BHIVA draft adult antiretroviral treatment guidelines: When to start treatment

2.0 When to start treatment

With currently-available antiretroviral agents, eradication of HIV infection is not likely to be possible (references). The aim of treatment is thus to prolong life and improve quality of life by maintaining suppression of viral replication for as long as possible.

The three groups of treatment-naive patients for whom treatment guidelines are required are: (i) patients with primary HIV infection; (ii) patients with asymptomatic HIV infection and (iii) patients with symptomatic HIV disease/AIDS. The recommendations are summarised in Table 2.

Table 2 - When to start treatment: summary of recommendations

Footnote: (1) It is essential to discuss the merits of treatment if patients present early (i.e. within 6 months). Store blood sample and perform resistance test before starting therapy.

2.1 Primary HIV infection

If it is recognised clinically, the diagnosis of primary HIV Infection (PHI) may represent an unique opportunity for therapeutic intervention.. It is likely that, at the time of PHI, (i) there is a narrowing of the genetic diversity of the infecting virus compared with the virus in the index case [14,15,

(ii) its ability to infect different cell types may be limited, (iii) the capacity to mount an immune response is at its height and (iv) the number of replicating viral particles is still small. Therefore, drug treatment may be particularly effective during this time.

A variety of triple-drug therapy regimens appear able to suppress viral replication in the plasma, lymph nodes and gut in the majority of patients treated within a few months of PHI [16,17]. Recent studies demonstrated that shortly after PHI there is a specific and strong CD4 helper HIV response [18,19]INSERT NATURE MEDICINE REFERENCE (Rosenberg) and QUEST. This is in contrast to chronic infection where, with the exception of long-term non-progressors [20], the HIV-specific CD4 helper response is generally lost [21]. These CD4 helper responses may be important in maintaining an adequate CD8 response. Such immune responses appear to be maintained in people treated with potent antiretroviral therapy shortly after PHI and perhaps represent the best biological evidence that treatment at this time might be beneficial. Recent data suggest that there is more rapid and complete immune reconstitution in patients starting therapy during PHI than in those starting later (Kaufmann et al.AIDS 2000). There is however no evidence to date that any of these immunological benefits persist indefinitely with continuing treatment or after treatment is withdrawn.

Control of viral replication with no return of viraemia after withdrawal of antiretroviral treatment has apparently occurred in a few patients treated very soon after PHI[22]. The role of drugs which are known to inhibit CD4 activation, such as hydroxyurea (reference Lori et al.) and cyclosporin A (reference Rizzardi et al.,CROI 2001 abstract 759) in the suppression of viral replication and boosting of CD4+ lymphocyte responses in this setting is unclear, and requires further evaluation. Furthermore, limited data propose a possible role for strategic treatment interruptions in stimulating the host immune response and reducing the virological set-point in patients treated very early during PHI (reference Walker CROI 2001). .

One study has suggested that many recently-infected patients have acquired their infection from others who were themselves recently infected with HIV. Identification and treatment of PHI might thus have some effect on reducing HIV incidence (Luc Perrin, Glasgow).

These putative benefits of treatment during PHI should be tempered by the known risks of toxicity including the development of lipodystrophy (ref Sydney group, Lisbon; Goujard et al., AIDS 2001; 15(2) 282-4.). Furthermore, there is evidence of ongoing HIV replication (ref Yerly AIDS 2000) with an associated risk of drug resistance. Given that the optimal duration of therapy is currently unknown, it should be assumed that lifelong treatment may be required even when initiated during PHI. The potential difficulties of long-term adherence to available regimens cannot be overstated.

Even if after consideration of the above, treatment is not started during PHI, there are many benefits of recognition of early HIV infection. These include recognition and monitoring of primary drug resistance, partner notification and contact tracing, and the possibility of preventing HIV transmission. Particular effort should thus be directed to identifying patients with PHI who may present to a wide range of healthcare providers.

2.1.2 Recommendations for starting treatment in primary HIV infection (CIII)

It is very important at the time of PHI that patients and physicians make the most appropriate decision based on the limited data available.

• As there are few data to guide us as to the best therapeutic option, entering patients into a clinical trial (where such trials exist) is the committee’s preferred choice.

• If patients are treated outside a clinical trial setting, a regimen appropriate for treating chronic HIV infection should be used (see later).

• The biological plausibility that early treatment may be beneficial for the immune system should be balanced against considerations of adherence to long-term therapy, potential toxicity and development of resistance.

• If treatment is not started within a few months of recognised PHI, a potential advantage may be permanently lost. The theoretical advantage of starting treatment should be weighed against the uncertainty of efficacy, the problems of adherence and the emergence of drug resistance.

