CAPE TOWN, South Africa, July 23 — Antiretroviral therapy starting in the third trimester of pregnancy continuing through six months of breastfeeding sharply reduces the risk of mother-to-child HIV transmission, a researcher said here.

The protection carries through at least six months of breastfeeding, a practice that has important health benefits in resource-poor societies, according to Roger Shapiro, MD, of Harvard Medical School.

In essence, treating the mother “saves the breastfeeding” and lowers the rate of transmission during that period to rates comparable to those seen in the developed world, he told attendees at the fifth International AIDS Society conference on pathogenesis, treatment, and prevention of HIV.

• Explain to interested patients that mother-to-child transmission of HIV remains a difficult issue in the developing world.
• Note that this study suggests that HAART in the third trimester of pregnancy, continuing through six months of breastfeeding to weaning, can sharply reduce the risk of infecting an infant.
• 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 the U.S. and other developed countries, infants born to HIV-positive mothers are usually bottle-fed. But in the developing world, bottle-feeding is often not practical because of expense or lack of clean water.

Even where bottle-feeding is possible, breastfeeding is preferred because it passes immunity from mother to child, preventing a range of other diseases, some of them fatal, Dr. Shapiro said.

He and his colleagues enrolled 739 women in Botswana who were HIV-positive. The 179 women who formed the control group met guidelines for immediate therapy and were placed on nevirapine (Viramune) and lamivudine/zidovudine (Combivir) between 18 and 34 weeks gestation and were continued on the therapy throughout the study.

The remaining 560 were randomized to get one of two highly active antiretroviral therapy (HAART) regimens, starting in the third trimester and continuing until weaning at six months.

Of the randomized women, the 285 in so-called Arm A were treated with abacavir/lamivudine/zidovudine (Trizivir) and the 275 in arm B were given lopinavir/ritonavir (Kaletra) and lamivudine/zidovudine, Dr. Shapiro said.

In more than 92% of women in all three arms, the therapy suppressed the virus to fewer than 400 copies of HIV RNA per milliliter of plasma both during delivery and over the first six months, Dr. Shapiro said.

Overall, there were five cases of mother to child transmission in utero, none during the intrapartum period, and two during breastfeeding. Both of the cases in the breastfeeding period came in Arm A.

He said the transmission rate during breastfeeding was 1%, which is the “lowest transmission rate ever reported by a breastfeeding program.”

There was no significant difference between the randomized arms, he added.

Dr. Shapiro said practical obstacles — such as the cost of antiretroviral drugs — may make applying the finding difficult. But “the science is clear,” he said.

The finding, combined with several other studies presented here, suggests that early intensive treatment of mothers has substantial benefits, said Timothy Farley, PhD, of the World Health Organization’s reproductive health department.

“The earlier you treat the mother, the better,” he said, “and the longer you treat the mother, the better in terms of reducing transmission.”

What’s exciting about the trials presented here, he said, “is that they really are moving the whole picture forward how it gets translated into practice . . . well, at least we know where we’re going.”

The study was supported by the National Institute of Allergy and Infectious Diseases. Medications were provided by the government of Botswana, GlaxoSmithKline , and Abbott. Dr. Shapiro did not report any conflicts.

Primary source: IAS Conference on HIV Pathogenesis and Treatment

Source reference:
Shapiro R et al. “A randomized trial comparing highly active antiretroviral therapy regimens for virologic efficacy and the prevention of mother-to-child HIV transmission among breastfeeding women in Botswana (The Mma Bana Study)” IAS 2009; abstract WELBB101.

CAPE TOWN, South Africa, July 23 — For patients doing well on their first anti-HIV regimen, the treatment can be simplified by dropping a controversial drug, a researcher said here.

• Explain to interested patients that many anti-HIV drugs are boosted by the use of ritonavir (Norvir), but the drug is not popular because of toxicity.
• Note that this study showed that in some cases a regimen that does not use ritonavir can be as effective as one that does.
• 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 the randomized section of a two-stage trial, patients treated without the protease inhibitor ritonavir (Norvir) did as well as those whose regimens included the drug, according to Kathleen Squires, MD, of Thomas Jefferson University in Philadelphia.

Indeed, the proportion of patients whose viral load was undetectable after 84 weeks of treatment tended to be slightly higher in the simplified arm — 86% versus 81% — Dr. Squires said at the fifth International AIDS Society conference on pathogenesis, treatment, and prevention of HIV.

For this study, an undetectable viral load was fewer than 50 copies of HIV RNA per milliliter of plasma.

