HIV AIDS medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]

Overview

The primary goal of antiretroviral therapy (ART) is to reduce HIV-associated morbidity and mortality. This goal is best accomplished by using effective ART to maximally inhibit HIV replication, as defined by achieving and maintaining plasma HIV RNA (viral load) below levels detectable by commercially available assays. Durable viral suppression improves immune function and quality of life, lowers the risk of both AIDS-defining and non-AIDS-defining complications, and prolongs life. Based on emerging evidence, additional benefits of ART include a reduction in HIV-associated inflammation and possibly its associated complications.

Medical Therapy

Anti-HIV medications (also called antiretrovirals) are grouped into six drug classes according to their mechanism of action. The six classes are as follows:

1. Non-nucleoside reverse transcriptase inhibitors (NNRTIs).
2. Nucleoside reverse transcriptase inhibitors (NRTIs).
3. Protease inhibitors (PIs).
4. Fusion inhibitors.
5. CCR5 antagonists.
6. Integrase inhibitors.

Multidrug regimen has proved to be very beneficial because of reduction in progression to AIDS, opportunistic infections, rate of hospitalizations and deaths.

Anti Retroviral Drug Classes

Drug Name	Dose	Adverse Events
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Abacavir (ABC)	300 mg BID or 600 mg once daily	Fever, rash, nausea, vomiting, diarrhea, abdominal pain, malaise, fatigue, sore throat, cough, shortness of breath.
Didanosine (ddI)	400 mg once daily In combination with TDF: 200 mg once daily	Pancreatitis, nausea, vomiting, peripheral neuropathy, retinal changes, optic neuritis, lactic acidosis with hepatic steatosis.
Emtricitabine (FTC)	200 mg once daily	Hyperpigmentation, skin discoloration
Zidovudine (AZT)	250-300 mg BID	Macrocytic anemia, neutropenia, nausea, vomiting, headache, insomnia, asthenia, nail pigmentation, lactic acidosis, severe hepatomegaly with hepatic steatosis (rare), hyperlipidemia, insulin resistance/diabetes mellitus, lipoatrophy, myopathy.
Lamivudine (3TC)	150 mg BID or 300 mg once daily	Minimal toxicity, severe acute exacerbation of hepatitis may occur in HBV coinfected patients who discontinue 3TC.
Stavudine (d4T)	>60 kg: 40 mg BID <60 kg: 250 mg BID	Peripheral neuropathy, lipoatrophy, pancreatitis, lactic acidosis, severe hepatomegaly with hepatic steatosis (rare), hyperlipidemia, insulin resistance/diabetes mellitus, rapidly progressive ascending neuromuscular weakness (rare).
Tenofovir Disoproxil Fumarate (TDF)	300 mg once daily	Renal insufficiency, Fanconi syndrome, osteomalacia, decrease in bone mineral density, severe acute exacerbation of hepatitis may occur in HBV coinfected patients who discontinue TDF, asthenia, headache, diarrhea, nausea, vomiting, and flatulence.
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz(EFV)	600 mg once daily	Rash, increased transaminase levels, hyperlipidemia, dizziness, somnolence, insomnia, depression, suicidality, confusion, abnormal thinking, impaired concentration, amnesia, agitation, depersonalization, hallucinations, and euphoria
Etravirine (ETR)	200 mg BID	Rash, Stevens-Johnson syndrome, nausea
Nevirapine (NVP)	200 mg once daily for 14 days, then 200 mg BID or 400 mg once daily	Rash, Stevens-Johnson syndrome, nausea, hepatitis
Rilpivirine (RPV)	25 mg once daily	Rash, depression, insomnia, headache, hepatotoxicity
Protease Inhibitors (PIs)
Atazanavir (ATV)	400 mg once daily In combination with TDF: 300 mg + RTV 100 mg once daily In combination with EFV: 400 mg + RTV 100 mg once daily	Indirect hyperbilirubinemia, PR interval prolongation, hyperglycemia, fat maldistribution, cholelithiasis, nephrolithiasis, renal insufficiency, increase in transaminase levels, hyperlipidemia, skin rash
Darunavir (DRV)	800 mg once daily	Skin rash, Stevens-Johnson syndrome, hepatotoxicity, diarrhea, nausea, headache, hyperlipidemia, fat maldistribution, hyperglycemia.
Fosamprenavir (FPV)	1400 mg BID or 700 mg + RTV 100 mg BID In combination with EFV: 700 mg + RTV 100 mg BID or 1400 mg + RTV 300 mg once daily	Skin rash, diarrhea, nausea, vomiting, headache, [[[hyperlipidemia]], hyperglycemia, increase in transaminase levels, nephrolithiasis, fat maldistribution.
Indinavir (IDV)	800 mg q8h	Nephrolithiasis, nausea, hepatitis, indirect hyperbilirubinemia, hyperlipidemia, headache, asthenia, blurred vision, dizziness, rash, metallic taste, thrombocytopenia, alopecia, hemolytic anemia, hyperglycemia, fat maldistribution.
Ritonavir-Boosted Lopinavir (LPV/r)	400 mg/100 mg BID or 800 mg/200 mg once daily	Diarrhea, nausea, vomiting, pancreatitis, asthenia, hyperlipidemia, hyperglycemia, fat maldistribution, increase in transaminase levels, PR interval prolongation, insulin resistance/diabetes mellitus.
Nelfinavir (NFV)	1250 md BID or 750 mg TID	Diarrhea, hyperlipidemia, hyperglycemia, fat maldistribution, increase in transaminase levels.
Ritonavir (RTV)	100-400 mg/d q12-24h	Diarrhea, nausea, vomiting, paresthesia, hyperlipidemia, hepatitis, asthenia, taste perversion, hyperglycemia, fat maldistribution.
Saquinavir (SQV)	1000 mg BID	Diarrhea, nausea, vomiting, headache, hyperlipidemia, hyperglycemia, fat maldistribution, PR interval prolongation, insulin resistance/diabetes mellitus.
Tipranavir (TPV)	500 mg BID	Hepatotoxicity, skin rash, hyperlipidemia, hyperglycemia, fat maldistribution.
Integrase Inhibitors
Dolutegravir (DTG)	50 mg q12-24h
Elvitegravir (EVG)	150 mg once daily
Raltegravir (RAL)	400 mg BID
Fusion Inhibitor
Enfuvirtide (T20)	90 mg SQ BID
CCR5 Antagonist
Maraviroc (MVC)	150-600 mg BID
Adapted from Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.

