HIV treatment recommendations 2022

 The International Antiviral Society-USA Panel issued their 2022 recommendations on antiretroviral drugs for treatment and prevention of HIV infections in adults (see hiv antiretrov recs 2022 in dropbox, or doi:10.1001/jama.2022.22246). 

 

Details of recommendations, along with commentary embedded in brackets 

 

Initiation of antiretroviral therapy (ART) 

-- Treat early and aggressively, preferably within seven days of diagnosis, but including the option of same-day initiation of ART on the day of diagnosis or the first clinic visit (though this assumes that there is no evidence of an opportunistic infection, which might delay starting the ART (see their Box 1 for more details on this) 

-- Early therapy initiation is beneficial for a few reasons: 

    -- starting therapy early leads to a higher likelihood that patients will get into therapy. [This is similar to starting statins in hospitalized patients who have an MI: starting meds right away leads to much improved long-term medication taking] 

    -- “treatment as prevention”: the new medications are so powerful and lead to much more rapid declines in viral load than older meds; early treatment therefore is even more powerful in preventing the spread of HIV to others 

    -- even in “elite controllers” who may have very low or undetectable HIV viral loads without therapy, they do have elevated levels of inflammation that are  reduced when ART is initiated. So treating elite controllers should be helpful, based on theoretical benefits of reducing inflammation [chronic inflammation is associated with an array of bad outcomes, including everything from cardiovascular disease to diabetes to depression… 

        -- the risk of cardiovascular disease remains high even in those on well-treated HIV, likely related to  the generalized inflammatory response, though diminished in those with virologic control [ie, even well-treated HIV should be incorporated into our cardiac risk model as an atherogenic risk factor] 

        -- the risk of cancer is also increased, even in those on ART (see https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2794862 ), reinforcing the importance of routine cancer screening.  Overall, the HIV-associated cancers (eg kaposi, non-Hodgkin lymphoma) are decreasing but some  non-HIV defining cancers have increased. For example, cervical cancer in women is higher in those with HPV (see https://www.researchgate.net/profile/Manuela-Ceccarelli-2/publication/334279700_Cervical_cancer_in_women_living_with_HIV_a_review_of_the_literature/links/5e7e23d8a6fdcc139c0c36b6/Cervical-cancer-in-women-living-with-HIV-a-review-of-the-literature.pdf ), which likely informs the need for increased cervical cancer screening (eg, every 3 years, with no cutoff at age 65) 

 

Initial ART regimens in those with HIV 

-- preferred regimens are those containing InSTIs, integrase strand transfer inhibitors: dolutegravir and bictegravir 

    -- bictegravir plus TAF (tenofovir alafenamide) plus FTC (emtricitabine) 

    -- dolutegravir plus TXF (this connotes either TAF or TDF) plus XTC (this connotes FTC or 3TC) 

    -- dolutegravir plus 3TC (dual therapy), but only if the HIV viral load is <500K and hepatitis B co-infection has been ruled out. Also, the studies done on this combo did not include patients with severe HIV infections and CD4 counts <200, so unclear if this dual therapy is adequate 

        -- also, initiation of this regimen should not be a rapid one, since genotype, HIV viral load, and HBV serology may not be available. See below for further commentary on this dual therapy 

        --  those who do not have measurable hepatitis B virus and are not immune to hepatitis B should be vaccinated and have immunity assessed  post-vaccination, just to make sure that they are getting adequate hepatitis B coverage and the decreased likelihood of hepatitis B resistance, as happens with a single agent of XTC 

    -- long-acting cabotegravir-rilpivirine (the parenteral option) is not recommended for initial ART 

    -- abacavir is no longer recommended as initial therapy (it is associated with cardiovascular disease, and has no advantage over the dolutegravir/3TC combo) 

-- in those with PrEP  failure: 

    -- if on cabotegravir for pre-exposure HIV prophylaxis: 

        -- important to get InSTI genotype before starting an InSTI-based regimen, given that cabotegravir may be present in the blood after stopping it for up to 2.5 years in males and 4 years in females 

        -- if resistant or genotype are not available, prescribe a boosted darunavir regimen with TXF/XTC 

    -- in those with a TXF-based PrEP, perform resistance testing but do not delay starting ART with a three drug InSTI-based regimen as above. If resistance is found (in the worst case: with both K65R and M184V mutations), these InSTI-based regimens seem to be active 

-- in pregnant women: 

    -- begin ART immediately but avoid any regimen with cobicistat;  dolutegravir with TAF/FTC is the preferred regimen, having lower rates of adverse events and improved infant outcomes (the preliminary data from the Tsepamo study suggesting increased neural tube defects was overturned in updated results) 

