Combining biomedical preventions for HIV: Vaccines with pre-exposure prophylaxis, microbicides or other HIV preventions

Figures & data

Figure 1. Biomedical HIV preventions are ranked from highest to lowest effect size. Confidence intervals are shown in ( ). MSM, men who have sex with men. Adapted from AVAC (www.avac.org/sites/default/files/resource-files/evidence_HIVprevention_feb2016.pdf) with permission, adapted from original figure in Ref. 55, p. 2060. Three vaccine trials are identified by italic text and an inverted triangle in the effectiveness bar. Two HIV-vaccine trials, the STEP and Phambili trials of an Ad5 subtype B gag/pol/nef vaccine, are not shown as there was no efficacy and HIV acquisition was enhanced in some subgroups.

Table 1. Non-human primate studies modeling combinations of candidate HIV vaccines with PrEP or microbicides.

Author Year Ref.	Macaques	Vaccine route (Efficacy)	Other biomedical prevention, route (Efficacy)	Viral challenge, route, timing	CBP effect (Efficacy)	Viral load effect in CBP	Comments
Cheng-Mayer 2011^43	46 female rhesus	DNA with SIVmac239 G/P prime rAd5 virus boost, i.m. T-cell inducing(25%)	SAMT-247 Zn finger inhibitor, 0.1% vaginal gel, 30 min before challenges (6%)	SHIV162P3, 20 escalating vaginal challenges 12 weeks after last vaccination	Probable (20%)	Reduced peak and AUC vs vaccine, gel or naive controls	Acquisition delayed vs vaccine or gel alone; 2 CBP animals had transient lowseronegative viremia, if included CBP efficacy was higher in CBP group; Ad-based vectors in human trials, SAMT-247 not; vaccine raised cellular immunity; large sample size
Barouch 2012^44	53 female rhesus Depo-Provera treated 30 d before challenge	Ad26/Ad5HVR48 with SIV G/P/E/N prime-boost, i.m. T-cell inducing(0%)	T-1249 fusion inhibitor, 200 ug/ml vaginal gel(0%)	SIVmac251 Single vaginal challenge 8 months after last vaccination	Probable(30%)	No	Acquisition not delayed; Ad-based vectors in human trials; Depo-Provera allowed single challenge; immune responses not reported
		Ad35/Ad26 with SIVsmE543 G/P/E/N prime-boost, i.m.(0%)	Maraviroc entry inhibitor vaginal gel(43%)	SHIV162P3 Single vaginal challenge 6 months after last vaccination	Probable(67%)	Reduced at peak and day 28 vs placebo and naïve controls	Acquisition not delayed; heterologous env challenge; Depo-Provera used; immune responses not reported; one control infected, hence efficacy <50%; maraviroc being evaluated in humans for PrEP and in use for treatment
Le Grand 2016^45	52 female cynomolgous	Gp140 (clades B,C) i.n. prime with R848, TLR 7/8 adjuvant, i.m. boosts with MF59 adjuvant; T and B-cell inducing (0%)	Tenofovir, 1% vaginal gel 1h before challenge(46% after 614% after 12 challenges)	SHIV162P3 < 22 vaginal challenges 11 weeks after last vaccination	Probable (81% after 6 63% after 12 challenges)	Not noted	CBP efficacy was 38% at 22 challenges with no gel for last 10; vaccine raised cellular and humoral immunity; TDF and TDF-DP reported in blood and vaginal tissues; phase III TFV gel trials complete; MF59 in human use; large sample size.
Ross 2014^47	13 male rhesus	DNA with SIVmac239 G prime, poly clade B VLP-alum-adjuvanted boosts i.m., i.n.; B-cell inducing (n/a, likely >50%)	FTC (22 mg/kg), TDF (20mg/kg), orally 2h before and 22h after challenge (∼50%, historical)	SHIV162P3 14 weekly rectal challenges 8 weeks after last vaccination	Probable (87.5%)	Yes, but only one animal	CBP interaction likely additive; vaccine raised humoral responses; challenges boosted G and E antibodies; CBP break-through animal had high antibody avidity and protective TFV-DP and FTC-TP levels; one CBP protected animal had transient viremia; only rectal study; only study with approved PrEP; small sample size.

Abbreviations (by column): Ad, adenovirus; G/P/E/N, Gag, Pol, Env, Nef; i.m., intramuscular; i.n., intranasal; VLP, virus like particle; CBP, combined biomedical prevention; interaction on acquisition or viral load; AUC, area under curve; Ab, antibody, PrEP, pre-exposure prophylaxis. Efficacy is as reported by the authors.

Table 2. Possible human combined biomedical prevention trial designs.

