Hospital Medicine

Antiretroviral Therapy (ART) targeting HIV

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Antiretroviral Therapy (ART)

I. Introduction

Since the first description of cases of acquired immunodeficiency syndrome (AIDS) in the early 1980s, management of patients infected with the human immunodeficiency virus (HIV) has evolved dramatically. The first medication to treat HIV (zidovudine, ZDV) came on the market in 1987. Nine years later, the first highly active antiretroviral treatment (HAART) regimens became available through use of a potent new drug class (protease inhibitors, PI). HAART has led to a dramatic reduction in HIV-related mortality. In the 21st century all treatment regiments against HIV should be highly active, and the term ART (antiretroviral therapy) is used instead of HAART. Most starting regimens, while highly active, do not contain PIs anymore. HIV-infected patients adherent to effective ART now have a quasi-normal life expectancy and many take a combination regimen that is contained in one pill once a day.

Hospitalists will most commonly encounter HIV-infected patients admitted for problems unrelated to their HIV-infection. A smaller proportion of patients will present with an opportunistic infection often leading to a new diagnosis of HIV. Finally, some patients markedly suppressed CD4 counts (well below 200/microliter) will need frequent inpatient care due to inability to adhere to effective treatment regimens.

In this chapter the principles of ART to treat HIV-infection as they pertain to inpatient care provided by hospitalists are discussed.

Overview of HIV medications (classes and its members) currently FDA approved

Medications to treat HIV (antiretrovirals) are commonly classified based on their mechanism of action. Currently, more than 20 individual compounds in 6 different classes are known and over 30 different formulations (single- and multi-drug) have been FDA approved. The drug classes to treat HIV are:

  • NRTIs = Nucleoside/Nucelotide Reverse Transcriptase Inhibitors

  • NNRTIs = Non-Nucleoside Reverse Transcriptase Inhibitors

  • PIs = Protease Inhibitors

  • INSTIs = Integrase Strand Transfer Inhibitors

  • FIs = Fusion Inhibitors

  • CCR5 Antagonists (also known as Chemokine (C-C motif) Receptor Blockers or HIV Co-Receptor Blockers)

  • Pharmacokinetic Enhancers

Currently FDA-approved and available compounds to treat HIV:

Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)

  • abacavir (ABC, Ziagen®)

  • didanosine (ddl, Videx EC®) – rarely used

  • emtricitabine (FTC, Emtriva®)

  • lamivudine (3TC, Epivir®)

  • stavudine (d4T, Zerit®) – rarely used

  • tenofovir DF (TDF, Viread®)

  • zidovudine (ZDV, AZT, Retrovir®), – infrequently used

  • abacavir+zidovudine+lamivudine (ABC+AZT+3TC, Trizivir®), – infrequently used

  • abacavir+lamivudine (ABC+3TC, Epzicom®, Kivexa®)

  • tenofovir DF+emtricitabine (TDF+FTC, Truvada®)

N.B.:

d4T, ddI and ZDV are now rarely prescribed in the U.S. because of their unfavorable side effect profile.

Zalcitabine (ddC) previously marketed under the name Hivid® is as of 2006 no longer available in the U.S.

Trizivir is not commonly used since it only has 3 NRTIs but no other class of drugs, and is thus not recommended as stand-alone ART.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

  • delavirdine (DLV, Rescriptor®), rarely used

  • efavirenz (EFV, Sustiva®, Stocrin®)

  • etravirine (ETR, Intelence®)

  • nevirapine (NVP, Viramune XR®), infrequently used in the U.S.

  • rilpivirine (RPV, Edurant®)

N.B.:

ETR and RPV are commonly referred to as "second-generation NNRTIs" due to their ability to resist one of the common NNRTI mutations, K103N, which renders the other three members of the class ineffective.

Protease inhibitors (PIs)

  • atazanavir (ATV, Reyataz®)

  • atazanavir/cobicistat (ATV/c, Evotaz®)

  • darunavir (DRV, Prezista®)

  • darunavir/cobicistat (DRV/c, Prezcobix®, Rezolsta®)

  • fosamprenavir (FPV, Lexiva®, Telzir®)

  • indinavir (IDV, Crixivan®), rarely used

  • lopinavir/ritonavir (LPV/r, Kaletra®, Aluvia®)

  • nelfinavir (NFV, Viracept®), infrequently used in U.S.

  • ritonavir (RTV, Norvir®), no longer used as full-dose PI, used only as pharmacokinetic enhancer

  • saquinavir (SQV, Invirase®), rarely used

  • tipranavir (TPV, Aptivus®)

N.B.:

IDV, NFV and SQV are infrequently used due to their unfavorable side effect profile.

Amprenavir (APV) is no longer marketed in the U.S. as of 2005; it has been replaced by its pro-drug FPV.

Integrase strand transfer inhibitors (INSTIs)

  • dolutegravir (DTG, Tivicay®)

  • elvitegravir (EVG, Vitekta®)

  • raltegravir (RAL, Isentress®)

N.B.:

Dolutegravir (DTG) is considered a second-generation INSTI, can be used when there is resistance to RAL (first-generation INSTI)

Fusion inhibitors

  • enfuvirtide (T-20, ENF, Fuzeon®), infrequently used given that it has to be injected

CCR5-inhibitor

  • maraviroc (MVC, Selzentry®, Celsentri®)

MVC is the only drug in its class to date.

Pharmacokinetic Enhancers

  • ritonavir (RTV, Norvir®), see also above under PIs

  • cobicistat (GS-9350, Tybost®)

Currently FDA-approved Multi-Class Combination Drugs (that contain a fully active regimen)

  • Atripla® (efavirenz + tenofovir DF + emtricitabine) (NNRTI-based)

  • Complera®, Eviplera® (rilpivirine + tenofovir DF + emtricitabine) (NNRTI-based)

  • Genvoya® (elvitegravir/cobicistat + tenofovir AF + emtricitabine (INSTI based)

  • Stribild® (elvitegravir/cobicistat + tenofovir DF + emtricitabine) (INSTI based)

  • Triumeq® (dolutegravir + abacavir + lamivudine) (INSTI based)

Goals and general concepts

The goal of ART

(i) Achieve sustained suppression of viral replication (maximally and durably). Reduce risk of selection of drug-resistant virus.

(ii) Restore and maintain normal immune function as best as possible by restoring/maintaining normal CD4 cell count, reduce inflammation.

(iii) Prevent transmission of virus to uninfected persons by suppressing the virus in the infected individuals.

With the currently available treatment options, eradication of HIV infection is not possible. Thus, ART, once initiated is to be continued for life and thus requires sustained commitment from patients and providers to achieve good long-term adherence. Treatment interruption should be avoided since it can increase morbidity and mortality.

