WEB ANNEX G. SAFETY AND EFFICACY OF ANTIRETROVIRAL DRUGS FOR POST-EXPOSURE PROPHYLAXIS

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WEB ANNEX G. SAFETY AND EFFICACY OF

ANTIRETROVIRAL DRUGS FOR POST-EXPOSURE PROPHYLAXIS

Zara Shubber, Nathan Ford

In:

Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV: interim guidelines. Supplement to the 2016 consolidated guidelines on the use of antiretroviral drugs for treating and

preventing HIV infection

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WHO/CDS/HIV/18.30

© World Health Organization 2018

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Suggested citation. Shubber Z, Ford N. Web Annex G. Safety and efficacy of antiretroviral drugs for post-exposure prophylaxis. In: Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV: interim guidelines. Supplement to the 2016 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Geneva: World Health Organization;

2018 (WHO/CDS/HIV/18.30). Licence: CC BY-NC-SA 3.0 IGO.

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This publication forms part of the WHO guideline entitled Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV: interim guidelines. Supplement to the 2016 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. It is being made publicly available as supplied by those responsible for its development for transparency purposes and information, as required by WHO (see the WHO handbook for guideline development, 2nd edition (2014)).

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1. Background

Post-exposure prophylaxis (PEP) involves the provision of antiretroviral drugs following exposure to the human immunodeficiency virus in order to inhibit virus replication and thereby prevent the establishment of chronic HIV infection.

PEP is recommended by various national and international guidelines for occupational, accidental and sexual exposure. The number and type of antiretroviral drugs that are recommended may differ, with certain guidelines recommending two drugs for most HIV exposures, with a three-drug regimen advised for exposures that pose an increased risk of HIV transmission (e.g. exposure to large volumes of blood, deep injuries, and blood containing known high levels of HIV). However, policy and practice varies and the evidence base supporting the various recommendations is uncertain.

WHO issued guidance on HIV PEP in 2014 (1) informed by systematic reviews of PEP regimens across all age groups.^2,3 This systematic review aims to assess the safety and efficacy of different PEP regimens to inform a 2018 update of this guidance.

2. Methods

Search strategy and study selection

The protocol for this systematic review is based on the review conducted for the 2014 WHO PEP guidelines.² An initial search strategy was developed, and the list of titles was cross-checked against existing PEP systematic reviews. Missing studies were then reviewed to identify additional terms to develop the final search strategy, which is provided in the Annex.

The following databases were searched in duplicate from 1 June 2014 (the date of the last review) to 1 April 2018: Medline via Pubmed, Embase, Cochrane Database of Systematic Reviews, and Lilacs. All Conferences of the International AIDS Society and the Conference on Retroviruses and Opportunistic Infections were searched from 2014 onwards to identify studies that have been completed but not yet published as full text. No date, language, or geographical exclusions were applied.

The following study designs were considered eligible for inclusion: randomized-controlled trials, prospective cohorts and case series >10 patients. In the absence of sufficient data for specific (ie WHO recommended) regimens from the above study designs, retrospective cohorts were also included. Studies reporting PEP outcomes among adults and children exposed to HIV and provided with a course of PEP were included irrespective of exposure type. Exclusions included PEP given as monotherapy; infants exposed in utero and provided with PMTCT; PrEP; and animal studies.

Studies were only included if they reported outcomes of PEP regimens using antiretroviral drugs

recommended in the WHO 2016 consolidated guidelines.⁴ We included studies reporting outcomes using a tenofovir (TDF) + emtricitabine or lamivudine (XTC) regimen as this is the preferred backbone regimen in WHO and other guidelines; studies using the alternative backbone (zidovidune (AZT)+XTC) were considered if information on a third candidate (i.e. WHO-recommended) drug was not available in combination with TDF+XTC.

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Data extraction and analysis

Outcomes of interest included the number of PEP initiators completing a full (28-day) course; PEP discontinuations/substitutions due to adverse events; and seroconversions. Risk of bias was assessed using the same risk of bias tool used in the prior review, and this information contributed to the assessment of the overall certainty of the evidence using the GRADE framework.

Point estimates and 95% confidence intervals were calculated for the proportion of individuals with each outcome. In instances where PEP was discontinued due to confirmation of prior HIV-positivity or HIV- negative exposure status, these cases were excluded from the denominators prior to analysis. Data were pooled using the DerSimonian-Laird random-effects method,⁵ with proportions transformed prior to pooling using the Freeman–Tukey double arcsine transformation⁶ and then back-transformed to the original scale.⁷ We prepared to report outcomes separately for children (defined as ≤10 years), but no studies enrolling children were identified. All analyses were conducted using Stata version 14.0 (StataCorp, College Station, Tex).

