CLEVELAND, June 25 — Despite public health initiatives, testing for HIV is still characterized by a “too little, too late” approach, with 45% of patients diagnosed only a year or two before the onset of AIDS, according to a CDC report released today.

Data from 34 states revealed that 38.3% of 281,421 patients diagnosed with HIV progressed to AIDS within a year of HIV diagnosis, and 6.78% had AIDS within one to three years of confirmed HIV infection.

There was, however, a bright spot in the CDC data: persons tested in 2003 were less likely to be diagnosed late in the course of the infection than those tested in 1996, researchers wrote in the June 26 Morbidity and Mortality Weekly Report.

In the absence of antiretroviral therapy, the elapsed time from HIV infection to AIDS is estimated to be 10 years. The CDC considers HIV diagnosed less than three years before AIDS to be a late diagnosis, according to R. Luke Shouse, MD, of CDC’s division of HIV/AIDS Prevention in the National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, and colleagues.

Although introduction of highly active antiretroviral medications has substantially improved the prognosis for AIDS patients, “persons who receive a diagnosis late in their course of HIV infection often are more severely immunosuppressed and more likely to experience increased morbidity and short-term mortality than persons with earlier diagnoses, in addition to being more likely to transmit HIV when unaware of their infection,” the MMWR editors wrote.

The CDC analyzed HIV diagnosis data from 1996 through 2005. Patients were followed through 2006 and cases reported through June 2008.

The researchers estimated the percentage of HIV patients who had an AIDS diagnosis at one year and three years, with breakdowns by age, ethnicity/race, sex, HIV transmission category, and year of HIV diagnosis.

Among the findings:

• The likelihood of late diagnosis increased with age: 63.2% of those age 60 or older at diagnosis had AIDS within three years, versus 31.6% of persons ages 20 to 29 and 22.7% of patients ages 13 to 19.
• Whites were less likely to have a late diagnosis: 42.6%, compared with African-Americans (46.1%), American Indians or Alaskan Natives (47.2%), Hispanics or Latinos (48.4%), or Asians (50.4%).
• Late diagnosis also varied by gender as 46.9% of men had late testing versus 41.9% of women.
• High-risk heterosexual males were more likely to delay testing (50.2%) than were men who had sex with men (47.8%) and those who had male-to-male sexual contact and were injection-drug users (47.2%).

In an editorial note, the editors said there were a number of limitations to the study — only 34 states representing just 66% of the nation’s AIDS diagnoses were included in the analysis. So the results might not be an accurate estimate of the national situation.

Additionally, some persons might have had earlier anonymous, unreported testing with positive results — and then followed up with confidential, reported HIV testing. This would result in “making the time from HIV diagnosis to AIDS diagnosis appear shorter than was actually the case.”

And finally, the reasons for late testing cannot be discerned from this study.

Primary source: Morbidity and Mortality Weekly Report

Source reference:

Shouse, RL et al “Late HIV Testing-34 States, 1996-2005″ MMWR 2009; 58: 661-665.

WHEELING, W.Va., May 14 — Mice lacking the gene for interleukin-21 were unable to halt a normally controllable viral infection, indicating that the cytokine is critical to the immune response, researchers said.

• Explain to interested patients that some chronic viral infections, including HIV, appear to disable parts of the immune system involved in antiviral responses.
• Explain that this study was performed in mice and that it is uncertain to what extent the findings apply to humans.
• Note that the findings have no immediate clinical implications but may lead to new treatments in the future.

CD8-positive cytotoxic T cells, known to be vital in suppressing viral infections, were effectively silenced in the IL-21 knockout mice, although CD4-positive cells still functioned normally, Allan Zajac, Ph.D., and colleagues at the University of Alabama at Birmingham, reported online in Sciencexpress.

With the CD8-positive cells rendered helpless, lymphocytic choriomeningitis virus (LCMV) ran rampant in the IL-21 knockout animals, whereas normal mice were able to bring the infection under control.

But when the knockout mice were treated with exogenous IL-21, their CD8-positive cells regained signs of normal function and LCMV infections were cut short.

The researchers also found that mice engineered to carry one copy of the gene for IL-21, instead of the normal two copies, produced CD8-positive cells that showed some activity but significantly less than normal.