General recommendations regarding ART

(i) Initiate treatment for HIV with at least three different active drugs from at least two different classes. Include an NRTI-backbone in the regimen.

(ii) Prior to initiation of treatment obtain baseline laboratory information which should include the following:

- HIV antibody testing

- CD4-T cell count

- HIV viral load (plasma)

- genotypic resistance testing

- other labs: CBC, CMP, lipid profile, Hepatitis A, B, C serology, STI testing

(iii) Take into consideration potency of a chosen regimen, HIV-resistance profile, adherence factors (pill burden / side effect profile) and cost.

(iv) For inpatients: also consider which compounds can be administered if the patient is unable to swallow (administration IV and or via feeding tube).

In general, treatment should be started in the outpatient setting under supervision of a trusted and knowledgeable HIV-provider. HIV replicates rapidly and with a remarkable ability to mutate. Problems with adherence to a given ART regimen are major risk factors for the development of resistance and traditionally this has been linked to subsequent treatment failure.

Recommendations when to start ART in treatment-naive patients

Initiation of treatment is recommended for all HIV-infected patients (usually in the outpatient setting) regardless of CD4 count and/or symptomatology.

Conditions that favor a more urgent starting of ART (even in the inpatient setting):

(i) Pregnancy (especially during second and third trimester)

(ii) Presence of any acute opportunistic infections (OIs), but particularly those without specific known therapies. Examples of the latter include JC-virus infection causing progressive multifocal leukeoncephalopathy (PML), GI-related microsporidium or cryptosporidium infection.

(iii) Low CD4 count (below 200/microliter) or rapidly declining CD4 count.

(iv) HIV associated nephropathy (HIVAN)

(v) Acute HIV (seroconversion)

(vi) Co-infection with Hepatitis B and or C

Deferring ART should be considered in the following conditions:

(i) Significant barriers to adherence to a proposed ART regimen.

(ii) Co-morbidities and conditions that may prohibit successful administration of ART (Examples: acute liver injury, short-term need to take other medications that have significant drug-drug interactions with available ART, conditions that temporarily prohibit enteral administration of medications).

(iii) Co-morbidities that carry a much worse prognosis than that of HIV-infection itself (i.e., non-HIV related malignancies, end stage liver disease, etc.). Notable exceptions: HIV associated malignancies like Kaposi's sarcoma and serious liver disease due to hepatitis B and/or C, dementia that may be due to or exacerbated by HIV-infection.

(iv) So-called elite controllers/long-term non-progressors who have been stable clinically and with HIV-viral loads below detection level for years.

Recommended starting regimens for treatment-naive patients

All regimens for treatment-naïve patients should consist of an NRTI backbone (two nucleoside/nucleotide analogues) plus a potent agent from a different class, most commonly an INSTI, occasionally a boosted PI. NNRTIs as the third active agent are currently considered secondary/alternative agents for HIV treatment.

Resistance testing results, drug-drug interactions, side effect profiles, co-morbidities, and ease of administration are important considerations when choosing a regimen.

Recommended first-line regimens:

A) INSTI-containing first-line regimens:

  • Dolutegravir + abacavir+lamivudine (Triumeq®) (if HLA-B*5701 negative)

  • Dolutegravir + abacavir+lamivudine (Tivicay® + Epzicom®) (if HLA-B*5701 negative)

  • Dolutegravir + tenofovir DF+emtricitabine (Tivicay® + Truvada®)

  • Elvitegravir/cobicistat+tenofovir AF+emtricitabine (Genvoya®) (CrCl > 30 mL/min)

  • Elvitegravir/cobicistat+tenofovir DF+emtricitabine (Stribild®) (CrCl > 70 mL/min)

  • Raltegravir + tenofovir DF+emtricitabine (Isentress® + Truvada®)

B) PI-containing first-line regimens:

  • Darunavir + ritonavir + tenofovir DF+emtricitabine (Prezista® + Norvir® + Truvada®)

Alternative first-line regimens:

NNRTI-containing regimens:

  • Efavirenz+tenofovir DF+emtricitabine (Atripla®)

  • Efavirenz + abacavir+lamivudine (Sustiva® + Epzicom®) (if HLA-B*5701 negative)

  • Rilpivirine+tenofovir DF+emtricitabine (Complera®) (HIV VL < 100k pre-treatment and CD4 >200)

PI-based regimens:

  • Atazanavir/cobicistat + tenofovir DF+emtricitabine (Evotaz® + Truvada®) (CrCl > 70 mL/min)

  • Atazanavir + ritonavir + tenofovir DF+emtricitabine (Reyataz® + Norvir®+ Truvada®)

  • Darunavir/cobicistat + abacavir+lamivudine (Prezcobix® + Epzicom®) (if HLA-B*5701 negative)

  • Darunavir + ritonavir + abacavir+lamivudine (Prezista® + Norvir® + Epzicom®) (if HLA-B*5701 negative)

  • Darunavir/cobicistat + tenofovir DF+emtricitabine (Prezcobix® + Truvada®) (CrCl > 70 mL/min)

Comments

Keep in mind that the regimen choice may depend on the following factors:

- Pre-treatment HIV level (viral load) and CD4 count

- Drug resistance testing, regimen's barrier to resistance

- HLA-B*5701 status (when using abacavir)

- Patient preference, and patient's anticipated adherence issues, potential adverse effects, cost

- Co-morbidities (cardiac disease, renal disease, etc.)

- Pregnancy or pregnancy potential

- Co-infection with Hepatitis B, Hepatitis C and or tuberculosis

- Known or potential drug-drug interactions

Things to remember when starting ART initially:

  • CD4 <200: do not use rilpivirine based regimen or DRV/r + raltegravir

  • HIV VL >100k: do not use rilpivirine based regimen or ABC/3TC with EVF or ATV/r, do not use DRV/r + RAL

  • No resistance testing available: avoid NNRTIs

  • Renal disease: avoid tenofovir DF, may not be able to use fixed NRTI combination medications

  • Psychiatric illness/dementia: avoid efavirenz

  • High cardiac risk: avoid abacavir

  • Hepatitis B co-infection: use TDF/FTC whenever possible

Recommendations regarding changing an ART regimen

(i) Change ART because of virologic failure (repeatedly detectable virus on ART, patient adherent):

  • Obtain resistance testing while patient is on the failing ART regimen

  • Switch to a new regimen that includes at least 2, ideally 3, fully active new drugs based on results of recent genotyping (resistance testing).

(ii) Change ART due to toxicity, tolerability or for convenience (viral load is suppressed):

  • Single agent switch is ok

  • Avoid treatment interruption

  • Change/discontinue ART in staggered manner if NNRTI (with much longer half life) is part of the old regimen

Follow-up laboratory evaluation after ART initiation

Monitor both, CD4 count and HIV viral load to gauge effectiveness of therapy. Suppression of circulating HIV to levels below detection should be achieved after 3-6 months. In rare circumstances, total suppression with an effective regimen will require more time.

