By Dr. Geoffrey Modest
The International Antiviral Society–USA panel just released their 2016 recommendations for antiretroviral drugs for treatment and prevention of HIV infection in adults (see Gunthard HF. JAMA 2016; 316(2): 191; and this group did include several HIV luminaries, such as Paul Sax from Brigham & Women’s and Paul Volberding from UCSF).
Summary:
- When to initiate therapy:
- Everyone who has detectable virus, independent of CD4 count; and as soon as possible after acute HIV infection (to reduce the latent HIV reservoir, immune activation and perhaps protection against infection of central memory T cells)
- Also in those with persistent undetectable virus without ART (antiretroviral therapy) if declining CD4 counts, which can occur in these “elite controllers”, since they have higher levels of immune activation and increased cardiovascular risk. [I had such a patient who died in his 40s from lung cancer and minimal smoking history. Though lung cancer can occur in such patients not infected with HIV, there is a higher risk of lung cancer in HIV patients, and my guess is that his “controlled HIV” off medications played a part. Unclear if meds would have helped, however]
- Start ART as soon as possible in patients with opportunistic infections (OIs), with the possible exceptions of cryptococcal meningitis (data from resource-limited settings showed poorer results with early treatment, though using flucytosine here seems to improve results). Need careful monitoring with active TB, esp TB meningitis, which has higher rates of immune reconstitution inflammatory syndrome (IRIS).
- Recommended initial regimens
- Dolutegravir/abacavir (ABC)/lamivudine (3TC)
- Dolutegravir plus tenofovir alafenamide (TAF)/embricitaine (FTC)
- Elvitegravir/cobistat/TAF/FTC
- Raltegravir/TAF/FTC
- A couple of comments:
- They replaced TDF (tenofovir disoproxil fumarate) with TAF because of increased bone loss and renal dysfunction/proximal renal tubular toxicity with TDF. However TAF should not be used with rifamycins and there are limited data on pregnant women. And TAF may have worse lipid profiles than TDF. But they note that TDF is basically fine to use if well-tolerated, more available in coformulation (i.e. with FTC), and potential concerns that TAF really has no long term data.
- Only use ABC if HLA-B*5701 negative. Also still use cautiously in those with high cardiovascular risk, since a few studies have suggested an association with MI
- All of these above regimens use InSTIs (integrase strand transfer inhibitors). suggested non-InSTI-based regimens include:
- Darunavir (boosted with cobicistat or ritonavir) plus TAF/FTC or TDF/FTC, or ABC/3TC
- Efavirenz/TDF/FTC (which, by the way, is generic, is associated with similar efficacy to the above regimens when patients are able to tolerate it, and would lead to a $900 million annual savings in the US over the prior branded version of Atripla -this study was done in 2012 prior to the newer ?more expensive regimens…. and efavirenz/TDF/FTC has been my go-to regimen for about 20 years and has done really, really well overall)
- Rilpivirine/(TAF or TDF)/FTC
- Special populations:
- Hep B coinfected
- Use regimen with TAF or TDF, 3TC or FTC, and a 3rd med for the HIV
- Pregnant women
- Treat the woman to improve her own health and decrease her likelihood of neonatal transmission
- AZT/3TC has the longest track record, though has more toxic effects
- Raltegravir is the recommended InSTI
- Boosted atazanavir/r daily or darunavir/r bid are recommended PIs
- Efavirenz is the recommended NNRTI after the 1st 8 weeks of pregnancy. Though if woman is on it before pregnancy, best to continue to maintain virologic suppression
- Hep C coinfected
- Use HIV meds that do not interact with Hep C virus therapies. Consult current HCV treatment guidelines
- At this point, recommended regimens include dolutegravir/ABC/3TC; and dolutegravir or raltegravir plus TAF/FTC.
- Specifically, would now avoid regimens with NNRTIs, boosted PIs or elvitegravir/cobicistat
- Renal disease
- Monitor all patients for development of kidney disease with eGFR, urinalysis, testing for glycosuria and albuminuria or proteinuria when ART initiated, changed, or every 6 months when HIV RNA is stable
- Worst offender seems to be TDF and especially in combo with boosted PIs [for unclear reasons, they do not comment that the D:A:D study, Mocroft A Lancet HIV 2016; 3: e23 found pretty equivalent declines in eGFR with atazanavir-r and lopinavir-r as with TDF]
- Not use or dose-adjust TDF if creatinine clearance<60
- Not use TAF if renal function gets worse (esp proximal tubule dysfunction) or if creat clearance <30
- Renal transplant is okay if ESRD, since high expectation of high rates of patient and graft survival [though, I should add, there are data that those with CD4<200 fare less-well, to the point that one of my patients on dialysis cannot get a renal transplant until his CD4 is consistently above 200]
- Osteoporosis/fractures
- Patients may lose 2-6% of bone mineral density at the hip and spine in first 1-2 years. greater initial decline with TDF-containing regimens, so avoid in osteopenicpatients
- Hep B coinfected
- CD4 count and primary OI prophylaxis
- Prior guidelines for OI prophylaxis were based on CD4 counts
- They feel that for patients achieving viral suppression with ART, the incidence of MAC (mycobacterium avium complex) has declined so much that primary prophylaxis is not recommended, though not enough data on PCP (pneumocysitis jirovecii pneumonia) so should still use prophylaxis (see my comment below)
- Lab monitoring (not much change):
- The usual: initial CD4, viral load, hepatitis serologies, comprehensive metabolic panel, urinalysis, STIs, lipids. Also genotype testing for resistance. Recheck 4-6 weeks after starting ART. Then every 3 months for a year. Then can go every 6 months for adherent patients with suppressed virus. They also suggest checking HLA B*-5701 prior to initiating ABC treatment (though I do check it routinely on initial presentation in case I need to change meds later)
- If pretreatment CD4<200, check every 3 months until viral load reliably suppressed and CD4>350 for 1 year. Then every 6 months until virus suppressed for at least 2 years and CD4>500
- When virus suppressed for >2 years and CD4>500, repeat monitoring of CD4 unnecessary unless virologic failure (defined as viral load >200)
- If viral load rebounds to >50, assess for causes of virologic failure (in particular medication adherence, and food-drug interactions)and repeat in 4 weeks
- Typically virologic suppression occurs within 24 weeks of ART initiation
- If virologic failure, check genotype (consider proviral DNA assays to estimate archived resistance if the viral load is below 500-1000, the limits of the regular genotype assay) and change ART meds (studies mostly suggest that viral loads in the 50-200 range should be monitored more closely, since the data are inconsistent about virologic failure)
- Can do InSTI resistance testing if patient fails therapy and has not stopped ART for >1 month.
