The Aim of Antiretroviral Therapy:

Antiretroviral therapy aims to :

1. Reduce the detectable viral load of HIV RNA as low as possible, ideally to below the current level of detection of 50 copies/ml.
2. Maintain this level of suppression for as long as possible.
3. By so doing to prevent opportunistic infections occurring, improve the quality to prolong the life of HIV infected persons.

Several years ago it was thought that HIV eradication was theoretically possible if HAART (Highly Active Antiretroviral Therapy) was able to control viral replication for a period of 2 - 3 years. More recent data shows that there is still ongoing low level HIV replication even when plasma HIV RNA is below the current level of detection (i.e. below 50 copies/ml) which results in some "reseeding" of lymphocytes. Further, data on the apparent half life decay of resting memory CD4 lymphocytes infected with latent HIV pro-virus have been revised, and are now considered to be at least 6 months, and may even be as long as 44 months. This means that HIV eradication using current antiviral therapies will be expected to take at least a decade or longer, if such a goal is indeed possible at all. The current realistic view then is that antiretroviral therapy should be considered long-term management of a chronic viral infection.

Recent evidence shows that the damaged immune system is capable of some restoration provided HIV replication is controlled. Recent data shows that there is a clinically significant immune reconstitution starting about 6 months after HAART has been initiated, and continuing as long as HIV replication is suppressed. This immune constitution can be measured with the return of HIV specific lymphoproliferative responses, and a gradual increase in native CD4 cells.

Current drug regimens have a number of difficulties. In clinical studies, only around 70% of those who are placed on HAART achieve the ideal level of suppression of HIV replication (below 50 copies/ml) and in clinical practice this figure may be as low as 50%. Those who fail to completely suppress viral replication show clinical progression with increasing viral load over a period of time. Further, current drug regimens are often complex, difficult to tolerate, have long-term side effects, and raise medical issues such as monitoring and adherence with therapy over time. For chronic therapy, regimens ideally should be simple, tolerable, have few side effects and afford a good quality of life. Current antiretroviral regimens fall short of these ideals, as drug combinations often have:

• Significant long term toxicity such as lipodystrophy or diabetes associated with protease inhibitors, or peripheral neuropathy associated with nucleoside agents
• Involve a large pill burden and complex ingestion regimens
• Often have awkward requirements with respect to time of food intake or in the case of Indinavir require a constant high fluid intake

Starting therapy therefore requires a patient to be mentally well prepared for this important step, committed to being compliant with therapy and often having to persist with therapy in face of mild/moderate adverse drug effects. Failure to comply with therapy results in the rapid recurrence of viral replication, occurring in the face of low or variable drug levels, which results rapidly in the emergence of a drug resistant mutant.

When to start therapy?

The risks and benefits of antiviral therapy need to be carefully considered in a situation where the patient and physician share the decision making. Drug regimens need to be carefully chosen so as to not compromise future drug options. Before prescribing therapy, it is useful to consider what subsequent choices are available if/when therapy fails. Increasingly the concept of planning future sequential drug combinations and avoiding for as long as possible using protease inhibitors with their known metabolic side effects, drives clinical decision making.

Both CD4 cell counts and plasma HIV RNA levels are independent predictors of clinical outcome. Of the two, plasma HIV RNA level has been shown to be the stronger predictor of progression rate, except in patients who have low CD4 counts. CD4 counts on the other hand are useful indicators of the likelihood of developing an opportunistic infection and can act as a useful guide as to which type of infection may occur at a particular CD4 count e.g. PCP infections with CD4 counts below 200, MAC or CMV infections with CD4 counts below 50. It is generally accepted that at least two viral loads and CD4 counts should be obtained, to ensure a consistency of these figures, before antiretroviral therapy is initiated.

For persons having a CD4 count >500 x 10 6/L and HIV RNA levels below 5000 copies/ml, the risk of progression over the next 3 years is low. Therapy is deferred in this situation, but monitoring should continue on a regular basis at 4 - 6 monthly intervals. See Table I below.

