Taking the Pulse of HIV Medicine in Europe
IAPAC Sessions 2004 -- Europe
September 23-24, 2004, London
A very English drizzle gave way to sunshine through the library windows of the Royal College of Physicians, bordering on Regent's Park in the center of London, as the IAPAC Sessions 2004 -- Europe were inaugurated. The 14-member faculty included Co-Chairs Mike Youle (Royal Free Hospital, London) and Bernard Hirschel (University Hospital of Geneva), delegates representative of Eastern and Western Europe, and observers from UK-based AIDS service organizations as well as the World Health Organization (WHO).
José M. Zuniga, President/Chief Executive Officer of the International Association of Physicians in AIDS Care (IAPAC), welcomed delegates, observing that the toll of AIDS has diminished, but is far from gone, in western industrialized countries: 50,610 died in the United States in 1995; 16,371 in 2002, despite a growing prevalence of HIV in the population over that period. There had been a similar decline in Western Europe, but deaths were still occurring for a variety of reasons.
Issues limiting the success of AIDS treatment prioritized by IAPAC members included: liver complications -- where hepatitis C virus (HCV) coinfection increases death risk even with successful HIV treatment; poor adherence; late diagnosis and late presentation for treatment, even when people are aware of their HIV status; non-Hodgkin's lymphoma; and non-AIDS cancers.
Youle, who with Hirschel is also an IAPAC Trustee, said the top of his own list was for people with HIV to be diagnosed. In the United Kingdom, anonymized serosurvey data imply that 35 percent of people with HIV are still unaware of their status. He called for the current paradigm of voluntary counseling and testing (VCT) to be scrapped, and for HIV testing in public health settings to be put on the same routine basis as HCV and syphilis tests. Why, he reasoned, should a diabetic entering hospital care for the first time not be tested for HIV alongside other routine investigations?
François Raffi (Nantes Medical University, France) reviewed current antiretroviral therapy (ART) options and posed what he thought remained some unanswered questions for ART guidelines writers.
There are now many potent antiretroviral (ARV) regimens to choose from, even when limited to the 20 European Medicines Agency (EMEA)-licensed ARV drugs, but some are better than others. A non-nucleoside reverse transcriptase inhibitor (NNRTI) plus two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) is better than triple NRTIs; ritonavir (RTV)-boosted protease inhibitors (PIs) are better than unboosted PIs.
Growing experience with the use of ART may not have led to the inexorable rise of ARV drug resistance that was once feared, at least on the evidence of cross-sectional surveys in the United States. The durability of current regimens might be three to five years or longer, yet there is still no sign of a return to previous mortality rates.
On the other hand, treatment across the global genetic diversity of circulating HIV strains has shown that patterns of ARV drug resistance vary with subtype. For example, patients with subtype C -- which is currently by far the most common -- are more disposed to nelfinavir (NFV) failures with L90M than with D30N as in subtype B.
Continuing issues with current ARV regimens include their complexity, the ease with which viral drug resistance is selected, and both short-term and long-term toxicity.
Still unresolved strategic questions include the CD4 count at which ART is best initiated. Is a CD4 count less than 200 cells/mm3 too late? Is a CD4 count greater than 350 cells/mm3 too early? Should the decision be influenced by viral load? Is there a case for induction and maintenance phases of ART, starting with the most powerful inhibitors of viral replication and shifting to those with least toxicity? Is there a role for ARV regimens based on less than three drugs? Are structured treatment interruptions finished as a strategy?
Tuberculosis (TB) treatment, where active disease must be controlled but deferral of ART can also be deadly, remains a particular challenge. Many patients seen in Europe present with active TB.
The safety and efficacy of drugs during pregnancy both for mother and baby is not easy to assess.
HIV/HCV coinfection -- especially where there is liver fibrosis -- raises questions about drug safety and possibly the need for drug level monitoring.
Hepatitis B virus (HBV) coinfection complicates treatment when specific drugs -- lamivudine (3TC) and emtricitabine (FTC) -- limit HBV viremia so their withdrawal risks viral rebound and immunological attack on the liver.
Questions about NRTIs include:
In discussion, the case for first-line d4T in developing countries was argued on economic grounds, that for widespread treatment access its low cost from generic manufacturers is crucially important. Zidovudine (ZDV), the next most affordable drug, is not an easy alternative, as there have been deaths from anemia induced by ZDV in populations which are already anemic for other reasons, in settings where emergency treatment is harder to deliver than ART itself.
With respect to NNRTIs and PIs, there is still a question as to whether RTV-boosted PIs or NNRTIs are preferable for first-line ART. Is the hepatotoxicity risk of NNRTIs (NVP, especially) limited to identifiable populations of patients? Is there any role in treatment for unboosted PIs? What can or should be done when boosted PIs fail?
