A. How far have we come?
  B. Aims of therapy
  C. Why use 3 drugs?

 

A. How Far Have We Come?

1981   First Cases of AIDS in USA

1984   HIV discovered

1988   Early trials of AZT on its own encouraging in people with advanced AIDS

1991   ddI (2nd antiretroviral) used in clinical trial

1992   PCP prophylaxis with Septrin (co-trimoxazole) introduced: first large reduction in death rate

1994   Concorde trial: no benefit for AZT on its own in asymptomatic HIV disease.

1/95    David Ho demonstrates enormous turnover of HIV in infected individuals.

11/95  Delta (Europe/Australia) and ACTG175 (USA) trials show convincing benefits of dual therapy   
            (AZT+ ddI or ddC) in symptomatic HIV disease in patients on their first combination

6/96   Data from first Protease Inhibitor trials show dramatic reductions in AIDS deaths.
            Era of ‘HAART’ and triple combination therapy begins

 

  B. The Aims of HAART

Primary aim:                    

 

 To reduce the impact of HIV related illness
To prevent HIV-related deaths   

Essential principals:            

 

Use at least 3 drugs 
Treatment should continue for life 
Monitor for treatment failure and toxicity regularly
If treatment has failed plan next combination to include at least 2 new drugs that are likely to work (preferably 1 from a new lass) 
Never just add 1 new drug to a failing combination 
Ensure patient knows what to take and when                                    

Watch for interactions between all drugs patient taking which might reduce the effectiveness of the combination    

 

A treatment is successful if:  

 

Plasma HIV viral load has fallen:

 ideally to undetectable levels                        
But at least to <10% of start VL
CD4 count rising
no further AIDS related illness happen after 3 months of starting

 
A treatment is failing:      Plasma HIV viral load:  rises on 2 consecutive occasion
Returns to >10% of starting VL
CD4 count falls
New AIDS related illness happen after 3 months of starting

 

Risk of developing AIDS in the next 3 years without treatment:  

 

 

HIV Viral load

 

 

CD4 count

Less than 1000

5,000 - 20,000

20,000 - 60,000

More than 60,000

More than 750

0%

3%

10%

33%

501-750

0%

3%

10%

35%

351-500

0%

8%

16%

48%

201-350

Less than 1%

8%

16%

64%

Less than 200

Less than 1%

8%

40%

86%

  (MACS study (Mellors et al 1996) 2000 gay men in US; 88% white; 10 yrs follow-up)


C. Why Use 3 Drugs?

 

Delta: 1418 individuals treated for 2.5 years:  

Medication

AZT

AZT + ddI

% not progressing to AIDS/ death

66%

77%

VL drop at week 4 (%)

68%

97%

 

  INCAS 153 individuals without AIDS, treated for 1 year:  

Medication

AZT + NVP

AZT + ddI

AZT + ddI + NVP

% not progressing to AIDS/ death

77%

75%

88%

VL drop at week 8 (%)

87.4%

97.2%

99.4%

% less than 20cpm at 1 year

0%

12%

51%

CD4 change at 1 year

-6

+87

+139

 

ACTG 320: 1156 individuals who never had a PI or 3TC; 10 month follow up  

Medication

AZT + 3TC

AZT + 3TC + IDV

% without progressing HIV disease

89%

94%

VL drop at week 8 (logs)

0.6

2.3

VL drop at week 8 (%)

75%

99.5

% less than 500cpm at 6 months

9%

60%

CD4 rise at end of study

40

121

 

So overall what are the costs and benefits combination therapy?

Benefits:      Maintenance and repair of immune system 
                       Reduction in HIV related illness 
                       Delayed emergence of viral resistance  

Costs:           Side effects 
                      Alterations in lifestyle and expectations for the future 
                      Reduced future options if treatment fails