Goals of Therapy

• Durable suppression of HIV viral load ( to <50 cells/mL ).
• Restoration of normal CD4 cell count.
• Prevention of transmission of the disease.
• Prevention of building of drug resistance.
• Improvement in quality of life of the patient.

Uncontrolled viremia causes inflammation and immune activation, which has an overall effect on cardiovascular, renal and hepatic systems. Controlling viremia also controls these effects.

Anti Retroviral Therapy (ART)

• Current optimal HAART options consist of drug combinations consisting of at least three drugs belonging to at least two classes of antiretroviral agents.
• Typical regimens consist of:

• Two nucleoside analogue reverse transcriptase inhibitors (NARTIs or NRTIs) PLUS
• Either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor (NNRTI).

• In treatment-naive patients, four drug regimen is not found to be more efficacious than three-drug regimens and is associated with more adverse events.

• Antiretroviral therapy should be initiated in the following patient populations:

• Patients with history of an AIDS-defining illness or with a CD4 count of less than 350/µL.
• Pregnant women with HIV infection.
• Patients with HIV associated nephropathy.
• Patients with HIV and hepatitis B virus (HBV) coinfection who require treatment for HBV infection.

• Fusion inhibitors (eg, enfuvirtide) are not approved for treatment-naive patients.

• Treatment failure is defined by the following factors:

• Virologic failure: which is defined as suboptimal viral suppression or loss of suppression (>50 HIV-1 RNA copies/mL).
• Immunologic failure : which is defined as failure to achieve or maintain CD4 cell count recovery despite effective viral suppression.
• Development of new opportunistic infections or neoplasms despite apparent CD4 count recovery.

Anti Retroviral Regimens

▸ Click on the following categories to expand treatment regimens.