New ARV drugs are still needed. In particular, NRTIs are needed that are better tolerated and/or active against virus resistant to current ARV drugs. Similarly, we need NNRTIs that can be used in salvage therapy. New classes of drugs, especially oral CCR5 inhibitors, integrase inhibitors, and immunomodulators, remain highly desirable.
Youle agreed that all ARV drugs are not equal, although as they are used in combinations, it is the combinations that matter. The number of effective drugs available is now considerably greater than for many other conditions. Nonetheless, resistance is an increasing problem, with a growing prevalence of multi-class resistant viruses.
In the best case scenario of a 29-year-old gay man with a job, a supportive partner, good mental health, and wild-type HIV infection, prospects on starting ART are vastly better than they were 10 years ago. Such a man, seen recently in his own clinic, would take his pills and might outlive his physician.
Youle contrasted this with the case of a man with schizophrenia, who has been through multiple ARV regimens and would only take a tablet "if it is white." (He had finally managed to persuade his patient that lopinavir (LPV) was indeed very white, despite being surrounded by an orange protective coating!)
The flow of new drugs has not stopped, although there are problems that may limit their use. Enfuvirtide (ENF) has not sold as well as its manufacturer had hoped, contributing to the decision to drop a successor molecule. It is also getting difficult to recruit patients into clinical trials; Youle relayed his frustration with a patient who said he was "too busy" to help future patients. In addition, he said that plans in the United Kingdom for domestic implementation of legislation from the European Union on the regulation of clinical trials threatened to eliminate investigator-led research on the use of pharmaceuticals, by imposing conditions like those for initial drug registration, regardless of the nature and purpose of the study.
Popular medical and health beliefs could sometimes be in competition with ARV drugs -- for example, a man with a CD4 count of 20 cells/mm3 thought that because he took antioxidants, ARV drugs were irrelevant to his treatment.
It is unavoidably difficult to compare new drugs with established drugs, given the lack of long-term data. Newer drugs might have fewer long-term effects than older ones, but there was no way to know this in advance.
Drug tolerability is mediated by the way the physician works to support the patient, and apart from cases of severe allergic reaction, most ARV drugs can be made tolerable for most patients. That said, better formulations also helped, and the regulatory environment for approval of reformulations has greatly improved in recent years. However, manufacturing issues have sometimes been a problem. For example, d4T extended release (XR) has been a severe problem for Bristol-Myers Squibb; NFV's 625 mg formulation had also been a problem for Roche Laboratories. Past problems with RTV -- which forced patients to switch from pill to liquid formulation for several months -- were matched by persistent delays in delivering and studying pediatric formulations of newer and much-needed ARV drugs for young children.
Discussing NRTIs, while the newer coformulated pairs -- ABC/3TC and FTC/TDF -- might be more potent and generally better tolerated than ZDV/3TC, there were no long-term data on their toxicities.
Considering FTC, there are no data yet on its durability as compared to 3TC. Will it give rise to peripheral neuropathy? Since this might be expected to take 18 months to emerge, Youle still did not know. There has been an unexpected problem with hyperpigmentation of the palms in African patients. How reversible is this side effect? We still do not know for certain.
Among other NRTIs in development, D-d4FC (DPC 817) may offer the best prospect of activity against virus with high-level resistance to NRTIs.
Turning to NNRTIs, it had taken cohort studies, not clinical trials, to link high CD4 counts to NVP-related liver toxicity. Men with a CD4 count over 400 cells/mm3 and women with a CD4 count above 250 cells/mm3 should not, he said, be started on NVP-based ART.
Despite the 2NN study (which suggested they were equivalent), the relative potency of NVP and EFV remains controversial. However, according to Youle, it is uncontroversial that the single mutation, K103N, still "blows your entire NNRTI options."
The most promising experimental NNRTI is Tibotec Virco's TMC 125, on which he commented that a compassionate access program is now needed for heavily ART pre-treated patients ineligible for current clinical trials. Treatment access has not disappeared as an issue, even in Europe.
In relation to PIs, he observed that the lipid abnormalities that had been associated with their use may be driven by NRTIs as much as by the PIs themselves. Preliminary studies of "monotherapy" with RTV-boosted LPV (LPV/r) had found lipid disturbance to be minimal compared to that seen when LPV/r is used with NRTIs.
Boosted PIs have been gaining on NNRTIs in popularity as first-line ART, if only in relatively high-resource settings. And PI reformulations to reduce pill count have reduced gastrointestinal side effects.
