Update: Subcutaneous Interleukin-2
Investigators observe dose-related increases in CD4 counts -- without increases in HIV RNA
Interleukin-2 has been studied for over a decade as a potential adjunct in the treatment of HIV -- and we have reported on the equivocal results of those clinical trials. Widespread adoption of IL-2 as an adjunct to antiretroviral therapy has been stalled for a number of reasons: it is not available in oral form, many patients find the side effects intolerable, and there has been concern about this cytokine's stimulatory effects on HIV replication. On the other hand, IL-2 is the only substance currently under study that stimulates CD4 cell production.
The role of IL-2 in treating patients with HIV infection remains to be determined, but because of the cytokine's potent immunomodulatory properties, research with this substance has continued. A recent multicenter study that added subcutaneous injections of IL-2 to a variety of HAART regimens suggests that routine use of this immune-system stimulator may be approaching. Davey et al. recruited 82 patients and randomized them to receive either HAART alone or HAART in combination with subcutaneous IL-2. The study did not include a placebo arm. Relevant baseline characteristics were as follows: absolute CD4 counts between 200-500 cells/mm3, no history of IL-2 use, no AIDS-defining events, and viral load less than 10,000 copies/mL.
Thirty-nine of these patients were randomized to receive 7.5 million units of IL-2 twice daily for five-day periods every eight weeks, in addition to HAART. Forty-three patients were randomized to HAART alone. Patients were followed for approximately one year, allowing for six treatment cycles. Broad latitude was allowed for HAART regimens; the study design stipulated that patients "were required to be receiving a stable regimen of either standard-of-care approved multidrug therapy or experimental antiretroviral agents available through expanded access for at least two weeks prior to study entry."
The most impressive results concerned CD4 values. The median increase in CD4 percent among IL-2 recipients was 112% at one year, compared to 18% for those on HAART alone. In terms of absolute numbers, the mean increases were 384 cells/mm3 and 64 cells/mm3, respectively. There was an impressive dose-response effect. Patients who received <3 MU/injection (the protocol allowed for dose reductions if patients could not tolerate 7.5 MU) had a 39% increase in absolute CD4 counts at one year, compared to 207% increase for those receiving 6-7.5 MU. Mean CD8 counts did not change appreciably in either group. In addition, expression of a high-affinity receptor for IL-2 on CD4 cells increased four-fold among drug recipients but remained essentially unchanged in the control group.
Viral load analysis showed no increase in HIV replication at one year for patients in the IL-2 arm. Indeed, there was a small, statistically insignificant decrease in HIV RNA among those receiving IL-2. Moreover, 67% of the IL-2 patients achieved non-detectable viral load burdens at one year, compared to 36% of control patients.
The adverse effects of IL-2 therapy are well established. Twenty IL-2 recipients reported grade 3 or greater side effects (asthenia, fever, athralgia, myalgia, increased LFTs, thrombophlebitis) compared to seven control patients. Despite this high incidence of serious side effects, only one patient in the IL-2 arm withdrew because of the toxicity of the treatment. Constitutional symptoms were managed with NSAIDs, acetaminophen, oral hydration, and narcotics to relieve rigors. Some patients developed antibodies to IL-2. Seven participants (3 in the IL-2 arm, one control) developed IgM and 11 (9 in the IL-2 arm, 2 controls) developed IgG. Further lab test showed that only three patients had sustained IgG antibodies. The clinical significance of these antibodies is unknown, and it did not correlate with CD4 increases.
Davey RT, Murphy RL, Graziano FM, Boswell SL, Pavia AT, Cancio M, et al. Immunologic and virologic effects of subcutaneous interleukin 2 in combination with antiretrovial therapy. JAMA 2000; 284 (2): 183-189.
Dr. Robert L. Murphy, a member of the editorial advisory board of HIV Newsline and a co-author of this study, comments:
In 1998 immunomodulatory therapies for the treatment of HIV got a shot in the arm, so to speak, when Carr et al. showed that CD4 counts could be increased with subcutaneous injections of IL-2 modified with a polyethylene glycol residue. Their protocol, which involved two injections two days apart every eight weeks, was compared with what was then regarded as standard therapy: continuous IL-2 infusions over a five-day period every eight weeks.
Although this group of Australian investigators found that subcutaneously injected IL-2 was not nearly as effective as continuously infused IL-2 in boosting CD4 levels in treated patients -- the median increase was only 44 cells/mm3 in the IL-2-PEG arm, versus 359 cells/mm3 in the IV IL-2 arm -- they were able to show an increase of 90 cells/mm3 compared with untreated controls. Moreover, they successfully demonstrated that IL-2 could be used to upregulate immune function when it was given subcutaneously rather than by continuous infusion -- thereby eliminating a chief stumbling block to its widespread application.
