Category Archives: 6.5. When to Start ART

6.5. When to Start ART

– Christian Hoffmann –

“It’s the most important question in HIV therapy” (A. Fauci)

The indication for antiretroviral therapy is based on clinical assessment, CD4 T cell count and viral load. These three important factors determine whether therapy should be started or if it should be deferred. At first glance, it appears straightforward, the lower the CD4 count and the higher the viral load, the higher the risk of AIDS (Mellors 1997, Lyles 2000) and the more urgent the indication for treatment.

Nevertheless, the best time for initiation of therapy remains the subject of controversial debate. The risk of AIDS must be weighed against the risks of long-term toxicity and viral resistance. In Table 5.1, the current guidelines in the US, Europe, Britain and Germany on starting therapy are summarized. Significant differences can be seen especially in patients with high CD4 T cells.

Table 5.1. Recommendations  from various guidelines on when to initiate therapy
Clinical

CD4 T cells/µl

Initiation of HAART is…
CDC B+C

All values

“Recommended” (DHHS, GA, EACS)
CDC A

<200

“Recommended” (DHHS, GA, EACS)
CDC A

200-350

“Recommended (DHSS, GA, EACS)
CDC A

350-500

“Recommended” (DHSS)“Generally advisable” with additional criteria*, otherwise ”acceptable” (GA)“recommended at viral load above 100,000, coinfection, age > 50, high risk of cardiovascular/malignant diseases” (EACS)
CDC A

>500

“Moderately recommended” or “optional”, controversial (DHSS)“Acceptable” with additional criteria, otherwise “Generally not recommended” (GA)“Generally procrastinated”, but “May be offered if one of the points listed in 350-500 apply” (EACS)
DHHS: US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. January 2011. http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
GA: Deutsch-Österreichische Leitlinien zur Therapie der HIV-Infektion. March 2010. http://www.daignet.de  Additional criteria refer to viral load above 100,000 copies/ml, HCV- or HBV-infection, age over 50 years, Framingham-Score above 20%/10 years and rapidly decreasing CD4 T cell count.
EACS: European AIDS Clinical Society (EACS). Guidelines for the clinical management and treatment of HIV-infected adults in Europe.November 2009. http://www.eacs.eu

The practice of treatment is ever changing. In Europe, the median CD4 T cell count at initiation of ART was 200 CD4 T cells/µl during the first years of this decade, after being 270/µl in 1998 (May 2006). But in more recent years, the pendulum is swinging back. With regard to new drugs which are more potent and better to tolerate, there is a strong trend towards earlier treatment initiation.

At least all international guidelines agree that all symptomatic patients as well as patients with less than 200 CD4 T cells/µl should be treated. Since 2007/2008, most guidelines have determined a CD4 T cell count of <350 CD4/µl, instead of 200 CD4/µl as a definitive threshold for initiation of ART. In the US, it has recently increased to 500 CD4/µl. Lack of randomized studies forces all guidelines to partially rely on cohort studies, meta-analyses and evaluation of larger databases. Such data is problematic, however, as important aspects such as compliance or prior treatment regimens are not captured, and very heterogeneous patient populations are included.

A recent Cochrane analysis concluded that evidence for initiating ART at CD4 levels higher than 200 or 250 cells/μl to reduce mortality rates in asymptomatic patients is of moderate quality. Guidelines merely provide points of reference and are not set in stone. Decisions must be made on a case-by-case basis, even if some health insurance providers tend to ignore this and use guidelines to their advantage. In some situations, therapy may be started earlier than recommended in the guidelines; in other cases, therapy might (or even should) be deferred. And last but not least, the patient should be ready to start ART. Experience as well as some intuition of the treating physician is mandatory.

How high is the individual risk of progression?

The following table lists the (selected) risks of developing AIDS within six months, as identified in 3326 patients from the pre-HAART era (Phillips 2004). The range of the individual risk of progression, calculated by using CD4 T cells, viral load and age only, varies widely – from 0 to almost 50%. This may also demonstrate how helpful these surrogate markers can be.

Table 5.2. Predicted six-month percentage risk of developing AIDS, according to age, viral load and CD4 T cell count (data from the pre-HAART era).

