HIV Update From the 2009 International AIDS Society Conference-Cape Town, South Africa

The Fifth International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2009) was held in Cape Town, South Africa, from July 19 to 22, 2009. More than 5500 delegates from more than 100 countries attended this annual event.

This article summarizes only a few of the more than 1000 presentations and focuses on new information on antiretrovirals. The entire conference program is available on the IAS 2009 conference Web site (http://www.ias2009.org).

Antiretroviral Comparison
The 84-week results from the African American Rosuvastatin Investigation of Efficacy and Safety (ARIES) trial have important implications for treatment, since simplification of regimens will result in fewer adverse events, lower costs, and greater convenience for patients.¹

Kathleen Squires, MD, of Thomas Jefferson University in Philadelphia, presented the 84-week results of the ARIES trial designed to test the efficacy, safety, tolerability, and durability of atazanavir (ATV, Reyataz) 300 mg boosted with ritonavir (Novir) 100 mg (ATV/r) plus abacavir/lamivudine (ABC/3TC, Epzicom), each administered once daily for 36 weeks. This was followed by randomization to either a simplified protease inhibitor component of unboosted ATV 400 mg or continuation of ATV/r for an additional 48 weeks, each in combination with fixed-dose combination ABC/3TC in antiretroviral-naive, HLA-B*5701–negative patients.

Eligibility for randomization at week 36 required an HIV RNA level of less than 50 copies/mL and no virological failure. Both regimens performed equally well at 84 weeks. The immunological outcomes were equivalent, with median CD4+ cell counts of 240/µL and 259/µL in the ATV and ATV/r groups, respectively. The proportion of persons who achieved less than 50 copies/mL at week 84 was 86% and 81% in the ATV and ATV/r arms, respectively. Similar and sustained efficacy was demonstrated regardless of baseline HIV-1 RNA level in the simplification and continuation regimens. After randomization, the percentage of grade 2-4 adverse effects was higher in the ATV/r group, 14% compared with 10% in the ATV arm.

Maraviroc: 96-Week Results
The CCR5 entry inhibitor maraviroc (Selzentry) has been shown to be equivalent to efavirenz (Sustiva) in terms of immunological and virological outcomes after 96 weeks of use.² (In 2007, maraviroc was approved for use in treatment-experienced patients with HIV-1 infection.)

Michael Saag, MD, of the University of Alabama at Birmingham, presented the results of MERIT, a phase 3 randomized, blinded, noninferiority trial. This trial compared the safety and efficacy of maraviroc 300 mg twice daily with that of efavirenz 600 mg once daily, both administered with fixed-dose combination zidovudine/ lamivudine (Combivir), in treatment-naive patients with CCR5-tropic HIV-1 infection.

The initial 48-week results of MERIT were presented in 2007. Approximately 15% of patients originally classified at baseline as having CCR5-tropic virus infection were reclassified as having dual or mixed tropic virus infection using enhanced tropism testing. This resulted in a reanalysis of the original study results excluding these patients (MERIT ES).

At 96 weeks, both the maraviroc and efavirenz arms had similar percentages of patients achieving undetectable HIV RNA levels (less than 50 copies/mL) (58.5% and 62.4%, respectively). Both arms showed increases in mean CD4⁺ cell counts, but this was greater in the maraviroc arm, with a median change from baseline of +212 compared with +171/µL. An analysis of lipid profiles revealed that maraviroc was associated with fewer lipid abnormalities, with both low-density lipoprotein and total cholesterol levels lower in patients receiving maraviroc. Discontinuation rates were similar for efavirenz (34.9%) and maraviroc (33.1%). No excess of malignancies was noted in patients taking maraviroc.

New Method to Determine CCR5 Tropism
A genotypic test is just as accurate as a more expensive tropism test in determining which treatment-experienced patients are suitable for treatment with maraviroc, researchers from the University of British Columbia reported.³ The finding opens the prospect for faster and less expensive testing to determine susceptibility to CCR5 inhibitor treatment and coincides with a reanalysis of 96-week results from the MERIT study discussed above.

The so-called tropism assay (Trofile), which can establish whether HIV is susceptible to a CCR5 inhibitor, is the only means of determining which patients will benefit from a CCR5 inhibitor. The drawbacks of this assay are its cost (launched in 2007 at about $1950 per test), the turnaround time for results (up to 3 weeks), and the fact that it can be used only when the HIV RNA level is higher than 1000 copies/mL.

