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News Briefs

Summer/Fall 2009

Conference Coverage

The 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention took place July 19-22 in Cape Town, South Africa. Alternating every other summer with the International AIDS Conference, the IAS meeting focuses primarily on the medical aspects of HIV prevention and management. This year, however, the conference's location prompted more emphasis on social and economic aspects of the epidemic in resource-limited settings.

Selected reports from the conference are included below, along with recent news from medical journals and other sources.

On the Web: IAS 2009


New HIV and OI Treatment Guidelines

The HIV Medicine Association (HIVMA) of the Infectious Diseases Society of America recently released new primary care guidelines for people with HIV, published in the September 1, 2009, issue of Clinical Infectious Diseases. The first update since 2004, the revised guidelines reflect changes to antiretroviral therapy (ART) guidelines issued by other organizations, along with a broader focus on basic health management. Topics include ART monitoring, recommended vaccines, metabolic complications, kidney and liver disease, and age-related concerns such as bone loss and menopause. According to the authors, the guidelines emphasize "the importance of adherence to care rather than focusing solely on adherence to medications." The complete guidelines are available online at www.journals.uchicago.edu/doi/full/10.1086/605292.

HIVMA, the National Institutes of Health, and the Centers for Disease Control and Prevention (CDC) recently published a collaborative revision of the Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. Merging separate prevention and treatment guidelines last updated in 2002 and 2004, respectively, the new version includes primary prophylaxis, treatment, and maintenance therapy recommendations. In addition to classic AIDS-defining opportunistic infections (OIs) and malignancies, the guidelines also discuss common coinfections, including herpes, syphilis, malaria, and hepatitis B and C. The revision features a greater emphasis on the role of ART and more information on immune reconstitution inflammatory syndrome (IRIS). Published in the April 10, 2009, issue of Morbidity and Mortality Weekly Report (MMWR), the guidelines are available online here.

In late February, the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children released updated Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Changes in this version include additional information on newer antiretroviral drugs and management of treatment failure. The guidelines are available online here. Finally, revised Guidelines for Prevention and Treatment of Opportunistic Infections among HIV-Exposed and HIV-Infected Children were published in the August 26, 2009, issue of MMWR and are available online here.


Raltegravir Approved for First-Line Therapy

On July 8, 2009, the U.S. Food and Drug Administration (FDA) approved the first integrase inhibitor, raltegravir (Isentress), as first-line therapy for treatment-naive HIV patients. The recommended dose for previously untreated adults is 400 mg twice daily, with or without food, as part of a complete combination antiretroviral regimen. Approval was based in part on findings from the STARTMRK trial, which demonstrated that raltegravir suppressed viral load as well as did efavirenz (Sustiva, also in the Truvada and Atripla coformulations) at 48 weeks (86% vs 82%, respectively, with HIV RNA <50 copies/mL), but with fewer adverse neuropsychological side effects and blood lipid abnormalities.


Etravirine Hypersensitivity Warning

In late August, Tibotec Therapeutics, in cooperation with the FDA, issued a "Dear Healthcare Professional" letter describing updated prescribing information for the next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine (Intelence). The revision strengthens a warning about the risk of severe skin rash and other signs of hypersensitivity reaction, including liver failure. A small percentage of people taking the drug have experienced life-threatening -- and in a few cases, fatal -- skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme. Rash usually occurs within the first six weeks after starting the drug. The revised label cautions that etravirine should be immediately discontinued if a patient develops signs and symptoms of severe skin or hypersensitivity reactions. Full etravirine prescribing information is available online here.


Boosted Darunavir Monotherapy

Researchers have studied monotherapy using a single ritonavir-boosted protease inhibitor (PI) as a means of simplifying therapy and avoiding side effects associated with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). The potent next-generation PI darunavir (Prezista) is a promising candidate for this strategy, according to two studies presented at the IAS conference.

The European MONET study (abstract TUAB106) included 256 participants with full HIV suppression (<50 copies/ mL) for at least six months using a standard three-drug ART regimen. Patients were randomly assigned to switch to once-daily darunavir/ritonavir (800/100 mg), either alone or in combination with two NRTIs. After 48 weeks, an intentto- treat analysis revealed that a similar proportion of patients maintained undetectable viral load in the monotherapy and triple-combination arms (84% vs 85%, respectively).

Temporary viral load increases, or "blips," were more common in the monotherapy arm, but most were low-level (50-400 copies/mL) and HIV RNA was resuppressed when NRTIs were reintroduced. Darunavir/ritonavir monotherapy was generally well tolerated, and participants in this arm were less likely to have elevated cholesterol. One person in each arm developed PI resistance mutations. The researchers concluded that darunavir/ritonavir monotherapy was noninferior to darunavir plus two NRTIs for maintaining viral suppression.

