A STRATEGY TO CONTROL THE U.S. HIV/AIDS EPIDEMIC, WITH KEY ROLES FOR CONTROL AT SOURCE, “TREATMENT AS PREVENTION”

 Ronald P. Hattis, MD, MPH, President, Beyond AIDS

ronhattis@beyondaids.org         www.beyondaids.org

NOTE: This position statement was originally prepared July 2012 and approved by the Board of the Beyond AIDS Foundation, and the Scientific Committee serving the Beyond AIDS Foundation. It was distributed at the XIX International AIDS Conference that month in Washington, D.C.  It was edited 8/4/12 after input from the conference; changes are subtly highlighted in brown font. Portions of the text highlighted in red are linked to Web references, and were last updated along with text adjustments in August 2013. Further changes to the section on pre-exposure prophylaxis were approved by the Foundation Board in December 2013 and appear subtly highlighted in purple font. The document briefly reviews the history of "treatment as prevention"; concisely outlines an integrated public health prevention strategy for the U.S. (also worth consideration globally), with greater emphasis on control of infection at the source including "treatment as prevention" as a centerpiece; and ends with a set of ten recommendations for action by U.S. agencies. The strategy and recommendations are highlighted in bold.  Comments are welcome, on this blog or by e-mail.

TWO APPROACHES TO THE CONTROL OF COMMUNICABLE DISEASES

Each year in the United States, an estimated 48,00-56,000 new HIV infections have occurred for the last several years. This trend has defied the full range of current and longstanding public health efforts to reduce this incidence. Efforts to date have tended to be directed mostly to population groups identified to be at risk, and to some extent to the general populations of countries or communities. They include education about the disease, as well as promotion of measures such as condom promotion and avoidance of needle sharing.

An alternative approach has been successfully utilized for other communicable diseases for which (like HIV) no vaccine or environmental control measure exists, and for which antimicrobial treatment can lead to a loss of infectiousness (through cure, as with syphilis, or suppression, as with tuberculosis). That approach focuses more heavily on control of infection at the source, helping each infected person to prevent passing on the organism. This reduces the microbial reproductive rate, R0 (a concept pioneered in the U.K. by Anderson and May).  

In our opinion, control of transmission at the source has been underemphasized for HIV/AIDS as a component of overall disease control and prevention. It is often said that if we do the same things over and over, we should not expect better results. 

Control of a communicable disease at the source generally requires identification of all or most infected persons, as soon as possible after infection occurs. Thereupon, methods of control can involve 1) reducing transmission-prone behaviors of those persons, or introducing barriers to the organism during such behaviors, and 2) reducing the shedding of the infectious organism by infected persons. In the absence of spontaneous recovery, the latter method generally requires antimicrobial therapy. Now that the second method has been proven to work for HIV/AIDS, both methods can be incorporated into a coordinated strategy for more effective control the disease.

THE EMERGENCE OF "TREATMENT AS PREVENTION"

Hattis and Jason Kibble first proposed the use of treatment as a major weapon to reduce HIV transmission at Loma Linda University in 1996, citing evidence that even the primitive treatment available up to that time with AZT alone could reduce both heterosexual and perinatal transmission. The concept was endorsed by the California Medical Association in that year; however it did not achieve national attention at that time. GlaxoSmithKline convened an advisory Board in 2002 to discuss the subject, and a mathematical model that year by Blower et al. using data from the San Francisco gay community predicted that treatment could eventually eradicate an epidemic with 30% seroprevalence.  

The use of treatment to prevent new infections was frustrated in part because the U.S. guidelines for HAART regimens from2001 until 2012 called for delaying treatment until CD4 counts dropped to levels that often took 5-10 years to occur. Starting treatment at a count of under 500 has been been referred to as “early” compared with under 350, but waiting until either level is reached permits much if not most transmission to occur before treatment has a chance to kick in preventively.

However, interest in “treatment as prevention” surged between 2009 and 2011, and peaked as a 9-country study published in August 2011 by Cohen et al. showed that antiretroviral treatment could reduce infections inserodiscordant partners by up to 96%. HIV “treatment as prevention” was named by Science Magazine as the scientific “breakthrough of the year” for 2011.  Modeling has meanwhile suggested that the resulting reduction in incidence might finally be able to control or even eventually end the epidemic in South Africa or in other countries that can bring all cases into early treatment.