Ritonavir, originally used to treat HIV, is now mainly employed as a booster of other drugs, because it slows the rate at which they are cleared from the system. But it is not popular with clinicians or patients because of toxicity and drug-drug interactions.

In this study, patients without previous HIV treatment were given the protease inhibitor atazanavir (Reyataz), boosted with ritonavir, in combination with abacavir and lamivudine (Epzicom) for 36 weeks.

The 419 patients whose viral load was undetectable at the end of that period were randomized to continue boosted atazanavir or to get a moderately higher dose of atazanavir (400 milligrams a day versus 300) but without ritonavir. All patients continued to get abacavir and lamivudine.

The goal was to compare efficacy and safety of the two regimens, Dr. Squires said in a late-breaker session on the final day of the conference.

Indeed, after 48 weeks there was no difference in efficacy, she said, with a significance level of P=0.14. The regimens remained equivalent regardless of patients’ viral load at baseline, Dr. Squires said.

Over the 84-week study, all patients gained CD4-positive T cells and at the end of the randomization period those in the boosted arm had gained a total of 259 cells, compared with 240, which was not significantly different.

During the randomization period, those getting the simplified regimen had a slightly better lipid profile, Dr. Squires said.

Specifically, the median changes in fasting lipids were:

• Cholesterol fell 14 milligrams per deciliter, compared with a gain of six in patients receiving ritonavir.
• High-density lipoprotein rose one milligram per deciliter, compared with a rise of two.
• Low-density lipoprotein fell five milligrams per deciliter, compared with a gain of four.
• Triglycerides fell 34 milligrams per deciliter, compared with a loss of four.

Dr. Squires said 10% of patients in the simplified arm reported grade 2 through 4 adverse events during the randomization phase, compared with 14% of those in the boosted atazanavir arm.

The most common event was high bilirubin, reported by 4% of those in the simplified arm and 10% in the boosted arm.

The finding makes “perfect sense,” said Pedro Cahn, MD, of Fundacion Huesped in Buenos Aires, Argentina. Dr. Cahn, the past president of the AIDS society, was not involved in the research.

If a patient’s virus is suppressed, he said, “you don’t have to use the full potency of the regimen” to keep it under control.

From a practical point of view, the regimen without ritonavir would reduce the cost of treatment by about $300 a month in developed countries, he said.

“And you would get rid of the drug-drug interactions that ritonavir produces,” Dr. Cahn added. The drug enhances the concentration of several drugs that are metabolized by the liver, he noted.

“Nobody likes ritonavir,” he added.

The study was supported by GlaxoSmithKline and several of the coauthors were employees of GlaxoSmithKline . Some study medication was provided by Bristol-Myers Squibb. Dr. Squires did not report any conflicts.

Primary source: IAS 2009

Source reference:
Squires K 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.” IAS 2009; abstract WELBB103.

CAPE TOWN, South Africa, July 23 — Three powerful new drugs can suppress human immunodeficiency virus (HIV) infections that are highly resistant to current antiretroviral medications for up to a year, researchers reported here.

• Even for HIV patients who have resistant mutations that make some drugs unusable there still appears to be regimens that work well.
• Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

After 48 weeks of treatment, 89 of 103 patients in a clinical trial maintained suppression of HIV to undetectable levels using the 50 copies/mL assay, according to Yazdan Yazdanpanah, MD, PhD, professor of Infectious Diseases at Tourcoing Hospital, University of Lille, France.

That was twice as long as previous studies of the drug combination.

“HIV-infected patients with highly resistant virus and few remaining options may benefit from an antiretroviral regimen containing these drugs and may achieve sustained virologic suppression comparable to treatment-naïve patients over the first 48 weeks,” he reported at the 2009 International AIDS Society Conference.

The drugs used in the aptly-named TRIO trial, conducted by the French National Agency for Research on AIDS and Viral hepatitis (ANRS) were:

• The non-nucleoside reverse transcriptase inhibitor etravirine (Intelence).
• The integrase inhibitor raltegravir (Isentress)
• The protease inhibitor darunavir (Prezista), boosted by ritonavir (Norvir).

Previously, the TRIO study investigators had shown suppression of virus among 90% of the patient to undetectable levels after 24 weeks of therapy.

“We are seeing that even patients with resistance to several classes of drugs can achieve undetectable virus, and they can maintain that suppression for at least a year,” commented Cal Cohen, MD, research director of the Community Research Initiative of New England.

Dr. Cohen did not participate in the TRIO study but moderated the overflow poster discussion session at which the study was presented.

