DRV/r versus LPV/r

(1)

GRADE tables: What ARV regimen to switch to in adults, pregnant women, adolescents and children living with HIV (once-daily PI regimens)?

ATZ/r versus LPV/r

Author(s): Larry W Chang, Alicen B Spaulding, George W Rutherford Date: 2012-09-19

Question: Should ATZ/r vs LPV/r be used for HIV treatment failure?

Settings: Low and Middle-Income Countries Bibliography: BMS 045 (2005, 2006)

Quality assessment No. of patients Effect

Quality Importance

No. of

studies Design Risk of bias Inconsistency Indirectness Imprecision Other

considerations ATZ/r LPV/r Relative

(95% CI) Absolute

Mortality (96 Weeks)

1 randomized

trials

no serious risk of bias

no serious inconsistency

very serious^1,2,3

very serious imprecision⁴

none 0/120

(0%) 2/123 (1.6%)

RR 0.2 (0.01 to 4.23)

13 fewer per 1000 (from 16 fewer to

53 more) ⊕OOO

VERY LOW

CRITICAL

Viral response (intent to treat, time to loss of viral response, <50 copies/ml, noncompleter = failure, 96 weeks)

1 randomized

trials

very serious^1,2,3

none 39/120

(32.5%) 44/123 (35.8%)

RR 0.91 (0.64 to 1.29)

32 fewer per 1000 (from 129 fewer to 104 more)

⊕OOO VERY LOW

CRITICAL

Severe adverse events (96 weeks)

1 randomized

trials

very serious^1,2,3

none 16/120

(13.3%) 13/123 (10.6%)

RR 1.26 (0.63 to 2.51)

27 more per 1000 (from 39 fewer to 160 more)

⊕OOO VERY LOW

CRITICAL

Immune response (96 weeks)

1 randomized

trials

very serious^1,2,3

none 120 123 - Median increase, 160 cells/mm³

versus 142 cells/mm³

⊕OOO VERY LOW

IMPORTANT

Retention on treatment (96 weeks)

1 randomized

trials

very serious^1,2,3

none 67/120

(55.8%) 65/123 (52.8%)

RR 1.06 (0.84 to 1.33)

⊕OOO VERY LOW

IMPORTANT

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1 The study was conducted primarily in high-income countries.

2 The regimens previously failing participants differed significantly from WHO first-line regimens, both in quantity and in content.

3 The NRTI backbones used in new regimen included tenofovir and another NRTI selected with guidance from phenotypic sensitivity testing, an option not available in most low- and middle-income settings.

4 Very few events.

DRV/r versus LPV/r

Author(s): Larry W. Chang, Alicen B. Spaulding, George W. Rutherford Date: 2012-12-10

Question: DRV/r versus LPV/r or boosted PI for second-line ART Settings: Low- and middle-income countries

Bibliography: POWER (2007, 2009); TITAN (2007, 2012)

No. of

studies Design Risk of

bias Inconsistency Indirectness Imprecision Other

considerations DRV/r LPV/r or boosted PI

Relative

Mortality (48 Weeks)

2 randomized trials

serious^1–5 very serious⁶ none 7/429 (1.6%)

4/421 (0.95%)

RR 1.7 (0.5 to 5.81)

7 more per 1000 (from 5 fewer to 46 more) ⊕OOO VERY LOW

CRITICAL

Virologic Response (intent to treat, time to loss of viral response, <50 copies/ml, 96 weeks)

2 randomized

trials

serious^1–5 no serious imprecision

none 231/429

(53.8%)

175/421 (41.6%)

RR 1.31 (1.14 to 1.5)

129 more per 1000 (from 58 more to 208 more) ⊕⊕⊕O MODERATE

CRITICAL

2 randomized

trials

serious^1–5 very serious⁶ none 54/429 (12.6%)

48/421 (11.4%)

RR 1.1 (0.76 to 1.58)

11 more per 1000 (from 27 fewer to 66 more) ⊕OOO VERY LOW

CRITICAL

Immune response (96 weeks) (better indicated by higher values)

2 randomized

trials

serious^1,2,3,4,5no serious imprecision

none 429 421 – First trial = median increase from baseline, 81 cells/mm³ versus 93 cells/mm³; second trial = mean absolute

increase, 133 cells/mm³ versus 15 cells/mm³

⊕⊕OO LOW

IMPORTANT

On Treatment Retention (48 Weeks)

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2 randomized trials

serious^1–5 no serious imprecision

none 339/429

(79%)

235/421 (55.8%)

RR 1.42 (1.29 to 1.57)

234 more per 1000 (from 162 more to 318 more) ⊕⊕⊕O MODERATE

CRITICAL

1 The study was conducted primarily in high-income countries.

2 The regimens previously failing participants differed significantly from WHO first-line regimens, both in quantity and in content.

