Call for Improving System of Patient Access to Investigational Drugs

I was part of this meeting and was very happy with the outcome. I hope the FDA and pharma listen to us. Representatives from the FDA, industry (Merck, Pfizer, Tibotec, Panacos and BI) , physician groups, Kaiser Permanente, researchers, and others were part of the discussion.

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HIV Research Group Calls for Improving System of Patient Access to Investigational Drugs

With the first agents from 2 new classes of antiretroviral drugs poised to receive regulatory approval this year, the Forum for Collaborative HIV Research, an independent advocacy group, has called for reassessment of the way investigational new drugs are made available to patients in need.

Below is the text of the group’s June 14 press release:

HIV Research Group Calls for Improving System of Patient Access to Cutting-Edge Investigational HIV Drugs

With New Treatments in the Pipeline, Scientists, Industry, Patient Groups Say Change is Needed if All are to Benefit

WASHINGTON, DC (June 14, 2007) — With at least three promising new HIV drugs in development, radical reform is needed of “expanded access programs” that allow patients to take new drugs before final federal approval.

Such programs can be critically important to HIV patients who no longer respond to current treatments. However, the system for providing access to experimental drugs is fragmented and under-funded, and discourages academic health centers and private physicians from participating, according to a report released today by the Forum for Collaborative HIV Research, an independent public-private partnership comprised of academic researchers, patient advocates, government officials and industry representatives.

The report reviews these problems and recommends guidelines for fixing the system, including a recommendation that drug companies consider reimbursing health care providers for Expanded Access Program (EAP) costs.

“The goal of expanded access programs is to make promising drugs in the late stages of clinical trials available to patients who urgently need treatment and have exhausted all currently approved therapies,” said Ben Cheng, Deputy Director of the Forum. “Unfortunately, the current mechanism for early access to these promising drugs serves neither patients, companies, nor regulators.”

The United States lacks data regarding the extent to which patients have run out of treatment options, but one estimate in the report suggests that as many as 13 percent of HIV patients have run out of treatment options. EAPs have provided critical medical options for such patients since the early years of HIV treatment, when HIV activists first pressed the Food and Drug Administration [FDA] for such options. But today EAPs are riddled with problems, according to the report, “Rethinking the Approach to Expanded Access Programs.”

Among the main problems, EAPs are:

• Expensive to administer, limiting the ability of many healthcare sites to participate, as they must cover such costs themselves. The costs of administration are currently not reimbursed by drug companies, though they are when drugs are provided to patients in clinical trials.• Poorly advertised;• Usually dependent on only one novel drug in treating patients. Though policies may recommend using at least two active therapies, many patients are resistant to the other drugs that are available. This can lead to virtual monotherapy, and to the risk of developing resistance to the new treatment.• Relatively inaccessible to minorities, women and rural residents;

• Failing to take advantage on a valuable opportunity to gather useful safety data on emerging drugs.

The associated expenses and administrative obstacles can be particularly onerous at academic medical centers, where financial and bureaucratic hurdles are greater than in private practices or community-based clinics.

As a result, many academic centers have opted out of participation in EAPs. But treatment opportunities offered by the emergence of simultaneous EAPs for three new drugs (raltegravir [Isentress, formerly MK-0518], etravirine [TMC125], and maraviroc [Celsentri]) are leading some of these institutions to reconsider their decisions so they can offer the new drugs to patients who need them.

But, according to the report, administrators warn that the programs will remain in jeopardy until reliable sources of funding are found to cover high expenses related to data collection requirements and approval processes from internal review boards.

The report is being released at a pivotal moment in the history of HIV drug development, according to its authors. There are a number of drugs in the development pipeline that offer novel approaches to treating HIV. Among these are: a new protease inhibitor, new entry inhibitor drugs that block the CCR5 receptor on immune cells, and new integrase inhibitors.
“Patients groups are particularly excited that so many new options are becoming available,” said Veronica Miller, Director of the Forum. “But it is clear that changes must be implemented to make sure that we can expand access to these new therapies as they are proven basically safe and effective.”

The report’s recommendations are based on the outcome of a recent Forum workshop, which brought together representatives of academic health centers, advocacy groups, pharmaceutical companies, and the Food and Drug Administration. It is particularly timely, given that the United States Food and Drug Administration is in the midst of revising its rules for the regulation of EAPs for other diseases.

Report Recommendations

The HIV Forum report identifies several key directions for improving the EAP system, suggesting that:

• Policymakers explore a two-tiered approach to EAPs. One would be an actual research protocol designed to answer specific questions leading to drug approval. The other would be a simplified system, with fewer data requirements. Both would be would eligible for reimbursement from drug companies, as are traditional clinical trials;

• Pharmaceutical companies work together and with regulatory agencies to design EAPs that simultaneously use several different new drugs in order to limit the use of “virtual monotherapy” and lessen the chance of developing drug-resistant strains of HIV;

• Changes be implemented to decrease the burden of paperwork, among them, standardization of EAP data collection requirements and safety reporting;• Pharmaceutical companies collaborate to standardize their case report forms and adverse events reporting for their EAPs;

• Develop a centralized electronic database, and other technological tools, to provide real-time access to analyse results, including adverse events for the EAP.

“Every time there is an adverse event, physicians have to report it,” Cheng said. “But there is no way to find out whether this is happening in five or 50 percent of patients. None of the information is being analyzed until the program is finished.”

Since EAPs were first initiated for HIV drugs in the 1980s, they have saved or prolonged the lives of thousands of HIV patients. Since 1998, however, the use of EAPs for HIV drugs has decreased, and that the size of the patient population that currently needs access to investigational antiretroviral drugs is difficult to estimate. Refining this estimate will be an important aspect of reforming EAPs, according to the study.

The Forum for Collaborative HIV Research is an independent public-private partnership whose mission is to facilitate discussion on emerging issues in HIV clinical research and the transfer of research results into care. It is comprised of international experts from government agencies, pharmaceutical companies, academia, advocacy and community organizations, and private foundations. The Forum is housed in the Department of Prevention and Community Health at The George Washington University School of Public Health and Health Services. For further information, visit: http://www.hivforum.org/ and click on “Rethinking the Approach to Expanded Access Programs

06/29/07

SourceForum for Collaborative HIV Research. HIV Research Group Calls for Improving System of Patient Access to Cutting-Edge Investigational HIV Drugs. Press release. June 14, 2007.