To be eligible for the study, patients had to have detectable HIV virus in the blood at levels greater than 1000 copies/mL, and then had to undergo genotype analysis.

For the patient to qualify, that analysis had to show the following:

• At least three major protease inhibitor resistance mutations
• At least three nucleoside reverse transcriptase inhibitor resistance mutations
• At least three non-nucleoside reverse transcriptase inhibitor mutations
• Fewer than three darunavir mutations

At baseline the mean viral load for the participants was about 40,000 copies/mL.

Dr. Yazdanpanah said that 15 patients experienced Grade 3 or 4 adverse events during the 48 weeks of the trial, including 4 events that were considered drug-related.

One patient discontinued treatment due to a grade 4 skin rash that was accompanied by fever. Grade 3 or Grade 4 laboratory abnormalities were observed in 20 patients, but none had to discontinue treatment.

Dr. Yazdanpanah said that the participants achieved a median decline in viral load of 2.4 log10, and also achieved a mean CD4-positive cell increase of 108/mm3.

Dr. Yazdanpanah and Dr. Cohen did not report financial disclosures. The marketers of the drugs, Merck, Sharp and Dohme, and Tibotec (a division of Janssen-Cilag), provided the medications used in the study.

Primary source: IAS Conference on HIV Pathogenesis and Treatment

Source reference:
Fagard C, et al “TUPDB204 — Efficacy and safety of raltegravir plus etravirine and darunavir/ritonavir in treatment experienced patients with multidrug-resistant virus: 48-week results from the ANRS 139 TRIO trial” IAS 2009; P. 85.

CAPE TOWN, South Africa, July 23 — Antiretroviral therapy starting in the third trimester of pregnancy continuing through six months of breastfeeding sharply reduces the risk of mother-to-child HIV transmission, a researcher said here.

The protection carries through at least six months of breastfeeding, a practice that has important health benefits in resource-poor societies, according to Roger Shapiro, MD, of Harvard Medical School.

In essence, treating the mother “saves the breastfeeding” and lowers the rate of transmission during that period to rates comparable to those seen in the developed world, he told attendees at the fifth International AIDS Society conference on pathogenesis, treatment, and prevention of HIV.

• Explain to interested patients that mother-to-child transmission of HIV remains a difficult issue in the developing world.
• Note that this study suggests that HAART in the third trimester of pregnancy, continuing through six months of breastfeeding to weaning, can sharply reduce the risk of infecting an infant.
• 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 the U.S. and other developed countries, infants born to HIV-positive mothers are usually bottle-fed. But in the developing world, bottle-feeding is often not practical because of expense or lack of clean water.

Even where bottle-feeding is possible, breastfeeding is preferred because it passes immunity from mother to child, preventing a range of other diseases, some of them fatal, Dr. Shapiro said.

He and his colleagues enrolled 739 women in Botswana who were HIV-positive. The 179 women who formed the control group met guidelines for immediate therapy and were placed on nevirapine (Viramune) and lamivudine/zidovudine (Combivir) between 18 and 34 weeks gestation and were continued on the therapy throughout the study.

The remaining 560 were randomized to get one of two highly active antiretroviral therapy (HAART) regimens, starting in the third trimester and continuing until weaning at six months.

Of the randomized women, the 285 in so-called Arm A were treated with abacavir/lamivudine/zidovudine (Trizivir) and the 275 in arm B were given lopinavir/ritonavir (Kaletra) and lamivudine/zidovudine, Dr. Shapiro said.

In more than 92% of women in all three arms, the therapy suppressed the virus to fewer than 400 copies of HIV RNA per milliliter of plasma both during delivery and over the first six months, Dr. Shapiro said.

Overall, there were five cases of mother to child transmission in utero, none during the intrapartum period, and two during breastfeeding. Both of the cases in the breastfeeding period came in Arm A.

He said the transmission rate during breastfeeding was 1%, which is the “lowest transmission rate ever reported by a breastfeeding program.”

There was no significant difference between the randomized arms, he added.

Dr. Shapiro said practical obstacles — such as the cost of antiretroviral drugs — may make applying the finding difficult. But “the science is clear,” he said.

The finding, combined with several other studies presented here, suggests that early intensive treatment of mothers has substantial benefits, said Timothy Farley, PhD, of the World Health Organization’s reproductive health department.

“The earlier you treat the mother, the better,” he said, “and the longer you treat the mother, the better in terms of reducing transmission.”

What’s exciting about the trials presented here, he said, “is that they really are moving the whole picture forward how it gets translated into practice . . . well, at least we know where we’re going.”