For persons with a CD4 count between 350 and 500 x 10 6/L, those with a low viral load (below 5000 copies) should consider whether they are ready to commit to therapy or not. One reasonable option is to continue monitoring viral load in such persons, whilst others may decide to start antiretroviral therapy. For persons with a viral load between 5,000 and 30,000, or >30,000 copies, antiretroviral therapy is recommended.

Therapy should be recommended for all persons with symptomatic established HIV infection, for persons who have suffered an AIDS defining opportunistic infection, and for persons with a confirmed plasma HIV RNA level >30,000 copies/ml irrespective of CD4 count.

Drug selection:

At present there are no definitive data regarding the superiority of one potent regimen against another so that recommendations for specific combinations of individual drugs cannot be made. Triple therapy is the accepted "standard of care" for HIV, with increasing interest being focused on 4-drug regimens (for which there is only limited data available currently).

The most commonly prescribed initial regimen consists of two nucleoside reverse transcriptase inhibitors (nRTI) and a protease inhibitor (PI), or two nRTI's and a non-nucleoside reverse transcriptase inhibitor (NNRTI). The advent of Abacavir (Ziagen) has raised the possibility of a 3-drug nRTI regimen with similar potency to the above combinations. There is some concern about the effectiveness of this regimen if there is a high baseline viral load. Table II lists currently available antiretroviral drugs in New Zealand.

Possible nRTI combinations include Zidovudine with Lamivudine or Didanosine or Zalcitabine; Stavudine with Didanosine or Lamivudine. Zidovudine and Stavudine should not be used together because of drug/drug antagonism. Zalcitabine with Didansone or Stavudine is not recommended because both drugs cause peripheral neuropathy.

Lamivudine should be reserved for regimens that maximally suppress replication as there is rapid emergence of the M184V mutation that results in loss of Lamivudine activity if replication is not fully suppressed. Abacavir is a new potent nRTI that is to be considered for initial treatment of drug native patients. Exposure to Zidovudine and Lamivudine can result in loss of Abacavir's effectiveness. Consequently, Abacavir will likely be used in initial regimens, but its effectiveness in combination with other nRTI's has not been fully defined.

Non-nucleoside reverse transcriptase inhibitors (NNRTI):

NNRTI's should only be used in drug combinations designed to maximally suppress HIV replication, as high level resistance can emerge due to the emergence of a single reverse transcriptase mutation. Currently, NNRTI's are not effective if resistance to a previous NNRTI has emerged so that consequently, in the course of treatment of an HIV infected person, only one NNRTI should be used over time.

There is no direct comparison of the effectiveness of different available NNRTI's. Efavirenz in combination with Zidovudine and Lamivudine in clinical trials has been shown to suppress HIV replication to a level that is at least comparable with Indinavir, Lamivudine, Zidovudine combination. This degree of suppression was irrespective of initial viral load.

Protease inhibitors are among the most potent drugs currently available for persistent suppression of HIV replication, which warrants their continued use in initial drug regimens until further data is available. Individual protease inhibitors have different adverse effects: Indinavir (Crixavan) is associated with nephrolithiasis (kidney stones) or crystal nephropathy and consequently requires a fluid intake of at least 2 litres of water daily. Saquinavir, Ritonavir and Nelfinavir are all associated with diarrhoea. The new soft gel Saquinavir (Fortovase) has improved oral bioavailability compared to the hard gel formulation (Invirase) and is currently regarded as the agent of choice.

The advantages and disadvantages of various antiretroviral regimens are summarised in Table III while Table IV summarises the common adverse effects of different agents.

Monitoring antiretroviral therapy:

Doctors need to constantly monitor a patient's adherence to their drug regimen. Patients should be encouraged to openly discuss any problems they experience with their drug regimen, particularly those doses they find hardest to remember or difficult to take for some reason. Adverse effects of regimens should be actively sought and inquired about (see Table IV), and should not be glossed over.

The continued monitoring of CD4 cell counts and HIV RNA levels is important to evaluate the response to treatment. With the introduction of effective therapy, the HIV RNA level should fall rapidly with at least a 1.5 - 2 log decline by 4 weeks. Depending upon the baseline viral load, it may take anywhere between 6 up to 24 weeks for viral load to fall below the desired target level of <50 copies.

