Clinical Challenges in HIVAIDS

ADR-12973; No of Pages 15
Advanced Drug Delivery Reviews xxx (2016) xxxxxx
Contents lists available at ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
1Q1 Clinical challenges in HIV/AIDS: Hints for advancing prevention and

2 patient management strategies
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3Q2 Omar Sued , Mara Ins Figueroa, Pedro Cahn
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4 Fundacin Husped, Clinical Research Department, Buenos Aires, Argentina
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6 a r t i c l e i n f o a b s t r a c t
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Article history: Acquired immune deciency syndrome has been one of the most devastating epidemics of the last century. The 17
8 Received 25 January 2016 current estimate for people living with the HIV is 36.9 million. Today, despite availability of potent and safe drugs 18
9 Received in revised form 8 April 2016 for effective treatment, lifelong therapy is required for preventing HIV re-emergence from a pool of latently 19
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Accepted 16 April 2016
infected cells. However, recent evidence show the importance to expand HIV testing, to offer antiretroviral treat- 20
11 Available online xxxx
ment to all infected individuals, and to ensure retention through all the cascade of care. In addition, circumcision, 21
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27 Keywords:
pre-exposure prophylaxis, and other biomedical tools are now available for included in a comprehensive preven- 22
28 Pre-exposure prophylaxis tive package. Use of all the available tools might allow cutting the HIV transmission in 2030. In this article, we
D 23
29 Microbicides review the status of the epidemic, the latest advances in prevention and treatment, the concept of treatment 24
30 Treatment as prevention as prevention and the challenges and opportunities for the HIV cure agenda. 25
31 26
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HIV cure 2016 Published by Elsevier B.V.
32 Nanotechnology
33 HIV nanoformulations
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38 Contents
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40 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
41 2. Current status of the epidemic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
42 3. HIV pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
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43 4. HIV and viral cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

44 5. Antiretroviral drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
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6. Prevention of HIV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
46 6.1. Behavioral change techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
47 6.2. HIV testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
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48 6.3. Condom provision . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

49 6.4. Male circumcision . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
50 7. ART-based prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
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51 7.1. Perinatal HIV transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

52 7.2. Occupational and non-occupational post-exposure prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
53 7.3. Pre-exposure prophylaxis and microbicides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
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54 8. Treatment update . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
55 9. Treatment as prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
56 10. New challenges and opportunities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
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57 11. Cure prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Abbreviations: AIDS, Acquired immune deciency syndrome; ACTG, AIDS Clinical Trials Group; ART, Antiretroviral therapy; CNS, Central nervous system; CWS, Commercial sex
worker; DNA, Deoxyribonucleic acid; DHHS, Department of Health and Human Services; EACS, European AIDS Clinical Society; EC, Elite controllers; FDA, Food and Drug
Administration; HAART, Highly activity antiretroviral therapy; HDACi, Histone deacetylase Inhibitor; HIV, Human immunodeciency virus; HPV, Human papillomavirus; HSV, Herpes sim-
plex virus; IVDU, Intravenous drug user; LMIC, Low- and middle-income countries; MC, Male circumcision; MSM, Men who have sex with men; NNRTIs, Non-nucleoside reverse transcrip-
tase inhibitors; NP, Nanoparticles; NRTIs, Nucleoside analog reverse transcriptase inhibitors; PAHO, Pan American Health Organization; PEP, Post-exposure prophylaxis; PIs, Protease
inhibitors; PLGA, Poly-lactide-co-glycolide; PrEP, Pre-exposure prophylaxis; PUD, People using drugs; PW, Pregnant women; RNA, Ribonucleic acid; STI, Sexually transmitted infections;
TAF, Tenofovir alafenamide; WHO, World Health Organization.
This review is part of the Advanced Drug Delivery Reviews theme issue on HIV/AIDS_dasNeves_Sarmento_Sosnik.
Corresponding author at: Fundacin Husped, Clinical Research Department, Peluffo 3932, Buenos Aires CP 1202, Argentina.
E-mail addresses: omar.sued@huesped.org.ar (O. Sued), maria.gueroa@huesped.org.ar (M.I. Figueroa), pcahn@huesped.org.ar (P. Cahn).
http://dx.doi.org/10.1016/j.addr.2016.04.016
0169-409X/ 2016 Published by Elsevier B.V.
Please cite this article as: O. Sued, et al., Clinical challenges in HIV/AIDS: Hints for advancing prevention and patient management strategies, Adv.
Drug Deliv. Rev. (2016), http://dx.doi.org/10.1016/j.addr.2016.04.016
2 O. Sued et al. / Advanced Drug Delivery Reviews xxx (2016) xxxxxx
58 11.1. Eradication studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

