When to Initiate Antiretroviral Therapy: Updated NYSDOH Guideline

Christopher J. Hoffmann, MD, MPH


December 01, 2015

Few infectious diseases have had such robust research and debate on the optimal timing of treatment initiation as HIV. Unlike most infectious diseases, HIV is chronic and characterized by a decline of immune function over years. At higher CD4 counts (>350 cells/mm3), HIV-infected people are similar immunologically to those without HIV and have minimal risk for most opportunistic infections.[1] At lower CD4 counts (<200 cells/mm3), illness from opportunistic infections can occur abruptly and may be fatal. After reviewing new clinical trial evidence demonstrating improved outcomes with initiating ART at CD4 counts >500 cells/mm3, as well as considering regimen tolerability and HIV prevention through treatment, the Medical Care Criteria Committee of the New York State Department of Health (NYSDOH) AIDS Institute has updated its guideline, When to Initiate ART.

Immune decline in HIV-infected patients has long been balanced with toxicity, tolerability, potency, and barrier to viral resistance of available agents. In the era when antiretroviral therapy (ART) agents such as zidovudine, stavudine, didanosine, and indinavir were the best available, deferring ART until immunodeficiency was general practice and endorsed by multiple treatment guidelines to spare an individual from drug toxicity and early treatment failure.[2]

Since then, three fundamental changes have emerged: (1) development of less toxic and more potent and tolerable ART regimens; (2) new knowledge of the association between HIV infection and other diseases occurring at high CD4 counts; and (3) the recognition of ART as part of a strategy to prevent HIV transmission.

Current ART regimens do not produce the significant side effects and long-term toxicity that characterized many older ART regimens. It is often possible to identify a regimen that does not cause side effects for a given patient. The one-pill, once-daily regimens substantially reduce pill burden, and the potency and barrier to viral resistance for any of the current preferred ART regimens are high.[3] A patient who takes 85%-90% of pills every month is still likely to achieve an undetectable viral load[4]—in contrast to previous years, when such a pill-taking pattern could easily lead to virologic failure and resistance.

Multiple studies have demonstrated the association between HIV viremia and higher morbidity and mortality, and uncontrolled viremia has emerged as a compelling explanation for the higher prevalence of end-organ disease among HIV-infected individuals, regardless of CD4 counts. The SMART study, published in 2006, provided surprising results for the time: higher cardiovascular and liver morbidity among individuals not receiving ART compared with those receiving ART.[5] These results were contrary to the anticipated finding: that reduced ART exposure would be associated with reduced end-organ morbidity. Subsequently, multiple observational studies identified prolonged exposure to viremia as a risk factor for morbidity and mortality, independent of either CD4 count or a current undetectable viral load.[6] Two other cohort studies estimated mortality and ART status, stratified by HIV RNA. Both studies suggested a mortality benefit with ART initiation at either 350 or 500 cells/mm3.[7,8] These results convinced many clinicians and the US Department of Health and Human Services (DHHS) Guidelines Committee to recommend offering ART regardless of CD4 count.[9] However, the benefit of ART at CD4 counts >500 cells/mm3 remained undefined. The multicountry START study resolved that uncertainty.[10] The study randomly assigned participants to initiate ART with a CD4 count >500 cells/mm3 or to defer ART until a CD4 count of ≤350 cells/mm3 was reached. The incidence of serious morbidity or death was 1.4 events per 100 person-years in the deferred group compared with 0.60 events per 100 person-years in the immediate group, for an absolute reduction in morbidity of 0.8 events per 100 person-years, or a >50% reduction in events. Mortality associated with uncontrolled HIV replication at higher CD4 counts is believed to be due to immune activation and an inflammatory milieu that promotes progression of end-organ disease. ART is known to reduce levels of multiple markers of immune activation and inflammation.

Another compelling reason for treating HIV at all CD4 counts is to prevent HIV transmission, the most persuasive evidence for which comes from two observational studies: the PARTNER study in Europe[11] and the Opposites Attract study in Australia, Bangkok, and Rio de Janeiro.[12] In these two studies, serodiscordant couples were prospectively followed. Although condom use was recommended, many of the couples reported not using condoms during sex. Among 767 serodiscordant couples in the PARTNER study (282 homosexual and 485 heterosexual couples) and 152 homosexual serodiscordant couples in the Opposites Attract study, no transmission events have been detected in over 894 and 150 couple-years of follow-up, respectively, when the HIV-infected partner had an undetectable viral load. In addition, the HPTN 052 study randomly assigned serodiscordant heterosexual couples to immediate ART or ART deferred until a CD4 count of <250 cells/mm3 was reached.[13] There were 35 infections in the deferred arm and four in the immediate arm, a 95% reduction in incidence.

Given the increased safety and tolerability of ART, the START trial results, and prevention considerations, the NYSDOH AIDS Institute updated its guidelines on when to initiate ART and now recommends prompt initiation of ART among nearly all adults with HIV. This is a change from "offer ART" to "recommend ART" that is similar to updated guidelines from the DHHS[14] and International Antiviral Society-USA[15] and endorses ART as the best option for nearly everyone with HIV.

This is a change from "offer ART" to "recommend ART"

The single group of patients in whom ART should be deferred are those initiating treatment for cryptococcal meningitis or tuberculosis meningitis. Deferring ART initiation until after the start of treatment of these conditions is most appropriate. The timing of ART initiation will depend on the patient's co-occurring illness and immune status.[14,15,16,17]

In an effort to avoid potential ART toxicity and attenuation of immune control, elite controllers and long-term nonprogressors have not traditionally been offered ART. Although limited data exist, a recent retrospective study reported higher rates of hospitalization for elite controllers compared with other HIV-infected people with undetectable viral loads.[18] Given the absence of high-quality data to guide recommendations, the NYSDOH AIDS Institute recommends that decisions regarding ART for elite controllers and long-term nonprogressors be individualized.

The largest group of individuals who often have not been offered ART includes those who are anticipated to have poor adherence: patients with severe psychiatric illness, homelessness, active substance use, or financial barriers to accessing ART. Even these patients, however, can be successfully treated with ART.[19,20,21,22] Although the NYSDOH AIDS Institute recommends individualizing decisions to initiate ART while barriers to adherence are addressed, outcomes will be best when ART is initiated as soon as patients are properly prepared. Although support for adherence remains critical to HIV care, concerns about adherence capability are not reasons to withhold ART. Most currently recommended ART regimens are highly potent, have high barriers to viral resistance, and are forgiving of occasional missed doses.

the era of monitoring and counseling until a patient reaches ART "eligibility" is over.

For patients who resist initiation of ART, their desire to delay treatment should be respected. However, in the RAPID study,[23] 95% of newly diagnosed individuals requested initiation of treatment by the day after they had been offered ART.[24] The idea of treatment for everyone with HIV is growing among communities of people living with HIV, and the era of monitoring and counseling until a patient reaches ART "eligibility" is over. We now know that ART initiation is a matter of urgency.


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