1998 revision to the British HIV Association guidelines for antiretroviral treatment of HIV seropositive individuals

Introduction

href="#Debates" target="_self">Debates about HIV management

Introduction

When the British HIV Association guidelines on the treatment of

HIV seropositive individuals with antiretrovirals were published in The Lancet

in April 1997,⁽¹⁾ it was clear that they would require updating on a

frequent basis. The guidelines have been useful in ensuring that viral load

testing and combination therapy are widely available in the United Kingdom.

However, standards of treatment are rapidly changing as new evidence becomes

available. Since formulation of the guidelines, data from two large clinical

endpoint studies have been presented which show superior clinical benefit for

the use of triple therapy compared with dual therapy in both treatment naïve

individuals and patients who have been given zidovudine.^{(2, 3)}

Here we update the BHIVA guidelines in some important respects.

This letter represents a consensus drawn from a wide range of UK medical

opinion. The guidelines include input from groups representing individuals

living with HIV. A more detailed reflection of these views may be found in

publications such as the National AIDS Manual and the AIDS Treatment Project’s

Doctor fax.^(4,5)

Debates about HIV

management

There is debate on approaches to the long-term management of

HIV infection.(2,3) The differing views agree that the virologic goal of therapy

should be to achieve a viral load below detection limits of current assays,

hence initial therapy should be uncompromising in its activity. However, some

physicians feel that with initial therapy we have not just the best chance at

achieving the virological goal of therapy, but essentially the only chance of

responding well to therapy. A therapy that rapidly achieves not just

undetectable by standard assays but also by the experimental ultrasensitive

assays (reliable cut off limits around 50 copies/ml) should be instituted. This

rapid reduction should be attained because the viral load nadir on therapy seems

to be critical to the durability of treatment response. Viral resistance, the

principle cause of treatment failure, is unlikely in such circumstances because

continued viral replication is required to generate viral diversity and hence

resistance. Therefore such a regimen could work indefinitely.

Others believe that in formulating an initial treatment regimen

we should consider that, over prolonged follow-up, for most if not all patients,

their initial regimen will fail for many reasons(e.g intolerance, adherence and

viral replication persisting in sanctuary sites) and they will require a

second-line regimen. Additionally, a proportion of treatment naïve patients,

generally 15-40%, in clinical studies of potent triple therapy regimens fail to

achieve an undetectable viral load by current assays. Therefore, the initial

regimen needs to be both uncompromising in terms of activity and also

strategically planned, taking into consideration the likely mechanism of

failure, resistance, such that the option of a salvage or second-line therapy is

available. This approach is sometimes known as treatment

sequencing.⁽⁶⁾ Insufficient evidence exists to guide us in deciding

which approach is best. Limited prospective data on salvage therapy in patients

experiencing virologic rebound on an initial protease inhibitor regimen are

available to guide sequence order with these agents⁽⁷⁾. The BHIVA

guidelines committee feel that a middle ground between these positions can be

sought, with a well considered initial regimen which achieves optimal

virological responses and allows potential benefit from subsequent therapy, if

changes of therapy are promptly instituted upon virological failure and multiple

components, preferably all components, of the regimen are modified.

Data from clinical trials using the ultrasensitive assay are

currently only published in abstract form. More information is required on the

rapidity of reliable undetectability with effective treatment, how frequently

HIV RNA becomes detectable transiently with this assay, whether durability of

response is truly longer with this cut-off and what therapies are required to

reliably reach this goal before its use is routinely recommended. However, given

understanding of its limitations, pursuit of less than 50 HIV-1 RNA copies seems

to be an appropriate treatment goal in principle. Changes in therapy after

virological rebound in treatment-adherent patients should be made promptly (e.g.

at <5,000 HIV-1 copies /per ml) and should involve change of multiple,

preferably all components of a regimen. At least one agent from a new class

should be included.

When to start treatment

US guidelines state that treatment should begin at any stage

when the viral load is either detectable or greater than 10,000 copies/ml

regardless of CD4 cell count ^{(8, 9)}. However, our advice remains that

start of treatment should be individualised and should begin before irreversible

damage has occurred to the immune system such as at a CD4 count above 350

cells/ml, when risk of opportunistic infections remains low. Those with high

viral loads prior to treatment are statistically more likely to develop clinical

illness over defined periods of follow-up than CD4 matched persons with low

viral load.⁽¹⁰⁾ However, HIV therapy should represent risk

management. This management should be a balance between the potential benefit of

therapy in delaying clinical events and the potential morbidities, both physical

and psychological, associated with the commitment to lifelong multi-drug

therapy. In particular, the impact of late toxicities of protease inhibitors

e.g. diabetes,⁽¹¹⁾ hyperlipidaemia, lipodystrophy ( 12, 13), risk of

accelerated ischaemic heart disease, renal calculi and crystalluria on morbidity

and mortality have not been fully assessed. Additionally, treatment adherence is

poorer in people with symptom free disease. Adherence is known to decline over

prolonged periods of follow-up in other potentially fatal

diseases.(14⁾

What to start treatment with

We believe that it is important to start treatment with

regimens that reliably reduce the plasma viral load of individuals below

detectable limits of the currently available assays (200-500 copies of virus/ml

and preferably to below 50 copies per/ml). Although the clinical outcome at one

year in one study was similar whether the viral load was below detectable

(<400 copies per ml) or below 5,000 copies/ml after start of

treatment,⁽¹⁵⁾ most clinicians believe that continuing viral

replication will eventually lead to drug resistance, loss of treatment options

and a poorer clinical outcome. There is also evidence that the nadir of viral

load achieved in response to treatment is directly related to the length of time

that the viral load remains suppressed by therapy.^{(16, 17)}

Regimens which are highly effective in reducing viral

replication include two nucleoside analogues and a protease inhibitor, two

nucleoside analogues and a non-nucleoside reverse transcriptase inhibitor

(NNRTI), or two protease inhibitors with or without nucleoside analogues. The

combination of an NNRTI with a PI is currently also under assessment. Short-term

data from one prospective study indicates, in an on-study analysis, similar

anti-viral effects of nucleoside analogue (2NA) and either indinavir or the new

NNRTI efavirenz, but with better tolerability with the NNRTI-containing

regimen.