• If a decision to start treatment is made, this can be reviewed (i.e. therapy can be stopped or continued) in the light of evolving data.

• It is appreciated that many patients will choose not to be treated at this time and, because of the inherent uncertainties, this choice should be respected and supported.

2.2 Symptomatic HIV infection

All patients with CD4+ lymphocyte counts consistently of 200 cells/mm3 or less, or who have been diagnosed with a major opportunistic infection or tumour should start therapy. This is because of the high risk of further opportunistic infections, which although treatable may cause irreversible damage or be life-threatening.

2.3 Asymptomatic HIV infection

There are no ongoing or planned controlled studies with sufficient power to address the optimum time to start therapy (ref Phillips, BMJ, circa 1996). Current guidelines are therefore based upon previous studies of monotherapy and data from large clinical cohorts. Since the quality of evidence is relatively poor, opinion is divided in this area. In the UK where patients are diagnosed with HIV infection at a late stage with over 1/3^rd presenting with a CD4 count of less than 200 cells/mm³ (ref Gupta, CDSC; AIDS 2000) the "early versus late" debate is irrelevant to many.

Table 3 - Treatment for asymptomatic HIV-infected individuals: arguments for and against early treatment

Data from cohort studies (Phillips, Cozzi-Lepri Glasgow,) have suggested that patients who delay starting therapy until the CD4+ lymphocyte count is below 200 cells have a poorer virological and immunological response. Similar data exist from prospective clinical studies (e.g. BI1090), although the effect of baseline CD4 response on therapy may not be the same for all drugs (Nelson, ECCMID abstract).

Further data from cohort studies suggest that patients who initiate therapy when the CD4+ count is

Taken together, these data suggest that ideally patients should start therapy earlier (i.e. before the CD4 count has fallen to 80 cells/mm3 per year on repeated testing), have a higher risk of CD4+ cell count decline to below 200 cells/mm3 in the next 6 months. This group may thus be considered for initiation of therapy relatively earlier within the CD4+ count range 200-350.

Previous guidelines have suggested starting therapy relatively early in patients with high plasma viral load (reference Carpenter et al; IAS guidelines; BHIVA guidelines 2000). There are three reasons why viral load measurement may help guide decisions about when to start antiretroviral therapy. Firstly, a higher viral load (e.g. > 55,000 copies/ml; reference Mellors MACS study) predicts a faster rate of decline of CD4+ cells. Secondly, a higher viral load has been demonstrated to be an independent risk factor for subsequent disease progression and death. However, these data are from the pre-HAART era, and may thus not be strictly relevant. Furthermore, recent cohort studies (Hogg et al. 2001 CROI; Sterling et al 2001 CROI) have suggested that baseline viral load does not predict subsequent mortality independently of baseline CD4 count after starting therapy. Thirdly, some data have suggested an adverse effect of baseline viral load on virological response to treatment in both cohort (Phillips, Glasgow 2000) and prospective studies (Staszewski 2000 [abacavir], SPICE Moyle Geneva 1998 ) though this is not consistent for all cohorts (Cozzi Lepri, Glasgow, 2000) or drug regimens (Staszewski NEJM 2000 [Dupont 006], Johnson Glasgow 2000 [ABT-378/r], Woods Durban 2000 [nevirapine, BI 1090] ). This perhaps represents the differential efficacy of different combinations in patients with higher viral loads, and may be a better indicator of what to start with rather than when to start.

It is our opinion that it should be the absolute CD4 count that should drive decisions about when to start. Individuals with a rapidly dropping CD4 count or high viral load may be considered for earlier therapy (within the range of CD4 counts 200-350) to ensure that the CD4 count does not fall below 200 cells/mm³ .

In asymptomatic patients with established chronic HIV infection and CD4+ cell counts consistently above 350 cells/mm3, there are few data that support starting therapy, and good reasons to consider deferring therapy to minimise long-term drug toxicity and the development of drug-resistant virus.

2.3.1. Recommendations for starting treatment in asymptomatic individuals

• Given the lack of compelling evidence to decide when treatment should begin, the pragmatic view must be to ensure that the benefit of presently available treatment outweighs the risk of deferring therapy.

• Currently, our recommendation is that patients should start therapy before their CD4 count falls below 200cells

• Given the available data and the limitations of currently available treatment, we do not believe that treatment is indicated in asymptomatic individuals with a CD4 count greater than 350

• Within the range 200 to 350 cells, individuals with a high viral load (>100,000) or a rapidly falling CD4 cell count (>80 cells per year) may be considered for earlier intervention

• If patients to whom these recommendations apply choose not to go on treatment, it is suggested that their CD4 counts and viral load be monitored intensively (e.g. every 2–3 months) and the decision to start treatment reviewed at regular intervals.