Twice-daily RTV-boosted fosamprenavir (FPV/r), appeared to be slightly less potent at 48 weeks than twice-daily LPV/r, though the difference was not statistically significant. The response did seem to be lower in a further group treated once daily, though this may be a useful option.
Once-daily atazanavir (ATV) 300 mg boosted with 100 mg RTV is being investigated as an option which appears to have greatly reduced impact on lipids compared to other PIs (though, as other contributors later stressed, it is not yet certain that this will translate into better performance in relation to lipodystrophy).
Tipranavir (TPV) -- now in Phase III trials -- seems to be more tolerable in earlier-stage HIV disease than it was in salvage settings, where there were particularly severe gastrointestinal effects.
Discussing new classes of investigational ARV drugs, Youle observed that recruiting ART-naive, relatively early-stage patients to clinical trials of CCR5 inhibitors may be problematic, since those patients who actually need treatment have well-established treatment options available to them already (and may not be particularly willing to commit to close monitoring in extended clinical trials).
Among the treatment strategies which are further from clinical use, short interfering RNAs (RNAi) stood out for him as the only conceivable prospect for eliminating HIV from the body, though this would depend on the ability to target conserved gene sequences and deliver the RNAi efficiently to all target (infected and susceptible) cells. So far, the concept has only been demonstrated in a mouse/herpes model and has years to go before it could enter clinical trials.
While treatment simplification is a worthy goal as a means to improve adherence, decrease pill burden, ameliorate toxicities, and reduce cost, as well as to preserve future treatment options, it is not an end in itself. And, according to Sharon Walmsley (University of Toronto), it should not be pursued at the expense of treatment efficacy, in particular.
Reduced dosing frequency is an advance, although the added benefit in switching from twice-daily to once-daily ART may be much smaller than the benefit of moving away from drugs that have to be taken three or four times a day.
On the other hand, pill or capsule size is definitely an obstacle to adherence: bigger and more numerous pills are harder to take.
An increasing number of drugs can be taken once daily, although there are suggestions that, in some cases, they are less potent or durable -- or more likely to give rise to ARV drug resistance -- than alternatives dosed more frequently. Where this balance of advantages and disadvantages rests will vary between patients.
For a patient to benefit from an ARV regimen, it clearly has to be acceptable to that patient at the time when they are taking it. Social and lifestyle factors may influence what is or is not acceptable, as well as likely medical benefits and risks.
For those who are able to stay on ART, LPV/r + d4T + 3TC has been very effective and durable, but over 250 weeks of an extended clinical trial (Study 720), as many as 30 percent have abandoned that particular regimen. LPV/r is still three tablets, twice a day, hopefully reducible soon to two tablets, twice a day.
A trial in which LPV/r was combined with TDF/FTC and taken once daily gave comparable results to the same combination taken twice daily. However, taking more tablets at one time did seem to give rise to more diarrhea.
The OK study is now examining whether it is possible to simplify LPV/r-based ART by dropping the NRTI components of the regimen once viral load is controlled. A substudy among treatment-experienced patients has found some maintenance failures, though it remains possible that the main study -- among treatment-naive patients -- will be more successful. However, lipids did not seem better among those treated with fewer drugs.
Simplification to an NNRTI with two NRTIs, as in the 2NN study which compared NVP to EFV (and to the combination of both), shows that while these combinations may be simpler to take, they leave new toxicities and some treatment failures in their wake. Perfect adherence may be less important for virological control than with PIs, on account of the longer half-life of NNRTIs, but when failure occurs, the risk of selecting a resistance mutation that will preclude further use of NNRTIs is much higher.
Triple NRTI strategies once seemed to offer once-daily and extremely simple ARV regimens, but there have been unacceptably high rates of virologic failure with ABC + 3TC + TDF, with TDF + didanosine (ddI) + 3TC, and with ABC + ddI + d4T (which also carries toxicity risks that most would reject).
Trizivir (ABC/ZDV/3TC), although clearly less potent than standard ARV regimens, may still be slightly more respectable than some would allow, based on the argument that for a few patients it may be easier to take. Even when it fails, Walmsley argued that the virus remains more treatable than if they were failed by another "more powerful" combination. Most patients who fail on Trizivir have either M184V or wild-type HIV, so would still have multiple treatment options.
Switching from a PI-based regimen to one using an NNRTI or ABC with two NRTIs could be an option for some patients, provided they have been successful on their first regimen and do not have NRTI resistance mutations. Any history of suboptimal therapy with NRTIs should rule out this strategy.
Intermittent therapy could take multiple forms. The STACCATO trial set out to compare continuous therapy with CD4-guided treatment interruption and one week on, one week off intermittent therapy. The last of these arms was abandoned due to too many treatment failures, but the CD4-guided arm failed to show hoped-for improvements in terms of quality of life and unwanted effects.
