Diana Mahoney

BOSTON — Elevations in inflammatory and coagulation biomarkers may explain the increased risk of cardiovascular disease and death in HIV-infected patients randomized to the treatment interruption arm of an international treatment strategy trial.

The Strategies for Management of Antiretroviral Therapies (SMART) trial was initiated in 2002 to compare CD4-cell-guided structured treatment interruptions with continuous antiretroviral therapy. The trial was halted in 2006 when interim data showed that patients randomized to intermittent therapy not only had significantly higher rates of AIDS-related opportunistic illnesses, but also of cardiovascular disease (CVD) and all-cause mortality, compared with patients on continuous therapy, Dr. Lewis Kuller said at the 15th Conference on Retroviruses and Opportunistic Infections.

To explore the possible mechanisms underlying the increased CVD risk, Dr. Kuller, of the University of Pittsburgh, and his colleagues in the SMART Study Group conducted a nested case-control analysis evaluating biomarkers that have been associated with mortality and CVD in the general population.

The investigators paired each of 85 SMART patients (55 in the treatment interruption group and 30 in the continuous therapy group) who died through 2006 with two age-, gender-, and country-matched controls from the remaining patient population. Estimating adjusted odds ratios for the fourth versus first quartile of each biomarker using logistic regression, they compared baseline and 1-month levels of four inflammatory makers (high-sensitivity C-reactive protein, interleukin-6, serum amyloid A, and amyloid P) and two coagulation markers (D-dimer and prothrombin fragment 1+2), Dr. Kuller said.

Compared with baseline, the 1-month D-dimer and interleukin-6 levels increased by 16% and 30%, respectively, among patients on intermittent treatment, and the progressive increases were directly related to increases in HIV viral load after treatment interruption. In contrast, the levels of both biomarkers remained stable in the continuous treatment arm. Mortality was strongly related both to baseline levels of these two biomarkers in the treatment interruption and continuous therapy groups, as well as to the progressive increases that occurred after treatment interruption, “with odds ratios greater than 12 for those in the fourth vs. first quartile,” Dr. Kuller said.

Calling the relationship between the increased levels of these two biomarkers and mortality risk “extraordinary,” Dr. Kuller noted that the association was far greater than that seen in general population studies of cardiovascular risk factors. “The findings indicate that elevated levels of D-dimer and interleukin-6 identify a subgroup of HIV-infected patients at high risk of death in both treatment groups, and the increases in both markers may partly explain the increased risk of mortality and CVD in the treatment interruption group,” he said at the conference, which was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.

The associations between the biomarkers and CVD were modest but significant, Dr. Kuller said.

BOSTON — Elevations in inflammatory and coagulation biomarkers may explain the increased risk of cardiovascular disease and death in HIV-infected patients randomized to the treatment interruption arm of an international treatment strategy trial.

The Strategies for Management of Antiretroviral Therapies (SMART) trial was initiated in 2002 to compare CD4-cell-guided structured treatment interruptions with continuous antiretroviral therapy. The trial was halted in 2006 when interim data showed that patients randomized to intermittent therapy not only had significantly higher rates of AIDS-related opportunistic illnesses, but also of cardiovascular disease (CVD) and all-cause mortality, compared with patients on continuous therapy, Dr. Lewis Kuller said at the 15th Conference on Retroviruses and Opportunistic Infections.

To explore the possible mechanisms underlying the increased CVD risk, Dr. Kuller, of the University of Pittsburgh, and his colleagues in the SMART Study Group conducted a nested case-control analysis evaluating biomarkers that have been associated with mortality and CVD in the general population.

The investigators paired each of 85 SMART patients (55 in the treatment interruption group and 30 in the continuous therapy group) who died through 2006 with two age-, gender-, and country-matched controls from the remaining patient population. Estimating adjusted odds ratios for the fourth versus first quartile of each biomarker using logistic regression, they compared baseline and 1-month levels of four inflammatory makers (high-sensitivity C-reactive protein, interleukin-6, serum amyloid A, and amyloid P) and two coagulation markers (D-dimer and prothrombin fragment 1+2), Dr. Kuller said.

Compared with baseline, the 1-month D-dimer and interleukin-6 levels increased by 16% and 30%, respectively, among patients on intermittent treatment, and the progressive increases were directly related to increases in HIV viral load after treatment interruption. In contrast, the levels of both biomarkers remained stable in the continuous treatment arm. Mortality was strongly related both to baseline levels of these two biomarkers in the treatment interruption and continuous therapy groups, as well as to the progressive increases that occurred after treatment interruption, “with odds ratios greater than 12 for those in the fourth vs. first quartile,” Dr. Kuller said.

Calling the relationship between the increased levels of these two biomarkers and mortality risk “extraordinary,” Dr. Kuller noted that the association was far greater than that seen in general population studies of cardiovascular risk factors. “The findings indicate that elevated levels of D-dimer and interleukin-6 identify a subgroup of HIV-infected patients at high risk of death in both treatment groups, and the increases in both markers may partly explain the increased risk of mortality and CVD in the treatment interruption group,” he said at the conference, which was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.

The associations between the biomarkers and CVD were modest but significant, Dr. Kuller said.

BOSTON — Elevations in inflammatory and coagulation biomarkers may explain the increased risk of cardiovascular disease and death in HIV-infected patients randomized to the treatment interruption arm of an international treatment strategy trial.

The Strategies for Management of Antiretroviral Therapies (SMART) trial was initiated in 2002 to compare CD4-cell-guided structured treatment interruptions with continuous antiretroviral therapy. The trial was halted in 2006 when interim data showed that patients randomized to intermittent therapy not only had significantly higher rates of AIDS-related opportunistic illnesses, but also of cardiovascular disease (CVD) and all-cause mortality, compared with patients on continuous therapy, Dr. Lewis Kuller said at the 15th Conference on Retroviruses and Opportunistic Infections.

To explore the possible mechanisms underlying the increased CVD risk, Dr. Kuller, of the University of Pittsburgh, and his colleagues in the SMART Study Group conducted a nested case-control analysis evaluating biomarkers that have been associated with mortality and CVD in the general population.

The investigators paired each of 85 SMART patients (55 in the treatment interruption group and 30 in the continuous therapy group) who died through 2006 with two age-, gender-, and country-matched controls from the remaining patient population. Estimating adjusted odds ratios for the fourth versus first quartile of each biomarker using logistic regression, they compared baseline and 1-month levels of four inflammatory makers (high-sensitivity C-reactive protein, interleukin-6, serum amyloid A, and amyloid P) and two coagulation markers (D-dimer and prothrombin fragment 1+2), Dr. Kuller said.

Compared with baseline, the 1-month D-dimer and interleukin-6 levels increased by 16% and 30%, respectively, among patients on intermittent treatment, and the progressive increases were directly related to increases in HIV viral load after treatment interruption. In contrast, the levels of both biomarkers remained stable in the continuous treatment arm. Mortality was strongly related both to baseline levels of these two biomarkers in the treatment interruption and continuous therapy groups, as well as to the progressive increases that occurred after treatment interruption, “with odds ratios greater than 12 for those in the fourth vs. first quartile,” Dr. Kuller said.

Calling the relationship between the increased levels of these two biomarkers and mortality risk “extraordinary,” Dr. Kuller noted that the association was far greater than that seen in general population studies of cardiovascular risk factors. “The findings indicate that elevated levels of D-dimer and interleukin-6 identify a subgroup of HIV-infected patients at high risk of death in both treatment groups, and the increases in both markers may partly explain the increased risk of mortality and CVD in the treatment interruption group,” he said at the conference, which was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.

The associations between the biomarkers and CVD were modest but significant, Dr. Kuller said.

BOSTON — The birth control landscape has transformed in recent years from a sparsely populated plain consisting of few effective choices to a more varied vista comprising a broader range of new and improved options, a researcher summarized.

In addition to new oral contraceptive formulations, several short- and long-acting hormonal contraceptive methods have emerged or been improved on, including the transdermal patch, the vaginal ring, and the progesterone intrauterine device (IUD), Dr. Carrie A. Cwiak said in a presentation at a conference on contraceptive technology sponsored by Contemporary Forums. “[These developments] have enabled women to better tailor their contraceptive choices to their lifestyles,” she said.

For example, the new combined oral contraceptives with continuous or extended dosing might be more appealing than those with cyclic dosing because they are associated with shorter withdrawal bleeds (Loestrin 24 Fe, Yaz), fewer withdrawal bleeds (Seasonique, Seasonale), or no withdrawal bleeding at all (Lybrel), noted Dr. Cwiak, an assistant professor at Emory University in Atlanta.

“If you look specifically at the regimens, you can see that these are all low-dose oral contraceptives using the ethinyl estradiol in the same range that we've seen with previous contraceptives and, with the exception of the pill that contains drospirenone [Yaz], we're talking about the same types of progestins in the same range of doses.”

Citing a 2006 Cochrane review comparing combined oral contraceptives based on continuous vs. cyclic dosing, Dr. Cwiak pointed out that the continuous regimens “showed either no difference or less bleeding and spotting, improvement in menstrual-associated symptoms, and no difference in patient compliance or adverse events” (Hum. Reprod. 2006;21:573–8).

The newest progestin, drospirenone, differs from other oral contraceptive progestins on the U.S. market because it is not derived from testosterone. Rather, it is an analogue of the aldosterone antagonist spironolactone and exhibits mild antimineralocorticoid properties, similar to natural progesterone, said Dr. Cwiak. “It has minimal diuretic and no androgenic effects and it has been associated with decreases [relative to placebo] in symptoms of premenstrual syndrome and premenstrual dysphoric disorder, which may appeal to patients who are still experiencing these symptoms on other regimens.”

Patches and Rings

The transdermal patch (Ortho Evra) is another effective contraceptive option that is especially appealing to women who don't want to remember to take a pill every day, said Dr. Cwiak. “The new information we have about the patch is related to the increased estrogen exposure. Specifically, patients are exposed to 60% more estrogen through the patch, compared with oral contraceptives, but we don't have any information on if or how that corresponds to clinical events,” she said.

Although the FDA recently approved changes to the Ortho Evra label to include the results of a new epidemiology study linking the patch to a twofold increase in the relative risk of developing venous thromboembolism, “that corresponds to maybe 20 out of 100,000 more clots in patch users vs. pill users, so we are still looking at minimal numbers and a risk of VTE less than that associated with pregnancy,” Dr. Cwiak said.

Because the patch is less effective in women who weigh more than 198 pounds, “it's important to counsel these women to use a backup method,” Dr. Cwiak cautioned. For such patients, she noted that “the vaginal ring might be a reasonable alternative because its efficacy does not appear to be affected by weight.”

Another benefit to the vaginal ring is that it is active for 35 days. “Previously, patients were told to remove it after 3 weeks, but recent data have shown that it's safe for continuous use,” Dr. Cwiak said. “It's much easier to change the ring on the same day of the month every month and not worry about those extra days.”

For patients who prefer quarterly injections over pills, patches, and rings, Depo Provera is now delivered by subcutaneous injection at a slightly lower dose than the earlier intramuscular injection (104 vs. 150 mg), said Dr. Cwiak. The lower dose has not affected the efficacy of the contraceptive, but neither has it affected the side-effect profile. “Some of us were thinking that the lower dose would correspond to lower side effects; unfortunately, the data show similar weight gain and similar bleeding patterns,” Dr. Cwiak noted. “The good news is that, as with the earlier formulation, bone mineral density changes return to normal upon discontinuation, even in adolescents.”

IUDs and Implantable Devices

With respect to long-term reversible contraceptives, IUDs and implantable progestin devices are among the most effective. The two IUDs currently approved by the FDA are the copper T 380A IUD (ParaGard) and the levonorgestrel intrauterine system (Mirena).

Although IUD use in the United States lags behind that in other developed countries, recent changes to medical eligibility criteria might lead to increased utilization, Dr. Cwiak stated. “The use of IUDs in women younger than 20 is now considered safe. Also, removal of the IUD is not required in patients with actinomyces, bacterial vaginosis, Trichomonas, or cervicitis,” she said. “If pelvic inflammatory disease occurs in an IUD user, treatment is the same as in nonusers and removal is not necessary.”

In addition, the new package insert for ParaGard states that eligible candidates now include nulliparous and nulligravid women, women not in a mutually monogamous relationship, women with a history of sexually transmitted infection or pelvic inflammatory disease who do not have current risks, and women with history of ectopic pregnancy—all previously considered contraindications.

“The important thing to remember here is that we don't want to have an active infection at the time of insertion because of its placement through the cervix into the uterus,” said Dr. Cwiak. “We don't want to make an existing infection worse.”

The Mirena levonorgestrel intrauterine system, which releases levonorgestrel to the endometrium over 5 years, has been associated with improvement in menorrhagia and decreased uterine size and bleeding with fibroids, “which is probably why we're seeing it being used more and more,” Dr. Cwiak noted. “Also, [insertion of the device] is an easy in-office procedure that takes only a few minutes.”

The only implantable contraceptive currently approved for use in the United States is Implanon, a progestin-only single rod implant that delivers 40 mcg of etonogestrel per day and is effective for 3 years. With only one rod to implant, the subdermal insertion and removal of this contraceptive is markedly easier than that of its six-capsule predecessor, Norplant.

On the Horizon

In terms of future contraceptive developments, there are a number of short-term and long-term prospects, said Dr. Cwiak. One is the Nestorone/ethynyl estradiol vaginal ring for cyclic monthly use, which is not yet on the market in the United States. “The ring delivers 150 mcg of Nestorone and 15 mcg ethinyl estradiol and has an extremely high rate of ovulation inhibition and low rates of breakthrough bleeding,” she said.

Another promising product on the horizon is the invisible condom, a microbicide that offers both a physical barrier, in the form of a gel that blocks the entry of pathogens into the mucosa, and a chemical barrier—sodium lauryl sulfate—within the gel that kills sexually transmitted pathogens including HIV, Dr. Cwiak said.

According to the findings of a recent phase I trial, the gel, which is applied with a special applicator that delivers the product uniformly throughout the vagina and cervix, does not disrupt vaginal epithelium or pH, and it is well tolerated. The product is currently being investigated in a phase I/II placebo-controlled trial (Contraception 2007;76:117–25).

BOSTON — The birth control landscape has transformed in recent years from a sparsely populated plain consisting of few effective choices to a more varied vista comprising a broader range of new and improved options, a researcher summarized.

In addition to new oral contraceptive formulations, several short- and long-acting hormonal contraceptive methods have emerged or been improved on, including the transdermal patch, the vaginal ring, and the progesterone intrauterine device (IUD), Dr. Carrie A. Cwiak said in a presentation at a conference on contraceptive technology sponsored by Contemporary Forums. “[These developments] have enabled women to better tailor their contraceptive choices to their lifestyles,” she said.