The CD4 cell count should rise by 50 to 150 cells/microliter in the first year. The largest increase is to be expected in the first 3 months on effective ART.

II. ART in the in-patient setting - summary points:

Treatment of HIV with ART requires long-term commitment from patient and provider. Adherence is of great importance. Usually ART is initiated in the outpatient setting.

For all HIV-infected patients admitted to the hospital, certain choices have to be made:

(i) If the patient had been on an ART prior to admission:

(a) continue same regimen, (b) modify (optimize) regimen, (c) stop ART (if compelling reason exist).

(ii) If the patient has known HIV but is not on any ART:

(a) continue to watch off ART, (b) (re)initiate ART while in the hospital.

(iii) If patient newly diagnosed with HIV during admission:

(a) start ART now, (b) start ART soon (as inpatient) but defer for now (risk of immune reconstitution inflammatory syndrome, unable to swallow, etc.), (c) defer ART to outpatient setting.

Generally, if possible, outpatient ART regimens should be continued. Exceptions include possible severe medication side effect, significant drug-drug interactions, inability to take medications by mouth, unreliable medication history, and poor adherence record.

If at all possible, consult with an experienced HIV provider or pharmacist knowledgeable in ART prior to starting treatment. Always get baseline blood work first (see above). Choose a regimen (usually 2 NRTIs and 1 drug from another class, usually INSTI) based on current guidelines. Also, for critically ill patients take into consideration whether medications can be given IV or via feeding tube.

If a regimen needs to be changed, distinguish between changing because of virologic failure or because of other reasons (side effects, drug-drug interactions, convenience, tolerability). For virologic failure start a new regimen that has 2 (or better 3) new fully active agents (based on resistance testing). When changing for other reasons (and HIV VL is suppressed), a single agent switch is o.k.

Risk of immune reconstitution inflammatory syndrome (IRIS) - know best timing of initiation of ART when OIs are being treated (to minimize risk of IRIS).

Check ART regimen of patients daily. Is the list of medications complete? Are the doses and frequencies correct? Pay attention to side effects, drug-drug interactions and the need for dose adjustments for renal and hepatic impairment of ART regimens.

A. Admission of patients on stable outpatient ART - continue regimen or not?

When patients with HIV get admitted to the hospital and are on ART, a decision must be made whether to continue their medications or not. In most cases, ART should be continued to avoid any treatment gaps.

From a simple virologic/immunologic standpoint it is desirable to continue existing ART (whether patient is fully or partially suppressed on a given reasonable regimen). Recovery from any HIV-related or –unrelated medical problem should theoretically be hastened as well. Finally, stopping an ART regimen may on its own trigger resistance since different components of a given regimen have different half lives (particularly many NNRTIs have a much longer half-life). There are nonetheless reasons why continuing ART for an inpatient may not be ideal.

Potential reasons to hold/stop ART

(i) Symptoms and signs suggesting significant medication side effects (hepatotoxicity, nephrotoxicity, GI symptoms, hypersensitivity reaction, rash etc.).

Notable exception: IRIS. If there is suspicion that symptoms are due to IRIS in patients recently started on ART, medications should in general be continued.

(ii) Patient unable to swallow pills (currently or expected to in near future due to surgery, upper Gi pathology, etc.).

(iii) Patient being started on new medication that will have significant drug-drug interactions with current ART regimen. If at all possible, preferentially patient should be switched to alternative ART regimen over stopping all ART.

(iv) Patient or patient's surrogate unable to give reliable medication history, or reported HIV medication regimen is clearly deviating from current recommendations and primary HIV provider cannot be reached.

(v) Known poor adherence to ART regimen as outpatient.

B. When to initiate ART in hospitalized patients

In general, earlier rather than later initiation of ART is recommended.

Earlier initiation of treatment confers a survival benefit, reduces risk of complications and improves overall quality of life. It is, nonetheless, not routinely recommended to initiate ART in the inpatient setting (when expected inpatient hospital stay is short). This is because currently available ART to suppress HIV must be given for life and adherence is of utmost importance for effective therapy to maximize effects and to avoid development of drug resistance. A good relationship with an outpatient primary HIV-care provider is crucial.

Unfortunately, in the U.S, roughly one third of all HIV-infected patients do not seek treatment until they need acute care in emergency rooms and on inpatient wards. Most of them, regrettably, will not follow-up as outpatients. Such patients tend to have more advanced HIV. A decision to initiate or withhold ART in this patient population should be made on a case-by-case basis. Barriers to adherence should be identified and removed and innovative strategies to engage patients in long-term outpatient HIV-care are of great importance.

Nonetheless, there are situations when ART should be started in hospitalized patients.

Strongly consider starting ART in inpatients

(i) Acute opportunistic infection (OI), especially if no specific effective therapy is known (i.e. for cryptosporidium, microsporidium, JC-virus causing progressive multifocal leukoencephalopathy [PML]).

(ii) HIV-associated nephropathy (HIVAN).

(iii) HIV-infection associated rapidly declining cognitive function.

(iv) CD4 count that is very low (<200/microliter) or rapidly declining (drop of more than 100 cells/microliter/year).

(v) Viral load that is very high (100,000 copies/mL).

(vi) Presence of an immunodeficiency related malignancy that requires treatment (central nervous system [CNS] lymphoma, Kaposi’s sarcoma etc.).

(vii) Acute HIV-infection.

For all indications listed above the indication to start ART is particularly strong in cases of anticipated prolonged hospitalization (including possible need for stay in a rehabilitation facility).

Baseline characteristics prior to starting ART

(i) HIV-antibody (if not on file, to confirm established HIV infection), CD4 cell count, HIV viral load.

(ii) Complete blood count (CBC), chemistry profile, LFTs, renal function, and urinalysis.

(iii) HIV-genotypic resistance testing.

(iv) Serology for hepatitis A, B and C as well as for syphilis, STI testing.

Look carefully for (sub)clinical OIs in the setting of low CD4 cell counts. Such OIs may have to be treated at the same time or prior to starting treatment for HIV.

Follow-up testing after initiation of ART

(i) Labs should be re-checked after 4 weeks (2-8 weeks). This must include CD4 count and HIV viral load. Until HIV viral load is below 200 copies/mL repeat every 1-2 months.

(ii) Treatment of HIV in the setting of a low CD4 count may unmask subclinical OIs.

Be on the lookout for IRIS.

C. ART and acute opportunistic infections

Mortality risk remains elevated for HIV-infected patients presenting with OIs and significantly reduced CD4 counts. HIV should be treated as soon as safely possible in this subset of patients, however, the exact time-point to initiate ART in the setting of an acute OI remains somewhat unclear for certain conditions. Data favors early rather than late HIV treatment with ART for most OIs.