Recommended Regimens   ▸  NNRTI-Based Regimen   ▸  PI-Based Regimen   ▸  INSTI-Based Regimen Alternative Regimens   ▸  PI-Based Regimen   ▸  INSTI-Based Regimen

Recommended Regimen NNRTI-Based Regimen ▸ Efavirenz/Tenofovir/Emtricitabine† NNRTI-based regimen for patients with HIV RNA < 100,000 copies/mL ▸ Efavirenz PLUS ▸ Abacavir/Lamivudine† (only for HLA-B*5701 negative patients) OR ▸ Rilpivirine/Tenofovir/Emtricitabine† (only for patients with CD4 < 200 cells/mm³) †Emtricitabine may be substituted for lamivudine or vice versa Adapted from Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Recommended Regimen PI-Based Regimen ▸ Atazanavir/Ritonavir(low dose) PLUS ▸ Tenofovir/Emtricitabine† OR ▸ Darunavir/Ritonavir(low dose) PLUS ▸ Tenofovir/Emtricitabine† PI-based regimen for patients with HIV RNA < 100,000 copies/mL OR ▸ Atazanavir/Ritonavir(low dose) PLUS ▸ Abacavir/Lamivudine† (only for HLA-B*5701 negative patients) †Emtricitabine may be substituted for lamivudine or vice versa Adapted from Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Recommended Regimen INSTI-Based Regimen ▸ Dolutegravir PLUS ▸ Abacavir/Lamivudine† (only for HLA-B*5701 negative patients) OR ▸ Dolutegravir PLUS ▸ Tenofovir/Emtricitabine† OR ▸ Elvitegravir/Cobicistat/Tenofovir/Emtricitabine†(contraindicated in patients with CrCl <70mL/min) OR ▸ Raltegravir PLUS ▸ Tenofovir/Emtricitabine† †Emtricitabine may be substituted for lamivudine or vice versa Adapted from Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Alternative Regimen PI-Based Regimens ▸ Darunavir/Ritonavir(low dose) PLUS ▸ Abacavir/Lamivudine† (only for HLA-B*5701 negative patients) OR ▸ Lopinavir/Ritonavir(low dose) PLUS ▸ Abacavir/Lamivudine† (only for HLA-B*5701 negative patients) OR ▸ Lopinavir/Ritonavir(low dose) PLUS ▸Tenofovir/Emtricitabine† †Emtricitabine may be substituted for lamivudine or vice versa Adapted from Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Alternative Regimen INSTI-Based Regimens ▸ Raltegravir PLUS ▸ Abacavir/Lamivudine† (only for HLA-B*5701 negative patients) †Emtricitabine may be substituted for lamivudine or vice versa Adapted from Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.

Monitoring CD4 and Viral Load

Scenario	CD4 Monitoring	Viral Load Monitoring
Before receiving ART	Yes	Yes
While receiving ART	3 month after initiation of ART	2-4 weeks after initiation of ART, then every 4-8 weeks
ART regimen is modified due to drug toxicity	Will depend on previous CD4 counts	4-8 weeks after modification of regimen
ART regimen is modified due to virologic failure	Every 3-6 months	2-4 weeks after initiation of ART, then every 4-8 weeks
During the first 2 years of ART	Every 3-6 months	Every 3-4 months
While on ART with detectable viremia (>200 copies/mL)	Every 3-6 months	Every 3 months
Change in clinical status (new HIV clinical symptom or initiation of interferon, chronic systemic corticosteroids, or antineoplastic therapy)	Will depend on the clinical scenario	Every 3 months
Adapted from Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.

Other Laboratory Monitoring

Time-point	Laboratory Tests
At HIV diagnosis	Hepatitis B Serology Hepatitis C Serology Serum Na, K, HCO3, Cl, BUN, creatinine ALT, AST, Bilirubin CBC with differential Lipid Profile HbA1c or fasting glucose Urinalysis Resistant testing
At initiation of ART	Hepatitis B serology Serum Na, K, HCO3, Cl, BUN, creatinine ALT, AST, Bilirubin CBC with differential Lipid Profile HbA1c or fasting glucose Urinalysis Pregnancy test Resistant testing HLA-B*5701 testing (if considering ABC in regimen)
After 2-8 weeks after ART initiation	Serum Na, K, HCO3, Cl, BUN, creatinine ALT, AST, Bilirubin CBC with differential Lipid Profile
Every 3-6 months	Serum Na, K, HCO3, Cl, BUN, creatinine ALT, AST, Bilirubin CBC with differential HbA1c or fasting glucose (if abnormal previously)
Every 6-12 months	Lipid profile Urinalysis (if taking TDF) HbA1c or fasting glucose (if abnormal previously)
Adapted from Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.