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Drug Treatment of HIV Infection

By

Edward R. Cachay

, MD, MAS, University of California, San Diego

Last full review/revision Mar 2019| Content last modified Mar 2019
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Because disease-related complications can occur in untreated patients with high CD4 counts and because less toxic drugs have been developed, treatment with antiretroviral therapy (ART) is now recommended for nearly all patients. The benefits of ART outweigh the risks in every patient group and setting that has been carefully studied.

ART aims to

  • Reduce the plasma HIV RNA level to undetectable (ie, < 20 to 50 copies/mL)

  • Restore the CD4 count to a normal level (immune restoration or reconstitution)

ART can usually achieve its goals if patients take their drugs > 95% of the time.

If treatment fails, drug susceptibility (resistance) assays can determine the susceptibility of the dominant HIV strain to all available drugs. Genotype assays may also be helpful.

Many patients living with HIV infection are taking complex regimens involving multiple pills. With the availability of new co-formulated HIV drugs, many patients could benefit from simplification of their ART regimen, guided by HIV DNA archive genotype testing (GenoSure Archive).

(See also Treatment in Human Immunodeficiency Virus (HIV) Infection.)

Classes of antiretrovirals

Multiple classes of antiretrovirals are used in ART (see table Antiretroviral Drugs). Two classes inhibit HIV entry, and the others inhibit one of the 3 HIV enzymes needed to replicate inside human cells; 3 classes inhibit reverse transcriptase by blocking its RNA-dependent and DNA-dependent DNA polymerase activity.

  • Nucleoside reverse transcriptase inhibitors (NRTIs) are phosphorylated to active metabolites that compete for incorporation into viral DNA. They inhibit the HIV reverse transcriptase enzyme competitively and terminate synthesis of DNA chains.

  • Nucleotide reverse transcriptase inhibitors (nRTIs) competitively inhibit the HIV reverse transcriptase enzyme, as do NRTIs, but do not require initial phosphorylation.

  • Non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind directly to the reverse transcriptase enzyme.

  • Protease inhibitors (PIs) inhibit the viral protease enzyme that is crucial to maturation of immature HIV virions after they bud from host cells.

  • Entry inhibitors (EIs), sometimes called fusion inhibitors, interfere with the binding of HIV to CD4+ receptors and chemokine co-receptors; this binding is required for HIV to enter cells. For example, CCR-5 inhibitors block the CCR-5 receptor.

  • Post-attachment inhibitors bind to the CD4 receptor and prevent HIV (that also binds to the CD4 receptor) from entering the cell.

  • Integrase inhibitors prevent HIV DNA from being integrated into human DNA.

Table
icon

Antiretroviral Drugs

Generic name

Abbreviation

Usual Adult Dosea

Some Adverse Effectsb

Entry (fusion) inhibitors

Enfuvirtide

T-20

90 mg sc bid

Hypersensitivity reactions, local injection site reactions, peripheral neuropathy, risk of bacterial pneumonia, insomnia, loss of appetite

Maraviroc (CCR5 inhibitor)

150–600 mg bid, depending on other drugs used

Myocardial ischemia or infarction

Integrase inhibitors

Bictegravir

50 mg once/day

Hypersensitivity reactions, including rash (occasionally severe or life threatening), headache, insomnia, and muscle aches

Dolutegravir

50 mg once/day

Hypersensitivity reactions, including rash (occasionally severe or life threatening), headache, insomnia, myositis

Possible increased risk of fetal neural tube defects if used during early pregnancyc

Elvitegravir

150 mg once/day

Nausea, diarrhea

Raltegravir

400 mg bid

Hypersensitivity reactions, including rash (occasionally severe or life threatening), myositis

Non-nucleoside reverse transcriptase inhibitors

Rash (occasionally severe or life threatening), liver dysfunction

Doravirine

100 mg once/day

Nausea, dizziness, headache, fatigue, diarrhea, abdominal pain, and abnormal dreams

