hiv treatment guidelines

The International AIDS Society-USA just published guidelines regarding hiv treatment (see hiv antiretrov rx recs 2014 jama​ in dropbox, or doi:10.1001/jama.2014.8722). recommendations (lots of changes since 2012):

When to start therapy:

    ​--Begin ART as soon as diagnosed HIV and independent of CD4 count, though recommendations more emphatic for those with CD4<500, or if pregnant, chronic hep B coinfection, HIV-associated nephropathy). should also be offered in acute infection, regardless of symptoms

    --Begin ART within 2 weeks of diagnosis of opportunistic infections (OI) and other AIDS-defining illnesses (eg lymphomas, HPV-related cancers)

    ​--for cryptococcal infections, optimal timing may be after 5 weeks of anti-cryptococcal infection [data are a bit mixed. in COAT trial there was increased mortality in those with severe disease, CD4<50 and CSF WBC<5 who were started on therapy in the 2-5 week range, vs >5 weeks -- increased mortality seemed to be from progressive cryptococcal meningitis and likely not immune reconstitution syndrome]

    --for TB, if CD4<50, start ART within 2 weeks. if higher CD4, then within 8-12 weeks. unclear timing for TB meningitis. if using rifampin-based therapy, best to use efavirenz plus 2 NRTIs. if efav is not tolerated, can use rifabutin-based TB therapy and give boosted PI plus 2 NRTIs. LTBI (latent TB infection)  can be treated with once-weekly INH with rifapentine for 3 months.

Recommendations for initial ART regimens (in alphabetical, not priority order -- all get the highest rating). should be guided by genotype

    --integrase strand transfer inhibitor plus 2 NRTIs

        --dolutegravir plus tenofovir/emtricitabine (can see increase in creatinine due to inhibited creat secretion, not from renal failure. tenof assoc with more decrease in bone mineral density and more kidney injury which is usually reversible. dolutegravir has higher barrier to resistance than elvitegravir or raltegravir, but not give simultaneously with divalent cations: calcium, magnesium, aluminum, iron)

        --dolutegravir plus abacavir/lamivudine (though abacavir in some combinations works less well with viral load>100,000, this combo seems to be fine at all viral loads. this combo to be a single pill in the future. use abacavir only if HLA-B*5701-negative, also abacavir may be assoc with more heart   disease.)

        --elvitegravir/cobicistat/tenofovir/emtricitabine (once daily combo pill, also increases creat  by inhibiting secretion. cobicistat has similar drug interactions as ritonivir)

        --raltegravir plus tenofovir/emtricitabine (raltegravir is twice daily. also less resistant to mutation than dolutegravir)

    --NNRTI plus two NRTIs

        --efavirenz/tenofovir/emtricitabine (combo pill atripla; efavirenz has CNS symptoms, usually for only 2-4 weeks, and is now considered okay in pregnant women -- though in my experience CNS effects can linger for years as vivid dreams for example. efavirenz assoc with more adverse lipids than dolutegravir/raltegravir or atazanavir)

        --efavirenz plus abacavir/lamivudine 

        --rilpivirine/tenofovir/emtricitabine (combo pill.  not recommended if viral load >100,000. also rilpivirine needs to have an acid stomach -- not with PPI or after gastric bypass)

    --Ritonivir-boosted PI plus 2 NRTIs

        --atazanavir plus tenofovir/emtricitabine (atazanavir assoc with nephrolithiasis, cholecystitis, chronic kidney injury -- combo of PI plus tenofovir assoc with more kidney injury and not always reversible. avoid atazanavir if taking on H2 blocker or PPI)

        --atazanavir plus abacavir/lamivudine

        --darunavir plus tenofovir/emtricitabine (during initial therapy, 800mg of darunavir plus ritonavir can be once daily)

    --alternatives (lower ratings): 

        --can use zidovudine/lamivudine twice daily if non-tolerant of abacavir or tenof

        --rilpivirine with abacavir/lamivudine

        --unboosted atazanavir (400mg/d), if not given with tenofivir, is acceptable

        --NRTI-sparing regimens, include boosted darunavir with raltegravir if CD4>200; lopinavir with raltegravir

        --raltegravir with abacavir/lamuvidine

        --nevirapine plus 2 NRTIs (avoid nevirapine if CD4>250 in women or >400 in men -- can get severe hepatotoxicity)

        --lopinavir plus either lamivudine or raltegravir  (lopinavir may be assoc with more heart disease.)

