New Antivirals Poised to Change the Face of HIV Infection
Dr Kirchner is Medical Director, Comprehensive Clinic for HIV, Lancaster General Hospital, Pa.
From the Conference on Retroviruses and Opportunistic Infections
LOS ANGELES—The goal of the Conference of Retroviruses and Opportunistic Infections (CROI) annual meeting is to provide a forum for translating research into medical applications. This year’s meeting was attended by more than 3800 HIV/ AIDS researchers and clinicians from around the world and included more than a dozen “late breakers.”
More than 1 Million HIV/AIDS Cases in the United States
This plenary lecture was presented by Harold Jaffe, MD, formerly of the Centers for Disease Control and Prevention (CDC) and now Professor of Public Health at the University of Oxford in the United Kingdom. Dr Jaffe noted that there have been approximately 1 million AIDS cases in the United States and more than 500,000 deaths since the epidemic began. Despite a significant decline in the AIDS death rate (that began with the introduction of combination antiretroviral therapy in 1995-1996), he said that about 17,000 AIDS deaths occurred in 2005—which is 10 times the number in the United Kingdom.
Men who have sex with men (MSM) continue to account for about one half of all new HIV infections. Case rates in black Americans are 10 times greater than in white Americans. Public health successes include a marked decline in transfusion-related infections and mother-to-child transmissions, with just 58 mother-to-child cases reported in 2005 and 47 cases in 2004.
Dr Jaffe quoted Kevin DeCock, MD, of the CDC, saying that “we cannot treat ourselves out of this epidemic,” emphasizing that proven prevention methods must be instituted. Funding priorities for HIV prevention must include what works and evaluations of what might work. Condom use is very effective in preventing both HIV and human papillomavirus transmission. Although abstinence-only education is actively promoted by the US government, a forthcoming Cochrane review of 8 randomized controlled trials (n = 13,191) did not find any reduction in self-reported sexual activity or in biological markers of pregnancy or sexually transmitted infections. Dr Jaffe notes that “public health cannot work if it wants more than what people want for themselves.” He also questioned whether we could really change human sexual behaviors significantly. Prevention leadership is greatly needed in the black and MSM communities to confront the enormous disparities in the epidemic.
New Antivirals: Maraviroc, Raltegravir
Data from ongoing clinical trials involving 2 new classes of antiviral agents were presented in late-breaking sessions.
We already know that HIV attaches to the primary CD4+ receptor as well as to 1 of 2 chemokine receptors known as CCR5 and CXCR4. Maraviroc (Pfizer) and vicriviroc (Schering-Plough), 2 small molecules that block the R5 chemokine receptor, have now been studied in phase 2 and 3 clinical trials.
The first 2 trials, known as MOTIVATE (Maraviroc plus Optimized Therapy in Viremic Antiretroviral Treatment Experienced Patients) 1 and 2, are placebo-controlled, double-blind studies involving maraviroc. Patients in these trials had documented resistance to all 3 classes of currently available antiretroviral agents (ie, protease inhibitors, nucleoside reverse transcriptase inhibitors, and non—nucleoside reverse transcriptase inhibitors). The 2 studies combined enrolled more than 1000 patients in Europe, Australia, Canada, and the United States.
Patients were randomized to receive antiviral combination therapy (based on viral resistance testing) known as “optimized background therapy” (OBT) plus placebo, or OBT plus 300 mg of maraviroc once or twice daily. In MOTIVATE 1, 46% of the patients who received maraviroc once daily and 41% who received maraviroc twice daily attained a viral load of <50 copies/mL at week 24. Among those assigned to OBT alone, only 21% attained this viral load level. The T-cell increases in the 2 maraviroc arms were 112 cells/mm3 and 102 cells/mm3, respectively, compared with 64 cells/mm3 in the OBT/placebo arm.
All these differences were statistically significant. In the MOTIVATE 2 trial, 42% of the patients in the maraviroc once-daily arm and 49% in the twice-daily arm achieved a viral load of <50 copies/mL compared with 25% in the placebo arm. Mean changes in CD4+ counts were 107 cells/mm3 and 111 cells/mm3, respectively compared with 52 cells/mm3 in the OBT/placebo arm.
Maraviroc is currently available in the United States under expanded access and will likely be approved by the FDA early this summer.