100 CD4/µl

200 CD4/µl

350 CD4/µl

35 years
    Viral load 10,000 copies/ml

5.3

2.0

1.1

    Viral load 100,000 copies/ml

10.6

4.1

2.3

55 years
    Viral load 10,000 copies/ml

10.7

4.6

1.8

    Viral load 100,000 copies/ml

20.5

9.2

3.6

VL = Viral load. (From: Phillips A, CASCADE Collaboration. AIDS 2004, 18:51-8.)

But even after initiation of ART individual risk may vary considerably. Table 5.3 shows individual risks after initiation of ART for different age groups. These data were derived from 12 cohorts in Europe and North America, in which more than 20,000 patients started antiretroviral therapy between 1995 and 2003 (May 2007). It is of note that the data apply only to asymptomatic patients without intravenous drug use (IVDU). In patients with AIDS and in IVDUs, progression risks can be much higher. On the other hand, it seems possible that these data overestimate the individual risk as risk may be lower with the newer drug combinations. Moreover, treatment interruptions were not taken into account (every patient who started with ART was regarded to be treated continuously). This fact may also have led to an overestimation of the risk of progression. Thus the values in Table 5.3 are only rough estimates and should be interpreted with caution. However, they could be helpful in any discussion with the patient, of course without browbeating or scaring them with statistics.

One important caveat of cohort studies is the fact that the individual treatment success of the patient is not taken into account. This was shown by an analysis of 13 cohort studies from Europe and North America including 9,323 adult treatment-naive patients who started ART with a combination of at least three drugs. At 6 months after starting ART, the current CD4 T cell count and viral load, but not values at baseline, were strongly associated with subsequent disease progression (Chene 2003).

Table 5.3. Probability (%) of experiencing a new AIDS-defining disease or death by the end of 1 year (5 years) after the patient starts ART. Only valid for patients without previous AIDS and non-IVDUs.

<25 CD4

25-49 CD4

50-99 CD4

100-199 CD4

200-350 CD4

>350 CD4

16-29 years
    VL <100.000

10 (19)

8 (17)

7 (16)

5 (11)

2 (7)

2 (6)

    VL >100.000

12 (23)

10 (21)

9 (19)

6 (13)

3 (8)

2 (7)

30-39 years
    VL <100.000

12 (22)

10 (19)

8 (18)

5 (12)

3 (8)

2 (6)

    VL >100.000

14 (26)

12 (23)

10 (22)

6 (15)

3 (10)

2 (8)

40-49 years
    VL <100.000

13 (25)

11 (22)

10 (20)

6 (14)

3 (9)

2 (7)

    VL >100.000

16 (29)

13 (26)

12 (24)

7 (17)

4(11)

3 (9)

>50 years
    VL <100.000

16 (29)

13 (26)

12 (24)

7 (17)

4 (11)

3 (9)

    VL >100.000

19 (35)

16 (31)

14 (29)

9 (21)

5 (13)

3 (11)

From http://www.art-cohort-collaboration.org. VL are copies/mL, CD4 cells/ml.

To evaluate the individual risk for a treatment-naïve patient, one can check http://www.art-cohort-collaboration.org (May 2007). Only a few parameters are needed. It is also possible to calculate the risk after 6 months on ART.

Practical experiences

Even if the indication for ART seems obvious, it should be clarified whether the patient is indeed prepared to start treatment (treatment readiness). The problem is not necessarily the initiation of ART, but the longer-term maintenance. The decision to initiate treatment is often made prematurely. It is usually unwise to prescribe antiretroviral medication to a patient in the very first consultation. One should first attain an overall picture of the patient, and try to get to know something about lifestyle and motives – why they have come to see a doctor and what they expect.

In some cases, patients put themselves under pressure unnecessarily, or allow others to pressure them. A single low CD4 count, a prolonged case of flu seeming to indicate a weakened immune system (“I never had anything like this before”), springtime lethargy, new study results, a promising new drug in the newspaper (“I’ve heard a lot about the new entry inhibitors”), a friend/partner who has started therapy – none of these are therapeutic indications. It is often particularly difficult to inform people from other cultures that not every person with an HIV infection needs immediate therapy.

On the other hand, the patient’s wish to start a therapy should be respected. If after a detailed discussion a well-informed patient wants to begin treatment, even though the results justify waiting, ART should not be withheld. For many patients, treatment can be a psychological support. Not everybody can sleep peacefully at night knowing that inside them a hundred million new viruses are being produced every day and a huge number of helper cells are being destroyed.

