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]; Ammu Susheela, M.D. [3]; Tarek Nafee, M.D. [4]

Overview

The primary goal of antiretroviral therapy (ART) is to reduce HIV-associated morbidity and mortality. This goal is best accomplished by using highly-active ART to maximally inhibit HIV replication, as defined by achievement and maintenance of plasma HIV RNA (viral load) below detectable levels, restoration of normal CD4 cell count, and prevention of transmission of the disease.. Major classes of agents used in the treatment of HIV are: Non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs), fusion inhibitors, CCR5 antagonists, and integrase inhibitors. All regimens are combinations of at least 3 agents, preferably with 2 NRTIs. 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 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.

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.

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

Anti Retroviral Regimens

WHO Recommendations in Adults

▸ Click on the following categories to expand treatment regimens.

ARV Regimens   ▸  First-Line Regimens   ▸  Second-Line Regimens

First-line Regimen Preferred Regimen ▸ Emtricitabine (FTC) OR ▸ Lamivudine (3TC) PLUS ▸ Tenofovir (TDF) PLUS ▸ Efavirenz (EFV) Alternative Regimen 1 (If preferred regimen is contraindicated or not available) ▸ Zidovudine (AZT) PLUS ▸ Lamivudine (3TC) PLUS ▸ Efavirenz (EFV) OR ▸ Nevirapine (NVP) Alternative Regimen 2 (If preferred regimen is contraindicated or not available) ▸ Tenofovir (TDF) PLUS ▸ Emtricitabine (FTC) OR ▸ Lamivudine (3TC) PLUS ▸ Nevirapine (NVP) Adapted from WHO 2013 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection Second-line Regimen If TDF + 3TC based regimen failed ▸ Zidovudine (ZDV) PLUS ▸ Lamivudine (3TC) PLUS ▸ Ritonavir-boosted Atazanavir (ATV/r) OR ▸ Ritonavir-boosted Lopinavir (LPV/r) If ZDV + 3TC based regimen failed ▸ Tenofovir (TDF) PLUS ▸ Lamivudine (3TC) PLUS ▸ Ritonavir-boosted Atazanavir (ATV/r) OR ▸ Ritonavir-boosted Lopinavir (LPV/r)

National Institute of Health (NIH) Recommendations

▸ 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 < 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 < 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.

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	Rash, insomnia, headache.
Elvitegravir (EVG)	150 mg once daily	Nausea, diarrhea, decrease bone density, severe acute exacerbation of hepatitis may occur in HBV coinfected patients.
Raltegravir (RAL)	400 mg BID	Rash, Steven-Johnson syndrome, toxic epidermal necrolysis, nausea, headache, diarrhea, pyrexia, CPK elevation.
Fusion Inhibitor
Enfuvirtide (T20)	90 mg SQ BID	Local injection reactions, increased incidence of bacterial pneumonia, rash, fever, nausea.
CCR5 Antagonist
Maraviroc (MVC)	150-600 mg BID	Abdominal pain, cough, dizziness, musculoskeletal symptoms, pyrexia, rash, upper respiratory tract infections, hepatotoxicity.
Adapted from Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.

CDC Grading of Recommendations and Levels of Evidence

Strength of recommendation	Level of evidence
A. Strong	I. One or more randomized trials with clinical outcomes and/or validated laboratory endpoint
B. Moderate	II. One or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes
C. Optional	III. Expert opinion based on evaluation of other evidence

Recommendations for Initiating Antiretroviral Therapy

• Antiretroviral therapy (ART) is recommended for all HIV-infected individuals. The strength of this recommendation varies on the basis of pretreatment CD4 cell count:
  • CD4 count <350 cells/mm3 (AI)
  • CD4 count 350 to 500 cells/mm3 (AII)
  • CD4 count >500 cells/mm3 (BIII)

• Regardless of CD4 count, initiation of ART is strongly recommended for individuals with the following conditions:
  • Pregnancy (AI)
  • History of an AIDS-defining illness (AI)
  • HIV associated nephropathy (HIVAN) (AII)
  • HIV/hepatitis B virus (HBV) coinfection (AII)
• Effective ART also has been shown to prevent transmission of HIV from an infected individual to a sexual partner; therefore, ART should be offered to patients who are at risk of transmitting HIV to sexual partners (AI [heterosexuals] or AIII [other transmission risk groups].
• Patients starting ART should be willing and able to commit to treatment and should understand the benefits and risks of therapy and the importance of adherence (AIII). Patients may choose to postpone therapy, and providers, on a case by case basis, may elect to defer therapy on the basis of clinical and/or psychosocial factors.

