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.