However, if a vacation is planned, it is better to delay therapy, so that treatment response and side effects can be adequately monitored. On the other hand, patients may sometimes find one reason after another (stress at work, exams, change of job, etc.) to delay initiation of treatment. Many patients are afraid of AIDS, but often just as afraid of ART (“the pills are the beginning of the end!”). They may have irrational or simply false expectations of ART and its consequences – starting therapy does not mean that one will be subjected to daily infusions and no longer able to work. Therapy should be explained to every patient from the outset. It is also useful to define individual threshold values for the commencement of therapy with patients early on, so that therapy is started only when these levels are reached. In our experience, patients are more motivated by this approach.

As a rule, as much time as is needed should be taken for the decision to start therapy. A well-informed patient will adhere better. We recommend that patients come for several consultations to get prepared for treatment. There are two exceptions: acute HIV-infection (see chapter on “Acute Infection”) and severe immunodeficiency. However, even in the presence of most AIDS-defining conditions, the acute disease should often be treated first before initiating ART, as the potential for complications with PCP, toxoplasmosis or CMV therapies unnecessarily jeopardize treatment options. In asymptomatic patients with very low CD4 T cells, it makes sense to start first with a PCP prophylaxis. Over the next few days, one can perform an exam (X-ray, ultrasound, fundoscopy, etc) and check the patient’s readiness. Does the patient come back? Are they really motivated?

We also tend to start ART earlier in older patients (>50 years). The regenerative capacity of the immune system in older patients is significantly reduced (Ledermann 2002, Grabar 2004). More importantly, the risk of developing opportunistic infections also depends on age (Phillips 2004). Another example from the CASCADE Study (Table 5.2) exemplifies this: a 25 year-old patient with 100 CD4 T cells/µl and a viral load of 100,000 copies/ml, has a risk of approximately 10% for developing AIDS within six months – for a 55 year-old this level of risk is reached at 150 CD4 T cells/µl and a viral load of 30,000 copies/ml. In Table 5.3 there is a strong association between age and progression.

By now, several guidelines have taken age considerations into account and state that therapy be offered to patients older than 50 years even if high CD4 T cells are high. Guidelines also recommend initiation of therapy in cases of hepatitis coinfection, HIV-associated nephropathy, but also cardiovascular risks and malignant diseases.

Practical tips for initiation of ART

Below 200 CD4 T cells/µl or an AIDS-defining event

  • Start immediately with ART. Do not wait until acute OI therapy is finished
  • Take time to get acquainted with the patient (What took him so long to start treatment?), undergo diagnostic procedures, give proper counselling and start treatment with prophylaxes in advance

Between 200 and 350 CD4 T cells/µl

  • More time can be spent getting to know each other and planning
  • Address fears and anxieties before starting therapy
  • Try not start with therapy before a holiday or other big event, but do not let the patient put off therapy forever

Above 350 CD4 T cells/µl

  • Here again talk about ART at an early stage, so the patient knows what to expect
  • Define thresholds below which ART can be initiated (follow present guidelines of 350µ)
  • Do not only consider the absolute CD4 T cells, but observe other individual factors: Coinfection? Age? Malignancy? Pregnancy? If so, start earlier!
  • Respect the patient’s wish for time of therapy initiation
  • Check to see if the patient is suitable for a clinical trial

It is also important to consider the percentage value along with the absolute value of the CD4 T cell count. In particular, when the CD4 T cell count is high and the immune status appears good, the CD4 percentage is the most important parameter for predicting the risk of developing AIDS. In one study, the risk of progression for patients with more than 350 CD4 T cells/µl was increased approximately four-fold if the percentage of CD4 T cells was below 17% (Hulgan 2005).

Finally, it should not be forgotten that the whole discussion is based on “minimum” figures, as CD4 T cells are actually surrogate markers. As a surrogate, they are a substitute for clinical endpoints. They are only a rough expression of the clinical reality. Although they usually do this very well, and even though the CD4 count is one of the best surrogate markers in medicine, it is not everything. The patient also has to be considered.

