Ten years of highly active antiretroviral therapy for HIV infection

NRTIs remain the most commonly prescribed ARVs and are always included in the initial treatment regimen. NRTIs are incorporated into the viral DNA, preventing reverse transcription and therefore inhibiting viral DNA synthesis. Viral replication is prematurely terminated and infection of new target cells is reduced. NRTIs are specific inhibitors of HIV reverse transcriptase, but also inhibit human mitochondrial DNA polymerase γ to varying degrees.

NNRTIs act at the same step in the HIV life cycle as NRTIs, but do not require intracellular phosphorylation and do not inhibit human DNA polymerases. Therefore, NNRTIs are not associated with mitochondrial toxicity. Nevirapine and efavirenz are the preferred NNRTIs in Australia.

Hepatotoxicity and rash can occur with both NNRTIs. Nevirapine-related hepatotoxicity is more common and can be fatal in rare cases.28 Efavirenz-related rash occurs more readily in children.29 NNRTIs are not associated with insulin resistance,30,31 although efavirenz is associated with mild hyper-cholesterolaemia.32,33

Nevirapine strongly induces CYP450 3A4 isoenzymes, while efavirenz is a mixed inducer/inhibitor of the same enzyme. NNRTIs have multiple drug interactions, including the oestrogen-based contraceptive pill (summarised in Box 2). Alternative methods of birth control are recommended if NNRTIs are used.

Efavirenz and nevirapine are equally effective, but differences in toxicity profile and potential for drug interaction lead to preferential use in particular settings (E2).32 Efavirenz should be avoided in patients with a history of severe psychiatric illness. Nevirapine is the drug of choice for women of childbearing potential or during pregnancy, but is avoided in patients taking antimycobacterial agents concurrently due to the risks of hepatotoxicity.

NNRTI-based regimens are commonly prescribed as initial therapy. These regimens generally have the advantage of established efficacy and a lower pill burden as compared with most of the protease inhibitor-based regimens.

The use of both nevirapine and efavirenz in the same regimen has not been shown to have additional efficacy over the use of either agent alone, and causes more adverse events than each drug separately (E2).32 Therefore, this approach is not recommended.

PIs prevent cleavage of viral precursor proteins into the subunits required for the formation of new virions (see Box 1). PIs block the production of virus from infected cells. Older PI-containing regimens are used less frequently now because of inconvenient dosing, food restrictions (indinavir, nelfinavir), and large pill burdens (amprenavir, saquinavir). PIs have extensive interactions with the CYP450 system (Box 2). Ritonavir, even at a low dose, is a potent inhibitor of the CYP450 3A4 isoenzymes. Low-dose ritonavir (usually 100 mg) together with a second PI is referred to as a “boosted PI” regimen, and this regimen is generally preferred to the use of a PI without ritonavir boosting. Low-dose ritonavir will inhibit metabolism of the second PI leading to an increase in serum levels and the need for less frequent dosing of the second PI. Newer PIs and ritonavir “boosted” PI regimens have improved pharmacokinetics, reduced pill burden, and a higher barrier to the development of ARV resistance.

All currently available PIs are substrates of the hepatic CYP450 system. CYP450 3A4 inducers such as rifamycins will reduce PI levels (rifabutin induces CYP450 3A4 to a lesser extent). All PIs inhibit CYP450 3A4, with ritonavir being the most potent. Thus, PIs have numerous and bidir-ectional drug interactions. Potential drug–drug interactions should always be checked before prescribing other medications for patients taking PIs.

Enfuvirtide (T20) prevents fusion of the HIV viral membrane with the target cell membrane and therefore blocks HIV entry into CD4+ T cells. Enfuvirtide is not orally bioavailable and requires reconstitution before subcutaneous injection. Injection site reactions are common. Randomised trials of enfuvirtide in individuals with multidrug resistant HIV have shown that addition of enfuvirtide to an “optimised” ARV regimen including at least another active agent leads to significant virological and immunological improvement (E2).40 Enfuvirtide is not licensed for use in treatment-naïve patients.

This class interferes with binding of HIV to its target cell. These drugs specifically block CCR5 or CXCR4 chemokine co-receptors and are called “co-receptor antagonists”. Only CCR5 antagonists have reached phase II/III clinical trials. Unfortunately, many CCR5 antagonists have unacceptable toxicities or limited virological efficacy. Although there was initial excitement with the prospect of a new class of ARVs, only one CCR5 antagonist remains in clinical trials.

