The first approach to the management of d4T-related peripheral neuropathy or lipoatrophy is to switch to alternative drugs that do not cause this side effect. Patients without other options and whose previous treatment history makes them reliant on d4T (stavudine, Zerit) have been managed, often successfully, by dose reduction.
Although guidelines widely recommend use of efavirenz (EFV, Sustiva, Stocrin) plus two nucleosides for initial therapy a percentage of patients find the associated CNS side effects substantially reduces their quality of life.
Although treatment guidelines now recognise that patients who started treatment with higher CD4 counts than currently recommended, may safely discontinue therapy, especially if they are experiencing toxicity from treatment, there is still a reluctance from some doctors to suggest this option to their patients. Several studies at Warsaw provided additional support for this option.
One of the controversial aspects of T20 (enfuvirtide, Fuzeon), the new entry inhibitor recently approved in both the US and Europe, is its cost. At over £14,000 per year it costs more than three times that of the most expensive currently available antiretrovirals.
In pre-clinical studies, efavirenz showed teratogenic effects in 3/13 exposed foetal monkeys, including severe neural tube defects in one. Efavirenz was given to the pregnant monkeys early in pregnancy in the period analogous to the human first trimester. As a result this drug is contraindicated in pregnancy.
In order to assess whether there is any evidence to support the widely held view that Africans living in the UK are less likely to accept and adhere to HAART, a small retrospective study from Newham General Hospital evaluated adherence levels and virological response in African vs non-African patients.
Antiretroviral regimens have demonstrated potent virologic and CD4 responses, but longer-term data are needed to evaluate the durability of these responses.
Two large ongoing investigator led studies are evaluating the role of interleukin-2 (IL-2) as an immune modulator in persons with treated HIV infection. The studies, known as SILCAAT and ESPRIT, are not simply evaluating CD4 numbers but are also looking for clinical endpoints (such as new HIV related infections, AIDS defining events and deaths). IL-2 is administered subcutaneously twice-daily for “cycles” of five days with subsequent cycles being given every eight weeks.
Spina and colleagues from the Italian Cancer Centre presented results from a phase-II study (started in June 1998) of the monoclonal antibody rituximab given with CDE therapy plus HAART in 64 HIV-positive patients with NHL. Sixty-nine percent of patients had advanced stage (III-IV) disease and 52% had B symptoms. Median baseline CD4 count was 161 cells/mm3 (range 3-691).
On 23 October, in an agreement with generic antiretroviral manufacturers Aspen, Cipla, Ranbaxy and Matrix, the Clinton Foundation HIV/AIDS Initiative announced a price of just 36 to 38 cents a day (less than $140 per year) for triple combination therapy in South Africa, Mozambique, Rwanda, Tanzania and the Caribbean - around half the current price for antiretrovirals in the developing world.
The World Health Organisation will soon formally approve three new combinations of three antiretroviral drugs in fixed doses for use in patients with HIV in sub-Saharan Africa. The approval could have a major impact on antiretroviral treatment for patients all over the world.
The South African Competition Commission has found that pharmaceutical firms GlaxoSmithKline South Africa (Pty) Ltd (GSK) and Boehringer Ingelheim (BI) have contravened the Competition Act of 1998. The firms have been found to have abused their dominant positions in their respective anti-retroviral (ARV) markets.
Early reports from using New-Fill to safely and successfully repair facial lipoatrophy provided hope for many patients, given that the procedure was inexpensive in the context of overall HIV therapy, that it indicated few safety concerns and most importantly, when given by an HIV-experienced practitioner, produced successful and natural-looking results for many patients.
Several large studies have addressed the concern that antiretroviral therapy could increase the risk of cardiovascular disease, and a useful analysis and summary (including the AIDS article reviewed here) was published earlier this year by the Forum for Collaborative Research and is now available online.
This is new information as compared to the message sent to you in July 2003 by GlaxoSmithKline, regarding a different triple nucleosides/nucleotide reverse transcriptase inhibitors combination containing Abacavir, Lamivudine and Tenofovir DF
CONFERENCE REPORT:
13th International Conference on AIDS and STIs in Africa (ICASA)
Nairobi, Kenya - 21-26 September 2003
"Current statistics show that about 29 million of the 40 million people infected with HIV worldwide are from sub-Saharan Africa. In the same region, about 55 per cent of those infected are women. While life expectancy has dipped to as low as 40 years, with some regions registering negative population growth. Thanks to HIV/AIDS. Yet, less than 33 per cent of countries in Africa have put in place National Strategic and Health Sector plans on how to tackle the epidemic and STI problems. Even those with the plans, only 11 of them are implementing them."
