Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

NEW FRONTIERS - Fifth International AIDS Society (IAS)

Cape Town, South Africa / July 19-22, 2009

More than 10 years after highly active antiretroviral therapy (HAART) transformed HIV from an almost inevitably fatal disease into a chronic infection, the average age of patients with HIV has shifted upwards, placing an increasing proportion of the 60,000 Canadians living with HIV into an age group in which major organs are at risk due to the aging process. Preventing and treating these diseases are essential for extending the survival of patients with HIV. However, priorities must be defined: the first priority is HIV suppression, which means an effective and well-tolerated regimen.

“We need to control HIV first and then all the rest comes afterwards,” confirmed Dr. Peter Reiss, Professor of Medicine, Department of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center, Amsterdam, The Netherlands. He stressed that regimens which have demonstrated reliable and sustained efficacy in the control of HIV should be changed cautiously if the risk is inferior HIV control. Once resistance develops, therapeutic options diminish. In most patients, the risk from immunodeficiency will far exceed the risk of non-AIDS-related morbidities associated with aging.

Background

In all patients, the primary goal of antiretroviral therapy (ART) is undetectable viremia (<50 copies/mL). This is achieved with effective therapies that are well tolerated and sufficiently convenient to permit sustained and strict adherence. Without adherence, regardless of the potency of the combination of the agents, HIV replication will rapidly recommence, leading to formation of resistant strains. For this reason, the improvement in ARTs depends on developing both new classes of therapies and better tolerated or more convenient therapies within existing classes. However, the aging of the HIV-infected population has added a new variable to antiretroviral drug selection: individualizing therapy to avoid exacerbating age-related processes.

Individualization of treatment is critical because not all patients are susceptible to the same risks from aging. For example, some may be more vulnerable to renal failure or heart disease, while others may be most at risk for cognitive impairments. This point is important because initial attention about the problem of accelerated aging was largely focused on cardiovascular (CV) risk stemming from the association of some protease inhibitors (PIs) with adverse effects on lipid metabolism. However, a variety of other organ systems have subsequently been identified to be vulnerable to accelerated aging in patients with HIV, and these do not necessarily occur in the same individuals. As most antiretroviral agents pose at least some risk of adverse events that may affect major organ systems, it becomes essential to assemble compounds in HAART that provide the best balance of risk and benefit for the particular individual.

Holistic Approach to HIV Treatment

The management of sometimes competing health risks within the critical issue of HIV suppression has produced a demand for a holistic approach to HIV care, particularly in the aging patient. Yet even within the holistic approach, no single clinical issue after effective HIV control should obscure others, according to Dr. Carlo-Federico Perno, Department of Experimental Medicine, University of Rome, Italy. Many aging individuals have multiple health issues, so attention to CV status in exclusion of other potential problems is a mistake. Moreover, he, like others, indicated that relative success in sustained suppression of HIV cannot be attributed to drug potency alone.

For example, Dr. Perno presented retrospective data suggesting that non-thymidine analogues such as tenofovir (TDF) and emtricitabine (FTC) are associated with more resistance than thymidine analogues such as zidovudine (AZT) and stavudine (d4T). However, Dr. Perno indicated that this might not be a potency issue. Rather, the importance of tolerability, adherence, convenience and other issues all conspire to determine whether one agent or one set of agents will provide an optimal outcome in an individual patient. For otherwise effective agents, average rates of efficacy may be less important than an individualized approach to drug selection that yields a good match for the given patient.

The thymidine analogues are particularly interesting for considering individualized therapy in an aging population. In a series of analyses from the D:A:D cohort database, abacavir (ABC) was associated with a significant increase in the risk of myocardial infarction (MI) relative to other nucleoside reverse transcriptase inhibitors (NRTIs). Conversely, ABC may be more attractive in patients with renal impairment. Several agents, including TDF, appear to pose an increased risk of renal dysfunction relative to other NRTIs as well as other ARTs. In turn, there is growing evidence that renal impairment may mediate other pathophysiological processes such as abnormal bone metabolism.

“The kidneys, parathyroid glands and bone are linked through calcium and phosphate homeostasis, thus kidney disease may result in osteomalacia, osteoporosis and bone fractures,” explained Dr. Patrick Mallon, Lecturer, School of Medicine and Medical Science, University College, Dublin, Ireland. Although he cautioned that TDF is not the only ART to be associated with increased risk of impaired kidney function and calcium dysmetabolism, he indicated that alternative NRTIs might be appropriate in individuals at risk for renal impairment.