For example, the new combined oral contraceptives with continuous or extended dosing might be more appealing than those with cyclic dosing because they are associated with shorter withdrawal bleeds (Loestrin 24 Fe, Yaz), fewer withdrawal bleeds (Seasonique, Seasonale), or no withdrawal bleeding at all (Lybrel), noted Dr. Cwiak, an assistant professor at Emory University in Atlanta.

“If you look specifically at the regimens, you can see that these are all low-dose oral contraceptives using the ethinyl estradiol in the same range that we've seen with previous contraceptives and, with the exception of the pill that contains drospirenone [Yaz], we're talking about the same types of progestins in the same range of doses.”

Citing a 2006 Cochrane review comparing combined oral contraceptives based on continuous vs. cyclic dosing, Dr. Cwiak pointed out that the continuous regimens “showed either no difference or less bleeding and spotting, improvement in menstrual-associated symptoms, and no difference in patient compliance or adverse events” (Hum. Reprod. 2006;21:573–8).

The newest progestin, drospirenone, differs from other oral contraceptive progestins on the U.S. market because it is not derived from testosterone. Rather, it is an analogue of the aldosterone antagonist spironolactone and exhibits mild antimineralocorticoid properties, similar to natural progesterone, said Dr. Cwiak. “It has minimal diuretic and no androgenic effects and it has been associated with decreases [relative to placebo] in symptoms of premenstrual syndrome and premenstrual dysphoric disorder, which may appeal to patients who are still experiencing these symptoms on other regimens.”

Patches and Rings

The transdermal patch (Ortho Evra) is another effective contraceptive option that is especially appealing to women who don't want to remember to take a pill every day, said Dr. Cwiak. “The new information we have about the patch is related to the increased estrogen exposure. Specifically, patients are exposed to 60% more estrogen through the patch, compared with oral contraceptives, but we don't have any information on if or how that corresponds to clinical events,” she said.

Although the FDA recently approved changes to the Ortho Evra label to include the results of a new epidemiology study linking the patch to a twofold increase in the relative risk of developing venous thromboembolism, “that corresponds to maybe 20 out of 100,000 more clots in patch users vs. pill users, so we are still looking at minimal numbers and a risk of VTE less than that associated with pregnancy,” Dr. Cwiak said.

Because the patch is less effective in women who weigh more than 198 pounds, “it's important to counsel these women to use a backup method,” Dr. Cwiak cautioned. For such patients, she noted that “the vaginal ring might be a reasonable alternative because its efficacy does not appear to be affected by weight.”

Another benefit to the vaginal ring is that it is active for 35 days. “Previously, patients were told to remove it after 3 weeks, but recent data have shown that it's safe for continuous use,” Dr. Cwiak said. “It's much easier to change the ring on the same day of the month every month and not worry about those extra days.”

For patients who prefer quarterly injections over pills, patches, and rings, Depo Provera is now delivered by subcutaneous injection at a slightly lower dose than the earlier intramuscular injection (104 vs. 150 mg), said Dr. Cwiak. The lower dose has not affected the efficacy of the contraceptive, but neither has it affected the side-effect profile. “Some of us were thinking that the lower dose would correspond to lower side effects; unfortunately, the data show similar weight gain and similar bleeding patterns,” Dr. Cwiak noted. “The good news is that, as with the earlier formulation, bone mineral density changes return to normal upon discontinuation, even in adolescents.”

IUDs and Implantable Devices

With respect to long-term reversible contraceptives, IUDs and implantable progestin devices are among the most effective. The two IUDs currently approved by the FDA are the copper T 380A IUD (ParaGard) and the levonorgestrel intrauterine system (Mirena).

Although IUD use in the United States lags behind that in other developed countries, recent changes to medical eligibility criteria might lead to increased utilization, Dr. Cwiak stated. “The use of IUDs in women younger than 20 is now considered safe. Also, removal of the IUD is not required in patients with actinomyces, bacterial vaginosis, Trichomonas, or cervicitis,” she said. “If pelvic inflammatory disease occurs in an IUD user, treatment is the same as in nonusers and removal is not necessary.”

In addition, the new package insert for ParaGard states that eligible candidates now include nulliparous and nulligravid women, women not in a mutually monogamous relationship, women with a history of sexually transmitted infection or pelvic inflammatory disease who do not have current risks, and women with history of ectopic pregnancy—all previously considered contraindications.

“The important thing to remember here is that we don't want to have an active infection at the time of insertion because of its placement through the cervix into the uterus,” said Dr. Cwiak. “We don't want to make an existing infection worse.”

The Mirena levonorgestrel intrauterine system, which releases levonorgestrel to the endometrium over 5 years, has been associated with improvement in menorrhagia and decreased uterine size and bleeding with fibroids, “which is probably why we're seeing it being used more and more,” Dr. Cwiak noted. “Also, [insertion of the device] is an easy in-office procedure that takes only a few minutes.”

The only implantable contraceptive currently approved for use in the United States is Implanon, a progestin-only single rod implant that delivers 40 mcg of etonogestrel per day and is effective for 3 years. With only one rod to implant, the subdermal insertion and removal of this contraceptive is markedly easier than that of its six-capsule predecessor, Norplant.

On the Horizon

In terms of future contraceptive developments, there are a number of short-term and long-term prospects, said Dr. Cwiak. One is the Nestorone/ethynyl estradiol vaginal ring for cyclic monthly use, which is not yet on the market in the United States. “The ring delivers 150 mcg of Nestorone and 15 mcg ethinyl estradiol and has an extremely high rate of ovulation inhibition and low rates of breakthrough bleeding,” she said.

Another promising product on the horizon is the invisible condom, a microbicide that offers both a physical barrier, in the form of a gel that blocks the entry of pathogens into the mucosa, and a chemical barrier—sodium lauryl sulfate—within the gel that kills sexually transmitted pathogens including HIV, Dr. Cwiak said.

According to the findings of a recent phase I trial, the gel, which is applied with a special applicator that delivers the product uniformly throughout the vagina and cervix, does not disrupt vaginal epithelium or pH, and it is well tolerated. The product is currently being investigated in a phase I/II placebo-controlled trial (Contraception 2007;76:117–25).

BOSTON — The birth control landscape has transformed in recent years from a sparsely populated plain consisting of few effective choices to a more varied vista comprising a broader range of new and improved options, a researcher summarized.

In addition to new oral contraceptive formulations, several short- and long-acting hormonal contraceptive methods have emerged or been improved on, including the transdermal patch, the vaginal ring, and the progesterone intrauterine device (IUD), Dr. Carrie A. Cwiak said in a presentation at a conference on contraceptive technology sponsored by Contemporary Forums. “[These developments] have enabled women to better tailor their contraceptive choices to their lifestyles,” she said.

For example, the new combined oral contraceptives with continuous or extended dosing might be more appealing than those with cyclic dosing because they are associated with shorter withdrawal bleeds (Loestrin 24 Fe, Yaz), fewer withdrawal bleeds (Seasonique, Seasonale), or no withdrawal bleeding at all (Lybrel), noted Dr. Cwiak, an assistant professor at Emory University in Atlanta.

“If you look specifically at the regimens, you can see that these are all low-dose oral contraceptives using the ethinyl estradiol in the same range that we've seen with previous contraceptives and, with the exception of the pill that contains drospirenone [Yaz], we're talking about the same types of progestins in the same range of doses.”

Citing a 2006 Cochrane review comparing combined oral contraceptives based on continuous vs. cyclic dosing, Dr. Cwiak pointed out that the continuous regimens “showed either no difference or less bleeding and spotting, improvement in menstrual-associated symptoms, and no difference in patient compliance or adverse events” (Hum. Reprod. 2006;21:573–8).

The newest progestin, drospirenone, differs from other oral contraceptive progestins on the U.S. market because it is not derived from testosterone. Rather, it is an analogue of the aldosterone antagonist spironolactone and exhibits mild antimineralocorticoid properties, similar to natural progesterone, said Dr. Cwiak. “It has minimal diuretic and no androgenic effects and it has been associated with decreases [relative to placebo] in symptoms of premenstrual syndrome and premenstrual dysphoric disorder, which may appeal to patients who are still experiencing these symptoms on other regimens.”

Patches and Rings

The transdermal patch (Ortho Evra) is another effective contraceptive option that is especially appealing to women who don't want to remember to take a pill every day, said Dr. Cwiak. “The new information we have about the patch is related to the increased estrogen exposure. Specifically, patients are exposed to 60% more estrogen through the patch, compared with oral contraceptives, but we don't have any information on if or how that corresponds to clinical events,” she said.

Although the FDA recently approved changes to the Ortho Evra label to include the results of a new epidemiology study linking the patch to a twofold increase in the relative risk of developing venous thromboembolism, “that corresponds to maybe 20 out of 100,000 more clots in patch users vs. pill users, so we are still looking at minimal numbers and a risk of VTE less than that associated with pregnancy,” Dr. Cwiak said.

Because the patch is less effective in women who weigh more than 198 pounds, “it's important to counsel these women to use a backup method,” Dr. Cwiak cautioned. For such patients, she noted that “the vaginal ring might be a reasonable alternative because its efficacy does not appear to be affected by weight.”

Another benefit to the vaginal ring is that it is active for 35 days. “Previously, patients were told to remove it after 3 weeks, but recent data have shown that it's safe for continuous use,” Dr. Cwiak said. “It's much easier to change the ring on the same day of the month every month and not worry about those extra days.”

For patients who prefer quarterly injections over pills, patches, and rings, Depo Provera is now delivered by subcutaneous injection at a slightly lower dose than the earlier intramuscular injection (104 vs. 150 mg), said Dr. Cwiak. The lower dose has not affected the efficacy of the contraceptive, but neither has it affected the side-effect profile. “Some of us were thinking that the lower dose would correspond to lower side effects; unfortunately, the data show similar weight gain and similar bleeding patterns,” Dr. Cwiak noted. “The good news is that, as with the earlier formulation, bone mineral density changes return to normal upon discontinuation, even in adolescents.”

IUDs and Implantable Devices

With respect to long-term reversible contraceptives, IUDs and implantable progestin devices are among the most effective. The two IUDs currently approved by the FDA are the copper T 380A IUD (ParaGard) and the levonorgestrel intrauterine system (Mirena).

Although IUD use in the United States lags behind that in other developed countries, recent changes to medical eligibility criteria might lead to increased utilization, Dr. Cwiak stated. “The use of IUDs in women younger than 20 is now considered safe. Also, removal of the IUD is not required in patients with actinomyces, bacterial vaginosis, Trichomonas, or cervicitis,” she said. “If pelvic inflammatory disease occurs in an IUD user, treatment is the same as in nonusers and removal is not necessary.”

In addition, the new package insert for ParaGard states that eligible candidates now include nulliparous and nulligravid women, women not in a mutually monogamous relationship, women with a history of sexually transmitted infection or pelvic inflammatory disease who do not have current risks, and women with history of ectopic pregnancy—all previously considered contraindications.

“The important thing to remember here is that we don't want to have an active infection at the time of insertion because of its placement through the cervix into the uterus,” said Dr. Cwiak. “We don't want to make an existing infection worse.”

The Mirena levonorgestrel intrauterine system, which releases levonorgestrel to the endometrium over 5 years, has been associated with improvement in menorrhagia and decreased uterine size and bleeding with fibroids, “which is probably why we're seeing it being used more and more,” Dr. Cwiak noted. “Also, [insertion of the device] is an easy in-office procedure that takes only a few minutes.”

The only implantable contraceptive currently approved for use in the United States is Implanon, a progestin-only single rod implant that delivers 40 mcg of etonogestrel per day and is effective for 3 years. With only one rod to implant, the subdermal insertion and removal of this contraceptive is markedly easier than that of its six-capsule predecessor, Norplant.

On the Horizon

In terms of future contraceptive developments, there are a number of short-term and long-term prospects, said Dr. Cwiak. One is the Nestorone/ethynyl estradiol vaginal ring for cyclic monthly use, which is not yet on the market in the United States. “The ring delivers 150 mcg of Nestorone and 15 mcg ethinyl estradiol and has an extremely high rate of ovulation inhibition and low rates of breakthrough bleeding,” she said.

Another promising product on the horizon is the invisible condom, a microbicide that offers both a physical barrier, in the form of a gel that blocks the entry of pathogens into the mucosa, and a chemical barrier—sodium lauryl sulfate—within the gel that kills sexually transmitted pathogens including HIV, Dr. Cwiak said.

According to the findings of a recent phase I trial, the gel, which is applied with a special applicator that delivers the product uniformly throughout the vagina and cervix, does not disrupt vaginal epithelium or pH, and it is well tolerated. The product is currently being investigated in a phase I/II placebo-controlled trial (Contraception 2007;76:117–25).

The Bacterial Meningitis Score correctly identified acute bacterial meningitis in 884 out of 889 affected children, indicating that the tool, while 99.6% sensitive, still missed cases, the authors of a French study reported.

“As with any rule, clinicians must remain aware that no rule can completely eliminate the possibility of bacterial meningitis and that cases of bacterial meningitis can occur among patients without [cerebrospinal fluid] pleocytosis as well as among rare patients with CSF pleocytosis and a [Bacterial Meningitis Score] indicating low risk,” Dr. Francois Dubos of Saint Vincent de Paul Hospital in Paris and his colleagues warned.

The investigators based their conclusion on a secondary analysis of data from children seen in emergency departments in France over a 4-year period. They undertook their study because of concerns regarding the tool's sensitivity.

The Bacterial Meningitis Score (BMS) was developed by the Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics (AAP), and its specificity has been well validated among more than 3,000 patients (Pediatrics 2002;110:712–9).

The sensitivity of the BMS, however, was evaluated only in 196 patients from the original test population and external populations, mainly in the United States,” they wrote. The current study was undertaken to evaluate the sensitivity of the BMS in a large population of children with bacterial meningitis in a country with a different epidemiology of the disease (J. Pediatr. 2008;152:378–82).

On the basis of the BMS, children with CSF pleocytosis are considered to be at very low risk of bacterial meningitis if they lack all of the following criteria: positive CSF Gram stain, CSF absolute blood neutrophil count (ANC) of at least 1,000 cells/mm3, CSF protein of at least 80 mg/dL, peripheral blood ANC of at least 10,000 cells/mm3, and a history of seizure before or at the time of presentation.

Because implementation of routine immunization for Haemophilus influenzae type b and pneumococcus has further reduced the chances that a febrile child with CSF pleocytosis will have bacterial meningitis rather than aseptic meningitis, the committee validated the BMS prediction rule as an accurate decision support tool in the era of these vaccines (JAMA 2007;297:52–60).

Dr. Dubos and his associates used data obtained from the Bacterial Meningitis French Surveillance Network to identify children who presented to French emergency departments between January 2001 and February 2005.

