Changing Antiretroviral Therapy

Drug Specific Adverse Events-Toxicities

Intolerable side effects
Drug interactions

Treatment failure

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

Changing ART 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: Types of toxicities associated with first and second-line ARV drugs (Refer to National Guidelines for Management of HIV and AIDS 7^th Edition 2019)

ARV	Major types of toxicity	Risk factors	Suggested management and substitution
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
AZT	Lactic acidosis or severe hepatomegaly with steatosis	BMI >25 (or body weight >75kg) Prolonged exposure to nucleoside analogues
LPV/r	Hepatotoxicity	Underlying hepatic disease HBV and HCV co-infection 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 & HCV co infection Concomitant use of hepatotoxic drugs	Indirect hyperbilirubinaemia 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
ATV/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, Stevens-Johnson syndrome Male gynaecomastia	Risk factors unknown
NVP	Hepatotoxicity	Underlying hepatic disease HBV and HCV co-infection 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
NVP	Severe skin rash and hypersensitivity reaction (Stevens-Johnson 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
RAL	Increased Cholesterol levels, Glucose, Aspartate Amino Transferase (AST), and 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

Figure 6.2: Substitution within first-line Antiretroviral Regimens

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

Changing ART due to Treatment Failure

Table 6.6: 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 six 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 six months of effective treatment.	The condition must be differentiated from IRIS

Switching to Third-line ARV regimens

It is crucial that before a regimen is declared to have failed, a multidisciplinary 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 1^st and 2^nd generation drugs and 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 1^st or 2^nd regimens may still be effective in third- line.