Drug Channelling Detected

Indeed, the reduced risk of renal impairment on ABC relative to TDF has been raised as a potential explanation for the D:A:D results. In an analysis performed by Dr. Dominique Costagliola, INSERM, Paris, France, the risk of both MI and renal disease were strong influences on channelling patients to ABC rather than other NRTIs, including TDF. She also noted substantial inconsistencies between D:A:D and other large studies regarding the MI risk of ABC.

“Without D:A:D, we would have found nothing,” contended Dr. Costagliola, whose assertions were supported by another analysis presented by Dr. Roger J. Bedimo, Veterans Administration (VA) North Texas Healthcare System, Dallas. Based on the VA database with more than 19,000 patients followed for a median of 3.9 years, far more individuals with renal impairment (glomerular filtration rate <60 L/min) were initiated on ABC than TDF (12.3% vs. 7.2%; P<0.0001). This is an important confounding factor because this degree of renal impairment was associated with a fourfold increase in the rate of MIs.

While both investigators are planning more studies to unravel the relative importance of renal and CV risks among NRTIs, it is also important to recognize that traditional risk factors, such as smoking or elevated lipids, pose far greater CV risk and a far more important target for risk management than ART choice. These relative risks are often overlooked.

However, other major organ systems are equally important. Recently, there has been substantial attention paid to the relative central nervous system (CNS) penetration of ARTs, which is relevant to protection from cognitive loss. A common but under-recognized problem in HIV patients, poor control of HIV in the CNS stems from differences in the ability of ARTs to cross the blood-brain barrier (BBB), according to Dr. Scott Letendre, Assistant Professor of Infectious Diseases, University of California, San Diego. Based on the potential importance of BBB penetration, Dr. Letendre and co-investigators have recently developed a three-tier rating system with which to compare all ARTs. The lowest tier, 1, represents poor penetration while the highest rating, 3, signals good penetration.

Within each class, drugs differ markedly. For example, ABC and AZT have the highest penetration of the BBB, while TDF has the lowest among NRTIs. Among PIs, ritonavir boosting places amprenavir, indinavir and lopinavir in the top rank, while ritonavir itself, saquinavir and ritonavir-boosted tipranavir are in the bottom rank. Penetration rank has correlated with HIV suppression in the CNS. These data suggest that ARTs with a high BBB penetration should be used first in an individualized approach to therapy in patients who demonstrate cognitive loss.

Inflammation as Risk of Complications

A holistic approach to controlling the aging process in HIV patients is needed because many diseases identified as non-HIV-related have been mislabelled, according to Dr. Wafaa El-Sadr, Director, International Center for AIDS Care and Treatment Programs, Columbia University, New York City. In her presentation, she suggested that the pro-inflammatory state driven by HIV may be the link for the high rates of age-related CV, renal and hepatic diseases. Citing preliminary data from the SMART (Strategies for Management of Antiretroviral Therapy) trial, which has associated HIV with increased expression of such inflammatory markers as C-reactive protein (CRP), Dr. El-Sadr speculated that it might be important to address control of inflammation independent of control of HIV.

In the past, treatment guidelines generally provided a step-by-step approach to optimal care of patients with HIV, but the importance of selecting the appropriate agent for the right patient is increasingly being recognized as crucial to optimal care. Selection must be driven by all the factors important to adherence and ability to permit sustained HIV suppression, but the so-called non-HIV-related morbidities may relate as much to the risks of uncontrolled disease as to the risks of specific therapies. More data are needed to confirm links between specific antiretroviral agents and outcomes, particularly when HIV is otherwise well-controlled. This is an important shift in direction.

“After HAART, there was decrease in AIDS-related mortality but no decrease in non-AIDS mortality and even a suggestion of an increase in mortality over the last several years,” observed Dr. El-Sadr. While data from New York City recorded a 90% reduction in mortality rates after the introduction of HAART, non-HIV mortality remains almost unchanged (Figure 1). An advocate of individualized HAART to avoid exacerbating progressive age-related diseases, Dr. El-Sadr emphasized that the need for individualized care stems from the fact that relative risks are different for each individual.

Figure 1.