Anal Cancer- Can it be prevented? Lecture in Houston this Thurs June 21

Rates of anal cancer among gay and bisexual men are 35 times greater than the general population

HIV+ men and women are 80 times more likely to have anal cancer.

THE GOOD NEWS IS THAT ANAL CANCER IS POTENTIALLY PREVENTABLE AND HIGHLY CURABLE.

Come to hear Houston’s Dr. Eric Haas speak about ways to detect and treat it early.
Location: United Way at 50 Waugh Drive, Houston
Map: Map of 50 Waugh Dr Houston, TX by MapQuest

When: This Thursday, June 21, 6:30 p.m. Light dinner provided. Limited seating. RSVP to 713-520-5288

This is the first seminar of its kind on this topic in Houston which is not talked about in the community

Sponsored by: Program for Wellness Restoration(www.powerusa.org ) and the Houston Buyers Club (http://www.houstonbuyersclub.com) )

ABOUT THE SPEAKER:

Dr. Eric Haas earned his medical degree from the University of Texas Medical School at Houston, did his General Surgery Internship at the M.D. Anderson Cancer Center and completed his General Surgery Residency at St Joseph Hospital. He is board certified by both the American Board of Surgery and by the American Board of Colon and Rectal Surgery. He is the Director of Aparoscopic Colon and Rectal Surgery and has received the 2005 Chief Resident Award for most outstanding Academic Faculty for the Methodist/St. Joseph Hospital General Surgery Residency Program. In addition, Dr. Haas serves as faculty surgeon at The Methodist Hospital, St Luke’s Hospital , and Memorial Hermann Hospital. More info on (http://www.houstoncolon.com)

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More on the subject:

Bay Area doctors promote Pap tests for gay men to combat cancer

(04-21) 13:18 PDT San Francisco (AP) —
Some Bay Area doctors are promoting Pap tests for gay men to reduce rising rates of anal cancer.
U.S. cases of anal cancer have risen 37 percent in the last 10 years, compared to a 1 percent increase in overall cancer cases. Part of the increase is believed to be because of better reporting.
Anal Pap smears would help doctors detect precancerous lesions before they turn malignant, said Dr. Joel Palefsky, director of the Anal Neoplasia Clinic at the University of California, San Francisco.
“We haven’t proven it yet, but we believe that we are likely to be preventing anal cancer,” said Palefsky, who is preparing a report on anal cancer prevention.
Other doctors say there is disagreement over whether the tests are necessary or effective. The test should be left to the doctor’s and patient’s discretion, said Dr. Michael Horberg, director of HIV-AIDS for Kaiser Permanente and an HIV specialist at Kaiser Santa Clara Medical Center.
The American Cancer Society said there were about 4,660 cases of anal cancer in the United States last year, resulting in 660 deaths. Anal cancer accounts for less than 1 percent of cancer cases and is readily treatable if detected.
Overall, more women than man get anal cancer. But the disease is disproportionately high among gay men and people who are HIV-positive or have other immune-suppressive conditions.
Studies have found rates of anal cancer as high as 35 cases for every 100,000 gay men, similar to rates for cervical cancer before women began routinely getting Pap tests 60 years ago. Cervical cancer rates have dropped 70 percent since then. Both cancers are caused by the same sexually transmitted virus.
“Anal cancer is a silent issue that’s been building for at least 10 years,” said Jason Riggs, a spokesman for the Stop AIDS Project. “And it’s sad because it’s incredibly preventable.”
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Information from: San Francisco Chronicle,
www.sfgate.com/chronicle

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Cancer Rates in HIV Positive People in the HAART Era

By Liz Highleyman
Past research has yielded conflicting data on rates of cancer in HIV positive individuals since the advent of HAART. While effective therapy has reduced in incidence of some opportunistic malignancies, other types of cancer may be more common now that people with HIV are living longer.
Review of Cancer in People with HIVIn the May 2007 issue of Oncology Reports, G. Barbaro and G. Barbarini of University La Sapienza in Rome presented a review of cancer studies in the HAART era.The authors noted that the majority of cancers affecting HIV positive individuals are AIDS-defining malignancies including Kaposi’s sarcoma (KS), non-Hodgkin’s lymphoma (NHL), and invasive cervical cancer (ICC). However, they added, other types of cancer — such as Hodgkin’s disease, anal cancer, lung cancer, and testicular tumors — appear to be more common among HIV positive people compared with the general population. While not classified as AIDS-defining, these cancers have been referred to as AIDS-associated malignancies. Some experts believe invasive anal cancer, like ICC, should be considered AIDS-defining.The mechanisms by which immune suppression could increase the risk for cancer are unclear, the authors wrote, except for KS and most subtypes of NHL, which are strictly associated with low CD4 counts. Although it remains unclear whether HIV acts directly as an oncogenic (cancer-causing) agent, the virus may contribute to the development of malignancies through several mechanisms, including impaired immune surveillance and/or an imbalance between cell proliferation and differentiation. While a significant decrease in the incidence of KS has been observed with the widespread use of combination antiretroviral therapy, they continued, HAART has not had a significant impact on the incidence of NHL (particularly systemic NHL), Hodgkin’s disease, ICC, anal cancer, or other non-AIDS-defining malignancies. Barbaro and Barbarini concluded that regardless of whether these cancers are directly related to HIV-induced immunodeficiency, “treating cancer in HIV-infected patients remains a challenge because of drug interactions, compounded side effects, and the potential effect of chemotherapy on CD4 count and HIV-1 viral load.””A better knowledge of viral mechanisms of immune evasion and manipulation will provide the basis for a better management and treatment of the malignancies associated with chronic viral infections,” they added.Cancer Rates in CaliforniaCalifornia researchers presented results from a study of cancer rates among HIV positive people in the May 15th American Journal of Epidemiology. The investigators analyzed data from adults in the San Francisco AIDS surveillance registry and patients in the California Cancer Registry matched for age, sex, and race. Adjusted standardized incidence ratios (SIRs) were computed, and proportional hazards models evaluated the effect of HAART use on cancer incidence and survival time. Results
• Among 14,210 adults with AIDS diagnosed in 1990-2000, 482 non-AIDS-defining cancers were diagnosed. • Overall, the risk of developing non-AIDS-related cancers was somewhat higher among all HIV positive individuals during the HAART era (a 43% increased risk), but slightly lower for those who actually used HAART (21% reduced risk).• Compared with rates for the general population, significantly higher incidence rates were observed for:- anal cancer (SIR 13.4);- Hodgkin’s lymphoma (SIR 11.5);- liver cancer (SIR 3.6);- cancers of the mouth and throat (SIR 2.6);- respiratory tract cancers (SIR 2.6);- leukemia (SIR 2.4);- melanoma of the skin (SIR 2.4);- prostate cancer (SIR 1.7). • The risk of liver cancer was lower with HAART use (relative hazard [RH] 0.32). • The risk of anal cancer increased after 1995 (RH 2.9). • Respiratory tract cancers (RH 0.40) and Hodgkin’s lymphoma (RH 0.17) showed increased cancer survival times with HAART use.• Survival with anal cancer may have decreased slightly (RH 1.4).
ConclusionIn conclusion, the authors wrote, “The impact of HAART on non-AIDS-defining cancer incidence rates and survival is not uniform, and the mechanism(s) responsible for these differences should be investigated further.””We found that HAART use does not appear to substantially reduce the risk of non-AIDS cancers, and the impact of HAART on specific non-AIDS-defining cancer incidence rates and survival time is not uniform,” lead author Nancy Hessol told Reuters Health. “The underlying etiology for each cancer type contributes to this observed variation, along with changes in HIV and cancer treatments.”
Hessol recommended better cancer screening and prevention for people with HIV. For example, she said, “given the high rate of anal cancers in HIV-infected men who have sex with men, anal Pap testing should be encouraged for early detection and treatment of pre-cancerous and cancerous lesions.”
Department of Medicine, University of California, San Francisco, CA; AIDS Office, San Francisco Department of Public Health, San Francisco, CA; California Cancer Registry, Public Health Institute, Sacramento, CA; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA.
06/19/07
ReferencesG Barbaro and G Barbini. HIV infection and cancer in the era of highly active antiretroviral therapy (Review). Oncology Reports 17(5): 1121-1126. May 2007.NA Hessol, S Pipkin, S Schwarcz, and others. The Impact of Highly Active Antiretroviral Therapy on Non-AIDS-Defining Cancers among Adults with AIDS. American Journal of Epidemiology 165(10): 1143-1153. May 15, 2007.