The study was supported by the National Institute of Allergy and Infectious Diseases. Medications were provided by the government of Botswana, GlaxoSmithKline , and Abbott. Dr. Shapiro did not report any conflicts.

Primary source: IAS Conference on HIV Pathogenesis and Treatment

Source reference:
Shapiro R et al. “A randomized trial comparing highly active antiretroviral therapy regimens for virologic efficacy and the prevention of mother-to-child HIV transmission among breastfeeding women in Botswana (The Mma Bana Study)” IAS 2009; abstract WELBB101.

CAPE TOWN, July 22 — Doctors should consider dropping non-active drugs from the revised regimens of HIV patients who are experiencing treatment failure, researchers suggested here.

• This study suggests that consideration should be given to dropping non-active drugs if the salvage therapy is unable to suppress virus to undetectable levels.
• Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Typically these inactive components are nucleoside reverse transcriptase inhibitors, according to Benoit Trottier, MD, research medical director at Clinique Medicale l’Actuel in Montreal.

“Keeping inactive nucleoside reverse transcriptase inhibitors in the regimen increases the cost of treatment and the risk of drug interactions and toxicity,” he told colleagues during a poster session at the 2009 International AIDS Society conference.

“Using non-active nucleoside reverse transcriptase inhibitors for multidrug resistance patients did not improve virologic outcomes,” he added.

Even though they know a drug may not be active, Dr. Trottier said, many physicians keep it in a patient’s regimen as they add new treatments to suppress stubborn HIV cases.

“They are often used in salvage regimens despite the lack of scientific evidence,” he said of the non-active drugs.

Dr. Trottier said his study of 116 highly-experienced, HIV-infected patients whose viral load was not being controlled showed that adding one, two, or three inactive drugs to their regimens failed to make a difference in suppression of the virus.

“The viral response was inversely correlated with the number of nucleoside reverse transcriptase inhibitors prescribed,” he said. “The more nucleoside reverse transcriptase inhibitors prescribed, the lower the proportion of patients with a virologic response.

The virologic response was 100% among the 9 patients who were not given a non-active nucleoside reverse transcriptase inhibitor. The response was 89% for patients give one non-active drug, 76% for those given two non-active drugs, and 40% if three non-active drugs were in the campaign (P=.009), Dr. Trottier said.

The salvage treatments include the newer antiretrovirals; the non-nucleoside reverse transcriptase inhibitor etravirine (Intelence); the entry inhibitor maraviroc (Selzentry) and the integrase inhibitor raltegravir (Isentress), either individually or in combination.

Other researchers suggested that doctors use caution in deciding whether to keep a drug in a regimen or abandon it.

“While it seems that inactive drugs are not needed among patients who can suppress their virus to undetectable levels with newer medications, there is still a possibility that these inactive drugs are having some impact among those who have an incomplete response,” said Cal Cohen, MD, research director of Community Research Initiative of New England.

Dr. Cohen moderated the session, but was not involved in the study itself.

Dr. Trottier said there might be some reasons for continuing use of inactive drugs, including those with the ability to cross into the brain to attack HIV reservoirs unaffected by other medications.

“The inactive drugs might also increase sensitivity to other nucleoside reverse transcriptase inhibitors or might be needed in order to build a regimen that otherwise might have only one or two drugs,” he said.

Even so, he concluded, “This study suggests that non-active nucleoside reverse transcriptase inhibitors or any other non-active antiretroviral should not be part of effective salvage regimens.”

The study was supported by Tibotec Canada and Merck Frost Canada. Dr. Trottier and Dr. Cohen did not report any financial disclosures. The IAS does not require that presenters make formal disclosure statements.

Primary source: Conference Progamme 5^th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19-22 July 2009

Source reference:
Trottier B, et al “TUPDB205 - Should inactive nucleoside/tide reverse transcriptase inhibitors (NRTIs) still be used in salvage regimens, with new classes/generations of antiretrovirals in three-class-experienced, multidrug
resistant patients?,” Conference Progamme 5^th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19-22 July 2009. P. 85.

CAPE TOWN. South Africa, July 24 — The anti-herpes drug acyclovir (net/26/1/Zovirax/”>Zovirax) failed to prevent transmission of HIV among discordant couples, but researchers suggest it may still have a role in treatment by slowing progression to full-blown AIDS.