“Interleukin-21 served as the key messenger between the T cells, whereas before we didn’t know exactly how the two types of cells communicated with each other,” Dr. Zajac said in a press release.

The findings may help explain why CD8-positive T cells are induced in some viral infections — including HIV and hepatitis C — but then fail to act effectively, the researchers said.

It has been known that in the absence of the CD4-positive cells, CD8-positive cells lack some or all of their full functionality.

CD4-positive cells are believed to be the main source of IL-21, which promotes a wide range of immune activities.

Consequently, Dr. Zajac and colleagues guessed that it could be a messenger molecule between the two cell types.

In their experiments, mice with normal IL-21 genes cleared LCMV infections within 50-75 days, whereas viral titers in blood of IL-21 knockout mice remained high for the full 150 days of monitoring, with no animals showing clearance.

In mice with one copy of the IL-21 gene, about half the animals showed LCMV clearance after 75 days, but others showed persistent high viral titers.

Examination of CD8-positive cells from the full knockouts in vitro “revealed severe functional exhaustion,” the researchers wrote.

Whereas interferon-gamma, IL-2, and tumor necrosis factor-alpha production was robust in CD8-positive cells taken from normal mice, cells from the knockouts were unable to produce significant levels of these cytokines.

The researchers also determined that induction of CD4-positive cells was reduced significantly during the early stages of LCMV infection.

“Collectively, our findings provide new insights into the determinants of the functional quality of CD8-positive T-cell responses and the role of IL-21 in ensuring the successful control of infection,” Dr. Zajac and colleagues wrote.

The impairment of initial CD4-positive T cell responses initially “could be a general feature of infections that elicit nonprotective adaptive immune responses,” they added.

Such infections include hepatitis B and C as well as HIV, they said.

The researchers suggested that it might be possible to develop therapies to modulate IL-21 directly or to boost the numbers or activity of cells that produce the cytokine.

Primary source: Sciencexpress

Source reference:

Yi J, et al “A vital role for interleukin-21 in the control of a chronic viral infection” Sciencexpress 2009; DOI: 10.1126/science.1175194.

TORONTO, June 22 — A Canadian-American research team may have found the places where HIV hides from drug therapy.

• Explain to interested patients that HIV is known to respond to antiretroviral therapy, but not completely, so that stopping therapy results in a resurgence of the virus.
• Note that this study identifies two types of long-lived cells that can harbor HIV and suggests that targeting both types simultaneously might eradicate the virus.

Even when antiretroviral therapy is effective, the virus persists in two types of long-lived immune cells that are maintained by different mechanisms, according to Rafick-Pierre Sekaly, PhD, of the Universite de Montreal, and colleagues.

The finding may open the possibility of actually eradicating the virus, rather than just controlling it, Dr. Sekaly and colleagues said online in Nature Medicine.

The researchers said a combination approach, targeting both types of immune cells, could potentially be used to eliminate both reservoirs of HIV.

“Our results argue in favor of a strategy similar to the one used against leukemia, which is targeted chemotherapy associated with a targeted immune treatment,” Dr. Sekaly said in a statement.

“This would make it possible to destroy the cells containing a virus, while giving the immune system time to regenerate with healthy cells,” he said.

In a series of experiments, the researchers showed that small subsets of two types of CD4-positive T cells — so-called central memory and transitional memory cells — can contain proviral DNA.

Other types of CD4 cells — including the so-called effector memory cells — are much less likely to harbor HIV.

Indeed, in a pool of 31 HIV patients whose virus was well-controlled, central memory cells made up 51.7% on average of the cells with HIV DNA, compared with 34.3% from transitional memory cells and 13.9% from effector memory cells.

Central memory cells are thought to be a sort of memory stem cell, able to recognize and respond to an invading pathogen, while effector cells do the actual killing. Transitional memory cells are intermediate forms.

In patients whose immune systems respond to highly active antiretroviral therapy (HAART) with a robust reconstitution of the CD4 cells, it is the central memory cells that mainly contain HIV DNA.

Those cells form a small reservoir that is slowly degraded over time by drug therapy.

But in patients whose immune system does not respond as well — often those whose treatment begins later in the course of the disease — the transitional memory cells form the main reservoir, the researchers said.

Those cells proliferate slowly as a response to cytokines such as interleukin-seven, maintaining the reservoir.

