Optimal timing for initiation of antiretroviral therapy (ART) has been controversial since zidovudine, the first antiretroviral agent, entered clinical use. Over the years, the pendulum has swung back and forth on the benefits of early ART. Finally, this long-running debate has been resolved by the results of a large, international, randomized trial of early compared with deferred ART.

In the START study,1 nearly 4700 patients with HIV with a CD4 count >500/mm3 were randomly assigned to immediate ART or deferral of ART until CD4 declined to <350/mm3 or the occurrence of a primary endpoint event, the composite of an AIDS-defining event, a serious non-AIDS illness, (cardiovascular disease [CVD], end-stage renal disease, hepatic decompensation or non-AIDS cancer) or death. 

More than half of the study participants were from low- or middle-income countries. An interim analysis at a mean follow-up of 3 years demonstrated a 57% reduction in primary end-point events in the immediate ART arm (1.8%) vs. the deferred ART arm (4.1%), yielding a hazard ratio of 0.43 (95% CI: 0.30-0.62, p<0.001), leading to early termination of the study.

Both AIDS and non-AIDS events were significantly reduced. The benefit of immediate ART was apparent when analyzed by gender, race, age, baseline CD4 and by country income level. Serious clinical adverse events not included in the primary endpoint were not increased by immediate ART and bacterial infections were significantly reduced.


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Early initiation of ART was also supported by a second trial of immediate vs. deferred ART conducted entirely in Africa. The TEMPRANO trial2, published simultaneously with START, noted a 44% reduction in a somewhat differently defined composite endpoint among a subset of 849 participants who entered the trial with CD4 >500/mm3.

START provides high level evidence supporting treatment of all patients with HIV, even those with normal CD4 counts.

Universal ART also fits well with current understanding of HIV pathogenesis, in which uncontrolled viral infection leads to an early and sustained inflammatory response that results in immune dysfunction and increases the risk of a spectrum of chronic co-morbidities.3 The results will have little effect on practice in wealthy countries, where guidelines already recommend broad treatment,4 but will greatly affect resource-limited countries that until now have restricted treatment to those with lower CD4.

The World Health Organization (WHO) recently issued new guidelines recommending ART for all.5 Delivering care consistent with these new guidelines will represent a huge challenge for public health officials and agencies that fund HIV care in limited-resource areas.

There may still be some objections to the conclusions of START. The AIDS events result was largely due to differences in tuberculosis and AIDS-related cancers, while the non-AIDS result was largely due to differences in non-AIDS cancers.1

If START had been conducted entirely in high-income countries with a lower risk of tuberculosis, the differences between arms may have been smaller. However, other benefits such as reduction in CVD and greater reduction in non-AIDs cancers may have emerged in a population at greater risk for these complications. Immediate ART did not significantly reduce mortality. The death rate was unsurprisingly low in a study population with high entry CD4 counts and carefully monitored in the context of a clinical trial.  Nevertheless, a non-significant trend favored the immediate ART arm (12 vs. 21 deaths, p=0.13).1

Although ART should now be considered appropriate for all patients, deferred initiation is prudent in certain situations. Untreated patients presenting with certain opportunistic illnesses may experience an immune response inflammatory syndrome (IRIS) due to the rapid improvement in immune function seen with ART.

Patients with tuberculosis (TB) or cryptococcal meningitis in particular may have paradoxical worsening of symptoms. Severe, even life-threatening clinical deterioration may occur within the first several weeks of beginning ART. The optimal time to start ART in TB co-infected patients has been carefully studied. Despite the increased risk of IRIS, patients with CD4 <50/mm3 cannot safely defer ART more than 2 weeks after initiation of TB treatment because of the very high risk of concurrent comorbidities.4 The same consideration applies to those with CD4 >50/mm3 but with severe TB illness or evidence or poor clinical status. Patients with higher CD4 and good clinical status can safely defer, but should begin ART after 8-12 weeks of effective TB treatment.4

Patients with cryptococcal meningitis also benefit from temporary deferral of ART because of the risk of life-threatening IRIS manifesting as increased intracranial pressure. ART should be delayed at least until completion of two weeks of amphotericin-based combination induction therapy, but deferral as long as 5-10 weeks may be needed.6 Patients who are elite controllers or long-term non-progressors are another controversial group. Arguments for and against ART exist and at present there is no evidence-based consensus.

All patients should be treated but not all patients are ready to begin. All patients still need careful evaluation for readiness to participate in treatment. Factors such as substance abuse, uncontrolled mental illness, homelessness, food insecurity, lack of insurance, poor understanding of the goals of treatment, and lack of motivation to be treated all may lead clinicians to defer therapy until these issues can be addressed. Once begun, ART is a life-long commitment. Some patients have great difficulty making that commitment.

HIV care providers may defer therapy on a case-by-case basis to allow the patient time to become as prepared as possible to be successful when ART is begun. Deferral of therapy does not mean withholding it indefinitely. For patients with early HIV and normal CD4 cell counts, it may be reasonable to devote considerable time and effort to addressing barriers to ART, while in those with advanced HIV, these issues should be addressed as quickly as possible and ART should be started concurrent with such efforts.

Although the science now clearly supports ART for all people with HIV, daunting obstacles to truly universal ART remain. Universal ART requires diagnosis, linkage and retention in care, and access to medication for all HIV-infected individuals.

The WHO has set an ambitious goal for the year 2020 known as “90-90-90”, meaning of all HIV-infected globally, 90% will be diagnosed, 90% of those will be in care and receiving ART, and 90% of those will achieve viral suppression. This translates to 73% of all patients with HIV suppressed on ART. In the United States, only about 30% are virally suppressed7and very few if any countries currently are meeting this goal, even those with comprehensive health systems.8 In addition to improving the health of individuals with HIV at all stages of infection, ART dramatically reduces HIV transmission.9 Dedication of additional resources to implement universal ART is a highly desirable public health goal that could lead to an end to the HIV epidemic.

References

  1. The INSIGHT START Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. 2015;373:795-807. DOI: 10.1056/NEJMoa1506816.
  2. The TEMPRANO ANRS 12136 Study Group. A trial of early antiretrovirals and isoniazid preventive therapy in Africa. N Engl J Med. 2015;373:808-22. DOI: 10.1056/NEJMoa1507198.
  3. Hunt PW. HIV and inflammation: mechanisms and consequences. Curr HIV/AIDS Rep. 2012;139-47. DOI: 10.1007/s11904-012-0118-8.
  4. Department of Health and Human Services. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. April 2015. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
  5. World Health Organization. Guidelines on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV. September 2015. Available at http://apps.who.int/iris/bitstream/10665/186275/1/9789241509565_eng.pdf.
  6. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf.
  7. HIV/AIDS Care Continuum. March 6 2015. Available at https://www.aids.gov/federal-resources/policies/care-continuum/.
  8. Kohler P, Schmidt AJ, Cavassini M, et al. The HIV care cascade in Switzerland: reaching the UNAIDS/WHO targets for patients diagnosed with HIV. AIDS. 2015;29:2509–15. DOI: 10.1097/QAD.0000000000000878.
  9. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365:493-505. DOI: 10.1056/NEJMoa1105243.