SAN FRANCISCO, July 31 — The elevated risk of human papillomavirus (HPV)-related cancers in AIDS patients rises with the degree of immunosuppression, researchers found.

The excess risk was at least 1.6-fold for invasive cancers and at least 8.9-fold for in situ tumors, Anil K. Chaturvedi, PhD, of the National Cancer Institute in Rockville, Md., and colleagues reported online in the Journal of the National Cancer Institute.

Low CD4 T-cell count at the time of AIDS onset predicted significantly higher risk of invasive anal cancer among men (P=0.006) and a trend for higher risk among women for in situ cancer of the vagina or vulva as well (P=0.077 and P=0.055).

Statistical power may have been an issue for the other, less common cancer types in association with immunity, Dr. Chaturvedi noted.

“Given that individuals currently infected with HIV may obtain little benefit from available HPV vaccines . . . our results underscore the need for effective screening for cervical cancer and anal cancer among persons with HIV infection or AIDS,” the authors wrote.

• Explain to interested patients that the study supported, but did not prove, a biological link between the risk of HPV-related cancers and AIDS-related immunosuppression.
• Note that the study revealed an excess risk of screen-detectable cancers — cervical and anal cancers — in AIDS.

These retrospective study findings add to mounting evidence for a biological link between HIV/AIDS — and immunosuppression in general — with risk of HPV-associated cancers, commented Howard D. Strickler, MD, MPH, of Albert Einstein College of Medicine in New York.

But his accompanying commentary cautioned that this relationship is still unproven and has only moderate strength that varies by cancer type.

Nevertheless, “as the population of HIV-infected patients survives longer through use of HAART [highly active antiretroviral therapy] and increasingly enters the older age groups in which HPV-related cancer rates reach their peak,” he wrote, “these tumors will represent an increasing clinical and public health burden (regardless of whether these are biological relationships).”

The researchers examined rates of HPV-associated cancers in cancer registries for 499,230 individuals diagnosed with AIDS from 1980 through 2004.

Compared with the general population, the standardized incidence ratios were significantly elevated for the following HPV-associated cancers in the five years after AIDS diagnosis:

• Anal cancer in men (SIR for in situ 68.6 and 34.6 for invasive)
• Anal cancer in women (SIR 33.0 for in situ and 14.5 for invasive)
• Cervical cancer (SIR 8.9 for in situ and 5.6 for invasive)
• Cancer of the penis (SIR 19.7 for in situ and 5.3 for invasive)
• Cancer of the vagina or vulva (SIR 27.2 for in situ and 5.8 for invasive)
• Oropharyngeal cancer (SIR 1.6 for invasive)

Extending the observation period to the five years before AIDS onset revealed significantly increasing trends in risk over time for all the HPV-related cancers except in situ anal cancer among women and invasive cancers of the penis or oropharynx.

Invasive cervical cancer — an AIDS-defining illness — was excluded from this analysis since no cases can occur before AIDS onset by definition.

Not only did individuals have greater risk of HPV-associated cancers with longer duration of immune-suppressing viral infection, but incidence rose across eras too.

For individuals diagnosed in the HAART era from 1996 through 2004, incidence in the five years after their diagnosis was higher than for those diagnosed in 1980-1989 or 1990-1995 for in situ (incidence rose from 1.7 to 18.3 cases to 29.5 cases per 100,000 person-years) and invasive anal cancer among men (incidence rose from 10.5 to 20.7 to 42.3 cases per 100 000 person-years).

Even after adjusting for calendar period, incidence rose with duration of AIDS diagnosis as well for the following cancers:

• Invasive anal cancer among men (P=0.043)
• In situ penile cancer (P=0.028)
• In situ vagina or vulva cancer (P=0.025)
• In situ anal cancer among men (P=0.093)

These findings suggest that immunosuppression during HIV before transition to AIDS plays a role in susceptibility, Dr. Chaturvedi’s group noted.

And because HAART does not substantially alter HPV persistence or progression of premalignant anal or genital lesions, “it has been speculated that the incidence of HPV-associated cancers may increase as persons with AIDS live longer in the HAART era,” they said.

Prior studies have found a significantly elevated risk of HPV-related cancers in AIDS but not the association with immunosuppression.

Part of the reason for the difference may have been the substantially larger size of Dr. Chaturvedi’s study, they suggested.