The study patients were between age 29 days and 18 years and had a diagnosis of acute bacterial meningitis, but no known neurosurgical disease, no known immunosuppression, no CSF culture revealing an organism usually associated with contamination, no clinical sepsis, no purpura fulminans, and no CSF red blood cell count greater than 10,000/mm. The mean age of the 889 patients was 3 years; the death rate was 6%, and the primary bacterial pathogens were Neisseria meningitidis (44%) and Streptococcus pneumoniae (42%).

With respect to four of the five BMS criteria, 14% of the patients had a history of seizure with the illness, 89% had a positive CSF Gram stain, 84% had a CSF protein level of 80 mg/dL or higher, and 55% had a CSF neutrophil count of 1,000 cells/mm3 or higher.

The blood neutrophil count was not collected by use of the standardized network data form, so the authors retrospectively collected data for this variable by searching the medical records of the 23 patients who did not have a bacterial meningitis diagnosis based on the other four variables. For 18 of the 23 patients, the ANC was 10,000 cells/mm3 or higher. “Thus, the sensitivity of the BMS was 99.6%,” they wrote.

“The main limitation of our study is that not all cases of [bacterial meningitis] were included in the database of the Bacterial Meningitis French Surveillance Network,” the researchers reported. “The exhaustiveness of this database for cases of pneumococcal meningitis has been estimated to be 61% and is unknown for cases of infection with other pathogens.”

Additionally, the data for the study were collected when immunization with pneumococcal conjugate vaccine was implemented in France. The estimated vaccination coverage at the end of the study period was 41%, and the vaccination coverage against meningococcus C during that time was very low.

“The rule might have different results in areas with differing vaccination patterns for pneumococcus and meningococcus,” the investigators stated.

Prospective studies in clinical practice are needed to assess whether use of the BMS can safely reduce hospital admissions and antibiotic use for children with aseptic meningitis, they concluded.

The Bacterial Meningitis Score correctly identified acute bacterial meningitis in 884 out of 889 affected children, indicating that the tool, while 99.6% sensitive, still missed cases, the authors of a French study reported.

“As with any rule, clinicians must remain aware that no rule can completely eliminate the possibility of bacterial meningitis and that cases of bacterial meningitis can occur among patients without [cerebrospinal fluid] pleocytosis as well as among rare patients with CSF pleocytosis and a [Bacterial Meningitis Score] indicating low risk,” Dr. Francois Dubos of Saint Vincent de Paul Hospital in Paris and his colleagues warned.

The investigators based their conclusion on a secondary analysis of data from children seen in emergency departments in France over a 4-year period. They undertook their study because of concerns regarding the tool's sensitivity.

The Bacterial Meningitis Score (BMS) was developed by the Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics (AAP), and its specificity has been well validated among more than 3,000 patients (Pediatrics 2002;110:712–9).

The sensitivity of the BMS, however, was evaluated only in 196 patients from the original test population and external populations, mainly in the United States,” they wrote. The current study was undertaken to evaluate the sensitivity of the BMS in a large population of children with bacterial meningitis in a country with a different epidemiology of the disease (J. Pediatr. 2008;152:378–82).

On the basis of the BMS, children with CSF pleocytosis are considered to be at very low risk of bacterial meningitis if they lack all of the following criteria: positive CSF Gram stain, CSF absolute blood neutrophil count (ANC) of at least 1,000 cells/mm3, CSF protein of at least 80 mg/dL, peripheral blood ANC of at least 10,000 cells/mm3, and a history of seizure before or at the time of presentation.

Because implementation of routine immunization for Haemophilus influenzae type b and pneumococcus has further reduced the chances that a febrile child with CSF pleocytosis will have bacterial meningitis rather than aseptic meningitis, the committee validated the BMS prediction rule as an accurate decision support tool in the era of these vaccines (JAMA 2007;297:52–60).

Dr. Dubos and his associates used data obtained from the Bacterial Meningitis French Surveillance Network to identify children who presented to French emergency departments between January 2001 and February 2005.

The study patients were between age 29 days and 18 years and had a diagnosis of acute bacterial meningitis, but no known neurosurgical disease, no known immunosuppression, no CSF culture revealing an organism usually associated with contamination, no clinical sepsis, no purpura fulminans, and no CSF red blood cell count greater than 10,000/mm. The mean age of the 889 patients was 3 years; the death rate was 6%, and the primary bacterial pathogens were Neisseria meningitidis (44%) and Streptococcus pneumoniae (42%).

With respect to four of the five BMS criteria, 14% of the patients had a history of seizure with the illness, 89% had a positive CSF Gram stain, 84% had a CSF protein level of 80 mg/dL or higher, and 55% had a CSF neutrophil count of 1,000 cells/mm3 or higher.

The blood neutrophil count was not collected by use of the standardized network data form, so the authors retrospectively collected data for this variable by searching the medical records of the 23 patients who did not have a bacterial meningitis diagnosis based on the other four variables. For 18 of the 23 patients, the ANC was 10,000 cells/mm3 or higher. “Thus, the sensitivity of the BMS was 99.6%,” they wrote.

“The main limitation of our study is that not all cases of [bacterial meningitis] were included in the database of the Bacterial Meningitis French Surveillance Network,” the researchers reported. “The exhaustiveness of this database for cases of pneumococcal meningitis has been estimated to be 61% and is unknown for cases of infection with other pathogens.”

Additionally, the data for the study were collected when immunization with pneumococcal conjugate vaccine was implemented in France. The estimated vaccination coverage at the end of the study period was 41%, and the vaccination coverage against meningococcus C during that time was very low.

“The rule might have different results in areas with differing vaccination patterns for pneumococcus and meningococcus,” the investigators stated.

Prospective studies in clinical practice are needed to assess whether use of the BMS can safely reduce hospital admissions and antibiotic use for children with aseptic meningitis, they concluded.

The Bacterial Meningitis Score correctly identified acute bacterial meningitis in 884 out of 889 affected children, indicating that the tool, while 99.6% sensitive, still missed cases, the authors of a French study reported.

“As with any rule, clinicians must remain aware that no rule can completely eliminate the possibility of bacterial meningitis and that cases of bacterial meningitis can occur among patients without [cerebrospinal fluid] pleocytosis as well as among rare patients with CSF pleocytosis and a [Bacterial Meningitis Score] indicating low risk,” Dr. Francois Dubos of Saint Vincent de Paul Hospital in Paris and his colleagues warned.

The investigators based their conclusion on a secondary analysis of data from children seen in emergency departments in France over a 4-year period. They undertook their study because of concerns regarding the tool's sensitivity.

The Bacterial Meningitis Score (BMS) was developed by the Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics (AAP), and its specificity has been well validated among more than 3,000 patients (Pediatrics 2002;110:712–9).

The sensitivity of the BMS, however, was evaluated only in 196 patients from the original test population and external populations, mainly in the United States,” they wrote. The current study was undertaken to evaluate the sensitivity of the BMS in a large population of children with bacterial meningitis in a country with a different epidemiology of the disease (J. Pediatr. 2008;152:378–82).

On the basis of the BMS, children with CSF pleocytosis are considered to be at very low risk of bacterial meningitis if they lack all of the following criteria: positive CSF Gram stain, CSF absolute blood neutrophil count (ANC) of at least 1,000 cells/mm3, CSF protein of at least 80 mg/dL, peripheral blood ANC of at least 10,000 cells/mm3, and a history of seizure before or at the time of presentation.

Because implementation of routine immunization for Haemophilus influenzae type b and pneumococcus has further reduced the chances that a febrile child with CSF pleocytosis will have bacterial meningitis rather than aseptic meningitis, the committee validated the BMS prediction rule as an accurate decision support tool in the era of these vaccines (JAMA 2007;297:52–60).

Dr. Dubos and his associates used data obtained from the Bacterial Meningitis French Surveillance Network to identify children who presented to French emergency departments between January 2001 and February 2005.

The study patients were between age 29 days and 18 years and had a diagnosis of acute bacterial meningitis, but no known neurosurgical disease, no known immunosuppression, no CSF culture revealing an organism usually associated with contamination, no clinical sepsis, no purpura fulminans, and no CSF red blood cell count greater than 10,000/mm. The mean age of the 889 patients was 3 years; the death rate was 6%, and the primary bacterial pathogens were Neisseria meningitidis (44%) and Streptococcus pneumoniae (42%).

With respect to four of the five BMS criteria, 14% of the patients had a history of seizure with the illness, 89% had a positive CSF Gram stain, 84% had a CSF protein level of 80 mg/dL or higher, and 55% had a CSF neutrophil count of 1,000 cells/mm3 or higher.

The blood neutrophil count was not collected by use of the standardized network data form, so the authors retrospectively collected data for this variable by searching the medical records of the 23 patients who did not have a bacterial meningitis diagnosis based on the other four variables. For 18 of the 23 patients, the ANC was 10,000 cells/mm3 or higher. “Thus, the sensitivity of the BMS was 99.6%,” they wrote.

“The main limitation of our study is that not all cases of [bacterial meningitis] were included in the database of the Bacterial Meningitis French Surveillance Network,” the researchers reported. “The exhaustiveness of this database for cases of pneumococcal meningitis has been estimated to be 61% and is unknown for cases of infection with other pathogens.”

Additionally, the data for the study were collected when immunization with pneumococcal conjugate vaccine was implemented in France. The estimated vaccination coverage at the end of the study period was 41%, and the vaccination coverage against meningococcus C during that time was very low.

“The rule might have different results in areas with differing vaccination patterns for pneumococcus and meningococcus,” the investigators stated.

Prospective studies in clinical practice are needed to assess whether use of the BMS can safely reduce hospital admissions and antibiotic use for children with aseptic meningitis, they concluded.

BOSTON — Genital herpes is a recurrent, lifelong viral disease. This is the one thing that patients and providers don't like to say, but there's no way around it, Laura J. Mulcahy said at a conference on contraceptive technology sponsored by Contemporary Forums.

Other difficult truths about infection with herpes simplex virus (HSV) type 2? The overwhelming majority of people infected with the virus don't know that they have it, and people with asymptomatic or unrecognized disease shed the virus intermittently in the genital tract, said Ms. Mulcahy, a certified family nurse practitioner who is assistant medical director of the STD Center for Excellence at Montefiore Medical Center in New York.

“When we ask patients prior to screening for HSV-2 if they have a history of genital herpes … about 90% of those who ultimately test positive for HSV-2 antibodies reported having no history or symptoms of the infection,” she said. This underrecognition can be attributed to the fact that the leading cause of HSV-2 infection is asymptomatic shedding of the virus.

“There is a misperception and some clinicians are still telling patients that the infection is spread only through [HSV-2] sores. This is absolutely not true. The virus can shed even when the skin looks normal, and that's when most infections occur,” she said.

Patient education about asymptomatic disease is critical to an effective screening protocol. Ms. Mulcahy stressed that patients who come in for STD screening are told that, “from this day forward, the fact that you or your partner have no symptoms means nothing; the fact that you and your partner look fine means nothing; and the fact that you or your partner had a negative screen 6 months ago, if you've had partners in the interim, means nothing.”

Another factor contributing to the high rate of unrecognized disease is that many patients who have been screened for STDs believe they have been tested for genital herpes. “A complete STD screen does not include testing for herpes. Many patients believe they are being tested for everything. If their STD screen is negative, they assume that means they don't have herpes,” said Ms. Mulcahy.

“Clinicians who don't routinely screen for herpes [as part of an STD screening protocol] must inform patients that they are not being tested and chart that in the patient record so there is no confusion,” she said.

If a patient asks to be screened for HSV-2, then several points need to be addressed before testing, Ms. Mulcahy stressed:

▸ The absence of symptoms does not predict a negative screen.

▸ In patients with lesions, a herpes culture has low sensitivity, especially as lesions heal. As such, a negative culture does not rule out HSV-2.

▸ In the event of a positive HSV-2 test in an asymptomatic person, it is not possible to determine how long the virus has been present, when or whether they will have outbreaks, or whether they will ever have a problem with herpes.

▸ In the event of a positive HSV-2 test, patients in some states have a legal obligation to inform current and future sexual partners of their infection status before genital to skin contact.

Counseling patients on these points before testing is imperative. “If you wait until after a positive screen, patients will no longer be listening. They must know what to expect before they hear the word positive,” she said.

Among the tools used to screen for HSV-2, clinical examination and history are insensitive and nonspecific. “Symptoms are easily confused with other conditions or may present atypically, for example, as redness rather than sores,” Ms. Mulcahy said. Viral culture is the most valid test available, despite the high rate of false negatives.

Polymerase chain reaction assays are another diagnostic option. They have increased sensitivity but are not approved by the Food and Drug Administration, nor are they available in all laboratories. Cellular detection methods, including Tzanck test and Pap smear, are not recommended for HSV detection because of their low sensitivity, she said.

Many type-specific serology tests, such as the older enzyme-lined immunoabsorbent assay tests, can result in false-positive results because of problems with cross reactivity. The newer type-specific HSV glycoprotein G1 (HSV-1) and G2 (HSV-2) tests are more reliable, but their sensitivities vary, she said, noting that a positive test should be confirmed with another test to reduce the risk of false-positive diagnoses. The Western blot is the reference standard serology test, but it is not approved and is only available from one laboratory at the University of Washington, Seattle.

“Do not underestimate the impact of this diagnosis on your patients. They will require extensive, thoughtful counseling [because] the physical impact of genital herpes is nothing compared to the psychological one,” Ms. Mulcahy said.

Such counseling should include information about the natural history of disease, the ability to bear children, the transmission risk to sexual partners, and the variations in severity of primary vs. recurrent episodes. It also is important to dispel cancer myths, reiterate the fact that the virus can be transmitted in the absence of symptoms or lesions, remind patients of their obligation to inform current and future partners, and recommend counseling and testing for sexual partners.

Risk-reduction strategies also should be discussed, including avoiding sexual contact when symptoms or lesions are present and using latex barrier protection and suppressive therapy. There are three oral antiviral drugs—acyclovir, valacyclovir, and famciclovir—approved for the treatment of genital herpes. Topical treatments, she stressed, “absolutely do not work and have no role in the treatment of genital herpes.”

BOSTON — Genital herpes is a recurrent, lifelong viral disease. This is the one thing that patients and providers don't like to say, but there's no way around it, Laura J. Mulcahy said at a conference on contraceptive technology sponsored by Contemporary Forums.

Other difficult truths about infection with herpes simplex virus (HSV) type 2? The overwhelming majority of people infected with the virus don't know that they have it, and people with asymptomatic or unrecognized disease shed the virus intermittently in the genital tract, said Ms. Mulcahy, a certified family nurse practitioner who is assistant medical director of the STD Center for Excellence at Montefiore Medical Center in New York.