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NATAP http://natap.org/
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Anal pre-cancer test for HIV-positive men

LOS ANGELES, March 22 (UPI) — A type of anal-canal Pap smear has been found to detect precancerous changes in the anal canals of HIV-positive men, a U.S. study found.The University of California at Los Angeles study found abnormal anal cytology — anal-canal Pap smear — was highly predictive of anal cell abnormalities that were subsequently confirmed by anal biopsy.The study, published in the International Journal of STD & AIDS, was based on data from 244 patients at the UCLA CARE clinic who had anal cytology screenings between February 2002 and December 2004.HIV-positive men who have sex with men are up to 90 times more likely than the general population to develop anal cancer, according to UCLA CARE clinic.The UCLA CARE Center is one of a few U.S. clinics offering anal dysplasia screening, a procedure that has not yet entered standard practice.“The prevalence, and predictive value, of abnormal anal cytology to diagnose anal dysplasia in a population of HIV-positive men who have sex with men”R D Cranston*, S D Hart- J A Gornbein , S L Hirschowitz-, G Cortina- and A A Moe§*Department of General Internal Medicine; -Department of Pathology; Department of Biomathematics;§ Department of Infectious Disease,University of California, Los Angeles, CA, USATo date, most of the information available on anal dysplasia is derived from a limited number of natural history studies. This current study reflects clinical practice in a HIV primary care setting and aims to (1) estimate the prevalence of anal cytologic abnormalities, (2) estimate the positive predictive value of anal cytology for any degree of dysplasia and for high-grade dysplasia.“…….screening for anal cytological abnormality, defining the abnormality pathologically by anal biopsy, and subsequently treating potentially premalignant lesion(s) has been proposed as a management strategy for the anal canal to prevent the progression of high-grade dysplasia to anal cancer….… detection of abnormal anal cytology is useful clinically in HIV-positive MSM to predict the presence of anal dysplasia. In this study, 96% of the samples were adequate for cytological interpretation. The majority of abnormal cytology samples showed lower grades of dysplasia while more than half of these abnormal cytology specimens had high-grade dysplasia on biopsy. Thus, any abnormality on anal cytology testing should prompt HRA follow-up to determine grade of dysplasia and allow consideration of treatment for high-grade disease.….anal cytology underestimated the degree of anal dysplasia… While only 6% of the cytology results indicated high-grade lesions or possible high0grade lesions, the researchers found, 52% of biopsy specimens were either grades 2 or 3 anal intraepithelial neoplasia……Despite the poor correlation of anal cytology with biopsy, empirically abnormal anal cytology identified subjects that were then referred for HRA and biopsy with over half of these subjects subsequently diagnosed with high-grade disease and referred for treatment….….Anal cytology grade showed poor correlation with the grade of dysplasia detected by paired HRA-directed anal biopsy. Ninety-two percent of the abnormal anal cytology was ASC-US or LSIL, however anal pathology reports showed high-grade dysplasia (anal intraepithelial neoplasia] [AIN] 2 or 3) in 52% of specimens, indicating that anal cytology underestimated the degree of anal dysplasia….Previous modalities used to treat high-grade dysplasia have included cold scalpel excision with electrofulguration that showed lower rates of treatment efficacy in an HIV-positive population.25 More recently, the use of infrared coagulation (IRC) to treat high-grade dysplasia has been associated with higher efficacy rates with reduced post procedure pain…”Summary: Due to the increasing incidence of anal cancer in HIV-positive men who have sex with men, and the potential to detect and treat high-grade anal dysplasia – the putative anal cancer precursor – we have introduced an anal cytology screening service. Patients with abnormal anal cytology have follow-up high-resolution anoscopy (HRA) with biopsy of lesions clinically suspicious for high-grade dysplasia. In total, 244 men were screened and 235 (96%) of the samples were adequate for cytological interpretation using the Bethesda 2001 system. One hundred and sixty-four (67%) men had abnormal anal cytology, and 93 of them had follow-up HRA and anal biopsy. The positive predictive value for any anal cytological abnormality to predict any degree of anal dysplasia was 95.772.1%, and for any anal cytological abnormality to predict high-grade anal dysplasia was 55.975.1%. Abnormal anal cytology was highly predicative of anal dysplasia on biopsy.INTRODUCTIONAnal cancer is a rare malignancy accounting for only 1.5% of all gastrointestinal tumours.1 However, in certain groups, the incidence of anal cancer is increased in comparison to the general population. Prior to the HIV pandemic, the incidence of anal cancer in men who have sex with men (MSM) who practice receptive analintercourse (RAI) was approximately 35 per 100,000,2 equivalent to the incidence rate of cervical cancer prior to the introduction of cervical cytology screening in developed countries. Currently, the incidence of anal cancer in HIV-positive MSM is estimated to be between 70 and 80 per 100,000 based on studies in both Europe and the USA.3,4The anal and cervical canal share a common embryological origin, are classified cytologically using the same 2001 Bethesda system, and both develop dysplasia in association with anogenital human papillomavirus (HPV) infection.5 HPV can be grouped phenotypically into high-risk and low-risk HPV related to its association with cervical cancer.6 High-risk HPV, most commonly HPV 16 or 18, is present in almost 100% of anal and cervical cancers,7,8 and is now considered essential for the development of cervical cancer in association with