    -- if patients are already stable on regimens with bictegravir, doravirine, cabotegravir, and dolutegravir/3TC, women may choose to stay on these meds but should be followed more frequently with HIV viral load monitoring (though these regimens should not be initiated during pregnancies) 

 

Switching ART regimens 

-- any switch should lead to more frequent clinical and laboratory follow-up until the regimen is demonstrated to be well-tolerated and effective, preferably the initial test being one month after changing therapy, whether patient has viral suppression are not 

-- in those with viral suppression, switching from a three drug strategy to dolutegravir/3TC/TAF is works well even in those who had historic M184V mutations (found in those with XTC resistance mutations) 

-- for those who are switching because of virologic failure, viral load testing should be repeated monthly until suppression is undetectable, and then every six months thereafter 

    -- the most common reason for virologic failure is poor med adherence. Should get genotypes when there is virologic failure 

 

Laboratory testing/monitoring 

-- HIV RNA viral load: every 3 months until suppressed, then every 6 months 

-- CD4: every 6 months until >250 for 1 year, then can stop if viral load continues to be suppressed 

-- cryptococcal antigen: if CD4 <100 

-- assess treatment adherence within 6 weeks of starting ART  [I usually have a nurse or HIV counselor reach out to patients in the first week to see if they have any adverse effects or issues with med adherence] 

 

Preexposure prophylaxis 

-- condoms remain the cornerstone of STI prevention, and clearly should be emphasized 

-- PrEP should be discussed with all sexually active adolescents and adults, and anyone who injects nonprescription drugs (e.g. opioids, methamphetamine) or anyone with a substance use disorder; also in populations with high HIV incidence rates 

-- there several options for PrEP, summarized in their table 4, including the following, though the most important factor is what is most acceptable to the patient: 

    -- for cisgender males, can use TDF/FTC (available as a generic), initiated as a double dose on the first day followed by daily single tablets, and they should not be discontinued until at least two days after the last sexual activity 

    -- for non-cisgender males, seven days of daily dosing is likely to be required to reach maximum protection and is recommended for at least seven days after last risky activity; this daily regimen is also suggested for people are pregnant or breast-feeding 

    -- on-demand oral dosing is also recommended for cisgender men of any sexual orientation, but there is insufficient data to support its use in people having receptive vaginal sex or injection drug use. For on-demand testing, there should be a double dose 2 to 24 hours before plan sexual activity and a single dose at 24 and 48 hours subsequently (see http://gmodestmedblogs.blogspot.com/2020/01/on-demand-prep-works-if-fewer-meds-and.html )

        -- if there is additional sexual activity within seven days of the initial planned activity, daily single dosing should be continued until two doses after the last planned activity 

       -- this regimen should be used with caution in transgender women receiving gender-affirming hormone therapy, especially with the first dose, or reinitiating TDF/FTC after a prolonged hiatus because rectal tissue concentrations may be somewhat lower early after starting the 2-1-1 regimens 

    -- daily TAF/FTC is preferred over TDF/FTC in people with creatinine clearance between 30 and 60, or when there is osteopenia or osteoporosis 

       -- TAF/FTC should be limited to cisgender  men of any sexual orientation and anyone whose risks do not include receptive vaginal sex, or those whose risk is exclusively posed by injection drug use 

    -- injectable regimen: long-acting injectable cabotegravir is recommended for the prevention of sexual transmission of HIV, but there is insufficient data on those with injection drug exposures (though it is still recommended for those who also have a sexual exposure) 

        -- there is no need for an oral lead-in of cabotegravir, as with HIV therapy noted below, other than those with severe atopic histories 

        -- onset of protection is likely about seven days after the first injection; barrier protection is therefore recommended for the first week of the first injection cycle 

        -- there is concern for InSTI resistance, given that there is potentially a prolonged pharmacologic “tail” after stopping the injections, with progressively decreasing blood levels 

    -- if there any questions, there is a very accessible PrEP Warmline at 855-HIV-PReP 

 

Postexposure prophylaxis 

-- a three-drug ART regimen for 28 days is recommended, beginning as rapidly as possible but within 72 hours of a percutaneous, mucous membrane, or sexual exposure to known or suspected HIV-positive blood, genital secretions, or visibly bloody secretions 

    -- medication should be given even before getting HIV testing on the source person if necessary for rapid initiation 

    -- if there is concern for drug-resistant HIV, or in the setting of pregnancy or breast-feeding, they advise expert consultation 

-- recommended regimen is either dolutegravir or bictegravir  with TXF/XTC 

 

There are also sections in these recommendations on substance use in persons at risk for and with HIV, Covid and HIV, and monkeypox and HIV. Please consult the full paper for these issues 

 

Further commentary: 

