US (DHHS) ARV guidelines updated (February 2013): moderate recommendation to treat at CD4 count >500 is based only on expert opinion
Simon Collins, HIV i-Base
The DHHS adult and adolescent treatment guidelines are widely seen as the most important US document to outline optimised care.
Although the guidelines are reviewed throughout the year (the panel has monthly calls), major updates are usually annually and the latest version was released on 13 February 2013. 
The document in an important summary of current evidence and as such, it is essential reading to follow changes in the recommendations. It is also important to see which studies over the last year are seen as sufficiently relevant to change care. As good practice, changes since the last significant update from March 2012, are highlighted in the PDF file with yellow background.
The guidelines are extensively referenced for their evidence base and the writing panel includes leading US doctors and advocates.
The main changes in this update are listed below.
- In the introduction, in addition to reducing mortality and morbidity, ART is effective at reducing risk of transmission. Also that less than one third of HIV positive people in the US have an undetectable viral load, predominantly due to undiagnosed and failure to link to care. Discussions about health and prevention benefits of treatment should be started when someone is first diagnosed.
- The most significant change, perhaps, is to recommend ART for all patients irrespective of CD4 count, including early infection (defined as within six months of infection). The rating for this is BIII for people in chronic infection but counter-intuitively BII for early infection. The B rating makes this a “moderately strong” recommendation. The quality of evidence rating for early treatment (the II) comes from “one or more well-designed, non-randomised trials or observational cohort studies with long-term clinical outcomes”. The quality of evidence for treatment at high CD4 counts in chronic infection is less reliable, being only “expert opinion”.
- Although the priority in the guidelines is the medical benefit for the patient, the impact of treatment on prevention of sexual transmission is frequently stressed and is part of the combined decision to recommend earlier treatment. The evidence rating for reducing heterosexual transmission in AI and is AIII for “other risk groups”.
- HCV coinfection includes a stronger recommendation to use ART including at CD4 counts >500 and in people with cirrhosis. HCV serology has also been added to list of recommended tests after HIV diagnosis.
- A paragraph on long-term slow progressors and elite controllers recommends treatment if viral load is detectable >200-1000 copies/mL or if the CD4 count is declining and notes higher levels of immune activation and inflammation markers (compared to HIV negative controls).
- All four preferred first-line combinations include the dual nucleoside option of tenofovir/FTC.
- The guidelines include a new discussion on the advantages and disadvantages of the choice for the other components of a combination: efavirenz, atazanaivr/ritonavir, darunavir/ritonavir and raltegravir (ordered by FDA approval date).
- The panel still strongly caution against the use of efavirenz in women who are not using contraception or who wish to conceive. For women who become pregnant while taking efavirenz, switching to an alternative drug is not recommended, because the period of risk if the first 5-6 weeks of pregnancy, usually prior to knowing about the pregnancy. Use of AZT is no longer recommended for women whose viral load is <400 copies/mL at delivery. The incidence of transmission is referenced at less than 0.5% in the context of the mothers viral suppression at delivery.
- Elvitegravir, coformulated with cobicistat, tenofovir and FTC (tradename Stribild, previously Quad) has a page to expand on why this is not currently a preferred combination, and to detail prescription restrictions.
- New discussions are included about the use of treatment in early infection, combining acute and recent infection with a definition of within six months of infection. This section emphasises that treatment is recommended for all HIV positive people but that in early infection “definitive data are lacking as to whether this approach will result in long-term virologic, immunologic, or clinical benefit”. The references for this come from the ACTG 5217, SPARTAC and Primo-SHM studies that reported small short term benefits from a period of treatment in early infection (from 12 – 48 weeks). However, the guidelines use these studies to recommend lifelong treatment as strongly as they discourage interrupting treatment later.
- Drug resistance testing is recommended for integrase resistance in people using integrase-based combinations. Previously this was just considered.
- Tropism testing prior to prescribing a CCR5 inhibitor now includes genotype alternatives to phenotype tests.
- Drug interactions tables are updated with main chances relating to integrase inhibitors, and also to recently approved treatment for hepatitis C.
- Although cost of treatment is not directly addressed in the guidelines, Appendix B Table 8 list the suggested wholesale price (SWP) for individual ARVs, coformulations, and fixed dose combinations.
It is important to note that the recommendation to treat at any CD4 count above 500 is only rated at BIII. This is a moderate strength recommendation but evidence grading of III is based on the least reliable evidence (expert opinion, with no evidence either from randomised studies or observational cohorts).
It is also notable that references to the positive impact of treatment on prevention are included throughout the document and that both the strength of recommendation (A rather than B) and quality of evidence (graded as I rather than III) are stronger for this use of ART than clinical benefits.
For individual treatment decisions about when to start, these two benefits have to be discussed separately. For a further discussion on the complexities of the “when to start” debate, please see the article earlier in this issue of HTB (“Why the “when to start” question is complex and informed by limited evidence: a response to Dr Myron Cohen”).
The inclusion of routine HCV screening on HIV diagnosis coincided with a new US study reporting a prevalence of 6% of HCV coinfection in a cohort of MSM followed from 1997 to 2009, and an incidence rate of 1.6/100 person years (95% CI 0.97–2.30) in approximately 400 men with more than one test. Only one-third of infections were in men who reported injecting drug use as a potential risk. 
- US Department of Health and Human Sciences (DHHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. February 2013.
- Garg S et al. Prevalent and incident hepatitis C virus infection among HIV-infected men who have sex with men engaged in primary care in a Boston community health center. Clin Infect Dis. (2013). First published online: 5 February 2013. doi: 10.1093/cid/cit054.