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6.2 Changing Antiretroviral Therapy

Table of Contents

This can be grouped into two major categories:

Drug adverse events-toxicities

  • Intolerable side effects
  • Drug interactions
  • During pregnancy if patient is on EFV

Treatment failure

  • Clinical failure-occurrence or persistence of HIV related OIs
  • Immunological failure
  • Virological failure

Changing antiretroviral therapy due to toxicity

From a clinical perspective, it is generally recommended that when changing a client’s regimen due to toxicity, only the toxic drug(s) should be replaced, wherever possible, by a drug without overlapping toxicities. Table 6.5 provides guidance on ARV drug combinations with some common toxicity substitution within first-line regimens.

Table 6.5: Common toxicity substitution in first-line drugs

First-line Problem Substitution
TDF + (3TC or FTC) + EFV 600 Nephrotoxicity due to TDF ABC + 3TC + EFV AZT + 3TC + EFV
Severe CNS effects due to EFV600 TDF+(FTC or 3TC)+DTG

AZT+3TC+NVP

TDF+3TC+EFV400

AZT + 3TC + (EFV or NVP) Anemia due to AZT TDF + FTC + EFV
Lipodystrophy due to AZT TDF + FTC + EFV
Severe CNS effects due to EFV600 AZT+3TC+(DTG or NVP)
Mild to Moderate

Hypersensitivity due to NVP

AZT + 3TC + EFV
Severe Hypersensitivity e.g. Steven-Johnson Syndrome or Hepatotoxicity due to NVP AZT+3TC+ DTG

AZT+3TC+ (ATV/r or

LPV/r)

AZT or TDF based

regimens

Both Anemia and

Nephrotoxicity

ABC+3TC+ EFV ABC+3TC+DTG


NOTE
: For TB co-infected patients, the dose for DTG should be given twice daily i.e. 50mg bid

Figure 6.2: Substitution within first-line Antiretroviral Regimens

Table 6.6: Types of toxicities associated with first and second-line ARV drugs

ARV Major types of toxicity Risk factors Suggested management
TDF Tubular renal dysfunction, Fanconi syndrome Underlying renal disease

Older age

BMI <18.5 (or body weight <50kg) Untreated diabetes

mellitus

Untreated hypertension Concomitant use of nephrotoxic drugs or a boosted PI

 

If TDF is being used in first-line ART,

substitute it with

AZT or ABC

 

If TDF is being used in second-line ART (AZT use in first line ART), substitute it with ABC

Decreases in bone mineral density History of osteomalacia and pathological fracture Risk factors for osteoporosis or bone loss
Lactic acidosis or severe hepatomegaly with

steatosis

Prolonged exposure to nucleoside analogues Obesity
Exacerbation of hepatitis B (hepatic flares) Discontinuation of TDF due to toxicity No available alternative drug in the country for treatment of hepatitis B e.g. Entecavir
ABC Hypersensitivity reaction Genetic predisposition (HLA-B 5701 gene) If ABC is being used in first-line ART,

substitute with TDF or AZT

AZT Anaemia, neutropaenia, myopathy, lipoatrophy or lipodystrophy Baseline anaemia or

Neutropaenia CD4 cell count ≤200 cells/mm3

If AZT is being used in first-line ART, substitute it with TDF

or ABC

 

If AZT is being used in second-line ART, substitute it with ABC

Lactic acidosis or severe hepatomegaly with

steatosis

BMI >25 (or body weight

>75 kg)

Prolonged exposure to nucleoside analogues

 

 

 

 

LPV/r

Hepatotoxicity

 

Underlying hepatic disease

HBV and HCV coinfection

Concomitant use of hepatotoxic drugs

 

 

 

 

Replace it with ATV/r

 

Pancreatitis Advanced HIV disease
Lipoatrophy or metabolic syndrome dyslipidaemia, severe diarrhea and risk of prematurity Risk factors unknown
ATV/r Indirect hyperbilirubinaemia

(clinical jaundice)

 

 

Underlying hepatic disease

HBV and HCV co infection

Concomitant use of hepatotoxic drugs

Indirect hyperbilirunemia is usually transient and ATV/r can be continued, however, if severe jaundice develops and is associated with significantly raised transaminases, then ATV/r should be

replaced with LPV/r

 

Nephrolithiasis and risk of prematurity Risk factors unknown Replace it with LPV/r