The French MONOI-ANRS 136 study (abstract WELBB102) included 242 participants with viral load below 50 copies/mL at study entry and below 400 copies/mL for at least 18 months using standard combination ART. Patients received darunavir/ritonavir (600/100 mg) plus two NRTIs for an eight-week induction period, then were randomly assigned to either stay on the combination regimen or discontinue NRTIs and continue on monotherapy. In a 48-week intent-to-treat analysis, 88% of people in the monotherapy arm maintained HIV RNA below 400 copies/mL, compared with 92% in the triple-combination arm, again demonstrating noninferiority.

Three participants in the monotherapy arm experienced virological failure, compared with none in the combination arm; one such individual, however, had a low blood drug level, suggesting poor adherence. No new darunavir/ritonavir resistance mutations were seen in patients who experienced virological breakthrough. Adverse events were similar overall, but there were three cases of central nervous system symptoms in the monotherapy arm. The researchers concluded that darunavir/ritonavir monotherapy is a "viable alternative to standard triple therapy" with "no significant downstream consequences." Principle investigator Christine Katlama noted, however, that the detrimental effects of less than perfect adherence are more apparent when using a single drug.


Integrase Inhibitor GSK-572

GlaxoSmithKline's second-generation integrase inhibitor S/GSK1349572 (GSK-572) demonstrated potent antiviral activity and promising pharmacokinetics in early studies, according to a set of presentations at IAS.

In a Phase IIa clinical trial, 35 HIV positive participants were randomly assigned to receive GSK-572 monotherapy at doses of 2, 10, or 50 mg, or else placebo, for ten days (abstract TUAB105). Patients had never taken integrase inhibitors, but otherwise could be either treatment-naive or treatment-experienced. After ten days on the drug, viral load fell between 1.51 and 2.46 log copies/mL in the GSK-572 arms, compared with 0.5 log copies/mL in the placebo arm. The investigators described the nearly 2.5-log decrease in the 50-mg arm as "unprecedented," while the 2-log reduction in the 10-mg arm was similar to that seen with other integrase inhibitors and potent drugs in other antiretroviral classes. Furthermore, 70% of patients in the highest dose arm achieved a lowest viral load below 50 copies/mL, and about 90% reached less than 400 copies/mL.

GSK-572 was generally well tolerated with no serious adverse events or early discontinuations. The most common adverse events were mild-to-moderate diarrhea, fatigue, and headache. No mutations associated with resistance to GSK-572 or other integrase inhibitors were identified. Investigators also reported in a series of posters that GSK-572 was active in vitro against HIV from patients experiencing treatment failure on raltegravir. The drug exhibited stable and consistent pharmacokinetics, has a long half-life permitting once-daily dosing, can be taken with or without food, does not require boosting, and did not interact with other drugs (abstracts WEPEA097, WEPEA098, WEPEA099, and WEPEB250). The 50-mg dose has been selected for ongoing Phase IIb trials (see "Open Clinical Trials").


Genotypic Test for Viral Tropism

HIV strains use one of two coreceptors -- CCR5 or CXCR4 -- along with the CD4 receptor to enter cells. Only people with exclusively CCR5-tropic HIV are considered eligible to use the CCR5 antagonist maraviroc (Selzentry), which prevents the virus from attaching itself to this coreceptor. Viral coreceptor preference, known as tropism, is typically determined using the Trofile assay, a phenotypic test that looks at how HIV behaves in vitro. But researchers at the IAS conference reported that a genotypic tropism test may predict equally well which patients are likely to respond to maraviroc and similar drugs (abstract WELBA101).

The genotypic test analyzes the V3 loop of the HIV-1 gp120 protein, which plays a role in interactions between the viral envelope and host cell coreceptors. In a retrospective analysis of stored plasma samples from 572 participants in the MOTIVATE-1 trial (which compared maraviroc vs placebo in treatment-experienced patients), virological response was similar regardless of whether tropism was determined using the genotypic test or the standard Trofile assay. Genotypic tests, which analyze viral genetic sequences, are easier to perform than phenotypic tests, and therefore are typically less expensive.


Abacavir Cardiovascular Risk and Efficacy

Recent studies provide further evidence in the ongoing debate about the safety and efficacy of abacavir (Ziagen, also in the Epzicom and Trizivir coformulations). As discussed in the Winter/Spring 2009 issue of BETA, the latest revision of the Department of Health and Human Services (DHHS) antiretroviral treatment guidelines removed abacavir/3TC (Epzicom) from the list of preferred NRTI backbones for first-line therapy due to data suggesting abacavir may not suppress HIV as well as does tenofovir in people with high baseline viral load, and may be associated with an increased risk of cardiovascular events.

