Dr. Julio Montaner is president of the International AIDS Society
Photograph by: Jenelle Schneider, Vancouver Sun Files

March 2, 2009

According to a computer simulation, tenofovir/emtricitabine pre-exposure prophylaxis (PrEP) could reduce lifetime HIV infection risk from 44% to 25% among high-risk men who have sex with men in the US, if it is 50% effective at preventing new HIV infections. However, the predicted overall increase in life expectancy was very small, and the average lifetime cost of PrEP provision was estimated at USD $151,600 per person. The study was published in the February 4 edition of Clinical Infectious Diseases.

The study of PrEP – the use of antiretroviral medications before exposure to HIV in the hope of reducing infection risk – has so far been limited to animal studies, preliminary findings of one human trial in at-risk women (previously reported at the Sixteenth International AIDS Conference and now published), and several analyses using computer models, by Desai and others.

This study also used a computer model which simulated both population characteristics – such as risk behaviour, the effects of prevention efforts, and the resulting incidence of new infections – and disease characteristics such as the progression of HIV disease, resulting complications, life expectancy and cost of care. The simulation was based on the following assumptions:

• PrEP consisted of full-dose tenofovir/emtricitabine (Truvada), at the current average wholesale price of USD $724 per month. An additional monthly cost of USD $28 was added to allow for quarterly laboratory monitoring.
  

• PrEP was used in an American population of high-risk men who have sex with men (MSM), with a mean age of 34 years and an annual HIV incidence of 1.6%. These characteristics matched those of men in the HIV Network for Prevention Trials (HIVNET) Vaccine Preparedness Study conducted in the US.
  

• PrEP was estimated to be 50% effective at preventing infection overall – the same estimate used in the Desai analysis, comparable to results from animal trials, and less than the 65% (non-statistically significant) estimate from the Peterson trial in human women. This estimate was also meant to account for behavioural effects such as possible increases in risky sex due to PrEP use.

In this high-risk group, current practices of prevention and care led to a 44% lifetime risk of HIV infection and a mean survival of 40 years, at a cost of USD $81,100 per person. Use of tenofovir/emtricitabine PrEP, as modeled in this analysis, reduced lifetime infection risk to 25%, but increased cost to USD $232,700 per person, and only increased mean survival time to 40.7 years. When translated into "quality-adjusted years of life" (QALY), the increase was even more meagre – from 21.7 to 22.2 QALYs, for a cost of USD 298,000 per QALY gained.

This "unattractive" estimate of cost-effectiveness raises many questions. First of all, it was much more pessimistic than the Desai analysis, which estimated a cost of USD $31,970 per QALY saved. However the Desai study also accounted for the benefits of secondary infections prevented – i.e., infections that were prevented in men not accessing PrEP directly themselves, but due to reduced HIV prevalence in the community. The current study did not look at this effect.

Any computer-modeled simulations are, of course, speculative – how PrEP would actually play out in the real world would depend on many factors such as how effective it actually is, the characteristics (including risk level) of the people who use it, and the number of people who receive it. The study team found that, according to their model, PrEP would be more cost-effective if it were used in higher-risk populations with higher HIV incidence, and – naturally – if it were more than 50% effective or was made available at a lower cost.

Despite the poor cost-effectiveness findings of this particular simulation, the researchers suggested that PrEP could "substantially reduce the lifetime risk of HIV infection in persons at high risk in the United States," - especially with improvements in efficacy, targeting, or pricing - and that "this finding alone justifies continued study of PrEP-based approaches." They also noted that prevention and treatment efforts are interdependent, and that "the costs and benefits of one can only be evaluated in the context of the other."

References:
Paltiel AD. HIV preexposure prophylaxis in the United States: impact on lifetime infection risk, clinical outcomes, and cost-effectiveness. Clin Infect Dis 48; 806-815. 2009.

Garcia-Lerma JG et al. Prevention of rectal SHIV transmission on macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir. PloS Medicine 5(2):291-299. 2008. (Read the study here.)

Peterson L et al. Tenofovir disoproxil fumarate for prevention of HIV infection in women: a phase 2, double-blind, randomized, placebo-controlled trial. PLoS Clin Trials 2:e27. 2007. (Read the study here.)

 

March 2, 2009

New findings may significantly improve the safety of methadone, a drug widely used to treat cancer pain and addiction to heroin and other opioid drugs, according to researchers at Washington University School of Medicine in St. Louis and the University of Washington in Seattle.

The researchers discovered that the body processes methadone differently than previously believed. Those incorrect assumptions about methadone have been making it difficult for physicians to understand how and when the drug is cleared from the body and may be responsible for unintentional under- or overdosing, inadequate pain relief, side effects and even death.