Asymptomatic patients with more than 200 CD4 cells/µl

200-350 CD4 cells/µl: Today, the guidelines all recommend an initiation of therapy in this patient group. Even if randomized studies are not available and the risk of infection is rather low, in the long run the risk of developing AIDS can not be excluded (Emery 2008). There is no reason to think the patient 100% safe. We have seen patients with these CD4 cell counts develop Kaposi’s sarcoma, PML or  lymphoma. A look at the calculation presented above (May 2007), gives a rough idea about the individual risk. After ART initiation, a 45 year-old asymptomatic patient with 200-350 CD4 T cells/µl, a viral load below 100,000 copies/ml and not a drug user has an AIDS mortality risk of 3.1% after one year, and 8.7% after five years. With above 350 CD4 T cells/µl at the time of ART initiation, the risk is reduced to 2.0% and 7.3% for the same patient. If the patient was 50 years old and the viral load over 100,000 copies/ml, the five year risk would reduce from 13.1% to 11.0%. Such a reduction of just 1 or 2% may seem insignificant at first. However, in times of well-tolerated antiretroviral therapies, the risk of developing AIDS or even dying from the infection is relevant. Is it worth exposing patients without urgent symptoms to the dangers of AIDS for the sake of a little more quality of life? How much long term toxicity is really saved by one, two or maybe even three years without therapy over a period of twenty or thirty years? The lesser the danger of toxicity, the earlier ART will be initiated in future.

A randomized study from Haiti published in the NEJM, showed that an immediate start also makes sense in developing countries: In 812 patients with 200-350 CD4 cell/µl, only 6 cases of mortality occurred in the group receiving ART immediately compared to 23 cases in the group who had just started an ART. The number of incident cases of tuberculosis was significantly reduced from 36 to 18 (Severe 2010).

Above 350 CD4 cells/µl: For this patient group according to the German-Austrian guidelines, therapy initiation is “acceptable” and, in the presence of additional criteria, “generally recommended” (i.e. hepatitis coinfection, older patients above 50). In the USA, therapy initiation is recommended unrestrictedly up to 500 CD4 cells/µl.

However, even beyond this level, there seems to be an associated risk with CD4 T cell counts and AIDS or mortality. In a large-scale British cohort (>30,000 patient years) with therapy-naïve patients the risk was 24.9 per 1,000 PY at 350-499 CD4 T cell/µl, compared to 15.4 at 500-649 CD4 T cells/µl and 9.6 with more than 650 CD4 T cells/µl. The US HOPS cohort also suggested a survival benefit of patients who initiated ART above 350 CD4 T cells/µl (Palella 2003). This study also evaluated patients who had started with a mono- or dual-therapy. Possibly a difference would not have been visible with contemporary therapies. In addition, the mortality risk was low. According to more recent information from this cohort (Lichtenstein 2006), the risk was 15.9/1000 PY at 200-349 CD4 T cells/µl (350-500 CD4 T cells/µl: 11.5/1000; over 500: 7.5/1000).

In a new study from the US, 17,517 asymptomatic patients were evaluated who started ART between 1996 and 2005 (Kitahata 2009). In this very complex (incomprehensible for the layman) and expensive analysis an advantage was observed already above 500 CD4 T cells/µl. Other studies have not confirmed these results (Sterling 2003). This also applies to the ART cohort collaboration, in which 20,000 patients from 15 mostly European-based cohorts were evaluated, who started antiretroviral therapy after 1997. There was no benefit of starting above 450 CD4 T cells/µl (Sterne 2009).

To raise a heretical question, does early therapy initiation have benefits only in the US, not in Europe? Or are methodological problems of cohort analysis and statistical distortion the reason for this discrepancy? This debate will be interesting to follow. A worldwide randomized study to evaluate optimal therapy initiation with asymptomatic patients with good CD4 T cells is urgently required. Since 2009, worldwide 3,000 patients with more than 500 CD4 T cells/µl are to be enrolled in the START study. One half will start with ART immediately, while the other half will wait until CD4 T cells are below 350 CD4 cells/µl or until symptoms appear. First results are expected in two to three years.