As reported at the IAS meeting (abstract MOAB202), investigators searched the U.S. Veterans Administration Clinical Case Registry to identify patients who experienced heart attacks or strokes, and performed a statistical analysis to determine the link between these events and type of antiretroviral therapy. A total of 19,424 patients were followed for an average of about four years between 1996 and 2004. During this period, 278 heart attacks (3.69 per 1,000 person-years [PY]) and 868 strokes (11.68 per 1,000 PY) were diagnosed. Individuals who experienced heart attacks were significantly more likely to have traditional cardiovascular risk factors, as well as hepatitis C and kidney disease.

In an unadjusted analysis, abacavir use was associated with an increased heart attack and stroke risk that was of borderline significance. After controlling for recognized cardiovascular risk factors and coexisting conditions, however, the link between abacavir and these events was no longer close to statistical significance. The researchers noted that since people with kidney disease were more likely to have heart attacks and also more likely to be prescribed abacavir -- because tenofovir, the most widely used alternative, can cause kidney dysfunction in susceptible individuals -- kidney disease may be a confounding factor that helps explain the apparent higher risk associated with abacavir.

In another presentation at the same session (abstract MOAB201), Dominique Costagliola with the French ANRS CO4 study, which appeared to show a link between abacavir and heart attacks, reported that further analysis indicated that cocaine and injection drug use were strong confounding cardiovascular risk factors that influenced the earlier results.

Adding to the data, Spanish researchers performed a retrospective analysis of 80 participants in the BICOMBO study, which compared the abacavir/3TC and tenofovir/emtricitabine coformulations (abstract MOAB203). The investigators measured blood levels of several biomarkers associated with cardiovascular risk, including C-reactive protein (CRP), interleukin 6 and 10, tumor necrosis factor-alpha, D-dimer, and insulin. After one year of therapy, changes in all biomarker levels were minor and were similar in the abacavir and tenofovir arms. The researchers concluded that among otherwise healthy HIV patients with suppressed viral load, starting abacavir did not lead to significant changes in biomarkers of inflammation, coagulation, endothelial (blood vessel) dysfunction, or insulin resistance, "argu[ing] against the involvement of abacavir in any of these mechanisms."

Finally, with regard to efficacy, investigators with the U.K. Collaborative HIV Cohort Study (CHIC) reported in the September 1, 2009, Journal of Infectious Diseases that abacavir suppressed HIV as well as did tenofovir, regardless of initial viral load. Among 1,548 patients who started ART since January 2002 using regimens containing abacavir or tenofovir, there was no significant difference in changes in viral load at weeks 2-8 (2.08 vs 2.14 log copies, respectively). Pretreatment viral load predicted the extent of HIV RNA decline, but decreases were similar in abacavir and tenofovir recipients at all viral load levels. After 24-48 weeks, there was no significant difference in rates of virological failure between patients taking the two drugs.


Elevated CRP in People With HIV

Elevated C-reactive protein, a widely used biomarker of inflammation, was linked to increased cardiovascular risk in HIV positive people in a study published in the July 2009 Journal of Acquired Immunodeficiency Syndromes. Two recent general population studies, however, called into question the value of CRP as a predictor of heart disease.

Researchers sought to determine whether HIV infection and elevated CRP were independently associated with acute myocardial infarction (MI, or heart attack). They analyzed 487 HIV positive and 69,870 HIV negative individuals receiving care through the Partners HealthCare system in Boston between January 1997 and December 2006. People with HIV were more likely to have elevated CRP than HIV negative participants (59% vs 39%, respectively). Within the HIV positive group, those taking PIs had elevated CRP more often than those using PI-sparing ART (67% vs 39%, respectively). In a univariate analysis, both elevated CRP and HIV infection more than doubled the rate of acute MI (odds ratio 2.51 and 2.07, respectively). The two factors remained significant MI predictors in an adjusted model controlling for age, smoking, abnormal blood lipid levels, diabetes, and other traditional cardiovascular risk factors. People who were both HIV positive and had elevated CRP were more than four times more likely to have an MI than HIV negative people with normal CRP levels.

But how reliable is CRP as a marker for heart disease? In a study of the general population in Sweden, described in the July 1, 2009, Journal of the American Medical Association, consideration of multiple biomarkers, including CRP, only slightly improved clinicians' ability to predict cardiovascular events, relative to traditional risk factors. Elevated CRP had a hazard ratio of just 1.19, where a ratio of 1 indicates no difference in risk. The researchers concluded that only 8% of participants were reclassified to higher or lower risk categories on the basis of biomarkers, and only 1% required different medical management according to National Cholesterol Education Program guidelines.

Furthermore, as reported in the same issue, a genomewide association study of nearly 18,000 individuals found that while several common genetic variations were associated with coronary heart disease risk, there was no observed link between variants in the CRP gene locus and heart disease, arguing against a causal role for CRP in atherosclerosis. "[D]evelopment of therapeutic strategies targeting specific reductions in plasma levels of CRP are unlikely to be fruitful," the investigators stated.