• Explain to interested patients that nothing in the trials suggests that acyclovir is not effective in treating herpes simplex virus-2 flare-ups.
• Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

The Partners in Prevention HSV/HIV Transmission Study team presented results of a pair of related questions regarding discordant couples — one of whom is HIV-positive and the other uninfected by the virus that causes AIDS — here at the International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention.

“We found there was no efficacy in the intention-to-treat analysis of all transmissions (P=0.88),” Connie Celum, MD, professor of global health and medicine at the University of Washington in Seattle, said in her late-breaker presentation.

In a study conducted at 17 sites in Africa, Dr. Celum and colleagues enrolled 3,408 HIV- and HSV-2-positive individuals who were in a regular sexual relationship with a partner who was not infected with HIV. The couples were counseled on how to avoid infection and were either treated with acyclovir 400 mg twice daily or placebo.

After follow-up of about two years, the researchers found no significant differences in the percentage of people who were infected in either the acyclovir arm (41 infections) or the placebo arm (43 infections).

They analyzed results in a number of ways and yet could find no significant advantage in the use of acyclovir in the prevention setting based on sex of the HIV-positive partner, genital ulcer disease, level of HIV in the blood at baseline, study drug adherence, circumcision status, or the herpes simplex virus-2 status of the HIV-negative partner.

As shown in other studies, Dr. Celum said, acyclovir therapy did result in a 0.25log10 fall in plasma HIV.

“This study demonstrated that a larger effect of interventions in HIV-infected persons is needed to decrease HIV infections,” she said.

In a companion study, presented by her colleague Jairam R. Lingappa, MD, PhD, researchers determined that treatment with acyclovir might slow the progression of the disease, and push back the time until treatment with antiretrovirals has to be initiated.

“Herpes simplex virus-2 suppression reduces the risk of HIV disease progression,” Dr. Lingappa said in his platform presentation. He calculated a 17% to 19% reduction in the relative risk of the need for antiretroviral medication (P=0.03).

“I think the door is closed on using acyclovir to prevent HIV transmission,” said Timothy Farley, MD, coordinator for control of sexually transmitted infections for World Health Organization, Geneva, Switzerland.

“There is clearly a role for acyclovir in patients with herpes symptoms and who have active disease,” Dr. Farley, the late-breaker session moderator, said.

Nevertheless, Dr. Farley added, “If acyclovir is going to prolong the time for the need for antiretrovirals, it might prolong the period that people are infectious, but that is in the context of treatment as prevention which, at this point, is theoretical.”

Basically, he said, “acyclovir now goes back to being used to treat herpes flare-up which is necessary for the person’s own health.”

Dr. Celum, Dr. Lingappa and Dr. Farley did not report any financial disclosures. The IAS does not require that presenters disclose possible financial conflicts of interest.

Primary source: Progamme Supplement 5^th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19-22 July 2009

Source reference:
Celum C, et al “WELBC101 - Twice-daily acyclovir to reduce HIV-1 transmission from HIV-1 / HSV-2 co-infected persons within HIV-1 serodiscordant couples: a randomized, double-blind, placebo-controlled trial,” Progamme Supplement 5^th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19-22 July 2009. P. 24.

Lingappa J, et al “WELBC102 - Daily acyclovir delays HIV-1 disease progression among HIV-1/HSV-2 dually-infected persons: a randomized trial,” Progamme Supplement 5^th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19-22 July 2009. P. 24.

CAPE TOWN, South Africa, July 24 — Men infected with human papillomavirus have an 80% increase in the risk of getting HIV, a researcher said here.

• Explain to interested patients that many sexually transmitted diseases are known to increase the risk of getting HIV.
• Note that this study found that infection with human papillomavirus, responsible for cervical cancer in women, is associated with and increased risk of getting HIV in men.
• 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.

The finding comes from analysis of data collected during the landmark trial of male circumcision in Kisumu, Kenya, according to Jennifer Smith, PhD, of the University of North Carolina Chapel Hill.

That study showed that circumcision reduced the risk of getting HIV by more than 50%, Dr. Smith noted at the 2009 International AIDS Society conference.

But as part of the study, researchers also collected data regarding other sexually transmitted diseases, including human papillomavirus (HPV), she said in a late-breaker session in the final day of the conference.

“Many (sexually transmitted infections) have been previously found to be associated with increased risk of HIV infection,” Dr. Smith said. “However, surprisingly few data are available currently on any potential effect of HPV on HIV acquisition risk.”

To help fill the gap, she and colleagues studied participants in the Kisumu trial, looking at the 42-month risk of HIV seroconversion among men positive for HPV at the start of the study, compared with those who were not.