Meanwhile, on March 29, 2012, new guidelines for antiretroviral treatment of HIV in the U.S. were issued by the National Institutes of Health (NIH), which encouraged treating all infected patients, regardless of CD4 counts, although some sub-populations are at highest priority for treatment. Immediate treatment was advocated primarily for the long-term benefit of the patient; however the guidelines did mention prevention as a secondary benefit. For public health however, prevention of transmission is a primary concern. The International Antiviral Society-USA followed soon after in July 2012 with similar guidelines, and likewise noted reduction of transmission in its rationale.

Some prominent federal health officials, and local public health departments in NewYork City and San Francisco, are already advocating publicly for early onset of treatment for its preventive benefits. Nevertheless, in a review of the current National AIDS Strategy and of posted Centers for Disease Control and Prevention (CDC) guidelines, we do not yet find at the national level any coordinated or comprehensive public health strategy document that lists treatment as prevention as a key strategic component for controlling the HIV/AIDS epidemic. We also do not yet find official guidelines that show how it integrates with other prevention strategies. 

At the XIX International AIDS Conference in Washington, DC in July 2012, "treatment as prevention" was a central topic, leading to probably over-optimistic predictions of a "generation without HIV" and even of the eradication of the disease. Despite the general enthusiasm, a minority of activists even voiced alarms that there could be forced treatment for public health purposes, raising the need to address human rights concerns. Actually, although the concept is simple, achieving the degree of penetration of treatment, and the longterm maintenance and adherence, necessary for "treatment as prevention" to steadily reduce incidence (and ultimately prevalence) of HIV/AIDS will be complicated and gradual, subject to the vagaries of voluntary individual choices and behaviors and group cultural responses, and prone to many pitfalls and limitations.  

In countries like the U.S., where patients with advanced disease already have treatment available but it has not reduced HIV incidence, the key to reduced incidence will be earlier onset of treatment than has been available until now, i.e., as soon as possible regardless of CD4 count, and before most transmission has occurred. However, although the phrase "test and treat" was heard at the conference, there was relatively little discussion of achieving early onset of treatment by systematic linkage to care immediately upon positive testing or of reporting. There was also little discussion of similar linkage to partner services. Representatives of most countries continued to plan based on treating everyone with a CD4 count of under 350, or in some cases under 500/ml, due to limited resources, as well as treatment guidelines in Europe and elsewhere that have not yet been adjusted to permit earlier use of antiretroviral drugs. This may be very helpful in countries where incidence is already declining, and/or where the majority of infected persons have had HIV for many years and have low CD4 counts. However, it is unlikely to achieve a turnaround in the U.S., or in other countries with similar epidemic trends and treatment practices.

AN INTEGRATED HIV CONTROL STRATEGY FOR THE UNITED STATES

The demonstrated preventive benefits of treatment, combined with the authorization of treatment for all infected persons, permit a more successful overall prevention strategy than was available until now, stressing control of transmission at the source, in which early and continuous “treatment as prevention” would be the central and most effective new element.

Such an integrated public health prevention strategy could include these critical elements:

·       Early identification of infection, through screening programs more effectively targeted at the demographics with the most recent transmission, and through routine testing in healthcare settings;

·     Outreach by public health to all newly reported case-persons and/or their providers, with referrals when indicated), to assure that persons with newly identified HIV infections are linked to immediate onset of effective treatment that suppresses viral load; that initial partner services are performed; and that referrals to prevention case management be available to assist with changes in high-risk behavior as indicated;

·       Incorporation of prevention into ongoing care of patients with HIV, including:

a) Routine questioning and counseling regarding sexual and drug-related behavior, 
b) monitoring of treatment adherence;

c) Monitoring of viral load suppression;

d) Ongoing questioning about new partners, and assuring confidential notification and voluntary testing through partner services.

None of these elements is really new; all have been successfully used before to some degree, individually or with some but not all of the others, in various prevention programs. (Even treatment has been used to prevent perinatal infections.) However, they are not universally practiced, nor are they fully integrated as a system in most public health jurisdictions. 

Prevention grants do not yet require the review of the epidemiology of recent HIV infections for purposes of retargeting testing and other outreach. Some states (Massachusetts) still require written consent for testing, while others have provided exemptions from written consent, but either impose complex pre-test requirements (California) or do not permit opt-out testing (New York). Reported case data in many locations is so severely sequestered that it cannot be utilized for prevention outreach, nor has there been funding for this to be done routinely.