-- I personally have switched to the dolutegravir plus 3TC regimen in almost all patients (there is a combination pill for this called Dovato, a once a day regimen), after using an initial treatment of bictegravir/TAF/ FTC (Biktarvy, a combination pill for this, also a once a day regimen) that yields viral suppression (which happens essentially all the time), for the following reasons: 

    -- HIV has become a chronic disease, and many patients are likely to live with HIV, often for many decades 

    -- TAF is associated with several potential adverse effects, especially with long-term therapy: 

        -- chronic kidney disease: I personally have seen two cases of people developing major increases in their creatinine after starting a TAF-containing medication, which has resolved relatively quickly after switching to one not including TAF. And, it is clear that TDF is associated with significant renal toxicity (in particular Fanconi syndrome: see http://gmodestmedblogs.blogspot.com/2015/06/tenofovir-nephrotoxicity.html but also increased creatinine levels), and long-term TAF may well have long-term renal complications 

    -- TDF is associated with decreased bone mineral density, and though TAF has less bone toxicity, over the long term there may be clinically significant bone demineralization 

    --  Tenofovir is associated with significant weight gain, in particular in the first year after starting the medication. This increased weight gain is more profound in those with TAF vs TDF 

        -- there was a Swiss cohort study finding that switching from TDF to TAF led to increased weight gain of about 1 kg (see http://gmodestmedblogs.blogspot.com/2021/03/hiv-taf-inc-weight-metabolic-changes.html

        -- a meta-analysis of 8 RCTs in treatment-naïve HIV patients found a 4 kg increases with INSTIs, 2 to 3 kg increases with NNRTIs, and varying high amounts of weight gain with TAF (4.25 kg),  abacavir (3.08 kg), TDF (2.07 kg), and ZDV ( 0.39 kg). Interestingly, TAF in this study had the highest weight gain of all, though only marginally higher than the InSTI (see http://gmodestmedblogs.blogspot.com/2020/10/hiv-treatmentprevention-guidelines-2020.html ) 

   -- and, baseline, why give tenofovir long-term when dolutegravir/3TC works as well for the vast majority of people (see the GEMINI-1 and -2 trials: Lancet. 2019; 393 (10167), or https://www.thelancet.com/article/S0140-6736(18)32462-0/fulltext ), and this dual therapy does not include an unnecessary and a potentially toxic medication???? 

 

-- As I have mentioned in prior blogs, I am very concerned about using ritonavir- or cobicistat-based  regimens, given the potential drug interactions with steroids, even from injected intra-articular steroids or those administered by nasal or pulmonary sprays (see http://gmodestmedblogs.blogspot.com/2019/05/hiv-meds-local-steroids-and-cushings.html )

 

-- another concern is renal dosing of medications. This is quite problematic given:

    -- the remarkable inaccuracy of estimated GFR readings versus measured GFR (see http://gmodestmedblogs.blogspot.com/2022/07/egfr-not-such-great-estimate-of-renal.html )

    -- the general lack of data in the studies of people with significantly abnormal GFRs (ie they were excluded from the studies), leading for example to specific eGFR limits for lamivudine (3TC) , for example. Paul Sax in his blogs cited an article suggesting that real-world experience in those with very low eGFRs suggests they did fine on higher lamivudine dosing (see https://academic.oup.com/ofid/article/5/10/ofy225/5094657?login=false#122156569, though this was a small study)

 

--  I am also somewhat concerned about using the injectable cabotegravir/rilpivirine combination, since the recommendation in general is to give a 1-month trial of oral meds to ensure tolerability. But oral rilpivirine should not be given with a proton-pump inhibitor (rilpivirine needs stomach acid) and there is a potential problem with an H2-blocker. 

    -- and, the concern is that both the PPIs and H2Bs are available over-the-counter and used often for GI symptoms  (and rilpivirine itself is occasionally associated with nausea, vomiting, and abdominal pain) 

    -- also, there is a 1-2% risk of treatment failure with this injection, leading to the potential emergence of  InSTI resistance, and this seems to be higher in those getting injections every 8 vs 4 weeks 

        --and, those with treatment failure should avoid NNRTI- and InSTI-based regimens given the potential for resistance to either component of the injection (eg they should get a boosted darunavir regimen with TXF/XTC) 

 

So, a useful resource for those of us treating HIV or helping patients prevent getting HIV. It is still mind-boggling to me how far we have come with HIV, to the point that it has evolved to a much more easily treatable condition than diabetes. But, we and the population in general must not let our guards down: HIV infections remain a problem, with 34,800 new cases in 2019, which means that we all must still keep testing for HIV, even in the elderly (we found 2 cases in 75yo people at our health center…), and promoting PrEP to those at high risk 

geoff

 

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