co-factors such as cigarette smoking.9The presence of either HPV or anal dysplasia, unlike other HIV-related infections or tumours, does not appear to be significantly influenced by the introduction of highly active antiretroviral therapy (HAART).10,11 Moreover, reports from San Diego and San Francisco Counties have shown that the incidence of anal cancer in these regions has increased from the pre- to the post-HAART era.12,13 While it is unlikely that HAART therapy per se increases the risk of anal dysplasia and anal cancer, this finding may be explained by the fact that individuals with HIV infection taking HAART are living longer and allowing the anal canal to have prolonged exposure to oncogenic HPV in the context of relative immunosuppression.14 In addition, there is in vitro evidence that HIV tat protein interacts with the HPV genome to increase oncoproteinexpression that leads to chromosomal dysregulation and the potential of malignant cellulartransformation.15,16Using the cervical paradigm, screening for anal cytological abnormality, defining the abnormality pathologically by anal biopsy, and subsequently treating potentially premalignant lesion(s) has been proposed as a management strategy for the anal canal to prevent the progression of high-grade dysplasia to anal cancer. Anal cytology screening has similar sensitivity to cervical cytology screening in HIV-positive MSM to detect the presence of dysplastic cells.17,18 Liquid-based cytology collection methods are increasingly being used for the cervix, and have the advantage that remnant liquid fixative may be tested for HPV, as occurs in the triage of cervical samples that show atypical squamous cells of undetermined significance (ASC-US). The liquid cytology method may additionally abrogate potential problems associated with hypocelluarity, air drying artefact and faecal contamination in anal samples.17,19 While no national or international guidelines exist for anal cytology screening, investigators from the largest natural history study at the University of California, San Francisco, have suggested the following screening algorithm in MSM:– Normal anal cytology is repeated in one year in an HIV-positive population and in two to three years in an HIV-negative population. — All abnormal anal cytology is referred for high-resolution anoscopy (HRA). At HRA a biopsy is taken of any lesion(s) suspicious for dysplasia based on standard colposcopic criteria.20 If no dysplasia is identified, the individual has routine anal cytology screening as above. Using this system, the aim of anal cytology testing is to detect either normal or abnormal results, as previous studies have shown that anal cytology grade is poorly predictive of anal dysplasia grade following HRA and biopsy, and should not be relied upon without histological confirmation.21 — Low-grade dysplasia on biopsy is followed up at six-monthly intervals with HRA due to the high rate of progression from low-grade to high-grade dysplasia.22 — High-grade dysplasia on biopsy is treated, or followed-up depending on the size of the lesion.To date, most of the information available on anal dysplasia is derived from a limited number of natural history studies. This current study reflects clinical practice in a HIV primary care setting and aims to (1) estimate the prevalence of anal cytologic abnormalities, (2) estimate the positive predictive value of anal cytology for any degree of dysplasia and for high-grade dysplasia.METHODSSubjectsAll subjects in this clinical study were MSM who attend the University of California Los Angeles (UCLA) Center for AIDS Research and Education (CARE) clinic. Anal cytology specimens were collected sequentially at the discretion of the treating clinician.Anal cytology collectionPrimary care physicians received anal cytology collection training. The cytology specimens were taken using a water-moistened Dacront swab and ThinPrept collection method with the patient in the left lateral position. The Dacront swab was introduced two inches beyond the anal margin, and removed with lateral pressure and a spiral motion over 10 seconds. After removal, the swab was immediately immersed and agitated in ThinPrept solution to disgorge the cells. Anal cytology samples were read by a UCLA cytopathologist and reported as ASC-US, atypical squamous cells cannot rule out high-grade (ASC-H), lowgradesquamous intraepithelial lesions (LSIL), or highgrade squamous intraepithelial lesions (HSIL) using Bethesda 2001 terminology.5High-resolution anoscopyOne practitioner performed all HRA exams. All patients with abnormal anal cytology were referred for further evaluation using HRA. This procedure uses a high-resolution anoscope (colposcope) set at 16 magnification to examine the peri-anal area and anal canal after the application of 3% acetic acid.23 The acetic acid causes acetowhitening of dysplastic anal epithelium similar to the effect on cervical squamous epithelium. Cervical colposcopic features of high-grade dysplasia such as coarse punctuation and mosiacism have been shown to similarly indicate high-grade disease in the anal canal.20 Abnormal acetowhite epithelium was biopsied using disposable Trilobites (ESCO medical Instruments, Stony Brook, NY, USA) endoscopic forceps with a 2.3mm non-serrated cup. The biopsy specimens were immediately fixed in 10% formalin. Haemostasis was achieved with Monsell’s solution prior to the end of the procedure.Biopsies were processed using standard paraffin processing and read following staining with haematoxylin and eosin.Statistical analysisBiopsy results are used as the gold standard in the statistical analysis. Since biopsies were performed only for patients with non-negative cytology, estimates of sensitivity, specificity or likelihood ratios based on sensitivity and specificity using this data are biased and uninformative. Negative predictive values (NPV) also cannot be computed since no negative patients were biopsied. The positive predictive value (PPV) is computed using those with AIN 1, 2 or 3 biopsy results as true positives and is also