59 11.2. Gene-based therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
60 11.3. Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
61 12. The place of nanotechnologies in the HIV prevention and treatment: A perspective from the clinical practice . . . . . . . . . . . . . . . . . . . 0
62 13. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
63 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
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65 1. Introduction became the rst country in the world to receive validation from the 118
World Health Organization (WHO) of the elimination of mother-to- 119
66 Acquired immune deciency syndrome (AIDS) is one of the most child transmitted HIV and syphilis and according to the Pan American 120
67 devastating epidemics of the last century. Since its rst description Health Organization (PAHO), 17 others American countries are on the 121
68 35 years ago, the virus has infected more than 75 million people, killed path to achieve this same success [6]. This accelerated progress has 122
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69 over 40 million [1], and caused signicant pain, despair, and family suf- supported and further encouraged the global vision of the elimination 123
70 fering. In addition, fear about HIV has fueled stigma and discrimination of mother to child HIV transmission by 2030. 124
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71 against men who have sex with men (MSM), intravenous drug users However, progress remains is uneven around the globe, and many 125
72 (IVDUs), commercial sex workers (CSWs) and migrants. During the areas require urgent attention. For example, in Eastern Europe and 126
73 rst decades of the epidemic, the complex effects of religion, economy, Central Asia, where HIV rates have been consistently rising since 2001, 127
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74 power, and poor disease understanding have allowed a steady spread of associated with their high rates of drug use [7]. 128
75 HIV until the availability of treatment, the generalization of the preven-
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76 tion efforts, and an unprecedented international response changed
3. HIV pathophysiology 129
77 the course of the epidemic. Now, the prospect of HIV elimination is
78 not seen as impossible.
130
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The typical hallmark of HIV infection is the progressive immunosup-
79 Today, lifelong therapy with antiretrovirals is required for preventing
pression that leads to a spectrum of manifestations such as opportunis- 131
80 HIV re-emergence from latently infected memory CD4+ T cells. Howev-
tic infections and tumors, wasting syndrome and severe central nervous 132
81 er, intense research is being done to look at different strategies to prevent
system (CNS) impairment. Immunosuppression is associated with a 133
82 this re-emergence of viral replication, to provide simplied ways of
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persistent decrease in CD4 T cell count due to several mechanisms in- 134
83 delivering antiretroviral therapy (ART), and ultimately, to eradicate
cluding the increased destruction of infected cells and the loss of non- 135
84 HIV. In this article, we will review the status of the HIV epidemic, the
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infected cells secondary to apoptosis, pyroptosis, and medullar blockage 136
85 latest advances in prevention and treatment, the concept of treatment
[8,9]. In addition to CD4 T cell depletion, other mechanisms help to 137
86 as prevention (TaSP), and the challenges and opportunities surrounding
explain the pathological features of HIV infection including immune 138
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87 the HIV cure agenda.

activation [10,11] and metabolic alteration induced by the virus [12]. 139
The rate of CD4 loss is inversely proportional to the increase of viral 140
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load and both parameters determine the individual's risk of clinical pro- 141
88 2. Current status of the epidemic
gression and death. CD4 count at baseline will determine short-term 142
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risk, likely disease manifestations, and the potential degree of immuno- 143
89 The current global estimate for people living with the HIV is 36.9
logical recovery after treatment initiation. 144
90 million [2] and the predominant mode of transmission is sexual. Two
Occasionally (1%), some patients may spontaneously control viral 145
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91 broad epidemiological patterns have been identied. The rst are

load at undetectable levels in the absence of treatment [13]. These 146
92 generalized epidemics, dened as a prevalence greater than 1% in
patients, called elite controllers (ECs), do not demonstrate the typical 147
93 pregnant women attending antenatal clinics, where heterosexual sex
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clinical progression course and are able to maintain high CD4 counts 148
94 is the major mode of transmission. The second are concentrated
for several years without treatment. Many studies have been performed 149
95 epidemics where HIV spreads in specic populations such as men
to try to explain the special characteristics of these patients but without 150
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96 having sex with men (MSM) or commercial sex workers (CSW) that
denitive conclusions. Research has shown that ECs have better innate 151
97 have prevalence rates over 5%, but with rates less than 1% in the general
CD8 T cell suppressive activity [14,15], more frequency of heterozygous 152
98 population [3]. However, these denitions must be interpreted with
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status for mutation on the chemokine co-receptors on their HIV target 153
99 caution. The label generalized epidemic usually neglects the occur-
cells (CCR5-32 allele), more frequent protective HLA alleles (HLA-B27 154
100 rence of concentrated epidemics within the same population, with a
and -B57) or proven infection with an attenuated virus [16]. Even with 155
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101 consequent underestimation of the need for targeted interventions in

