HLA-B57 screening test not done at inclusion

Degree of significance between treatment arms \* p< 0,05 \*\* p<0,005 \*\*\*p<0.001

#### **2.3 Resistance development during treatment with anti-retroviral backbones**

Inadequate compliance is the most important cause of virologic failure and resistance development **(23,24)**. Repeated virologic failure with cumulation of resistances will lead to a decrease of the number of CD4 cells (immunologic failure), leading to HIV-related diseases, AIDS and death (clinical failure).

Development of resistance varies per class of anti-retroviral drugs and also within a class of antiretrovirals. For NRTIs, the development of resistance after initiation of cART is stongly associated with adherence. Resistance to antiretrovirals from the start of cART will develop first and during follow-up in highest frequency to lamivudine, followed by development of resistance to NNRTIs, NRTIs and PIs **(32).**

A distinction between the different mutations to NRTI's is made between thymidine analoge mutations (TAMs), TAMs-associated mutations, evolving mainly during virologic failure when on therapy with thymidine analogues ZVD and d4T and the discriminatory mutations and the Q151M pathway mutations conferring for multiresistance. Mutations, an acumulation of mutations or the occurrence of multi-resistant mutations limit the number of effective combinations of NRTIs in the backbone for a second or third regimen.

For instance the K65R mutation (discriminatory mutation) can develop during failing therapy with TDF and will make ABC and ddI ineffective.

These drug-resistant viruses can be tranmitted and may limit the treatment options in treatment naïve patients.

The prevalence of transmitted drug resistance viruses since 2004 is similar in different Eropean countries and the Netherlands. In the Netherlands the prevalence of NRTI drug resistance in recent infection (naïve patients) is found to be around 5-6% and for intermediate or high level of resistance is around 2% **(33)**

Since2003 treatment guidelines recommend onbtaining a genotypic sequence at the start of cART.

#### **3. Safety of anti-retroviral backbones**

366 Recent Translational Research in HIV/AIDS

and less toxic only in the 144-week follow-up data (two trials, 1,119 patients). ABC/3TC had similar efficacy to its comparators, but more AIDS-defining events **(29**). In the Swiss cohort study, including 1318 naïve patients, between 2005 and 2008 drug toxicity remained a frequent reason for treatment modification. Initial treatment with ZVD/3TC was associated with a high rate of drug toxicity. **(30)** In general QoL is beter with a higher CD4 cell count and QoL is decreased in patients with a high VL. The effects of adverse events on QoL are

Third drug ITT analysis:

Table 1. Major characteristics and parameters of effectiviness of the seven important clinical

Inadequate compliance is the most important cause of virologic failure and resistance development **(23,24)**. Repeated virologic failure with cumulation of resistances will lead to a decrease of the number of CD4 cells (immunologic failure), leading to HIV-related diseases,

Development of resistance varies per class of anti-retroviral drugs and also within a class of antiretrovirals. For NRTIs, the development of resistance after initiation of cART is stongly associated with adherence. Resistance to antiretrovirals from the start of cART will develop

trials comparing different backbones of during 48 to 96 weeks of treatment

Degree of significance between treatment arms \* p< 0,05 \*\* p<0,005 \*\*\*p<0.001

**2.3 Resistance development during treatment with anti-retroviral backbones** 

atazanavir/r or efavirenz

% patients with VL< 50 cop/mL

% patients with screening

lopinavir/r 68% vs 67% 63% vs 65% 214 vs 193 up to week 96:

efavirenz 67% vs 63% 67% vs 63% 158 vs 163 up to week 48:

efavirenz 78% vs 59%\*\*\* 67% vs 50%\*\*\* 168 vs 134 up to week 60:

efavirenz 82% vs 81% not available 169 vs 167 up to week 48:

similar 75% vs 80% 194 vs 199 up to week 112:

158\*

155\*\*

CD4 increase cells/mm3  % patients stopping study drugs due to adverse events

6% vs 6%

5% vs 4%

up to week 48: 5% vs 19%\* up to week 144: 13% vs 34%\*

up to week 48: 14% vs 18%

14% vs 26%

7% vs 15%

9% vs 9% up to week 96: 14% vs 15%

VL >100.000 copies/mL with VL< 50 copies/mL

efavirenz 77% vs 68%\*\* not available 190 vs

efavirenz 70% vs 69% 67% vs 67% 209 vs

independent of CD4 cell count and VL **(31).**

Treatment arms Number of patients in each treatment arm ()

ABC/3TC (343) versus TDF/FTC (345)

ABC/3TC (388) versus TDF/FTC (393)

TDF/FTC(258) versus ZVD/3TC (259)

ABC/3TC (327) versus ZVD/3TC (327)

ddI/3TC (189) versus ZVD/3TC (187)

ddI/FTC (286) versus d4T/ddI (285)

TDF/FTC (299) versus d4T/3TC (303)
