7.1.1 When to start ART in adults and adolescents

Consolidated ARV guidelines, June 2013

Rationale and supporting evidence: Initiating ART regardless of CD4 cell count

HIV-positive partners in HIV-serodiscordant couples iii

The results of the HPTN052 study (18) strongly support the use of ART to prevent HIV transmission among HIV-serodiscordant couples. The Guidelines Development Group therefore endorsed the recommendations established in the 2012 WHO guidance on HIV testing and counselling including ART for treatment and prevention in serodiscordant couples (49) that the sexual partner with HIV in such a couple should be offered ART regardless of CD4 count.

Treating active TB disease iv

In 2010, WHO recommended starting ART in all people with HIV and active TB regardless of CD4 cell count, and that TB treatment should be started first, followed by ART, as soon as possible afterwards (and within the first eight weeks). The Guidelines Development Group reviewed evidence from three randomized clinical trials that showed for people with TB and severe immunodeficiency (CD4 count ≤50 cells/mm3), starting ART before eight weeks has a clinical benefit compared with deferring treatment to later than eight weeks (50–52) , and endorsed the 2010 recommendations. Implementation of the recommendations on HIV and TB management may be facilitated by integration of services (Chapter 9).

HIV and HBV coinfection with evidence of severe chronic liver disease v

HIV coinfection affects almost every aspect of the natural history of HBV infection. The consequences include higher rates of chronicity; less spontaneous HBV clearance; accelerated liver fibrosis progression with increased risk of cirrhosis and hepatocellular carcinoma; higher liver-related mortality and decreased ARV response (53–56). Liver disease has emerged as a leading cause of death in people coinfected with HIV and HBV (57,58).

The 2010 WHO ART guidelines (2) recommended initiating ART among all individuals coinfected with HIV and HBV who require treatment for their HBV infection (defined as chronic active hepatitis), regardless of CD4 cell count or WHO clinical stage. However, in the absence of routine screening for HBV, most people are unaware of their HBV status. In addition, there is limited access to costly diagnostic tools for staging liver disease (liver biopsy, transient elastography, HBV-DNA and serum biomarkers) needed to establish the presence of chronic active liver disease and eligibility for HBV treatment.

A meta-analysis (59) and a subgroup analysis of a randomized controlled trial (60) provide low-quality evidence of the overall impact of ART on liver-related morbidity and mortality among individuals coinfected with HIV and HBV, but these studies did not examine the benefit of initiating ART at higher CD4 counts.

Overall, the Guidelines Development Group considered that there was not sufficient evidence and/or a favourable risk–benefit profile to support initiating ART among all people coinfected with HIV and HBV with a CD4 count >500 cells/mm3 or regardless of CD4 count or stage of liver disease. There are also risks associated with initiating ART earlier (hepatotoxicity, immune reconstitution inflammatory syndrome and hepatic flares).

However, the Guidelines Development Group does recommend providing ART to all people coinfected with HIV and HBV regardless of CD4 count in people with evidence of severe chronic liver disease, who are at greatest risk of liver disease progression and mortality. The term severe chronic liver disease was used instead of chronic active hepatitis (as in the 2010 guidelines), as this is a term that is more widely understood and applicable using clinical criteria alone. In settings where ART cannot be provided to all individuals with HIV with CD4 counts ≤500 cells/mm3, giving priority to diagnosing and treating individuals coinfected with HIV and HBV should be considered.

As reported in the 2010 WHO ART guidelines (2), data from one randomized controlled trial support the use of at least two agents with activity against HBV (TDF + 3TC or FTC) in terms of improved viral load response and reduced development of HBV drug resistance (61,62).

Critical research gaps in this area include the need for more data on the impact of ART on liver-related outcomes in HBV-coinfected people in resource-limited settings and on the relative impact of ART in people with CD4 cell counts >500 cells/mm3 and early-stage liver disease.

iii An HIV-serodiscordant couple is a couple in which one of the sexual partners is HIV-positive and one is HIV-negative. Although one partner is currently HIV-negative, this does not mean that this partner is immunized or protected against getting HIV in the future.

iv Active TB disease refers to TB infection where the person has symptoms and clinical disease. Latent TB infection refers to TB infection where the person does not have symptoms or clinical disease. Not all persons with latent TB infection will develop TB disease, but the risk of progressing to disease is very high in people with HIV.

v Severe chronic liver disease includes cirrhosis and end-stage liver disease and is categorized into compensated and decompensated stages. Decompensated cirrhosis is defined by the development of clinically evident complications of portal hypertension (ascites, variceal haemorrhage and hepatic encephalopathy) or liver insufficiency (jaundice).