A.
Prevention	Theoretical Efficacy (%)	Theoretical Incidence (%)	Study arms	Sample size	Comments
None		2	Nothing or double placebo	1200+	May not be possible if PrEP or vaccine are standard of care
HIV vaccine	30	1.4	Vaccine +/- placebo PrEP	1200+
Other prevention	30	1.4	PrEP +/- placebo vaccine	1200+
CBP, model	?		Vaccine + PrEP	1200+
*CBP modelling estimates on efficacy and incidence
Additive	51	0.98		May increase	May need to detect > 200 infections, increasing sample size
Synergistic	> 51	0.67		May increase	Detecting 80 incident infections may suffice, overall sample size ∼ 4900 for 80% power
Enhancing^	?	2.6		No estimate	Effect may be determined during interim monitoring
B.
Prevention	Theoretical Efficacy (%)		Study arms	Sample size	Comments re number of incident infections, sample size and power
None			Double placebo	1900	May not be possible if PrEP or vaccine are standard of care
HIV vaccine	40		Vaccine + PrEP placebo	1900
Other prevention	60		PrEP + vaccine placebo	1900
CBP, model	?		Vaccine + PrEP	1900
**CBP modelling estimates on efficacy
Additive	76	Can be evaluated
Synergistic	88	Can be evaluated
Antagonistic	64	Can be evaluated

Designs are presented for illustrative purposes only and may not be possible if an HIV vaccine or PrEP are standard of care or in widespread use. Then, alternative designs would be necessary.

A. Incidence-based 4 arm test-of-concept trial design to evaluate CBP. This is described in “scenario B” in Excler et al. 2011.³⁹ Assumptions are: background incidence of 2%; no viral load in model; vaccine and PrEP effects, both = 30%; vaccine and PrEP occur sequentially; 18 months of follow up. The design does not allow comparison of CBP to vaccine alone or PrEP alone unless the synergistic effect is large, but might allow ranking of preventions. Sample sizes are available (not shown) for 30 months in trial with 10% loss to follow up. *Additive calculation: 1.4 - (1.4 × 0.3) = 0.98, i.e. a 51% reduction. Synergistic incidence assigned as 0.67 empirically, assuming an effect >51%. ^Enhancing effect set at 30%.

B. Efficacy based 4 arm study design to evaluate CBP. This is described in trial design “A” in Janes et al. 2013.⁴⁰ Assumptions are: background incidence of 4%; 2 sided, 0.05 level likelihood ratio test under Cox proportional hazard model. Powered to detect: 40% vaccine efficacy rejecting null hypothesis of <0% vaccine efficacy; 76% efficacy of CBP; rejecting null hypothesis that CBP efficacy is <30% and to compare vaccine to CBP groups and rejecting null hypotheses that vaccine efficacy is not superior to CBP efficacy. **CBP calculations: additive, 1-(1-0.4) x (1-0.6) = 1-0.24 = 0.76, (Relative risk [RR] vaccine + PrEP); synergistic with decreased RR of 50, 1-(0.24 -0.12) = 0.88, (RR vaccine + PrEP < RR vaccine x RR PrEP); antagonistic with increased RR of 50%: 1-(0.24+0.12) = .64, (RR vaccine + PrEP > RR vaccine x RR PrEP). Power to evaluate interactions varies.

Karim SSA. HIV pre-exposure prophylaxis in injecting drug users. Lancet 2013; 381(9883):2060–2062; http://dx.doi.org/10.1016/S0140-6736(13)61140-X

 Google Scholar

Cheng-Mayer C, Huang Y, Gettie A, Tsai L, Ren W, Shakirzyanova M, Sina S, Trunova N, Blanchard J, Jenkins L, et al. Delay of simian human immunodeficiency virus infection and control of viral replication in vaccinated macaques challenged in the presence of a topical microbicide. AIDS 2011; 25:1833-41; PMID:21750420; http://dx.doi.org/10.1097/QAD.0b013e32834a1d94

 PubMed Web of Science ®Google Scholar

Barouch DH, Klasse PJ, Dufour J, Veazey RS, Moore JP. Macaque studies of vaccine and microbicide combinations for preventing HIV-1 sexual transmission. Proc Natl Acad Sci U S A 2012; 109:8694-8; PMID:22586094; http://dx.doi.org/10.1073/pnas.1203183109

 PubMed Web of Science ®Google Scholar

LeGrand R, Bosquet N, Dispinseri S, Hopewel N, Gosse L, Desjardins D, Shen X, Tolazzi M, Ochsenbauer C, Saidi H, et al. Microbicide-vaccine combination provides significant protection against vaginal SHIV 162P3 challenge in cynomolgous monkeys. HIV Research for Prevention Conference, Durban, SA, October 2014. Abstract A08.06 LB.

 Google Scholar

Ross TM, Pereira LE, Luckay A, McNicholl JM, García-Lerma JG, Heneine W, Eugene HS, Pierce-Paul BR, Zhang J, Hendry RM, Smith JM. A polyvalent clade B VLP HIV vaccine combined with partially protective Truvada pre-exposure prophylaxis prevents SHIV infection in macaques and primes for virus-amplified immunity. AIDS Res Hum Retroviruses 2014; 30:1072-81; PMID:24914761; http://dx.doi.org/10.1089/aid.2014.0030

 PubMed Web of Science ®Google Scholar