The alternative is to look at a region of HIV’s envelope protein, the V3 loop, to determine tropism. This can be done with a standard genotyping test for drug resistance, at no extra cost, according to the study presenters. The genotype is then used to predict the phenotype, or tropism, an approach called “geno2pheno.” The test, SensiTrop II (Quest Diagnostics), is now commercially available.

Harrigan and associates,³ from the University of British Columbia Centre for Excellence in HIV/AIDS in Vancouver, analyzed the performance of the 2 tests in predicting virological response to maraviroc in treatment-experienced patients who participated in maraviroc’s pivotal trials. Using stored blood samples, the researchers compared the ability of the baseline testing methods to predict virological response to treatment at weeks 8 and 24.

They found that the Trofile assay and genotyping produced comparable results in terms of detecting viral phenotype and in predicting virological response. Based on viral tropism and the degree of genotypic sensitivity to drugs in the background regimen, the researchers were also able to predict the degree of virological suppression and the proportion of patients with HIV RNA levels of less than 50 copies/mL, and they found very high levels of agreement between the 2 assays. Patients identified as having R5-tropic virus infection had almost identical degrees of viral load reduction (22.5 log₁₀ at week 8).

The investigators concluded that the V3 genotyping shows promise as a significantly faster and more cost- effective way to correctly identify patients who would benefit from treatment with CCR5 antagonists, such as maraviroc. The study was supported by maraviroc’s manufacturer, Pfizer. According to Pharmacogenomics Reporter (http://www.genomeweb.com), Monogram Biosciences is testing fewer than 2500 samples per quarter for CCR5 tropism, indicating the small size of the market for a drug that was initially expected to be a blockbuster HIV product.

Since pricing and reimbursement for this new assay may vary, providers are advised to check with third-party payers and their laboratory before ordering.

Update: Abacavir and Cardiovascular Disease
As patients with HIV infection live longer, medical problems associated with aging and lifestyle take on new importance. Two studies presented in Cape Town found no association between the use of abacavir (Ziagen) and increased risk of heart attack or stroke and highlighted the importance of confounding risk factors.^4,5

In 2008, researchers first reported that participants in the large Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study who used abacavir were at greater risk for heart attacks than those who took other nucleoside reverse transcriptase inhibitors (NRTIs).⁶ Several subsequent studies examining this link, however, have produced conflicting results.

In the first study, investigators searched the US Veterans Health Administration’s Clinical Case Registry to identify patients who had experienced heart attacks or cerebrovascular events, such as strokes.⁴ Patients were allocated to 1 of 4 categories according to the type of antiretroviral therapy they received between 1996 and 2004:
• Combination antiretroviral therapy including abacavir.
• Combination antiretroviral therapy including other NRTIs but not abacavir.
• Antiretroviral treatment that does not meet the definition of a highly active antiretroviral therapy (HAART) regimen.
• No antiretroviral therapy.

A statistical analysis assessed the link between these different treatment strategies and heart attacks or strokes and how this was influenced by other risk factors, including demographic characteristics (sex, age); traditional cardiovascular risk factors (elevated blood lipid levels, smoking); and coexisting medical conditions, such as high blood pressure, diabetes, hepatitis C, and kidney disease.

The present analysis focused on kidney disease, a recognized risk factor for heart disease in the general population. Patients with kidney problems are more likely to be given abacavir because the alternative NRTI often used instead, tenofovir (Viread), can cause kidney dysfunction in a small proportion of susceptible patients.

A total of 19,424 patients were followed for a median of close to 4 years, representing 76,376 person-years of follow-up. A total of 278 heart attacks and 868 strokes were diagnosed. Those who had heart attacks were significantly more likely to have traditional risk factors as well as hepatitis C and kidney disease.

The overall heart attack rate was 3.69 per 1000 person-years, while the overall stroke rate was 11.68 per 1000 person-years. In a multivariate analysis, the associations between abacavir and heart attack or stroke were not statistically significant.

The researchers noted that patients with kidney disease were significantly more likely to have heart attacks and more likely to be given abacavir, indicating that kidney dysfunction may be an important confounding factor. In fact, kidney disease was associated with a significantly higher risk of heart attacks and strokes even when no other risk factors were considered.