“When we ask patients prior to screening for HSV-2 if they have a history of genital herpes … about 90% of those who ultimately test positive for HSV-2 antibodies reported having no history or symptoms of the infection,” she said. This underrecognition can be attributed to the fact that the leading cause of HSV-2 infection is asymptomatic shedding of the virus.

“There is a misperception and some clinicians are still telling patients that the infection is spread only through [HSV-2] sores. This is absolutely not true. The virus can shed even when the skin looks normal, and that's when most infections occur,” she said.

Patient education about asymptomatic disease is critical to an effective screening protocol. Ms. Mulcahy stressed that patients who come in for STD screening are told that, “from this day forward, the fact that you or your partner have no symptoms means nothing; the fact that you and your partner look fine means nothing; and the fact that you or your partner had a negative screen 6 months ago, if you've had partners in the interim, means nothing.”

Another factor contributing to the high rate of unrecognized disease is that many patients who have been screened for STDs believe they have been tested for genital herpes. “A complete STD screen does not include testing for herpes. Many patients believe they are being tested for everything. If their STD screen is negative, they assume that means they don't have herpes,” said Ms. Mulcahy.

“Clinicians who don't routinely screen for herpes [as part of an STD screening protocol] must inform patients that they are not being tested and chart that in the patient record so there is no confusion,” she said.

If a patient asks to be screened for HSV-2, then several points need to be addressed before testing, Ms. Mulcahy stressed:

▸ The absence of symptoms does not predict a negative screen.

▸ In patients with lesions, a herpes culture has low sensitivity, especially as lesions heal. As such, a negative culture does not rule out HSV-2.

▸ In the event of a positive HSV-2 test in an asymptomatic person, it is not possible to determine how long the virus has been present, when or whether they will have outbreaks, or whether they will ever have a problem with herpes.

▸ In the event of a positive HSV-2 test, patients in some states have a legal obligation to inform current and future sexual partners of their infection status before genital to skin contact.

Counseling patients on these points before testing is imperative. “If you wait until after a positive screen, patients will no longer be listening. They must know what to expect before they hear the word positive,” she said.

Among the tools used to screen for HSV-2, clinical examination and history are insensitive and nonspecific. “Symptoms are easily confused with other conditions or may present atypically, for example, as redness rather than sores,” Ms. Mulcahy said. Viral culture is the most valid test available, despite the high rate of false negatives.

Polymerase chain reaction assays are another diagnostic option. They have increased sensitivity but are not approved by the Food and Drug Administration, nor are they available in all laboratories. Cellular detection methods, including Tzanck test and Pap smear, are not recommended for HSV detection because of their low sensitivity, she said.

Many type-specific serology tests, such as the older enzyme-lined immunoabsorbent assay tests, can result in false-positive results because of problems with cross reactivity. The newer type-specific HSV glycoprotein G1 (HSV-1) and G2 (HSV-2) tests are more reliable, but their sensitivities vary, she said, noting that a positive test should be confirmed with another test to reduce the risk of false-positive diagnoses. The Western blot is the reference standard serology test, but it is not approved and is only available from one laboratory at the University of Washington, Seattle.

“Do not underestimate the impact of this diagnosis on your patients. They will require extensive, thoughtful counseling [because] the physical impact of genital herpes is nothing compared to the psychological one,” Ms. Mulcahy said.

Such counseling should include information about the natural history of disease, the ability to bear children, the transmission risk to sexual partners, and the variations in severity of primary vs. recurrent episodes. It also is important to dispel cancer myths, reiterate the fact that the virus can be transmitted in the absence of symptoms or lesions, remind patients of their obligation to inform current and future partners, and recommend counseling and testing for sexual partners.

Risk-reduction strategies also should be discussed, including avoiding sexual contact when symptoms or lesions are present and using latex barrier protection and suppressive therapy. There are three oral antiviral drugs—acyclovir, valacyclovir, and famciclovir—approved for the treatment of genital herpes. Topical treatments, she stressed, “absolutely do not work and have no role in the treatment of genital herpes.”

BOSTON — Genital herpes is a recurrent, lifelong viral disease. This is the one thing that patients and providers don't like to say, but there's no way around it, Laura J. Mulcahy said at a conference on contraceptive technology sponsored by Contemporary Forums.

Other difficult truths about infection with herpes simplex virus (HSV) type 2? The overwhelming majority of people infected with the virus don't know that they have it, and people with asymptomatic or unrecognized disease shed the virus intermittently in the genital tract, said Ms. Mulcahy, a certified family nurse practitioner who is assistant medical director of the STD Center for Excellence at Montefiore Medical Center in New York.

“When we ask patients prior to screening for HSV-2 if they have a history of genital herpes … about 90% of those who ultimately test positive for HSV-2 antibodies reported having no history or symptoms of the infection,” she said. This underrecognition can be attributed to the fact that the leading cause of HSV-2 infection is asymptomatic shedding of the virus.

“There is a misperception and some clinicians are still telling patients that the infection is spread only through [HSV-2] sores. This is absolutely not true. The virus can shed even when the skin looks normal, and that's when most infections occur,” she said.

Patient education about asymptomatic disease is critical to an effective screening protocol. Ms. Mulcahy stressed that patients who come in for STD screening are told that, “from this day forward, the fact that you or your partner have no symptoms means nothing; the fact that you and your partner look fine means nothing; and the fact that you or your partner had a negative screen 6 months ago, if you've had partners in the interim, means nothing.”

Another factor contributing to the high rate of unrecognized disease is that many patients who have been screened for STDs believe they have been tested for genital herpes. “A complete STD screen does not include testing for herpes. Many patients believe they are being tested for everything. If their STD screen is negative, they assume that means they don't have herpes,” said Ms. Mulcahy.

“Clinicians who don't routinely screen for herpes [as part of an STD screening protocol] must inform patients that they are not being tested and chart that in the patient record so there is no confusion,” she said.

If a patient asks to be screened for HSV-2, then several points need to be addressed before testing, Ms. Mulcahy stressed:

▸ The absence of symptoms does not predict a negative screen.

▸ In patients with lesions, a herpes culture has low sensitivity, especially as lesions heal. As such, a negative culture does not rule out HSV-2.

▸ In the event of a positive HSV-2 test in an asymptomatic person, it is not possible to determine how long the virus has been present, when or whether they will have outbreaks, or whether they will ever have a problem with herpes.

▸ In the event of a positive HSV-2 test, patients in some states have a legal obligation to inform current and future sexual partners of their infection status before genital to skin contact.

Counseling patients on these points before testing is imperative. “If you wait until after a positive screen, patients will no longer be listening. They must know what to expect before they hear the word positive,” she said.

Among the tools used to screen for HSV-2, clinical examination and history are insensitive and nonspecific. “Symptoms are easily confused with other conditions or may present atypically, for example, as redness rather than sores,” Ms. Mulcahy said. Viral culture is the most valid test available, despite the high rate of false negatives.

Polymerase chain reaction assays are another diagnostic option. They have increased sensitivity but are not approved by the Food and Drug Administration, nor are they available in all laboratories. Cellular detection methods, including Tzanck test and Pap smear, are not recommended for HSV detection because of their low sensitivity, she said.

Many type-specific serology tests, such as the older enzyme-lined immunoabsorbent assay tests, can result in false-positive results because of problems with cross reactivity. The newer type-specific HSV glycoprotein G1 (HSV-1) and G2 (HSV-2) tests are more reliable, but their sensitivities vary, she said, noting that a positive test should be confirmed with another test to reduce the risk of false-positive diagnoses. The Western blot is the reference standard serology test, but it is not approved and is only available from one laboratory at the University of Washington, Seattle.

“Do not underestimate the impact of this diagnosis on your patients. They will require extensive, thoughtful counseling [because] the physical impact of genital herpes is nothing compared to the psychological one,” Ms. Mulcahy said.

Such counseling should include information about the natural history of disease, the ability to bear children, the transmission risk to sexual partners, and the variations in severity of primary vs. recurrent episodes. It also is important to dispel cancer myths, reiterate the fact that the virus can be transmitted in the absence of symptoms or lesions, remind patients of their obligation to inform current and future partners, and recommend counseling and testing for sexual partners.

Risk-reduction strategies also should be discussed, including avoiding sexual contact when symptoms or lesions are present and using latex barrier protection and suppressive therapy. There are three oral antiviral drugs—acyclovir, valacyclovir, and famciclovir—approved for the treatment of genital herpes. Topical treatments, she stressed, “absolutely do not work and have no role in the treatment of genital herpes.”

BOSTON — "Genital herpes is a recurrent, lifelong viral disease. This is the one thing that patients and clinicians don't like to say, but there's no way around" it, Laura J. Mulcahy said at a conference on contraceptive technology sponsored by Contemporary Forums.

Other difficult truths about infection with herpes simplex virus (HSV) type 2? The overwhelming majority of people infected with the virus don't know that they have it, and people with asymptomatic or unrecognized disease shed the virus intermittently in the genital tract, said Ms. Mulcahy, a certified family nurse practitioner who is assistant medical director of the STD Center for Excellence at Montefiore Medical Center in New York.

"When we ask patients prior to screening for HSV-2 if they have a history of genital herpes … about 90% of those who ultimately test positive for HSV-2 antibodies reported having no history or symptoms of the infection," she said. This underrecognition can be attributed to the fact that the leading cause of HSV-2 infection is asymptomatic shedding of the virus.

"There is a misperception and some clinicians are still telling patients that the infection is spread only through [HSV-2] sores. This is absolutely not true. The virus can shed even when the skin looks normal, and that's when most infections occur," she said.

Patient education about asymptomatic disease is critical to an effective screening protocol. "When patients come in and have no symptoms, it means nothing to us," Ms. Mulcahy stressed.

Patients who come in for STD screening are told that, "from this day forward, the fact that you or your partner have no symptoms means nothing; the fact that you and your partner look fine means nothing; and the fact that you or your partner had a negative screen 6 months ago, if you've had partners in the interim, means nothing," she said.

Another factor contributing to the high rate of unrecognized disease is that many patients who have been screened for STDs believe they have been tested for genital herpes. "A complete STD screen does not include testing for herpes. Clinicians don't always tell this to patients, so many patients believe they are being tested for everything. If their STD screen is negative, they assume that means they don't have herpes," said Ms. Mulcahy.

For this reason, "clinicians who don't routinely screen for herpes [as part of an STD screening protocol] must inform patients that they are not being tested and chart that in the patient record so there is no confusion," she added.

If a patient asks to be screened for HSV-2, there are several points that should be addressed before testing, Ms. Mulcahy stressed:

P The absence of symptoms does not predict a negative screen.

P In patients with lesions, a herpes culture has low sensitivity, especially as lesions heal. As such, a negative culture does not rule out HSV-2.

P In the event of a positive HSV-2 test in an asymptomatic person, it is not possible to determine how long the virus has been present, when or whether they will have outbreaks, or whether they will ever have a problem with herpes.

P In the event of a positive HSV-2 test, patients in some states have a legal obligation to inform current and future sexual partners of their infection status before genital to skin contact. "It is a misdemeanor in New York state, for example, to knowingly pass on or put someone else at risk for a sexually transmitted disease," said Ms. Mulcahy.

Counseling patients on these points before testing is imperative. "If you wait until after a positive screen, I can guarantee patients will no longer be listening. They need to know what to expect before they hear the word positive," she said.

Among the tools used to screen for HSV-2, clinical examination and history are insensitive and nonspecific. "Symptoms are easily confused with other conditions or may present atypically, for example, as redness rather than sores," Ms. Mulcahy said. Viral culture is the most valid test available, despite the high rate of false negatives.

Polymerase chain reaction assays are another diagnostic option. They have increased sensitivity but are not approved by the Food and Drug Administration, nor are they available in all laboratories. Cellular detection methods, including Tzanck test and Pap smear, are not recommended for HSV detection because of their low sensitivity, she said.

Many type-specific serology tests, such as the older enzyme-lined immunoabsorbent assay tests, can result in false-positive results because of problems with cross reactivity. The newer type-specific HSV glycoprotein G1 (HSV-1) and G2 (HSV-2) tests are more reliable, but their sensitivities vary, she said, noting that a positive test should be confirmed with another test to reduce the risk of false-positive diagnoses. The Western blot is the reference standard serology test, but it is not approved and is only available from one laboratory at the University of Washington, Seattle.

"Do not underestimate the impact of this diagnosis on your patients. They will require extensive, thoughtful counseling [because] the physical impact of genital herpes is nothing compared to the psychological one," Ms. Mulcahy said.

Such counseling should include information about the natural history of disease, the ability to bear children, the transmission risk to sexual partners, and the variations in severity of primary vs. recurrent episodes. It also is important to dispel cancer myths, reiterate the fact that the virus can be transmitted in the absence of symptoms or lesions, remind patients of their obligation to inform current and future partners, and recommend counseling and testing for sexual partners, she said.

Risk-reduction strategies also should be discussed, including avoiding sexual contact when symptoms or lesions are present and using latex barrier protection and suppressive therapy. There are three oral antiviral drugs—acyclovir, valacyclovir, and famciclovir—approved for the treatment of genital herpes. Topical treatments, she stressed, "absolutely do not work and have no role in the treatment of genital herpes."

BOSTON — "Genital herpes is a recurrent, lifelong viral disease. This is the one thing that patients and clinicians don't like to say, but there's no way around" it, Laura J. Mulcahy said at a conference on contraceptive technology sponsored by Contemporary Forums.

Other difficult truths about infection with herpes simplex virus (HSV) type 2? The overwhelming majority of people infected with the virus don't know that they have it, and people with asymptomatic or unrecognized disease shed the virus intermittently in the genital tract, said Ms. Mulcahy, a certified family nurse practitioner who is assistant medical director of the STD Center for Excellence at Montefiore Medical Center in New York.

"When we ask patients prior to screening for HSV-2 if they have a history of genital herpes … about 90% of those who ultimately test positive for HSV-2 antibodies reported having no history or symptoms of the infection," she said. This underrecognition can be attributed to the fact that the leading cause of HSV-2 infection is asymptomatic shedding of the virus.

"There is a misperception and some clinicians are still telling patients that the infection is spread only through [HSV-2] sores. This is absolutely not true. The virus can shed even when the skin looks normal, and that's when most infections occur," she said.

Patient education about asymptomatic disease is critical to an effective screening protocol. "When patients come in and have no symptoms, it means nothing to us," Ms. Mulcahy stressed.

Patients who come in for STD screening are told that, "from this day forward, the fact that you or your partner have no symptoms means nothing; the fact that you and your partner look fine means nothing; and the fact that you or your partner had a negative screen 6 months ago, if you've had partners in the interim, means nothing," she said.

Another factor contributing to the high rate of unrecognized disease is that many patients who have been screened for STDs believe they have been tested for genital herpes. "A complete STD screen does not include testing for herpes. Clinicians don't always tell this to patients, so many patients believe they are being tested for everything. If their STD screen is negative, they assume that means they don't have herpes," said Ms. Mulcahy.