computed using only AIN 2 or 3 as true positive. The weighted kappa statistic is computed as a measure of agreement beyond chance between the ordered cytology versus biopsy results and the Spearman rank correlation (rs) is computed as a measure of association between the ordinal cytology versus biopsy results. Computations were carried out using StatXact version 5.0 (Cytel Software Inc., Cambridge, MA, USA). Results are reported as estimate7standard error.RESULTSA total of 244 patients had anal cytology screening between February 2002 and December 2004. The average age of patients was 44.1 years (range of 22-71 years), and ethnic breakdown was African American 8% (19), Asian 4% (9), Caucasian 72% (176), and Latino 16% (39) and Others 0% (1) – consistent with the general clinic population. The mean CD4 count at screening cytology was 457 cells per mm3 (range 1-1408 cells/mm3).Twenty-nine percent (71) of patients had normal anal cytology, 67% (164) had abnormal anal cytology and 4% (9) of samples were unsatisfactory for interpretation due to hypocellularity (5), bacterial excess (2) and a predominance of anucleated squames (2). Abnormal cytology was reported as — ASC-US in 48% (78) (atypical squamous cells of undetermined significance)– ASC-H in 3% (5) (atypical squamous cells-high grade)– LSIL in 46% (76) ( low-grade squamous intraepithelial lesions)– HSIL in 3% (5) (high-grade squamous intraepithelial lesions)Of the 166 patients with abnormal anal cytology, 93 had follow-up HRA and anal biopsy (Table 2). Patients who did not have HRA had either elected not to have the procedure or have yet to make an appointment.Anal cytology grade showed poor correlation with the grade of dysplasia detected by paired HRA-directed anal biopsy. Ninety-two percent of the abnormal anal cytology was ASC-US or LSIL, however anal pathology reports showed high-grade dysplasia (anal intraepithelial neoplasia] [AIN] 2 or 3) in 52% of specimens, indicating that anal cytology underestimated the degree of anal dysplasia. The weighted kappa statistic is 0.0370.06 (P1/40.6337) and the Spearman correlation is rs1/40.05670.106 (P1/40.5956),confirming poor agreement and correlation within the group of positive tests.The PPV for any grade of anal cytological abnormality to predict any grade of anal dysplasia (AIN 1, 2 or 3) on biopsy was 95.772.1%. The PPV for any grade of anal dysplasia to predict high-grade anal dysplasia (AIN 2 or 3) on biopsy was 55.975.1%.No significant adverse events such as infection, haemorrhage or pain uncontrolled with simple analgesia were reported in the study.DISCUSSIONThe clinicians in this study received one short training session on how to take an adequate anal cytology specimen and were able to collect adequate anal cytology samples in the majority of cases similar to a previous study.24 However, compared with previous studies, the grade of cytology was predominantly ASC-US and LSIL with fewer samples showing HSIL.21 This may have been due to the technique employed by the sampling clinicians or may reflect cytopathological reporting. Assuming this result is more likely to reflect anal cytological sampling technique, repeating sampling technique instruction may have resulted in specimens that more closely reflect the anal cellular environment.This study corroborates the poor correlation between the cytological grade of anal dysplasia and the histopathological examination of matched anal biopsy collected during HRA.21 As no patients with normal anal cytology were referred for HRA, sensitivity, specificity or NPV could not be reported for this population. However, given the high- PPVs of abnormal anal cytology to detect any grade of anal dysplasia, clinicians may be confident that an abnormal cytology result is likely to indicate the presence of some grade of anal dysplasia.Despite the poor correlation of anal cytology with biopsy, empirically abnormal anal cytology identified subjects that were then referred for HRA and biopsy with over half of these subjects subsequently diagnosed with high-grade disease and referred for treatment. Previous modalities used to treat high-grade dysplasia have included cold scalpel excision with electrofulguration that showed lower rates of treatment efficacy in an HIV-positive population.25 More recently, the use of infrared coagulation (IRC) to treat high-grade dysplasia has been associated with higher efficacy rates with reduced post procedure pain.26 This device is used in an outpatient setting and delivers infra red light in aliquots of 0.5-3 second intervals (1.5 seconds for anal dysplasia) to previously anesthetized anal epithelium producing a focal shallow burn that reflects the time setting in mm, i.e. setting the IRC at 1.5 seconds will deliver a burn depth of 1.5mm26,27 Early clinical reports indicate efficacy (with follow-up biopsies showing normal or low-grade dysplasia) of 72% at six months.27If referral for HRA is not available, patients with abnormal anal cytology should be informed about the risk of progression to anal cancer particularly with high-grade cytology results. Additionally, they should be made aware of common presenting symptoms of anal cancer such as pain, bleeding and the presence of a mass that would allow early investigation and referral for treatment.The result of this study is likely to be reflective of other HIV primary care settings in the USA that have a predominance of Caucasian MSM over the age of 40 years. Thus, these clinics may also have a high burden of undiagnosed anal dysplasia.In conclusion, detection of abnormal anal cytology is useful clinically in HIV-positive MSM to predict the presence of anal dysplasia. In this study, 96% of the samples were adequate for cytological interpretation. The majority of abnormal cytology samples showed lower grades of dysplasia while more than half of these abnormal cytology specimens had high-grade dysplasia on biopsy. Thus, any abnormality on anal cytology testing should prompt HRA follow-up to determine grade of dysplasia and allow consideration of treatment for high-grade disease.