Recommendations for ART monitoring:

    --check viral load about 4 weks after treatment initiation and then every 3 months

    ​--CD4 at least every 3 months, esp if initial CD4<200 to determine when can stop OI prophylaxis

    --when HIV viral load is suppressed for 1 year and CD4>350, can monitor every 6 months [though in my experience, HIV mortality is largely confined to those who either never took meds regularly, or in those after taking meds regularly but have "pill-fatigue".  so i routinely do every 3-month check-ins,             reinforce med adherence, and check viral load and CD4]

    --when viral load is suppressed>2 years and CD4 persistently >500, can just monitor viral loads (but check CD4 if virologic failure or intercurrent immunosuppressive treatments or conditions)

    --detectable viral load (>50) should be rechecked within 4 weeks, before changing management [per other studies not cited here: treatment failure is viral load >200 checked twice, though those not completely suppressed may be more likely to fail over time]

    --HIV viral load >200 should evaluate for factor leading to failure and considering changing ART [in my experience, in patients who are not totally adherent to regimen, reinforcing adherence has brought the viral load to undetectable in many cases, even with less "lenient" regimens, such as             efavirenz-based ones]

    --check genotype before starting meds and if there is virologic failure

    --monitor for ART toxicity after week 16 of treatment [though i combine it with the 3-month check] then can be every 3-6 months, guided by presence or absence of comorbidities.

Recommendations for changing the ART regimen in treatment-experienced patients:

    --consider resistance patterns (genotype) and prior history of meds in generating new regimen. may need to check viral tropism assay etc, depending on regimen chosen. may be best to use boosted PI with newer drug (integrase strand transfer inhibitor or maraviroc -- to my reading and limited                 ​experience, dolutegravir is a pretty amazing, though expensive drug)

    --not use monotherapy with boosted PI [though pretty impressive recent article on utility of boosted lopinavir in resource-poor countries]

    ​--if switching regimen to simplify for virally-suppressed person, usually works well but consider prior resistance patterns, esp in those drugs with low barrier to resistance (NNRTIs, unboosted PIs, integrase inhibitors -- esp raltegravir). maintaining virologic suppression is paramount.

a few other comments: HIV care has become simpler and more complex -- the simple part is that patients have much much easier and more tolerable and more effective regimens (i remember many patients of old who were taking more volume of pills near the end of their lives than food, and at weird times of the day -- some spaced out 5x/day). the complex part is that there are so many options, more resistance and complex genotypes to interpret. one really helpful service for us guys in primary care is the San Francisco HIV warmline (which recently changed its name to the Clinician Consultation Center), a group of hiv doctors, pharmacists, etc available for free for consultation and suggestions, including faxing them genotype reports to help choose the best regimen. their phone number is 1-800-933-3413 and i have called them many times with great success. and they are usually available to answer the calls right away.

another comment: there is a push to using one-pill therapies. they make a lot of sense, are much easier for patients, but use drugs (eg tenof, FTC, 3TC) which need to be renally-dosed (and tenof is pretty renal-toxic).  

and, one issue with the combo pills is that there are no generic equivalents (ie, drug companies do very well from them). as of today, there is no generics for either tenof or FTC, though there is for 3TC (lamivudine), which is therapeutically equivalent to FTC (emtricitabine) -- ie, it would be cheaper to have 2 separate pills of tenof plus 3TC than brand-name Truvada....  and as more meds become generic, there will be more incentive of the drug companies to figure out combos that they can control