Stepped Efavirenz Dosing

Efavirenz is among the most widely used, effective, and generally safe antiretroviral drugs, but it causes neuropsychiatric symptoms (e.g., anxiety, insomnia, unusual dreams) in about half of patients who use it. Though usually mild or moderate and often temporary, these side effects lead many people to either avoid or discontinue the drug. A study published in the August 4, 2009, issue of the Annals of Internal Medicine suggested that gradually increasing the dose when starting efavirenz reduces the frequency and lessens the severity of neuropsychiatric adverse events, without compromising efficacy.

In this trial, 114 patients at seven HIV clinics in Spain were randomly assigned to receive the standard full 600 mg/day dose of efavirenz beginning on day 1, or else to start with 200 mg/day on days 1-6, stepping up to 400 mg/day on days 7-13, and finally to 600 mg/day from day 14 onward. Overall rates of virological suppression were similar in both groups (one case of viral breakthrough in each), but significantly more patients in the full-dose arm than in the stepped-dose arm experienced neuropsychiatric or sleep-related side effects during the first week (66% vs 47%, respectively). This was also the case for specific side effects, including dizziness (66% vs 33%), "hangover" (46% vs 21%), impaired concentration (23% vs 9%), and hallucinations (6% vs 0%).

From week 2 onward, the incidence of adverse events was statistically similar in both study groups (58% vs 49%), but severity remained greater in the full-dose arm. By week 4, when everyone was receiving full-dose efavirenz, 52% of patients still reported some neuropsychiatric or sleep-related side effects. Despite early differences in side effect frequency and severity, however, overall rates of efavirenz discontinuation due to adverse events were similar in both arms. The investigators concluded that "stepwise dose escalation of efavirenz over two weeks reduces the incidence and intensity of efavirenz-related neuropsychiatric adverse events while maintaining efficacy."


Women and Men Respond Equally in GRACE Trial

Researchers at the IAS meeting presented findings from the Phase IV GRACE (Gender, Race and Clinical Experience) trial, evaluating the safety and efficacy of ritonavir-boosted darunavir in treatment-experienced women and men from diverse racial/ethnic backgrounds. The GRACE study -- sponsored by darunavir manufacturer Tibotec -- demonstrated that it is possible to recruit a large number of African- American and Latina women into an HIV treatment trial, a feat that has previously proven difficult. Among more than 400 GRACE participants, about two-thirds were women and 84% were people of color.

Kathleen Squires and colleagues (abstract MOPEB042) reported that after 48 weeks on 600/100 mg darunavir/ ritonavir plus an optimized background regimen, there were no statistically significant differences in virological response between women and men. In a TLOVR (time to loss of virological response) analysis, 51% of women and 59% of men achieved undetectable viral load (<50 copies/mL). Excluding patients who discontinued therapy for reasons other than virological failure, 73% of both women and men had undetectable HIV. In accordance with prior studies, women experienced significantly larger CD4 cell gains than men. Although overall frequency and types of side effects were generally similar, women were more likely than men to drop out due to adverse events (7.7% vs 4.2%, respectively). "Addressing the unique needs and challenges of women during the screening process and throughout the study may improve study retention," the investigators concluded.


New HIV Strain Discovered

In the August 2009 issue of Nature Medicine, French researchers reported that they identified a previously unknown strain of HIV-1 closely related to a type of simian immunodeficiency virus (SIV) that infects gorillas. The new viral strain, which the investigators proposed to designate HIV-1 group P, was detected in blood samples from a 62-year-old woman from Cameroon now living in Paris.

The woman reported no prior contact with gorillas or with "bush meat" -- primates hunted as food -- which some experts believe is how SIV crossed over to humans. The most widely distributed types of HIV-1 are thought to have jumped from chimpanzees to humans somewhere in the region around Cameroon. HIV-2, which is concentrated in western Africa and typically causes a less aggressive form of immune deficiency disease, is believed to have originated in a different primate species, possibly the sooty mangabey.

To date, the woman has shown no AIDS symptoms and is not on antiretroviral therapy, but her CD4 cell count has fallen to 300 cells/mm3 (below the threshold for initiating therapy in current U.S. treatment guidelines). The new strain is not detected by standard HIV tests; the researchers suggested that if it causes only mild disease, it may be circulating unnoticed in the population. "The discovery of this novel HIV-1 lineage highlights the continuing need to watch closely for the emergence of new HIV variants, particularly in western central Africa, the origin of all existing HIV-1 groups," they concluded.