The study had data on HPV status for 2,168 men, including 1,089 who had the virus at baseline. Of those, 754 had high-risk strains of HPV (those that cause cancer in women) and 335 had low-risk strains.

Samples were taken from the penile shaft and foreskin, and from the glans and coronal sulcus, Dr. Smith said. The researchers controlled for the effect of circumcision, the main intervention in the study.

It turned that that only positive samples from the glans were associated with increased risk of HIV, she said.

For those men, the risk of getting HIV over the study period was 5.8%, compared with 3.7% for men whose glans samples were negative at baseline. The difference was significant at P=0.01.

The acquisition rates translated into a hazard ratio of 1.8 (95% CI 1.1 to 2.9), Dr. Smith said. (In contrast, the hazard ratio for positive samples collected from the shaft was 1.1, but the confidence interval crossed unity.)

The type of HPV isolated (high- or low-risk) was not associated with any difference in the chance of getting HIV.

Dr. Smith said more research is needed to explain the increase in risk. Possible explanations, she said, include residual confounding because of sexual behavior, or some sort of biological mechanism.

For instance, she said, the HPV virus might induce local cytokines, such as macrophage inflammatory protein-3 and interleukin-8, which play a role in susceptibility to HIV.

Or, the immunological process of clearing an HPV infection might bring increased numbers of CD4-positive T cells — the targets of HIV — to sites where they could be infected, she said.

The association “could be a marker for (risky) sexual behavior,” said Timothy Farley, PhD, of the World Health Organization’s reproductive health department, who chaired the session at which the research was presented.

Whatever the case, he said, it’s interesting to theorize that the process of clearing the papillomavirus — which can occur repeatedly — may have immunological consequences that increase susceptibility to HIV.

“It’s speculation as to what the mechanism might be, but it’s an intriguing one,” he said.

Whether a vaccine approach might affect the risk is also up in the air, he said, noting that current vaccines target the high-risk, cancer-causing strains of HPV, while Dr. Smith’s study showed no difference in HIV risk based on the HPV strain involved.

Dr. Farley noted that another circumcision trial, conducted in South Africa, had also showed an increased HIV risk for men infected with HPV.

The Kisumu study was supported by the National Institute of Allergy and Infectious Diseases. Dr. Smith did not report any conflicts.

Primary source: IAS Conference on HIV Pathogenesis and Treatment

Source reference:
Smith JS et al. “Risk of HIV acquisition among men with and without human papillomavirus infection in Kisumu, Kenya” IAS 2009; abstract WELBC104.

HOUSTON, July 24 — Patients with HIV-associated nephropathy have elevated urinary levels of a protein associated with tubular injury, suggesting the marker has potential as a test for early diagnosis, investigators reported.

• Explain to patients that a protein associated with kidney injury may offer a means of early diagnosis of patients with HIV-associated kidney disease.
• The marker has been evaluated in only a few patients with HIV kidney disease.

A mouse model of HIV-associated nephropathy revealed upregulation of neutrophil gelatinase-associated lipocalin (NGAL), providing additional evidence of the protein’s diagnostic potential, Jonathan Barasch, MD, PhD, and colleagues reported online in the Journal of the American Society of Nephrology.

“NGAL was very specifically expressed in renal cysts — generating the new idea that NGAL may control the development of cysts in HIV-associated nephropathy,” Dr. Barasch, of Columbia University in New York, said in a statement.

Since the discovery of NGAL in the kidney 10 years ago, “almost every paper is positive for the association of NGAL with kidney dysfunction/disease,” he added. (See Urine Test Predicts Kidney Injury in ICU Patients)

Occurring predominantly in patients of African descent, HIV-associated nephropathy is characterized by nephrosis and rapid decline in kidney function. Histologically, the condition is a collapsing focal segmental glomerulosclerosis with prominent tubular damage.

NGAL’s association with tubular injury provided a rationale for evaluating urinary levels of the protein as a marker of HIV-associated nephropathy.

Investigators studied 13 patients with biopsy-proven HIV-associated nephropathy and 24 race-matched HIV patients with normal kidney function, defined as an estimated glomerular filtration rate ?60 ml/min and no evidence of proteinuria.

The patients with HIV-associated nephropathy also were compared with other HIV-positive and HIV-negative patients with other types of chronic kidney disease.

To obtain additional information about NGAL and HIV-associated nephropathy, investigators studied HIV-transgenic mice, which exhibit a syndrome identical to HIV nephropathy.

