Maria Ciardi9, Antonella D’Arminio Monforte10
To assess the relationship between: 1) different indirect measures of HAART adherence (patient-report, physician-estimate) and plasma drug levels; 2) these adherence measures and HIV RNA.
To analyse the attitude and knowledge of German physicians involved in HIIV treatment on the role of adherence in ARV treatment, their assessment of their patients' degree of adherence, the factors influencing adherence and their intervention strategies they use to support and increase adherence to HAART.
Interruption of treatment and non-adherence are fairly common in management of HIV/AIDS patients especially in developing and resource limited settings. In this study, reasons for drug interruptions and non-adherence as well as the prevalence in the various drug classes were studied in five HIV/AIDS clinical centers in Nigeria.
Rita Murri, Adriana Ammassari, Andrea De Luca, Patrizia Marconi, Cecilia M J Drapeau, Rosaria Politi, Roberto Cauda, Antonella Cingolani1
Adherence (Adh) to drugs is crucial for treatment efficacy. Objective of the study was to evaluate predictors of virological failure (VF) in HIV positive pts taking HAART.
The aim of this study was to examine the role of objective and subjective barriers to optimal adherence to HAART. In a cross-sectional study in 9 UK centres, patients completed questionnaire measures of subjective barriers to adherence including concerns, perceived necessity and perceptions of the intrusiveness of HAART.
Brian Conway, Salima Jutha, Michelle Jones, Jennie Prasad, Amanda Roze des Ordons, Robert Reynolds, John Farley1, Annabel Mead, Stanely DeVlaming, Nadine Smith2
The treatment of HIV-infected IDUs presents unique challenges, including the need for high levels of adherence. The availability of directly observed therapy (DOT) allows us to address this issue in a meaningful way, but many of the patients may already have received treatment and experienced a virologic breakthrough, potentially compromising the success of any future interventions.
P95: Drug-specific measures of adherence to PI therapy most predictive of short and long-term clinical outcome
C A Donnelly, R M Anderson, N M Ferguson, A C Ghani1, J Hooper2, S Mayer3, D Lapins4, J Stansell5
Anna Gatti, Fabio Arpinelli, Giovanni Visonà, Ruggero Panebianco1, Giuliano Rizzardini2 on behalf of ADEQUA Study Team
Adherence to HIV therapy and QoL are becoming the most important factors in conditioning long term treatment outcome. ADEQUA is a perspective, multicentre observational survey aiming to measure adherence to anti-HIV treatment and quality of life (QoL) of Italian patients (pts).
James Jordan, Jerry Tolson1, Tom Delea, Miwako Hagiwara, Gerry Oster2, Anke Richter, Beth Sherrill3
This study was conducted to assess whether fixeddose combinations (FDC) improve HIV-1-infected patients' adherence to antiretroviral therapy (ART) in community practice.
James Jordan1, Pedro Cahn2, Frank Goebel3, Sophie Matheron4, Clare Bradley5, Alison Woodcock5
In all three studies, therapy with ABC containing regimens resulted in significantly greater patient satisfaction with treatment than single PI containing regimens.
Although few patients are currently receiving once-daily therapy there is clear patient demand. Patients anticipate that reducing the number of pills taken by even 2 pills per day would have a positive effect on adherence and that reducing the number of intakes would reduce the likelihood of forgetting to take medication.
Giustino Parruti, Giuseppina Placido, Luciana Alterio, Augusta Consorte, Patrizia Marani Toro, Vittoria Graziani, Adriana Agostinone, Alessandro Pieri, Giuseppe D’Amico, Rocco Vittorio Graziani, Giuseppe Marani Toro
Our results add further evidence to the knowledge that longterm adherence to HAART is a major determinant of persistent suppression of HIV1 replication once undetectable viremia has been reached with any association of drugs. Furthermore, our data provide clear evidence that favourable socio-economical conditions may be predictive of good adherence to therapy, at least during the first 18 to 24 months of HAART treatment.
D Sedlacek, R Sedlackova1, I Subrt2, I Vobrubova2, M Stankova3, S Snopkova4, J Kolcakova5, V Chmelik6
Relatively high number of heterozygous 32-bp deletions among studied patients was found. The development of new medications and treatment approaches (STI, simplifications etc.) can be expected in the future. Therefore, we suggest that patients are tested for the presence of deletion of 32-bp for CCR5 gene before the start of the treatment with HAART therapy. The influence of further chemokine receptors statuses on the treatment with HAART therapy should be subject to further research.
Delay in the diagnosis of advanced HIV infection may lead to avoidable morbidity and mortality, particularly in the modern era of highly effective anti-retroviral drug therapy. Clinicians need to consider HIV infection in the differential diagnosis of a variety of common presenting symptoms to ensure timely diagnosis and therapeutic intervention.