Finally, Walmsley discussed the impact of the use of single-dose NVP given to a mother at the start of labor, to prevent HIV transmission to her baby, on the woman's subsequent ability to benefit from ART. There is now evidence that the resistance mutations frequently detectable following such a single treatment can indeed reduce the response to subsequent triple ART. There is, therefore, a strong argument to avoid this use of NVP on its own, and to explore strategies for combining it with other drugs to avoid the selection of NNRTI resistance.
In discussion, Hirschel observed that his clinic is now treating African women with PI-based first-line combinations. Youle reported that he was now carrying out ARV drug resistance tests before starting any African patients on ART, as there was a reluctance to disclose past histories of suboptimal ART.
Walmsley was asked whether stopping a triple ARV regimen might be just as likely to lead to NVP resistance as monotherapy, given the longer half-life of NVP compared to NRTIs. She replied that she is now conducting a study in which drugs are stopped at same time and there is intensive testing for resistance mutations.
Hirschel observed that when stopping triple ARV regimens in his clinic, he extends NRTI treatment to cover the period when NNRTI concentrations are declining.
Janossy was a recent recipient of an IAPAC Hero in Medicine award for his work with the AffordCD4 group, an international network of laboratory researchers determined to match expanded global access to ART with better and cheaper monitoring and diagnostics.
Over lunch, Janossy argued for flow cytometry over supposedly lower-tech alternative technologies, to obtain CD4 counts and CD4/CD8 ratios. The CD45 marker enables CD4 and/or CD8 cells to be enumerated as a proportion of all white blood cells, which can be counted accurately and inexpensively in a dual-platform system. Low-cost sample fixing reagents (TransFix), initially developed for quality assurance purposes, could extend sample life to five days without loss of assay reliability. Volumetric flow cytometry offers the prospect of accurate, high-speed, single-platform counts, subject to validation of particular systems.
He cautioned against other assays for CD4, which failed to distinguish properly between T cells and monocytes. Patients with active TB had large numbers of monocytes, which could be mistaken for CD4 T cells in systems that lyse cells before performing the assay. He also cautioned against manual counting systems such as DynaBeads, which are inappropriate for programs due for rapid scale-up.
He also strongly supported observations made by Anthony Fauci (US National Institutes of Health [NIH]) at the XV International AIDS Conference in Bangkok, highlighting the importance of CD8 activation in HIV pathogenesis. Flow cytometry can be used to monitor CD8 activation states, which may be as sensitive as viral load as a marker of viral rebound, and have the potential to be cheaper, simpler and faster.
Specifically, this means using CD38 in conjunction with CD8, which can be offered at a price of US$3 to US$7 per test -- substantially less than any viral load test in prospect.
It has been shown, using blood samples taken during the course of the QUEST study of treatment in primary HIV infection, that CD38 activation rises during primary HIV infection, falls when HIV is treated, and rises rapidly when treatment is discontinued, all correlating with viral load.
Translating this into standardized values which could be used in clinical guidelines clearly needs further research on clinical populations in the settings where these tests would be deployed. However, if it uses the same equipment deployed for CD4 counts, it is obvious that it could be made equally available.
Nelson said that for all the success of the treatments where patients are able to adhere to therapy for extended periods, a substantial proportion of patients are in fact unable to do so, as Walmsley previously observed. When treatment fails, major opportunistic infections, tumors, and deaths can still be seen. The reasons for failure may be attributed to factors related to the virus, the drug (potency or toxicity), or the patient's inability to take the drug consistently, but the impact is comparable whatever the reason(s).
More primary resistance is being seen in the United Kingdom, especially to NNRTIs -- as, he observed, there has been a British "boycott" of PIs in first-line ART for some years. A study of 1,633 treatment-naive patients in Europe from 1998 to 2002 found a significantly higher rate of resistance mutations among those believed (on various grounds) to have been infected within the previous year compared to those believed infected earlier -- 10.9 percent versus 7.5 percent. Among patients actually on ART, the prevalence of at least one resistance mutation varied between 50 percent and 80 percent across three European and one Brazilian populations.
With respect to toxicities, nausea and diarrhea are probably the biggest everyday challenges to proper adherence. However, lipodystrophy as well as cardiovascular and cerebrovascular concerns are real, and may be joined by concerns over bone toxicity and renal toxicity.
When drugs fail, especially through nonadherence or poor drug efficacy, the outcome is likely to be viral resistance, which requires careful and expert evaluation.
It is obviously very unlikely that one dose of any of these ARV drugs will be ideal for all patients, so therapeutic drug level monitoring may also have an important role to play in tailoring treatment to the patient.
