HIV Update: Clinical Implications for Primary Care Physicians

Medical Director, Comprehensive Clinic for HIV, Lancaster General Hospital, Lancaster, Pa

DENVER, Colo—Many believe that the Conference on Retroviruses and Oppor?tunistic Infections has become the most important scientific meeting on the topic of HIV/AIDS. More than 3900 clinicians/researchers attended this year’s meeting, 48% of whom were international attendees. The conference included 6 major plenary lectures, 7 symposia panels, 9 oral poster discussions, and >900 abstracts on HIV/AIDS. Several papers have important clinical implications for primary care physicians who treat both HIV-infected as well as noninfected patients.

Protease Inhibitors May Increase Susceptibility to MI

This update was reported (Friis-Moller N. Abstract 144) from an ongoing study known as D:A:D (Data Collection on Adverse Events of Anti-HIV Drugs) that includes 23,437 patients in 11 cohorts from the United States, Europe, and Australia. All patients (median age, 39 years; 24% women) are taking at least 3 antiretroviral (ARV) drugs, including a protease inhibitor (PI) and/or a non-nucleoside reverse transcriptase inhibitor (NNRTI). Data from this study, which started in 1999, have been presented at previous meetings and were published in the New England Journal of Medicine (2003;349: 1993-2003). The primary outcome of this study is myocardial infarction (MI) risk with duration of ARV therapy.

Findings presented this year involved patients who were followed through December 2005, with a median duration to last follow-up of 6.3 years. A total of 79% of patients had been receiving a PI, 62% an NNRTI, and 93% a nucleoside reverse transcriptase inhibitor. The model was adjusted for age, sex, previous cardiovascular disease, and smoking. There were 345 MIs in 94,469 person-years, for an incidence of about 4 MIs per 1000 person-years. For the entire D:A:D cohort, the risk of MI actually fell by 50% between 1999 and 2004. However, when looking specifically at patients who had been taking a PI, the relative risk was 16% for each year of therapy. This translates into a doubling of the risk for MI over a 5-year period. Even after adjusting for lipid profiles, the relative annual risk was 10% for patients taking PI therapy. Patients taking an NNRTI were at no increased risk. The investigators concluded that PIs appear to increase risk for MI, irrespective of traditional Framingham risk factors, such as total cholesterol, triglyceride, and high-density lipoprotein levels.

Until the reason for this association is clarified, it is incumbent on clinicians to aggressively manage other cardiovascular risk factors in their patients whose ARV regimen includes a PI. Physicians may also want to consider non-PI regimens in patients at high risk for cardiovascular disease.

Postexposure Prophylaxis Often Begins Too Late

This study (Kindrick A. Abstract 906) was conducted by the National HIV/AIDS Clinicians’ Consultation Center at the University of California, San Francisco (UCSF). It has been known for several years that rapid initiation of antiretroviral ARV therapy after occupational exposure to HIV effectively prevents infection. The Centers for Disease Control and Prevention (CDC) has also issued recommendations for the use of ARV therapy to prevent nonoccupational HIV infection, including sexual exposure (MMWR. 2005;54:1-20). The optimal time to treatment for both occupational and nonoccupational exposure, based on biologic evidence and animal data, is probably just a few hours, although the guidelines state treatment can be given up to 72 hours after HIV exposure.

Physicians and patients are unaware of the existence of nonoccupational exposure guidelines and the specific protocols that should be followed.

—Jeffrey T. Kirchner, DO

The National Clinicians’ Post-Exposure Prophylaxis Hotline (PEPline) at the UCSF provides postexposure advice based on current CDC/US Public Health Service guidelines. The investigators reviewed all calls that involved questions about management following sexual exposure received at the hotline from January 2004 through August 2005 and examined exposure characteristics, individuals exposed, sources, and treatment recommendations. During the 18-month study, there were 12,895 calls to the PEPline, of which 880 (5%) involved sexual exposure; 168 calls were from emergency department physicians, and 183 were from family physicians. An almost equal number of men and women were exposed, although 76% of the sources were men.

The majority of the phone calls involved exposures that would have qualified for postexposure prophylaxis. However, only 283 (32%) of the calls came within 24 hours, while 259 (29%) came between 24 and 72 hours, and 248 (28%) came after 72 hours. Another 10% occurred after an unknown time period. Thus most calls were made well beyond the 24-hour time frame during which optimal benefit can be expected. Specific reasons for the delay could not be ascertained, and it is unknown whether the patient or the care provider was responsible. Other studies are under way to identify potential barriers to timely management. My personal opinion is that both physicians and patients are unaware of the existence of nonoccupational exposure guidelines and the specific protocols that should be followed.