For many years, methadone has been a mainstay in the treatment of opioid addiction. Taken orally, it suppresses withdrawal and reduces cravings. In recent years, doctors have prescribed methadone more frequently as an effective treatment for acute, chronic and cancer pain. Use of the drug for pain treatment rose 1,300 percent between 1997 and 2006. As more methadone was prescribed, however, adverse events increased by approximately 1,800 percent, and fatalities were up more than 400 percent (from 786 to 3,849) between the years 1999 and 2004.

"Unfortunately, increased methadone use for pain has coincided with a significant increase in adverse events and fatalities related to methadone," says principal investigator Evan D. Kharasch, M.D., Ph.D., an anesthesiologist and clinical pharmacologist at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis. "The important message is that guidelines used by clinicians to direct methadone therapy may be incorrect."

Kharasch, the Russell D. and Mary B. Shelden Professor and director of the Division of Clinical and Translational Research in Anesthesiology at the School of Medicine, and his colleagues report the findings in the March issue of the journal Anesthesiology and online in the journal Drug and Alcohol Dependence.

The investigators wanted to understand how protease inhibitors, drugs that keep the immune system functioning in patients with HIV, interact with methadone. For years, the enzyme P4503A was believed to be responsible for clearing methadone from the body. But when healthy volunteers were given a low dose of methadone together with protease inhibitors that caused profound decreases in the activity of P4503A, there was no reduction in the clearance of methadone.

There were two reasons to study what happened to methadone when taken together with those drugs: First, HIV-AIDS patients may receive methadone for pain and, in some cases, for accompanying substance abuse problems, along with one or more protease inhibitors. In addition, many protease inhibitors interact with the P4503A enzyme that traditionally was thought to be important to methadone clearance. In these studies, Kharasch and his team looked at interactions among methadone, the P4503A enzyme in the intestine and liver and the protease inhibitors nelfinavir, indinavir and ritonavir.

They gave study volunteers a combination of the protease inhibitors ritonavir and indinavir. Both drugs profoundly inhibited the actions of the enzyme. If that enzyme were responsible for methadone clearance, then inhibiting it should have caused methadone to build up in the body. But the researchers found that it had no effect on methadone levels.

Volunteers in the second study received the protease inhibitor nelfinavir. Again, the drug inhibited the action of the P4503A enzyme. That should have meant methadone concentrations would rise, but they actually decreased by half.

"For more than a decade, practitioners have been warned about drug interactions involving the enzyme P4503A that might alter methadone metabolism," Kharasch says. "The package insert says inhibiting the enzyme may cause decreased clearance of methadone, but our research demonstrates that P4503A has no effect on clearing methadone from the body. So the package insert appears to be incorrect, or certainly needs to be reevaluated, as do guidelines that explain methadone dosing and potential drug interactions."

That can be dangerous, Kharasch explains, because a clinician may prescribe too much or too little methadone for patients taking drugs that interact with P4503A, having been informed that they also would influence methadone clearance. Too little methadone will not relieve pain. Too much can contribute to the unintentional build-up of methadone in the system, which can cause slow or shallow breathing and dangerous changes in heartbeat. Physicians could be unintentionally prescribing methadone incorrectly.

"The highest risk period for inadequate pain therapy or adverse side effects is during the first two weeks a patient takes methadone," Kharasch says. "If we can provide clinicians with better dosing guidelines, then I believe we will be able to better treat pain and limit deaths and other adverse events."

About a dozen related liver enzymes are part of the P450 family, and Kharasch believes another enzyme from that family may be the one actually involved in methadone metabolism and clearance. His laboratory is determined to identify the correct enzyme to limit over-and under-dosing of patients taking methadone to improve addiction and pain treatment as well as patient safety. Currently, he's testing the related enzyme P4502B. Laboratory studies and preliminary clinical results indicate that P4502B may be involved, but he says more clinical research is needed.

"The research also is important for the treatment of HIV-AIDS," Kharasch says. "Protease inhibitors can interfere with the activity of P4503A but increase the activity of P4502B. This paradox is highly unusual, and because these two enzymes metabolize so many prescription drugs, there are many potential drug interactions that we'll be able to understand better if we can get a better handle on how these pathways absorb drugs into the system and clear them from the body."

