Biology Reference
In-Depth Information
including lactic acidosis, peripheral neuropathy, lipodystrophy, pancreatitis,
myopathy, and anemia). All drugs in the NRTI class may cause potentially fatal
lactic acidosis with hepatic steatosis. A potential explanation is mitochondrial
toxicity, generally attributed to inhibition of mitochondrial DNA polymerase
by nucleoside analogs. Dyslipidemia and changes in body fat distribution (often
termed lipodystrophy), although more common with PI, have also been ob-
served in patients treated exclusively with NRTIs and could also be associated
with the prolonged use of nRTI regimens.
All drugs in the NNRTI class (nevirapine, delavirdine, and, to some extent,
efavirenz) may cause rash and liver toxicity. Most cases of rash are mild or
moderate. However, cases of Stevens-Johnson syndrome have been described.
Elevations of aminotransferases, and cases of fatal hepatitis have been reported,
particularly with nevirapine. Efavirenz may cause transient central nervous sys-
tem disturbances that manifest as a complex of sleep and mood disturbances.
Metabolic dysfunctions with dyslipidemia and/or changes in body fat dis-
tribution are more commonly associated with use of PI-containing regimens
(Carr, 1999). Symptoms are variable and may include peripheral fat loss and
central fat accumulation, often associated with hypercholesterolemia, hyper-
triglyceridemia, insulin resistance, and, rarely, hyperglycemia. Overall cumula-
tive incidence may be 30% to 60% after 1 to 2 years of therapy and increases
with the duration of therapy (Maus, 2000).
In most cases, we have to admit that the pathophysiology of the adverse
e¨ects of antiretroviral drugs is not fully understood and that universally e¨ec-
tive therapeutic interventions to counteract them are lacking or not established.
Delaying the initiation of antiretroviral therapy seems today the only option.
However, alternatives may arise in the future, particularly if clinical predictors,
and genetic or pharmacological correlates are identi®ed, and toxicity prophy-
laxis and treatment strategies are developed. Among these, intermittent therapy
is being explored as a promising approach, together with substituting protease
inhibitor with other classes of compounds to minimise PI-related toxicities and
ease adherence. Both abacavir and nevirapine can be substituted for a PI, and
data was recently presented to show that efavirenz could also be a useful sub-
stitutes. It should be emphasised that before recommending substitution, such
strategies are only suitable for patients who have suppressed viral load and
have never had virological failure on the current or prior regime.
TREATMENT FAILURE AND HIV RESISTANCE TO
ANTIRETROVIRAL DRUGS
Treatment Failure
The reasons for treatment failure in HIV-1 infection are multifactorial, includ-
ing evolution of drug resistance, pharmacokinetic and metabolic factors, in-