Efavirenz

EFV

600 mg at bedtime

CNS symptoms, false-positive cannabinoid test results, excessive blood levels if the drug is taken after fatty meals

Etravirine

200 mg bid

Severe, potentially life-threatening rashes

Nevirapine

NVP

200 mg once/day for 2 weeks, then 200 mg bid

Severe, potentially life-threatening hepatotoxicity and rashes, especially during the first 18 weeks of treatment

Increased cytochrome P-450, reducing levels of protease inhibitors, and other drugs (eg, efavirenz, clarithromycin, ethinyl estradiol, ketoconazole, itraconazole, methadone, certain antiarrhythmics, anticonvulsants, calcium channel blockers, immunosuppressants, cyclophosphamide, ergot alkaloids, fentanyl, cisapride, warfarin)

Rilpivirine

25 mg once/day

Fewer CNS adverse effects than efavirenz

Nucleoside reverse transcriptase inhibitors

Lactic acidosis (which can be life threatening), steatohepatitis

Abacavir

ABC

300 mg bid

Severe, potentially fatal hypersensitivity reactions with fever, rashes, nausea, vomiting, diarrhea, pharyngitis, dyspnea, and/or cough (risk is 100-fold higher in patients with HLA-B*57:01, which can be detected by genetic testing)

Anorexia, nausea, vomiting

Rechallenge contraindicated

Emtricitabine

FTC

200 mg once/day

Minimal; skin hyperpigmentation

Lamivudine

3TC

150 mg bid or 300 mg once/day

Peripheral neuropathy, rarely pancreatitis

Stavudine

d4T

40 mg bid if 60 kg

30 mg bid if < 60 kg

Peripheral neuropathy, possibly life-threatening pancreatitis (rare), hepatic steatosis, fat redistribution with lipoatrophy of face and extremities

Zidovudine

ZDV, AZT

300 mg bid

Anemia and leukopeniad, rarely pancreatitis, hepatic steatosis, myopathy, myositis

Nucleotide reverse transcriptase inhibitors

Tenofovir alafenamide fumarate

TAF

10 mg/day

Less renal and bone mineral density issues than with TDF

Tenofovir disoproxil fumarate

TDF

300 mg once/day

Mild renal insufficiency (uncommon), other serious renal diseases (rare)

Increased levels of ddI; otherwise minimal

Post-attachment inhibitors

Ibalizumab

TMB-355, TNX-355

Single loading dose: 2000 mg IV infused over at least 30 min; after 2-week subsequent infusions (maintenance doses) 800 mg IV q 2 weeks infused over at least 15-30 min

Infusion reactions, diarrhea, rash

Protease inhibitorse

Nausea, vomiting, diarrhea, abdominal discomfort, increased serum glucose and hypercholesterolemia (common), increased abdominal fat, liver dysfunction, bleeding tendency (particularly in hemophiliacs)

Atazanavir

ATV

400 mg once/day

Rash, hyperbilirubinemia

Darunavir

800 mg once/day, taken with ritonavir 100 mg, or 600 mg bid, taken with ritonavir 100 mg bid and with food

Severe rash, hypersensitivity, fever

Fosamprenavir

None

1400 mg bid

Rash

Lopinavir

LPV

400 mg bid (in a fixed combination with 100 mg ritonavir) with food

Altered taste, circumoral paresthesias

Nelfinavir

NLF

1250 mg bid with food

Diarrhea, drug interactions due to inhibition of CYP3A

Ritonavir

RIT

600 mg bid with food

Altered taste, circumoral paresthesias

Possibly decreased incidence and severity of adverse effects with dose reduction

Saquinavir

SQV

1200 mg tid, within 2 hours of a meal (trough levels and efficacy possibly increased when used with ritonavir)

Nausea, vomiting, and diarrhea when used with ritonavir

Tipranavir

TPV

500 mg with ritonavir 200 mg bid

Possibly life-threatening hepatitis and intracranial hemorrhage

aDoses are given orally, unless otherwise specified.