The second set of trials, known as BENCHMARK 1 and 2, are evaluating an integrase inhibitor (MK-0518) now referred to as raltegravir (Merck). This first-in-its-class agent blocks the integration of viral DNA into host-cell DNA that occurs during the early part of the viral life cycle.
Each trial included 350 patients who were failing their current antiviral drug regimen and had evidence of resistance to all 3 available classes of oral antivirals. Two thirds of the participants in each study were randomized to receive 400 mg of raltegravir twice daily plus OBT, or placebo plus OBT. As required by the European component of the study protocol, data were analyzed at 16 weeks, although the studies are planned to continue for at least 48 weeks.
After 16 weeks of therapy, 77% of the patients in BENCHMARK 1 had viral loads <400 copies/mL and 61% had <50 copies/mL. In BENCHMARK 2, these percentages were 77% and 62%, respectively. By comparison, approximately 41% and 43% of the placebo groups in the 2 trials had <400 copies/mL. The treatment arms also showed significantly greater increases in mean CD4+ counts from baseline. Raltegravir was well-tolerated in both trials, with adverse event rates similar to those seen with placebo. These results persisted throughout 24 weeks; 48-week data will be presented later this year.
As with maraviroc, FDA approval of raltegravir is expected early this summer. The challenge for clinicians and patients will be in determining where these new classes of agents fit into the current treatment paradigm. It is likely that early use will mirror the inclusion criteria used in their clinical trials, with the agent being mainly prescribed for patients with high-level resistance.
With the availability of these drugs, as well as the 2 newer protease inhibitors—tipranavir (Aptivus) and darunavir (Prezista)—physicians will be able to offer patients with drug-resistant virus at least 2 active agents, the number typically thought to be required for full viral suppression. New trials will be needed to define the roles of the CCR5 and integrase inhibitors as initial or second-line therapy, either alone or possibly in combination.
Benefits of Early HAART Therapy Still Debated
Beginning treatment with highly-active antiretroviral therapy (HAART) when a patient is in the early or primary stage of infection (typically defined as <6 months’ duration) continues to be controversial. Studies presented at past meetings or previously published have provided conflicting results. At this meeting, Radjin Steingrover, MD, of the Academic Medical Center, University of Amsterdam, the Netherlands, and colleagues presented data from 2 large cohorts of patients who began HAART within 180 days of seroconversion. Decline in CD4+ count and viral load setpoint (ie, the level at which the viral load remains stable) in untreated patients were compared with those in patients who interrupted early therapy. Of the 322 patients who met the inclusion criteria, 64 started HAART. There were no significant differences in prognosis (progression to AIDS or death) in the 32 patients who stopped HAART early, compared with untreated patients. In addition, no difference was seen in the decline in CD4+ cell counts between untreated patients and those who stopped HAART. However, the viral load setpoint reached at 7 weeks after seroconversion or treatment interruption was 0.6 log lower in patients who received HAART.
A second study presented by Christine Koegl, BS, of MUC Research, Munich, Germany, and colleagues included 2 large cohorts of patients with primary infection who were treated with HAART or who elected to defer therapy. Data were compared at 12 months after seroconversion or 12 months after stopping initial HAART. The study included 200 patients; 144 were treated immediately, and 56 remained untreated. At baseline, median CD4+ counts were 629 cells/mm3 in the untreated patients and 453 cells/mm3 in the treated group, and viral loads were 240,000 copies/mL and 500,001 copies/mL, respectively. A total of 100 of the 144 treated patients stopped therapy after a median of 9.5 months. At that time, 82% had undetectable viral loads, and median CD4+ count was 799 cells/ mm3. At 12 months after stopping treatment, median viral load was 38,056 copies/mL, and median CD4+ count was 538 cells/mm3. In untreated patients, median viral load was 52,880 copies/mL, and the CD4+ count was 525 cells/mm3. The authors note that, overall, early treatment did not affect the viral load setpoint, but it did result in a median increase in CD4+ count of +60 cells/mm3 compared with a median loss of 87 cells/mm3 in the untreated group.
