Treatment of HIV-1 infection: is it time to hit early again?

Highly active antiretroviral therapy (HAART) for the treatment of HIV-1 infection has dramatically reduced morbidity and mortality [1,2]. Triple combination therapy including a protease inhibitor was introduced widely in 1996 and, since then, numerous studies have demonstrated a clear survival benefit if patients were treated when they had CD4⁺ T-cell counts of fewer than 200/µl, or severe symptoms. At the same time, basic research revealed that the lentivirus HIV-1 induces a massive turnover of viral particles and CD4⁺ target cells [3]. Availability of effective therapy and knowledge about viral pathogenesis led to the ‘hit-hard and hit-early’ treatment approach [4].

For several years, patients were treated solely for elevated HIV-1 viral-load values, irrespective of their CD4 cell counts. Unfortunately, in the early years of HAART, problems, such as high pill burden, unexpected long-term toxicities and selection of drug resistance, severely limited the success of treatment. As a consequence, the ‘hit-hard and hit-early’ approach was changed to a strategy best described as ‘hit hard, but only if necessary’ [5]. It was clear that patients with symptomatic HIV-1 infection (AIDS-defining disease or severe symptoms) and asymptomatic patients with fewer than 200 CD4⁺ T cells/µl should be treated [6,7]. However, the optimal time to initiate therapy in asymptomatic patients with CD4 cells greater than 200/µl was (and still is) unclear. Data from the Multicenter AIDS Cohort Study (MACS) [8] demonstrated that the 3-year risk for disease progression to AIDS was 38.5% in patients with CD4 cell counts of 201–350/µl and 14.3% in patients with CD4 cell counts of more than 350/µl. However, the MACS data were generated prior to availability of HAART, so there were no therapeutic interventions to avoid disease progression at any given CD4 strata. Observational studies of HAART-treated cohorts provided valuable information for initiation of antiretroviral therapy in asymptomatic patients.

In 2001, analysis of data from more than 12,500 patients derived from 13 European and North American cohort studies clearly demonstrated an increased 3-year probability of progression to AIDS or death in patients with CD4 cell counts less than 200/µl [9]. However, the 3-year probability of progression to AIDS or death of 4.7% among patients with CD4 cells of 200–349/µl was not significantly statistically different from the risk of 3.4% among patients with CD4 cell counts of more than 350/µl. Most guidelines recommended to consider treatment in patients with CD4 cells of 200–350/µl and to defer treatment in patients with CD4 cell counts of more than 350/µl. However, the availability of several new drugs with new mechanisms of action, higher potency, optimized dosing convenience and improved safety profiles, as well as the accumulation of data from patients receiving their first antiretroviral regimens, demonstrating fully suppressive and well-tolerated HAART for almost a decade of therapy, fueled the discussion regarding earlier treatment. The Department of Health and Human Services (DHHS) guidelines list the potential benefits and risks of early therapy (see following) [101].

Potential benefits of early therapy include:

•	Maintenance of a higher CD4 count and prevention of potentially irreversible damage to the immune system;

•	Decreased risk of HIV-associated complications that can sometimes occur at CD4 counts of more than 350 cells/µl, including tuberculosis, non-Hodgkin’s lymphoma, Kaposi’s sarcoma, peripheral neuropathy, human papillomavirus-associated malignancies and HIV-associated cognitive impairment;

•	Decreased risk of nonopportunistic conditions, including cardiovascular disease, renal disease, liver disease and non-AIDS-associated malignancies and infections;

•	Decreased risk of HIV transmission to others, which will have positive public-health implications.

Potential risks of early therapy include:

•	Development of treatment-related side effects and toxicities;

•	Development of drug resistance owing to incomplete viral suppression, resulting in loss of future treatment options;

•	Less time for the patient to learn about HIV and its tr-eatment and less time to prepare for the need for adherence to therapy;

•	Increased total time on medication, with a greater chance of treatment fatigue;

•	Premature use of therapy before the development of more effective, less toxic and/or better studied combinations of antiretroviral drugs;

•	Transmission of drug-resistant viruses in patients who do not maintain full virologic suppression.