bAll classes of antiretroviral drugs may contribute to chronic metabolic adverse effects, which include elevated cholesterol and triglycerides, insulin resistance, and centripetal redistribution of body fat. Adverse effects listed for drug class can occur when any drug in that class is used.

c Exposure to dolutegravir at the time of conception may be associated with neural tube defects (NTD) among infants. Recently there were 4 registered cases in Botswana of different types of NTD among over 400 women who were taking dolutegravir at the time of pregnancy. An estimated additional 600 women exposed to dolutegravir while pregnant are being observed. Previous studies did not show any increased rates of teratogenicity. No other integrase inhibitors have been found to cause neural tube defects. Meanwhile the interim antiretroviral recommendations of the World Health Organization mention that an efavirenz-based regimen is safe and effective first line and can be used among women of childbearing potential during the period of potential risk for NTD (see World Health Organization: Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV: interim guidance).

dAnemia can be treated with transfusions or other drugs such as erythropoietin; leukopenia can be treated with colony-stimulating factor (granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor).

eAll are metabolized by the cytochrome P-450 system, creating potential for many drug interactions.

Antiretroviral regimens

Combinations of 2, 3, or 4 drugs from different classes are usually necessary to fully suppress replication of wild-type HIV. The specific drugs are chosen based on the following:

  • Anticipated adverse effects

  • Simplicity of regimen

  • Concomitant conditions (eg, hepatic or renal dysfunction)

  • Other drugs being taken (to avoid drug interactions)

To maximize adherence, clinicians should choose an affordable, well-tolerated regimen that uses once/day (preferable) or bid dosing. Guidelines from expert panels for initiating, selecting, switching, and interrupting therapy and special issues concerning treatment of women and children change regularly and are updated on the U.S. Department of Health and Human Services website, AIDSinfo.

Tablets containing fixed combinations of ≥ 2 drugs are now widely used to simplify regimens and improve adherence. Common combination tablets include

  • Stribild: Elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, plus tenofovir disoproxil fumarate 300 mg, taken po once/day with food

  • Atripla: Efavirenz 600 mg, tenofovir disoproxil fumarate 300 mg, plus emtricitabine 200 mg, taken po once/day on an empty stomach, preferably at bedtime

  • Complera: Rilpivirine 25 mg, emtricitabine 200 mg, plus tenofovir disoproxil fumarate 300 mg, taken po once/day with food

  • Truvada: Emtricitabine 200 mg plus tenofovir disoproxil fumarate 300 mg, taken once/day po with or without food

  • Triumeq: Dolutegravir 50 mg, lamivudine 300 mg, plus abacavir 600 mg, taken po once/day with or without food

  • Descovy: Emtricitabine 200 mg plus tenofovir alafenamide fumarate 25 mg, taken po once/day with or without food

  • Genvoya: Eviltegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, plus tenofovir alafenamide fumarate 10 mg, taken po once/day with food

  • Odefsey: Emtricitabine 200 mg, rilpivirine 25 mg, plus tenofovir alafenamide fumarate 25 mg, taken po once/day with food

  • Symtuza: Darunavir 800 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg, taken po once/day with food

  • Delstrigo: Doravirine 100 mg, lamivudine 300 mg, and tenofovir disoproxil fumarate 300 mg, taken po once/day with or without food

  • Juluca: Rilpivirine 25 mg plus dolutegravir 50 mg, taken po once/day (for patients who have been on a stable antiretroviral regimen for ≥ 6 mo)

Tablets containing fixed combinations of one drug with cobicistat, which is a pharmacokinetic enhancer devoid of anti-HIV activity to increase the amount of medicine with HIV activity in the blood, can be used. These combinations include

  • Evotaz: Atazanavir 300 mg plus cobicistat 150 mg, taken po once/day with food

  • Prezcobix: Darunavir 800 mg plus cobicistat 150 mg, taken po once/day with food

Adverse effects with combination tablets are the same as those for the individual drugs included.