It is important that all asymptomatic patients with allegedly good values are still regularly checked. One should not only watch out for absolute CD4 T cell count, but other factors should also be observed, see following box

Important factors to be considered even with good CD4 T cells

  • Is a tendency of an absolute CD4 drop visible: how fast is it? Always look at relative values (percentage), observe CD4/CD8-ratio, absolute values often vary widely.
  • Because variations exist, a CD4 T cell count should always be controlled before starting therapy. One measurement is not enough.
  • How high is the viral load, does the overall picture make sense? CD4 T cell count drops are rare at lower viral loads <10,000 copies/ml.
  • What levels did the patient previously have? Someone, whose CD4 T cells have always been at 1000 and suddenly falls to 350 probably has a higher immune defect than someone who goes from 450 CD4 T cells to 350.
  • Is the patient ready for therapy? How well informed is he? How compliant will he be? If the patient is reluctant and anxious, more time must is needed for preparation prior to therapy initiation.
  • How old is the patient? The immunologic regeneration capacity decreases with age. The older the patient, the earlier one should start.
  • Are there symptoms which the patient has not noticed or considers not worth mentioning? Examine physically on a regular basis! OHL, thrush, mycoses etc.
  • A drop of 50-100 CD4 cells/µl per year is too much. Do not wait too long with these patients.

Late Presenter: AIDS and/or below 200 CD4 T cells/µl

Although treatment possibilities have dramatically improved, many patients still present at a very late stage of the infection. Questions about beginning an optimal therapy are superfluous as these patients are more or less classified as urgent. There is no consensus regarding the definition of “late presenter”. In most cases, a CD4-cell count below 200/μl and/or a manifest AIDS disease at the time of HIV-diagnosis serves as criterion. “At the time of HIV diagnosis”, however, is broadly defined and ranges from three months to three years. Moreover, some authors also classify the groups “late testers”, “very late presenters” and even “long-term non-presenters”.

At the second “HIV in Europe” conference in November 2009, it was agreed that those patients with a CD4 cell count below 350/µl at initial presentation are to be referred to as late presenters (Antinori 2011). In the US and probably in other countries, they still constitute more than half of all patients (Althoff 2011). Even if this definition makes sense in terms of health policy (patients come “late”, because they have fallen below the recommended threshold value for therapy initiation), it is yet to be seen if this definition prevails. For clinical research, it already raises problems, as very heterogenic patient groups are being put together. Below, late presenters are restricted to patient groups showing symptoms or with less than 200 CD4 T cells/µ.

Incidence and risk factors of a late HIV diagnosis

How frequent are late presenters? Lacking an overall valid definition, rates between 10-44% are currently being reported in different European countries and the US with a recently slightly downward trend (table 5.4).

Table 5.4. frequency of late diagnosis in Europe.
Country Period (n) Definition of late diagnosis % (ADE) Trend over time
Italy(Borghi 2008)

1992-2006

(884)

CD4 <200 cells/μl or AIDS <3 months

39 (24)

Decline from 43 to 35%

France(Delpierre 2008)

1996-2006

(6.805)

CD4 <200 cells/μl or AIDS <1 year

38 (17)

Decline from 43 to 32%

Spain(Carnicer 2009)

1987-2006

(6.186)

AIDS <3 months

(44)

Not stated

Great Britain(HPA 2009)

2008

(7218)

CD4 <200 cells/μl

32

Not stated

USA(CDC 2009)

1996-2005

(281,421)

CD4 <200 cells/μl or AIDS <1 year

38

Decline from 43 to 36%

Great Britain(UK Chic 2010)

1996-2006

(15,775)

CD4 <200 cells/μl

27 (10)

Not stated

Switzerland(Wolbers 2009)

1998-2007

(1915)

CD4  <200 cells/μl

31

No clear trend

Explanation: ADE = AIDS-defining disease.

In the last few years several studies have looked at the risk factors of a late diagnosis (Table 5.5). The characteristics of late presenter, observed in several countries (advanced age, migrant origin, heterosexual transmission, see above) indicate more complex reasons for a late diagnosis. They probably involve patients (less access to health system, lack of information, fear of stigmatization), as well as doctors and members of the health system (among others lack of HIV awareness with certain patient groups). Several studies enforce the notion that, even with high risk patients, many chances of diagnosing HIV at an earlier stage are missed (Duffus 2009, Jenness 2009). As much as 76% out of 263 African patients living in London had visited a general doctor a year before HIV was diagnosed. Of note, 38% were in outpatient care and 15% had received inpatient treatment in the year before HIV diagnosis (Burns 2008).