NEW HIV DRUGS AND THEIR STUDIES- COMMENTS FROM RESPECTED DOCTORS

THIS GREAT INFORMATION WAS PROVIDED BY CLINICAL CARE OPTIONS. THESE ARE COMMENTS ABOUT CLINICAL STUDY DESIGN ISSUES THAT I FOLLOW VERY CLOSELY AS AN ACTIVIST. IT IS VERY INTERESTING TO ME HOW SOME COMPANIES CHOSE TO SHOW THEIR DATA AND HURRY THEIR STUDY ENROLLMENT AT THE EXPENSE OF PATIENT VOLUNTEERS.

THE NEXT HIV DRUG TO BE APPROVED : MARAVIROC – COMMENTS FROM Daniel R. Kuritzkes, MD ABOUT MOTIVATE 1/2 STUDIES AND PFIZER’S EXCLUSION OF FUZEON DATA IN ITS ANALYSIS…

One interesting aspect of this study was that there was no discernable increase in the rate of virologic suppression among maraviroc patients who also received enfuvirtide. This contrasts with data from the A4001029 study, which evaluated the use of maraviroc in patients with dual/mixed-tropic virus; in this study, a similar reduction in HIV-1 RNA was observed with maraviroc vs placebo, but there was a slightly greater reduction in HIV-1 RNA when enfuvirtide was coadministered with maraviroc

One possible interpretation of why enfuvirtide had no discernable benefit in the MOTIVATE studies is that the background regimen may already have been so potent that the use of enfuvirtide did not result in any additional HIV-1 RNA reduction. Moreover, the virologic response data did not differentiate between enfuvirtide recipients who were using enfuvirtide for the first time from those with previous enfuvirtide experience. Overall, approximately 60% of the study population was enfuvirtide naive at baseline, and 40% was enfuvirtide experienced. This suggests that perhaps one fourth to one third of the patients initiated enfuvirtide for the first time with maraviroc; this may be too small a proportion to have a discernable impact in the subgroup analysis.

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THE NEXT DRUG TO BE APPROVED AFTER MARAVIROC: MK 518 (RALTEGRAVIR, MERCK’S INTEGRASE INHIBITOR) – COMMENTS FROM Daniel R. Kuritzkes, MD ABOUT THE BENCHMRK STUDY AND ITS OBR (OPTIMIZED BACKGROUND THERAPY)

Baseline resistance scores showed that approximately two thirds of patients had a genotypic susceptibility score of either 0 or 1 for the background regimen. It is worth noting that patients were considered to be resistant to a drug if the fold-change in susceptibility to that drug exceeded the lower cutoff in the phenotypic assay. The lower cutoff marks the transition between full activity and reduced activity, rather than no activity, so drugs that had partial activity could have been assigned a score of 0; in other words, the phenotypic susceptibility scores could have slightly underestimated the activity of the OBR. Approximately 20% of patients were naive to enfuvirtide at study entry; in the case that enfuvirtide was used in a previously enfuvirtide-naive patient, a score of 1 was assigned to the phenotypic susceptibility score. Phenotypic susceptibility testing for darunavir was not available at the study outset, so darunavir was also assigned an activity score of 1 when administered to a patient who had previously been darunavir naive; this approach may have overestimated the activity of darunavir in some patients. Approximately 25% of patients in BENCHMRK‑1 and nearly 50% in BENCHMRK‑2 were darunavir naive and received darunavir as part of their OBR; this is probably the major difference between the trials.

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COMMENTS ABOUT GILEAD’S INTEGRASE INHIBITOR (ELVITEGRAVIR) STUDY AND ITS HURRIED IMPLEMENTATION THAT EXPOSED PATIENTS TO VIRTUAL MONOTHERAPY

Daniel R. Kuritzkes, MD:I agree that the failure kinetics of elvitegravir appear to resemble that of lamivudine or an NNRTI, with which a single-point mutation confers resistance and is associated with rapid viral rebound, whereas failure with raltegravir appears similar to failure with a PI, that is, resistance requires mutations at multiple loci and rebound is more gradual. Whether similar failure kinetics would have been observed with raltegravir if PIs had been excluded from the BENCHMRK studies is a matter of speculation.

Development of elvitegravir has been complicated somewhat by the fact that it has many drug-drug interactions. The manufacturer had to decide whether to elucidate all those interactions first, so that studies could allow the concomitant use of as many other drugs as possible, or to proceed with studies more rapidly but restrict the drugs that could be combined with elvitegravir. The consequences of choosing the latter approach was that in this treatment-experienced patient population, there were insufficient drugs available to provide an effective background regimen to support the integrase inhibitor. Most patients received NRTIs only, and approximately one half of them contributed no activity, meaning that those patients received de facto monotherapy with elvitegravir.

Joseph J. Eron, Jr, MD:Although I agree about the limitations of the current study, the goal of a phase IIb study is to identify the best dose to take forward into phase III development, and it does seems likely that the right dose of elvitegravir was identified.

Daniel R. Kuritzkes, MD:You are correct. However, if the investigators had chosen to perform a 14‑day study of different doses in treatment‑experienced patients, they might have come up with the same result. Unfortunately, the patients who received up to 16 weeks of treatment with the lowest dose (20 mg) before that arm was discontinued—as well as the patients who experienced virologic failure in the other arms because of the lack of an effective OBR—are now likely resistant to this integrase inhibitor and may or may not be cross‑resistant to other drugs in the class. The challenge for all investigational drugs is how to generate the key data that are essential for drug development while minimizing the risk to the patients enrolled in early studies.

Joseph J. Eron, Jr, MD:I agree. Patients in the elvitegravir study had an even higher median CD4+ cell count than those in the maraviroc and raltegravir trials, so most were not in urgent need of a new regimen, yet some of these patients may now have restricted future options because they received elvitegravir combined with NRTIs only.

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COMMENTS ABOUT RELPIVIRINE (TMC 278- A NON NUCLEOSIDE) FROM TIBOTEC:

William G. Powderly, MD:The lipid data from this study were intriguing. Results in the efavirenz arm were as expected: a mean 31 mg/dL (0.80 mmol/L) increase in total cholesterol, a 16 mg/dL (0.41 mmol/L) increase in low density lipoprotein (LDL) cholesterol, and a 12 mg/dL (0.31 mmol/L) increase in high density lipoprotein (HDL) cholesterol. Triglyceride levels also increased in the efavirenz arm by a mean of 18 mg/dL (0.20 mmol/L). By contrast, there were virtually no significant lipid changes in the rilpivirine arms: a 5 mg/dL (0.13 mmol/L) median increase in total cholesterol, no change in LDL cholesterol, a 5 mg/dL (0.13 mmol/L) increase in HDL cholesterol, and a 10 mg/dL (0.11 mmol/L) decrease in triglycerides. This is a potential advantage to rilpivirine over efavirenz, although it is not clear how these changes might translate into differences in cardiovascular risk, since the larger increase in HDL cholesterol in the efavirenz arm might counterbalance the larger increase in LDL cholesterol and triglycerides also seen in that arm.