no viral replication detected by standard methodologies, ECs have higher 156
102 the higher risk groups [4]. During 2014, there were 2 million of new
levels of inammation and immune activation than HIV-negative indi- 157
103 HIV infections and 1.2 million of deaths [2]. Although these gures
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viduals, and some cohort studies suggest a worse clinical outcome 158
104 represent an unacceptable burden of infection, they also highlight a
[17,18]. Based on these ndings, some experts advocate the treatment 159
105 signicant reduction compared with the 3.4 million new infections
of these individuals in spite of having an undetectable viral load. 160
106 seen in 2001 and the 2.4 million deaths during 2005. It is estimated
107 that between 1990 and 2013, 19 million life years were saved by HIV
108 prevention and treatment programs [5]. 4. HIV and viral cycle 161
109 The implementation of the Millennium Development Goals and
110 their commitment to tackling HIV has been crucial in managing an epi- HIV is a Lentivirus belonging to the Orthoretroviridae subfamily and 162
111 demic that is having devastating effects worldwide. The number of peo- Retroviridae family, two linear RNA molecules that replicate by 163
112 ple receiving ART increased from 200,000 people in the year 2000 to retrotranscription form the genome. The viral core consists of a protein 164
113 more than 15 million in 2015, illustrating one of the biggest public capsid, two linear RNA molecules ,and three enzymes called reverse 165
114 health achievements of the last century. One of the most successful transcriptase, integrase, and protease. The virus is a spherical particle 166
115 stories is the control of vertical transmission. The mother-to-child HIV surrounded by a lipid envelope with spikes, each made of an external 167
116 transmission prevention program has reduced the number of new in- glycoprotein gp120 and a transmembrane glycoprotein gp41 needed 168
117 fections in children by 58% between 2000 and 2014 [2]. In 2015, Cuba for cell entry. The HIV genome consists of three structural genes 169
O. Sued et al. / Advanced Drug Delivery Reviews xxx (2016) xxxxxx 3
170 common to all the retrovirus (gag, pol and env) and six other regulatory At a cellular level, HIV entry involves interaction between gp120 and 186
171 genes (Tat, Rev., Nef, Vif, Vpr, Vpx, and Vpu) [19]. The R5 strain of HIV has the CD4 receptor. This produces conformational changes that then favor 187
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172 an afnity for the CCR5 receptor and is the predominant type of HIV at the exposure of the V3 domain. These changes allow the interaction be- 188
173 early phase of infection as opposed to the X4 strain that is generally tween gp120 and the natural chemokine receptors CCR5 and CXCR4 for 189
174 seen later in the course of HIV disease [20,21]. HIV anchorage and entry into the host cell [25]. After entry into the host 190
175 Establishment of infection involves a series of steps. Initially, the cell, the virus penetrates the host cell nucleus in activated cells or can 191
176 virus needs to overcome the mucosal barrier at the site of exposure in persist in latent status in the cytoplasm [26]. Once in the nucleus, the re- 192
177 order to make contact with cells that will sustain replication [22]. Ero- verse transcriptase enzyme transcribes the HIV-RNA to form two DNA 193
178 sions, ulcers, co-infections, or hormonal changes may alter the integrity molecules called proviral DNA that are then integrated into the host 194
179 of the mucosa and facilitate infection. Once in the epithelium, the virus DNA by the integrase enzyme. Due to the reverse transcriptase lack of 195
180 infects CD4 lymphocytes, Langerhans cells, or submucosal dendritic proof-reading capacity, different mutants or variants will be produced 196
181 cells, which imposes a bottleneck that explains the homogeneity of in each cycle of replication. Integrated DNA is the blueprint for making 197
182 the viral population during acute HIV infection [23]. After 4872 h, the messenger RNAs that are transported outside of the nucleus to form 198
183 virus reaches the regional lymph nodes, where it is exposed to other new viral particles. During assembly, protease cuts long strands of 199
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184 lymphocytes, resulting in high levels of replication that allows the proteins into pieces in order to construct new viral cores that will 200
185 virus to spread to all tissues [24]. then mature and be released by budding from the surface to infect 201
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Fig. 1. Viral cycle of HIV. Some steps of this cycle are target of antiretroviral therapy, namely, enfuvirtide blocks step 1, maraviroc and fostemsavir blocks steps 2, NRTI and NNRTI block step
3, integrase inhibitors block step 4, protease inhibitors blocks step 6, and maturation inhibitors block step 7. (Illustration from NIAID collection used under a creative commons license.)
t1:1 Table 1
t1:2 FDA-approved antiretroviral drugs currently in use (for more information see DHHS HIV guidleines) [32].
t1:3 Drug Mechanisms of action Characteristics Side effects
t1:4 NRTIs/NtRTIs: (nucleotide reverse transcriptase inhibitor)