3. Results

Of an initial screen of 5408 titles, 10 additional studies were identified since the previous review was conducted in 2014, resulting in 17 studies reviewed overall (Fig. S1). ^8-24 One study was a final report of a study that was previously only available as a conference abstract.^17,25 All studies evaluated outcomes in adults. Characteristics of included studies are included in Table S1.

Risk of bias overall was judged to be moderate and the certainty of evidence was very low for most comparisions (Tables S2 and S3).

PEP completion and discontinuations/substitutions

PEP Completion ranged from 12.2% (95% CI 0–29.7%) for AZT+XTC+EVF to 93.3% (89.4-97.2%) for TDF+XTC+DRV/r. Regimens with a PEP completion rate >75% included TDF+XTC (64.8%, 95%CI 40.7-89.0%), TDF+XTC+RAL (75.1%, 95%CI 55.4-94.7%), TDF+XTC+DRV/r and

TDF+XTC+DTG (89.6%, 95%CI 83.7-95.5%). No studies were identified that combined ATV(r) with TDF+XTC. Completion rates for ATV combined with AZT+XTC were 79.7% (55.2-100%), while completion rates for ATV/r combined with AZT+XTC were 63.3% (55.1-71.4%). The proportion of individuals completing PEP, per regimen, is summarized in Fig. 2.

The proportion of individuals discontinuing/substituting PEP due to adverse events ranged from 0.7%

for both TDF+XTC (95%CI 0-2.4%) to 87.8% (70.3-100%) for AZT+XTC+EFV. Apart from EFV, LPV/r and ATV(r) regimens had the highest proportion of individuals discontinuing/substituting PEP;

for all other regimens it was <5%. The proportion of individuals completing PEP, per regimen, is summarized in Fig. 2.

Adverse events leading to discontinuation or substituting of PEP are described in Table S2

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Fig. 1. Proportion completing HIV PEP

TDF+XTC TDF+XTC TDF+XTC+LPV/r TDF+XTC+RAL TDF+XTC+DRV/r TDF+XTC+DTG

AZT+XTC AZT+XTC+ATV AZT+XTC+ATV/r AZT+XTC+EFV Regimen

4 (136/231) 7 (567866) 4 (210/291) 1 (145/155) 1 (90/100)

2 (202/245) 1 (83/131) 1 (1/11) (n/N) Studies

71.60 (53.60, 89.40) 65.80 (51.50, 80.10) 75.10 (55.40, 94.70) 93.30 (89.40, 97.20) 89.60 (83.70, 95.50)

79.70 (55.20, 100.00) 63.30 (55.10, 71.40) 12.20 (0.00, 29.70)

% (95% CI)

71.60 (53.60, 89.40) 65.80 (51.50, 80.10) 75.10 (55.40, 94.70) 93.30 (89.40, 97.20) 89.60 (83.70, 95.50)

79.70 (55.20, 100.00) 63.30 (55.10, 71.40) 12.20 (0.00, 29.70)

% (95% CI)

% Completing PEP 0

0 20 40 60 80 100

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Fig. 2. Proportion discontinuing/substituting HIV PEP

Seroconversions

There were 7 seroconversions reported out of 644 exposures (1%). All were reported 3-6 within months post PEP completion. Among these, 3 were attributed to ongoing high-risk behavoir post PEP. In the other 3 cases (all receiving AZT+3TC+ATV), none had virus resistant to any of the PEP drugs.

Seroconversions are described in Table S3.

TDF+XTC TDF+XTC TDF+XTC+LPV/r TDF+XTC+RAL TDF+XTC+DRV/r TDF+XTC+DTG

AZT+XTC AZT+XTC+ATV AZT+XTC+ATV/r AZT+XTC+EFV Regimen

4 (0/231) 7 (53/866) 3 (4/291) 1 (1/155) 1 (1/100)

2 (18/245) 1 (22/131) 1 (10/11) (n/N) Studies

0.90 (0.00, 2.60) 5.20 (2.10, 8.30) 2.70 (0.40, 4.90) 0.90 (0.00, 2.40) 1.40 (0.90, 3.80)

9.30 (0.00, 26.30) 17.00 (10.70, 23.40) 87.80 (70.30, 100.00)

% (95% CI)

0.90 (0.00, 2.60) 5.20 (2.10, 8.30) 2.70 (0.40, 4.90) 0.90 (0.00, 2.40) 1.40 (0.90, 3.80)

