Rockstroh 12/5/08 12:12 pm Page 15
Evolution of HIV Therapy—A Review of the Literature
monotherapy with combinations of AZT with didanosine (ddI) or zalcitabine
Figure 1: Approval of Antiretroviral Substances Over Time
(ddC). This large international trial included 3,207 patients and reported a
significant difference in survival between the treatment groups, with a relative
Mono/dual
HAART era
therapy era
reduction in mortality of 33% for AZT plus ddl and 21% for AZT plus ddC
1987–1991 1992–1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
compared with AZT only.
6
In the AIDS Clinical Trials Group (ACTG) 175 study,
ZDV
which assessed the efficacy of single NRTI treatment versus double NRTI
ddl
ddC
d4T
treatment in HIV-infected patients with CD4 cell counts of 200–500 per cubic 3TC, SQV
RTV, IDV, NVP
mm, progression to the primary end-points (>50% decline in the CD4 cell
NFV, DLV, ZDV/3TC, SQV-gc
count, development of AIDS, or death) was significantly more frequent with
EFV, ABC
APV
LPV/r, ddl-EC, ZDV/3TC/ABC
AZT only (32%) than with AZT plus didanosine (18%), AZT plus zalcitabine
TDF
EFV-600, 3TC-300
(20%), or didanosine only (22%).
7
Based on the highly significant differences
PIs ENF, NFV 625, ATV, FTC, fAPV
NNRTIs
ABC/3TC, TDF/FTC, ddl generic
in progression to the clinical end-points of AIDS and death reported in these
NRTIs
Fusion inhibitors
SQV 500, TPV, generic ZDV, LPV/r tabs
DRV, TDF/FTC/EFV
trials, it became clear that the combined use of two NRTIs was superior to ARV
therapy with AZT only.
3TC = lamivudine; APV = aprenavir; ATV = atazanavir; d4T = stavudine; ddC = zalcitabine;
ddI = didanosine; DLV = delavirdine; DRV = darunavir; EFV = efavirenz; ENF = enfuvirtide; FTC = emtricitabine;
HAART = highly active antiretroviral therapy; IDV = idinavir; LPV/r = lopinavir/ritonavir; NFV = nelfinavir;
The First Protease Inhibitors
NNRTIs = non-nucleoside reverse transcriptase inhibitors; NRTIs = nucleoside reverse transcriptase inhibitors;
NVP = nevirapine; PIs = protease inhibitors; RTV = ritonavir; SQV = saquinavir; TDF = tenofovir disoproxil fumarate;
With the development of the first three PIs—saquinavir (SQV), ritonavir (RTV),
TPV = tipranavir; ZDV = zidovudine.
and indinavir (IDV)—in 1996, a new class of ARV drugs was introduced,
Figure 2: Mortality and Incidence of HIV/AIDS in Germany,
broadening treatment options in HIV practice. Cameron et al. reported a highly
1979–2006
significant difference in the occurrence of AIDS-defining illness or death of
8,000
37.5% in patients treated with RTV versus 21.9% in those receiving placebo
after a median follow-up of 29 weeks in 1998.
8
The superior effects of the RTV 7,000
treatment arm continued to be of significance at a median follow-up of 51
6,000
weeks. The first results of clinical trials assessing the efficacy of combined ARV
therapy with an NRTI backbone and PIs were encouraging. The ACTG 320 trial
5,000
was terminated early because of the apparent superiority of dual NRTI therapy Cases
4,000
plus IDV versus treatment with NRTIs only in 1,156 pre-treated patients with
3,000
CD4 cell counts <200/ml.
9
After 38 weeks of follow-up, 6% of patients
with triple therapy reached the primary end-points of a new AIDS-defining 2,000
event or death, compared with 11% in the group receiving NRTI therapy only.
1,000
The First Non-nucleoside Reverse Transcriptase Inhibitors
0
8
0
8
1
8
2
8
3
8
4
8
5
8
6
8
7
88 8
9 8
1979 19 19 19 19 19 19 19 19 19 19 1990 1991 1992 1993 1994 1995 1996 1997 199 1999 2000 2001 2002 2003 2004 2005 2006
Following the extension of therapeutic options by the new class of PIs, in June Time
1996 the NNRTI nevirapine (NVP) introduced the third class of ARV active
Mortality Incidence HIV Incidence AIDS
agents. The Italy, Netherlands, Canada, and Australia (INCAS) trial in 1998 lopinavir/r group (0%) than in the nelfinavir group (33%). The boosting of
showed a substantially greater and sustained decline in HIV plasma viral load PI-containing ARV regimens with low-dose RTV thus appeared to lower the risk
in NVP-containing triple-drug therapy compared with the two-drug regimens of AIDS complications and to prolong survival in HIV-infected patients.
studied.
10
Combination of triple reverse transcriptase inhibitors including NVP
prolonged life and delayed disease progression in AIDS patients with advanced Highly Active Antiretroviral Therapy
immune suppression.
11
Adding NVP to a double NRTI regimen improved the ARV combination regimens with drugs from the different ARV classes leading
long-term immunological and virological effects of therapy. However, severe to persistent control of HIV replication became known as HAART and caused
rashes were more common among patients assigned to the triple combination a paradigm shift in HIV practice. While in the era of AZT monotherapy an early
including NVP compared with those receiving a non-NVP-containing regimen initiation of ARV therapy in asymptomatic patients was discouraged, the new
(9 versus 2%; p=0.002).
12
concept was to ‘hit hard and early.’ The majority of patients were treated
with HAART regardless of cellular immunity and clinical status. The impact of
Boosting Protease Inhibitors HAART is reflected in the rates of AIDS morbidity and mortality in Germany
The finding that the addition of low-dose RTV to PI-containing HAART from 1995 to 1999, with a decrease in new cases of AIDS from 2,332 in 1995
regimens significantly decreased progression to AIDS and death was another to 1,322 in 1999, and a drop in mortality from 2,551 patients in 1995 to 839
milestone in the development of HIV therapy. In 1997, Kempf et al. first patients in 1999. The incidence of HIV infections over this time decreased
described that co-administration of RTV 100mg enhanced the plasma levels of slightly from 2,000 to 1,550 (see Figure 2). From 2000, however, HIV incidence
other HIV PIs as a result of the inhibition of the cytochrome P450 in rat and in Germany has risen again to approximately 2,700 new cases in 2006.
human liver microsomes,
13
allowing the design of pharmacologically more
robust regimens. In clinical practice, the combination of the PI lopinavir with Downsides of Highly Active Antiretroviral Therapy
low-dose RTV proved to have considerably higher virological response rates Because of the growing number of ARV substances and the prolonged periods
than treatment with a single PI (nelfinavir).
14
Furthermore, the development of for which patients were taking these drugs, reports of increasing adverse
resistance-associated mutations in HIV protease was significantly lower in the effects and toxicities raised interest and caused concern. Reports of
US INFECTIOUS DISEASE 15
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