Sexual Transmission of HCV

Evidence continues to accumulate regarding ongoing outbreaks of apparently sexually transmitted hepatitis C virus (HCV) infection among HIV positive men who have sex with men (MSM). In the May 2009 issue of Gastroenterology, researchers published results from a phylogenetic analysis of relationships among HCV strains from more than 200 HIV positive gay and bisexual men diagnosed with acute hepatitis C between 2000 and 2006. The analysis included 107 men in the U.K., 58 in the Netherlands, 25 in Germany, 24 in Australia, and 12 in France. Overall, participants had well-preserved immune function, with a median CD4 count of 518 cells/mm3.

The most common HCV genotype was 1a (59%), but 23% of the men had genotype 4d, which is otherwise uncommon in Europe. The analysis revealed that 156 sequences, or 78%, could be linked in 11 clusters. Each cluster included between four and 37 individual sequences, and larger clusters were more likely to include men from multiple countries. These findings, the researchers concluded, reveal "a large international network of HCV transmission among HIV positive MSM." Evolutionary analysis suggests occasional introduction and transmission of HCV among MSM between 1975 and 1996, followed by a more rapid increase since 1996. "The reason for a change in HCV transmission pattern since the late 1990s remains unclear, but it probably relates to biologic and behavioral factors," they wrote. "Temporally, this epidemic coincides with the introduction of highly active antiretroviral therapy and associated increases in sexual risk behaviors."

In various studies of the recent outbreaks, acute HCV infection has been linked to unprotected anal intercourse, fisting, multiple sex partners, group sex, use of sex toys, nasal drug use, and other concurrent sexually transmitted infections (STIs), but not so much to traditional risk factors such as injection drug use.

Presumed sexual transmission of HCV has mostly been reported among HIV positive men, which the researchers suggested may be due to impaired immunological control of HCV. However, they noted that several similar cases were found among HIV negative men in Brighton, U.K., where all STI clinic patients received HCV screening. HIV negative people normally do not receive routine HCV screening or liver function tests, which HIV positive individuals typically undergo as part of routine ART monitoring. This raises the possibility that HCV sexual transmission may be occurring in both HIV positive and HIV negative men, but only positive men are being identified during the often asymptomatic acute phase of hepatitis C.

In the July 31 issue of AIDS, investigators published a more detailed update on the HCV epidemic in Amsterdam. The analysis included 689 MSM (out of a total 3,125 clients) at a large STI clinic who were screened for HCV and interviewed about risk factors in 2007-2008. Only two of 532 HIV negative MSM (0.4%) were found to have HCV, compared with 28 of 157 HIV positive MSM (17.8%), suggesting that the higher rate for HIV positive men seen in other studies is not solely attributable to diagnostic bias. Seven of the 28 coinfected men had acute HCV infection acquired within the prior six months. Genetic analysis of HCV strains revealed a high degree of clustering within networks of gay and bisexual men. HIV infection, injection drug use, fisting, and use of the club drug GHB were significant HCV risk factors.

Investigators with both studies recommended expanded public health efforts to address the epidemic of HCV infection among gay and bisexual men, including increased education and screening of HIV positive men, and perhaps at-risk HIV negative men, as well.

This recommendation takes on greater urgency given recent reports from Daniel Fierer and colleagues at Mt. Sinai Medical Center in New York City, indicating that people who are already HIV positive when they acquire HCV may be prone to especially rapid liver disease progression. At the 2009 Conference on Retroviruses and Opportunistic Infections (CROI), the investigators reported that out of 45 HIV positive MSM with acute hepatitis C, only four (9%) spontaneously cleared HCV, considerably lower than the approximately 25% typically seen in studies of HIV negative people. A subset of 24 coinfected patients underwent liver biopsies a median of four months after their first abnormal liver function test. Even at this early stage, one person already had stage 3 or advanced liver fibrosis (on a scale of 0 to 4), 18 had stage 2 or moderate fibrosis, three had stage 1 or mild fibrosis, and only two had no evidence of fibrosis.

These findings are a concern because it usually takes years or decades for people with hepatitis C to develop advanced liver disease. The process tends to be more rapid in HIV/HCV coinfected individuals, but this study has reported the most extensive liver damage yet observed among patients with such early-stage disease. These results suggest that HIV positive people may especially benefit from early interferon-based therapy for hepatitis C. Further studies are needed, however, since European researchers -- who often use the non-invasive but less accurate FibroScan imaging method rather than liver biopsy to assess fibrosis -- have not yet reported similar advanced liver disease among HIV/HCV coinfected people with acute or early chronic HCV infection.


H1N1 "Swine" Flu

The ongoing worldwide epidemic of H1N1 influenza A -- commonly referred to as "swine flu," though it features a unique combination of elements of swine, bird, and human influenza viruses -- raises concerns for people with HIV and other underlying medical conditions.