CONFERENCE REPORT:
Reports from 43rd ICAAC
Chicago, Illinois, USA - 14-17 September 2003
A randomised study compared addition of either ddI (n=110) or placebo (n=68) for four weeks to current therapy of treatment experienced patients with detectable viral loads over 1,000 copies/mL. The primary endpoint was change in viral load between baseline and week 4. Resistance was analysed by genotype at baseline and week 4.
As the pendulum governing prescription of antiretroviral therapy swings farther away from “hit hard and hit early” towards “the treatment is worse than the disease”, clinicians around the world are testing ways to minimise exposure to antivirals. Trials examining drug interruption or cycled therapy, as well as using fewer drugs, were presented. Clinicians should consider these concepts carefully, without forgetting the evolving benefits of potent, simpler, and less toxic drugs, or the difficulty of achieving full functional immune reconstitution once severe immunodeficiency has been allowed to develop, and recent evidence that minor populations of resistant HIV can expand when therapy is interrupted.
Despite the proliferating frequency of meetings, it was encouraging to hear reports of steady advances in the development of new antivirals. Most exciting was the progress of multiple entry inhibitor drugs, creating optimism that we are moving towards combination therapy at the point of virus entry into the T cell.
New data on the adverse effects of antiretroviral therapy were fairly thin on the ground at this year's ICAAC (September 14-17, 2003, Chicago, IL). However, there were valuable points raised, most notably with regard to the more favourable tolerability profiles of recently approved antiretrovirals and re-formulations of established agents. Notably lacking were new insights into the etiology and management of metabolic and morphological abnormalities.
Several studies presented at ICAAC drove home the important lesson that we cannot do without careful testing of novel antiretroviral regimens. Drug interactions on many levels are complex and unpredictable, and the "one from column A and two from column B" approach cannot be depended upon.
Douglas Slain and colleagues from University of West Virginia presented results from a diet-controlled longitudinal study PK study that found an interaction between Vitamin C and indinavir.
Indinavir levels were also significantly reduced when coadministered with the proton-pump inhibitor omeprazole. It is generally thought that this would not cause a clinically significant interaction.
Tenofovir (TDF, Viread) is generally a well tolerated medication with a low pill burden and demonstrates potent antiretroviral activity. These characteristics have led to its widespread use in clinical practice. Unlike other NRTIs, however, tenofovir use is associated with several drug interactions, most notably the reduction in levels of atazanavir (ATV, Reyataz) and an increase in levels of ddI (didanosine, Videx).
There were a large number of other PK and interaction studies included at the conference. Summary results are included below but please review the abstract for full details.
Although most countries are increasing spending on combating HIV, the resources that have been earmarked so far are "woefully inadequate", says the United Nations.
The Generic Anti-Retroviral Procurement Project (GARPP) and the Treatment Action Campaign (TAC) Treatment Project have requested permission from the originator company Boehringer Ingelheim for the right to import generic nevirapine to South Africa. Refusal to grant this voluntary licence will lead GARPP and the TAC to apply to the Commissioner of Patents for compulsory licenses through the courts.
Canada's industry minister says his government will try by Christmas to exempt generic forms of drugs to treat AIDS and other drugs destined for poor countries from patent laws.
Atazanavir, is a once-daily protease inhibitor from Bristol Myers Squibb that was approved in the US in June 2003. The UK expanded access programme quickly enrolled, and unlike other countries the numbers for the programme were then capped. Access has now been extended through a new Individual Patient Supply (IPS) scheme, which allows doctors to request a drug for any patient who is considered in need. Administration costs are £360 per month – the licensed price is expected to be slightly lower.
The suboptimal performance of triple-nucleoside therapy (for Trizivir, and abacavir/tenofovir/3TC), means that triple-nucleoside therapy is no longer a recommended treatment approach in UK and US treatment guidelines.
Revisions were recently made to the product labeling for Norvir (ritonavir) 100mg soft gelatin capsules and Norvir (ritonavir) 80mg/mL oral solution, marketed by Abbott Laboratories.
When the French GIGA-HAART study reported significant short-term benefits from a two-month treatment interruption (followed by an eight- or nine-drug GigaHAART regimen with PI drug levels optimised by therapeutic drug monitoring) compared to continuous treatment, the study was stopped early. Whether this strategy resulted in longer-term benefit was therefore not established.
Two recently published studies, each based on different interruption protocols, have both shown disappointing results, with higher rates of treatment failure and development of resistance.