For this reason, "clinicians who don't routinely screen for herpes [as part of an STD screening protocol] must inform patients that they are not being tested and chart that in the patient record so there is no confusion," she added.

If a patient asks to be screened for HSV-2, there are several points that should be addressed before testing, Ms. Mulcahy stressed:

P The absence of symptoms does not predict a negative screen.

P In patients with lesions, a herpes culture has low sensitivity, especially as lesions heal. As such, a negative culture does not rule out HSV-2.

P In the event of a positive HSV-2 test in an asymptomatic person, it is not possible to determine how long the virus has been present, when or whether they will have outbreaks, or whether they will ever have a problem with herpes.

P In the event of a positive HSV-2 test, patients in some states have a legal obligation to inform current and future sexual partners of their infection status before genital to skin contact. "It is a misdemeanor in New York state, for example, to knowingly pass on or put someone else at risk for a sexually transmitted disease," said Ms. Mulcahy.

Counseling patients on these points before testing is imperative. "If you wait until after a positive screen, I can guarantee patients will no longer be listening. They need to know what to expect before they hear the word positive," she said.

Among the tools used to screen for HSV-2, clinical examination and history are insensitive and nonspecific. "Symptoms are easily confused with other conditions or may present atypically, for example, as redness rather than sores," Ms. Mulcahy said. Viral culture is the most valid test available, despite the high rate of false negatives.

Polymerase chain reaction assays are another diagnostic option. They have increased sensitivity but are not approved by the Food and Drug Administration, nor are they available in all laboratories. Cellular detection methods, including Tzanck test and Pap smear, are not recommended for HSV detection because of their low sensitivity, she said.

Many type-specific serology tests, such as the older enzyme-lined immunoabsorbent assay tests, can result in false-positive results because of problems with cross reactivity. The newer type-specific HSV glycoprotein G1 (HSV-1) and G2 (HSV-2) tests are more reliable, but their sensitivities vary, she said, noting that a positive test should be confirmed with another test to reduce the risk of false-positive diagnoses. The Western blot is the reference standard serology test, but it is not approved and is only available from one laboratory at the University of Washington, Seattle.

"Do not underestimate the impact of this diagnosis on your patients. They will require extensive, thoughtful counseling [because] the physical impact of genital herpes is nothing compared to the psychological one," Ms. Mulcahy said.

Such counseling should include information about the natural history of disease, the ability to bear children, the transmission risk to sexual partners, and the variations in severity of primary vs. recurrent episodes. It also is important to dispel cancer myths, reiterate the fact that the virus can be transmitted in the absence of symptoms or lesions, remind patients of their obligation to inform current and future partners, and recommend counseling and testing for sexual partners, she said.

Risk-reduction strategies also should be discussed, including avoiding sexual contact when symptoms or lesions are present and using latex barrier protection and suppressive therapy. There are three oral antiviral drugs—acyclovir, valacyclovir, and famciclovir—approved for the treatment of genital herpes. Topical treatments, she stressed, "absolutely do not work and have no role in the treatment of genital herpes."

BOSTON — "Genital herpes is a recurrent, lifelong viral disease. This is the one thing that patients and clinicians don't like to say, but there's no way around" it, Laura J. Mulcahy said at a conference on contraceptive technology sponsored by Contemporary Forums.

Other difficult truths about infection with herpes simplex virus (HSV) type 2? The overwhelming majority of people infected with the virus don't know that they have it, and people with asymptomatic or unrecognized disease shed the virus intermittently in the genital tract, said Ms. Mulcahy, a certified family nurse practitioner who is assistant medical director of the STD Center for Excellence at Montefiore Medical Center in New York.

"When we ask patients prior to screening for HSV-2 if they have a history of genital herpes … about 90% of those who ultimately test positive for HSV-2 antibodies reported having no history or symptoms of the infection," she said. This underrecognition can be attributed to the fact that the leading cause of HSV-2 infection is asymptomatic shedding of the virus.

"There is a misperception and some clinicians are still telling patients that the infection is spread only through [HSV-2] sores. This is absolutely not true. The virus can shed even when the skin looks normal, and that's when most infections occur," she said.

Patient education about asymptomatic disease is critical to an effective screening protocol. "When patients come in and have no symptoms, it means nothing to us," Ms. Mulcahy stressed.

Patients who come in for STD screening are told that, "from this day forward, the fact that you or your partner have no symptoms means nothing; the fact that you and your partner look fine means nothing; and the fact that you or your partner had a negative screen 6 months ago, if you've had partners in the interim, means nothing," she said.

Another factor contributing to the high rate of unrecognized disease is that many patients who have been screened for STDs believe they have been tested for genital herpes. "A complete STD screen does not include testing for herpes. Clinicians don't always tell this to patients, so many patients believe they are being tested for everything. If their STD screen is negative, they assume that means they don't have herpes," said Ms. Mulcahy.

For this reason, "clinicians who don't routinely screen for herpes [as part of an STD screening protocol] must inform patients that they are not being tested and chart that in the patient record so there is no confusion," she added.

If a patient asks to be screened for HSV-2, there are several points that should be addressed before testing, Ms. Mulcahy stressed:

P The absence of symptoms does not predict a negative screen.

P In patients with lesions, a herpes culture has low sensitivity, especially as lesions heal. As such, a negative culture does not rule out HSV-2.

P In the event of a positive HSV-2 test in an asymptomatic person, it is not possible to determine how long the virus has been present, when or whether they will have outbreaks, or whether they will ever have a problem with herpes.

P In the event of a positive HSV-2 test, patients in some states have a legal obligation to inform current and future sexual partners of their infection status before genital to skin contact. "It is a misdemeanor in New York state, for example, to knowingly pass on or put someone else at risk for a sexually transmitted disease," said Ms. Mulcahy.

Counseling patients on these points before testing is imperative. "If you wait until after a positive screen, I can guarantee patients will no longer be listening. They need to know what to expect before they hear the word positive," she said.

Among the tools used to screen for HSV-2, clinical examination and history are insensitive and nonspecific. "Symptoms are easily confused with other conditions or may present atypically, for example, as redness rather than sores," Ms. Mulcahy said. Viral culture is the most valid test available, despite the high rate of false negatives.

Polymerase chain reaction assays are another diagnostic option. They have increased sensitivity but are not approved by the Food and Drug Administration, nor are they available in all laboratories. Cellular detection methods, including Tzanck test and Pap smear, are not recommended for HSV detection because of their low sensitivity, she said.

Many type-specific serology tests, such as the older enzyme-lined immunoabsorbent assay tests, can result in false-positive results because of problems with cross reactivity. The newer type-specific HSV glycoprotein G1 (HSV-1) and G2 (HSV-2) tests are more reliable, but their sensitivities vary, she said, noting that a positive test should be confirmed with another test to reduce the risk of false-positive diagnoses. The Western blot is the reference standard serology test, but it is not approved and is only available from one laboratory at the University of Washington, Seattle.

"Do not underestimate the impact of this diagnosis on your patients. They will require extensive, thoughtful counseling [because] the physical impact of genital herpes is nothing compared to the psychological one," Ms. Mulcahy said.

Such counseling should include information about the natural history of disease, the ability to bear children, the transmission risk to sexual partners, and the variations in severity of primary vs. recurrent episodes. It also is important to dispel cancer myths, reiterate the fact that the virus can be transmitted in the absence of symptoms or lesions, remind patients of their obligation to inform current and future partners, and recommend counseling and testing for sexual partners, she said.

Risk-reduction strategies also should be discussed, including avoiding sexual contact when symptoms or lesions are present and using latex barrier protection and suppressive therapy. There are three oral antiviral drugs—acyclovir, valacyclovir, and famciclovir—approved for the treatment of genital herpes. Topical treatments, she stressed, "absolutely do not work and have no role in the treatment of genital herpes."

BOSTON — Male circumcision does not reduce the risk of HIV transmission from HIV-positive men to their female partners, but it does offer some protection to HIV-negative men and their female partners against the acquisition of genital infections associated with the spread of HIV, according to data presented at the 15th Conference on Retroviruses and Opportunistic Infections.

Heralded as “an HIV intervention that can really work,” male circumcision has previously been shown to reduce heterosexual acquisition of HIV in men, said Dr. Maria Wawer, a family health researcher at Johns Hopkins University, Baltimore, and cofounder of the Rakai (Uganda) Health Sciences Program—one of the largest HIV research, prevention, and care programs in Africa.

To determine whether the earlier findings would also hold true with respect to rates of heterosexual transmission of the virus by HIV-positive men to their wives, Dr. Wawer and colleagues randomized more than 1,000 HIV-positive men to immediate or delayed (by 24 months) circumcision and asked the 770 men in the study who were married to invite their wives to participate. A total of 566 wives enrolled, of whom 245 were HIV negative. The investigators' intent-to-treat analysis was based on 165 HIV-discordant couples, including 94 in the male circumcision arm and 71 in the control arm.

The men in the study were examined postoperatively if they underwent circumcision and then at 1, 6, 12, and 24 months, and the women were seen at 6, 12, and 24 months. At follow-up, the cumulative incidence of HIV in wives of circumcised men was actually higher than that observed in the wives of the noncircumcised men, at 13.8 per 100 person-years compared with 9.6 per 100 person-years, respectively.

Although the difference between the two groups was not statistically significant and could be a product of chance, “we were not seeing a trend toward protection that we would have expected and hoped for,” Dr. Wawer said.

The researchers did observe that in both arms of the study, the incidence of HIV was highest in the first 6 months of follow-up and, in the circumcision arm specifically, the excess transmissions during this period occurred in couples who resumed intercourse more than 5 days before the circumcision wound was certified as fully healed, Dr. Wawer said.

“We're still analyzing the data, but it appears that after 6 months there is a trend toward protection in the circumcision group.” This finding, she noted, stresses the importance of waiting to have sex until the circumcision wound is fully healed to minimize the risk of HIV transmission.

Reporting on another of the Rakai studies that looked at the efficacy of male circumcision in the prevention of herpes simplex virus type 2 (HSV-2) among HSV-2- and HIV-negative men, Dr. Aaron Tobian, also of Johns Hopkins, noted that the relative risk of HSV-2 acquisition among the 1,400 men randomized to immediate circumcision was 7.6%, compared with 10.1% in the 1,387 men randomized to delayed circumcision.

In a nested study comprising 825 wives of men in the circumcision arm and 783 wives of men in the control arm who were followed for 1 year, the respective rates of symptomatic genitourinary disease in the intervention and control arms were 12.5% and 16.8%. The respective prevalence rates of trichomoniasis were 5.9% vs. 11.2%, and rates of bacterial vaginosis were 40.3% and 50.6%. Severe bacterial vaginosis was observed in 2.0% of the intervention wives and 6.5% of the control wives, Dr. Tobian said.

“HSV-2 infections, genital ulcer disease, and bacterial vaginosis are all cofactors for HIV infection,” he said.

By reducing the occurrence of these cofactors, “male circumcision offers some protection against HIV in these women,” he asserted.

BOSTON — Male circumcision does not reduce the risk of HIV transmission from HIV-positive men to their female partners, but it does offer some protection to HIV-negative men and their female partners against the acquisition of genital infections associated with the spread of HIV, according to data presented at the 15th Conference on Retroviruses and Opportunistic Infections.

Heralded as “an HIV intervention that can really work,” male circumcision has previously been shown to reduce heterosexual acquisition of HIV in men, said Dr. Maria Wawer, a family health researcher at Johns Hopkins University, Baltimore, and cofounder of the Rakai (Uganda) Health Sciences Program—one of the largest HIV research, prevention, and care programs in Africa.

To determine whether the earlier findings would also hold true with respect to rates of heterosexual transmission of the virus by HIV-positive men to their wives, Dr. Wawer and colleagues randomized more than 1,000 HIV-positive men to immediate or delayed (by 24 months) circumcision and asked the 770 men in the study who were married to invite their wives to participate. A total of 566 wives enrolled, of whom 245 were HIV negative. The investigators' intent-to-treat analysis was based on 165 HIV-discordant couples, including 94 in the male circumcision arm and 71 in the control arm.

The men in the study were examined postoperatively if they underwent circumcision and then at 1, 6, 12, and 24 months, and the women were seen at 6, 12, and 24 months. At follow-up, the cumulative incidence of HIV in wives of circumcised men was actually higher than that observed in the wives of the noncircumcised men, at 13.8 per 100 person-years compared with 9.6 per 100 person-years, respectively.

Although the difference between the two groups was not statistically significant and could be a product of chance, “we were not seeing a trend toward protection that we would have expected and hoped for,” Dr. Wawer said.

The researchers did observe that in both arms of the study, the incidence of HIV was highest in the first 6 months of follow-up and, in the circumcision arm specifically, the excess transmissions during this period occurred in couples who resumed intercourse more than 5 days before the circumcision wound was certified as fully healed, Dr. Wawer said.

“We're still analyzing the data, but it appears that after 6 months there is a trend toward protection in the circumcision group.” This finding, she noted, stresses the importance of waiting to have sex until the circumcision wound is fully healed to minimize the risk of HIV transmission.

Reporting on another of the Rakai studies that looked at the efficacy of male circumcision in the prevention of herpes simplex virus type 2 (HSV-2) among HSV-2- and HIV-negative men, Dr. Aaron Tobian, also of Johns Hopkins, noted that the relative risk of HSV-2 acquisition among the 1,400 men randomized to immediate circumcision was 7.6%, compared with 10.1% in the 1,387 men randomized to delayed circumcision.

In a nested study comprising 825 wives of men in the circumcision arm and 783 wives of men in the control arm who were followed for 1 year, the respective rates of symptomatic genitourinary disease in the intervention and control arms were 12.5% and 16.8%. The respective prevalence rates of trichomoniasis were 5.9% vs. 11.2%, and rates of bacterial vaginosis were 40.3% and 50.6%. Severe bacterial vaginosis was observed in 2.0% of the intervention wives and 6.5% of the control wives, Dr. Tobian said.

“HSV-2 infections, genital ulcer disease, and bacterial vaginosis are all cofactors for HIV infection,” he said.

By reducing the occurrence of these cofactors, “male circumcision offers some protection against HIV in these women,” he asserted.

BOSTON — Male circumcision does not reduce the risk of HIV transmission from HIV-positive men to their female partners, but it does offer some protection to HIV-negative men and their female partners against the acquisition of genital infections associated with the spread of HIV, according to data presented at the 15th Conference on Retroviruses and Opportunistic Infections.

Heralded as “an HIV intervention that can really work,” male circumcision has previously been shown to reduce heterosexual acquisition of HIV in men, said Dr. Maria Wawer, a family health researcher at Johns Hopkins University, Baltimore, and cofounder of the Rakai (Uganda) Health Sciences Program—one of the largest HIV research, prevention, and care programs in Africa.