Drug interactions

Interactions between antiretrovirals may increase or decrease efficacy.

For example, efficacy can be increased by combining a subtherapeutic dose of ritonavir (100 mg once/day) with another PI (eg, darunavir, atazanavir). Ritonavir inhibits the hepatic enzyme that metabolizes the other PI. By slowing clearance of the therapeutically dosed PI, ritonavir increases the other drug’s levels, maintains the increased levels longer, decreases the dosing interval, and increases efficacy. Another example is lamivudine (3TC) plus zidovudine (ZDV). Use of either drug as monotherapy quickly results in resistance, but the mutation that produces resistance in response to 3TC increases the susceptibility of HIV to ZDV. Thus, when used together, they are synergistic.

Conversely, interactions between antiretrovirals may decrease the efficacy of each drug. One drug may increase elimination of another drug (eg, by inducing hepatic cytochrome P-450 enzymes responsible for elimination). Another, poorly understood effect of some NRTI combinations (eg, ZDV plus stavudine [d4T]) results in decreased antiretroviral activity without increasing drug elimination. This later combination is rarely used in clinical practice anymore.

Combining drugs often increases the risk that either drug will have an adverse effect. Possible mechanisms include the following:

  • Hepatic metabolism of PIs by cytochrome P-450: The result is decreased metabolism (and increased levels) of other drugs.

  • Additive toxicities: For example, combining first-generation NRTIs, such as d4T and didanosine (ddI), increases the chance of adverse metabolic effects and peripheral neuropathy. Also, using a tenofovir disoproxil fumarate in a ritonavir-boosted regimen increases the plasma levels of tenofovir disoproxil and, in susceptible patients with certain comorbidities, causes renal dysfunction.

Many drugs may interfere with antiretrovirals (see Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents: Drug Interactions); thus, interactions should always be checked before any new drug is started.

In addition to drug interactions, the following influence activity of some antiretroviral drugs and should be avoided:

  • Grapefruit juice, which inhibits an enzyme in the GI tract that degrades the PI saquinavir and thus increases bioavailability of saquinavir

  • St. John's wort, which can enhance metabolism of PIs and NNRTIs and thus decrease plasma PI and NNRTI levels

Adverse effects of antiretrovirals

Antiretrovirals can have serious adverse effects (see table Antiretroviral Drugs). Some of these effects, notably anemia, hepatitis, renal insufficiency, pancreatitis, and glucose intolerance, can be detected by blood tests before they cause symptoms. Patients should be screened regularly, both clinically and with appropriate laboratory testing (CBC; blood tests for hyperglycemia, hyperlidemia, hepatic and pancreatic damage, and renal function; urinalysis), especially after new drugs are started or unexplained symptoms develop.

Metabolic effects consist of interrelated syndromes of fat redistribution, hyperlipidemia, and insulin resistance. Subcutaneous fat is commonly redistributed from the face and extremities to the trunk, neck, breasts, and abdomen—a cosmetic effect that can stigmatize and distress patients. Treating the resulting deep facial grooves with injected collagen or polylactic acid can be beneficial.

Central obesity, hyperlipidemia, and insulin resistance, which together constitute the metabolic syndrome, increase the risk of MI, stroke, and dementia.

Antivirals from all classes appear to contribute to these metabolic effects, but PIs are the most clearly involved. Some older ART drugs, such as ritonavir or d4T, commonly have metabolic effects. Others, such as tenofovir disoproxil fumarate, etravirine, atazanavir or darunavir (even when combined with low-dose ritonavir), raltegravir, and maraviroc, appear to have small to minimal effects on lipid levels.

Mechanisms for metabolic effects appear to be multiple; one is mitochondrial toxicity. Risk of metabolic effects (highest with PIs) and mitochondrial toxicity (highest with NRTIs) varies by drug class and within drug classes (eg, among NRTIs, highest with d4T).