This is the second time that a study of a novel agent in treatment-naive patients has demonstrated fewer lipid effects than efavirenz. The first was a phase II study in which raltegravir was associated with significantly smaller changes in cholesterol and triglycerides than those observed with efavirenz (P < .05 for 200-mg, 400-mg, and 600-mg doses of raltegravir) . This type of result challenges the notion that a proportion of the lipid changes observed in treatment-naive patients who start antiretroviral therapy represent a “return to normal” in the form of a reversal of the effects of unchecked HIV replication. The results of these studies question that hypothesis and raise the possibility that lipid changes may indeed be a form of drug toxicity in the majority of patients. ******************************************************** COMMENTS ABOUT THE X4 INHIBITOR AMD 11070:

Daniel R. Kuritzkes, MD: There were very few reports on agents in the early stages of development. Two pilot studies of AMD 11070, a CXCR4 inhibitor, were presented at this meeting. The ACTG 5210 trial was an open-label dose-escalating 10-day monotherapy study in patients who had been off therapy for ≥ 14 days and who had X4 or dual/mixed virus detected 18] A total of 6 patients in the first cohort were treated with AMD 11070 200 mg every 12 hours for 10 days (20 doses). Three of the 6 patients had ≥ 1 log10 reduction in the X4 virus population by Day 10 as measured by luciferase assay. Five of the 6 subjects had dual/mixed virus at Day 10, and the sixth had R5 virus. However, none of the patients experienced a ≥ 1 log10 copies/mL reduction in HIV-1 RNA.

The XACT study had similar results. This was a 10-day monotherapy study in treatment-naive and treatment-experienced patients with X4 virus detected (N = 10; 8 received 200 mg twice daily and 2 received 100 mg twice daily). One patient was unevaluable based on discrepancies in tropism assay results. Four of the remaining 9 patients had ≥ 1 log10 reduction in the X4 virus population by luciferase assay by Day 10, and 3 of these 4 had only R5 virus detected at Day 10. However, there were no changes in HIV-1 RNA or CD4+ cell count among the 4 responders.

The fact that reduction in X4 virus was not associated with an overall reduction in HIV-1 RNA would present a huge challenge for subsequent development of an X4 inhibitor because one is unable to demonstrate an impact on what are considered traditional endpoints—decrease in HIV-1 RNA and increase in CD4+ cell count. Development of AMD 11070 is now on hold because of serious toxicity demonstrated in animal models.

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COMMENTS ABOUT RACIVIR

Joseph J. Eron, Jr, MD: Clinical data were also presented on racivir, a racemic mixture of enantiomers of an emtricitabine-like molecule.[20] In this study, patients failing therapy with M184V on a lamivudine-containing regimen were randomized 2 to 1 to substitute racivir for lamivudine (n = 26) or continue lamivudine (n = 16) in a double-blind fashion. Among those receiving racivir, the mean HIV-1 RNA change after 28 days was a decrease of 0.4 log10 copies/mL, whereas those on lamivudine experienced a 0.13 log10 copies/mL increase (P = .0004). In a subgroup analysis of patients with M184V < 3 thymidine analogue mutations with or without NNRTI or PI mutations (n = 14), the HIV-1 RNA decreased 0.7 log10 copies/mL over same period (P = .0002) The lack of clinical data on drugs at early stages of development highlights an important concern. Within the next year, 3 new drugs may be approved. However, in the next few years beyond that, very few new drugs are likely to become available. Those that do become approved will most likely be second or third in class and therefore more likely to be of incremental benefit, as opposed to the potentially dramatic benefit that may be associated with the first agent in an entirely new class, to which even the most experienced patient is likely to remain fully susceptible. This underscores once again the critical importance of using the current batch of new agents optimally—in combination with other active agents and with the goal of achieving undetectable HIV-1 RNA—in the hope that today’s treatment-experienced patients can achieve durable responses.

Ziagen (Abacavir) Can Cause Anxiety in Some Patients

I have received emails in the past about people asking why they feel anxious or moody on Ziagen. This problem has happened to me and others and it is rarely discussed in the literature or in physician-patient conversations.

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In response to the persons who said they cannot sleep and feel anxious on Epzicom (Ziagen+Epivir or Abacavir+ 3TC)…

I took Ziagen and it caused horrible anxiety. I found out it was the drug when I stopped it for a week and restarted it again. The symptoms would disappear and reappear in one or two days. Several friends report the same problem. Only two reports were found in the literature. This problem has not been discussed in most HIV information sources.

More on abacavir-induced neuropsychiatric reactions:


[CORRESPONDENCE]
Foster, Russella; Taylor, Chrisb; Everall, Ian Paulc
aHIV Mental Health Team, Maudsley Hospital, London, UK; bDepartment of Sexual Health, Caldecot Centre, King’s College Hospital, London, UK; and cDepartment of Psychiatry, University of California, San Diego, La Jolla, CA 92083-0603, USA.

Received: 8 September 2004; accepted: 27 September 2004.

It is increasingly recognized that antiretroviral medications may induce severe, but transient, changes in mental state. These are uncommon and idiosyncratic, with the literature containing only two published reports suggesting that abacavir (Ziagen), a nucleoside reverse transcriptase inhibitor, may induce a range of neuropsychiatric disorders in seropositive individuals. These include depression, suicidal thoughts, auditory hallucinations [1] and frank psychosis [2]. Of note is the fact that the subjects in these cases were all female with CD4 cell counts below 500 cells/µl. Here we report, for the first time, a case of a possible abacavir-induced neuropsychiatric reaction in a seropositive Caucasian man with a higher CD4 cell count.
The patient was a 44-year-old gay man who was diagnosed HIV positive in 1993. He was referred to psychiatric services in 2000 after the psychologist whom he had been seeing became concerned about the patient’s ongoing depressive symptoms. He had previously been treated with various antidepressants and triple therapies for HIV, and was currently receiving citalopram 30 mg a day in addition to tenofovir 245 mg per day, nevirapine 200 mg twice a day and abacavir 300 mg twice a day. He had previously been taking didanosine, but this was changed to abacavir because of lipodystrophy.

Approximately one week after commencing abacavir, the patient started to complain of feeling tired and ‘stoned’. He also complained of headaches, which were described as ‘constant and throbbing’ and ‘located in the middle of my brain’. He reported the onset of bad dreams, which he referred to as ‘night terrors’. These were described as vivid and terrifying, but the actual content could not be recalled. He denied any associated physical symptoms such as night sweats or any recent physical illness. His CD4 cell count at this time was 557 cells/µl and his viral load was less than 50 copies/ml. Of note is the fact that despite his dreams he now felt that his previously low mood had improved to the extent that he was expressing the desire to cease taking citalopram.

