WHO Gets Aggressive With Its HIV Treatment Guidelines

Pursuing the goal of an "AIDS-free generation," the World Health Organization (WHO) issued updated recommendations at IAS 2013 that call for earlier, safer and simpler antiretroviral therapy (ART). The WHO's estimation is that this move could avert an additional 3 million deaths and prevent 3.5 million more new HIV infections between now and 2025. Its new guidelines could increase the number of people eligible to receive ART to a total of 25.9 million worldwide.

The new recommendations encourage all countries to initiate treatment in adults living with HIV when their CD4+ cell count falls to 500 cells/mm³ or less, replacing the 350 cells/mm³ threshold in the previous guidelines, which were issued in 2010. The WHO qualified its updated recommendation as "strong" and backed by "moderate-quality" evidence.

The recommendation for initiating ART at CD4+ cell counts between 350 and 500 is based on a systematic review with GRADE evidence profiles that assessed the quality and strength of the evidence from 21 observational studies and three randomized controlled trials reporting morbidity and mortality, as well as immunological and virological outcomes. They showed that initiating ART at a CD4+ cell count >350 cells/mm³ compared with a CD4+ cell count <350 cells/mm³ reduced the risks of progression to AIDS and/or death, the development of tuberculosis and the development of a non-AIDS-defining illness; conversely, it increased the likelihood of immune recovery. (Although no studies suggest that earlier ART causes individual harm, these studies were of limited duration.)

Not everyone agrees with the WHO's new recommendations. The co-chairs of the START study argued that only four out of the 21 studies cited were appropriate, and they graded this body of evidence as insufficient to make recommendations because the size of the beneficial effect from earlier treatment was relatively small, the findings were inconsistent between studies (some found an effect, while others did not -- and the discrepancy was not clarified) and appropriate confounders were not adjusted for.

Regardless, the main point of increasing the CD4+ cell count threshold for ART initiation is probably not to protect the health of HIV-infected individuals (which could be debated), but to prevent HIV transmission, based on results of the HPTN 052 study.

The new WHO recommendations also suggest providing antiretroviral therapy -- irrespective of CD4+ cell count -- to all children with HIV under 5 years of age, all pregnant and breastfeeding women with HIV, all individuals with HIV who have active tuberculosis or hepatitis B (but not hep C), and all HIV-infected people in a relationship where one partner is uninfected.

Another new recommendation is to offer all adults starting ART the same daily, fixed-dose combination pill: tenofovir + lamivudine (or emtricitabine) + efavirenz. This recommendation even applies to pregnant women in the first trimester of pregnancy and women of childbearing age. This combination is easier to take and safer than alternative combinations previously recommended; it can be used in adults, pregnant women and adolescents.

If that combination pill is contraindicated or not available, one of the following options is strongly recommended (based on "moderate-quality" evidence):

• zidovudine + lamivudine + efavirenz
• zidovudine + lamivudine + nevirapine
• tenofovir + lamivudine or emtricitabine + nevirapine

A lopinavir/ritonavir-based regimen should be used as first-line ART for all children infected with HIV younger than 3 years (36 months) of age, regardless of NNRTI exposure, the guidelines say. If lopinavir/ritonavir is not feasible, treatment should be initiated with a nevirapine-based regimen. (This too is a strong recommendation based on "moderate-quality" evidence.)

Which other studies presented at IAS 2013 will have lasting impact long after memories of the conference itself have faded? Read more of Dr. Llibre and Dr. Young's top picks.