Current Recommended Initial Oral ART for Most Persons with HIV Infection

Bictegravir– FTC–TAF (50 mg/200 mg/25 mg),once daily as single-tablet regimen

• Adverse effects: Gastrointestinal symptoms (nausea, diarrhea), headache, immune reconstitution inflammatory syndrome (IRIS), lactic acidosis, hepatic steatosis.
• Not recommended in patients with creatinine clearance <30 ml/min or Child–Pugh class C liver function, contraindicated with dofetilide or rifampin, avoid divalent cations (Ca++, Mg++, Fe++), phenytoin, carbamazepine, and rifapentine, and use with caution with metformin.

Dolutegravir (50 mg),once daily

• Adverse effects: Gastrointestinal symptoms (nausea, diarrhea), headache, IRIS, lactic acidosis, hepatic steatosis.
• Not recommended in patients with creatinine clearance <30 ml/min or Child–Pugh class C liver function, contraindicated with dofetilide or rifampin, avoid divalent cations (Ca++, Mg++, Fe++), phenytoin, carbamazepine, and rifapentine, and use with caution with metformin.

Plus TAF–FTC (25 mg/200 mg), once daily as single-tablet regimen

• Adverse effects: Gastrointestinal symptoms (nausea, diarrhea), headache, IRIS, lactic acidosis, hepatic steatosis.
• Not recommended in patients with creatinine clearance <30 ml/min or Child–Pugh class C liver function, contraindicated with dofetilide or rifampin, avoid divalent cations (Ca++, Mg++, Fe++), phenytoin, carbamazepine, and rifapentine, and use with caution with metformin.

Plus TDF–FTC (300 mg/200 mg), once daily as single-tablet regimen

• Adverse effects: Gastrointestinal symptoms (nausea, diarrhea), headache, IRIS, lactic acidosis, hepatic steatosis.
• Not recommended in patients with creatinine clearance <30 ml/min or Child–Pugh class C liver function, contraindicated with dofetilide or rifampin, avoid divalent cations (Ca++, Mg++, Fe++), phenytoin, carbamazepine, and rifapentine, and use with caution with metformin.

Plus TDF–3TC (300 mg/300 mg), Individual tablets each once daily

• Adverse effects: Gastrointestinal symptoms (nausea, diarrhea), headache, IRIS, lactic acidosis, hepatic steatosis.
• Not recommended in patients with creatinine clearance <30 ml/min or Child–Pugh class C liver function, contraindicated with dofetilide or rifampin, avoid divalent cations (Ca++, Mg++, Fe++), phenytoin, carbamazepine, and rifapentine, and use with caution with metformin.

Dolutegravir–3TC (50 mg/300 mg), once daily as single-tablet regimen

• Typically used after 12-wk lead-in period with other three-drug antiretroviral regimen).

• Adverse effects: Gastrointestinal symptoms (nausea, diarrhea), IRIS, lactic acidosis, hepatic steatosis.

• Do not use with lamivudine resistance (M184V or M184I mutation) or HBV infection; not recommended in patients with creatinine clearance <30 ml/min or Child–Pugh class B or C liver function; contraindicated with dofetilide; avoid divalent cations (Ca++, Mg++, Fe++), phenytoin, carbamazepine, and rifapentine; use with caution with metformin.
• Dolutegravir–3TC is not recommended for patients with rapid start of ART or for patients with chronic HBV infection, HIV RNA greater than 500,000 copies per milliliter, or a CD4 cell count of less than 200 cells/mm3.