Expansion of a Therapeutic Class

The ability to focus on age-related diseases in HIV patients is wholly dependent on the pipeline of new ARTs that permit infection control to be maintained even in highly treatment-experienced patients. Of emerging therapies, one of the most significant may be a new agent in the integrase inhibitor class, the fifth class of ARTs. Like second-generation agents in previous antiretroviral classes, the newest agent, S/GSK1349572, appears to be following a common path of drug development. While the new molecule retains the efficacy of the first-generation agent, raltegravir, it offers several potential advantages, including more convenient dosing and a unique resistance profile.

“Next-generation integrase inhibitors need to show improvement in resistance profile as well as convenience in dosing. Specifically, they should aim for once-daily dosing as well as a unique resistance profile,” stated Dr. Sherene Min, Department of Medicine, University of North Carolina, Chapel Hill. Presenting new data on S/GSK1349572, Dr. Min maintained that initial results have been promising.

In the study presented by Dr. Min, 35 patients with a viral load of at least 5000 RNA copies/mL and >100 CD4+ cells were randomized to 2 mg, 10 mg or 50 mg of S/GSK1349572 or to placebo. All doses were administered once daily.

Viral load reductions were measured on day 11. On day 11, viral loads were unchanged in the placebo group but reduced substantially by all three doses of the integrase inhibitor, ranging from 1.51 log10/copies with the 2-mg dose to 2.46 log10/copies with the 50-mg dose. Dr. Min characterized the antiviral activity of this experimental integrase inhibitor as “unprecedented.” Similar studies conducted with the only licensed integrase inhibitor, raltegravir, or another experimental agent, elvitegravir, had not previously achieved this degree of viral suppression in similar short-term trials.

On the highest dose, 70% of patients achieved a viral load <50 copies/mL despite treatment with a single agent. Even in the two lowest dose groups, 56% achieved a viral load <400 copies/mL on the single-agent therapy. Except for headache, which occurred in 20% of those on the highest dose of the integrase inhibitor, the type and rates of side effects were similar in the active therapy and placebo groups.

Study Findings

Interest in the clinical potential of S/GSK1349572 has been encouraged by a series of in vitro studies that suggest this agent may have a high genetic barrier to resistance relative to other integrase inhibitors. A series of experiments was conducted with HIV virus capable of replicating in the presence of raltegravir at a concentration of 4000 nM. Results indicated that there was a dramatic reduction in HIV replication at concentrations of S/GSK1349572 as low as 32 nM and no replication at concentrations of 160 nM. There has also been limited cross-resistance to the experimental integrase inhibitor elvitegravir in similar studies.

New drug classes generally provide the greatest opportunity to treat resistant HIV, but resistance to one agent within a given class does not necessarily mean cross resistance to others in the same class. For example, the PI tipranavir was often able to achieve undetectable viremia in patients with key resistance mutations to other PIs, and several non-NRTIs in development appear to pose a low risk of cross resistance to existing non-NRTIs.

However, in addition to the efficacy of the drugs in the regimen, HAART must possess characteristics, such as tolerability and convenience, that promote compliance. This was a point emphasized by Dr. El-Sadr. She indicated that the story of HIV treatment began rather than ended when a combination of compounds was finally found to provide sustained HIV suppression.

“After the introduction of HAART in 1996, there was a decrease in death hazard by almost 95%,” explained Dr. El-Sadr, but “with the benefits there are also the risks,” which include loss of efficacy. For this reason, there must be continuous development of new options in regard to HIV control that include drugs which lend themselves to simple regimens or that pose a low risk of adverse events that may jeopardize compliance. With strict compliance, persistent suppression of HIV replication means a low risk of developing resistance.

Summary

As the HIV epidemic matures, the primary goal of undetectable viremia remains unchanged. While it is now important to individualize therapy to minimize the contribution of treatments to age-related diseases, it is also essential to stay ahead of drug resistance. This may be entering a new phase as the focus shifts from introducing newer agents that not only pose a low risk of cross resistance to existing agents but may also provide advantages in regard to tolerability and convenience of dosing. These latter attributes are not trivial. The effort to keep drugs viable in an infection with a strong potential for quickly generating resistant strains depends on very strict compliance, which is influenced by both tolerability and the burden of adhering to the assigned regimen. New data on experimental integrase inhibitors promise that upcoming agents will expand this class by offering strategies with unique characteristics, including a non-overlapping resistance profile.