The second study was a retrospective analysis of data from the Spanish BICOMBO study, a randomized comparison of abacavir plus lamivudine (Epivir) versus tenofovir plus emtricitabine (Emtriva).⁵ The original study included more than 300 patients with suppressed viral load who were randomly assigned to switch to the ABC/3TC fixed-dose combination or tenofovir/emtricitabine (TDF/FTC, Truvada) combination pill. This analysis included a subset of 80 patients. Of these, 46 were taking ABC/3TC; the rest were being treated with TDF/FTC. Participants had been receiving antiretroviral therapy for an average of nearly 4 years.

The investigators measured several biomarkers associated with an increased risk of cardiovascular disease. These included C-reactive protein, monocyte chemoattractant protein-1, osteoprotegrin, adiponectin, interleukin-6, interleukin-10, tumor necrosis factor- α, E selectin, P selectin, D-dimer, and insulin.

There were no significant differences in baseline biomarker levels between the abacavir-treated patients and those taking tenofovir. After a year of treatment, changes in all biomarker levels were relatively minor and were comparable for the 2 groups. The researchers concluded that among otherwise healthy HIV-infected patients with a suppressed viral load, starting abacavir therapy did not lead to significant changes in biomarkers of inflammation, coagulation, blood vessel dysfunction, or insulin resistance. These results “argue against the involvement of abacavir in any of these mechanisms” and do not explain the higher risk of heart attack seen in some recent cohort studies.

The results of these studies settle the debate about whether abacavir is a risk factor for cardiovascular events and emphasize the importance of looking carefully at potentially confounding factors.

CD4 Count and AIDS-Free Survival
A study by Loutfy and associates⁷ of the University of Toronto underscores the importance of immunological recovery-a CD4⁺ cell count above 200/µL-in achieving good outcomes in HIV care. A discordant response to antiretroviral therapy characterized by an undetectable viral load without improvement in the CD4 count does not adequately protect against disease progression. This appears to be more pronounced in HIV-positive patients who do not begin treatment until their CD4⁺ cell count is less than 200/µL.

The researchers retrospectively reviewed the medical records of HIV-positive patients starting triple-drug HIV treatment, beginning in 2000, at clinics in British Columbia, Ontario, and Quebec.⁷ The analysis included 1721 patients whose viral load measurements and CD4 counts were monitored for at least 2 years.

At initiation of treatment, the median CD4⁺ cell count was 171/µL and the median HIV RNA level was 100,000 copies/mL. After 2 years, the median CD4⁺ cell count was 410/µL (2-year median change from baseline, 230/µL). Despite undetectable viral loads, CD4 counts did not increase to more than 200/µL in 176 patients after 2 years of treatment.

There were 43 clinical events (new AIDS-related disease in 7, or death in 36) during follow-up. Injection drug use and a CD4⁺ cell count below 200/µL after 2 years of treatment were significantly associated with a greater risk of a clinical event.

Men, persons with a history of injection drug use, those entering the study with very low CD4 counts, and those beginning treatment with a lopinavir/ritonavir (Kaletra)-based regimen were less likely to have their CD4⁺ cell count increase above 200/µL.

These results underscore the need to closely monitor both viral load and CD4 count responses to treatment, according to the authors. Moreover, they highlight the importance of earlier access to HIV testing and antiretroviral therapy before CD4+ cell counts fall below 200/µL.

Antiretrovirals as Prevention
In his plenary remarks, Reuben Granich, MD, medical officer for HIV/TB in the HIV/AIDS Program of the World Health Organization, examined the role of potent, combination antiretroviral therapy as part of a combined approach to HIV prevention that includes behavioral, structural, and biomedical prevention interventions.⁸ Granich outlined the context and basic assumptions regarding this emerging strategy, including when to start antiretroviral therapy for maximal clinical and prevention benefit. He also highlighted the essential roles of human rights, dignity, and community engagement in the use of HAART for prevention and discussed the outstanding biological, feasibility, impact, and cost issues related to research in this arena.

The premise is based on the assumption that earlier, effective HIV treatment can reduce HIV transmission and is effective as a prevention tool. Before going any further, here are the assumptions: “The expansion of HIV testing programs and the advocacy of universal testing and treatment of those who test positive as a means of prevention must not violate the human rights of target populations,” according to Julio Montaner, MD, president of the International AIDS Society.⁹ In other words, testing remains voluntary and confidential.

Several speakers discussed scaling up of HIV testing to support the “Treatment as Prevention” initiative. They concluded that the new outcome for HIV testing should be the delivery into medical care of patients who test positive, in contrast to the old paradigm of merely giving patients their test results.