In high-income countries, the availability of highly active antiretroviral therapy (HAART) has greatly decreased the risk of illness from AIDS-related complications. Although HAART can prolong life, it is not a cure. HAART also can have side effects; in some cases, users develop increased levels of fatty substances or lipids (cholesterol and triglycerides) and sugar in the blood. In theory, these changes increase the risk of developing cardiovascular disease (CVD)—heart attacks, strokes and other complications.
Valacyclovir is a more effective prophylaxis than acyclovir against recurrent herpes simplex in HIV-positive people, according to an international placebo-controlled trial.
A report in the 17 October issue of AIDS investigates intracellular zidovudine triphosphate and lamivudine triphosphate concentrations in HIV-positive individuals, and the associations between these concentrations and patient characteristics and anti HIV activity.
A retrospective analysis of data from 53 women and 60 men, published in the 5 September issue of AIDS, compared the immunological responses of women to men in patients with suppressed viral load <400 copies/ml at 24 weeks.
A research letter published in the 26 September issue of AIDS describes fast turnaround of point of care testing in labour and delivery using the OraQuick Rapid HIV-1 antibody test recently approved by the FDA.
A report published in the 13 September issue of The Lancet indicates that reduction of mother to child transmission achieved with single dose nevirapine at six-eight weeks (as demonstrated in earlier findings in the HIVNET 012 study) was sustained at 18 months follow up with an absolute reduction of 10.1% (95% CI 3.5-16.6) in breastfed babies.
Several adult studies have suggested that use of the monoclonal antibody rituximab, in addition to chemotherapy, may provide additional benefit in treatment of CD20+ Non-Hodgkins Lymphoma (NHL), although this is also associated with increased toxicity.
A report from the French Perinatal Study published in the September issue of AIDS found that perinatal exposure to zidovudine might result in a small but significant and durable effect on haematopoiesis up to the age of 18 months.
Recent clinical implications for management of patients with Hepatitis C and HIV coinfection include an opportunity to recognise non-responders at 12 weeks, and therefore reduce exposure to unnecessary treatment, and at the other extreme, that a longer period of treatment may be necessary for others.
This issue of HTB leads with a treatment alert circulated to doctors in the US. The reasons for its inclusion are made clear in the comments section on page 4. It is still the general rule that European patients have to wait at least six months more than people in the US for drugs to be fully licensed.
Bristol-Myers Squibb Company would like to make clinicians caring for HIV-infected patients aware of important new pharmacokinetic (PK) data concerning the coadministration of atazanavir sulfate (Reyataz™) and tenofovir disoproxil fumarate (Viread®, Gilead Sciences Inc.).
The Medicines Control Council (MCC) of South Africa issued a press release on 12 September announcing that in view of additional data brought to their attention since the decision to deregister nevirapine for use in combating mother to child transmission, the time period for Boehringer Ingelheim to submit new evidence had been extended. It explains that new data must be submitted on the use of nevirapine in combination with other antiretrovirals for use for this indication.
Two years after being told - in paragraph six of the 2001 Doha Declaration - to find a solution to the conflicting interests of pharmaceutical companies and the needs of poor people requiring medicine in developing countries, the World Trade Organisation reached agreement in Geneva on 30 August to allow developing countries to import cheap, generic drugs. Or, they sold the poor down the river to protect the patents and profits of the rich western pharmaceutical companies. Take you choice.
The TRIPS (trade-related aspects of intellectual property rights) Agreement, right from its very beginning, had nothing to do with innovation or scientific advancement but was a treaty signed through coercion and blackmail for market control, market dominance, market segmentation and market exclusion.
The 30 August WTO deal on exports of generic medicines is being presented as a gift to the poor. However, it is a "gift" bound tightly in red tape. As a measure of trade policy, it contradicts the basic principles of the WTO and free trade.
Some protesters wanted to be as colourful and disruptive as they were when the World Trade Organisation met in Seattle in 1999, which gave birth to a global protest movement, but attention focused on the WTO's meeting at Cancun in September for different reasons. The real drama involved the delegates from 147 nations engaged in negotiations aimed at making life fairer for poor countries struggling against a rigged global trading system.
The South African government has instructed its health minister, Manto Tshabalala-Msimang, to draw up, within one month, a plan to make antiretroviral therapy available in public hospitals. There have been false dawns and apparent u-turns by the South African government in the past, but this move does seem to bring to an end four years of inactivity by President Thabo Mbeki's government.
The Indian government is being taken to the country's Supreme Court in a public interest petition that says poor people with HIV who require hospital care and drugs are given no treatment "in any public hospital" and are "simply left to die".