There is still no prospective, randomized clinical trial that definitively addresses the optimal time to start HAART in asymptomatic patients with CD4 cell counts of more than 200/µl. However, there are now data from the Antiretroviral Therapy Cohort Collaboration [10], including almost 62,000 patient-years of follow-up, demonstrating a significantly reduced risk for AIDS or death at 3–5 years after starting HAART in patients who started therapy with CD4 cell counts of 200–350/µl compared with patients with CD4 cell counts fewer than 200/µl. In October 2007, the European AIDS Clinical Society (EACS) issued their updated ‘Guidelines for the Clinical Management and Treatment of HIV-Infected Adults in Europe’ during the 11th European Aids Conference in Madrid (Spain), which were later published in print [11]. These guidelines marked a first shift because, instead of considering treatment, HAART was recommended for patients with CD4 cells of 200–350/µl. Only 5 weeks later, on the 1st December 2007, the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents published their ‘Guidelines for the use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents.’ [101], in which HAART was also clearly recommended for patients with CD4 cell counts of 200–350/µl. At the last Conference on Retroviruses and Opportunistic Infections, held in Boston (MA, USA) in February 2008, several speakers tended toward an even earlier initiation of HAART.

Recommendations are based upon expert opinion and scientific evidence. When appropriate data are not available or data from small studies are contradictory, recommendations are based on expert opinion. In other words, if we do not have evidence-based medicine, we will have eminence-based medicine. In the past, expert opinions were sometimes based on promising (but insufficient) data and attractive (but unproven) hypotheses. Examples for expert opinion-based strategies are discussed in the following sections.

Immediate treatment of acute HIV-1 infection to preserve immune functions

This strategy has been tested in a series of controlled trials and there are no convincing data to support immediate therapy. Treatment of acute HIV-1 infection is still based largely on theoretical considerations. It remains an individual option but cannot be generally recommended. Patient enrollment in clinical studies or precise documentation for retrospective analyses is desirable.

Strategic treatment interruptions to limit toxicities & to improve quality of life

The Strategies for Management of Antiretroviral Therapy (SMART) study [12], the largest interventional study in HIV-1 medicine to date, with more than 5000 participating patients, has definitely shown that planned long-term treatment interruptions should not be recommended. Patients remaining on HAART had significantly less clinically significant adverse events and fewer died compared with patients whose therapy was ceased.

Hit the virus hard & hit it early

In the first few years of the HAART era, this expert opinion-based strategy led to high rates of unacceptable side effects of long-term treatment, limited quality of life and increased emergence of drug resistant HIV-1 due to suboptimal potency of individual HAART components.

As explained previously, increasing numbers of optimized drugs with higher potency, better tolerability and fewer toxicities, approval of drugs with new target structures (CCR5 inhibitors, integrase inhibitors) and increasing knowledge about immunopathogenesis of HIV-1 infection make the ‘hit-hard and -early’ strategy more reasonable again. The near future will bring us results from a prospective, randomized clinical trial, which will, hopefully, shed more light on the optimal time to initiate HAART. This clinical trial is called Strategic Timing of Antiretroviral Treatment (START) [102]. START will analyze AIDS diagnoses, serious non-AIDS events and death from any cause in patients with more CD4 cells than 500/µl. These patients will be randomized into one of two arms; patients in the early-antiretroviral treatment (ART) arm will immediately initiate HAART, whereas patients in the deferred ART arm will wait to initiate HAART until their CD4 cell count drops to less than 350/µl or until symptoms develop. The study is planning to recruit 1500 patients per study arm. Therefore, START will be one of the largest clinical trials in HIV-1 medicine that will change the status of the ‘hit hard and early’ strategy from eminence- to evidence-based medicine. Clinicians are asked to recruit patients for the START trial in order to help answer the question: is it time to hit HIV-1 early again? Patients not recruited for the START trial should be managed according to current guidelines.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.