Potential advantages to start ART

(i) Prevention of further loss of immune function, improved immune recovery,

(ii) Aid in the treatment of the OI (for some OIs, the only available treatment is immune recovery via ART).

(iii) Overall mortality risk reduction.

(iv) Risk reduction to develop other OIs.

Potential disadvantages to start ART

(i) High pill burden (treatment of HIV and OI at the same time).

(ii) Increased risk of unwanted drug-drug interactions and drug toxicity.

(iii) Increased morbidity and mortality related to IRIS (see below).

Optimal timing of ART initiation in the setting of an acute OI thus is a balance between noted advantages and disadvantages and possibly depends on the type as well as the location of any given opportunistic infection. Furthermore, not uncommonly, in patients with severely depressed CD4 cells, one OI may be predominant and causing most symptoms but other OIs may co-exist.

According to existing data and expert opinion, some OIs should be treated with ART "immediately" (cryptosporidium, microsporidium, PML), or "without delay" [Pneumocystis jirovecii pneumonia (PCP)]. Others should be initiated on ART with some delay (cryptococcus, tuberculosis). No formal recommendations are made for CMV or toxoplasma infection.

Specific recommendations to start ART in setting of OI:

(See also paragraph on IRIS below)

1) Cryptosporidium/microsporidium causing chronic diarrhea and or cholangitis: initiate ART immediately, no specific proven treatments for the underlying OI known.

2) PML caused by JC-virus: No effective treatment against JC-virus is known. Start ART immediately.

Tuberculosis: First start the TB treatment regimen. Add ART soon after:

  • For CD4 less than 50/microliter: within 2 weeks

  • For CD4 equal or greater than 50/microliter: by 8-12 weeks

  • If patient already on ART, continue regimen and start treatment for TB (beware of drug-drug interactions)

PIs and NNRTIs to treat HIV and rifamycins to treat TB have significant drug-drug interactions and require dose adjustments. CNS infection with TB (TB meningitis, tuberculoma) has a high mortality regardless of the timing of ART initiation, patients should be started on ART within 2-4 weeks. Remember use of steroids for TB meningitis.

3) PCP (Pneumocystis jirovecii pneumonia): Patients with PCP should be started on ART within the first two weeks. More severe infections (causing hypoxemia) are routinely treated with steroids (started on day one) thus reducing the risk of IRIS.

4) Cryptococcal meningitis: Optimal timing of initiation of ART in this setting remains controversial. Immediate therapy with ART may increase risk of serious IRIS with increased morbidity and mortality. A delay of at least 2 weeks, possibly up to 10 weeks before initiating ART may be warranted.

5) CNS toxoplasmosis: reactivation or acute infection with this parasite in AIDS patients is an uncommon OI in the era of effective ART. The best timing for initiation of antiretroviral therapy remains unclear, but earlier (within 2-3 weeks) rather than later treatment seems preferable given that most patients will have a severely depressed CD4 count and good data exists suggesting that treatment of such patients overall helps reduce mortality risk. Watch for drug-drug interactions.

6) CMV infection (especially CMV retinitis): CMV retinitis has become quite rare in the era of effective ART. It almost always occurs only at very low CD4 counts. While there is no good data, earlier rather than later initiation of ART seems beneficial and most experts would start within the first 2 weeks. Watch for IRIS.

D. Side effects

Despite the fact that overall HIV medications have become safer and are associated with fewer side effects, significant potential toxicities must be remembered. Certain classes of antiretrovirals are commonly associated with specific side effects. Likewise, certain side effects are more common for certain drugs. This is not a complete list and individual medications should always be queried for more information.

Class-specific side effects:

  • NRTIs (especially the "d-drugs" ddI and D4T): lactic acidosis, mitochondrial toxicity, peripheral neuropathy (didanosine, stavudine), pancreatitis (didanosine), leukopenia and anemia (zidovudine)

  • NNRTIs: hypersensitivity reaction (rash +/- hepatitis), CNS toxicity (efavirenz, rilpivirine)

  • PIs: GI side effects (nausea, diarrhea, bloating), hyperglycemia, hyperlipidemia, lipodystrophy

  • INSTIs: well tolerated.

  • FIs: injection site irritation.

  • CCR5-blockers: well tolerated.

Common side effects

  • Anemia/bone marrow suppression and macrocytosis: zidovudine.

  • Central nervous system (CNS) toxicity: efavirenz and possibly rilpivirine (somnolence, abnormal dreams, psychosis, etc.), much less so with etravirine.

  • Dyslipidemia: all PIs, especially if ritonavir is boosted, also efavirenz and stavudine.

  • Gastrointestinal (GI) intolerance: all PIs: nausea, vomiting, diarrhea; stavudine and zidovudine: upper GI problems; didanosine and stavudine: pancreatitis. Didanosine is contraindicated in patients with history of pancreatitis.

  • Hepatitis: all PIs especially tipranavir/ritonavir, nevirapine (and other NNRTIs), NRTIs. Remember that nevirapine is contraindicated in treatment naïve patients with CD4 count above 250 cells/μL (women) and above 400 cells/µL (men). Both tipranavir and nevirapine are contraindicated for hepatic insufficiency (Child-Pugh class B and C).

  • Indirect hyperbilirubinemia (benign): seen with atazanavir and tipranavir.

  • Lactic acidosis: seen with NRTIs (especially with stavudine, also with zidovudine and didanosine), uncommon now, more common in female obese patients. Symptoms also include GI prodromes, fatigue, rapidly progressive cases have been described.

  • Hypersensitivity reaction (rash): most commonly seen with NNRTIs, nevirapine (with hepatic toxicity and rash), usually within 6 weeks of treatment. Also seen with abacavir - usually in Caucasians (much more common in setting of positive test for the HLA*B-5701 allele), worse with continuation of drug and especially when re-challenged, NEVER re-challenge patients with abacavir if they had hypersensitivity reaction on the drug.

  • Lipodystrophy and lipoatrophy: mostly due to NRTIs (in association with mitochondrial toxicity), PIs.

  • Elevated creatine phosphokinase (CPK): zidovudine, raltegravir.

  • Nephrotoxicity: tenofovir DF (especially when some renal impairment is already present). Tenofovir AF does not cause the same kidney damage.

    Indinavir can cause increased creatinine levels as well. Renal stones have been described with indinavir (4% of patients) and atazanavir (infrequently).

  • Peripheral sensory neuropathy: with didanosine and stavudine.

Common drug-drug interactions

  • All PIs and NNRTIs are metabolized by the hepatic cytochrome P450 system. The list of drugs that may have significant drug-drug interactions is constantly expanding. In particular, certain drug classes that are commonly described to patients with HIV must be considered. Always check medication list when treating patients with PI or NNRTI based regimen.