CONFERENCE REPORTS
43rd Annual ICAAC, Chicago, 14-17 September 2003
The 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) took place as this issue of HTB went to press. HTB reports of data from this meeting will be included in the next issue. The conference abstracts are available for a limited time on the conference website. Click on the 'itineray builder' link for browse or search access to abstracts.
South African AIDS Conference, Durban, 3-6 August, 2003
A poster from Medecins sans Frontiers (MSF) describes their rigorous selection procedure, adherence support and excellent outcome of Africa's best known - and model - pilot antiretroviral programme, in Khayelitsha, South Africa.
Established in February of this year by a group of 19 South African treatment projects, the Generic Antiretroviral Procurement Project (GARRP) aims to improve access to ART through the promotion of good quality generic antiretrovirals at the lowest possible cost.
The MTCT-Plus initiative provides HIV care including antiretrovirals to HIV-positive women identified during pregnancy, and their families. This project was launched in 2001 as a response to Kofi Annan's "Call to Action". It utilises antenatal care as an entry point to HIV treatment and acknowledges that MTCT programmes in resource poor settings have generated cohorts of HIV-positive women without access to treatment for their own health.
Further reports from 2nd IAS Conference on HIV Pathogenesis and Treatment
Paris, 13-16 July 2003
Although the percentage of patients who had <50 c/ml were about the same for both treatment groups, observers were confused as to why the viral response to EFV was so low and why it was lower than seen in other EFV studies. Regarding <400 c/ml, the previously reported data from Study 034 was that 70% of patients taking ATV had <400 c/ml and 64% of patients taking EFV had <400 c/ml at week 48 (ITT).
New data on the use of antiretroviral regimens in individuals who have experienced failure on at least one prior antiretroviral combination mainly focused on comparative data between different protease inhibitor based regimens. The main contenders for this market currently dominated by lopinavir/r (Kaletra) are atazanavir and saquinavir.
In this study there was a strong correlation between the CCR5 expression and viral load rebound. For R5 densities <8,000 molecules/cell viral load rose to <100,000 copies/ml whereas those who rebounded to >100,000 copies/ml had densities over 8,000 molecules/cell (r=0.71; p<0.001). These results emphasise the role of CCR5 density in in vivo HIV replication. Thus, therapies such as the new CCR5 receptor blockers SCH D (Schering) and UK-427,857 (Pfizer) may offer a therapy, which not only is effective but also has a greater efficacy in those patients with the greatest potential for progression. Only clinical studies will inform as to whether this is true, however it is tantalising to hope that the arrival of these blockers may have an added advantage to those with high viral loads.
There is little data regarding the true incidence of primary pulmonary hypertension (PPH) among HIV-infected patients. Autopsy series prior to the introduction of HAART suggested that PPH was significantly more common among people infected with HIV (incidence of 0.5%) compared to the "general population" (incidence 0.01-01%). Prognosis is extremely poor among persons with PPH and it is estimated that the survival rate among HIV-infected patients with PPH at two years is between 32-46%.
Dyslipidaemia is a common problem affecting HIV-infected patients receiving antiretroviral therapy. Since publication of preliminary guidelines in 2000, numerous studies have addressed the risk of cardiovascular disease, the mechanisms of dyslipidaemia, drug interactions, and the treatment of lipid disorders in HIV-infected patients.
Of all of the changes that are included in the umbrella-term, 'lipodystrophy', fat loss or lipoatrophy has been the most difficult to manage. Treatment options are limited; no therapy has received FDA approval. Several studies have suggested that factors which influence the development of lipoatrophy, and those that promote fat accumulation, are different. The treatments proposed for lipoatrophy and fat accumulation differ as well. Treatments for fat accumulation that have been reported in the literature include diet and exercise, growth hormone (Serostim), and metformin (Glucophage). Treatments for lipoatrophy that have been reported include antiretroviral switches and treatment with thiazolidinediones (glitazones).
HAART is associated with metabolic adverse events such as insulin resistance and lipodystrophy, that is, atrophy of subcutaneous fat and/or accumulation of intra-abdominal fat. Currently, there is no pharmacological treatment for lipoatrophy (fat loss).
On 29 August 2003 the US Food and Drug Administration (FDA) granted full approval for Serostim (somatropin; recombinant growth hormone for injection), which is indicated for the treatment of HIV patients with wasting or cachexia to increase lean body mass and body weight, and improve physical endurance.
Low testosterone levels are common in both men and women with human immunodeficiency virus (HIV) infection and may contribute to loss of lean body mass and AIDS wasting. Causes of low testosterone levels are complex and may include chronic illness, HIV infection and its complications, medications used to treat HIV and opportunistic diseases, and normal aging-related declines.