 

 

 

 

 

 

EFV

 

Persistent central nervous system toxicity

(such as dizziness,abnormal dreams, depression or mental confusion)

Depression or other mental disorder

(previous or at baseline) Taking with high fat meal

Replace it with DTG or NVP. If the person cannot tolerate either INSTI or NNRTI, use boosted PIs
Hepatotoxicity Underlying hepatic disease – HBV and HCV

co infection Concomitant use of hepatotoxic drug

Convulsions History of seizure
Hypersensitivity reaction, StevensJohnson syndrome  

 

Risk factors unknown

Potential risk of neural tube birth defects

(very low risk in humans)

Male gynecomastia
NVP Hepatotoxicity Underlying hepatic disease

HBV and HCV coinfection

Concomitant use of hepatotoxic drugs CD4 >250 cells/mm3 in women

CD4 >400 cells/mm3 for men

First month of therapy (if lead-in dose is not used)

EFV. If the person cannot tolerate either NNRTI, use DTG or a boosted PI
Severe skin rash and hypersensitivity reaction (StevensJohnson syndrome) Risk factors unknown
DTG Increase in cholesterol levels; mild elevated liver enzymes; significant rises in

creatinine levels;

Insomnia and headache

may also be experienced.

History of dyslipidemia, diabetes, hypertension Monitor cholesterol levels; monitor Liver function especially in HBV and HCV. Provide symptomatic treatment
ETV Common: Skin rash, allergic reactions, Nausea, increased low

density Lipids, Gastrointestinal disorders and Fatigue Rare: Severe skin rash, Peripheral neuropathy and renal failure

No known risk factors Monitor severity and occurrence of fever and other symptoms. Provide symptomatic treatment
RAL Increased Cholesterol levels, Glucose,

Aspartate Amino

Transferase (AST),

Bilirubin. Rash, Cough, Fatigue, dizziness and insomnia

History of dyslipidemia, diabetes, hypertension In case of severe adverse effects, switch to DTG if patient is >12 years old
DRV/r Increased Cholesterol levels, triglycerides; Diarrhea, Headache, Rash, Abdominal pain and Nausea History of dyslipidemia Monitor severity and occurrence of fever and other symptoms. Provide symptomatic treatment

Changing antiretroviral therapy due to treatment failure

Table 6.7: WHO definitions of treatment failure in chronological order of occurrence: virological, immunological and clinical failure for the decision to switch ART regimens

Failure Definition Comments
Virological Plasma viral load above 1000 copies/ ml based on two consecutive viral load measurements after 3 months, with adherence support An individual must be taking ART for at least 6 months before it can be determined that a regimen has failed.
Immunological CD4 cell count falls to the baseline (or below)

or Persistent CD4 levels below

100 cells/mm3

Without concomitant or recent infection or steroid use to cause a transient decline in the CD4 cell count

Immunological and clinical characteristics of treatment failure develop much later after virological failure. Immunological and clinical criteria of treatment failure may also misclassify treatment failure and lead to unnecessary ARV switch to subsequent (line of treatment) regimen

Clinical New or recurrent clinical event indicating severe immunodeficiency (WHO clinical stage 4 conditions) after 6 months of effective treatment. The condition must be differentiated from IRIS

 

Transient rises in viral load are called viral blips and are not due to treatment failure. A diagnosis of treatment failure requires two consecutive viral load levels after >6months of treatment above 1000 copies/mL within an interval of 3 months and after adherence intensification.

Treatment failure should be distinguished from IRIS in which case the viral load will be low and the CD4 cell count will be high.

Switching To Third-Line Arv Regimens

It is crucial that before a regimen is declared to have failed, a multidisplinary switch team is convened to rule out non-adherence which is the commonest cause of reduced CD4 cell count and a VL rise, but is often not associated with HIV drug resistance. This team will also plan for enhanced adherence and support, for a period of 3 months before a second VL test. In case of non-adherence, these measures will lower the VL, increase CD4 cell count and avert a switch to a subsequent regimen

Before switching to third-line ARV regimens, genotypic HIV drug resistance is recommended to rule cross resistance between 1st and 2nd generation drugs and also assist in the determination of whether treatment failure is from non-adherence. Genotyping will also inform possibility of recycling drugs used in previous regimens i.e. some drugs used in 1st or 2nd regimens may still be effective in third-line.

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