This exciting new class of ARVs irreversibly inhibit the integration of HIV DNA into the host genome. Some agents have shown high potency in both treatment-naïve and treatment-experienced patients. An agent in this class has recently become available for use in patients with multidrug resistant HIV and advanced immuno-deficiency via the Special Access Scheme.38

Several international bodies publish guidelines for the use of antiretroviral therapy. The rapid changes in available agents, descriptions of new adverse events, and information on resistance and treatment strategies require that recommendations in guidelines are frequently updated. For this reason, Australia does not publish its own guidelines, but a set of extensive commentaries on the United States Department of Health and Human Services (US DHHS) guidelines provides information and guidance on Austra-lian specific scenarios. Both US DHHS guidelines and the Austra-lian commentaries are updated 6 monthly (http://www.ashm.org.au/guidelines). (Box 3)

Current recommendations for initial therapy for HIV infection include the use of dual NRTI (AZT/3TC, TDF/FTC, ABC/3TC) with either an NNRTI (efavirenz or nevirapine) or a boosted PI (lopinavir/ritonavir). The selection of a suitable HAART regimen should account for factors such as pill burden, adverse effects, pregnancy potential, co-infection with hepatitis B or C, efficacy, and comorbidities such as renal disease or metabolic syndrome. The management of HIV infection is a complex and rapidly changing arena. Studies have shown better outcomes for patients who receive care from physicians with experience in HIV medicine.41

Mitochondrial toxicity can manifest as hyperlactataemia, myopathy, peripheral neuropathy, hepatic steatosis and lipodystrophy. Its pathogenesis in an HIV-infected individual is debated, but is commonly attributed to inhibition of mitochondrial DNA polymerase γ by NRTIs. Mitochondrial toxicity is less common now, as the newer NRTIs (lamivudine, tenofovir, and abacavir) have low affinity for mitochondrial DNA polymerase γ compared with “older” NRTIs (didanosine, stavudine [d4T], zalcitabine, often referred to as “D-drugs”).

Lipodystrophy is a syndrome of both increased fat deposition (lipohypertrophy) and subcutaneous fat loss (lipoatrophy).42 Fat accumulation occurs in the dorsal cervical fat pad (buffalo hump), abdominal visceral fat, and breast tissue. Lipoatrophy occurs predominantly in the extremities, resulting in prominence of veins, and loss of bilateral buccal fat pads. Both NRTIs and PIs have been associated with lipodystrophy, which can occur with or without dyslipidaemia. The risk of lipodystrophy increases with prolonged ARV exposure (E4).43 Switching to a non-PI regimen is associated with reduction in visceral fat deposition (E32).44 Switching the thymidine analogue (stavudine or zidovudine) to an abacavir- or tenofovir-based regimen is associated with a slow increase in peripheral subcutaneous fat.45,46

Dyslipidaemia can result from ARV administration. Regular monitoring is required and lipid-lowering agents are often indicated. The metabolic syndrome, type 2 diabetes and vascular events are also complications of ARVs. An association between PI exposure and risk for increased cardiovascular events is well established (E2).30,31 The link (although weaker) has also been demonstrated with NRTIs and NNRTIs. New ARV drugs with less effect on lipids and insulin resistance are under development.

Adherence is a critical component to the success of HAART. There is good evidence that sustained virological response is strongly correlated with drug adherence (E1).47 Greater than 95% adherence is required to achieve viral suppression in 80% of individuals using PIs,48 although the adherence requirement may be less rigorous for NNRTIs than PIs.49

Lack of adherence causes suboptimal viral suppression and promotes development of drug resistance. It is hoped that the use of fixed-dose combinations together with daily dosing will improve adherence, thereby prolonging viral suppression and reducing emergence of resistance.

Education regarding potential drug interactions is important. Many ARVs inhibit, induce or are substrates for the CYP450 system, and undesirable pharmacokinetic interactions not uncommonly result (Box 2). Drug–drug interactions may occur between ARVs themselves, leading to reduced antiretroviral activity. Only combinations of ARVs that have undergone formal pharmaco-kinetic evaluation should be used. As the list of drug–drug interactions is extensive, it is recommended that physicians consult a pharmacist or online resources before prescribing medications in individuals receiving ARVs (http://www.hiv-druginteractions.org/).

Episodic treatment strategies were evaluated clinically with the hope that intermittent therapy might conserve ARV options (while the risk of disease progression was low), as well as reduce toxicity, minimise drug resistance and even boost immunity against HIV.

Numerous strategies have been studied to identify a safe and effective approach to treatment interruptions. A large randomised study showed an increased risk of HIV disease progression and death with intermittent CD4-guided ARV therapy compared with continuous therapy.50 Once treatment is initiated in chronic HIV infection, it is recommended that it be continued without interruption (E2).

Drug resistance rapidly emerges if viral replication is not fully suppressed in the presence of drugs.51 Increased transmission of drug-resistant HIV has been reported in many parts of the developed world,52-54 and expert opinion now recommends resistance testing before initiation of ARV therapy (E32).55 In Australia, viral resistance is measured by sequencing the reverse transcriptase and protease genes to detect mutations that are associated with drug resistance. Use of antiviral susceptibility testing in the management of chronic infection, especially in the setting of a failing regimen, has been shown to improve outcome (E32), and is widely used in Australia.