The relative contributions of the two reservoirs are highly variable from person to person, the researchers said.

In people with high CD4 counts, the central memory cells were the major reservoir, a trend that was significant at P=0.004.

Conversely, in patients with low CD4 counts, the HIV was mainly seen in transitional memory cells (significant at P=0.006).

Low CD4 counts are associated with high levels of proliferation, the researchers found, suggesting that blocking cytokines involved in cell proliferation might help eliminate the transitional memory reservoir.

One implication of the findings is that “ongoing viral replication is unlikely to be responsible for the persistence of HIV-infected cells,” the researchers said.

Instead, they argued, T cell proliferation is “a major mechanism to ensure HIV persistence.”

Blocking such proliferation, in tandem with antiretroviral therapy, should form the basis of new therapies, they said.

“We now have brand-new options to fight HIV,” said lead author Nicolas Chomont, PhD, also of the Universite de Montreal. “The combination of fundamental and clinical approaches led to amazing results that allow us to elucidate another mystery of this virus of a thousand faces.”

Primary source: Nature Medicine

Source reference:

Chomont N et al. “HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation” Nature Med 2009; DOI: 10.1038/nm.1972.

TORONTO, April 24 — People with HIV do just as well as others after a liver transplant — as long as they don’t have hepatitis C as well, researchers said in Copenhagen.

• Explain to interested patients that many patients with HIV also have hepatitis C.
• Note that this study suggests that HIV alone is no barrier to a liver transplant, but that the outcome for patients with both diseases is significantly poorer.
• Note that this study was published as an abstract and presented orally at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

In one of the few studies with data on long-term outcomes, those with HIV had one- and five-year survival rates of 86.5% and 74% respectively, according to John O’Grady, M.D., of Kings College Hospital in London.

By comparison, HIV-negative liver transplant patients in the prospective UK Transplant Database had rates of 87.1% and 78%, which were not significantly different, Dr. O’Grady reported at the annual meeting of the European Association for the Study of the Liver.

“In terms of HIV, the clinical guidance is that theses patients do very well, (and) they should be considered for transplant in the normal way,” he said. “They don’t present any particular different clinical problem than the general liver transplant population.”

On the other hand, he said, patients with both HIV and hepatitis C are a significantly greater challenge.

“They need to be counseled that severe recurrence of hepatitis may be a problem after the transplant,” he said, adding that he and other specialists are anxiously awaiting new medications.

“We are desperate to get the newer agents, evolving agents, tested in this population at an early stage, because they have clearly an urgent need for drugs to control hepatitis C replication,” Dr. O’Grady said.

Dr. O’Grady and his colleagues analyzed outcomes of all patients having a liver transplant in the U.K. from March 1994 through April 2008.

The database includes 33 people with HIV, 847 with hepatitis C, and 5,435 HIV-negative patients. Of the HIV-positive patients, 22 also had hepatitis C.

The researchers compared patients with both HIV and hepatitis C, those with HIV, and those with hepatitis C only.

The analysis found that:

• Model for End Stage Liver Disease (MELD) scores were comparable between the three groups.
• Patients with both viruses lived, on average, for 29 months post-transplant, compared with 47.7 months for those with hepatitis C only, a difference that was significant at P=0.04.
• One- and five-year survival rates were 73% and 53% for those with both diseases, compared with 100% and 100% for those with just HIV, and 87% and 69% for those with just hepatitis C. The differences were significant at P=0.04.

Interestingly, despite the promising one- and five-year survival rates, patients with HIV had a mean post-transplant survival rate of 44 months compared with 57.1 months for HIV-negative patients, a difference that was significant at P=0.0001.

Dr. O’Grady said that difference is probably an artifact of the changing face of HIV — the analysis included only a few patients transplanted early in the HIV pandemic, who tended to do very poorly.

In a univariate analysis, hepatitis C infection was a significant predictor of death after transplant in HIV-positive patients, with an odds ratio of 10 and a 95% confidence interval from 1.03 to 97.04.

But in a multivariate logistic regression model, the effect of hepatitis C was not independent of other covariates, such as MELD score and recipient and donor ages.

Primary source: European Association for the Study of Liver

Source reference:
Joshi D, et al “UK liver transplant experience of HIV: Long term outcomes” EASL 2009;