Raltegravir (600 mg), two tablets once daily

• Adverse effects: Gastrointestinal symptoms (nausea, diarrhea), headache, IRIS, lactic acidosis, hepatic steatosis.
• Not recommended in patients with creatinine clearance <30 ml/min or Child–Pugh class C liver function, contraindicated with dofetilide or rifampin, avoid divalent cations (Ca++, Mg++, Fe++), phenytoin, carbamazepine, and rifapentine, and use with caution with metformin.

Plus TAF–FTC (25 mg/200 mg), once daily as single-tablet regimen

• Adverse effects: Gastrointestinal symptoms (nausea, diarrhea), headache, IRIS, lactic acidosis, hepatic steatosis.
• Not recommended in patients with creatinine clearance <30 ml/min or Child–Pugh class C liver function, contraindicated with dofetilide or rifampin, avoid divalent cations (Ca++, Mg++, Fe++), phenytoin, carbamazepine, and rifapentine, and use with caution with metformin.

Plus TDF–FTC (300 mg/200 mg), once daily as single-tablet regimen

• Adverse effects: Gastrointestinal symptoms (nausea, diarrhea), headache, IRIS, lactic acidosis, hepatic steatosis.
• Not recommended in patients with creatinine clearance <30 ml/min or Child–Pugh class C liver function, contraindicated with dofetilide or rifampin, avoid divalent cations (Ca++, Mg++, Fe++), phenytoin, carbamazepine, and rifapentine, and use with caution with metformin.

Plus TDF–3TC (300 mg/300 mg), Individual tablets each once daily

• Adverse effects: Gastrointestinal symptoms (nausea, diarrhea), headache, IRIS, lactic acidosis, hepatic steatosis.
• Not recommended in patients with creatinine clearance <30 ml/min or Child–Pugh class C liver function, contraindicated with dofetilide or rifampin, avoid divalent cations (Ca++, Mg++, Fe++), phenytoin, carbamazepine, and rifapentine, and use with caution with metformin.

Abbreviations

FTC emtricitabine

TAF tenofovir alafenamide fumarate,

TDF tenofovir disoproxil fumarate,

3TC lamivudine.

Treatment Failure

Definitions of Treatment Failure
Clinical Failure	New or recurrent WHO stage 4 condition
CD4 Cell Failure	Fall of CD4 count to pre-therapy baseline (or below), OR 50% fall from the on-treatment peak value (if known), OR Persistent CD4 levels below 100 cells/mm3
Virological Failure	Plasma viral load > 1 000 copies/ml
Table adapted from WHO Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection

Treatment Failure Criteria	Stage 1	Stage 2	Stage 3	Stage 4
CD4 cell failure	Not recommended to switch regimen. Repeat CD4 count in 3 months	Not recommended to switch regimen. Repeat CD4 count in 3 months	Consider switching to second-line regimen†	Recommend to switch to second-line regimen†
CD4 cell failure and viral load failure	Consider second-line regimen†	Consider second-line regimen†	Recommended to switch to second-line regimen†	Recommended to switch to second-line regimen†
† Switching should not be done until the first regimen has been given sufficient time to succeed (at least 6 months). Table adapted from WHO GUIDELINES ON ANTIRETROVIRAL THERAPY FOR HIV INFECTION IN ADULTS AND ADOLESCENTS

Special Considerations

• HAART allows the stabilization of the patient’s symptoms and viremia, but it neither cures the patient of HIV, nor alleviates the symptoms, and high levels of HIV-1, often HAART resistant, return once treatment is stopped.
• It would take more than the lifetime of an individual to be cleared of HIV infection using HAART.
• Many HIV-infected individuals have experienced remarkable improvements in their general health and quality of life, which has led to the plummeting of HIV-associated morbidity and mortality.

HIV in Children

Because HIV disease progression in children is more rapid than in adults, and laboratory parameters are less predictive of risk for disease progression, particularly for young infants, treatment recommendations are more aggressive for children than for adults.