“Prevention with Positives” programs have proven effective, but there are not enough of them, and case patients with high-risk behavior histories are not systematically referred to them upon being reported. Ryan White funding provides support groups and case managers on a large scale, but these are often neither trained nor required to deal with prevention issues. Partner services are not performed for all patients even when first diagnosed, let alone on an ongoing basis as they acquire new partners. Funding and training for this essential activity are inadequate in many jurisdictions, even though it permits the highest theoretical yield of potentially preventable infections, as well as the earliest possible identification of new infections. 

Treatment providers often fail to address recent risk behavior and treatment adherence at each visit, and viral load suppression and monitoring are often sub-optimal. Word about initiating treatment immediately, and on new guidelines for treating all infected patients, has not yet reached many providers. Many clinics still have large posted signs recommending treatment when the CD4 count is below 500, as per the last set of guidelines from 2011.

Emphasizing control at the source should not of course imply the abandonment of efforts to reduce risk behavior of the general population, and especially on the part of persons with high-risk behavior patterns. In fact, the most effective proven methods should be promoted more widely and effectively than at present. Efforts to increase abstinence and reduce multiple partners have proven effective in actually reducing HIV incidence and prevalence in Uganda and a few other countries, but at times when the population was seeing AIDS deaths all around them. They require a massive effort to change the culture of an entire society, something for which the will and commitment have not been seen in the United States. Barrier protection for oral sex is rarely addressed in public health programs anywhere. The relative priority of such approaches in partnership with source-based interruption of transmission should be considered. 

CONCERNS ABOUT PRE-EXPOSURE PROPHYLAXIS

A complicating recent element is the FDA approval of emtracitabine/tenofovir (Truvada) for pre-exposure prophylaxis (PrEP), and the controversies it has engendered. It will take tremendous efforts and greatly increased financing to provide antiretroviral treatment to the 72% of U.S. persons with HIV not yet receiving it according to CDC (higher in many countries, where the expansion will also be much harder to afford). The toxicity and cost of treatment can be justified for persons who are actually infected, but are more problematic for persons who might merely be exposed. There are good precedents for post-exposure treatment, but not for pre-exposure treatment for a communicable disease where equivalent protection can be achieved by treating the infected persons. 

There is a puzzling inconsistency between CDC recommendations for PrEP, and its recommendations of 2005 for non-occupational HIV post-exposure prophylaxis (nPEP). The latter call for preventive treatment with 3 drugs, only if there has been definite exposure to a known infection, or to a likely infection in which case a risk-benefit discussion has been conducted between the provider and the patient regarding a specific exposure. For PrEP, 2 drugs are used, and there is no such limitation. Other concerns include likely substitution by some people of PrEP for regular condom use, possible ineffective episodic use, and potential drug resistance due to sub-optimal two-drug treatment, e.g., when persons using PrEP already have acquired HIV infection, or if they become infected despite PrEP.

Treatment of a defined population of already-infected persons should logically be much more cost-effective, and should have a higher risk-benefit ratio, than treating a larger, ill-defined population of persons, including many who will not even become exposed. On the other hand, we recognize that some persons who engage in high-risk behavior refuse to use condoms, and that some infected persons may refuse both to take treatment and to use condoms. Therefore, a limited adjunctive role for PrEP can be justified, at least for the time being. With an increased emphasis on identifying all infected persons, and in turn on linking and retaining all infected persons to treatment that suppresses viral load, the need for PrEP should decrease over time.

In addition, there are persons who cannot avoid unprotected exposure to HIV, e.g., partners in sero-discordant couples who do not have the power to refuse sex, and where the source refuses treatment and condom use; for partners of patients in early treatment whose viral loads have not yet become undetectable; or for partners of infected persons, where condoms are deferred because pregnancy is intended and treatment of both partners is substituted. In such situations, PrEP for the partner, concurrent with treatment of the infected person, might provide the best available protection. Unfortunately, concurrent treatment of both partners was not studied prior to the approval of PrEP, so there were no data to guide CDC and FDA recommendations. 

BEYOND AIDS RECOMMENDATIONS

Our organization, Beyond AIDS, has worked since 1998 to promote underutilized public health strategies for HIV/AIDS that have shown promise with other communicable diseases. Many of our efforts have focused on a greater emphasis on control of HIV at the source, including our ultimately successful 10-year campaign for HIV reporting, and our advocacy of partner services, for using reporting for prevention purposes, for more routine screening with an aim to earlier detection of infections, and for “de-exceptionalizing” in general the public health response to HIV/AIDS.  We therefore are drawn to the above approach, but agree that strategy should be based on science and cost-effectiveness, and recognize continuing debate about what it can practically achieve, and the need for human rights assurances.