The patients with HIV-associated nephropathy had a mean urinary NGAL of 748 µg/g creatinine, which turned out to be:

• 11 times greater than the 68 µg/g creatinine mean in HIV-positive controls without kidney disease (P=0.006)

• Five times greater compared with HIV-positive patients who had other types of kidney disease (P<0.05)
• 34 times greater compared with HIV-negative patients with various types of chronic kidney disease (P<0.05)

In the transgenic mice, urinary NGAL was expressed most prominently in dilated microcystic tubules. Investigators detected NGAL RNA in 39% of 2,698 microcysts but not in any noncystic tubules.

“These data suggest the possibility that urinary NGAL may be useful to monitor the formation of renal tubular cysts and consequently distinguish HIV-associated nephropathy from common forms of chronic kidney disease . . . presenting in the HIV patient,” the authors said.

“In this light,” they said, “the very high levels of urinary NGAL associated with HIV-associated nephropathy may provide a rationale for biopsy and aggressive HAART therapy to prevent progression of HIV-associated nephropathy to end-stage renal disease.”

The authors acknowledge, though, that more research is needed, especially “in a large cohort where we can determine the temporal relationships between NGAL expression and disease onset and between NGAL expression and HAART.”

The authors disclosed that Columbia University and Cincinnati Children’s Hospital Medical Center (institution of one coauthor) have received licensing fees from Biosite and Abbott Diagnostics.

Primary source: Journal of the American Society of Nephrology

Source reference:

Paragas N et al. “Urinary NGAL marks cystic disease in HIV-associated nephropathy” J Am Soc Nephrol 2009; 20: 1687-1692.

Related Article(s):

• Urine Test Predicts Kidney Injury in ICU Patients

WHEELING, W.Va., July 27 — Heavy drinking and HIV infection combine to degrade certain types of memory much more than either condition alone, researchers said.

Episodic memory, but not working memory, showed significant impairment in alcoholic patients with HIV compared with normal controls, nonalcoholic HIV patients, and HIV-uninfected alcoholics, according to Edith V. Sullivan, PhD, of Stanford University, and colleagues.

The impairment in episodic memory — the ability to remember information for more than 30 seconds — was seen both at baseline and after one year, the researchers reported online in Alcoholism: Clinical and Experimental Research.

Specific patterns of memory deficits suggested that the main problem for alcoholic HIV patients involved initial storage of information rather than its subsequent retrieval.

• Explain to interested patients that memory impairments have been seen in association with alcoholism and HIV infection separately.
• Explain that such impairments can interfere with successful treatment, such as by causing patients to forget to take medications on schedule.

In general, memory test scores for the individuals with single diagnoses (either alcoholism or HIV infection) did not differ from those of normal controls.

However, Dr. Sullivan and colleagues cautioned against interpreting the study to mean that alcoholism or HIV infection alone do not impair cognitive function.

They noted that the instrument they used to assess memory was designed for screening purposes “and as such is likely not a sensitive enough measure for detecting subtle memory compromise.”

But the very ability of this insensitive instrument to detect significant deficits in patients with comorbid alcoholism and HIV infection testifies to the magnitude of the impairment, the researchers suggested.

Dr. Sullivan and colleagues recruited 164 participants overall, with roughly 40 each in the groups of comorbid patients, healthy controls, and patients with either alcoholism or HIV infection.

Participants were excluded if they had a history of major psychiatric or neurological disease or of drug dependence outside their primary diagnosis.

Alcoholics were defined as those meeting DSM-IV criteria for alcohol dependence within the previous three years.

Memory was tested with the MicroCog instrument, which includes a battery of separate tests for working and episodic memory. These include short-term recognition and recall of numbers and letters, along with simple arithmetic operations.

MicroCog assesses episodic memory with tests that require participants to remember a name and address, as well as details of short narrative stories.

The researchers found that immediate episodic memory was significantly poorer in the comorbid group at baseline and at follow-up (F (3,120)=5.39, P=0.002).

At baseline, mean scores on the 11-point subscale for immediate episodic memory were 7.7 for the comorbid patients versus 9.0, 8.3, and 8.8 for the HIV-infected, alcoholic, and normal control groups, respectively.

There were no differences among groups in delayed memory or the amount of information retained from immediate memory. Nor were there any differences in working memory scores.

Response times showed few differences among groups. However, information-processing rates were modestly but significantly lower for the comorbid patients versus the alcoholic-alone group at baseline and at follow-up for story reading, Dr. Sullivan and colleagues found.

Such potential confounding factors as depressive symptoms, lifetime alcohol consumption, use of antiretroviral drugs, and CD4-positive cell counts did not appear to affect the findings significantly.