  • When lipid-lowering agents need to be co-administered with a PI-containing ART regimen, lovastatin and simvastatin must be avoided (contraindicated). Instead pravastatin (alternatively, rosuvastatin or fluvastatin) should be used and started at the lowest possible dose. If needed, atorvastatin may be tried. Darunavir/ritonavir will increase the drug levels of pravastatin. Pitavastatin may be used with unboosted atazanavir.

  • When patients need treatment for HIV and for mycobacterial disease, rifampin and rifapentine must be avoided when co-administered with a PI or NNRTI based regimen. Instead use rifabutine (dose adjusted).

  • The benzodiazepines midazolam and triazolam must not be co-administered with any PI based regimen. Instead use temazepam, lorazepam or oxazepam. Note that in controlled settings IV midazolam may be used with caution as a onetime dose for procedural sedation. Avoid the use of diazepam.

  • Ritonavir's and cobicistat's inhibitory effect on CYP3A are commonly used to boost drug levels of other HIV drugs (wanted side effect). However, because of this, they may have significant drug-drug interactions. Beware of effects when using methylprednisolone, prednisolone and triamcinolone (risk of Cushing's syndrome and adrenal insufficiency).

  • The CCR5 antagonist maraviroc is a substrate of CYP3A. Thus co-administration with potent CYP3A inhibitors (ritonavir, other PIs except tripranavir/ritonavir) and potent CYP3A inducers (efavirenz, rifampin) warrants dose adjustment.

  • The INSTI raltegravir is metabolized by the liver, drug concentrations may be reduced when rifampin is co-administered. Also, efavirenz and tipranavir/ritonavir can lower drug concentrations of raltegravir.

  • NRTIs do not undergo hepatic transformation and thus fewer drug-drug interactions have to be considered.

  • There are no drug-drug interactions to consider when administering the FI enfuvirtide.

Possible reduced drug absorption with elevated gastric pH

  • Antacids: atazanavir/ritonavir fosamprenavir, tipranavir and rilpivirine should be avoided or administered separately (by at least 2 hours).

  • H2-blockers: atazanavir/ritonavir, rilpivirine – avoid concomitant use, if needed, use low dose and space (give 2 hours before or 10 hours after H2 blocker, avoid use of unboosted atazanavir.

  • Proton pump inhibitor: unboosted atazanavir not recommended. Atazanavir boosted with ritonavir or cobicistat for treatment naïve patients can be used if the PPI is given at low dose (omeprazole dose of 20 mg) and 12 hours apart.

  • Do not use Stribild® since low pH is needed for absorption of elvitegravir.

  • Other medications that can potentially cause significant drug-drug interactions are calcium-channel blockers, immunosuppressants (cyclosporine, tacrolimus), anticonvulsants, agents to treat erectile dysfunction, azole-antifungals, macrolides, oral contraceptives and methadone.

  • Always consult an experienced pharmacist or reliable reference prior to adding any medications from above drug classes.

Renal impairment

Adjustment needed with all NRTIs (except abacavir) and maraviroc:

  • NRTIs: abacavir is the only NRTI that does not need dose adjustment for renal impairment. For all other members of the class dose reduction is recommended. N.B. Lamivudine could be given at a dose as low as 25mg daily in patients on hemodialysis (HD), in clinical practice 150mg is often given daily (lowest dose that comes in tablet form, drug well tolerated).

  • Avoid tenofovir DF when patient has known renal impairment, tenofovir AF has less nephrotoxicity.

  • NNRTIs: no dose adjustment needed. N.B. there is limited data for the dosing of nevirapine in HD patients.

  • PIs: in general, as a class, no dose adjustment needed. Avoid QD dosing of lopinavir/ritonavir in patients on HD. Also, avoid use of atazanavir in any formulation in antiretroviral experienced HD patients.

  • FI: no dose adjustment needed for enfuvirtide.

  • INSTI: no dose adjustment needed for raltegravir.

  • CCR5 antagonist maraviroc: for CrCl less than 30 or patient on HD, it is not recommended when given with potent CYP3A inducers or inhibitors (i.e. all PIs except tipranavir/ritonavir,or the NNRTIs efavirenz and etravirine), otherwise give 300 mg BID, reduce dose to 150mg BID if postural hypotension occurs.

  • Remember: Stribild® is not approved in patients with a CrCl less than 70.

Hepatic impairment

Adjustment needed: abacavir, PIs, nevirapine:

  • NRTIs: no adjustment needed except for abacavir. Reduce dose of abacavir to 200 mg BID for Child-Pugh class A. Abacavir is contraindicated for class B or C.

  • NNRTIs: no dose adjustments recommended. Use with caution for Class C for all NNRTIs. Remember that nevirapine is contraindicated in class C hepatic failure.

  • PIs: caution in use, since PIs are cleared by the liver. Recommendations range from dose adjustment to strict contraindications. For Child-Pugh class C hepatic failure the following PIs are contraindicated: saquinavir, tipranavir and nelfinavir. Not recommended are: atazanavir, atazanavir/ritonavir, darunavir/ritonavir. Fosamprenavir and fosamprenavir/ritonavir may be used with caution at lower doses, as maybe indinavir. Lopinavir/ritonavir likewise may be used, no dose recommendations are given.

  • FI: no dose adjustment needed for enfuvirtide.

  • CCR5 antagonists: no clear recommendations given about dose reduction in hepatic impairment for maraviroc, likely levels will be increased.

  • INSTI: no clear recommendations about dosage in severe hepatic impairment, no dose adjustment needed for raltegravir in patients with mild or moderate hepatic impairment.

G. ART in patients co-infected with hepatitis B

Some HIV medications are also active against hepatitis B. Current FDA approved HIV medications are: tenofovir, lamivudine and emtricitabine. When patients are co-infected with HIV and chronic active hepatitis B requiring treatment, a regiment must be chosen that includes drugs active against hepatitis B.

A regiment that includes 2 active hepatitis B drugs is preferred (tenofovir/emtricitabine or tenofovir/lamivudine). If tenofovir cannot be used, in addition to ART, entecavir (Baraclude®) to treat hepatitis B should be used. Do not treat patients with dual infection with entecavir alone (and no ART) since entecavir has activity against HIV and can induce NRTI resistance (mutation M184V).

Stopping a regimen for treatment of dual infection (HIV and hepatitis B) can cause rebound hepatitis with potentially significant damage to the liver in an IRIS-like fashion.

H. ART and immune reconstitution inflammatory syndrome (IRIS)

IRIS describes a paradoxical worsening of clinical symptoms and/or signs after initiation of ART. Another commonly used term is immune reconstitution disease, IRD.