To determine whether the earlier findings would also hold true with respect to rates of heterosexual transmission of the virus by HIV-positive men to their wives, Dr. Wawer and colleagues randomized more than 1,000 HIV-positive men to immediate or delayed (by 24 months) circumcision and asked the 770 men in the study who were married to invite their wives to participate. A total of 566 wives enrolled, of whom 245 were HIV negative. The investigators' intent-to-treat analysis was based on 165 HIV-discordant couples, including 94 in the male circumcision arm and 71 in the control arm.

The men in the study were examined postoperatively if they underwent circumcision and then at 1, 6, 12, and 24 months, and the women were seen at 6, 12, and 24 months. At follow-up, the cumulative incidence of HIV in wives of circumcised men was actually higher than that observed in the wives of the noncircumcised men, at 13.8 per 100 person-years compared with 9.6 per 100 person-years, respectively.

Although the difference between the two groups was not statistically significant and could be a product of chance, “we were not seeing a trend toward protection that we would have expected and hoped for,” Dr. Wawer said.

The researchers did observe that in both arms of the study, the incidence of HIV was highest in the first 6 months of follow-up and, in the circumcision arm specifically, the excess transmissions during this period occurred in couples who resumed intercourse more than 5 days before the circumcision wound was certified as fully healed, Dr. Wawer said.

“We're still analyzing the data, but it appears that after 6 months there is a trend toward protection in the circumcision group.” This finding, she noted, stresses the importance of waiting to have sex until the circumcision wound is fully healed to minimize the risk of HIV transmission.

Reporting on another of the Rakai studies that looked at the efficacy of male circumcision in the prevention of herpes simplex virus type 2 (HSV-2) among HSV-2- and HIV-negative men, Dr. Aaron Tobian, also of Johns Hopkins, noted that the relative risk of HSV-2 acquisition among the 1,400 men randomized to immediate circumcision was 7.6%, compared with 10.1% in the 1,387 men randomized to delayed circumcision.

In a nested study comprising 825 wives of men in the circumcision arm and 783 wives of men in the control arm who were followed for 1 year, the respective rates of symptomatic genitourinary disease in the intervention and control arms were 12.5% and 16.8%. The respective prevalence rates of trichomoniasis were 5.9% vs. 11.2%, and rates of bacterial vaginosis were 40.3% and 50.6%. Severe bacterial vaginosis was observed in 2.0% of the intervention wives and 6.5% of the control wives, Dr. Tobian said.

“HSV-2 infections, genital ulcer disease, and bacterial vaginosis are all cofactors for HIV infection,” he said.

By reducing the occurrence of these cofactors, “male circumcision offers some protection against HIV in these women,” he asserted.

In the absence of exogenous glucocorticoid use, patients with multiple and progressive features that are highly discriminatory for Cushing's syndrome should be tested for the endocrine disorder, according to new clinical practice guidelines developed by a task force of the Endocrine Society.

Testing is also recommended for patients with adrenal incidentaloma compatible with adenoma and children with combined reduced linear growth and increased weight, wrote lead author Dr. Lynnette K. Nieman of the National Institute of Child Health and Human Development and task force colleagues.

Although the signs and symptoms of full-blown Cushing's disease are clinically unmistakable, “the spectrum of clinical presentation is broad, and the diagnosis can be challenging in mild cases,” the authors wrote, noting that the guidelines were developed to help facilitate this process. Because the strength of the recommendations varies depending on the quality of evidence supporting them, “careful consideration of the patient's circumstances, values, and preferences is appropriate to determine the best course of action,” the authors wrote (J. Clin. Endocrinol. Metab. 2008 March 11 [doi:10.1210/jc.2008-0125]).

Pretest Probability

Before conducting any biochemical testing, physicians should obtain a thorough drug history to rule out iatrogenic Cushing's syndrome associated with excessive exogenous glucocorticoid exposure.

After exclusion of exogenous glucocorticoid use, diagnostic testing is recommended for individuals with multiple features considered discriminatory for the disease, including easy bruising, facial plethora, proximal myopathy, reddish-purple striae, thin skin in the young, and weight gain with decreasing growth velocity in children, the authors wrote.

In addition, because Cushing's syndrome is progressive, patients who demonstrate an accumulation of new features should be tested, as should patients who develop features of the condition, such as osteoporosis and hypertension, which are atypical in the general population for individuals their age. Finally, the presence of an incidentally found adrenal nodule contributes to the pretest probability of Cushing's syndrome. “Such patients usually do not present with overt clinical features of Cushing's syndrome, but biochemical hypercortisolism is present in a large fraction,” the authors wrote.

The authors recommend against widespread testing in any other patient group, including obese children, unless their statural growth has slowed.

Diagnostic Tests

With respect to initial diagnostic testing, the task force recommended any of the following: at least two urinary free cortisol (UFC) measurements, two late-night salivary cortisol measurements, a 1-mg overnight dexamethasone suppression test (DST), or the longer low-dose 2 day/2 mg per day DST.

The guidelines recommend against testing for any of the following because of their low diagnostic accuracy for Cushing's syndrome: random serum cortisol or plasma ACTH levels; urinary 17-ketosteroids; insulin tolerance test; loperamide test; and tests designed to determine the cause of Cushing's syndrome, such as pituitary and adrenal imaging and the 8-mg DST.

Patients with normal test results who have a high pretest probability for Cushing's syndrome based on clinical features, adrenal incidentaloma, or suspected cyclic hypercortisolism should be referred for further evaluation by an endocrinologist, while those with normal test results and a low pretest probability should be reevaluated in 6 months if symptoms persist. Patients with at least one abnormal test result should also be referred to an endocrinologist for further evaluation to confirm or exclude the diagnosis, the authors wrote.

Although the four recommended diagnostic tests have “acceptable” accuracy when the suggested cutoff points are used, “no test has optimally high specificity, so false positives may occur,” the authors noted. To minimize the possibility of a misdiagnosis, the guidelines recommend subsequent evaluation of abnormal initial test results using another one of the high-sensitivity tests. “We suggest the additional use of the dexamethasone-CRH test or the midnight serum cortisol test in specific situations,” the authors wrote. They recommended against the use of the desmopressin test, “except in research studies,” because its utility has not been validated.

With the exception of patients of having “the very rare case of cyclical disease,” further testing is not recommended for patients with negative results on two different tests, the authors noted. For patients with concordantly positive results from two different tests for whom there is no concern regarding possible non-Cushing's hypercortisolism, “we recommend tests to establish the cause of Cushing's syndrome,” they wrote. Finally, further evaluation and follow-up is suggested for those few patients with concordantly negative results who are suspected of having cyclical disease, and for those patients with discordant results in whom the pretest probability is high.

Special Populations

The guidelines also addressed diagnostic testing in special populations, recommending the use of UFC (and against the use of dexamethasone testing) in the initial evaluation of pregnant women, and suggesting the use of the 1-mg overnight dexamethasone suppression test rather than UFC for initial testing in patients with renal failure and in those suspected of having mild Cushing's syndrome. In patients who take antiepileptic drugs that are known to enhance dexamethasone clearance, dexamethasone testing was not recommended. Instead, the guidelines recommended measurements of nonsuppressed cortisol in blood, saliva, or urine. When cyclic Cushing's syndrome is suspected, “we suggest the use of UFC or midnight salivary cortisol tests rather than dexamethasone suppression tests,” the authors wrote.

There are limited data linking diagnostic strategies to patient outcomes in Cushing's syndrome because “much of the work has focused on developing, validating, and ascertaining diagnostic test performance,” the authors wrote. As a result, “the evidence on which many of these recommendations have been made is of low to very low quality,” they stated. Additionally, the published data is potentially biased toward more severe cases with higher pretest probability, and thus might not accurately represent the tests' performance in unselected populations in usual clinical practice.

Possible research initiatives that could improve the future care of patients with Cushing's syndrome include the establishment of databases of consecutive patients tested for the syndrome, “allowing for prospective pooling of the diagnostic test information,” the authors wrote. Standardization of assays and improved clinical outcome data and targeted clinical trials are also on the authors' wish list.

In the absence of exogenous glucocorticoid use, patients with multiple and progressive features that are highly discriminatory for Cushing's syndrome should be tested for the endocrine disorder, according to new clinical practice guidelines developed by a task force of the Endocrine Society.

Testing is also recommended for patients with adrenal incidentaloma compatible with adenoma and children with combined reduced linear growth and increased weight, wrote lead author Dr. Lynnette K. Nieman of the National Institute of Child Health and Human Development and task force colleagues.

Although the signs and symptoms of full-blown Cushing's disease are clinically unmistakable, “the spectrum of clinical presentation is broad, and the diagnosis can be challenging in mild cases,” the authors wrote, noting that the guidelines were developed to help facilitate this process. Because the strength of the recommendations varies depending on the quality of evidence supporting them, “careful consideration of the patient's circumstances, values, and preferences is appropriate to determine the best course of action,” the authors wrote (J. Clin. Endocrinol. Metab. 2008 March 11 [doi:10.1210/jc.2008-0125]).

Pretest Probability

Before conducting any biochemical testing, physicians should obtain a thorough drug history to rule out iatrogenic Cushing's syndrome associated with excessive exogenous glucocorticoid exposure.

After exclusion of exogenous glucocorticoid use, diagnostic testing is recommended for individuals with multiple features considered discriminatory for the disease, including easy bruising, facial plethora, proximal myopathy, reddish-purple striae, thin skin in the young, and weight gain with decreasing growth velocity in children, the authors wrote.

In addition, because Cushing's syndrome is progressive, patients who demonstrate an accumulation of new features should be tested, as should patients who develop features of the condition, such as osteoporosis and hypertension, which are atypical in the general population for individuals their age. Finally, the presence of an incidentally found adrenal nodule contributes to the pretest probability of Cushing's syndrome. “Such patients usually do not present with overt clinical features of Cushing's syndrome, but biochemical hypercortisolism is present in a large fraction,” the authors wrote.

The authors recommend against widespread testing in any other patient group, including obese children, unless their statural growth has slowed.

Diagnostic Tests

With respect to initial diagnostic testing, the task force recommended any of the following: at least two urinary free cortisol (UFC) measurements, two late-night salivary cortisol measurements, a 1-mg overnight dexamethasone suppression test (DST), or the longer low-dose 2 day/2 mg per day DST.

The guidelines recommend against testing for any of the following because of their low diagnostic accuracy for Cushing's syndrome: random serum cortisol or plasma ACTH levels; urinary 17-ketosteroids; insulin tolerance test; loperamide test; and tests designed to determine the cause of Cushing's syndrome, such as pituitary and adrenal imaging and the 8-mg DST.

Patients with normal test results who have a high pretest probability for Cushing's syndrome based on clinical features, adrenal incidentaloma, or suspected cyclic hypercortisolism should be referred for further evaluation by an endocrinologist, while those with normal test results and a low pretest probability should be reevaluated in 6 months if symptoms persist. Patients with at least one abnormal test result should also be referred to an endocrinologist for further evaluation to confirm or exclude the diagnosis, the authors wrote.

Although the four recommended diagnostic tests have “acceptable” accuracy when the suggested cutoff points are used, “no test has optimally high specificity, so false positives may occur,” the authors noted. To minimize the possibility of a misdiagnosis, the guidelines recommend subsequent evaluation of abnormal initial test results using another one of the high-sensitivity tests. “We suggest the additional use of the dexamethasone-CRH test or the midnight serum cortisol test in specific situations,” the authors wrote. They recommended against the use of the desmopressin test, “except in research studies,” because its utility has not been validated.

With the exception of patients of having “the very rare case of cyclical disease,” further testing is not recommended for patients with negative results on two different tests, the authors noted. For patients with concordantly positive results from two different tests for whom there is no concern regarding possible non-Cushing's hypercortisolism, “we recommend tests to establish the cause of Cushing's syndrome,” they wrote. Finally, further evaluation and follow-up is suggested for those few patients with concordantly negative results who are suspected of having cyclical disease, and for those patients with discordant results in whom the pretest probability is high.

Special Populations

The guidelines also addressed diagnostic testing in special populations, recommending the use of UFC (and against the use of dexamethasone testing) in the initial evaluation of pregnant women, and suggesting the use of the 1-mg overnight dexamethasone suppression test rather than UFC for initial testing in patients with renal failure and in those suspected of having mild Cushing's syndrome. In patients who take antiepileptic drugs that are known to enhance dexamethasone clearance, dexamethasone testing was not recommended. Instead, the guidelines recommended measurements of nonsuppressed cortisol in blood, saliva, or urine. When cyclic Cushing's syndrome is suspected, “we suggest the use of UFC or midnight salivary cortisol tests rather than dexamethasone suppression tests,” the authors wrote.

There are limited data linking diagnostic strategies to patient outcomes in Cushing's syndrome because “much of the work has focused on developing, validating, and ascertaining diagnostic test performance,” the authors wrote. As a result, “the evidence on which many of these recommendations have been made is of low to very low quality,” they stated. Additionally, the published data is potentially biased toward more severe cases with higher pretest probability, and thus might not accurately represent the tests' performance in unselected populations in usual clinical practice.

Possible research initiatives that could improve the future care of patients with Cushing's syndrome include the establishment of databases of consecutive patients tested for the syndrome, “allowing for prospective pooling of the diagnostic test information,” the authors wrote. Standardization of assays and improved clinical outcome data and targeted clinical trials are also on the authors' wish list.

In the absence of exogenous glucocorticoid use, patients with multiple and progressive features that are highly discriminatory for Cushing's syndrome should be tested for the endocrine disorder, according to new clinical practice guidelines developed by a task force of the Endocrine Society.

Testing is also recommended for patients with adrenal incidentaloma compatible with adenoma and children with combined reduced linear growth and increased weight, wrote lead author Dr. Lynnette K. Nieman of the National Institute of Child Health and Human Development and task force colleagues.

Although the signs and symptoms of full-blown Cushing's disease are clinically unmistakable, “the spectrum of clinical presentation is broad, and the diagnosis can be challenging in mild cases,” the authors wrote, noting that the guidelines were developed to help facilitate this process. Because the strength of the recommendations varies depending on the quality of evidence supporting them, “careful consideration of the patient's circumstances, values, and preferences is appropriate to determine the best course of action,” the authors wrote (J. Clin. Endocrinol. Metab. 2008 March 11 [doi:10.1210/jc.2008-0125]).

Pretest Probability

Before conducting any biochemical testing, physicians should obtain a thorough drug history to rule out iatrogenic Cushing's syndrome associated with excessive exogenous glucocorticoid exposure.

After exclusion of exogenous glucocorticoid use, diagnostic testing is recommended for individuals with multiple features considered discriminatory for the disease, including easy bruising, facial plethora, proximal myopathy, reddish-purple striae, thin skin in the young, and weight gain with decreasing growth velocity in children, the authors wrote.