Treatment Adherence

Adherence is taking the correct dose of each anti-HIV medication at the correct time and exactly as prescribed. Adherence is very important for successful HIV treatment. The reasons for non-adherence and non-persistence with HAART are varied and overlapping. Major psychosocial issues, such as poor access to medical care, inadequate social supports, psychiatric disease and drug abuse contribute to non-adherence. The complexity of these HAART regimens, whether due to pill number, dosing frequency, meal restrictions or other issues, along with side effects that create intentional non-adherence, also has a weighty impact.

Difficulty in Adherence

There are several reasons why adhering to an HIV treatment regimen can be diicult. Most treatment regimens involve taking several pills every day with or without food, or before or after other medications. Other factors that can make treatment adherence difficult include:

• Difficulty taking medications (such as trouble swallowing pills).
• Side effects from medications (for example, fatigue or diarrhea).
• Daily schedule issues (including a busy schedule, shift work, or travel away from home) .
• Being sick or depressed .
• Alcohol or drug abuse.

Importance of Adherence

Adherence effects the success of HIV treatment in two ways:

• Good adherence to an HIV treatment regimen helps anti-HIV medications work effectively to reduce the viral load. Skipping medications, even occasionally, gives HIV to multiply rapidly. Preventing the virus from multiplying is the best way to stay healthy.
• Good adherence to an HIV treatment regimen also helps prevent drug resistance. One or more anti-HIV medications in a treatment regimen can become ineffective as a result of drug resistance.

Skipping medications makes it easier for drug resistance to develop. HIV can develop resistance to the anti-HIV medications in a person’s current regimen or to other, similar anti-HIV medications not yet taken, limiting options for successful HIV treatment. And drug-resistant strains of HIV can be transmitted to others, too. Although there are many different anti-HIV medications and treatment regimens, studies show that a person’s first regimen offers the best chance for long-term treatment success. Adhering to the regimen from the start will help ensure that the HIV treatment is successful.

Virologic Response

The most reliable indicator of response to ART is plasma HIV RNA and should be measured in all patients at baseline and regularly during therapy. It is thus useful in predicting clinical progression.

Viral load reduction may be more rapid in following patients:

• Having high CD4 cell count.
• Having lower levels of baseline viremia.
• In treatment-naive patients.

Time	Expected decrease in Viral load
1 week	Decrease by 0.75 to 1 log10 copies/mL
1 month	Decrease by 1.5 to 2 log10 copies/mL to <5000 copies/mL .
2 to 4 months.	<500 copies/mL
4 to 6 months.	< 50 copies/mL.

Transient increase in the viral load can be present in acute illness and vaccinations.

Virologic Failure

It is defined either as primary failure to achieve a viral load <50 copies/mL or any sustained recurrence of viremia to >50 copies/mL after initial viral suppression.

Two main causes of the failure are:

1. Drug resistance.
2. Failure of the drugs to reach the target site.

Viral Blips

It refer to an isolated low-level of detectable HIV RNA (>50 to 500 copies/mL) that occurs during long-term monitoring on a stable ART regimen.

Department of Health and Human Services (DHHS) have suggested that viral blips do not require intervention with a new regimen unless the viral load is sustained at >200 copies/mL.

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.

Treatment Regimen

• 1. Antiretroviral regimen options for treatment-naive patients

• 1.1. Integrase strand transfer inhibitor-based regimens

• Preferred regimen (1): Dolutegravir 50 mg PO qd AND Abacavir 600 mg-Lamivudine 300 mg PO qd in patients who are HLA-B*5701-negative
• Preferred regimen (2): Dolutegravir 50 mg PO qd AND Tenofovir 300 mg-Emtricitabine 200 mg PO qd
• Preferred regimen (3): Elvitegravir 150 mg-Cobicistat 150 mg-Tenofovir 300 mg-Emtricitabine 200 mg PO qd in patients with estimated CrCl ≥ 70 mL/min/1.73
• Preferred regimen (4): Raltegravir 400 mg PO bid AND Tenofovir 300 mg-Emtricitabine 200 mg PO qd
• Alternative regimen (1): Efavirenz 600 mg PO qd OR Tenofovir 300 mg-Emtricitabine 200 mg PO qd
• Alternative regimen (2): Rilpivirine 25 mg PO qd AND (Tenofovir 300 mg PO qd OR Emtricitabine 200 mg PO qd) for patients with CD4 count >200 cells/microL
• Alternative regimen (3): Raltegravir 400 mg PO bid AND (Abacavir 600 mg PO qd OR Lamivudine 300 mg PO qd) in patients who are HLA-B*5701-negative