Table 5.5. Risk factors for late diagnosis in Europe.
Italy (Borghi 2008) Advanced age, male, foreign origin
France (Delpierre 2008) Age over 30 years, non-MSM, hepatitis coinfection, HIV diagnosis before 2003
Spain (Carnicer 2009) Male, age under 30 or over 40 years, MSM or heterosexual transmission. Protective: IVDU.
USA (CDC 2009) Advanced age, male, ethnic origin non-white
Great Britain (UK Chic 2010) Heterosexual transmission
Switzerland (Wolbers 2009) Advanced age, ethnic origin non-white. Protective: MSM, IVDU, living alone

Morbidity, mortality – consequences of a late HIV diagnosis

Up to 90% of AIDS-defining diseases today, appear with viremic – mainly untreated – patients. This applies greatly to classical opportunistic infections such as PCP or CMV retinitis, but also, when not as strict, to tuberculosis or Non-Hodgkin lymphoma (ART-CC 2009). In the German Lymphoma Cohort, two-thirds of patients with newly diagnosed NHL had not previously received ART. 40% of patients with AIDS, a group associated with the highest mortality rate even today, are diagnosed with NHL and HIV infection simultaneously (Hoffmann 2009). In a British analysis counting 387 deaths of HIV-infected patients in the years 2004/2005, as much as 24% of all deaths and 35% of HIV/AIDS-related deaths were ascribed to a late HIV diagnosis (Lucas 2008). An account analysis showed that, treating expenditures increased by 200% with less than 200 CD4 T cells at the time of HIV diagnosis (Krentz 2004). This may be attributed to the immune reconstitution syndrome (IRIS) frequently observed in late presenters (see chapter on “AIDS”).

There is no doubt that a late HIV diagnosis is associated with higher mortality and morbidity risk. The risk increases with lower CD4 T cells at therapy initiation (Egger 2002, Sterne 2009). An analysis of therapy-naive patients in three major European cohort trials observed 8.3 new AIDS cases per 100 patient years with patients showing less than 200 CD4 cells/μl at the beginning of  therapy – and only 1.8/100 patient years with at least 350 CD4 T cells/μl. The mortality rate was slightly higher with 2.9 versus 0.7/100 (Phillips 2001). Several other cohort trials also found a clear association between CD4 T cells at therapy initiation and AIDS and mortality rates (Cozzi-Lepri 2001, Kaplan 2003, Palella 2003, Braitstein 2006). The lesser the CD4 T cell count, the higher the risk for the following time period, for many years (Lanoy 2007). Increased mortality remains with very low rates (less than 25 CD4 cells/μl) even six years after starting ART (and maybe longer) (ART-CC 2007).

A complete reconstitution of the immune system is rarely the case if the patient’s initial situation is poor – the worse the immune system, the more unlikely a complete recovery (Garcia 2004, Kaufmann 2005, Gras 2007). Viral suppression over several years cannot change that. In a study with patients on ART showing a constant low viral load below 1000 copies/ml for at least 4 years, 44% of patients with less than 100 CD4 cells/μl at initiation of ART failed to reach to 500 CD4 T cells/μl even after 7.5 years. Patients with 100-200 CD4 T cells/μl still showed a risk of 25% (Kelley 2009). Another risk factor, besides low CD4 T cells, is advanced age, which has been observed frequently with late presenters. The ability to regenerate the immune system decreases with age and is probably caused by the degeneration of the thymus (Lederman 2000, Viard 2001, Grabar 2004). A consequence of a late start of ART can also mean that the antigen-specific immune reconstitution against HIV, as well as opportunistic viruses, remain poor. Many studies suggest that the qualitative immune reconstitution can not keep up with the quantitative (Gorochov 1998, Lange 2002). It seems obvious. Where there was once a desert, it takes time to grow a flowerbed. First you will grow weeds. Only, why does the risk of AIDS drop so dramatically with rising CD4 T cell count? How can patients with severe immunosuppression safely discontinue a prophylaxis, as soon as their CD4 T cell count are above 200/ µl? Clinical observations seem to show differently, at least for the time being.

However, the relevance of a limited immune constitution in the long run, is not yet clear. Recent data from the ClinSurv Cohort suggests that a discordant response (low CD4 T cells in spite of good viral suppression) is only associated with higher AIDS risk in the first few months. With virally well-suppressed patients, the CD4 T cells are no longer a good surrogate marker for risk of AIDS (Zoufaly 2009).