However, higher CD4 counts in the comorbid group (but not in nonalcoholics with HIV) were associated with greater improvement in memory retention from baseline to follow-up. On the other hand, changes in CD4 counts between sessions did not predict changes in memory test scores.

The researchers said their results were in line with earlier studies that had found impairments in memory and executive functions associated with both alcoholism and HIV infection.

But the study did not support their initial expectation that performance would worsen from baseline to follow-up, especially in the comorbid patients.

Raw scores improved on average between sessions for most measures in all groups, suggesting a practice effect.

“Lack of significant worsening in performance over time may have been due to the relatively short interval between testing sessions or lack of sensitivity of the MicroCog measure,” Dr. Sullivan and colleagues offered.

To the extent that patients suffer impairment in episodic memory, they said, the comorbidities can have genuine clinical significance.

“Episodic memory deficits put affected individuals at risk for difficulties in maintaining medication regimes, following through on work and family responsibilities, and effectively using information available to them,” they said. “Even subtle deficits in episodic memory can adversely affect functional capabilities for activities of daily life.”

The study was funded by the National Institute on Alcohol Abuse and Alcoholism. Potential conflicts of interest were not reported.

Primary source: Alcoholism: Clinical and Experimental Research

Source reference:
Fama R, et al “Working and episodic memory in HIV infection, alcoholism, and their comorbidity: Baseline and 1-year follow-up examinations” Alcohol Clin Ex Res 2009; DOI: 10.1111/j.1530-0277.2009.01020.x.

CAPE TOWN, South Africa, July 22 — In early trials, a novel integrase inhibitor produced “unprecedented” anti-HIV activity in patients who have never used a drug in the class, a researcher said here.

• Explain to interested patients that the integrase inhibitors are one of the new classes of anti-HIV drugs.
• Note that this study reports on a new member of the class, but caution that the data come from early studies and more research is needed.
• 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.

At the highest dose tested — 50 mg daily — the drug resulted in a 2.5-log₁₀ decline in HIV viral load, according to Sherene Min, MD, of GlaxoSmithKline .

That is a greater decline than is seen with either of the other two available integrase inhibitors, raltegravir (Isentress) and elvitegravir, Dr. Min said at the 2009 International AIDS Society conference on pathogenesis, treatment, and prevention of HIV.

Raltegravir is approved and is in clinical use, while elvitegravir is still in clinical trials. All three drugs block the integration of HIV genetic information into the host cell’s genome.

Dr. Min’s comparison of the drugs is based on a 35-patient randomized trial testing three doses of the new integrase inhibitor — so far known only as S/GSK1349572 — as monotherapy against placebo over a 10-day period.

But the comparison may be going a bit too far, according to Stefano Vella, MD, of the Istituto Superiore di Sanità in Rome, the Italian equivalent of the NIH. Dr. Vella, a former president of the AIDS society, chaired the session at which the research was presented.

“I think it’s a little premature to do this comparison,” Dr. Vella said. “Potency is very important, but we are already giving a score” even though only a handful of patients have been treated for a short period of time.

That said, Dr. Vella agreed the early results are “very encouraging. We need new generations, even of the new drugs.”

Dr. Min said the compound neither blocks nor enhances cytochrome p450, has a predictable exposure-response relationship, and does not have a significant food effect.

Also, she noted, there is “limited cross-resistance” to raltegravir and elvitegravir.

In the study, patients with a viral load of at least 5,000 copies of HIV RNA per milliliter of plasma and a CD4 cell count of at least 100 cells per cubic millimeter were randomized to a placebo or to 2, 10, or 50 mg of the drug daily.

After 10 days, only one of the patients in the two lower-dose groups had undetectable virus, defined as fewer than 50 copies per milliliter, compared with seven of the 10 patients getting 50 mg, Dr. Min said.

Adverse events were generally mild to moderate, including diarrhea, headache, and fatigue, Dr. Min said. Although there were four Grade 3 events, they were all different and there was no pattern of occurrence, she reported.

The data support longer studies, Dr. Min said, adding that a phase IIb trial will start later this month.

The study was sponsored by GlaxoSmithKline and Shionogi and Co. Dr. Min is an employee of GlaxoSmithKline .

Primary source: IAS Conference on HIV Pathogenesis and Treatment

Source reference:
Lalezari J et al. “Potent antiviral activity of S/GSK1349572, a next generation integrase inhibitor (INI), in INInaïve HIV-1-infected patients” IAS 2009; abstract TUAB105.

Newer Posts »