In addition, because Cushing's syndrome is progressive, patients who demonstrate an accumulation of new features should be tested, as should patients who develop features of the condition, such as osteoporosis and hypertension, which are atypical in the general population for individuals their age. Finally, the presence of an incidentally found adrenal nodule contributes to the pretest probability of Cushing's syndrome. “Such patients usually do not present with overt clinical features of Cushing's syndrome, but biochemical hypercortisolism is present in a large fraction,” the authors wrote.

The authors recommend against widespread testing in any other patient group, including obese children, unless their statural growth has slowed.

Diagnostic Tests

With respect to initial diagnostic testing, the task force recommended any of the following: at least two urinary free cortisol (UFC) measurements, two late-night salivary cortisol measurements, a 1-mg overnight dexamethasone suppression test (DST), or the longer low-dose 2 day/2 mg per day DST.

The guidelines recommend against testing for any of the following because of their low diagnostic accuracy for Cushing's syndrome: random serum cortisol or plasma ACTH levels; urinary 17-ketosteroids; insulin tolerance test; loperamide test; and tests designed to determine the cause of Cushing's syndrome, such as pituitary and adrenal imaging and the 8-mg DST.

Patients with normal test results who have a high pretest probability for Cushing's syndrome based on clinical features, adrenal incidentaloma, or suspected cyclic hypercortisolism should be referred for further evaluation by an endocrinologist, while those with normal test results and a low pretest probability should be reevaluated in 6 months if symptoms persist. Patients with at least one abnormal test result should also be referred to an endocrinologist for further evaluation to confirm or exclude the diagnosis, the authors wrote.

Although the four recommended diagnostic tests have “acceptable” accuracy when the suggested cutoff points are used, “no test has optimally high specificity, so false positives may occur,” the authors noted. To minimize the possibility of a misdiagnosis, the guidelines recommend subsequent evaluation of abnormal initial test results using another one of the high-sensitivity tests. “We suggest the additional use of the dexamethasone-CRH test or the midnight serum cortisol test in specific situations,” the authors wrote. They recommended against the use of the desmopressin test, “except in research studies,” because its utility has not been validated.

With the exception of patients of having “the very rare case of cyclical disease,” further testing is not recommended for patients with negative results on two different tests, the authors noted. For patients with concordantly positive results from two different tests for whom there is no concern regarding possible non-Cushing's hypercortisolism, “we recommend tests to establish the cause of Cushing's syndrome,” they wrote. Finally, further evaluation and follow-up is suggested for those few patients with concordantly negative results who are suspected of having cyclical disease, and for those patients with discordant results in whom the pretest probability is high.

Special Populations

The guidelines also addressed diagnostic testing in special populations, recommending the use of UFC (and against the use of dexamethasone testing) in the initial evaluation of pregnant women, and suggesting the use of the 1-mg overnight dexamethasone suppression test rather than UFC for initial testing in patients with renal failure and in those suspected of having mild Cushing's syndrome. In patients who take antiepileptic drugs that are known to enhance dexamethasone clearance, dexamethasone testing was not recommended. Instead, the guidelines recommended measurements of nonsuppressed cortisol in blood, saliva, or urine. When cyclic Cushing's syndrome is suspected, “we suggest the use of UFC or midnight salivary cortisol tests rather than dexamethasone suppression tests,” the authors wrote.

There are limited data linking diagnostic strategies to patient outcomes in Cushing's syndrome because “much of the work has focused on developing, validating, and ascertaining diagnostic test performance,” the authors wrote. As a result, “the evidence on which many of these recommendations have been made is of low to very low quality,” they stated. Additionally, the published data is potentially biased toward more severe cases with higher pretest probability, and thus might not accurately represent the tests' performance in unselected populations in usual clinical practice.

Possible research initiatives that could improve the future care of patients with Cushing's syndrome include the establishment of databases of consecutive patients tested for the syndrome, “allowing for prospective pooling of the diagnostic test information,” the authors wrote. Standardization of assays and improved clinical outcome data and targeted clinical trials are also on the authors' wish list.

BOSTON — Regarding Pap smears in adolescents: Don't do them in the first 3 years after their sexual debut, Dr. Michael S. Policar stressed.

Pap testing in this population is no longer recommended “because it can do more harm than good,” he said. “High-grade lesions are rare in teenagers, occurring in 3 cases per 1,000 15- to 19-year-olds, and they take years to develop. For example, it takes 3 years after sexual debut for high-grade squamous intraepithelial lesions to develop and 5 years for invasive cancers to emerge,” he said at a conference on contraceptive technology sponsored by Contemporary Forums.

Additionally, “approximately 91% of low-grade lesions in teens, such as cervical intraepithelial neoplasia 1 [CIN 1] often resolve spontaneously, while 6% remain stable and only 3% progress to high-grade dysplasia.” Biopsy-proven CIN 2 lesions in teenagers often regress spontaneously, as well, said Dr. Policar. Recognition of these early cytologic abnormalities on Pap testing could easily lead to unnecessary intervention and consequent risks, said Dr. Policar of the department of obstetrics, gynecology, and reproductive sciences at the University of California, San Francisco.

For these reasons, the American College of Obstetricians and Gynecologists recommends that Pap testing should not be initiated in young women until age 21 or 3 years after first intercourse, Dr. Policar said. Even so, he noted, many clinicians are still screening virginal 18-year-olds as per the previous guidelines.

Restraint is also warranted in the management of teens whose Pap tests show atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL), Dr. Policar stated.

Although consensus guidelines for the general population call for reflex human papillomavirus (HPV) testing for women with ASC-US and colposcopic examination of the cervix for those with evidence of HPV infection, LSIL, and high-grade squamous intraepithelial lesion (HSIL), these guidelines do not apply to adolescents and young women, he said.

“Colposcopy and reflex HPV triage are no longer recommended as initial options,” he stated, referring to the American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines for the management of women with abnormal cervical screening tests that were released late last year (Am. J. Obstet. Gynecol. 2007;197:346–55).

Approximately 80% of female adolescents become HPV-DNA positive soon after their first sexual encounters and the majority of these infections clear spontaneously within 2 years.

The identification of abnormal cervical cytology on HPV-DNA testing in adolescents could lead to the unnecessary referral of many teens for colposcopy despite their low cervical cancer risk, Dr. Policar warned.

Rather than immediate colposcopy, adolescents with ASC-US or LSIL on Pap testing should undergo a repeat Pap smear in 12 months. “If the repeat Pap shows high-grade squamous intraepithelial lesions, the adolescent should be referred for colposcopy,” said Dr. Policar. Those patients with less than HSIL, however, should undergo a repeat Pap in another 12 months, at which point, evidence of ASC-US or greater warrants a colposcopy referral, he said.

While the same 24-month conservative pathway should be followed for adolescent patients with biopsy-proven CIN 1 or CIN 2 to allow for regression, the management options for adolescents and young women with a histologic diagnosis of CIN 2,3 include treatment using either excision or ablation of the T-zone depending on the adequacy of the colposcopic exam, or colposcopic and cytologic observation at 6-month intervals for 24 months, “as long as colposcopy results are normal and cytology is negative,” said Dr. Policar.

“If colposcopy worsens or high-grade cytology or colposcopy persists, the biopsy should be repeated,” he said. “If, on repeat biopsy, CIN 3 or CIN 2,3 persists for 24 months [the initial diagnosis], treatment should be undertaken to reduce the potential risk of cervical cancer.”

Dr. Michael Policar disclosed that he is a speaker for Graceway Pharmaceuticals LLC, Merck & Co., and TyRx Pharma Inc.

BOSTON — Regarding Pap smears in adolescents: Don't do them in the first 3 years after their sexual debut, Dr. Michael S. Policar stressed.

Pap testing in this population is no longer recommended “because it can do more harm than good,” he said. “High-grade lesions are rare in teenagers, occurring in 3 cases per 1,000 15- to 19-year-olds, and they take years to develop. For example, it takes 3 years after sexual debut for high-grade squamous intraepithelial lesions to develop and 5 years for invasive cancers to emerge,” he said at a conference on contraceptive technology sponsored by Contemporary Forums.

Additionally, “approximately 91% of low-grade lesions in teens, such as cervical intraepithelial neoplasia 1 [CIN 1] often resolve spontaneously, while 6% remain stable and only 3% progress to high-grade dysplasia.” Biopsy-proven CIN 2 lesions in teenagers often regress spontaneously, as well, said Dr. Policar. Recognition of these early cytologic abnormalities on Pap testing could easily lead to unnecessary intervention and consequent risks, said Dr. Policar of the department of obstetrics, gynecology, and reproductive sciences at the University of California, San Francisco.

For these reasons, the American College of Obstetricians and Gynecologists recommends that Pap testing should not be initiated in young women until age 21 or 3 years after first intercourse, Dr. Policar said. Even so, he noted, many clinicians are still screening virginal 18-year-olds as per the previous guidelines.

Restraint is also warranted in the management of teens whose Pap tests show atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL), Dr. Policar stated.

Although consensus guidelines for the general population call for reflex human papillomavirus (HPV) testing for women with ASC-US and colposcopic examination of the cervix for those with evidence of HPV infection, LSIL, and high-grade squamous intraepithelial lesion (HSIL), these guidelines do not apply to adolescents and young women, he said.

“Colposcopy and reflex HPV triage are no longer recommended as initial options,” he stated, referring to the American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines for the management of women with abnormal cervical screening tests that were released late last year (Am. J. Obstet. Gynecol. 2007;197:346–55).

Approximately 80% of female adolescents become HPV-DNA positive soon after their first sexual encounters and the majority of these infections clear spontaneously within 2 years.

The identification of abnormal cervical cytology on HPV-DNA testing in adolescents could lead to the unnecessary referral of many teens for colposcopy despite their low cervical cancer risk, Dr. Policar warned.

Rather than immediate colposcopy, adolescents with ASC-US or LSIL on Pap testing should undergo a repeat Pap smear in 12 months. “If the repeat Pap shows high-grade squamous intraepithelial lesions, the adolescent should be referred for colposcopy,” said Dr. Policar. Those patients with less than HSIL, however, should undergo a repeat Pap in another 12 months, at which point, evidence of ASC-US or greater warrants a colposcopy referral, he said.

While the same 24-month conservative pathway should be followed for adolescent patients with biopsy-proven CIN 1 or CIN 2 to allow for regression, the management options for adolescents and young women with a histologic diagnosis of CIN 2,3 include treatment using either excision or ablation of the T-zone depending on the adequacy of the colposcopic exam, or colposcopic and cytologic observation at 6-month intervals for 24 months, “as long as colposcopy results are normal and cytology is negative,” said Dr. Policar.

“If colposcopy worsens or high-grade cytology or colposcopy persists, the biopsy should be repeated,” he said. “If, on repeat biopsy, CIN 3 or CIN 2,3 persists for 24 months [the initial diagnosis], treatment should be undertaken to reduce the potential risk of cervical cancer.”

Dr. Michael Policar disclosed that he is a speaker for Graceway Pharmaceuticals LLC, Merck & Co., and TyRx Pharma Inc.

BOSTON — Regarding Pap smears in adolescents: Don't do them in the first 3 years after their sexual debut, Dr. Michael S. Policar stressed.

Pap testing in this population is no longer recommended “because it can do more harm than good,” he said. “High-grade lesions are rare in teenagers, occurring in 3 cases per 1,000 15- to 19-year-olds, and they take years to develop. For example, it takes 3 years after sexual debut for high-grade squamous intraepithelial lesions to develop and 5 years for invasive cancers to emerge,” he said at a conference on contraceptive technology sponsored by Contemporary Forums.

Additionally, “approximately 91% of low-grade lesions in teens, such as cervical intraepithelial neoplasia 1 [CIN 1] often resolve spontaneously, while 6% remain stable and only 3% progress to high-grade dysplasia.” Biopsy-proven CIN 2 lesions in teenagers often regress spontaneously, as well, said Dr. Policar. Recognition of these early cytologic abnormalities on Pap testing could easily lead to unnecessary intervention and consequent risks, said Dr. Policar of the department of obstetrics, gynecology, and reproductive sciences at the University of California, San Francisco.

For these reasons, the American College of Obstetricians and Gynecologists recommends that Pap testing should not be initiated in young women until age 21 or 3 years after first intercourse, Dr. Policar said. Even so, he noted, many clinicians are still screening virginal 18-year-olds as per the previous guidelines.

Restraint is also warranted in the management of teens whose Pap tests show atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL), Dr. Policar stated.

Although consensus guidelines for the general population call for reflex human papillomavirus (HPV) testing for women with ASC-US and colposcopic examination of the cervix for those with evidence of HPV infection, LSIL, and high-grade squamous intraepithelial lesion (HSIL), these guidelines do not apply to adolescents and young women, he said.

“Colposcopy and reflex HPV triage are no longer recommended as initial options,” he stated, referring to the American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines for the management of women with abnormal cervical screening tests that were released late last year (Am. J. Obstet. Gynecol. 2007;197:346–55).

Approximately 80% of female adolescents become HPV-DNA positive soon after their first sexual encounters and the majority of these infections clear spontaneously within 2 years.

The identification of abnormal cervical cytology on HPV-DNA testing in adolescents could lead to the unnecessary referral of many teens for colposcopy despite their low cervical cancer risk, Dr. Policar warned.

Rather than immediate colposcopy, adolescents with ASC-US or LSIL on Pap testing should undergo a repeat Pap smear in 12 months. “If the repeat Pap shows high-grade squamous intraepithelial lesions, the adolescent should be referred for colposcopy,” said Dr. Policar. Those patients with less than HSIL, however, should undergo a repeat Pap in another 12 months, at which point, evidence of ASC-US or greater warrants a colposcopy referral, he said.

While the same 24-month conservative pathway should be followed for adolescent patients with biopsy-proven CIN 1 or CIN 2 to allow for regression, the management options for adolescents and young women with a histologic diagnosis of CIN 2,3 include treatment using either excision or ablation of the T-zone depending on the adequacy of the colposcopic exam, or colposcopic and cytologic observation at 6-month intervals for 24 months, “as long as colposcopy results are normal and cytology is negative,” said Dr. Policar.

“If colposcopy worsens or high-grade cytology or colposcopy persists, the biopsy should be repeated,” he said. “If, on repeat biopsy, CIN 3 or CIN 2,3 persists for 24 months [the initial diagnosis], treatment should be undertaken to reduce the potential risk of cervical cancer.”

Dr. Michael Policar disclosed that he is a speaker for Graceway Pharmaceuticals LLC, Merck & Co., and TyRx Pharma Inc.