Based on these data, as well as on previous studies, if HAART is to be given during primary HIV infection, the earlier it is initiated, the greater the potential benefit in terms of immune preservation. However, this should be done in the setting of a clinical trial or, if on an individual basis, patients should be duly informed that no data are available to guide the selection of a specific regimen or to prove the benefits of therapy in terms of potential morbidity and mortality. As with the question regarding when to initiate therapy in chronically infected patients, the absolute answer regarding the treatment of primary HIV infection can only be definitively answered with a randomized controlled prospective trial.
Circumcision Can Prevent HIV
New data from Ronald Gray, MBBS, MSc, of the Johns Hopkins University Bloomberg School of Public Health, Baltimore, Md, and colleagues contribute to a growing body of information from several observational studies, as well as another randomized controlled trial done in South Africa, showing a significant reduction in HIV incidence among men who undergo elective circumcision.
This study from Uganda randomized 4996 men (ages 15-49 years) to immediate circumcision or to circumcision that was delayed for 24 months. Testing for HIV, counseling, and physical examination were done at baseline and at 6, 12, and 24 months. Because of a significant difference in outcomes, the trial was stopped early, with only 72% of the expected data accumulated. There were 22 new infections in the circumcision group compared with 45 in the control group. This translated into a cumulative incidence of 0.66 for HIV infection per 100 person-years in the intervention arm, and 1.33 in the control arm.
Lancet
Moderate-to-severe adverse events occurred in about 4% of the circumcised men, all of which resolved with treatment. This study, and a similar one conducted in Kenya that also found that circumcision reduced the relative risk of HIV acquisition by >50%, were published concurrently in the (2007; 369:635, 708-713). So there is now firm evidence that circumcision can reduce the incidence of HIV infection by preventing transmission. The challenge will be implementation, from a practical as well as an ethical perspective. Ideally, it can complement other prevention methods, such as condom use, treatment of sexually transmitted diseases, and eventually female microbicides.
Lessons from Routine HIV Testing
The HIV testing guidelines the CDC issued in September 2006 call for routine, voluntary HIV screening for persons between the ages of 13 and 64 years. It was recommended that screening be performed in all healthcare settings, including acute care hospitals. This study included adult patients admitted to the general internal medicine service of a teaching hospital in New York City—an area known to have high prevalence of HIV infection.
All patients were asked to complete a survey that addressed potential HIV risk factors. They were then given the option to undergo testing using the OraQuick Rapid HIV test. Of the 420 patients approached for the study, only 113 completed the survey, and 100 agreed to be tested. Patients who refused testing were more likely to be female, older than age 50, and to believe that they did not have any risk factors for HIV infection. On a positive note, 25% said they had been previously tested.
Of the 113 patients who did complete the survey, 37% did not perceive themselves to be at risk for HIV infection, despite reporting ≥1 risk factor. Of the 100 patients who underwent testing, 3 new cases were diagnosed, including 2 in patients who admitted to high-risk behaviors. The third patient was a 68-year-old man who reported no risk factors.
Based on their data, the researchers concluded that despite 25 years of educational programs regarding HIV infection, nearly 40% of patients in this cohort did not see themselves as being at risk, even though they had at least 1 traditional risk factor. These data support the CDC stance that risk-based HIV testing alone will miss a significant number of infected persons, and that routine, voluntary screening should be done. The study also shows that rapid HIV testing can be done in a hospital setting.
In speaking with lead author Charu Jain, MD, of Mt. Sinai School of Medicine, New York City (who performed all the testing herself), it was obvious that the testing was quite labor-intensive. However, a study published last year in the Mayo Clinic Proceedings (2006; 81:452-458) found an HIV prevalence rate of almost 4% on an in-patient teaching service. A significant number of these patients were not admitted to the hospital for reasons that would have made treating physicians suspect HIV infection. So although admittedly challenging, regular testing of patients admitted to acute care hospitals, with standard ELISA or rapid antibody testing, can help identify the 250,000 persons in the United States who are unaware of their HIV status and who account for >50% of the 40,000 new infections that occur each year.
Correction
In the February 2007 issue (page 18), the "Rapid Test for C Difficile" item contained erroneous information. We cited information about the OIA CdTOX AB assay, which is not yet available in the United States. Instead, BioStar OIA CdTOX A test, an optical immunoassay for rapid diagnosis Clostridium difficile toxin A, is available. This test (from Inverness Medical Professional Diagnostics) can identify C difficile bacteria in 10 minutes.