9.30 (0.00, 26.30) 17.00 (10.70, 23.40) 87.80 (70.30, 100.00)

% (95% CI)

% Stop/substitution 0

0 20 40 60 80 100

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Fig. S1. Study selection process

5302 Database abstracts 106 Conference abstracts

92 articles screened As full text

7 articles included from bibliography screen

33 studies included for full review

Not relevant to study question

60 excluded after full text review – Data not disaggregated by regimen 4 – Regimen not described 9 – Outcomes of interest not reported 21 – PEP switch study 1

– Retrospective report 7

– Outcomes not provided per regimen 5 – Not HIV PEP 9

– Duplicate report 4

17 studies included for review of candidate regimens

16 studies reported outcomes using regimens not recommended in the WHO 2016 Consolidated ART guidelines,

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Table S1. Characteristics of included studies

Study Country Study design Exposure Regimens Number

needing PEP

Mayer, 2008⁸ USA Observational Non-occupational TDF+XTC 116

Sonder, 2010⁹ Netherlands Observational Non-occupational AZT+XTC+ATV 151 Tosini, 2010¹⁰ France Observational Non-occupational TDF+XTC+LPV/r 215 Burty, 2010¹¹ France Observational Non-occupational AZT+XTC+ATV/r 131 Diaz-Brito, 2012¹² Spain RCT Non-occupational AZT+XTC+ATV 94 McAllister, 2013¹³ Australia Observational Non-occupational TDF+XTC+RAL 86 Tan, 2014¹⁴ Canada Observational Non-occupational TDF+XTC+LPV/r 124

Landowitz²⁴ USA RCT Non-occupational TDF+XTC 40

Bogoch, 2015¹⁵ USA Observational Non-occupational TDF+XTC+LPV/r TDF+XTC+RAL TDF+XTC

88

Leal (1), 2016¹⁶ Spain RCT Non-occupational TDF+XTC+RAL TDF+XTC+LPV/r

198

Fatkenheueur, 2016¹⁷ Germany RCT Non-occupational TDF+XTC+LPV/r TDF+XTC+DRV/r

305

Leal (2), 2016¹⁸ Spain RCT Non-occupational TDF+XTC+LPV/r 93 Wiboonchutikul,

2016¹⁹

Thailand Observational Occupational AZT+XTC+EFV 11

Milinkovic, 2017²⁰ United Kingdom

RCT Non-occupational TDF+XTC+LPV/r 106

Inciarte, 2017²¹ Spain RCT Non-occupational TDF+XTC+LPV/r 37 McAllister, 2017²² Australia Observational Non-occupational TDF+XTC+DTG 100 Mayer, 2017²³ USA Observational Non-occupational TDF+XTC+RAL 100

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Table S2. GRADE Assessment: PEP completion

Quality assessment

Events/

Participants

Proportion

(95%CI) Certainty No of

studies Design Risk of

bias Inconsistency Indirectness

Imprecision

TDF+XTC

4 Observational No serious risk of bias

No serious inconsistency

No serious indirectness

Serious imprecision³

136/231 71.6%

(53.6-89.4%)



LOW

LPV/r

7 5 RCTs

3 observational

Serious risk of bias¹

567/866 65.8%

(51.5-80.1%)



LOW

ATV

2 1 RCT

1 observational

202/245 79.7%

(55.2-100%)



LOW

ATV/r

83/131 63.3%

(55.1-71.4%)



LOW

RAL

4 1 RCT

3 observational

210/291 75.1%

(55.4-94.7%)



LOW

DRV/r

1 RCT Serious risk

of bias¹

No serious imprecision

145/155 93.3%

(89.4-97.2%)



MODERATE

DTG

90/100 89.6% (83.7-

95.5%) 

LOW

EFV

1 Observational

(retrospective)

Serious risk of bias²

1/11 12.2%

(0-29.7%)

 VERY LOW

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Table S3. GRADE Assessment: PEP Discontinuation/substitution

Quality assessment

Events/

Participants

Proportion

(95%CI) Certainty No of

studies Design Risk of

bias Inconsistency Indirectness

Imprecision

TDF+XTC

0/231 0.7%

(0.0-2.4%)



LOW

LPV/r

8 5 RCTs

3 observational

53/866 5.2%

(2.1-8.3%)



LOW

ATV

2 1 RCT

1 observational

18/245 9.3%

(0-26.3%)



LOW

ATV/r

22/131 17%

(10.7-23.4%)