Circumcision and HIV Transmission: The Cutting Edge

In a plenary talk (Abstract 120), Thomas Quinn, MD, of the National In?stitute of Allergy and Infectious Diseases/ National Institutes of Health, and the Johns Hopkins School of Medicine in Baltimore, noted that only about 20% to 25% of men worldwide are circumcised, compared with >50% of men in the United States. There is great cultural and geographic variability associated with this practice. Dr Quinn cited data showing a decreased incidence of cervical cancer and human papillomavirus in Jewish and Muslim women whose husbands were circumcised. There is also a lower incidence of herpes simplex virus and other sexually transmitted diseases (STDs) in circumcised men. However, medical indications for circumcision are currently limited to phimosis and balanitis. In addition, the complication rate from routine circumcision is 1% to 3%.

Population-based studies show that HIV transmission and acquisition are associated with blood and genital viral load, stage of disease, viral subtype, presence of STDs, and male circumcision. In many Asian and African countries where circumcision rates are <20%, the prevalence of HIV is considerably higher than in countries in the same geographic regions where circumcision rates are >80%. Dr Quinn described a systematic meta-analysis of 38 studies that found a &#381;50% reduction in HIV infection among circumcised men compared with uncircumcised men. A 2-year study from Uganda looked at male partners of HIV-positive women and found that 40 of 137 uncircumcised men became infected, compared with none of the 50 men who had been circumcised. A randomized trial in South Africa (n = 1538) demonstrated that circumcision resulted in a 61% reduction in HIV transmission, even after controlling for behavioral factors. The results were significant enough that the study was stopped early. Two other similar trials are ongoing in Rakai, Uganda, and in Kenya. Preliminary data from the first trial (Abstract 128) show a reduced incidence of HIV acquisition among women whose husbands are circumcised.

Dr Quinn presented some biologic explanations for the association between circumcision and HIV transmission. The penile foreskin mucosa is rich in the HIV target cells that allow more efficient absorption of the virus. During intercourse the skin is retracted, allowing exposure to the mucosa of the unkeratinized foreskin. In addition, the internal foreskin is more prone to abrasions and tears and subsequent infection by HIV as well as by other STDs.

Dr Quinn concluded his talk by emphasizing that there is epidemiologic, biologic, and clinical trial evidence that male circumcision significantly decreases the risk of HIV acquisition and transmission. He presented a model showing that approximately 16 circumcisions would need to be performed to prevent 1 case of HIV infection. Based on an estimated $69 per procedure, the overall cost would be about $1000 per case of HIV prevented. Public policy implications for widespread circumcision in high-risk countries must consider cultural norms, national and local laws, and religious traditions. Any circumcision programs would also need to be integrated into other STD and HIV prevention programs and not promote a false perception of security in circumcised men that could undermine future prevention efforts.

Evidence Argues Against ARV Drug Holidays

There has been a growing interest over the past several years in strategies that allow patients taking ARV therapy to interrupt their treatment and take a so-called &#8220;drug holiday.&#8221; Some early studies failed to prove any immunologic benefit with this strategy. However, ongoing concerns over drug toxicity and costs have prompted continued research. The results of 2 trials presented at this meeting found that stopping ARV therapy may not be a wise strategy for certain patients.

The SMART (Strategies for the Management of Anti-Retroviral Therapy) study was an international randomized controlled trial that began in January 2003 at 318 sites in 33 countries (El-Sadr W. Abstract 106LB). The median age of patients was 46 years; 27% of the participants were women.

Patients in the first arm of the trial who had a CD4+ count >350 cells/mm3 continued to receive ARV therapy, with a goal of maintaining an undetectable viral load. Patients in the second arm, known as the drug conservation group, were kept off medications until their CD4+ count fell below 250 cells/mm3. Therapy was again stopped if the CD4+ count went above 350 cells/mm3. The primary end point was death. The trial was designed to enroll 6000 patients but was stopped in January 2006 after it was found that patients in the discontinuation group had a 2.5-fold increased risk of HIV disease progression or death, a 1.5-fold increased risk of severe complications, and a 6.1-fold increased risk of serious HIV disease progression. Of note, most of the deaths, including those due to cardiovascular, hepatic, and renal disease, were not specifically AIDS related.

A second study conducted in Cote d&#8217;Ivoire, West Africa, ANRS 1269 Trivican, found similar results. This study included 840 adults who were randomized to continuous ARV therapy; 2 months of treatment followed by 4 months off treatment; or discontinuation of therapy if their CD4+ count was >350 and not restarting until the count was <250 cells/mm3. Similar to the SMART trial, this study found that patients in the latter group who stopped therapy with a CD4+ count <250 had a 2.6-fold increased risk of morbidity and mortality, mainly due to serious bacterial infections. The third arm of the study was stopped as well.