Beyond AIDS recommends the following ten steps:

1. CDC should continue to review the evidence, and should perform cost-effectiveness and risk-benefit estimates, to determine the full potential and limitations of “treatment as prevention.” These should be contrasted with similar calculations for pre-exposure prophylaxis (PrEP). Human rights concerns should be fully addressed as well. The Scientific Committee serving our educational and research arm, the Beyond AIDS Foundation, includes experienced medical epidemiologists and infectious disease specialists, alumni of the Epidemic Intelligence Service, and former members of the Presidential Council on HIV/AIDS (PACHA). We would be pleased to participate in any future consultation on this issue.
2. The National AIDS Strategy, CDC recommendations and grant criteria, and PACHA recommendations should all be updated to present a clear and consistent direction on how “treatment as prevention” will be applied; and on the application of the other elements of the comprehensive prevention approach proposed above. The revised recommendations should give increased emphasis to control of transmission at the source, and should address a cost-effective balance between this and efforts targeted toward entire at-risk populations.
3. As soon as possible, and independent of the above review, the Health Resources and Services Administration (HRSA), NIH and CDC should collaborate (including determination of the lead responsibility and funding) on vigorously publicizing, to all HIV providers in the U.S., and soon after to the HIV/AIDS community, the changes in recommendations on when to start treatment as per the March 2012 treatment guidelines, and their benefits for both clinical care and prevention.  Guidelines for incorporation of prevention into treatment (including the four elements outlined above) should also be promoted for providers. These efforts should be supplemented by publicity and discussions with international governmental health agencies and NGO foundations funding HIV/AIDS treatment globally, with the recognition that resource limitations may temporarily dictate later treatment onset in some jurisdictions.
4. CDC prevention grants, in the next renewal cycle, should  require recipient departments and agencies to frequently review the demographics and transmission dynamics of the most recently acquired infections, and to adjust the targeting of testing and prevention programs. We applaud and encourage the intent of CDC leaders as communicated to us, to proceed in this direction.
5. Pressure and financial incentives should be applied to encourage those states that still impose legal barriers or special pre-test requirements, to simplify their HIV testing processes and to eliminate all impediments to routine opt-out testing.
6. Integrated screening for HIV together with other sexually and bloodborne diseases of public health importance, for which millions of persons are not aware of their infections (e.g., hepatitis C), should be considered. (This would seem an appropriate project for unified  involvement by the NCHHSTP at CDC, and we applaud and encourage the intent of CDC leaders as communicated to us, to proceed in this direction.) The development of test panels for multi-organism screening should also be promoted. Such an effort would benefit from CDC and NIH assistance in developing methodology, and from efforts by private industry to develop reagent kits and testing equipment. New testing methodology would also require FDA approval, and test panels would require Current Procedural Terminology (CPT) code approval by the American Medical Association's CPT Editorial Panel, and acceptance by the Centers for Medicare and Medicaid Services (CMS), to assure compensation.
   
7. Prevention grants should require that reporting data be utilized for outreach to newly reported patients or their providers, for purposes of partner services, linkage to treatment, and risk triage with referral for prevention case management counselors or groups as appropriate. We likewise applaud and encourage the intent of CDC leaders as communicated to us, to proceed in this direction.
8. Where grants already require the provision of partner services, better monitoring by CDC and other funding agencies should determine the degree of compliance, and the outcome. We understand that this, too, is planned by CDC, and look forward to improved performance.
9. Ryan White funding for HIV support groups and social work case management should include cross-training on prevention issues, and requirements that these be addressed.
10. Indications for pre-exposure prophylaxis should be clearly prioritized by FDA and CDC, with the highest priority assigned to situations of ongoing unavoidable exposure (which might be called intra-exposure prophylaxis). Most antiretroviral treatment resources should be dedicated to infected persons, for whom combined clinical benefits and “treatment as prevention” can be achieved, and both risk-benefit and cost-effectiveness ratios are expected to be maximal. Studies should be facilitated, to determine the added benefit of antiretroviral regimens, for partners of infected persons who are already being treated, at detectable and undetectable viral loads, and with and without condoms.