The H1N1 flu, which was first identified in Mexico in March 2009, appears to cause relatively mild illness compared with typical seasonal flu. It is generally susceptible to the flu drug oseltamivir (Tamiflu), but resistant cases have been identified in various regions. H1N1 influenza initially appeared to cause severe illness in healthy young adults -- unlike most seasonal flu, which usually causes more complications in children and elderly people, but similar to the deadly 1918 pandemic flu. In the U.S., however, most cases of hospitalization or death due to H1N1 flu have involved pregnant women and people with chronic underlying illnesses.

To date, however, it does not appear that HIV positive people are at significantly greater risk for complications related to H1N1 influenza. Researchers with the French Institute of Public Health recently reported that an analysis of 564 H1N1 flu deaths reported through mid-July, of which 213 had detailed information available, revealed that obesity and diabetes were the conditions most often associated with death (57 cases). In addition, 37 fatal cases involved respiratory disease, 36 involved heart disease, and 19 involved unspecified infectious diseases. Although 16 people who died with H1N1 flu had suppressed immune function -- including five with cancer, two transplant recipients, and three with autoimmune diseases -- HIV was not identified as a risk factor.

While HIV positive individuals overall do not appear more susceptible to H1N1 infection or complications, people with advanced immune suppression (indicated by a CD4 count of 200 cells/mm3 or less) may be at greater risk. In April, the CDC issued interim guidance for flu management for clinicians treating people with HIV. The agency noted that no unusual adverse effects of flu drugs have been reported among HIV positive people, and there are no known contraindications for using these medications with antiretroviral therapy.

In August, the CDC's Advisory Committee on Immunization Practices issued a list of priority groups to receive the H1N1 vaccine, which includes children and pregnant women, but not people with HIV. Experts do not know how H1N1 influenza will evolve, how widespread the outbreak will be during the North American winter flu season, or how H1N1 might interact with normal seasonal flu variants. HIV positive people are advised to consult their clinicians and keep abreast of the latest public health recommendations, available online at www.cdc.gov/h1n1flu.


HPV Infection and Anal and Cervical Cancer

Several recent studies have looked at human papillomavirus (HPV) and associated cancers in people with HIV. Certain types of HPV cause genital warts, while others -- predominantly types 16 and 18 -- cause cervical, anal, genital, and oral cancers.

Two research teams at IAS presented data indicating that people with HPV infection may be at higher risk for contracting HIV. Both studies included sexually active men taking part in circumcision trials in Africa. An analysis of 2,168 young men in Kisumu, Kenya, found that half tested positive for HPV DNA at study entry (abstract WELBC104). Men with detectable HPV in cell specimens from the penis glans were significantly more likely than those without to become infected with HIV during the study period (5.8% vs 3.7%, respectively). The increase in risk was similar for circumcised and uncircumcised men. After controlling for circumcision status, men with HPV had nearly twice the likelihood of HIV infection (odds ratio 1.8). The researchers suggested that HPV infection might alter local cytokine levels or attract HIVsusceptible immune cells to the genital area.

A second analysis looked at 1,683 men at the end of a circumcision trial in South Africa (abstract TUAC202). Investigators found that 17.5% were infected with at least one low-risk HPV type, while 14.3% had one or more highrisk (cancer-causing) types. After adjusting for other factors, men with HPV were 4.6 times more likely to acquire HIV. The risk rose among men with multiple HPV types, reaching about 20% for those with five or more. In this study, however, only high-risk HPV types were associated with greater HIV infection risk, while in the previous study the risk increased with both high-risk and low-risk types.

A study published in the August 19, 2009, Journal of the National Cancer Institute indicated that people with AIDS have a higher likelihood of developing HPV-related malignancies. Anil Chaturvedi and colleagues collected data from 499,230 individuals diagnosed with AIDS between January 1980 and December 2004. Compared with the general population, people with AIDS had a significantly higher risk of all HPV-associated in situ (localized) cancers, ranging from nearly nine times higher for cervical cancer to nearly 70 times higher for anal cancer among men. People with AIDS also had a higher rate of HPV-related invasive cancers.

People with a lower CD4 cell count were at higher risk for invasive anal cancer. But this analysis agreed with prior studies showing that while immune suppression increases the risk of anal cancer, rates have not fallen since the introduction of combination ART, presumably because prolonged survival allows more time for cancer to develop. In this study, the rate of in situ anal cancer increased by 61% between 1990-1995 and 1996-2004, while the rate of invasive anal cancer rose by 104%.

Looking at HIV positive people rather than those with AIDS, Nancy Crum-Cianflone and colleagues also found that anal cancer rates have increased in the ART era. As reported at IAS (abstract WEAB101), the investigators assessed incidence of and risk factors for anal squamous cell carcinoma among 4,901 HIV positive individuals (more than 90% men) receiving care at military medical facilities. The anal cancer incidence rate increased five-fold from the pre-ART to the ART era, from 11 to 55 cases per 100,000 PY. The rate continued to rise, reaching 128 per 100,000 PY in 2006-2008. By comparison, the incidence of anal cancer among the general population is only about 1.5 cases per 100,000 PY.