The aim of this cross-sectional analytical study was to describe the alterations in the bone metabolism of HIV-seropositive patients and evaluate the effects of antiretroviral therapies. Published in the September 5, 2003 issue of AIDS, this cross-sectional analytical study was undertaken by researchers at the Medical Science School of the National University of Cordoba and Rawson Hospital, Cordoba, Argentina.
Early results from the large international ESPRIT study presented to the IAS conference this summer confirmed the ability of several courses of IL-2 to dramatically increase CD4 counts. However, IL-2 is associated with difficult side effects during the five-day administration periods including moderate to severe fatigue, myalgia and fever in up to 90% of subjects.
Prescribed interruptions in antiretroviral therapy - so-called "drug holidays" - may hasten disease progression in a subset of HIV-infected individuals, namely those whose treatment has been rendered significantly less effective by the development of resistance to multiple anti-HIV drugs (MDR-HIV).
Postnatal transmission of HIV-1 is of great concern among populations where breastfeeding is common practice. It is also speculated that risk of postnatal transmission could be greater following a maternal intervention due to rebound in maternal viral load after antiretroviral discontinuation.
Results from a large African mother to child transmission (MTCT) cohort study reported in July AIDS, evaluated the impact of HIV-1 group M subtype variation on transmission rates in this setting where multiple subtypes are circulating.
Mother to child HIV transmission interventions that ignore maternal health are unlikely to confer longer term benefit to child health and survival, irrespective of a child's serostatus.
Nevirapine (NVP, Viramune)) has been available for paediatric use in the UK since August 1997 through a compassionate access scheme (running until March 1999).
To assess the factors associated with liver fibrosis in HIV and hepatitis C virus (HIV/HCV) coinfected patients eligible for anti-HCV therapy, researchers performed an observational, single centre, cross-sectional study of 180 HIV/HCV coinfected patients who underwent liver biopsy between May 1998 and November 2001.
Hepatitis coinfection, and in particular hepatitis C virus (HCV), have become significant causes of morbidity and mortality among HIV-infected patients. Unfortunately, response rates to interferon and ribavirin, the primary treatment for HCV, appear to be lower in HIV/HCV coinfected than in HCV monoinfected patients.
Treatment of latent TB with a two-month therapy regimen of rifampin and pyrazinamide (RZ) can cause severe liver damage and even death, according to a study by the US Centers for Disease Control and Prevention (CDC).
Reports by Simon Collins, Polly Clayden, Graham McKerrow and Steve Taylor for HIV i-Base
Probably the most useful insights into the importance of future clinical developments come from the annual Resistance Workshop, restricted to around 150 researchers and this year only one HIV-positive community place. So while we'd like to bring you an in-depth report from the meeting, we will have instead to report from the abstracts.
Reports by Simon Collins, Polly Clayden, Graham McKerrow and Steve Taylor for HIV i-Base
Several abstracts provided additional data on cases of HIV superinfection or coinfection. The term coinfection is usually preferred when there is evidence that the initial infection occurred with two or more different viral strains at the same time, or before an immune response to the first virus has developed. (the latter is sometimes called serial infection).
Reports by Simon Collins, Polly Clayden, Graham McKerrow and Steve Taylor for HIV i-Base
Although there has always been an element of concern over this strategy - and certainly the recent IAS conference in Paris saw something of a “nevirapine backlash” with much discussion around alternative approaches (see IAS report later in this issue) – single dose nevirapine (NVP), given to the mother at onset of labour followed by a dose to the infant is a low cost and simple strategy to reduce mother to child transmission (MTCT) of HIV in resource poor settings.
Reports by Simon Collins, Polly Clayden, Graham McKerrow and Steve Taylor for HIV i-Base
All mutations present in composite genotype were detected by SGS. However, mutations present in <10% of single genomes, with one exception, were not detected by composite genotype. Mutations present in 10%-35% of single genomes were only detected in 25% of composite genotypes.
Commercially available resistance assays are unable to detect minority virus that is present at less than 10-20% of an individual's viral population and this is recognised as one of their limitations. It may also explain why randomised trails for these tests are difficult to design to show the additional benefit that they undoubtedly offer.
At the 2003 Retrovirus Conference, a late breaker by Steven Deeks showed that some of his patients failing on PI+2 nukes regimens who discontinued the PI component showed little consequent effect on CD4, viral load or development of resistance over the subsequent year.[1] In contrast, those that discontinued their nukes experienced disease progression and higher viral rebound.
The unique co-transfection step inherent to single-cycle HIV resistance assays, can result in even relatively small amounts of wild-type virus (WT) within a viral population significantly affecting the apparent replication capacity (RC) and phenotype of mutant strains, conclude researchers from Abbott Laboratories in Illinois, USA.