Two weeks after reporting the above problems, the patient was reviewed by the HIV physician who changed the abacavir back to didanosine. Within 24 h of this the patient reported that his headaches and bad dreams had stopped, and that he was feeling less fatigued. At one month follow-up he remained free of these symptoms, and his mood remained settled. The citalopram was eventually reduced gradually and finally stopped.

This case suggests that abacavir may, in rare cases, induce unpleasant but non-specific neuropsychiatric side-effects, which can resolve rapidly upon stopping this medication. Although it has been suggested that abacavir may be associated with new-onset depression [1], this was not apparent in the current case. In that earlier publication [1], depression and night sweats were reported in one patient, with depression, suicidal ideation, headache, auditory hallucinations and anorexia in the second. The patients in those cases were both HIV positive Caucasian women. Similarly, a more recent publication described a case of putative abacavir-induced psychosis occurring in an African woman [2] who became symptom-free after the cessation and substitution of this medication.

The current report suggests that men can also be adversely affected by abacavir-associated neuropsychiatric problems, even at a higher CD4 cell count accompanied by a low viral load. Furthermore, symptoms may rapidly resolve upon discontinuation of abacavir and the substitution of a suitable alternative antiretroviral agent. It is possible that headache and mood alterations may be early indicators of neuropsychiatric sequelae associated with abacavir. These should be investigated and monitored closely to exclude possible organic factors. Management should be carried out in collaboration with both HIV physicians and specialist psychiatrists.

References

1. Colebunders R, Hilbrands R, De Roo A, Pelgrom J. Neuropsychiatric reaction induced by abacavir. Am J Med 2002; 113:616.
2. Foster R, Olajide D, Everall IP. Antiretroviral therapy-induced psychosis: case report and brief review of the literature. HIV Med 2003; 4:139–144. Accession Number: 00002030-200412030-00021

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Neuropsychiatric Reaction Induced by Abacavir in a Pediatric Human Immunodeficiency Virus-Infected Patient

[Departments: Letters to the Editors]

Palacin, Pere Soler MD; Aramburo, Angela; Moraga, Fernando A.; Cabañas, Maria Josep; Figueras, Concepció
Pediatric Infectious Diseases Unit, Vall d’Hebron Hospital, Barcelona, Spain(Palacin, Aramburo, Moraga, Figueras)
Pharmacy Service, Vall d’Hebron Hospital, Barcelona, Spain(Cabañas)

To the Editors:

Although most commonly reported abacavir-related side effects are mild and transient, and because of hypersensitivity reactions in the first 1 or 2 weeks after starting treatment with this drug, even severe neuropsychiatric reactions have been recently described in human immunodeficiency virus (HIV)-infected adult patients. These may include depression, suicidal thoughts, auditory hallucinations and frank psychosis. To our knowledge, there is no case described in pediatric HIV-infected population receiving abacavir (Ziagen; GlaxoSmithKline).
The patient we here describe is now an 11-year-old Caucasian boy who was found to be vertically transmitted HIV-positive at the age of 2 years. At the age of 3 years, he started taking antiretroviral drugs (zidovudine and lamivudine). He started highly active antiretroviral therapy (stavudine, lamivudine and nelfinavir) when he was 5 years old. He had been well since the present time with good virologic (plasma viral load below 50 copies/mL), immunologic (CD4% always >35%) and clinical situation (Centers for Disease Control and Prevention classification 1994 B2). The patient was admitted to the hospital at the age of 6 years because of indinavir-related nephrolithiasis. He did not present any acquired immunodeficiency syndrome-defining illness.

At the age of 11 years, his antiretroviral regimen was simplified to abacavir, lamivudine and efavirenz with the aim to change to lamivudine-abacavir when available, to reduce pill burden. One month after the initiation of this regimen, the parents referred that the patient had mood changes and complained of headaches, anxiety and bad dreams. During the following weeks, he developed major depression with refusal to attend school and to have any social interaction with both his friends and family. He was then referred to our center’s Department of Pedopsychiatry, the diagnosis of major depression was confirmed (DSM IV) and no exogenous triggering factor was observed. He then weighed 29 kg, and his height was 139 cm. No abnormalities were observed at physical examination. His CD4+ lymphocyte count was 888/mm3 (38%), and his plasma viral load was below 50 copies/mL. Neither the patient nor his parents had a history of psychiatric disorders.

Because of the coincidence of the beginning of neuropsychiatric manifestations and the start of a new antiretroviral drug (he had been taking lamivudine and efavirenz for a long period before) and the risk of abacavir-induced neuropsychiatric reactions, the drug was then discontinued and treatment was changed to stavudine. No other clinical or analytical signs of abacavir-related side effects were observed. Two weeks after the drug discontinuation, the patient began to improve without adding any antidepressive agent, bad dreams and headache disappeared and he accepted school attendance. After 3 months of follow-up, psychiatric problems did not reappear and the patient’s mood remained settled.

This case supports the idea that, as described in the adult HIV-infected population,1–3 abacavir can induce several neuropsychiatric side effects in pediatric patients that resolve rapidly when this medication is stopped. The appearance of symptoms a few weeks after starting the new antiretroviral regimen, coupled with the rapid resolution of symptoms with cessation of treatment, provides further support for abacavir as a possible cause of neuropsychiatric symptoms in our patient.

Because headache and mood alterations may be early indicators of neuropsychiatric manifestations in patients receiving abacavir or other antiretroviral drugs, these symptoms must be closely investigated. If early recognized, this situation can be easily managed by cessation of abacavir and change to other suitable antiretroviral regimen with symptomatic treatment (antipsychotics, antidepressive agents, etc) if necessary.

2Pere Soler Palacin, MD
Angela Aramburo
Fernando A. Moraga
Pediatric Infectious Diseases Unit
Maria Josep Cabañas
Pharmacy Service
Concepció Figueras
Pediatric Infectious Diseases Unit
Vall d’Hebron HospitalBarcelona, Spain

REFERENCES

1. Colebunders R, Hillbrands R, De Roo A, Pelgrom J. Neuropsychiatric reaction induced by abacavir. Am J Med. 2002;113:616.

2. Foster R, Olajide D, Everall IP. Antiretroviral therapy-induced psychosis: case report an brief report of the literature. HIV Med. 2003;4:139–144. 3. Foster R, Taylor C, Everall IP. More on abacavir-induced neuropsychiatric reactions. AIDS. 2004;18:2449.