The Australian study of IL-2-PEG was conducted in patients who were receiving dual-nucleoside antiretroviral therapy, and we wondered if patients whose viremia was maximally suppressed on more potent regimens might respond more favorably to adjunctive therapy with subcutaneous IL-2. Our results suggest that this is indeed the case. Moreover, we were able to achieve impressive increases in CD4 counts in treated patients without stimulating viral replication. In fact, our group felt that the addition of IL-2 might have potentiated the anti-HIV effects of HAART. We will need to know how these surrogate benefits translate into clinical outcomes. A large trial that is currently under way in this country, and two international studies, should provide useful data regarding clinical outcomes.
Several presentations made at the recently concluded 8th Conference on Retrovirus and Opportunistic Infections suggest that CD4 counts, not HIV/RNA levels, are the most accurate marker of disease progression and survival. If these observations hold up, they should spark renewed interest in drugs that enhance overall immunologic function and support the bodys natural response to HIV infection.
Update: Treatment of Lipodystrophy
Metformin reduces insulin resistance and visceral fat deposits
A syndrome of insulin resistance, hyperlipidemia, and lipodystrophy has been identified in patients taking protease inhibitors. These disorders may appear individually or in combination. As with many other side effects of therapy, the risk for increased morbidity and mortality posed by this syndrome is not knownand the need to quantify that risk is great. Thanks to the advent of maximally suppressive antiretroviral therapy, HIV-infected patients are living much longer than they did a few short years ago, and the longer they live, the more crucial it becomes for care providers to understand the long-term impact of the side effects of chronic antiretroviral therapy.
In mid-1997 the F.D.A. issued a public health advisory in the wake of reports of hyperglycemia and new-onset diabetes mellitus related to the use of protease inhibitors. At that time a total of 83 cases of hyperglycemia had been reported, six of which involved life-threatening reactions. Since that time reports of hyperglycemia, peripheral insulin resistance, diabetes, ketoacidosis, and reduced beta-cell function have been published. In one recent study, the rate of new-onset hyperglycemia (two serum glucose values > 250 mg/dL or a diabetes diagnosis) was roughly 1% of nearly 1,400 clinic patients.
Most patients with hyperglycemia also have increased concentrations of insulin, C-peptide, proinsulin, and glucagon, but the mechanism of insulin resistance in patients taking protease inhibitors is unknown. Potential hypotheses include direct effects of protease inhibitors or indirect mechanisms related to changes in body fat. All patients starting antiretroviral therapy with a drug combination that includes a protease inhibitor should have baseline and follow-up fasting blood glucose concentrations measured, to help assess if insulin resistance or hyperglycemia is likely to develop. Individuals who have no diabetes or insulin resistance prior to the initiation of therapy should be counseled to report any signs of fatigue, polydipsia, or polyuria immediately. Patients should have a serum blood glucose test whenever these symptoms present. An oral glucose tolerance test may elucidate glucose intolerance.
Because insulin resistance and hyperinsulinemia are significant risk factors for coronary artery disease, patients who take protease inhibitors may be at increased risk for CAD in addition to frank diabetes. For this reason, clinicians feel increasingly compelled to treat hyperglycemia and hypercholesterolemia when these conditions develop in patients who are taking protease inhibitors -- although this increases the patient's pill burden, the likelihood of drug-drug interactions, and the prospect of additional therapy-induced toxicities.
Hadigan et al. designed a trial to test metformin, a biguanide used in the treatment of NIDDM, in patients with insulin resistance who also had visceral adiposity. Metformin reduces hepatic glucose production and facilitates glucose uptake by peripheral tissues. It is associated with lower fasting glucose and hemoglobin A1C levels, as well as decreased total cholesterol and triglycerides. The principle adverse events are GI disturbances and lactic acidosis.
The study enrolled 26 patients, all of whom had been on a stable regimen of antiretrovirals for at least six weeks, and randomized them to receive metformin 500 mg b.i.d. or placebo in a double-blind fashion. Subjects were "moderately overweight" and had laboratory evidence of impaired glucose tolerance (glucose between 140-200 mg/dL at 120 minutes following 75 g oral glucose load) as well as evidence of fat redistribution. The primary outcome measurement was a change in insulin area under the curve. Secondary outcomes included changes in glucose AUC, lipid levels, body-mass index, diastolic blood pressure, waist-to-hip circumference, and assessment of the ratio of visceral abdominal fat to subcutaneous abdominal fat by CT images.
After three months, treatment with metformin was associated with significant decreases in insulin AUC <(-20%), diastolic blood pressure, and body-mass index. Glucose AUC levels and lipid levels were not significantly different in the treatment and placebo arms of the study. Visceral abdominal fat decreased by 6% in metformin recipients and increased by 8% in placebo patients. The drug was well tolerated; there were no incidents of lactic acidosis and no patient dropped out of the study because of adverse events.