Metabolic effects are dose-dependent and often begin in the first 1 to 2 years of treatment. Lactic acidosis is uncommon but can be lethal.

Nonalcoholic fatty liver disease is being increasingly recognized among patients living with HIV. Certain early-generation ART drugs caused steatosis, and as their use decreased, incidence of steatosis decreased. Nonetheless, even with newer-generation ART drugs, there appears to be a risk of steatosis.

Long-term effects and optimal management of metabolic effects are unclear. Lipid-lowering drugs (statins) and insulin-sensitizing drugs (glitazones) may help. Patients should be counseled about maintaining a healthy diet and regular physical activity as ways to help promote health. (See also the recommendations of the HIV Medicine Association of the Infectious Diseases Society of America and the Adult AIDS Clinical Trials Group: Guidelines for the evaluation and management of dyslipidemia in HIV-infected adults receiving antiretroviral therapy.)

Bone complications of ART include asymptomatic osteopenia and osteoporosis, which are common. Uncommonly, osteonecrosis of large joints such as the hip and shoulder causes severe joint pain and dysfunction. Mechanisms of bone complications are poorly understood.

Immune reconstitution inflammatory syndrome (IRIS)

Patients beginning ART sometimes deteriorate clinically, even though HIV levels in their blood are suppressed and their CD4 count increases, because of an immune reaction to subclinical opportunistic infections or to residual microbial antigens after successful treatment of opportunistic infections. IRIS usually occurs in the first months of treatment but is occasionally delayed. IRIS can complicate virtually any opportunistic infection and even tumors (eg, Kaposi sarcoma) but is usually self-limited or responds to brief regimens of corticosteroids.

IRIS has two forms:

  • Paradoxical IRIS, which refers to worsening symptoms due to a previously diagnosed infection

  • Unmasked IRIS, which refers to the first appearance of symptoms of an infection not previously diagnosed

Paradoxical IRIS typically occurs during the first few months of treatment and usually resolves on its own. If it does not, corticosteroids, given for a short time, are often effective. Paradoxical IRIS is more likely to cause symptoms and symptoms are more likely to be severe when ART is started soon after treatment of an opportunistic infection is started. Thus, for some opportunistic infections, ART is delayed until treatment of the opportunistic infection has reduced or eliminated the infection.

In patients with unmasked IRIS, the newly identified opportunistic infection is treated with antimicrobial drugs. Occasionally, when the symptoms are severe, corticosteroids are also used. Usually, when unmasked IRIS occurs, ART is continued. An exception is cryptococcal meningitis. Then ART is temporarily interrupted until the infection is controlled.

Determining whether clinical deterioration is caused by treatment failure, IRIS, or both requires assessment of the persistence of active infections with cultures and can be difficult.

Interruption of antiretroviral therapy

Interruption of ART is usually safe if all drugs are stopped simultaneously, but levels of slowly metabolized drugs (eg, nevirapine) may remain high and thus increase the risk of resistance. Interruption may be necessary if intervening illnesses require treatment or if drug toxicity is intolerable or needs to be evaluated. After interruption to determine which drug is responsible for toxicity, clinicians can safely restart most drugs as monotherapy for up to a few days.

Pearls & Pitfalls

  • If patients who had an adverse reaction to abacavir are reexposed to the drug, they may have a severe, potentially fatal hypersensitivity reaction, so they should not be given the drug again.

  • Risk of an adverse reaction to abacavir is 100-fold higher in patients with HLA-B*57:01, which can be detected by genetic testing.

Note: The most important exception is abacavir; patients who had fever or rash during previous exposure to abacavir may develop severe, potentially fatal hypersensitivity reactions with reexposure. Risk of an adverse reaction to abacavir is 100-fold higher in patients with HLA-B*57:01, which can be detected by genetic testing.

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