- Engagement in care/adherence
- Early diagnosis is important. We should use an opt-out strategy for testing (i.e., present testing to the patient as a usual lab test, allowing for patients to actively opt out of testing)
- Retention in care is key: 30% of new HIV infections are in people with undiagnosed infections, 60% in those not engaged in care
- Predictors of not being engaged in care include:
- Substance use (and methadone maintenance programs/opioid substitution therapy are great ways to retain patients in HIV care)
- Depression
- Directly observed treatment is helpful (as in methadone programs or other daily contacts with patients)
- Patient navigators and care coordinators help
- Prevention (not much change):
- Treatment as prevention is primary strategy
- Pre-exposure prophylaxis (PrEP), especially if population has HIV incidence >2%/yr. can be daily TDF/FTC (which they prefer) or intermittent (see blogs below)
- Immunize against hep A,B. Check for STIs. Follow at least every 3 months
- Post-exposure prophylaxis as soon as possible after exposure (prior to test results, and within 72 hours per most guidelines). Use TDF/FTC plus raltegravir bid or dolutegravir daily and continue 28 days. Check HIV serologies at 4-6 weeks, 3 months, and 6 months later. Can also use TDF/FTC plus boosted darunavir or TDF/FTC/cobicstat/elvitegravir
Commentary:
- In terms of OI prophylaxis, I’m not sure I’m ready to stop MAC prophylaxis based just on viral suppression. I have seen a few patients on long-term ART with consistent viral suppression but who maintain very low CD4 counts (on the order of 50). The data supporting not using MAC prophylaxis is from a small study (see Yangco BG. AIDS Patient Care STDS 2014; 28(6): 280) of 41 patients eligible for MAC prophylaxis by CD4 count but not on it, put on ART with subsequent viral loads <1000, and finding no MAC infections. BUT, this was an observational study; of the only 11 MAC infections in the overall cohort (n=369), the infections happened 43-126 days after starting ART; and there are no data on how their CD4 counts changed after 1-2 months on therapy (i.e., did these patients remain below the 50 cells/mL level while on therapy???). The paper’s conclusion was “primary MAC prophylaxis may not be required for virologically suppressed patients with CD4<50 cells/ml”. So, out of caution and without a clear study, I personally would still keep patients on prophylaxis until their CD4 counts increase sufficiently (>50).
- A still unanswered and not so uncommon situation is immunologic failure: patients who continue to have viral suppression but have deterioration of their CD4 counts. I have had several patients with this, and my very anecdotal experience is that patients have a pretty sustained increase in CD4 when I have added/switched to dolutegravir.
- So, this guideline reflects the fact that the treatment of HIV infection has been transformed more rapidly and dramatically than any treatment I have seen. It has gone from a disease with essentially 100% mortality, despite taking >30 pills/day with meds up to every 4-5 hours throughout the day and night, and lots of adverse reactions, to an essentially 100% treatable disease with 1 pill a day and no adverse reactions. In fact HIV infection is now much easier to treat than hypertension and much much easier than diabetes…
See:
https://stg-blogs.bmj.com/bmjebmspotlight/2015/12/23/primary-care-corner-with-geoffrey-modest-md-hiv-therapy-without-nrtis/ for a blog on HIV therapy without NRTIs, in those intolerant or resistant
https://stg-blogs.bmj.com/bmjebmspotlight/2015/10/05/primary-care-corner-with-geoffrey-modest-md-hiv-pre-exposure-prophylaxis/ for a blog on the PROUD trail of daily TDF/FTC as PrEP
https://stg-blogs.bmj.com/bmjebmspotlight/2015/12/18/primary-care-corner-with-geoffrey-modest-md-on-demand-hiv-pre-exposure-prophylaxis/ for the IPERGAY trial of on-demand TDF/FTC PrEP
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