t1:5 AZT: zidovudine NRTI's compete with host nucleotides to serve as the Long half-life AZT: Nausea, headache, lactic
t1:6 300 mg BID substrate for reverse transcriptase chain elongation. Viral Little food effect acidosis, anemia, peripheral
t1:7 DNA chain elongation is aborted and viral replication Good penetration CNS neuropathy, pancreatitis,
t1:8 3TC: lamivudine ceases. Backbone based on two NRTI for HAART design lipodystrophy
t1:9 150 mg BID or 300 mg OD All NRTIs require sequential phosphorylation to the Limited drugdrug interactions TDF: nephrotoxicity, Fanconi's
t1:10 triphosphate form to become active, with the exception of High toxicity of older NRTI limited the current syndrome, bone mineralization
t1:11 ABC: abacavir tenofovir that only requires diphosphorylation. use to the combinations of ABC or TDF disorders
t1:12 300 mg BID or 600 mg OD Individual and cross resistance can occur by specic associated to 3TC or FTC, respectively. ABC: hypersensitive reaction, that
t1:13 mutations ABC requires screening for HLAB*5701 can be severe or fatal, more
t1:14 FTC: emtricitabine previous their use. frequent in individuals carrying
t1:15 200 mg OD NRTI sparing regimens or regimens using only HLAB*5701 allele.
t1:16 3TC or FTC are being investigated for reducing
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t1:17 TDF: tenofovir pill burden, cost and toxicity.
t1:18 300 mg OD
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t1:19
t1:20 NNRTIs (non-nucleoside reverse transcriptase inhibitors)
t1:21 EFV: efavirenz NNRTIs inhibit the HIV reverse transcriptase by binding a Not active against HIV-2 NVP: severe hypersensitivity
t1:22 600 mg OD hydrophobic pocket close to the active site. Specic Metabolized by CYP3A4 isoenzyme of the reaction, with skin and hepatic
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t1:23 mutations produce changes in the pocket structure. ETV hepatic cytochrome p450 system. Potent involvement, occasionally fatal.
t1:24 NVP: nevirapine and RPV are exible molecules that can maintain activity inducers or inhibitors of CYP3A4. Potential for StevensJohnson
t1:25 200 mg OD (requires a 200 dosis against resistant variants. major drug interactions syndrome
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t1:26 during the rst 2 weeks) NNRTIs have low genetic barrier and potential cross EFV plus 2 NRTI is the most used ART in LMICs EFV: Rash, neurocognitive
t1:27 resistance. impairment, neuropsychiatric
t1:28 ETR: etravirine effects
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t1:29 200 mg BIS ETV and RPV rash and less
t1:30 neurocognitive effects.
t1:31 RPV: rilpivirine
t1:32 50 mg OD D
t1:33
t1:34 PIs (protease inhibitors) limited to atazanavir, lopinavir and darunavir that are the PIs currently in use.
t1:35 DRV: darunavir Inhibit HIV protease by binding to its active site, Metabolized by the CYP3A4 isoenzyme of the Gastrointestinal disturbances,
t1:36 600 mg +100 mg of ritonavir preventing the cleavage of gag and gag-pol precursor hepatic p450 system. diarrhea.
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t1:37 BID for experienced patients proteins. Ritonavir is one of the most potent CYP3A4 Lipodystrophy, insulin resistance
t1:38 inhibitors and it is required for boosting and dyslipidemia that are more
t1:39 800 mg + 100 mg of ritonavir New PI have are less susceptible to cross resistance. other PIs to therapeutic levels. frequent with LPV than DRV or
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t1:40 OD for nave patients Recently, cobicistat 150 mg OD has been ATV.
t1:41 High genetic barrier. introduced as a boosting alternative to aterosclerosis
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t1:42 ATZ: atazanavir ritonavir 100 mg.