3 DRV/r was twice-daily 600 mg/100 mg dosing rather than daily dosing.

4 Comparison group in POWER 1, 2 studies included a mix of boosted PIs; only 36% were on a LPV/r-based regimen.

5 NRTI backbones were used in a new regimen selected using resistance testing data and may have included antiretroviral drugs not typically available in most low- and middle-income settings.

6 Very few events.

Use of ATZ/r or DRV/r in first-line regimens

Author(s): George W. Rutherford, Tara Horvath Date: 2012-11-09

Question: ATV/r versus LPV/r for second-line antiretroviral therapy among people living with HIV (first-line therapy trials)

Settings: Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Columbia, Costa Rica, France, Germany, Hong Kong SAR, Indonesia, Italy, Mexico, Netherlands, Norway, Panama, Peru, Portugal, Puerto Rico, Singapore, Spain, South Africa, Sweden, Thailand, United Kingdom, United States

Bibliography: Molina 2008, Molina 2010, Josephson 2010

No. of

considerations ATV/r LPV/r Relative

Mortality (96 weeks)

1 randomized

trials

serious¹ very serious² none 6/440

(1.4%) 5/443 (1.1%)

RR 1.21 (0.37 to 3.93)

2 more per 1000 (from 7 fewer to 33

more) ⊕OOO

VERY LOW

CRITICAL

Plasma VL <50 copies/ml (96 weeks)

1 randomized

trials

serious¹ no serious imprecision

none 326/440

(74.1%) 295/443 (66.6%)

RR 1.09 (1 to 1.19)

60 more per 1000 (from 0 more to 127 more)

⊕⊕⊕O MODERATE

CRITICAL

2 randomized

trials

none 405/508

(79.7%) 400/508 (78.7%)

RR 1.01 (0.95 to 1.08)

⊕⊕⊕O MODERATE

CRITICAL

Increase in CD4 cells/mm³ (96 weeks) (better indicated by higher values)

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1 randomized trials

none 440 443 – Mean difference 21.2 lower (43.3

lower to 0.9 higher)

⊕⊕⊕O MODERATE

CRITICAL

1 randomized

trials

serious¹ serious³ none 62/441

(14.1%) 48/437 (11%)

RR 1.28 (0.9 to 1.82)

⊕⊕OO LOW

CRITICAL

Retained in care (96 weeks)

1 randomized

trials

(16.4%) 95/440 (21.6%)

RR 1.07 (1 to 1.14)

15 more per 1000 (from 0 more to 30

more) ⊕⊕OO

LOW

CRITICAL

<100% adherence (self-report) (96 weeks)

1 randomized

trials

very serious^1,4

no serious imprecision

none 361/440

(82%) 372/443

(84%)

RR 0.98 (0.92 to 1.04)

⊕⊕OO LOW

CRITICAL

1 First-line therapy.

2 Very few events.

3 Few events.

4 Self-report.

Author(s): George W. Rutherford, Tara Horvath Date: 2012-11-09

Question: DRV/r versus LPV/r for second-line antiretroviral therapy among people living with HIV (first-line therapy trials)

Settings: Argentina, Australia, Austria, Belgium, Canada, Chile, Costa Rica, Denmark, France, Germany, Greece, Guatemala, Italy, Malaysia, Mexico, Panama, Puerto Rico, Russian Federation, Singapore, South Africa, Spain, Switzerland, Taiwan, China, Thailand, United Kingdom, United States

Bibliography: Orkin 2012

No. of

considerations DRV/r LPV/r Relative

Mortality (192 weeks)

1 randomized

trials

serious¹ very serious² none 4/343 (1.2%)

7/346 (2%)

RR 0.58 (0.17 to 1.95)

⊕OOO VERY LOW

CRITICAL

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1 randomized trials

none 236/343

(68.8%) 198/346 (57.2%)

RR 1.2 (1.07 to 1.35)

114 more per 1000 (from 40 more to 200 more)

⊕⊕⊕O MODERATE

CRITICAL

Increase in CD4 cells/mm³ (192 weeks) (better indicated by higher values)

1 randomized

trials

none 343 346 – Mean difference 5 lower (19.93 lower

to 9.93 higher)

⊕⊕⊕O MODERATE

CRITICAL

≥1 grade 3 or 4 adverse events (192 weeks)

1 randomized

trials

(30%) 110/346 (31.8%)

RR 0.94 (0.76 to 1.18)

19 fewer per 1000 (from 76 fewer to

57 more) ⊕⊕OO

LOW

CRITICAL

>95% adherence (Modified Medication Adherence Self-Report Inventory) (192 weeks)

1 randomized

trials

none 286/343

(83.4%) 271/346 (78.3%)

RR 1.06 (0.99 to 1.15)

⊕⊕⊕O MODERATE

CRITICAL

1 First-line therapy.

2 Very few events.

3 Few events.