48-Week raltegravir Data Confirm Salvage Safety, Potency, and Tolerability

Raltegravir (Isentress) is the first FDA approved medication in a new class of HIV drugs called integrase inhibitors. raltegravir is approved for use in combination with other agents in patients who have developed resistance to other antiretroviral therapy.

The efficacy and safety of raltegravir is being evaluated in two ongoing phase III, randomized, double-blind, placebo-controlled trials (BENCHMRK 1 and 2). At entry, all patients were failing treatment and demonstrated resistance to three classes of antiretroviral therapy. The 3 primary endpoints for both studies are changes in CD4 count from baseline, percentage of participants with viral load reduction to 400 copies/ml, and percentage of participants with viral load reduction to 50 copies/ml.

Interim analyses at 16 and 24 weeks demonstrated that raltegravir produced superior efficacy compared with placebo in all 3 endpoints. Approximately 75% of study participants experienced a decrease in HIV viral load to 400, and approximately 60% reached a viral load of 50. On average, CD4 counts increased by 80/mm3.

More recently, combined 48 week data from BENCHMRK 1 and 2 was presented at the 15th Conference on Retroviruses and Opportunistic Infections (CROI) (Cooper et al, poster #788). The 48 week data demonstrated that the response rates exhibited at weeks 16 and 24 have been maintained to 48 weeks. Encouragingly, this agent has shown benefit even in a significant number of patients who have low CD4 counts, highly resistant virus, and viral loads >100,000.

Of note, approximately 45% of patients who had no other active agents in the optimized background therapy (as assessed by genotype and phenotype) maintained 50 copies/ml at 48 weeks. Although this response in highly resistant patients is encouraging, every effort should still be made to utilize raltegravir in combination with at least one other fully active agent. raltegravir has been very well tolerated, on par with placebo. Thusfar, treatment with raltegravir has not lead to cross resistance to other approved antiretroviral agents.

Data was also presented at CROI regarding the substitution of raltegravir for efuvirtide (Fuzeon) in patients who have an undetectable viral load. (Harris et al, Abstr. 99). Although this study involved only 29 patients with a maximal follow-up of only 4 months, all patients maintained an undetectable HIV viral load. If confirmed by further data, this may provide a useful option for those patients who are unwilling or unable to continue with a Fuzeon based regimen.

Mascolini, Mark. 15th Conference on Retroviruses and Opportunistic Infections, Boston, February 3-6 2008.

California Governor Requests $7 Billion for Prison Health Care

In 2001, a class action law suit was brought against the State of California over the quality of medical care in the state's 33-prison system. The court found that the care was a violation of the Eighth Amendment of the U.S. Constitution, which forbids cruel and unusual punishment of the incarcerated.

The state settled the suit in 2002, agreeing to a range of remedies that would bring prison medical care in line with constitutional standards. However, the court ruled that the state failed to comply with the settlement, and therefore established a Receivership in June 2005. This Receivership has full authority to manage medical care operations in the prison system.

In his 2008/2009 budget, California Governor Arnold Schwarzenegger has requested an additional $7 billion for building and upgrading prison medical and mental health care facilities. Most of the $7 billion Schwarzenegger is requesting would be borrowed. This request is in addition to $7.4 billion in bonds voters approved last year to pay for prison and jail construction, and comes at a time that California is wrestling with a projected budget deficit of $16 billion.

"Medical facilities, when they exist at all, are in an abysmal state of disrepair. Basic medical equipment is often not available," CDCR Receiver Clarke Kelso said in a strategic plan he released last month. "Indeed, it is a misnomer to call the existing chaos a 'medical delivery system'—it is more an act of desperation than a system."

Don Thompson. Associated Press Writer; San Jose Mercury News; California Prison Health Care Receivership Corp, http://www.cprinc.org/about.htm

Trials of NIH HIV Vaccine Candidate Scaled Down After Failure of Merck Vaccine

In September 2007, Merck abruptly halted a large-scale clinical trial of its candidate HIV vaccine after initial analysis suggested that the vaccine not only failed to prevent HIV infection in participants or delay the virus’s progression to AIDS, but might have made some participants more susceptible to HIV infection. Subsequently, the NIH has announced that it will significantly scale down its trials of the PAVE-100 HIV vaccine from the original proposal.

The vaccine candidate uses a combination of the cold virus adenovirus-5 and DNA in order to stimulate cells to produce proteins that will generate an immune response against HIV. Merck researchers found that individuals who had a high baseline immunity to adenovirus-5 were at an increased risk of contracting HIV.

Anthony Fauci, director of NIH’s National Institute of Allergy and Infectious Diseases, has announced that future trials of the candidate vaccine will not include anyone who has a high immunity to the cold adenovirus-5, so as to minimize risk of HIV-infection to the trial’s participants. As part of the scale down, the trial will only include 2,000 participants from Africa and the U.S., a marked decrease from the original 8,500 planned participants. The trial will require that male participants be circumcised, a practice that has recently been found to reduce risk of HIV-infection in men.