• 1.2. Protease inhibitor-based regimen

• Preferred regimen: Darunavir 800 mg-Ritonavir 100 mg PO qd AND Tenofovir 300 mg-Emtricitabine 200 mg PO qd
• Alternative regimen (1): Atazanavir 300 mg-Cobicistat 150 mg PO qd AND Tenofovir disoproxil fumarate 300 mg-Emtricitabine 200 mg PO qd only for patients with pre-treatment estimated CrCl ≥70 mL/min
• Alternative regimen (2): Atazanavir 300 mg-Ritonavir 100 mg PO qd AND Tenofovir 300 mg-Emtricitabine 200 mg PO qd
• Alternative regimen (3): (Darunavir 800 mg-Cobicistat 150 mg PO qd OR Darunavir 800 mg-Ritonavir 100 mg PO qd) AND Abacavir 600 mg-Lamivudine 300 mg PO qd only for patients who are HLA-B*5701 negative
• Alternative regimen (4): Darunavir 800 mg-Cobicistat 150 mg PO qd AND Tenofovir disoproxil fumarate 300 mg-Emtricitabine 200 mg PO qd only for patients with pre-treatment estimated CrCl ≥70 mL/min
• Alternative regimen (5): Atazanavir 300 mg-Ritonavir 100 mg PO qd AND Abacavir 600 mg-Lamivudine 300 mg PO qd in patients who are HLA-B*5701-negative and with pre-treatment HIV RNA <100,000 copies/mL
• Alternative regimen (6): Lopinavir 400 mg-Ritonavir 100 mg PO qd or bid AND Abacavir 600 mg-Lamivudine 300 mg PO qd only for patients who are HLA-B*5701 negative
• Alternative regimen (7): Lopinavir 400 mg-Ritonavir 100 mg PO qd or bid AND Tenofovir disoproxil fumarate 300 mg-Emtricitabine 200 mg PO qd

• 1.3. A non-nucleoside reverse transcriptase inhibitor (NNRTI) based regimen

• Alternative regimen (1): Efavirenz 600 mg-Tenofovir 300 mg-Emtricitabine 200 mg PO qd
• Alternative regimen (2): Rilpivirine 25 mg-Tenofovir 300 mg-Emtricitabine 200 mg PO qd

• 1.4. Other regimen options

• 1.4.1. A non-nucleoside reverse transcriptase inhibitor (NNRTI) based regimen

• Preferred regimen (1): Efavirenz 600 mg PO qd AND Abacavir 600 mg-Lamivudine 300 mg PO qd only for patients who are HLA-B*5701 negative and with pre-treatment HIV RNA <100,000 copies/mL.

• 1.4.2. Other regimens when tenofovir or abacavir cannot be used

• Preferred regimen (1): Darunavir 800 mg-Ritonavir 100 mg PO qd AND Raltegravir 400 mg PO qd only for patients with pre-treatment HIV RNA <100,000 copies/mL and CD4 cell count >200 cells/mm3.
• Preferred regimen (2): Lopinavir 400 mg-Ritonavir 100 mg PO bid AND Lamivudine 300 mg PO bid

• 1.5. Pediatric doses

• Abacavir 300 mg PO bid
• Lamivudine 4 mg/kg/dose PO bid; maximum 150 mg PO bid
• Stavudine 1 mg/kg/dose PO bid
• Tenofovir 8 mg/kg/dose PO bid
• Zidovudine 180-240 mg/m²/dose PO bid or 160 mg/m²/dose PO tid (range 90 mg/m²/dose-180 mg/m²/dose)
• Lopinavir 400 mg PO bid
• Nelfinavir 50 mg/kg/dose PO bid
• Raltegravir 300 mg PO bid
• Didanosine