LOW

RAL

4 1 RCT

3 observational

4/291 2.7%

(0.4-4.9%)



LOW

DRV/r

1 RCT Serious risk

of bias¹

1/155 0.9%

(0-2.4%)



MODERATE

DTG

1/100 1.4%

(0.9-3.8%)



LOW

EFV

1 Observational

(retrospective)

Serious risk of bias²

10/11 87.8%

(70.3-100%)

 VERY LOW

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Table S4. Description of severe adverse events

Study Regimen Adverse event Number of

affected patients (%)

Action taken

Sonder, 2010⁹ AZT+XTC+ATV Nausea, diarrhea, fatigue, and a rash with hives (normal ALT)

1 (0.7%) ATV switched to nelfinavir Tosini, 2010¹⁰ TDF+XTC+LPV/r Rash (n=2); renal lithiasis (n=1),

rhabdomyolysis (n=1) (others not described)

4 (1.9%) For rhabdomyolysis, regimen substituted (ZDV+3TC+DDI).

Those with rash and renal lithiasis stopped PEP

Diaz-Brito, 2012¹²

AZT+XTC+ATV Gastrontestinal (n=4); asthenia (n=2); neuropsychiatric (n=2);

jaundice (n=4); vertigo (n=1)

10 (9.4%) Stopped PEP (Individuals reported more than 1 symptom that led to

discontinuation).

Bogoch, 2015¹⁵ TDF+XTC+LPV/r TDF+XTC+RAL TDF+XTC

Gastrointestinal 10 (25%) Changed to TDF/FTC plus RAL (n=4), stopped PEP (n=4);

switched to

TDF/FTC (n=1) and 2 switched to DRv/r Leal (1), 2016¹⁶ TDF+XTC+RAL

TDF+XTC+LPV/r

3 patients experienced a total of 10 AEs and gastrointestinal toxicity was the most frequently reported adverse event leading to PEP non-completion”

3 (3%) PEP stopped

Leal (2), 2016¹⁸ TDF+XTC+LPV/r Gastrointestinal toxicity 5 (4%) PEP stopped Wiboonchutikul,

2016¹⁹

AZT+XTC+EFV Severe dizziness 10 (91%) EFV withdrawn.

Patients continued on 2 drugs (6) or given LPV/r (2) or ATV/r (2)

McAllister, 2017²²

TDF+XTC+DTG Headache 1 (1%) PEP discontinued

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Table S5. Description of seroconversion events

Study PEP Regimen Number of

seroconversions

Reasons given

Sonder, 2010 AZT+XTC+ATV 5 Did not match with the virus isolated

from the source (n=1); unsafe sexual contacts between PEP initiation (n=1);

viruses were sequenced and

revealed no resistance to any PEP drugs (n=3)

Leal (1), 2016 TDF+XTC+RAL 1 Multiple potential sexual risk exposures before and after receiving PEP.

Landovitz 2012 TDF+XTC 1 Stopped PEP at 16 days; multiple repeat

exposures subsequent to PEP treatment and laboratory evidence of incident STIs at the time of serconversion

Landovitz 2014 TDF+XTC 1 Repeat exposures

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Annex. Search strategy

1. HIV Infections[MeSH] OR HIV[MeSH] OR hiv[tiab] OR hiv-1*[tiab] OR hiv- 2*[tiab] OR hiv1[tiab] OR hiv2[tiab] OR hiv infect*[tiab] OR human

immunodeficiency virus[tiab] OR human immunedeficiency virus[tiab] OR human immuno-deficiency virus[tiab] OR human immune-deficiency virus[tiab] OR ((human immun*[tiab]) AND (deficiency virus[tiab])) OR acquired immunodeficiency

syndrome[tiab] OR acquired immunedeficiency syndrome[tiab] OR acquired immuno-deficiency syndrome[tiab] OR acquired immune-deficiency syndrome[tiab]

OR ((acquired immun*[tiab]) AND (deficiency syndrome[tiab])) OR "sexually transmitted diseases, Viral"[MeSH:NoExp]

2.

Post exposure prophylaxis

[tiab]

OR postexposure prophylaxis

[tiab]

OR post-exposure prophylaxis

[tiab]

OR PEP

[tiab] OR anti-infection

prophylaxis[tiab] OR post-exposure HIV prophylaxis[tiab] OR chemoprevention[tiab]

OR exposure prophylaxis

3. 1 AND 2

(18)

WEB ANNEX G. SAFETY AND EFFICACY OF ANTIRETROVIRAL DRUGS FOR POST-EXPOSURE PROPHYLAXIS