The use of two nucleoside analogues and an NNRTI is attractive

because it allows protease inhibitors to be reserved for later. However,

evidence has indicated that although treatment with zidovuine, didanosine and

nevirapine causes the viral load of a high proportion of individuals to fall

from less than 50,000 copies to below detectable limits, this was less likely to

be true in those with higher viral loads(17) Although this may not be true for

newer NNRTI regimens such as zidovudine, lamivudine and efavirenz,(18

) it seems prudent to recommend that patients with viral loads above

50,000 copies/ml should be started on a protease inhibitor-containing regimen.

However, this advice is likely to change once efavirenz becomes available.

Additionally, patients with very high viral loads and low CD4 counts at baseline

as well as those who have had extensive prior nucleoside analogue therapy may be

less likely to achieve an undetectable viral load on triple therapy

⁽¹⁹⁾ and therefore may be considered candidates for multiple-therapy

regimens.

An initial combination of two nucleoside analogues is no longer

considered a reasonavble standard of care and therefore should only be

considered in very exceptional exceptional circumstances. If the viral load is

below 5,000 copies/ml at baseline two nucleoside analogues will cause plasma

viral load to fall below detectable limits of standard assays in over 70% of

patients after one year’s follow-up.(19 )Although many physicians and patient

advocates feel the durability of response to two nucleoside analogues, even in

selected patient populations, is unlikely to be sustained, continuation of

closely monitored short-term trials of some therapies in which mechanism of

failure may not be related to the development of viral resistance, such as

d4T/ddI ²² seems reasonable. Treatment intensification with two

additional agents has, in incomplete responders to two or three drugs, yielded a

high proportion of optimum responses and may therefore be a useful strategy in

these circumstances. However, deintensification in an induction followed by

maintenance model, whilst attractive, does not represent a feasible

approach.

How to monitor treatment

For most patients who have triple drug therapy a plasma viral

load that is undetectable on standard assays can be achieved. However, the

definition of failure remains elusive. Specifically, it may be important to

differentiate between an inadequate treatment response, not achieving a value

below assay detection within 24 weeks of initiating treatment, and virological

rebound, as treatment approaches may differ depending on circumstances.

It seems appropriate to use measurement of viral load as the

primary definer of failure. However, in doing so, it is important to remember

that detectable plasma HIV RNA is neither immediately nor inevitably associated

with clinical events. Additionally, definitions of failure and the treatment

goals may be different for those very experienced with antiretrovirals who have

few remaining treatment options compared with those receiving initial therapy. A

rise in viral load to more than 0.51og₁₀ above detectable or above

the virological nadir have been used in one study ⁽¹⁶⁾ and is in

keeping with biological variations in viral load tests.⁽¹⁾ A more

conservative view would be to wait until viral load has returned to a level

where treatment would be normally initiated (i.e. > 10,000-50,000 copies/ml).

However, longer duration on failing therapy at the time of switch seems to be

associated with an accumulation of greater numbers of mutations in the HIV

genome and a probable greater chance of cross-resistance.

Some patients may experience clinical events despite

undetectable viral loads and rising CD4 cell counts. Others may have rising CD4

cell counts but detectable viral load, or falling CD4 counts but undetectable

viral load. The management of these individuals is currently unclear but should

include consideration of the treatment history, short-term and long-term risks

of maintaining current therapy versus switching therapy and consideration of the

patients’ personal goals and quality of life.

The optimum initial protease inhibitor used in combination

therapy is unknown. In the previous BHIVA guidelines we suggested that a drug

with a low potential for cross resistance should be given

priority.⁽¹⁾ Recent evidence, however, indicates that accumulation of

multiple mutations in the protease gene under the selective pressure of any of

the protease inhibitors is associated with cross resistance to all available

protease inhibitors.⁽²⁴⁾ The longer the duration of the viral

replication in the presence of inhibitor, the greater the likelihood of multiple

mutations occurring.⁽²⁴⁾ Such a likelihood emphasises the importance

of viral load monitoring, because it is still possible that switching from one

protease inhibitor to another (or a combination of two protease inhibitors)

might be effective in some individuals shortly after viral re-emergence in the

plasma but may be less likely after sustained virological failure.⁽⁷⁾

Limited evidence from small comparative studies suggests that activity of the

four different protease inhibitors now available is similar ^{(20, 26)}.

Therefore, the choice of initial protease inhibitor should be governed by issues

such as its short and long-term toxicity, frequency of drug interactions, and

convenience of administration.⁽¹⁾ The same principles apply to

selection of nucleoside analogues, a discussion of which was included in the

original guidelines.⁽¹⁾

Table 1 summarises the current guidelines relating to treatment

initiation.

Table 1. Revised by BHIVA Guidelines:

initiating antiretroviral therapy.

 Authors: Prof. Brian Gazzard and Dr. Graeme Moyle on behalf

of the BHIVA guidelines Writing Committee ⁽¹⁾

Correspondence to Prof. Brian Gazzard, St Stephen’s Clinic.

Chelsea and Westminster Hospital, 369 Fulham Rd, London SW10 9NH.

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