• 20 to < 25 kg: 200 mg PO qd
• 25 to < 60 kg: 250 mg PO qd
• ≥60 kg: 400 mg PO qd

• Efavirenz

• 10 to < 15 kg: 200 mg PO qd
• 15 to <20 kg: 250 mg PO qd
• 20 to < 25 kg: 300 mg PO qd
• 25 to < 32.5 kg: 350 mg PO qd
• 32.5 to <40 kg: 400 mg PO qd
• ≥ 40 kg: 600 mg PO qd

• Nevirapine maximum 200 mg per dose

• Between 1 day and 8 years: 200 mg/m²/dose PO qd for 14 days, then 200 mg/m²/dose PO bid
• 8 years and above: 120-150 mg/m²/dose PO qd for 14 days, then 120-150 mg/m²/dose PO bid

• Note (1): Anti retroviral therapy for treatment naive patients is a life long therapy.
• Note (2): Tenofovir disoproxil fumarate should be avoided in patients with a creatinine clearance <50 mL/min.
• Note (3): Rilpivirine should be used in patients with a CD4 cell count >200 copies/mL and should not be used with proton pump inhibitors.
• Note (4): Efavirenz should not be used in pregnant women.

• 2. Pre-exposure prophylaxis (PrEP)

• Preferred regimen: Tenofovir disoproxil fumarate 300 mg-Emtricitabine 200 mg PO qd for ≤90-days
• Note (1): People with high risk behavior such as men who have sex with men, intravenous drug abusers, HIV-positive sexual partner, recent bacterial STI, high number of sex partners, history of inconsistent or no condom use, commercial sex work, people in high-prevalence area or network are advised to take pre-exposure prophylaxis of drugs.
• Note (2): Follow-up visits at least every 3 months to provide the following: HIV test, medication adherence counseling, behavioral risk reduction support, side effect assessment, STI symptom assessment, pregnancy testing.
• Note (3): At 3 months and every 6 months thereafter, assess renal function.
• Note (4): Every 6 months, test for bacterial STIs.

• 3. Post- exposure prophylaxis

• Preferred regimen: Raltegravir 400 mg PO bid AND Tenofovir disoproxil fumarate 300 mg-Emtricitabine 200 mg PO qd
• Preferred basic regimen for low-risk exposures (Eg: mucus membrane):
  • Zidovudine 100 mg PO qd AND Lamivudine 300 mg PO qd
  • Zidovudine 100 mg PO qd AND Emtricitabine 200 mg PO qd
  • Tenofovir 300 mg PO qd AND Lamivudine 300 mg PO qd
  • Tenofovir 300 mg PO qd AND Emtricitabine 200 mg PO qd
• Preferred expanded regimen for high-risk exposure (Eg: percutaneous needle stick)
  • Zidovudine 100 mg PO qd AND Lamivudine 300 mg PO qd AND Lopinavir 400 mg-Ritonavir 100 mg PO qd
  • Zidovudine 100 mg PO qd AND Emtricitabine 200 mg PO qd AND Lopinavir 400 mg-Ritonavir 100 mg PO qd
  • Tenofovir 300 mg PO qd AND Lamivudine 300 mg PO qd AND Lopinavir 400 mg-Ritonavir 100 mg PO qd
  • Tenofovir 300 mg PO qd AND Emtricitabine 200 mg PO qdAND Lopinavir 400 mg-Ritonavir 100 mg PO qd
• Note: Ideally therapy should be started within hours of exposure and continued for 28 days.