IRIS may occur when potent antiretrovirals rapidly suppress replication of HIV (up to 90% of the virus may be suppressed within 2 weeks) and thus allow relatively rapid recovery of immune function (which was impaired both qualitatively and quantitatively by the virus). Such a boost of the immune system will allow a vigorous inflammatory response to existing clinical or subclinical opportunistic infections. To date, there are no clear-cut clinical definitions for the entity of IRIS.

Certain conditions should be present when entertaining the diagnosis of IRIS:

  • low pre-treatment CD4 count, generally below 100 cells/microliter (maybe with the exception of MTB)

  • recent initiation of effective ART (i.e. suppression of viral load, increase in CD4 count (absolute and/or relative)

  • clinical picture consistent with inflammatory condition

  • clear temporal relationship between ART initiation and onset of inflammation (usually in the range of 1 week to 3 months).

IRIS is usually a diagnosis of exclusion, i.e. other causes for an inflammatory conditions should be ruled out, particularly: (a) side effects to newly started ART medications, especially abacavir, (b) worsening of OI due to resistance, non-adherence, etc., (c) presence of second (or third) OI or erroneous initial diagnosis, (d) other clinical conditions.

IRIS is particularly likely when encountering the following OIs: tuberculosis, disseminated MAI, CMV, PCP, cryptococcosis, hepatitis B.

IRIS is more likely in the following setting:

  • the patient is relatively young (the immune system can still recover)

  • CD4 nadir well below 100 cells/μL

  • pre-treatment viral load was high

  • ART includes a boosted PI

  • CD4 count recovered rapidly.

Tuberculosis (TB)

ART treatment in the setting of recent diagnosis and treatment for TB often triggers IRIS. Patients may have fevers, weight loss, and a worsening respiratory status. IRIS has been described after initiation of anti-tuberculous drugs even in the absence of HIV. The syndrome is self-limited. For mild cases NSAIDs can be given. More severe cases need supportive treatment with steroids (prednisone 1mg/kg body weight up to 80mg) with tapering after one week.

Cryptococcal meningitis

ART can trigger IRIS and paradoxical worsening can occur up to 6 months. Symptoms are usually localized to the CNS. Clinical findings may be indistinguishable from those associated with the acute infection.

Disseminated or pulmonary infection with Cryptococcus

ART may trigger IRIS here as well, leading to cavitary lesions, worsened respiratory status in the setting of dissemination lymphadenitis and sometimes hypercalcemia.

Cytomegalovirus (CMV) retinitis

When treating patients with CMV retinitis, immune recovery uveitis may occur after treatment with ART is initiated. Since this complication often leads to longstanding inflammatory changes with visual impairment, close monitoring by an experienced ophthalmologist is prudent. Fortunately, this condition is now rare.

Progressive multifocal leukencephalopathy (PML)

Patients who are started on ART after diagnosis of PML may have paradoxical clinical worsening. This may be due to the immune system’s reaction to JC virus. Since no specific treatment for the OI exists, ART should be continued for at least 3-6 months before a judgment can be made as to the effectiveness of ART to reverse or halt the neurologic decline.

Pneumocystis jirovecii pneumonia (PCP)

IRIS in the setting ofPCP is common. Adjunct therapy with steroids for moderate to severe cases (room air pO2 less than 70 mmHg or Alveolar-arterial O2 gradient 35 mmHg or more) is therefore always recommended. If patients are started on ART only after a full course of treatment for PCP has been completed IRIS (with fevers and worsening respiratory symptoms) may develop.

Hepatitis B and/or C

IRIS can also happen in patients co-infected with hepatitis B or C. Patients typically have systemic symptoms (fevers, chills, fatigue, anorexia) and show elevated liver enzymes. However, it is often very difficult to distinguish IRIS from drug side effects (especially nevirapine and older NRTIs), other OIs affecting the liver, Kaposi sarcoma, other hepatotropic viruses. Thus IRIS should be a diagnosis of exclusion.

Management of IRIS in the setting of opportunistic infections (OIs)

In general, ART should be continued unless serious or life-threatening complications that may be related to IRIS occur in hospitalized patients. In such rare cases, treatment for OIs should be continued and ART held for some period of time. If IRIS is related to ART for progressive multifocal leukoencephalopathy (PML) treatment with antiretroviral agents should be continued since no specific treatment for infection with JC virus is known.

With or without continued treatment with ART patients may benefit from anti-inflammatory agents with steroids (usually prednisone). Milder cases may respond to NSAIDs. Anecdotal evidence that treatment with TNF-alpha blocking agents may be beneficial in severe cases of IRIS in the setting of HIV/TB co-infection but no recommendations to this extent exist to date.

Other, non-infectious conditions

Finally, certain other conditions may flare when ART is initiated. This includes sarcoidosis, rheumatoid arthritis, systemic lupus erythematosus (SLE), autoimmune thyroiditis, and Graves’ disease. In the setting of fever, anemia and encephalitis co-infection with parvovirus B19 may have to be considered.

Prevention

IRIS should always be prevented if possible. For treatment of PCP this is well established with the addition of prednisone in cases of moderate to severe infection. For other OIs the risk of IRIS must be weighed against the benefit of earlier ART therapy and associated immune reconstitution (see section on OIs). With the possible exception of cryptococcal disease for most OIs earlier initiation of ART seems to have an overall benefit when looking at both morbidity and mortality. A thorough history and physical examination should look for evidence of OIs that have not been diagnosed prior to initiating ART in patients with low CD4 counts to further reduce the risk of IRIS. Some experts advocate to look for cryptococcal disease with a serum antigen test when the CD4 count is less than 50.

I. ART in patients who cannot swallow pills

Hospitalized HIV-infected patients, especially in the ICU may not be able to swallow pills. Virtually all antiretroviral medications are only available orally. Exceptions include zidovudine which can be administered IV and enfuvirtide (T-20) which is administered subcutaneously. Knowledge about formulations of antiretroviral agents that allow administration via feeding tube is thus of great value for inpatient care of HIV infected patients. Below is a listing of agents by class and of combination formulations with information about options for administration via feeding tubes.

Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)

  • Abacavir, emtricitabine, lamivudine and zidovudine are available as an oral solution; didanosine, stavudine and tenofovir are available as powder for solution.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

  • Only nevirapine is available as an oral solution. Efavirenz, etravirine and the 100 mg delavirdine tablets can be crushed. Efavirenz oral solution is available through an expanded access (compassionate use) program in the U.S. There is currently no reliable option delivering rilpivirine via feeding tube, the tablet does not readily disperse in water and should not be crushed.

Protease inhibitors

  • Darunavir, fosamprenavir, lopinavir/ritonavir, ritonavir, and tipranavir are available as oral solutions; nelfinavir and atazanavir are available as an oral powder for suspension. Indinavir capsules can be opened. Nelfinavir and saquinavir tablets can be crushed.