Failure to show an appropriate drop in viral load should raise concerns about adherence, drug absorption or drug resistance. It is prudent to check viral load within 4 - 6 weeks of starting therapy, and monthly until the viral load is at its lowest, and then 2 - 3 monthly thereafter. CD4 increments rise sharply early on, and then progressively throughout the next year or two provided HIV replication is suppressed. CD4 counts should usually be checked at the same time as performing tests for viral load.

Switching therapy

The main reasons for changing an antiretroviral drug regimen would be evidence of drug failure, adverse effects, or a regimen that a person was finding intolerable and for whom adherence is likely to be compromised. Drug failure is recognised where there is either inadequate suppression of viral load early on, or having been suppressed the viral load starts to rise. It is not clear currently what increase in viral load should result in a switch in drug regimen. The doctor has to balance up issues relating to:

1. The likelihood of resistance developing if low level HIV replication persists in face of drug exposure
2. What drug options are subsequently open to the person
3. The likelihood of immunologic damage occurring in the near future

Any detectable viral load in persons who have previously had undetectable levels should result in review of these considerations. When the viral load is between 1000 and 5000 copies, the decision when to switch therapy becomes increasingly important. One potential option at this stage may be intensification, with the addition of a new agent such as Hydroxyurea that has been shown to slow viral replication.

A variety of other strategies such as drug holidays, multiple (>4) drug combinations, recycling of previous used agents, could also be considered. The decision as to whether treatment should be stopped altogether, because of persisting high level viraemia, in patients with advanced disease and few if any remaining antiretroviral options, needs to be individualised between doctor and patient.

There is data indicating that even where there is significant viral load in the presence of antiretroviral drugs, the dominant viral species is "less fit" than wild type virus i.e. viral replication is slowed but not controlled. In this situation, it may be reasonable to continue treatment as long as possible. This decision would have to be tempered by the need for other agents necessary to suppress or control opportunistic infections e.g. Rifabutin for MAC infection.

In the last 15 years, antiretroviral therapy has come a long way: from single agent treatment to double and now triple therapy. The advent of the latter has seen sharp declines in the number of people currently dying of AIDS. The future looks promising, with a number of new drugs entering clinical trials. HIV infection has changed from an inevitable death sentence, to becoming a chronically managed viral infection. What has also become clear is that drug regimens we use in 2000 will become rapidly outdated as our knowledge base grows.

Table 1

CD4 count	Plasma HIV	RNA level	Copies/ml
	<5000	5000 - 30000	>30000
<350	Recommend therapy	Recommend therapy	Recommend therapy
350 - 500	Consider therapy	Recommend	Recommend
>500	Defer	Consider	Recommend

Table II

Antiretroviral drugs currently available in New Zealand:

Table III

Advantages and disadvantages of various antiretroviral regimes

Therapy Regime	Advantages	Disadvantages
2nRTI + PI	Best developed clinical data. Longest experience for viral suppression.	Complex regimes with high pill burdens. Compromises future use of protease inhibitors. Long term PI toxicity of lipodystrophy, hyperlipidaemia, possible diabetes. Multiple drug interactions.
2nRTI + NNRTI	Delays use of PI. Low pills burden.	Limited long term data. Compromises future use of other NNRTI. May not be fully effective with high viral load (Nevirapine).
nRTI (1 or 2) + 2PI	Highly potent. Convenient dosing.	Long term toxicity unknown. Multiple drug interactions. Compromises future use of other PI. (The option of 2nRTI + 2 PI is currently not funded in New Zealand).
3nRTI (incl. Abacavir)	Delays use of PI and NNRTI. Low pill burden.	Lower potency in patients with high viral load, compared with 2nRTI + PI. Limited long term data. May compromise future nRTI choices.
PI + NNRTI + nRTI	High potent.	Complex. Limited term data. Compromises future drug choices. Multiple drug toxicity.

Table IV

Common adverse effects of antiretroviral drugs

All PI's can cause lipodystrophy (changes in body fat) and elevated body lipids. Rarely hyperglycaemia. All may cause bleeding episodes in persons with haemophilia.