Margit Halvarsson1 ,Björn Södergård2, Pehrolov Pehrson3
The decreasing amount of reported side effects might be explained with better drugs. Adherence has increased during all three measuring-periods and one possible explanation might be our increased attention on adherence at the clinic but the number of pills has also decreased and the dosing schedule is becoming easier. The level of social support seems on the other hand to decrease possibly effecting adherence negatively. Even if the median treatment time in total is as long as 66 months, 50 % of the patients still report that they never miss a dose.
B Clotet1, F Pulido2, J Carmena3, I Luque4 on behalf of Trizivir 1000 Study Group
Subjects who switched from current treatment to TZV demonstrated an improved lipid profile and reported high levels of adherence and increased general satisfaction.
The results from this study indicate that simpler medication regimens containing fewer tablets, and the use of reminder devices may help to improve adherence. Adherence levels varied between different patient groups in our study population indicating the need for adherence enhancing strategies and support targeted for certain groups, such as IVDUs and non-Norwegians.
Annabel Mead, Stanley de Vlaming, Nadine Smith1, Amanda Roze des Ordons, Brian Conway2
We have evaluated 10 patients, 4 of whom were treatment naïve. Concomitant medication included 2 NRTIs for all patients, with one patient also receiving an NNRTI. Median baseline CD4 counts and plasma viral load measures were 140 cells/mm3 and 92,000 copies/mL respectively. After a median follow-up period of 6 months, these values were 250 cells/ mm3 and 120 copies/mL, with 8/10 individuals showing virological suppression of <400 copies/mL. There was ongoing cocaine use in 8/10 patients (> 80% of drug urine screens positive in half of the patients). The two patients who did not experience good virological suppression were heavy cocaine users with poor adherence. The mean methadone dose prior to the initiation of HAART was 88 mg/day, and stabilized at a similar level (92 mg/day) on therapy. Similarly, there was no significant change in ALT (55 IU/L vs. 42 IU/L).
The above study shows that the effectiveness and success of TB prophylaxis in HIV-positive patients does not depend on strict adherence to antiretroviral treatment, there are other factors like resistance to drugs and poor nutrition which should be considered as well.
M Hooker, R L Goodall1, B Conway, D Churchill, P-M Girard, A Mijch, F Mulcahy, B Salzberger, S De Wit2 for the INITIO Co-ordinating Committee
Rates of LAS/SHL were observed to be significantly increased in people with high BMI, and higher in women, although the differences between the sexes was not significant.
Francisco Blanco, Teresa García-Benayas, Vincent Soriano, Juan González-Lahoz1, Juan José De La Cruz2
In naïve HIV-positive pts who start HAART, ddI-d4T regimens induce a higher increase in lactate levels as compared with AZT-3TC combinations, even within the first months of therapy. This fact should be considered when deciding the first-line antiretroviral regimen, in order to prevent future clinical toxicity such as lactic acidosis. An increase in LDH and amilase levels could alert on the possibility of hyperlactatemia, and lactate levels monitoring could be advisable in such cases.
Helena Brett-Smith, Victoria Rutkiewicz, Anne Cross
Stavudine XR/PRC is well tolerated in combination with 3TC and EFV and shows comparable overall safety to the matching IR regimen. The data suggest a trend towards lower rates of medically important PNS events with the XR/PRC formulation.
Teresa García-Benayas, Francisco Blanco, Vicente Soriano, Juan González-Lahoz
Replacement of d4T by ABC is safe and provides early and sustained metabolic benefit achieving significant and progressive reductions in lactate levels at 6 and 12 mo. This strategy confirms in vitro data regarding different degree of d4T and ABC induced mitochondrial damage and might be useful to lower potential toxicity, as long as NA remain an essential part of HAART.
K Prime, S G Edwards, M R Pakianathan1, F Scaravilli2, R Miller3
Since the introduction of HAART, the spectrum of problems encountered by HIV physicians has widened to include pathology related to antiretroviral (ARV) therapy. Furthermore as patients survive longer, an ageing cohort of HIV positive patients is being encountered who may develop other chronic medical conditions.
Patients treated with antiretroviral therapy must be promptly stopped to take some specific NA in case of symptoms correlated to lactic acidosis. This study shows, like many others, that in patients treated with NA the most frequent correlation with HL is linked to some specific drugs. In our opinion the routine measurements of lactate level is not necessary because of low incidence of symptomatic patients despite the moderate rate of asymptomatic HL.