• 4. Perinatal antiretroviral regimen

• 4.1. Antepartum

• 4.1.1. Protease inhibitor-based regimen

• Preferred regimen: (Tenofovir 300 mg-Emtricitabine 200 mg PO qd (fixed dose combination) OR Tenofovir 300 mg-Lamivudine 300 mg PO qd OR Abacavir 600 mg-Lamivudine 300 mg PO qd OR Zidovudine 100 mg-Lamivudine 300 mg PO qd) AND (Atazanavir 300 mg-Ritonavir 100 mg PO qd OR Lopinavir 400 mg-Ritonavir 100 mg PO qd)

• 4.1.2. A non-nucleoside reverse transcriptase inhibitor (NNRTI) based regimen:

• Preferred regimen (1): Efavirenz 600 mg-Tenofovir 300 mg-Emtricitabine 200 mg (fixed dose combination) PO qd
• Preferred regimen (2): Efavirenz 600 mg-Tenofovir 300 mg-Lamivudine 300 mg PO qd
• Alternative regimen: (Abacavir 600 mg-Lamivudine 300 mg PO qd OR Zidovudine 100 mg-Lamivudine 300 mg PO qd) AND Efavirenz 600 mg PO qd

• 4.2. Intrapartum

• Note (1): HIV RNA <1000 copies/mL and good adherance-Continue the regimen during delivery or cessarean section.
• Note (2): HIV RNA >1000 copies/mL near delivery, possible poor adherence, or unknown HIV RNA levels- Intravenous Zidovudine 2 mg/kg IV over 1 hr should be given three hours before cesarean section or delivery and then 1 mg/kg/hr IV continuous infusion until umbilical cord clamping.

• 4.3. Postpartum

• Note: Initiate anti retroviral therapy (ART) and continue after delivery and cessation of breastfeeding.

• 5. Infant antiretroviral prophylaxis for prevention of mother-to-child transmission of HIV

• 5.1 Prophylaxis for HIV-exposed infants of women who received antepartum antiretroviral prophylaxis

• Preferred regimen: Zidovudine (ZDV) 100 mg PO given at birth and continued till six weeks
• Note (1): Dose based on gestational age at birth and weight, initiated as soon after birth as possible and preferably within 6 to 12 hours of delivery.
• Note (2): ≥35 weeks gestation at birth: 4 mg/kg/dose orally (or, if unable to tolerate oral agents, 3 mg/kg/dose IV) every 12 hours.
• Note (3): ≥30 to <35 weeks gestation at birth: 2 mg/kg/dose orally (or 1.5 mg/kg/dose IV) every 12 hours, advanced to 3 mg/kg/dose orally (or 2.3 mg/kg/dose IV) every 12 hours at age 15 days.
• Note (4): <30 weeks gestation at birth: 2 mg/kg/dose orally (or 1.5 mg/kg/dose IV) every 12 hours, advanced to 3 mg/kg/dose orally (or 2.3 mg/kg/dose IV) every 12 hours after age four weeks.

• 5.2. Prophylaxis for HIV-exposed infants of women who received no antepartum antiretroviral prophylaxis

Nevirapine

• Dose based on birth weight, initiated as soon after birth as possible.
• Birth weight 1.5 to 2 kg: 8 mg/dose orally.
• Birth weight >2 kg: 12 mg/dose orally.

AND

Zidovudine (ZDV)

• Dose based on gestational age at birth and weight, initiated as soon after birth as possible and preferably within 6 to 12 hours of delivery.

• ≥35 weeks gestation at birth: 4 mg/kg/dose orally (or, if unable to tolerate oral agents, 3 mg/kg/dose IV) every 12 hours.
• ≥30 to <35 weeks gestation at birth: 2 mg/kg/dose orally (or 1.5 mg/kg/dose IV) every 12 hours, advanced to 3 mg/kg/dose orally (or 2.3 mg/kg/dose IV) every 12 hours at age 15 days.
• <30 weeks gestation at birth: 2 mg/kg/dose orally (or 1.5 mg/kg/dose IV) every 12 hours, advanced to 3 mg/kg/dose orally (or 2.3 mg/kg/dose IV) every 12 hours after age four weeks.

• Note (1): Three doses in the first week of life.
• Note (2): First dose within 48 hours of birth (birth to 48 hrs).
• Note (3): Second dose 48 hours after first.
• Note (4): Third dose 96 hours after second.