INSTI and CCR5 blocker

There is an oral suspension available for raltegravir. No data on use of dolutegravir via feeding tube.

There is no data regarding crushing of maraviroc pills.

Fixed combination drugs

Of the existing combination medications that include NRTIs efavirenz/emtricitabine/tenofovir (Atripla®) should not be crushed. For the others including rilpivirine/emtricitabine/tenofovir (Complera®), abacavir/lamivudine (Epzicom®), abacavir/lamivudine/zidovudine (Trizivir®), emtricitabine/tenofovir (Truvada®), lamivudine/zidovudine (Combivir®), and elvitegravir/cobicistat/tenofovir/emtricitabine (Stribild®) no information is available as to whether crushing is safe and thus individual components should be given as solution, powder or crushed tablets when possible.

Background

HIV has a remarkable ability to adapt in order to allow ongoing replication in the presence of antiretroviral agents. Many of such mutations confer resistance. Some are the result of a single point mutation leading to a single amino acid substitution; some involve more complex changes. It is generally believed that mutants, while potentially conferring the ability to survive under drug pressure, are virologically less fit. It is thus preferable to keep a patient on a “failing” regimen rather than stopping ART altogether.

Ultimately, the goal is to change the regimen to include at least two new active agents (i.e. not affected by mutations). Genotypic (or sometimes phenotypic) analysis to look for the presence of resistant virus should always be performed while the patient is still taking his (failing) ART regimen or within 20 days of stopping.

Management of patients who are infected with a resistant virus is complex and often requires expert knowledge about the different mechanisms of resistance. Changing ART or choosing a new regimen should only be done with the help of an experienced HIV-care provider.

Basic concepts

  • Obtain prior treatment regimens (number, duration, drugs used) and adherence record. Perform genotyping while patient still on old ART (or within 20 days of stopping).

  • Traditional sequencing may miss so-called minority variants (drug resistant mutants in lower copy numbers), consider “deep sequencing”.

  • Remember that genotype after patient has been off ART more than one month will likely only give information about the initial wild-type strain.

Some mutations are considered “signature mutation” i.e. are associated with a particular drug. Other mutations confer cross-resistance to other drugs (in the same class). Finally, some mutations cause resistance to one drug but make another drug more potent (“hypersusceptibility”). In general the class of PIs, especially when used in boosted form has the lowest risk of development of resistance (“high genetic barrier to resistance”). NNRTIs of the first generation have a very low genetic barrier to resistance.

Nucleoside/nucleotide reverse transcriptase inhibitors mutations

  • Common NRTI mutations include the so-called TAMs (thymidine analog mutations) that usually follow one of two pathways (successive accumulation of mutations).

  • Zidovudine and stavudine have a higher barrier to mutations but are less commonly used in the U.S. because of side effects.

  • Some mutations are associated with resistance to most if not all NRTIs. Q151M eliminates all NRTIs except tenofovir. T69 insertion mutation will confer resistance to all NRTIs if a TAM is also present at codons 41, 210 or 215.

  • M184V renders lamivudine and emtricitabine ineffective, may affect abacavir and didanosine (if TAMs present too), will make zidovudine, stavudine and tenofovir more effective

  • K65R will affect tenofovir, abacavir, didanosine, as well as lamivudine and emtricitabine. It increases susceptibility to zidovudine.

  • L74V affects abacavir and didanosine, increases susceptibility to zidovudine.

  • HIV virus with several acquired NRTI resistant mutations may not infrequently be hypersusceptible to zidovudine. Thus very treatment experienced patients may be on a regimen that includes zidovudine.

Non-nucleoside reverse transcriptase inhibitors mutations

  • NNRTIs of the first generation (efavirenz and nevirapine) have a low genetic barrier to resistance. The classic mutations leading to resistance against the two first-generatioin NNRTIs are K103N and Y181C. Several others have been described.

  • Second generation NNRTI’s like etravirine and rilpivirine can overcome the K103N and Y181C mutations.

  • Beware: NNRTI resistance often emerges quickly in patients who have low-level viremia due to non-compliance or other reasons.

Protease inhibitor mutations

  • Mutations in the protease gene of HIV that render PIs ineffective may confer resistance to one particular PI or may confer cross-resistance to other PIs. In general, when boosted regimens are used the risk of development of resistance is lower than for mutations leading to NRTI or NNRTI resistance.

  • For atazanavir the signature mutation is I50L (other PIs will still be active).

  • Darunavir/ritonavir and tipranavir/ritonavir appear to be somewhat less likely to lose efficacy due to mutations than other PIs, and can remain a good choice despite multiple mutations in the protease gene. Sometimes phenotypic resistance testing is necessary.

  • In the past lopinavir/ritonavir was used for treatment experienced patients with existing mutations in the protease gene; nowadays darunavir/ritonavir (or sometimes tipranavir/ritonavir) is preferred.

  • Mutations that do render darunavir less effective (I50V, I54L, L76V) seem to render another PI, tipranavir more active. Vice versa, some mutations that affect tipranavir have no effect on darunavir.

INSTI mutations

Raltegravir failure is associated with mutations in the integrase gene. There is a relatively low genetic threshold. Several different locations in at least 3 different genetic pathways have been described. Major mutations include Q148H/K/R N155H or Y143R/H/C as well as E92Q. Minor mutations have been described as well. Elvitegravir and dolutegravir mutations have been described as well.

CCR5 receptor mutations

Maraviroc is rendered ineffective once the virus is no longer an R5 virus, i.e. is able to use the co-receptor CXCR4 (dual/mixed or X4 virus). Testing for this shift is currently done using the tropism (Trofile®) assay (phenotypic analysis). Mutations most commonly involve the so-called V3 loop. There is currently no consensus on specific signature mutations, thus genotyping is not possible as of yet.

IV. Common pitfalls.

  • Medication errors do happen. Double-check HIV medications for correct dosages and frequency. Make sure that all components of the ART regimen are ordered and administered. List them side-by-side in your daily progress note. Do not allow any of the members of the cocktail to "fall off the list". Use generic names (and if unfamiliar with HIV medications, list drug class next to the medication).

  • Know the active ingredients of any HIV pill. Patients may take 3 different ART pills and are only on 2 active drugs (one drug being ritonavir or cobicistat for boosting). Others may take only 1 or 2 pills but still have 3 active drugs (combination pills).

  • Patients with HIV are often very particular about their ART regimen. Verify that patients understand that the regimen has not been changed and that all medications, including HIV-medications will be given by the hospital nurse and that the patient must not take his own medications.