BOSTON — The increased risk of HIV infection observed in the now-defunct trial of Merck's experimental trivalent HIV vaccine V520 was greatest in uncircumcised men with high preexisting immunity to the vaccine's delivery vector, the adenovirus type 5, according to a post hoc analysis of the trial data.

“Uncircumcised men with high immunity to [adenovirus type 5] were more than four times more likely to develop HIV infection than men given the placebo vaccine,” Dr. Susan Buchbinder reported at the 15th Conference on Retroviruses and Opportunistic Infections.

The international clinical trial of V520 was halted in September 2007 because it failed to block or slow the rate of HIV infections in the high-risk study population (primarily gay men and female sex workers who had multiple sex partners in the 6 months prior to study initiation). Additionally, the HIV infection rate was higher in the vaccine arm than in the placebo arm, said Dr. Buchbinder of the San Francisco Department of Public Health.

Overall, 49 of 914 vaccine recipients developed HIV infection, compared with 33 of 922 placebo recipients. Because all but one of the reported infections occurred among the study's male volunteers, post hoc analyses have concentrated on the men in the study, she said.

Although the difference in infection rates between the vaccine and placebo groups across the entire study population was only “marginally statistically significant,” in the subgroup of participants with high levels of adenovirus type 5 (Ad5) immunity—defined as antibody levels greater than 200 U—the statistical significance between the two groups was more robust. In univariate and multivariate models, high Ad5 immunity was associated with a threefold increased risk of HIV infection in vaccine recipients, Dr. Buchbinder noted.

Univariate and multivariate analyses also identified the lack of circumcision as a risk factor for infection. “Uncircumcised males [with high Ad5 immunity] who received the vaccine were approximately four times more likely than those who received placebo to become infected with HIV,” Dr. Buchbinder reported. Circumcision, on the other hand, appeared to blunt the increased vulnerability to infection associated with Ad5 immunity, in that the HIV infection risk among circumcised men with high titers to Ad5 was not statistically significant, she said. Similarly, the increased infection risk observed in uncircumcised men with low titers was not statistically significant.

Men in the study with high Ad5 immunity tended to come from countries and communities with low rates of circumcision.

An evaluation of viral loads across the study population did not identify an obvious correlation between Ad5 immunity and viral load. “We are awaiting additional data on herpes simplex virus 2, [human leukocyte antigen] typing, and sexual network clustering to explore possible confounding factors for HIV acquisition,” Dr. Buchbinder added.

The conference was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.

BOSTON — The increased risk of HIV infection observed in the now-defunct trial of Merck's experimental trivalent HIV vaccine V520 was greatest in uncircumcised men with high preexisting immunity to the vaccine's delivery vector, the adenovirus type 5, according to a post hoc analysis of the trial data.

“Uncircumcised men with high immunity to [adenovirus type 5] were more than four times more likely to develop HIV infection than men given the placebo vaccine,” Dr. Susan Buchbinder reported at the 15th Conference on Retroviruses and Opportunistic Infections.

The international clinical trial of V520 was halted in September 2007 because it failed to block or slow the rate of HIV infections in the high-risk study population (primarily gay men and female sex workers who had multiple sex partners in the 6 months prior to study initiation). Additionally, the HIV infection rate was higher in the vaccine arm than in the placebo arm, said Dr. Buchbinder of the San Francisco Department of Public Health.

Overall, 49 of 914 vaccine recipients developed HIV infection, compared with 33 of 922 placebo recipients. Because all but one of the reported infections occurred among the study's male volunteers, post hoc analyses have concentrated on the men in the study, she said.

Although the difference in infection rates between the vaccine and placebo groups across the entire study population was only “marginally statistically significant,” in the subgroup of participants with high levels of adenovirus type 5 (Ad5) immunity—defined as antibody levels greater than 200 U—the statistical significance between the two groups was more robust. In univariate and multivariate models, high Ad5 immunity was associated with a threefold increased risk of HIV infection in vaccine recipients, Dr. Buchbinder noted.

Univariate and multivariate analyses also identified the lack of circumcision as a risk factor for infection. “Uncircumcised males [with high Ad5 immunity] who received the vaccine were approximately four times more likely than those who received placebo to become infected with HIV,” Dr. Buchbinder reported. Circumcision, on the other hand, appeared to blunt the increased vulnerability to infection associated with Ad5 immunity, in that the HIV infection risk among circumcised men with high titers to Ad5 was not statistically significant, she said. Similarly, the increased infection risk observed in uncircumcised men with low titers was not statistically significant.

Men in the study with high Ad5 immunity tended to come from countries and communities with low rates of circumcision.

An evaluation of viral loads across the study population did not identify an obvious correlation between Ad5 immunity and viral load. “We are awaiting additional data on herpes simplex virus 2, [human leukocyte antigen] typing, and sexual network clustering to explore possible confounding factors for HIV acquisition,” Dr. Buchbinder added.

The conference was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.

BOSTON — The increased risk of HIV infection observed in the now-defunct trial of Merck's experimental trivalent HIV vaccine V520 was greatest in uncircumcised men with high preexisting immunity to the vaccine's delivery vector, the adenovirus type 5, according to a post hoc analysis of the trial data.

“Uncircumcised men with high immunity to [adenovirus type 5] were more than four times more likely to develop HIV infection than men given the placebo vaccine,” Dr. Susan Buchbinder reported at the 15th Conference on Retroviruses and Opportunistic Infections.

The international clinical trial of V520 was halted in September 2007 because it failed to block or slow the rate of HIV infections in the high-risk study population (primarily gay men and female sex workers who had multiple sex partners in the 6 months prior to study initiation). Additionally, the HIV infection rate was higher in the vaccine arm than in the placebo arm, said Dr. Buchbinder of the San Francisco Department of Public Health.

Overall, 49 of 914 vaccine recipients developed HIV infection, compared with 33 of 922 placebo recipients. Because all but one of the reported infections occurred among the study's male volunteers, post hoc analyses have concentrated on the men in the study, she said.

Although the difference in infection rates between the vaccine and placebo groups across the entire study population was only “marginally statistically significant,” in the subgroup of participants with high levels of adenovirus type 5 (Ad5) immunity—defined as antibody levels greater than 200 U—the statistical significance between the two groups was more robust. In univariate and multivariate models, high Ad5 immunity was associated with a threefold increased risk of HIV infection in vaccine recipients, Dr. Buchbinder noted.

Univariate and multivariate analyses also identified the lack of circumcision as a risk factor for infection. “Uncircumcised males [with high Ad5 immunity] who received the vaccine were approximately four times more likely than those who received placebo to become infected with HIV,” Dr. Buchbinder reported. Circumcision, on the other hand, appeared to blunt the increased vulnerability to infection associated with Ad5 immunity, in that the HIV infection risk among circumcised men with high titers to Ad5 was not statistically significant, she said. Similarly, the increased infection risk observed in uncircumcised men with low titers was not statistically significant.

Men in the study with high Ad5 immunity tended to come from countries and communities with low rates of circumcision.

An evaluation of viral loads across the study population did not identify an obvious correlation between Ad5 immunity and viral load. “We are awaiting additional data on herpes simplex virus 2, [human leukocyte antigen] typing, and sexual network clustering to explore possible confounding factors for HIV acquisition,” Dr. Buchbinder added.

The conference was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.

BOSTON — Recent use of the nucleoside analogues abacavir and didanosine is associated with a significantly increased risk of myocardial infarction in HIV-infected individuals, whereas treatment with the thymidine analogues appears to convey no such risk, according to findings presented at the 15th Conference on Retroviruses and Opportunistic Infections.

Using data from the DAD (Data Collection of Adverse Effects of Anti-HIV Drugs) study, a prospective study of more than 33,000 patients from 11 existing cohorts in Europe, Australia, and the United States, Dr. Caroline Sabin of the Royal Free Hospital, London, and her colleagues determined previously that antiretroviral treatment as a whole and protease inhibitor use specifically were associated with an increased risk of cardiovascular disease.

In the current study, 517 myocardial infarctions occurred during the approximately 7 years of follow-up. The study, which looked at the effect of five individual nucleoside reverse transcriptase inhibitors (NRTIs), showed that treatment with abacavir (Ziagen) was associated with a 90% increased risk of MI, and didanosine was associated with a 49% increased risk. Neither of the thymidine analogues—zidovudine or stavudine—nor the nucleoside analogue lamivudine was associated with increased MI risk, Dr. Sabin said. She reported no conflicts of interest pertaining to the study drugs.

The findings were unexpected, she noted, in that the current investigation was undertaken to test the hypothesis that thymidine analogues, because of their known association with dyslipidemia and insulin resistance, might also be associated with an increased risk of heart attack in HIV-infected individuals.

To assess the effect of cumulative, recent (defined as current or within the past 6 months), and past (defined as outside the past 6 months) use of the five NRTIs, the investigators generated Poisson regression models, adjusting for various factors.

Neither cumulative nor recent use of the two thymidine analogues or lamivudine was associated with risk of MI, whereas recent use of abacavir and didanosine predicted risk of MI, Dr. Sabin reported. Additionally, the risks of MI associated with recent abacavir and didanosine use were independent of duration of use and remained after adjustment for HIV-RNA levels, CD4 count, dyslipidemia, and other metabolic factors, she said. Past use of both drugs was not associated with increased risk of MI, which suggests that the unknown biological mechanism for increased MI risk may be reversible upon cessation of the drugs, she added.

To determine the absolute risk of MI among nucleoside analogue users, the investigators incorporated the Framingham predicted 10-year coronary heart disease risk into the main regression model, and determined that the rate of MI was increased by 119% in patients with a moderate 10-year risk and by 222% in patients with a high 10-year risk, relative to those with a low 10-year risk, Dr. Sabin reported. As such, the clinical implications of the findings depend on an individual patient's underlying cardiovascular risk, she said.

The conference was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.

BOSTON — Recent use of the nucleoside analogues abacavir and didanosine is associated with a significantly increased risk of myocardial infarction in HIV-infected individuals, whereas treatment with the thymidine analogues appears to convey no such risk, according to findings presented at the 15th Conference on Retroviruses and Opportunistic Infections.

Using data from the DAD (Data Collection of Adverse Effects of Anti-HIV Drugs) study, a prospective study of more than 33,000 patients from 11 existing cohorts in Europe, Australia, and the United States, Dr. Caroline Sabin of the Royal Free Hospital, London, and her colleagues determined previously that antiretroviral treatment as a whole and protease inhibitor use specifically were associated with an increased risk of cardiovascular disease.

In the current study, 517 myocardial infarctions occurred during the approximately 7 years of follow-up. The study, which looked at the effect of five individual nucleoside reverse transcriptase inhibitors (NRTIs), showed that treatment with abacavir (Ziagen) was associated with a 90% increased risk of MI, and didanosine was associated with a 49% increased risk. Neither of the thymidine analogues—zidovudine or stavudine—nor the nucleoside analogue lamivudine was associated with increased MI risk, Dr. Sabin said. She reported no conflicts of interest pertaining to the study drugs.

The findings were unexpected, she noted, in that the current investigation was undertaken to test the hypothesis that thymidine analogues, because of their known association with dyslipidemia and insulin resistance, might also be associated with an increased risk of heart attack in HIV-infected individuals.

To assess the effect of cumulative, recent (defined as current or within the past 6 months), and past (defined as outside the past 6 months) use of the five NRTIs, the investigators generated Poisson regression models, adjusting for various factors.

Neither cumulative nor recent use of the two thymidine analogues or lamivudine was associated with risk of MI, whereas recent use of abacavir and didanosine predicted risk of MI, Dr. Sabin reported. Additionally, the risks of MI associated with recent abacavir and didanosine use were independent of duration of use and remained after adjustment for HIV-RNA levels, CD4 count, dyslipidemia, and other metabolic factors, she said. Past use of both drugs was not associated with increased risk of MI, which suggests that the unknown biological mechanism for increased MI risk may be reversible upon cessation of the drugs, she added.

To determine the absolute risk of MI among nucleoside analogue users, the investigators incorporated the Framingham predicted 10-year coronary heart disease risk into the main regression model, and determined that the rate of MI was increased by 119% in patients with a moderate 10-year risk and by 222% in patients with a high 10-year risk, relative to those with a low 10-year risk, Dr. Sabin reported. As such, the clinical implications of the findings depend on an individual patient's underlying cardiovascular risk, she said.

The conference was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.

BOSTON — Recent use of the nucleoside analogues abacavir and didanosine is associated with a significantly increased risk of myocardial infarction in HIV-infected individuals, whereas treatment with the thymidine analogues appears to convey no such risk, according to findings presented at the 15th Conference on Retroviruses and Opportunistic Infections.

Using data from the DAD (Data Collection of Adverse Effects of Anti-HIV Drugs) study, a prospective study of more than 33,000 patients from 11 existing cohorts in Europe, Australia, and the United States, Dr. Caroline Sabin of the Royal Free Hospital, London, and her colleagues determined previously that antiretroviral treatment as a whole and protease inhibitor use specifically were associated with an increased risk of cardiovascular disease.

In the current study, 517 myocardial infarctions occurred during the approximately 7 years of follow-up. The study, which looked at the effect of five individual nucleoside reverse transcriptase inhibitors (NRTIs), showed that treatment with abacavir (Ziagen) was associated with a 90% increased risk of MI, and didanosine was associated with a 49% increased risk. Neither of the thymidine analogues—zidovudine or stavudine—nor the nucleoside analogue lamivudine was associated with increased MI risk, Dr. Sabin said. She reported no conflicts of interest pertaining to the study drugs.

The findings were unexpected, she noted, in that the current investigation was undertaken to test the hypothesis that thymidine analogues, because of their known association with dyslipidemia and insulin resistance, might also be associated with an increased risk of heart attack in HIV-infected individuals.

To assess the effect of cumulative, recent (defined as current or within the past 6 months), and past (defined as outside the past 6 months) use of the five NRTIs, the investigators generated Poisson regression models, adjusting for various factors.

Neither cumulative nor recent use of the two thymidine analogues or lamivudine was associated with risk of MI, whereas recent use of abacavir and didanosine predicted risk of MI, Dr. Sabin reported. Additionally, the risks of MI associated with recent abacavir and didanosine use were independent of duration of use and remained after adjustment for HIV-RNA levels, CD4 count, dyslipidemia, and other metabolic factors, she said. Past use of both drugs was not associated with increased risk of MI, which suggests that the unknown biological mechanism for increased MI risk may be reversible upon cessation of the drugs, she added.

To determine the absolute risk of MI among nucleoside analogue users, the investigators incorporated the Framingham predicted 10-year coronary heart disease risk into the main regression model, and determined that the rate of MI was increased by 119% in patients with a moderate 10-year risk and by 222% in patients with a high 10-year risk, relative to those with a low 10-year risk, Dr. Sabin reported. As such, the clinical implications of the findings depend on an individual patient's underlying cardiovascular risk, she said.

The conference was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.