Further information about tenofovir resistance and approaches to using this new drug were provided in several abstracts. Much of this information, and the discussions it generates involve the development of the tenofovir-associated K65R mutation and this has an overlapping cross-resistance profile with abacavir and ddI.
Important findings may explain the different responses that have been reported following treatment interruptions and the results appear to have little to do with the immunological effects that were being closely studied.
American and Israeli researchers have used a conceptual model to consider the distinct patterns of the virological and immunological response to antiretroviral therapy. They interpret recent data in terms of 'proximal immune activation and virus transmission' (PAT) and believe it may explain why resistance mutations are rarely observed below 50-100 copies RNA/ml despite clear evidence of ongoing viral replication.
Two studies, one using isolates from women and one using isolates from men, show viral mutations in genital tracts that are different to those in blood plasma, and which persisted sometimes for years even without selective pressure of treatment.
CONFERENCE REPORT:
The 5th International Workshop on Adverse Drug Reactions and Lipodystrophy
Paris, France - 8-11 July 2003
An excellent overview of the recent basic science presented at the workshop, particularly relating to nucleoside therapy, was provided by Professor Capeau at the subsequent IAS conference. Many of the presentations focused on the effect of HIV treatment on insulin resistance, and altered cytokines that in turn leads to reduced ability to store fat and adipocyte apoptosis.
David Nolan presented updated results form the Western Australian HIV Cohort showing that adipocyte depletion and mitochondrial toxicity are prominent in subcutaneous fat samples from 46 RTI-treated patients, compared to 24 HIV-positive treatment naïve patients and seven HIV-negative controls.
Modest increases in carotid intima media thickness (IMT) were reported in a new French study by Mercie and colleagues. [14] IMT increases are a marker for atherosclerosis and a recognised risk factor for cardiovascular disease, but at the 2003 Retrovirus Conference two separate studies reported contradictory results on whether this was occurring.
Increased bone resorption, together with altered nutritional status, hormonal function and body composition may be responsible for these changes and, given that women are at increased risk for osteopenia, suggests that integrating bone density monitoring should be an important part of care for HIV-positive women.
A study of rosiglitazone (a thiazolidinedione agonist of PPAR gamma) at a dose of 4mg/day for three months followed by 8mg/day for a further three months in 28 patients with hyperinsulinaemia and lipoatrophy led to increases in subcutaneous and total body fat, but fasting triglycerides and cholesterol also increased.
Driscoll and colleagues reported that exercise training (one hour of aerobic plus strength training three times a week) together with metformin (850mg BID) significantly improved cardiovascular risk markers (waist-to-hip ratio, resting systolic and diastolic blood pressures and aerobic capacity to exercise) compared to metformin alone.
Raghavan and colleagues found small but statistically significant differences in the rate of change in BMI, body cell mass, total body fat and circumferences and skin folds between patients using ddI/d4t compared to those using abacavir/3TC in both peripheral and central sites.[
Numerous studies reported ways of measuring, monitoring and classifying stages of facial lipoatrophy, much of which is particularly frustrating for patients who clearly have symptoms but no access to treatment.
In humans, serum levels of uridine achieved protective levels in the in vitro model following a single 36g dose of a dietary supplement Mitocnol and studies of uridine therapy in HIV-positive patients are now underway.
Breast enlargement in male patients was reported in 28/2,310 patients attending a Barcelona clinic from November 2001 to November 2002 (incidence 1.2%). This was bilateral in just under half the cases and in 57% cases the patients had other symptoms of lipodystrophy.
Mike Allin and colleagues from King's College Hospital in London reported on a small group of six patients who had been referred over a two-year period from a single London hospital with acute severe psychiatric symptoms including suicide ideation out of a total of 200 patients who had started medication with efavirenz. All symptoms resolved when efavirenz was withdrawn.
A presentation from Emmanuel Trenado of results from a prospective cohort study of 725 HIV patients, almost 600 of whom had answered a questionnaire distributed by the French community organisation AIDES, and of the 80% on treatment almost 40% said that on their 'stable' combination they experienced mild to moderate side effects.
CONFERENCE REPORT:
2nd IAS Conference on HIV Pathogenesis and Treatment
Paris, France - 13-16 July 2003
This biannual conference alternates with the years of the International AIDS conference. Location is also planned to alternate between a developed country and one where access to treatment is still not widely available - the first meeting was held in Buenos Aires in 2001 – in order to maintain a balance between new science and the importance of access issues.
More than 20 oral presentations and more than 50 posters evaluated various aspects of transmission from mother to child, but as usual data on maternal health before, during or after pregnancy, delivery and breastfeeding was scant.