Geretti observed that there must be a relationship between viral fitness and drug resistance, given that heavily treated patients may have stable CD4 counts in the presence of detectable viral load. However, it is hard to see how to use this, as viral resistance pathways are unpredictable. Even for M184V with 3TC, it has been very hard to see a clinical benefit from keeping 3TC in the regimen to maintain this mutation.
Is there an advantage to using FTC instead of 3TC? In vitro studies imply that FTC selects for M184V more slowly than 3TC, but it is not clear if this will translate into greater clinical durability.
Is there an advantage to choosing TDF over ABC, aside from the ABC hypersensitivity issue? Her personal view was that ABC and TDF are equivalent, and equally likely to be active following treatment with ZDV.
The activity of ATV/r in the presence of PI-resistance mutations is not clear, though it seems ATV/r may be affected a little more than LPV/r or FPV/r.
In the event of treatment failure on a first-line ARV regimen, she would favor an early switch to try and avoid accumulating multiple mutations in the same viruses. With more highly experienced patients, it would be better to keep them on treatment and wait until multiple effective agents were available for a switch.
Asked about virtual phenotypes, Geretti observed that they inevitably do not work as well for newer ARV drugs as they do for older ones, given the relative lack of data to correlate phenotypes and resistance mutations. The way values are given to physicians -- as X-fold reductions -- needs careful interpretation for clinical relevance.
From reviewing clinical guidelines, therapeutic drug-level monitoring is (rightly) perceived as a niche procedure, to be reserved for circumstances where it is likely to be of most value. This is primarily in relation to PIs but also arguably for NNRTIs, especially EFV. A growing prevalence of HCV-associated liver damage over time may also expand the role of therapeutic drug-level monitoring in ART.
Saye Khoo (University of Liverpool) reported recent findings on the pharmacokinetics of combining boosted PIs, which offer yet another level of complexity for ART, and may point to another potential growth area for therapeutic drug-level monitoring.
The window in which clinical trials to test the value of therapeutic drug-level monitoring might have been possible has probably now closed. To prove added clinical value from using therapeutic drug-level monitoring -- especially when combined with the use of resistance tests -- would now require impossibly large numbers of patients.
Finding that a drug level is within a target range can sometimes be very useful; for example, in establishing that a particular drug interaction with a long-term non-HIV medication, such as an anticonvulsant, is not problematic (so that is one less issue to worry about) or in directing attention to another area of concern.
Inhibitory quotients (IQs) may be of additional value in individualizing ART, although there is a long way to go before these tests are standardized and validated.
The ideal for an IQ is to compare the trough concentration of the drug in a patient (Cmin) with the IC50 value for the patient's own virus (e.g., the phenotypically determined susceptibility of the virus to the drug). In practice, cost dictates that genotypic surrogates must be used. A further refinement is normalization, comparing individual values to those for a population treated with that drug.
Studies using IQs have so far been small, mostly with LPV/r, some with APV. Followup has often been too short -- this should be 24 weeks to 48 weeks for any meaningful results.
He argued that while this might be a helpful guide to dosage for a particular drug in a particular patient, claims that one ARV drug is superior to another based on comparisons of IQ data should not be taken seriously. Also, in isolating one component of an ARV regimen, its clinical meaning is inevitably restricted.
Costs of therapeutic drug-level monitoring in the United Kingdom, offered nationally by the University of Liverpool, are largely defrayed by a consortium of ARV manufacturers: a charge just over US$100 is levied for each drug assayed.
Khoo was asked how to respond to high serum levels of EFV; for example, five times over target, associated with central nervous system side effects. As the dose relationship is nonlinear, he would advise a limited dose reduction (e.g., from 600 mg to 400 mg) followed by retesting.
Opening the second day of the meeting, Stefan Mauss (Center for HIV and Hepatogastroenterology, Düsseldorf) observed that it is a big step forward to be aiming for quality of life rather than fighting death and prolonging survival.
Lipodystrophy is a problem for patients because it is stigmatizing, and has social implications that take it to the top of the list of many patients' concerns. However, research in this area continues to be hampered by the lack of a workable and accepted case definition, and the limitations of available scanning methods. Among those limitations are the fact that scan results are highly sensitive to alignment between the patient's body and the equipment, creating problems with repeatability over time and standardization between centers.
In many cases, facial wasting can be successfully addressed cosmetically with fillers, though there were continuing difficulties in a number of countries in getting reimbursement from healthcare systems. In a minority of cases where the primary problem was a substantial accumulation of visceral fat, recombinant human growth hormone (rHGH) could help correct the problem, at the price of some small additional loss of peripheral fat -- and, again, considerable financial cost.