The International AIDS Vaccine Initiative, however, has announced plans to withdraw from the planned trials. The group had intended to enroll 1,000 African participants in the trial, but has stated that the new trial is “a safety unknown” given the general lack of “clear understanding of why” the Merck vaccine candidate failed. Similarly, many researchers have questioned new HIV vaccine trials in the wake of the unanticipated failure of the Merck vaccine.

Kaiser Daily HIV/AIDS Report. Trials of NIH HIV Vaccine Candidate Scaled Down After Failure of Merck. March 25, 2008. http://www.kaisernetwork.org/Daily_reports/rep_index.cfm?DR_ID=51109

HPV in Heterosexuals, Prevalence and Factors Associated with Anal Lesions Mediated by HPV in Men with HIV/AIDS

Researchers at the University Hospital in Pemambuco, Brazil are investigating the relationship between human papillomavirus and anal lesions in men who are HIV-positive. Such co-infections with HIV and HPV are relatively widespread, as both are transmitted through sexual contact. Persons who are co-inected with these viruses stand a greater likelihood of having premalignant and malignant anogenital lesions due to HIV’s compromising effect on the immune system. While antiretroviral therapy has been effective in reducing the prevalence of opportunistic infections in persons infected with HIV, such treatment has had little effect in preventing anogenital lesions.

In response to a lack of information in this field, researchers in northern Brazil developed a study population of sixty HIV-positive men who, on average, had been living with HIV-infection for 6.8 years. Approximately 88% of the men had been on highly active antiretroviral therapy for over six years. 43.3% of the study’s participants were homosexual, while heterosexuals comprised 41.7% of the patients. The remaining 15.0% of the patients identified themselves as bisexual. Over 60% of all participants reported having had receptive anal intercourse, and all participants submitted to a series of diagnostic tests for anogenital lesions.

Anal lesions were found in 16.7% of patients according to anal cytology, 35.0% according to anoscopy under colposcopic vision, and 23.3% according to anal biopsy. Over 85% of patients with abnormal histology were homosexuals or bisexuals and 78.6% of patients with anal lesions reported having had 10 or more same-sex partners during their lifetime. Interestingly, CD4 cell count, viral load, and use of antiretroviral therapy seemed to have little impact on anal biopsy results.

The results of this study call in to question the use of anal cytology as the sole screening test for anal lesions. Researchers suggest that the screening process also include anoscopy under colposcopic vision and biopsy as a means of preventing and diagnosing anal lesions in men co-infected with HIV and HPV. While a large portion of this study’s participants were homosexual or bisexual men, it is important to note that HIV/HPV co-infected heterosexual men with no reported history of receptive anal intercourse can also be at risk for anal cancer.

HPV in Heterosexuals. Prevalence and factors associated with anal lesions mediated by human papillomavirus in men with HIV/AIDS. H R Lacerda and R R Barros. International Journal of STD & AIDS 2008;19:192-96.

Is Jail Screening Associated With a Decrease in Chlamydia Positivity among Females Seeking Health Services at Community Clinics? San Francisco, 1997-2004

San Francisco’s Jail Health Services has partnered with the Center for Disease Control and Prevention’s Epidemic Intelligence Service in order to research how chlamydia screening and treatment programs in jails would impact chlamydia positivity among females attending neighborhood medical clinics.

Although chlamydia can lead to long-term health problems in women, including infertility and pelvic inflammatory disease, the infection is generally asymptomatic and can go undetected if a patient is not tested for it. Like most sexually transmitted infections (STIs), chlamydia disproportionately infects both incarcerated persons and ethnic and racial minorities. As such, programs to screen and treat adults entering jail for chlamydia might decrease chlamydia positivity in the neighborhoods where a substantial number of persons in jail usually reside.

In order to determine the impact of chlamydia screenings in jail on neighborhoods in San Francisco, researchers compared jail screening rates by neighborhood from 1997 to 2004 to chlamydia positivity in two neighborhood health clinics. Approximately 45% of eligible males and 38% of eligible females entering jail during the eight year evaluation period were tested for chlamydia, resulting in 6.1% positivity in males and 7.3% positivity among females. Of those inmates who tested positive for chlamydia, an estimated 81% were known to have received treatment for their infection. Testing for chlamydia was conducted at health Clinics O and S among females aged 15 to 25 years. Females tested at Clinic S were predominantly black and patients tended to reside in neighborhoods with jail testing density. In contrast, only a small percent of females tested at Clinic O were black and from neighborhoods with high jail testing density.

Chlamydia positivity at Clinic S decreased significantly over the evaluation period, from 16.1% in 1997 to 7.8% in 2004. In contrast, positivity remained constant at 4.7% in patients at Clinic O.

These results demonstrate that chlamydia screening in jail can have a significant impact on chlamydia positivity in the outside community. Moreover, chlamydia screening was widely accepted amongst persons entering jail and the vast majority of those who tested positive were able to be treated, despite the short length of jail stays. This study underscores both the feasibility and importance of STI screening in jail as incarceration represents an important opportunity to test and treat at-risk populations.

Is Jail Screening Associated With a Decrease in Chlamydia Positivity among Females Seeking Health Services at Community Clinics? – San Francisco, 1997-2004. Barry, P et al. Sexually Transmitted Diseases. 2008;35(12).

Compiled by Christine Devore