Of the 20 people who developed anal cancer in this study, three-quarters were on combination ART, about 40% had HIV viral load below 400 copies/mL, and the median current CD4 count was 375 cells/mm3, although the nadir (lowest-ever) level was considerably lower. Crum-Cianflone suggested that "low-level chronic immunosuppression, which is not completely corrected by HAART, is driving these cancers."

In more encouraging news, a study reported in the August 15, 2009, issue of Alimentary Pharmacology and Therapeutics showed that HIV positive people with anal cancer can be treated according to standards of care for HIV negative patients and can achieve equally good results. This retrospective analysis compared long-term outcomes among 44 HIV positive and 107 HIV negative patients at six French hospitals between 1998 and 2004. After radiation and chemotherapy, similar proportions of HIV positive and negative people experienced severe (grade 3-4) toxicities. Likewise, similar percentages achieved a complete response to treatment (82% vs 75%, respectively). After three years of follow-up, survival rates were 85% and 84%, respectively. Among the HIV positive patients, duration of HIV infection, viral load, and CD4 cell count had no effect on survival.

In contrast with Chaturvedi's findings regarding invasive anal cancer, most studies have not shown an increased incidence of invasive cervical cancer among women with HIV in the ART era, which experts have attributed to the fact that women -- both HIV positive and negative -- are advised to receive regular Pap smears to detect cervical cancer at an early, treatable stage. A recent study in the August 1, 2009, Journal of Acquired Immune Deficiency Syndromes, however, found that nearly 25% of HIV positive women do not receive recommended annual Pap screenings.

Unlike cervical screening, anal Pap tests are not considered part of the standard of care for people with HIV, although many experts believe they should be. HPV vaccines such as Gardasil and Cervarix, which are currently recommended only for young women, have been shown to be protective against precancerous cell changes in HIV negative young men, and are currently being tested in men with HIV.


Male Circumcision for HIV Prevention

Two large trials in Africa previously demonstrated that adult male circumcision reduced the risk of HIV infection among young heterosexual men by as much as 60%. The procedure also offers some protection against herpes simplex virus type 2 (HSV-2) and HPV, according to a study published in the March 26, 2009, New England Journal of Medicine.

Aaron Tobian and colleagues evaluated more than 5,000 initially HIV negative men aged 15-49 in two circumcision trials in Rakai, Uganda. Participants were randomly assigned to undergo circumcision immediately or after a two-year waiting period. About one-third of the men tested positive for HSV-2 at enrollment. After two years of follow-up, 7.8% of initially uninfected men in the immediate circumcision group and 10.3% in the uncircumcised group had acquired HSV-2. After adjusting for other factors, circumcision was associated with a 28% reduction in risk of HSV-2 infection, reflecting a significant protective effect. The effect was even greater -- a risk reduction of about 35% -- for high-risk and low-risk HPV types. No protective effect was seen, however, for syphilis.

"In addition to decreasing the incidence of HIV infection, male circumcision significantly reduced the incidence of HSV-2 infection and the prevalence of HPV infection, findings that underscore the potential public health benefits of the procedure," the investigators concluded. Given that both HSV-2 and HPV have been linked to increased incidence of HIV, reducing the likelihood of these infections may contribute to the protective effect of circumcision against HIV infection.

But the public health benefits do not extend to circumcised men's female partners, researchers reported in the July 18, 2009, issue of The Lancet. This study team looked at 922 men in one of the Rakai circumcision trials and 167 of their initially HIV negative female partners enrolled in a companion study. The companion trial was stopped early due to "futility," after interim results showed that circumcision had no protective effect for the women.

In a modified intent-to-treat analysis, 18% of women whose partners were in the immediate circumcision group and 12% with partners in the deferred circumcision group became infected with HIV during follow-up (not a statistically significant difference). At 24 months, the cumulative probability of HIV infection was 21.7% for women whose partners were circumcised immediately compared with 13.4% for women with uncircumcised partners. While the difference did not reach statistical significance, and therefore could have been due to chance, previous research has suggested that women may be at increased risk for HIV infection if couples resume having sex before the circumcision wound is completely healed. The researchers concluded that "condom use after male circumcision is essential for HIV prevention," which may contradict one of the primary motives for adult circumcision.

The benefits of circumcision in preventing HIV transmission among MSM -- who still account for the largest proportion of new infections in industrialized countries -- remains unclear. At the IAS meeting, investigators with the Soweto Men's Study presented findings from a study of 378 MSM with an overall HIV prevalence rate of 13.2% (abstract MOPDC105). Among men who reported engaging exclusively in insertive anal intercourse with other men (about 76% of the cohort), uncircumcised men had about a 4.5-times higher risk of HIV infection compared with circumcised men.