How real and substantial is the cardiovascular risk of ART? Mauss argued that the signals from large cohort studies are still weak, with small numbers of events in the relatively young treated populations, and methodological limitations due to incomplete and biased data. Nonetheless, patients should be assessed individually for their cardiovascular risks.
Using data from large studies of cardiovascular risk factors in HIV-negative populations, what becomes clear is that these interact in ways that give elevated low-density lipoprotein (LDL) cholesterol a very different significance for some patients than for others. In an older male smoker with a positive family history, it becomes far more important than it would be for a younger non-smoking woman.
There is evidence that different ARV regimens have different implications for lipids, but some patients may have their choice restricted for other reasons, so this probably cannot be the sole basis for choosing between regimens. His take-home message for those of his patients who smoke: "You can stop smoking, but you cannot stop being HIV positive!"
Devaki Nair (Royal Free Hospital, London) is a lipidologist now working with an HIV clinic, in which, as she explained in discussion, she saw her role as strictly limited to treating the lipid problems that were brought to her attention. It was for her HIV specialist colleagues, and not for her, to advise the patient on which ARV drugs they should be taking. When she started the clinic three years ago, Nair said she felt inadequate because the patients expected her to be a "lipodystrophyologist." This highlights one of the key issues in the current management of HIV/AIDS, which is that patients' concerns are not always the same as those of treating physicians.
Changes in lipid metabolism are common in the context of HIV disease and of its treatment, in ways that are likely to increase the risk of ischemic heart disease (IHD), diabetes, and pancreatitis. However, the significance of these changes and the need to treat them must be considered for each patient individually, taking into account "conventional" risk factors for cardiovascular disease. Some of these -- such as smoking and excessive salt intake -- can be modified, whereas HIV status and the need for treatment cannot.
During HIV infection, there are a number of lipid changes that are typical of ANY acute infection, not just HIV. These include:
While a number of mechanisms have been proposed for changes linked to disease and also for changes linked to treatment, she regarded all of them as speculative with no conclusive evidence to identify those of clinical importance.
Serum cholesterol in itself is not a major problem, but does become so when combined with other risk factors for cardiovascular disease.
On assessment of patients, the first priority is therefore to identify potential therapeutic lifestyle changes that can reduce risks without additional medication. For example, smoking cessation, increased exercise, and reduced dietary salt intake.
The primary aim of treatment is to reduce LDL-C, and the most effective drugs for this purpose are statins, which are well tolerated by 90 percent to 95 percent of HIV-positive patients for whom they are prescribed. A secondary aim is to reduce all non-HDL-C lipids, which includes a reduction in TG where these are elevated. This may be achievable with statins alone or may require specific drugs to lower TGs.
In discussion, Nair confirmed that when a patient is offered treatment with a statin, on account of raised cholesterol and other risk factors for heart disease, they would also be offered low-dose aspirin.
The choice of statins is influenced for HIV-positive patients by interactions with the cytochrome P450 system. This means, on the basis of pharmacokinetic studies carried out in AIDS Clinical Trials Group (ACTG) study 5047 with RTV/SQV, that simvastatin and lovastatin should not be used. Pravastatin has no interaction with these PIs, and atorvastatin should start at the lowest recommended dose (10 mg).
Triglycerides raise two concerns. Cardiovascular risk is elevated with moderate elevation of TG (peaking at 4.6 to 8 mmol/l) but actually falls with the highest levels of TG observed. Very high levels of TG probably reflect a different disease process and should be treated on account of the increased risk of pancreatitis, not for the risk of heart disease. There may be different classes of TG with differing effects, just as there are different classes of cholesterol.
High levels of TG also complicate the measurement of cholesterol levels and block the measurement of LDL-C in particular; though it may be assumed that elevation is likely whenever high levels of TG are observed.
Fish-oil supplements would be the initial treatment for high TG, preferred for lack of any interactions with other medications. Supplements are needed to deliver dosages that would be difficult to achieve by eating fish.
Niaspan (nicotinic acid slow release formulation) is better tolerated than in the general population, perhaps because the side effects are moderate compared to those to which HIV-positive patients on ART may be accustomed. And, bile acids have no place in treating people with HIV because of their complex dosing schedules.
In relation to ethnicity, Nair observed that high blood pressure, stroke risk, and diabetes are more common in African populations than among ethnic Europeans. This would argue for increased importance of treating high lipids in those populations.
Changes in body shape through peripheral fat loss and gains in visceral fat are distressing and may be stigmatizing for people living with HIV/AIDS. These are definitely associated with ART, although the linkage is complex and varies between patients as well as between different ARV regimens. There is limited scope for reversing or cosmetically correcting these changes, thus prevention is an inherently more desirable objective. In fact, polylactic acid (New Fill) has been successful in correcting facial wasting, although longer follow-up remains desirable.