Kharasch ED, Walker A, Whittington D, Hoffer C, Sheffels Bedynek P. Methadone metabolism and clearance are induced by nelfinavir despite inhibition of cytochrome P4503A (CYP3A) activity. Drug and Alcohol Dependence, in press, available online Feb. 18, 2009. doi:10.1016/j.drugalcdep.2008.12.009

Kharasch ED, Hoffer C, Whittington D, Walker A, Sheffels Bedynek P. Methadone pharmacokinetics are independent of cytochrome P4503A (CYP3A) activity and gastrointestinal drug transport. Anesthesiology, vol. 110 (3), pp. 660-672. March 2009.

March 3, 2000

March 4, 2009

Antiretroviral therapy - but not treatment for chronic hepatitis C virus (HCV) infection - was associated with significantly improved survival in HIV/HCV co-infected individuals with liver cirrhosis, researchers reported on February 10^th at the Sixteenth Conference on Retroviruses and Opportunistic Infections (CROI) in Montreal, Canada.

Maria Luisa Montes from Hospital Universitario La Paz in Madrid, Spain, presented findings from a prospective multicentre study looking at the effect of hepatitis C treatment in HIV/HCV co-infected patients with compensated cirrhosis or advanced fibrosis.

Compensated cirrhosis means that even though the liver has been heavily scarred, it is still able to perform most of its normal functions. Chronic hepatitis C is responsible for more than 90% of cirrhosis cases in HIV-positive people, the researchers noted.

A total of 248 co-infected participants were assessed to determine factors associated with survival and time to a first episode of liver decompensation, and in particular whether hepatitis C treatment improved the prognosis of patients with compensated cirrhosis.

The investigators used an expanded definition of survival that included development of liver cancer and liver transplantation in addition to death.

Liver decompensation included bleeding in the oesophagus or stomach, abdominal fluid accumulation (ascites), brain damage (encephalopathy), spontaneous bacterial infection of the abdominal lining (peritonitis) and kidney failure (hepatorenal syndrome).

The factors the investigators included in their analysis were current and nadir (lowest-ever) CD4 cell count, HIV viral load, type of antiretroviral therapy, HCV genotype, whether patients had received hepatitis C treatment and whether they achieved sustained virological response (continued undetectable HCV viral load 24 weeks after completing treatment), concurrent chronic hepatitis B, and Child-Pugh score (a measure of liver disease prognosis).

More than three-quarters (78%) of the study participants were men and the median age was 42 years. Most had a history of injecting drug use. Overall, they had well-controlled HIV disease, with 88% taking combination antiretroviral therapy at baseline, 60% receiving continuous antiretroviral treatment without interruptions for the duration of the study, and 60% with undetectable HIV viral load; the median CD4 cell count was 437 cells/mm³.

With regard to liver disease, participants had been infected with HCV for 23 years on average and had cirrhosis or advanced bridging fibrosis, diagnosed for one year on average. About three-quarters had the harder to treat HCV genotypes 1 and 4. In addition, 27% were heavy alcohol drinkers and 4% also had chronic hepatitis B.

About three-quarters were currently taking or had received treatment for hepatitis C - mostly using the standard of care regimen of pegylated interferon plus ribavirin - and the sustained virological response rate was 24%, leaving 74% as relapsers or non-responders (1% were still undergoing treatment).

During a median 34 months of follow-up, a total of 30 endpoints were recorded: 25 deaths, 2 cases of liver cancer and 5 liver transplants. In addition, 28 patients experienced a first episode of liver decompensation, most often ascites.

The overall survival rate for co-infected patients with compensated cirrhosis was 85% at three years. In a univariate analysis, participants treated for hepatitis C were significantly more likely than untreated patients to survive during the follow-up period (91% vs 71% at three years), but the difference between sustained responders and non-responders was not significant (95% vs 90% at three years).

Hepatitis C treatment did not increase the time to a first episode of decompensation, nor did sustained response compared with non-response.

In a multivariate analysis controlling for potential confounding factors, only a baseline Child-Pugh score of 'B' or 'C' (indicating 81% and 45% probability of one-year survival, respectively) and non-continuous use of antiretroviral therapy were significantly associated with first liver decompensation and decreased survival, whilst decompensation during follow-up also predicted death, liver cancer or transplantation.

Although treatment of chronic hepatitis C was significantly associated with increased survival over three years in the univariate analysis, the investigators noted, this association disappeared after controlling for other factors.

“Continuous antiretroviral therapy and Child-Pugh scores are more important prognostic factors than anti-hepatitis C treatment”, they concluded.

They added the caveat that this study does not rule out a possible survival benefit of sustained response to hepatitis C treatment due to the low number of participants, and said longer follow-up might be needed to see an effect.

Because the success rate of hepatitis C treatment in co-infected individuals with liver cirrhosis is low, the researchers recommended that "every effort should be made to avoid progression to cirrhosis" in HIV/HCV co-infected patients - an argument for timely HCV screening, regular monitoring of liver health and prompt treatment when indicated.