More intensive screening for anal and cervical cancer in persons with AIDS may have been an alternative explanation for the changes seen over time, but the lack of changes in staging over time argued against this, the investigators said.

An important limitation of the study was lack of repeat CD4 T-cell counts — which typically rise with HAART as a marker of immunosuppression from the virus.

The researchers argued, though, that CD4 counts at AIDS onset reflect immunosuppression during HIV infection and also track with CD4 count improvements during treatment.

Primary source: Journal of the National Cancer Institute

Source reference:
Chaturvedi AK, et al “Risk of human papillomavirus-associated cancers among persons with AIDS” J Natl Cancer Inst 2009; 101: 1-11.

Additional source: Journal of the National Cancer Institute

Source reference:
Strickler HD “Does HIV/AIDS have a biological impact on the risk of human papillomavirus-related cancers?” J Natl Cancer Inst 2009; 101: 1103-04.

The new antiretroviral raltegravir (Isentress) is an effective first treatment for HIV and suppresses HIV replication far more rapidly than efavirenz, with fewer adverse events according to a study funded by the manufacturer

• Explain to interested patients that in this study, that raltegravir acted more quickly on HIV than efavirenz and with fewer adverse events.
• Note that the study was funded by Merck, the manufacturer of raltegravir.

Of patients given raltegravir as their first treatment for HIV, 86.1% saw their virus load (vRNA concentration) drop below 50 copies per milliliter of blood after 48 weeks, compared to 81.9% of patients given efavirenz, an older but commonly used drug (difference 4.2%, 95% CI -1.9 to 10.3)), according to results published online August 3 in The Lancet.

The viral suppression occurred more quickly for patients on raltegravir than on efavirenz (log-rank test P<0·0001), with 50% of the raltegravir group achieving virologic suppression by week four of treatment, compared with less than 20% of the efavirenz group.

Of the patients on raltegravir, 44% experienced adverse drug-related clinical adverse events, compared to 77% of those on efavirenz (95% CI -40.2 to -25, P<0·0001). For both drugs, less than 2% of patients experienced serious adverse events.

“Raltegravir-based combination treatment had rapid and potent antiretroviral activity, which was non-inferior to that of efavirenz at week 48,” Jeffrey L. Lennox, MD, of Emory University School of Medicine, and colleagues wrote. “Raltegravir is a well tolerated alternative to efavirenz as part of a combination regimen against HIV-1 in treatment-naive patients.”

Produced by Merck, raltegravir was approved by the U.S. Food and Drug Administration in October 2007, making it the first of a new class of drugs on the market known as “integrase inhibitors.” The drug works by disrupting the action of integrase, the enzyme that inserts HIV genetic material into human chromosomes.

Efavirenz, which was first approved in 1998, is a non-nucleoside reverse transcriptase inhibitor and works by inhibiting an enzyme vital for producing HIV viral DNA in host cells.

Previous studies have shown that use of raltegravir with optimum background therapy is effective and well tolerated in patients who have already undergone treatment for multidrug-resistant HIV-1 infection.

But the safety and efficacy of raltegravir in patients who have not yet begun treatment had only been explored in a much smaller study.

To study the use of raltegravir as a first medication for HIV patients, Lennox and colleagues enrolled 566 HIV patients from 67 study centers on five continents between Sept 14, 2006, and June 5, 2008.

The patients were at least 18 years old and had vRNA counts of at least 5,000 copies per milliliter blood.

At the beginning of the phase II trial, 297 patients had a vRNA concentration of more than 100,000 per milliliter and 47% had counts of 200 or fewer CD4 cells per milliliter.

Participants were randomly assigned to receive either 400 milligrams of oral raltegravir twice daily or 600 milligrams of oral efavirenz once daily. Both were taken in combination with tenofovir and emtricitabine, two other HIV drugs that are often administered along with efavirenz as part of a combination treatment approved by the FDA in 2006.

Of the participants, 281 received raltegravir, 282 received efavirenz and three were never treated.

Successful treatment with raltegravir was defined as the reduction of vRNA concentration to less than 50 copies per milliliter of blood at week 48 of the study.

The proportion of the patients reaching this endpoint in the raltegravir group had to be within 12% of that of the efavirenz group for raltegravir to be considered equivalent to efavirenz.

The authors noted efavirenz-based combination treatment can be given once daily as one pill, but that raltegravir must be taken twice daily, which might have effect on treatment adherence in clinical practice.