Peter Reiss (University of Amsterdam) discussed a number of approaches to treatment, all of which are still experimental.
Recombinant Human Growth Hormone (rHGH) is expensive and is "not a clean drug." The most convincing results have been in reducing excessive visceral fat accumulation, although some loss of peripheral fat was seen at the same time.
Metformin is far cheaper than rHGH and shows some efficacy in reducing fat accumulation, compared to placebo, when taken 500 mg twice daily by 14 patients for 12 weeks. There was decreased weight and waist circumference, but only borderline difference in visceral adipose tissue. There was also some reduction in subcutaneous adipose tissue, which is a concern. A lactate problem seen with metformin treatment for diabetes was not seen here, probably because of the lower dose used. The mechanism by which metformin raises lactate levels is unrelated to mitochondrial function and is therefore unlikely to compound the risks associated with NRTIs.
Rosiglitazone can protect liposomes from PI or NRTI damage in vitro, but the largest clinical trial so far, which evaluated limb fat by DEXA at baseline, 24 weeks, and 48 weeks found no overall difference from placebo. Other studies have also failed to show any consistent gain in peripheral fat, though there may be some evidence for improvements in insulin sensitivity.
NRTI comparative and switching studies do support the idea that some NRTIs are more, and others less, damaging in terms of lipoatrophy. ACTG 384 showed that limb fat declined more rapidly in a group treated with ddI/d4T than in a comparison group with ZDV/3TC.
In discussion, the consensus seemed to be that switching d4T for ZDV would not generally be expected to reverse lipoatrophy but at best to slow the rate of decline.
On the other hand, the MITOX study showed that switching from ZDV or d4T to ABC could lead to some reversal of lipoatrophy, and when ABC was used in place of ZDV or d4T from the outset, limb fat increased through 72 weeks rather than first rising and then declining.
There is also promising preliminary evidence that TDF + 3TC + EFV is substantially better than d4T + 3TC + EFV in terms of loss of limb fat.
As for ATV/r, although there is evidence that this is superior to other PIs in relation to lipid metabolism, it is still unclear if this will translate into better performance in regard to lipodystrophy. The problem in assessing this, despite three-year follow-up in clinical trials, is that trials have often combined ATV/r with d4T.
The continuing lack of simple and practical methods for assessing fat loss and inability to agree on definitive clinical case definitions for lipodystrophy has limited data collection in trials. Even Gilead's TDF trials have only included DEXA scans relatively late. DEXA scans, while arguably among the better measures available, are still sensitive to orientation and fail to measure socially vital facial wasting. Trials are geared to 48-week data for drug approval, which may not be long enough to see differences in lipoatrophy.
The long-promised d4T extended release formulation should be evaluated for lipodystrophy from the outset of clinical trials, Reiss observed.
Asked about studies of dose reductions of d4T and other drugs as a strategy to limit lipodystrophy, he argued that it was hard to justify such studies.
In discussion, a North-South split emerged. Hirschel said that as d4T is "pretty dead" in Western Europe and North America, there was no rationale for Bristol-Myers Squibb to invest in further studies. Reiss would prefer mass access to better drugs such as TDF, but others observed that cost constraints will continue to ensure that d4T is widely used. In Thailand, for example, switching from d4T to ZDV in combination with 3TC and NVP increases the daily cost of treatment from US$1 to US$1.50. In Botswana, where ZDV/3TC is the first-line option (combined with NVP or EFV) there have been deaths from anemia. However, concerns over d4T-related lipoatrophy are just as high as in Europe or North America.
Recent claims of an increase in HIV cases in Britain and Switzerland need to be treated with more caution than has too often been the case. The impression given to the public of a rising threat has sometimes been misleading.
In 2003, the Stop AIDS Campaign ran an advertising campaign saying "a 25 percent increase in cases of HIV last year: Is that reason enough for the Swiss to start taking AIDS seriously again?"
Hirschel argued that although there are very good reasons to take AIDS seriously, this may not have been one of them, and identified a series of "traps" into which researchers, HIV agencies, the media and public could fall.
In conclusion, while there is some evidence of an upturn in diagnoses of sexually transmitted infections in the United Kingdom between 1990 and 2003, and of an increase in HIV diagnoses, especially since 1998 (though this does include some "old" infections), there is next to no evidence for an ongoing rise in HIV in Switzerland. In fact, the number of cases reported in 2003 was below the number in 2002 -- but this received no coverage.