In contrast, a recent U.S. study presented at the National HIV Prevention Conference in August did not observe a similar protective effect. Researchers with the CDC evaluated data from about 5,000 men who reported anal sex with an HIV positive partner, and found that the likelihood of becoming infected was about 3.5%, a risk that did not differ significantly according to circumcision status. The investigators concluded that circumcision "is not considered beneficial" for preventing sexual transmission of HIV among MSM.

These contradictory findings contribute to the ongoing debate about whether circumcision is warranted as a public health measure in the U.S. The World Health Organization and UNAIDS recommend circumcision as part of a comprehensive prevention program in developing countries with a high HIV prevalence. The CDC is currently considering whether to recommend routine infant circumcision. About 60% of baby boys now undergo the procedure (down from about 85% in the mid-1960s), which is not currently recommended by the American Academy of Pediatrics. Proponents point to the protective effect against HIV as demonstrated in Africa, while opponents argue against medically unnecessary surgery for protection that can be achieved by using condoms.


HIV Positive Visitor Restrictions Slated to End

In late June, the federal government issued a proposed policy change intended to remove the current controversial restrictions on HIV positive visitors and immigrants seeking to enter the U.S. In the late 1980s, Congress declared HIV to be a "communicable disease of public health significance" that can be used to exclude HIV positive foreign nationals. Under the current policy, people with HIV who wish to visit the country are required to disclose their status and obtain a special waiver.

Last year's legislation reauthorizing the President's Emergency Plan for AIDS Relief (PEPFAR) removed the statutory ban and returned the authority to determine whether HIV belongs on the list of excludable diseases to the Secretary of Health and Human Services. This past summer, DHHS laid out a proposed new policy, the Office of Management and Budget reviewed and approved the plan, and the change was published in the Federal Register for a 45-day public comment period.

"While HIV infection is a serious health condition, it does not represent a communicable disease that is a significant threat for introduction, transmission, and spread to the U.S. population through casual contact," the proposed policy states. "An arriving alien with HIV infection does not pose a public health risk to the general population through casual contact. As a result of these proposed regulatory changes, aliens would no longer be inadmissible into the United States based solely on the grounds they are infected with HIV."

"Today we are one step closer to ending a discriminatory practice that stigmatizes those living with HIV, squanders our moral authority, and sets us back in the fight against AIDS," Senator John Kerry (D-Mass.) argued in support of the change. "By proposing this rule, the Obama administration has made a powerful statement in favor of overturning the HIV travel and immigration ban that has no foundation in public health or common sense."

The public comment period ended in late August, and advocates have expressed hope that the ban will be lifted by the end of the year. In late September, the U.S. Citizenship and Immigration Services instructed officers to place a hold on green card applications subject to denial due to HIV status. The International AIDS Society has indicated that if the restrictions are repealed, the organization will consider holding its 2012 International AIDS Conference in the U.S., for the first time since 1990.


Fate of Needle Exchange Funding Ban Unclear

In July, Democrats in the House of Representatives proposed a change to a Labor and Health and Human Services appropriations bill that would end the long-standing ban on federal funding for needle exchange. Instituted in the late 1980s, the ban prohibits state and local governments and organizations from spending any funds received from the federal government to provide clean needles to injection drug users.

The policy has been retained for two decades by means of a clause in appropriations legislation, despite the fact that needle exchange has proven effective in reducing transmission of HIV and hepatitis B and C. "Scientific studies have documented that needle exchange programs, when implemented as part of a comprehensive prevention strategy, are an effective public health intervention for reducing infections and do not promote drug use," said House Appropriations Committee Chair David Obey (D-Wis.).

Democrats on the Labor, Health, and Human Services subcommittee removed the relevant clause from the spending bill for fiscal year 2010. Republican House members did not succeed in amending the bill to retain the overall ban, but did introduce an amendment that would continue to ban funding for needle exchange or distribution within 1,000 feet of a day care center, elementary or secondary school, college or university, public swimming pool, park, playground, video arcade, or youth center. Advocates noted that in most large cities there would be few, if any, locations that do not fall within these restrictions. The Senate had not yet voted on the bill as BETA went to press, and the amendment could be removed or changed before the legislation goes to President Obama for a final signature.

Liz Highleyman (liz@black-rose.com) is a freelance medical writer and editor based in San Francisco.

Want to read more articles in the Summer/Fall 2009 issue of Bulletin of Experimental Treatments for AIDS? Click here.



  
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This article was provided by San Francisco AIDS Foundation. It is a part of the publication Bulletin of Experimental Treatments for AIDS. Visit San Francisco AIDS Foundation's Web site to find out more about their activities, publications and services.
 
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