The take-home message from these trials is that patients receiving stable therapy without drug side effects or complications should be maintained on therapy. Of note, 3 other smaller studies presented at the meeting found no significant mortality risk with treatment interruptions, but their designs did not allow patients to stop ARV therapy unless CD4+ counts were in the range of 350 to 450 cells/mm3. I suspect we will continue to see more treatment discontinuation or intermittent therapy trials in the future, but with more specific and safer immunologic criteria.

Normalizing HIV Testing in Health Care Settings

Timothy Mastro, MD, of the CDC, participated in a session dedicated to public health strategies and harm reduction for HIV prevention (Abstract 164). He described updated epidemiologic data showing that between 1 million and 1.2 million persons in the United States are living with HIV/AIDS, but about 25% are unaware of their status. When individuals do not know they are infected, they are more likely to transmit the virus to unsuspecting partners. These individuals are believed to be responsible for about 60% of the 40,000 infections that occur in the United States each year. In addition, many persons are tested late in the course of the disease when ARV therapy is less effective. Finally, voluntary testing of all HIV-infected pregnant women, which has been a CDC recommendation for >10 years, is still inconsistently performed.

To increase knowledge of HIV status and help link patients with prevention, medical care, and treatment services, the CDC will be issuing new testing guidelines in late spring or early summer 2006. Current CDC guidelines were issued in November 2001 and recommend screening only in settings where seroprevalence is &#381;1%, targeted testing based on risk assessment, and yearly testing for men who have sex with men. Dr Mastro pointed out several reasons for the proposed changes in the guidelines, including that many HIV-infected persons access health care but are not tested for HIV until they are symptomatic (usually with an AIDS diagnosis), despite knowing that very effective treatments are available. Awareness of HIV infection substantially reduces high-risk sexual behavior. In?creasing knowledge about HIV has lessened the need for pretest counseling. More clinicians have had experience with HIV testing, including the use of rapid tests. Finally, evidence about the ?preventive benefits of typical counseling for persons who test negative has been inconclusive.

The new guidelines will recommend routine HIV testing in a variety of health care settings. They will focus on the model of &#8220;opt-out testing,&#8221; meaning that HIV testing will be performed after notifying the patient, and consent would be inferred unless the patient declines. Several studies, including a 2005 study from Texas, have demonstrated that opt-out testing can increase the number of persons tested by up to 59% and identify an additional 100 HIV-positive individuals compared with an opt-in strategy (Texas Department of State Health Services, 2005). There are similar data for prenatal settings, with one study showing that 88% of women agreed to testing when an opt-out approach was used compared with 35% with an opt-in approach (BMJ. 1999;318: 1660-1661). Dr Mastro also cited 2 recent studies published in the New England Journal of Medicine (2005;352:570-585; 2005; 352:586-595) that found routine HIV testing to be cost-effective even in settings where prevalence was 0.1%.

The process for revising the testing guidelines included an HIV prevention leadership summit in San Francisco in August 2005 and 2 meetings in Atlanta attended by both physicians and community members. The preliminary recommendations include the following:

&#8226; Routine voluntary HIV screening in health care settings for all persons aged 13 to 64 years, regardless of risk or prevalence

&#8226; Repeat screening, at least annually, for persons with known risk factors

&#8226; Opt-out testing, with the opportunity to ask questions and the option to decline; HIV consent included with general consent for care and communication of test results

&#8226; Not requiring prevention counseling in conjunction with screening in health care settings.

These guidelines are intended to apply to all health care settings, including ?inpatient services, emergency departments, urgent care clinics, STD clinics, tuberculosis clinics, community clinics, and public health clinics. Dr Mastro noted that state and local regulations vary and should be reviewed and revised as needed. In low-prevalence settings, a &#8220;sunset&#8221; provision should be considered (ie, after screening is initiated, if the prevalence of HIV in a community is found to be <0.1%, ?continued routine screening could be ?discontinued).

Insurance reimbursement is not anticipated to be a problem when HIV screening becomes more widespread. Adequate public funding would also be expected to be available to support widespread testing. Finally, assuring access to HIV care is critical if we are to identify the &#381;250,000 persons in the United States with HIV whose status is unknown.

Dr Mastro emphasized that there will be further discussion and debate before the guidelines are finalized. Clearly new testing guidelines are overdue, and it is only through more widespread routine testing that we can decrease the annual rate of 40,000 new infections in the United States.