HIV and Cardiovascular Disease
Two studies using new methods to detect vascular changes help in our understanding of cardiovascular disease and HIV.^10,11

The first study used high-resolution B-mode ultrasonography of the right common carotid artery to test the hypothesis that duration of HIV infection is associated with carotid artery stiffness.¹⁰ Carotid artery stiffness was quantified using a distensibility index-specifically, a ratio of arterial diameter at systole to arterial diameter at diastole. The researchers found that long-term HIV infection was independently associated with the carotid artery’s stiffness, resulting in higher systolic blood pressure.

Seaberg and colleagues¹⁰ presented results of 115 HIV-positive men from the Multicenter AIDS Cohort Study, the world’s longest-running HIV cohort study (launched in 1984), enrolled between 2004 and 2006 into a substudy investigating coronary atherosclerosis. Arterial function in these men was compared with that of 325 HIV-negative men. Nearly half (56) of the HIV-positive men had had the diagnosis for more than 15 years, and 91% were receiving antiretroviral therapy. The mean age was 52 years; 74% were white, and 19% were classified as obese (body mass index [BMI] more than 30 kg/m²).

The researchers performed an analysis to determine what factors were associated with hardening of the arteries. The analysis took into consideration factors associated with a risk of heart disease (age, race, smoking, family history, diabetes, cholesterol levels, and BMI) as well as HIV-related factors (duration of HIV infection, CD4 count, viral load, and use of antiretroviral drugs).

Multiple regression analysis revealed that older age, higher systolic blood pressure, and HIV infection for more than 15 years were independently associated with decreased carotid artery distensibility (P < .05). The magnitude of the decrease in carotid distensibility among men infected with HIV for more than 15 years (213.4%) was comparable to the effect of aging 10 years (211.5%) and a 10 mm Hg increase in systolic blood pressure (211.5%). There was a pronounced threshold effect after 15 years of HIV infection and no association between HIV infection and arterial hardening in men who had had a shorter duration of infection.

Seaberg commented that it was impossible to tell whether his findings were directly associated with the length of HIV infection or whether some other aspect in the medical history of a fairly select group of long-term HIV survivors from the pre-HAART era had caused the increased rate of arterial stiffness.

In the second study, Kristoffersen and colleagues,¹¹ of Copenhagen University in Denmark, monitored coronary artery perfusion in 11 men starting antiretroviral therapy for the first time. The men were given coronary perfusion tests before they started antiretroviral therapy, then were given tenofovir/emtricitabine/efavirenz (n = 9), zidovudine/lamivudine/efavirenz, or zidovudine/ lamivudine/raltegravir. Using positron emission tomography and CT scans to map coronary perfusion, the researchers found a 31% reduction in coronary blood flow when the patients were subjected to maximum cardiac stress.

Coronary perfusion was tested again 5 weeks after the start of therapy. Perfusion was measured at rest; with the patient’s foot in a bowl of iced water, which simulates sympathetic nervous system stress; and then after a dose of dipyridamol, which dilates the arteries and mimics intense exercise. After antiretroviral therapy was started, coronary perfusion was the same in patients at rest but was decreased by 31% in patients who were given dipyridamol (P = .021), representing a decrease from 2.6 to 1.7 mL/g/min.

Kristoffersen commented that it was unusual to see rapid changes in coronary blood flow of this degree a month apart. He said that this technique could be a useful tool to study the pathophysiology of antiretroviral- associated changes in cardiovascular risk. It is not known whether the changes seen were short-term effects associated with antiretroviral initiation or represented permanent changes or changes that would accumulate over time.

Less AIDS for the Money
At IAS 2009, Stefano Bertozzi, MD, executive director of the Center for Evaluation Research and Surveys at the National Institute of Public Health in Mexico, discussed the topic of financing the long-term response to HIV.¹² He said that greater emphasis should be placed on “getting value from investments,” which would require a shift in thinking from a short-term emergency response to a more efficient, long-term approach. He made a plea for scientists and researchers to think not only about “more money for AIDS” but, more importantly, “less AIDS for the money.” Bertozzi echoed the alarm raised by another speaker in his session who cited data on HIV infection rates in young women from a South Africa clinic: 0% of 15-year-olds, about 10% of 16-year-olds, and a staggering 66% of 22-year-olds.