M Harris, HCF Cote, JW Chan, J Asselin, M Valyi, PR Harrigan, MV O’Shaughnessy, JSG Montaner
No significant change in lactate level was observed in 8 patients who had normal baseline lactate and were switched to TDF for other reasons (p=0.95). The switch from d4T to TDF maintained antiviral effect and resulted in decreased MCV, increased mtDNA/nDNA, and decreased lactate in patients with hyperlactatemia at baseline.
S López1, A Beato, J Casademont, F Cardellach, Ò Miró2, M García, E Martínez, A Milinkovic, J L Blanco3, B Rodríguez4,
Depletion in MtDNA occurs during HAART leading to a primary general MRC dysfunction and, consequently to hyperlactatemia as a final phenotypic expression. Our data seems to confirm that mitochondrial dysfunction relies at the basis of developed hyperlactatemia during HAART.
Discontinuation of NRTIs, as well as a supportive treatment with physiotherapy, analgesics and vitamin B lead to a quick clinical improvement. After approximately one month all biochemical parameters had returned to normal, although, three months were needed for the patient to recover completely, motor weakness being the most persistent symptom.
A Arenas-Pinto, I V D Weller1, A D Grant2, S Edwards3
NRTIs use and female gender appear to be risk factors for the development of LA. What other factors are involved is still not clear but might include; duration of NRTI therapy, specific drug use and genetic predisposition. A case-control study would provide more robust information on the important pre-disposing factors associated with the development of severe LA.
Daniela Gey, R. Boit, T. Lorenz, M. Hartmann1, F. Mosthaf2, P. Langmann, H. Klinker3
Evidence of mitochondrial toxicity, such as high lactate levels and polyneuropathy and lipoatrophy from NRTIs are common problems and often necessitate a change of the current regimen of antiretroviral therapy (ART). So far, only few studies investigated NRTI-free regimens.
Alteration of serum lactic acid levels, although asymptomatic in the majority of cases, is a novel and emerging complication of HIV disease and its treatment, interesting over one third of HIV-infected patients in our experience. Although most of literature data are anecdotal, and we lack of controlled, prospective studies dealing with frequency, risk factors, and out- come of this phenomenon, mythocondrial damage possibly caused by antiretroviral drugs is the first possible origin, from a pathogenetic point of view, although our series failed in demonstrating a correlation with each single nucleoside analogue. A relationship with the overall duration of anti-HIV therapy (including HAART, and always based on nucleoside analogues), and other emerging toxicity with common or related pathogenetic pathways (i.e. dyslipidaemia, skeletal muscle damage), is highly suspected.
Pharmacokinetic data released by the manufacturers of TDF have confirmed that simultaneous administration of TDF and ddI increases ddI AUC and Cmax by 60% and 64% respectively (1). Pancreatitis is a wellrecognised complication of ddI and since TDF increases systemic exposure to ddI it is reasonable to assume that co-administration of ddI and TDF will increase the incidence of ddI-related toxicities – as was the case with our patient. We therefore advise extreme caution in the combination of ddI and TDF in any regime, but if unavoidable dose reduction of ddI should be considered and should be closely monitored for ddI-associated adverse events.
M Ribell Bachs, A Soler, M Perez, G Casas, E Pedrol1, C Villa2
NRTIs have been associated with mitochondrial toxicity. Mitochondrial dysfunction leads to different clinical features, being lactic acidosis (LA) one of the most threatening events. Suppletion of essential co-factors such as thiamine, L-carnitine, piridoxine; artificial electron acceptors and antioxidants such as vitamin C, have been tried out on mitochondrial diseases with varying success.
Mitochondrial toxicity causing hyperlactataemia, lactic acidosis and hepatic steatosis are well-recognised adverse effects of Nucleoside Reverse Transcriptase Inhibitors (NRTI). We report four HIV-positive patients who were on stavudine (d4T) and didanosine (ddI) as part of anti-retroviral therapy (ART).
Stephanie Badiou, Corinne Merle de Boever, Anne Marie Dupuy, Vincent Baillat, Jacques Reynes, Jean Paul Cristol
Advanced stage of HIV infection is associated with an atherogenic lipid profile including a high prevalence of small dense LDL. Lopinavir/ ritonavir-containing regimen accentuate the reduction of LDL size. Since fibrates decrease APOCIII expression and increase LDL size, they appear as a logical strategy to manage HAART-induced HTG [4,5].
Leonardo Calza, Roberto Manfredi, Francesco Chiodo
All used statins and fibrates revealed a similar, significant efficacy in the treatment of diet-resistant hyperlipidaemia, but further studies seem necessary in order to establish the most appropriate guidelines for the management of dyslipidaemia associated with highly active antiretroviral therapy.