Given raltegravir’s fast-action and lower-risk of adverse events, however, the authors were bullish about the new drug.

In particular, they wrote, raltegravir may be warranted in cases of efavirenz-resistant HIV, or where efavirenz raises concerns of drug interactions, side effects or teratogenicity, its potential to cause physical abnormalities in an unborn fetus.

“Our findings that raltegravir-based combination treatment is effective and generally well tolerated in treatment-naive patients, compared with efavirenz, are supported by follow-up data to week 96 in a phase II study of treatment-naive patients,” Lennox and colleagues wrote.

“Raltegravir is an important additional drug for initial treatment of HIV-1 infection, and should be regarded as an alternative to efavirenz as part of a first-line combination regimen with tenofovir and emtricitabine in treatment-naive patients.”

In an accompanying editorial, Sean Emery, MD, of the National Centre in HIV Epidemiology 1and Clinical Research in Sydney, and Alan Winston, MD, of Imperial College London in London, wrote that raltegravir seems to have an edge over efavirenz in terms of safety and tolerability.

Moreover, Raltegravir seems to be free of clinical drug-drug interactions, is not likely to be vulnerable to transmitted HIV drug resistance and can increase the number of plausible drug regimens that could be used during an individual’s lifetime, they wrote.

“Unfortunately up to now, adverse side-effects and unfavourable drug-drug interactions have unerringly constrained progress with every antiretroviral drug class,” they wrote.

“However, today’s data are very encouraging for treatment and research. Raltegravir is an impressive drug and we hope other integrase inhibitors in development offer similar benefits.”

Primary source: The Lancet

Source reference:
Lennox J, et al. “Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial” The Lancet 2009; DOI:10.1016/S0140-6736(09)60918-1

• Explain to interested patients that advances in HIV treatment have improved the prognosis for many patients but also present new challenges to the physician.
• Note that these guidelines reflect the primary care needs of HIV patients in an era of better treatment and longer life.

Doctors caring for people with HIV need to ensure that their patients adhere not only to medications but also to the wider spectrum of care.

That’s the bottom line of the 2009 primary care guidelines for management of HIV patients issued by the HIV Medicine Association and the Infectious Diseases Society of America.

Such “adherence to care” is important because patients who don’t keep medical appointments and actively engage in their care have been found to have about a 50% higher mortality rate, according to Judith Aberg, MD, of New York University School of Medicine, and colleagues.

The guidelines -– last updated in 2004 -– appear in the Sept. 1 issue of Clinical Infectious Diseases.

Although advances in therapy have improved the prognosis for many HIV patients, Aberg said in a statement, “data from recent studies suggest those living with HIV are at higher risk for developing common health problems, such as heart disease, diabetes, or cancer,”

“Now more than ever,” she said, “it’s imperative that HIV care providers be aware of the primary care needs of their patients, and that includes routine screening for these kinds of conditions.”

“It’s not just about adherence to medication, it’s also about adherence to care,” Aberg said. “These patients must have access to a range of services to help them stay engaged in their medical care and should receive the regular monitoring and medical attention this chronic infection demands.”

The guidelines include a suite of changes that reflect improvements in HIV diagnosis and care. Among the changes:

• The list of HIV diagnostic tests has been expanded.
• The guidelines now suggest genotypic resistance tests when a patient enters care, even if antiretroviral therapy will not be started immediately.
• Testing for the HLA-B*5701 haplotype -– which increases the risk of an abacavir (Ziagen) hypersensitivity reaction — should be done before starting therapy with the drug. Patients positive for the haplotype should not be treated with abacavir.
• Baseline urinalysis and calculated creatinine clearance should be considered, especially in black patients, because of an increased risk of HIV-associated nephropathy, and the tests should also be done before starting treatment with drugs with a potential for nephrotoxicity.
• Before starting treatment with a CCR5-antagonist -– one of the new classes of antiretroviral drugs -– patients should be tested to see if their virus is likely to be susceptible.

The guidelines urge a team approach to HIV care -– the so-called “medical home” -– that addresses all of a patient’s medical needs, according to Michael Saag, MD, of the University of Alabama at Birmingham, who is also chair-elect of the HIV Medicine Association.

“Many HIV programs are effectively using the medical home model today to manage the complex needs of HIV patients,” Saag said in a statement. “This successful track record offers a valuable lesson, not only for HIV care but for all patients, as lawmakers finalize healthcare reforms.”