Two studies at the IAS meetings using triple nucleoside combinations reported very poor results and a third study was closed the week before the meeting on a preliminary analysis of the results. This article will report on all three studies.
The increasing link between nucleoside analogues and lipoatrophy and increased potency of ritonavir-boosted protease inhibitors have led to a number of so-called nucleoside sparing strategies, both in treatment naïve and experienced patients. Summary reports from the main studies are included below.
In France, Raguin and colleagues presented 48 week results of the PUZZLE 1 study (ANRS 104) which looked at an additional 200mg/day ritonavir added to different combinations that included lopinavir/r and amprenavir (with NRTIs) in heavily experienced patients on current failing therapy. [5] While the resistance profile of these two drugs make the combination of interest, both lopinavir and amprenavir levels drop when used together.
In this highly ARV-experienced population, the efficacy of ATV/RTV QD is similar to LPV/RTV BID through 16 weeks. ATV, when boosted with RTV or combined with SQV, is safe, well-tolerated and with a more favourable lipid profile than LPV/RTV.”
An Italian-English study of 'unsupervised' treatment interruptions (TIs), which are common in clinical practice, concludes that TIs of 12 weeks or more are associated with clinically significant increased risk of AIDS or death. A d'Arminio Monforte and colleagues looked at 2,832 patients of the ICONA cohort starting their first HAART. Only TIs of at least 12 weeks were considered.
An intriguing in vitro study was presented at the 2nd IAS Conference in Paris evaluating the potential of uridine to prevent and treat nucleoside reverse transcriptase inhibitor (NRTI) related mitochondrial toxicity. A preliminary pharmacokinetic study was also reported on an extract of sugar cane, which may be used in humans to raise plasma levels of uridine.
Distal sensory peripheral neuropathy (DSPN) is the most common neurological dysfunction experienced by patients with HIV-infection. It is complex in that it may be caused by HIV-infection itself and some antiretrovirals used to treat HIV-infection that may themselves be neurotoxic. It manifests as tingling, burning and other paraesthesias predominantly affecting the feet but also involving the hands in more advanced cases and may be extremely disabling.
Preliminary results of the multinational ESPRIT (Evaluation of Subcutaneous Proleukin in a Randomised International Trial) showed that CD4 cell count response after the first three cycles of IL-2, used in addition to HAART in patients with baseline CD4 counts >300 cells/ml, at month eight, is associated with higher nadir CD4 count, higher baseline CD4 and younger age.
An analysis of 2,614 antiretroviral naïve people under 50 years of age, and 401 over that age, who started on HAART in France between 1997 and 2001, reveals that patients over 50 exhibit an immune response after HAART, but that their CD4 cell reconstitution was significantly slower than in younger patients. The researchers conclude that this may explain why older patients have a higher risk of clinical progression.
Two studies highlighted the problems of rectal disease in HIV-positive patients, with one study showing anal infection by Human Papillomavirus (HPV) to be almost universal in men infected with HIV. The second study concluded that routine rectal Pap screening is feasible and warranted as part of HIV primary care.
The Group of Eight most industrialised nations (G8) and the Global Fund to fight HIV, TB and Malaria have announced new donations by rich countries to the fund – but there is widespread criticism that the donations are far too small, and one activist group says an American "ambush" will divert money to bilateral agreements between donor countries and developing countries and leave the fund impotent.
President Bush signed landmark legislation Tuesday authorizing $15 billion to fight AIDS in Africa and the Caribbean, and now the spotlight switches to making sure Congress' notoriously independent-minded appropriators actually come up with the money.
As President Bush signed a new global AIDS bill, the Global AIDS Alliance released a new report that details how the President's spending proposals will make the bill almost impossible to implement. The report calls on the President to immediately change course to avert a major shortfall in AIDS funding.
The World Health Assembly, the governing body of the World Health Organisation, has approved a resolution stating that countries and pharmaceutical companies should consider public health factors when making policies on access to drugs, including antiretroviral medications. The resolution, sponsored by Brazil, addresses concerns from the pharmaceutical industry by encouraging research and development of new drugs and by recognising intellectual property rights.
The most promising outcome of the Assembly was the statement by the newly elected Director-General, JW Lee, that he "committed" the WHO to achieving the Barcelona goal of "three by five", or three million people living with HIV/AIDS in developing countries put onto antiretroviral treatment by the end of 2005.
Billionaire Microsoft founder Bill Gates will donate one million dollars to Brazil's fight against AIDS, the Bill and Melinda Gates Foundation announced Wednesday.