  • Drug-drug interactions are common. Acid suppressants, especially proton pump inhibitors (PPIs), benzodiazepines, calcium channel blockers, cyclosporine and tacrolimus, rifamycins, sildenafil, rifamycins, azole antifungals, macrolides, oral contraceptives, and methadone, all may effect the drug concentrations of ART medications. Likewise ART regimens that use pharmacokinetic boosters (ritonavir, cobicistat) may have significant effects on concentrations of other drugs.

  • Do not forget about herbal remedies. Ask all HIV-infected patients about use of alternative and supplemental medications. Especially St. John’s wart can lower drug levels of ART.

  • Antacid use, including use of PPIs is common in hospitals. Monitor use of antacids, especially PPIs. Particularly in patients on (unboosted) atazanavir and rilpivirine as well as for patients on Stribild® look for alternatives since PPIs are not recommended. PPIs should likewise not be used in treatment-experienced patients on atazanavir and in patients on saquinavir.

  • Acute Kidney injury is common. Follow serum BUN and creatinine. Ensure dose adjustment in patients with fluctuating renal function for all NRTIs (except for abacavir) and for maraviroc, especially in kidney transplant patients. Remember that Stribild® is not approved for initiation of treatment in patients with a CrCl less than 70 and should be stopped if the CrCl is below 50.

  • Beware of a co-infection with hepatitis B. ART regimens in patients with active hepatitis must include drugs active against both viruses (tenofovir, emtricitabine, lamivudine). Stopping ART that includes drugs active against hepatitis B virus can trigger a hepatitis flare. Starting ART may trigger a hepatitis-like picture due to IRIS.

  • Efavirenz is potentially teratogenic. Confirm that your patient is not pregnant prior to starting any regimen containing efavirenz in women of childbearing age.

  • Co-treatment of patients on ART with voriconazole for fungal infections. NNRTIs and PIs (especially boosted) may have significant drug-drug interactions.

  • Information about the HIV genotype (prior to starting ART) is important. Confirm that a genotype was sent correctly prior to starting ART. Do not rely on the label “pending”. Once the virus is fully suppressed a genotype cannot be re-sent.

  • Response to ART must be monitored to ensure that the regimen is effective. Remember to order follow-up testing if patient is started on ART under your watch. Repeat CD4 and HIV viral load testing after 4 (2-8) weeks.

  • Absolute CD4 T-cell counts are unreliable in acutely ill patients. Do not overly rely on the absolute CD4 count as the sole marker of immune status. Any event/drug that is marrow suppressive, including acute illnesses, can lower the count (often together with a total lymphocyte count drop). In contrast, splenectomy and co-infection with HTLV-1 may lead to increased CD4 counts. Monitor the percentage (relative number) of CD4 positive T-cells in addition to the absolute count.

  • With ART and drug rashes, examine the patient’s skin. When patients on ART develop rash, think drug reaction, especially if the regimen was started recently. The most common agents to cause a rash are members of the NNRTI group. Others include PIs like atazanavir, darunavir, fosamprenavir, or maraviroc.

  • Correct boosting of PIs. PI boosting with ritonavir is usually done with 100 mg (occasionally 200 mg). Both PIs should always be given together, i.e. both given QD or BID. Notable exception: use of fosamprenavir/ritonavir in antiretroviral treatment experienced patients with hepatic impairment where fosamprenavir is given BID and ritonavir QD.

  • Confirmation of absence of HLA-B*5701 allele via genetic testing before starting abacavir for the first time. The test should also be performed when abacavir has been used in past but allele testing has not been done or results are not available.

  • Use of statins (cholesterol lowering drugs) is common. If patients on PI containing ART regimen are to be started on an HMG-CoA reductase inhibitors remember that lovastatin and simvastatin are contraindicated. The statin of choice for patients infected with HIV is pravastatin since it has the least drug-drug interactions. Darunavir/ritonavir will increase the drug levels of all statins including pravastatin.

  • Know about interactions with grapefruit juice. Be sure to know whether your patients like grapefruit juice since it is a potent inhibitor of the CYP 3A4 enzyme and thus can interfere with adequate drug levels of HIV medications.

  • Know that atazanavir (and tipranavir) can cause benign indirect hyperbilirubinemia. When patients are started on ART follow their hepatic function periodically. Isolated elevation of unconjugated bilirubin is common and the regimen can be continued (especially if the elevation is not exceeding 5 times the upper limit of normal). The bilirubin levels will return to normal if the drug is discontinued. Elevated levels of transaminases must be evaluated separately.

  • Remember the long half-life of NNRTIs. When treatment interruptions are needed, remember that patients may potentially be on a single drug regimen with an NNRTI if all drug are stopped at the same time. Try to continue all medications, otherwise consider discontinuation of ART medication in a staggered fashion.

V. National Standards, Core Indicators and Quality Measures.

Current clinical guidelines for the treatment of HIV-infected adults and adolescents can be found on the AIDSinfo website (sponsored by the Department of Health and Human Services).

The only clinical performance measure directly linked to ART relates to management of HIV infected pregnant women (mainly dealing with outpatient visits):

  • HAB HIV Core Clinical Performance Measures for Adult/Adolescent Clients: Group 1.

  • Antiretroviral Therapy for Pregnant Women in their 2nd and 3rd trimesters.

  • Goal: 100% of patients in target group are on antiretroviral therapy.

What's the evidence?

Akgün,, KM,, Miller, RF:. "Critical Care in Human Immunodeficiency Virus-Infected Patients.". Semin Respir Crit Care Med. vol. 37. 2016. pp. 303-17.

Lawn, SD,, Torok, ME,, Wood, R:. "Optimum time to start antiretroviral therapy during HIV-associated opportunistic infections.". Curr Opin Infect Dis. vol. 24. 2011. pp. 34-42.

Metsch, LR,, Bell, C,, Pereyra, M,. "Hospitalized HIV-infected patients in the era of highly active antiretroviral therapy.". Am J Public Health. vol. 99. 2009. pp. 1045-9.

Rastegar, DA,, Knight, AM,, Monolakis, JS:. "Antiretroviral medication errors among hospitalized patients with HIV infection.". Clin Infect Dis. vol. 43. 2006. pp. 933-8.

Schneider, JA,, Zhang, Q,, Auerbach, A,. "Do hospitalists or physicians with greater inpatient HIV experience improve HIV care in the era of highly active antiretroviral therapy? Results from a multicenter trial of academic hospitalists.". Clin Infect Dis. vol. 46. 2008. pp. 1085-92.

Commers, T,, Swindells, S,, Sayles, H,. "Antiretroviral medication prescribing errors are common with hospitalization of HIV-infected patients.". J Antimicrob Chemother:. vol. 69. 2014. pp. 262-7.

Günthard, HF,, Aberg, JA,, Eron, JJ,. "Antiretroviral Treatment of Adult HIV Infection. 2014 Recommendations of the International Antiviral Society-USA Panel.". JAMA. vol. 312. 2014. pp. 410-25.

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