In contrast to the immunologic response, the virologic response in combination with poor starting conditions is generally not worse than with other patients. Nevertheless, 89% out of 760 patients with AIDS disease at HIV diagnosis showed a viral load below 500 copies/ml after initiating ART (Mussini 2008).

When to start ART?

Patients with a poor immunological state should begin ART quickly. This recommendation applies for CDC stage C (AIDS-defining diseases) and for all stage B diseases. However, it has not yet been agreed on how quickly one should start ART within the context of an acute opportunistic infection (OI). Up to now, many therapists preferred to tend to the acute disease first and to wait a few weeks before beginning ART. They hoped to avoid the unnecessary high complication potential of OI therapies. The first randomized trial addressing this idea has made this strategy questionable (Zolopa 2009). In ACTG A5164, 282 patients with acute OI (63% PCP, cases of tuberculosis were omitted) were randomized to start ART either immediately or at earliest after completing OI therapy. On average, the “immediate” group started ART 12 days after initiation of OI therapy, whereas the “later” treated group after 45 days. Although the intervals were not so wide apart, already distinct differences were observed after 48 weeks: the group treated immediately showed significantly less fatalities and less new AIDS cases. The risk to have to adjust ART was slightly higher, but not the number of severe undesired incidents, hospitalization or cases of IRIS. The authors concluded that patients with an acute OI (at least of PCP) should immediately start ART. In Germany, the IDEAL study with PCP-and toxoplasmosis patients will check these results in 2011 (contact: Hoffmann@ich-hamburg.de).

Two randomized trials, SAPIT and STRIDE  involving patients with culturally verified TBC and CD4 T cells <500/µ1 also showed a significant advantage of immediate ART (Abdool 2010, Havlir 2011). In contrast, two other randomized studies showed undesired effects with cryptococcus meningitis and tuberculosis meningitis when initiating ART early (Makadzange 2009, Torok 2009) – it is likely that differentiated recommendations depending on the OI must be given (Lawn 2011). There is also some controversial debate, as to whether patients with malignant lymphomas and newly diagnosed HIV infections should receive ART immediately or after chemotherapy (see chapter on “Lymphoma”).

ART for late presenters – What to start with?

An active OI is an obligatory exclusion criteria in almost every clinical trial. Thus, this patient group is always underrepresented in evaluation of clinical efficacy data. The question, if late presenters should be treated with a special antiretroviral therapy is therefore not clear and depends more than with other patients on individual decision-making (Manzardo 2007) (see chapter on “What to Start With?”). Regarding immunologic success, no relevant difference was measured between NNRTI- and PI-based regimens with late presenters (Landay 2003, Samri 2007). New ARV classes are also considered for late presenters. In favor of raltegravir, are its low interaction potential, its overall tolerance and effectiveness in reducing viral load compared to efavirenz, especially in the first weeks (Murray 2007). As for the CCR5 antagonist maraviroc (not yet permitted in Europe for primary therapy), a meta-analysis showed that CD4 cell increase was overall better than with other agents (Wilkin 2008). Results for its application as an immune modulator have been disappointing (Stepanyuk 2009, Wilkin 2010). This applies also for raltegravir (Hatano 2010) and T-20 (Joly 2010), both showing no effects regarding immune reconstitution.

It should also be noted that increased dual tropic viruses can be expected in late presenters, which does not allow the use of CCR5 antagonists. A more recent study, however, showed relatively high rates of R5-tropic virus strains in late presenters, making this patient group a possible candidate for treatment with coreceptor antagonists (Simon 2010).

References to therapy start and late presenters

Abdool Karim SS, Naidoo K, Grobler A, et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med 2010, 362:697-706.

Althoff KN, Gange SJ, Klein MB, et al. Late presentation for human immunodeficiency virus care in the United States and Canada. Clin Infect Dis 2010, 50:1512-20.

Antinori A, Coenen T, Costagiola D, et al. Late presentation of HIV infection: a consensus definition. HIV Med 2011, 12:61-4.

ART Cohort Collaboration. Importance of baseline prognostic factors with increasing time since initiation of highly active antiretroviral therapy: collabora-tive analysis of cohorts of HIV-1-infected patients. J AIDS 2007;46:607-15.

ART-CC, Mocroft A, Sterne JA, et al. Variable impact on mortality of AIDS-defining events diagnosed during combination antiretroviral therapy: not all AIDS-defining conditions are created equal. Clin Infect Dis 2009, 48:1138-51.

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