Renato Maserati (University of Pavia) reviewed the meaning of disease prevention in relation to HIV, beginning with HIV transmission. While a vaccine remains elusive, treatment that suppresses viral load is likely to limit transmission by sexual routes as well as from mothers to infants. There is limited evidence for superinfection with HIV, although the number of reported cases has been sufficient for some to argue for sustaining safer sex among HIV-positive people, on or off ART.
Looking at reasons given for not using condoms in a recent telephone survey of adults, cost was rarely cited. Yet in Louisiana, the introduction in 1996-1997 of a charge of 25 [US] cents each to buy condoms that had been distributed freely for the previous three years, led to a 98 percent reduction in usage. Maserati argued that even in the world's richest country, the correct price for condoms is "free."
While he was skeptical about the existence of a separate compartment for the virus in genital secretions as distinct from plasma, the potential value of treatment in controlling transmission was limited by misperceptions of their own viral load by people living with HIV/AIDS, and a continuing tendency for condom use to be less frequent or consistent in regular ongoing relationships than with "casual partners."
Globally, HCV has an estimated prevalence of more than 170 million, compared to some 35 million or more people living with HIV. Yet there are only two licensed drugs for HCV treatment.
HCV infection rates among people with HIV vary across Europe, being highest in Southern Europe and Eastern Europe, where the HIV epidemic is most strongly driven by transmission among injecting drug users. HIV coinfection appears to accelerate fibrosis and cirrhosis among people with HCV. Fibrosis is influenced by CD4 count (below or above 200 cells/mm3), age at infection (below or above 25 years), male sex, and alcohol consumption (below or above 50g/day).
As overall mortality rates among people with HIV decline, so the proportion due to liver disease associated with HCV increases.
Some studies -- such as the Swiss cohort study -- but by no means all, find accelerated HIV progression in coinfected populations.
While it is possible that effective HIV treatment will lead to improved immune control over HCV, it is abundantly clear that ART-associated hepatotoxicity is greater in coinfected people. Similar issues arise for isoniazid and rifampicin in TB treatment.
Before the mid-1980s, HCV was widely transmitted through blood and pooled blood products. Effectively, every person with hemophilia treated with factor VIII before 1985 is now HCV positive.
Other transmission routes have included tattoo parlors, especially in the 1970s and 1980s; medical treatment with intramuscular injections for bilharzia in Egypt; possibly intranasal drug use; and some cases of household transmission, and through other routes such as poor hygiene in barber shops.
More unusual possibilities, which had given rise to either HBV or HCV outbreaks, included "alternative therapy" (an "ozone clinic" which gave rise to 150 cases of HBV) and 10 cases of HBV among gay men in Brighton who had shared a needle at a sex party to administer Caverject.
A striking rise in new cases of HCV infection has been seen between 2001 and 2004 among HIV-positive gay men in London and Brighton, in particular. It is particularly striking as a large-scale anonymized serosurvey of patients at 14 genitourinary medicine clinics in the United Kingdom found an HCV antibody prevalence below 1 percent among patients who did not report injecting drug use.
All of the men included in these reports have previously tested HCV negative, arguing against an epidemic driven purely by screening. Fifty-two new cases had been seen among 1,200 gay men treated at the Royal Free Hospital's clinic, with comparable numbers at two other London clinics and one in Brighton, on the South Coast (a city with a large gay male population and an HIV prevalence rate comparable to London).
There was a strong association between HCV transmission and "fisting" -- which was reported in all of the cases seen at the Royal Free Hospital. Unprotected anal intercourse was also very common and many men reported intranasal use of cocaine and/or ketamine, which could take the form of "bullets" passed from one person to another. A small minority, between 2 percent and 5 percent, reported injecting drug use.
Sanjay Rasiklal Bhagani (Royal Free Hospital, London) gave an interim report of an ongoing study of response to treatment in this population. The majority of cases were genotype 1, none were genotype 2, and there were equal numbers that could not be typed, or were genotype 3 or 4. Some 25 percent spontaneously cleared HCV, as detected by repeatedly undetectable viral load (using bDNA assays with a 50-copy threshold). Among 15 who started treatment, with pegylated IFNa 2B and ribavirin, 71 percent (7/9) had undetectable viral load at end of therapy (48 weeks), implying clearance. One patient was lost to follow-up, one stopped due to drug intolerance, and three stopped due to depression. Other adverse events reported included anemia (no treatment or dose changes needed), a transient decline in CD4 counts (by a median of 128 cells per microlitre), and neutropenia (18 percent of patients requiring intermittent G-CSF treatment). HIV viral load was not affected.
British International Development Secretary Urges European Union Ministers to Approve HIV/AIDS, Global Health Action Plan
This article was provided by International Association of Physicians in AIDS Care. It is a part of the publication IAPAC Monthly.