Reference
Montes ML et al. Survival of HIV/HCV-co-infected patients with compensated liver cirrhosis: effect of HCV therapy. Sixteenth Conference on Retroviruses and Opportunistic Infections, Montreal, abstract 106, 2009.

By Liz Highleyman & Michael Carter, http://www.aidsmap.com

March 4, 2009

Lower levels of beneficial high-density lipoprotein (HDL) cholesterol - but not of harmful low-density lipoprotein (LDL) - were associated with cardiovascular disease in the SMART treatment interruption study, researchers reported on February 11^th at the Sixteenth Conference on Retroviruses and Opportunistic Infections in Montreal, Canada.

Briefly, SMART was a large international treatment strategy trial comparing CD4 cell-guided structured treatment interruption versus continuous antiretroviral therapy. More than 5000 participants were randomly assigned either to stop antiretroviral treatment when their CD4 count was above 350 cells/mm³ and resume when it fell below 250 cells/mm³ or to remain on continuous therapy throughout the study.

SMART’s headline finding, first reported three years ago, was that individuals in the treatment interruption arm had a higher rate of opportunistic disease or death, as well as an unexpected increase in serious heart, kidney and liver problems. The following year, SMART investigators reported that individuals who interrupted therapy had a slightly elevated risk of cardiovascular disease, and in 2008 they reported that people who interrupted treatment had higher levels of blood biomarkers of inflammation and coagulation (clotting).

LDL cholesterol plays a role in the build-up of plaque on artery walls, a process that can result in loss of elasticity (atherosclerosis), inflammation, clotting and ultimately blockage of blood flow to the heart or brain. Very low-density lipoprotein (VLDL) particles contain more triglyceride and are also considered harmful. Conversely, HDL carries cholesterol away for disposal and therefore helps prevent atherosclerosis. HDL particles are roughly one-third the size of LDL particles, whilst VLDL particles are many times larger.

Studies in the general population have shown that high LDL (especially small, dense LDL particles) and low HDL levels are predictors of cardiovascular disease. Since HDL was found to decline significantly more in SMART participants who interrupted treatment than in those who remained on continuous therapy, this unfavourable lipid change could offer a possible explanation for the increased risk of cardiovascular events seen in the treatment interruption arm.

In the analysis presented at this year's meeting, SMART investigators looked at the relationship between lipoprotein particle size and concentration and the risk of cardiovascular disease, noting that individuals with the same overall HDL level can have different distributions of HDL particle sizes.

Using nuclear magnetic resonance spectroscopy, they measured lipoprotein concentration and size in 248 individuals who experienced cardiovascular events such as heart attacks or strokes by study closure in July 2007, comparing them with 480 age- and sex-matched control patients who did not develop cardiovascular disease.

Most study participants (about 80%) were men and the median age was 49 years. Not surprisingly, those in the cardiovascular disease group were more likely to have cardiovascular risk factors including smoking, diabetes and high blood pressure. Baseline total cholesterol, LDL and triglyceride levels were similar in both groups, but those with cardiovascular disease had a lower median HDL level.

Participants in the treatment interruption arm experienced a greater decrease in HDL levels one month after stopping therapy compared with patients who remained on continuous therapy.

In an unadjusted analysis, the researchers found that lower total HDL and small HDL particle concentrations were associated with a significant 40% to 50% increase in the risk of cardiovascular events (odd ratios of 0.41 and 0.53, respectively).

This association remained after adjusting for demographic characteristics, antiretroviral treatment, HIV viral load, CD4 count, hepatitis B or C coinfection, cardiovascular risk factors, and inflammation and coagulation biomarkers (high-sensitivity C-reactive protein, interleukin 6 and D-dimer).

However, the investigators found that LDL and VLDL particle concentrations and sizes were not significantly associated with cardiovascular disease.

"In the SMART trial, lower total HDL particles and especially small HDL particles are predictive of cardiovascular events in HIV patients," the researchers concluded.

Discussing the findings, presenter Daniel Duprez noted that lipoprotein particle size alone could not explain the detrimental outcomes in the treatment interruption arm, suggesting there are probably multiple interacting factors.

He also said that while lower HDL is associated with higher cardiovascular risk, experts do not know what an optimal HDL level would be for HIV-positive or HIV-negative individuals.

Reference
Duprez D et al. High-density lipoprotein particles but not low-density lipoprotein particles predict cardiovascular disease events in HIV patients: strategies for management of ART study. Sixteenth Conference on Retroviruses and Opportunistic Infections, Montreal, abstract 149, 2009.