It is a widely held assumption that people in resource poor settings will be unable to be adherent to antiretroviral therapy, providing yet another barrier to their access to medicines essential to their care. A paper published in AIDS reports findings from an investigation designed to measure adherence in a cohort of semi-urban South Africans living in extreme poverty.
The annual Conference on Retroviruses and Opportunistic Infections (CROI) remains one of the most important scientific meetings for presentation of new research and this year's meeting in Boston from 10-14 February was no exception.
CONFERENCE REPORTS 10th Conference on Retroviruses and Opportunistic Infections (CROI) February 10-14, 2003 - Hynes Convention Center, Boston, MA
Early data was presented on several new agents at the first of the opening oral sessions on new antiretrovirals. Many of these new molecules included new targets and mechanisms of action, but were also still only in pre-clinical stages of development. These included pyranodiprymidine integrase inhibitors, AK605 CCR5 inhibitor and TAK-220 and UK-427,857 CCR5 agonists and PA-457, a new budding inhibitor (see abstract 9, 10, 11, 12 and14).
Scientists in Germany, the USA, London and Brazil reported in a poster the 96-week preliminary interim results of a blinded, randomised study looking at the safety and efficacy of tenofovir disoproxil fumarate (TDF, Viread) vs stavudine (d4T, Zerit) when used in combination with lamivudine (3TC, Epivir) and Efavirenz (EVF, Sustiva) in ARV-naïve patients.
Among the most anticipated study results were those from the IATEC run and Boehringer sponsored 2NN study, and these were presented in the last session of oral poster presentations at the conference.
This conference had a strong emphasis on international issues and treatment in resource limited settings. Production of generic antiretrovirals by generic manufacturers has reduced the cost of HAART to as little as $1 a day. Several sessions included reports of programmes using these affordable drugs in their treatment strategies, including data from Malawi using Triomune and India and Mozambique using nevirapine (NVP)-containing generic HAART regimens.
Dr David Margolis, University of Texas, for NATAP.org
Interruption of antiretroviral therapy occurs every day as part of clinical practice, and as part of everyday life for many with HIV infection. Over the past several years prescribed interruptions of therapy have been proposed to accomplish a variety of goals: to improve the immune response via auto-vaccination with HIV, to diminish the proportion of circulating drug-resistant HIV and improve the response to salvage therapy, or to reduce the exposure to antiretrovirals and ameliorate drug-related toxicities.
The New Year, traditionally a time to look back and review achievements and acknowledge goals unmet, but also a time to look forward and institute change. This particular New Year welcomes a change for HIV i-Base and our “ HIV Treatment Bulletin” publication. It accompanies a change in focus for myself, the editor, Paul Blanchard.
CONFERENCE REPORTS: 6th International Congress on Drug Therapy in HIV Infection 17-21 November 2002, Glasgow, UK
One of the most notable presentations at the Glasgow meeting was a pharmacokinetic evaluation of lamivudine, stavudine and nevirapine given as a fixed dose combination pill (Triomune) versus the same three drugs given separately in healthy human volunteers.
The 6th International Congress on Drug Therapy in HIV infection followed the format of the previous meetings, consisting predominantly of oral plenary sessions with 'experts' summarising the current state of the art in treatment-related issues, a small number of oral presentations of new data and a poster session extending to around 300 posters of data predominantly derived from European treatment centres.
The trials and tribulations of amprenavir have not been a happy story, consisting of a drug with a high-pill burden and frequent gastro-intestinal side effects, mainly diarrhoea and bloating. Fosamprenavir (GW433908, 908) is a new formulation with a distinct and now well-characterised resistance profile. The change in formulation allows for once daily dosing (QD) when combined with 200mg of ritonavir (RTV).
There is a pressing need for simple and effective treatment strategies for HIV infection that result in long-term virologic control and avoidance of toxicities. Many novel therapeutic approaches are being explored.
Enfuvirtide (Fuzeon, formerly T-20) has been evaluated into randomised, comparative studies in which individuals who have been experienced with all three approved drug classes were given a new antiretroviral regimen optimised by the use of resistance testing with or without enfuvirtide in a 2:1 ratio. Both studies, known as TORO 1&2, demonstrated substantial virological and immunological advantage to including enfuvirtide in the new treatment regimen.
In a special report, the 4 January issue of the Lancet offers 12 opinion pieces that make recommendations as to the role the new director general of the World Health Organization should play, the issues that need to be addressed and the direction in which the organisation should proceed. Several of the pieces examine HIV/AIDS-related issues.
Download .pdf document of this issue.
This information is designed to support, not replace, the relationship that exists between you and your doctor.