Hadigan C, Corcoran C, Basgoz N, Davis B, Sax P, Grinspoon S. Metformin in the treatment of HIV lipodystrophy syndrome. JAMA 2000; 284 (4): 472-77.
Dr. William G. Powderly, the editor-in-chief of HIV Newsline, comments:
The finding that maximally suppressive antiretroviral therapy leads to lipid derangements and may predispose treated patients to both diabetes and coronary artery disease is a serious problem, and one that complicates our efforts to develop long-term treatment strategies for HIV infection. Although this was short-term study involving only two dozen participants, its findings are encouraging and merit further investigation.
The work of Hadigan et al. reaffirms results obtained by Touraine and Saint-Marie in 1999. Those investigators administered metformin for two months to a group of patients who had developed abdominal fat accumulation, elevated triglycerides, and hyperinsulinemia on protease-inhibitor-based antiretroviral regimens. All of the participants experienced significant improvements in glucose tolerance and triglyceride levels compared with controls, but no changes were evident in total serum cholesterol levels between the metformin and placebo arms. Visceral abdominal fat accumulation decreased by 13.3% in the metformin group and by 5.7% in the control group. Although metformin produced intolerable GI disorders in two patients taking the drug, these data -- when combined with those of Hadigan and coworkers -- suggest that metformin may be useful in the management of patients who develop insulin resistance, hypertriglyceridemia, and visceral fat accumulation as a result of protease-inhibitor-based therapy.
Scrub Typhus and HIV Co-Infection
Does O. tsutsugamushi inhibit syncytia formation in seropositive patients?
Conventional wisdom -- and clinical evidence -- tell us that adding other pathogens to the mix when HIV infection is present is bad chemistry. Is it possible that another infection could actually facilitate a host's fight against HIV? Two groups of Thai researchers, working in collaboration with investigators at Walter Reed and St. George's Hospital in London, believe they might have evidence to support this novel notion. Watt et al. took viral-load measurements in HIV-positive patients diagnosed with acute scrub typhus infection, citing earlier observations concerning scrub typhus in patients with HIV, which hinted at potentially beneficial interactions between Orientia tsutsugamushi and HIV.
O. tsutsugamushi, the etiologic agent of scrub typhus, is a gram-negative obligate intracellular rickettsial organism that is transmitted to humans from mites. The infection occurs almost exclusively in Japan, Australia, and the islands of the South Pacific. Also known as river or flood fever, scrub typhus is a febrile illness that can manifest as myocarditis, meningoencephalitis, and pneumonitis. The site of the bite develops into a papular lesion that may harden into an eschar. It has been reported that HIV patients with scrub typhus do no worse than patients without HIV, which is an unusual observation concerning infections in those already harboring HIV. Furthermore, the rate of positive blood cultures for O. tsutsugamushi is actually lower among patients co-infected with HIV.
To study the relationship between these two pathogens, ten adults with both infections were compared to five other individuals with HIV and either malaria or leptospirosis. None of the patients in either group received antiretroviral therapy. Patients were examined clinically and viral-load measurements were done on days 3, 7, 14, and 28 after admission. Treatments administered were chloramphenicol or doxycycline for scrub typhus, quinine or chloroquine for malaria, and penicillin for leptospirosis. Investigators documented a statistically significant increase in HIV RNA in the five patients who did not have scrub typhus compared to the ten with scrub typhus. Four of the ten patients with scrub typhus experienced a dramatic drop in viral load; two became non-detectable.
HIV strains from all ten of the patients with scrub typhus were found to be non-syncytia-inducing, a characteristic that is associated with less facile cell-to-cell transmission of HIV. By contrast, five of seven isolates from patients without scrub typhus were syncytia-inducing. The authors postulate that inhibition of syncytia formation may be the mechanism by which scrub typhus suppresses HIV. They encourage further study of this phenomenon.
While no one is saying, at this point, that patients with HIV should be intentionally coinfected with O. tsutsugamushi, it is the only organism that has been shown to possibly benefit a host with HIV. This paper raises intriguing questions about manipulation of the immune system in ways to optimize the host's response to HIV. The authors also note that more than 90% of individuals with HIV infection cannot afford antiretroviral therapy and that cheaper approaches to treatment are desperately needed.
Watt G, Kantipong P, de Souza M, Chanbancherd P, Jongsakul K, Ruangweerayud R, et al. HIV-1 suppression during acute scrub-typhus infection. Lancet 2000; 356: 475-79.
Back to the February 2001 HIV Newsline contents page.
This article was provided by San Francisco General Hospital. It is a part of the publication HIV Newsline.