Despite billions of dollars spent on prevention, we are not, in fact, getting less AIDS for the money. Instead, we need to strive for improved efficiency in light of the figures above, the fact that 2.7 million new infections occurred in 2007, and the sobering statistics showing that twice as many untreated patients as treated patients still die of AIDS.

Bertozzi indicated that the global economic crisis affects funding and that global funding will not continue to increase at the rate that was seen in the past. “We need to stop spending billions implementing large-scale interventions without measuring effectiveness,” he said, citing another example-the billions spent on abstinence campaigns without any measure of whether these campaigns help prevent HIV infection.

He said there also was a critical need to focus on interventions where maximum benefit could be derived. For example, in Russia where HIV infection occurs predominantly among injection drug users, little is spent on targeting this group.

While the focus of Bertozzi’s talk was global, he also offered advice for those of us who provide HIV care, one patient or client at a time. For example, how efficiently are you delivering your interventions? Recognizing the enormous variation in unit costs, do you know your cost per patient/client served? He suggested monitoring costs at the point of service to improve efficiency, citing the need for better integration of services.

In conclusion, Bertozzi advised us to consider lost opportunities and to maximize long-term benefits of our interventions-and not just produce results for the annual report.

References:

References
1. Squires K, Young B, DeJesus E, et al. Similar efficacy and tolerability of atazanavir (ATV) compared to ATV/ritonavir (RTV, r), each in combination with abacavir/lamivudine (ABC/3TC), after initial suppression with ABC/3TC + ATV/r in HIV-1 infected patients: 84 week results of the ARIES trial. Presented at: 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2009; Cape Town, South Africa. Abstract WELBB103.
2. Heera J, Ive P, Botes M, et al. The MERIT study of maraviroc in antiretroviral-naive patients with R5 HIV-1: 96-week results. Presented at: 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2009; Cape Town, South Africa. Abstract TUAB103.
3. Harrigan PR, McGovern R, Dong W, et al. Screening for HIV tropism using population-based V3 genotypic analysis: a retrospective virological outcome analysis using stored plasma screening samples from MOTIVATE-1. Presented at: 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2009; Cape Town, South Africa. Abstract WELBA101.
4. Bedimo R, Westfall A, Drechsler H, Tebas P. Abacavir use and risk of acute myocardial infarction and cerebrovascular disease in the HAART era. Presented at: 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2009; Cape Town, South Africa. Abstract MOAB202.
5. Martinez E, Larrousse M, Perez I, et al. No evidence for recent abacavir/ lamivudine use in promoting inflammation, endothelial dysfunction, hypercoagulability, or insulin resistance in virologically suppressed HIV-infected patients: a substudy of the BICOMBO randomized clinical trial. Presented at: 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2009; Cape Town, South Africa. Abstract MOAB203.
6. Sabin C, Worm S, Weber R, et al. Do thymidine analogues, abacavir, didanosine and lamivudine contribute to the risk of myocardial infarction? The D:A:D Study. Presented at: 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston. Abstract 957c.
7. Loutfy M, Genebat M, Moore D, et al. Increased clinical events in HIV- infected patients who achieve full virologic suppression but fail to attain a CD4 count ≥ 200 cells/mm3 after two years of combination antiretroviral therapy. Presented at: 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2009; Cape Town, South Africa. Poster abstract MOPEB001.
8. Granich R. HAART as prevention. Presented at: 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2009; Cape Town, South Africa. Plenary presentation MOPL101.
9. Montaner J. Clinical principle of treatment as prevention; benefits of earlier treatment to the individual and the community. Presented at: 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2009; Cape Town, South Africa. Satellite presentation SUSAT0501.
10. Seaberg EC, Sharrett AR, Hodis HN, et al. Duration of HIV infection is associated with carotid artery stiffness. Presented at: 5th IAS Conference on HIV Treatment, Pathogenesis and Prevention; July 19-22, 2009; Cape Town, South Africa. Abstract MOAB204.
11. Kristoffersen US, Lebech AM, Gerstoft J, et al. Coronary vasomotor function is reduced after initiation of antiretroviral therapy in treatment naive patients: a prospective myocardial perfusion PET study. Presented at: 5th IAS Conference on HIV Treatment, Pathogenesis and Prevention. Abstract MOAB205.
12. Bertozzi S. Financing the long-term response to HIV. Presented at: 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2009; Cape Town, South Africa. Abstract TUPL103.