t1:43 300 mg +100 mg of ritonavir Homology with some proteins involved in the Less frequently: hepatotoxicity,
t1:44 OD lipid metabolism might contribute to some nausea, vomiting, rash or
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t1:45 adverse effects. headache

t1:46 In selected patients 400 mg OD
t1:47 without ritonavir can be used
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t1:48
t1:49 LPV: Lopinavir
t1:50 400 mg + 100 mg of ritonavir
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BID
t1:51
t1:52 Entry inhibitors (this include maravicoc, a chemokine receptor antagonists and enfuvirtide, a fusion inhibitor)
t1:53 MVC: Maraviroc MVC is a CCR5 antagonist that prevents entry by Usually is used in salvage therapy and is expose No signicant toxicity was
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t1:54 300 mg BID, with ritonavir binding to the chemokine coreceptor on the host to signicant drug interactions. reported with MVC. In clinical
t1:55 reduce dose to 150 mg BID, with CD4+ cell chemokine, therefore the efcacy is limited The virus requires viral tropism assay showing trials 20% of upper tract infections
t1:56 EFV or rifampim increase dose to R5 virus only. R5 virus. was reported.
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t1:57 to 600 mg BID Does not induce resistance but tropism switch
might emerge.
t1:58 ENF ENF binds to gp41 envelope glycoprotein preventing the Only available as injectable form, therefore Injection-site reactions
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t1:59 Enfuvirtide formation of an entry pore in the viral capside. limited to salvage therapy or when other Hypersensitivity
t1:60 90 mg SC BID options are not possible to be used. Clinical trials showed an increased
risk of bacterial pneumonia
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t1:61
t1:62 INSTIs (integrase strand transfer inhibitors)
t1:63 RAL Inhibits DNA strand transfer into host-cell genome and Very potent drug family, in vitro and in vivo Very safe family of drugs.
t1:64 Raltegravir thus prevents viral integration. DTG and RAL proved to be superior to the RAL: Some cases of myopathy and
t1:65 400 mg BID RAL and EVG have lower genetic barrier, resistance classical EFV-based regimen rhabdomyolysis
t1:66 emergence has been documented in failing patient. DTG was superior to DRV/r DTG: can increase depression
t1:67 EVG Cross resistance can compromise DTG efcacy.
t1:68 Elvitegravir 150 mg + 150 mg Cobicistat is an inhibitor of the p450 system,
t1:69 of cobicistat as booster important drugdrug interactions are expected.
t1:70
t1:71 DTG DTG increase the levels of metformin.
t1:72 Dolutegravir
t1:73 50 mg OD
t1:74 50 mg BID for patients failing to
t1:75 RAL or EVG
202 other cells and begin the replication process all over again [27] (Fig. 1). package that follows social justice and human rights principles is re- 254
203 Antiviral drugs target many steps of this replication cycle including quired. This must then be tailored to the needs of different high-risk 255
204 fusion, entry, retrotranscription, integration, budding, and maturation. populations to ensure their meaningful participation in design and im- 256
plementation alongside considering the multiple layers of risks to 257
205 5. Antiretroviral drugs which an individual might be exposed [34]. The objective of community 258
participation is to allow people at risk to exert more control over their 259
206 Many discoveries have shaped the course of HIV management and ability to prevent HIV. Examples of individual interventions that are 260
207 the development of ART. Examples include the understanding of the considered to be more effective in combined packages include commu- 261
208 mitochondrial toxicity mechanism related to thymidine nucleosides nity empowerment and mobilization; advocacy, housing, and economic 262
209 that prompted the phasing-out of zalcitabine, stavudine, and didanosine strengthening programs; legal and protection services; voluntary test- 263
210 due to lactic acidosis and lipodystrophy [28] and the identication ing and linkage; condom distribution programs; health friendly services; 264
211 of specic pharmacogenomics hallmarks associated with abacavir, harm reduction programs; and behavior change driven by peers. Accord- 265
212 efavirenz, and nevirapine toxicities [29]. Others include the identica- ing to one mathematical model, a combined prevention program that 266
213 tion of the metabolic impact of early protease inhibitors (PI) that result- includes HIV testing, early ART, male circumcision, and the use of 267
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214 ed in the discovery of new PIs with better pharmacokinetic and safety microbicides and pre-exposure prophylaxis (PrEP) can avoid 62% of 268
215 proles [30] and the discovery of the new family of integrase inhibitors new HIV infections, while programs including only HIV screening and 269
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216 that demonstrate superiority to current drugs [31]. In addition, the early ART would reduce infections by just 34% [35]. One of the main con- 270
217 co-formulation of three drugs as a single pill to be taken once daily was siderations when designing public health interventions is cost. Although 271
218 critical in the scaling up of treatment program in developing countries. no formal cost-effectiveness analysis of combined prevention were 272
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219 Currently, the US FDA has approved 26 medicines as single ARV made, a review of a number of studies of single interventions of various 273
220 agents that can be grouped into six drug families according to their natures (behavioral, biomedical, and structural interventions) showed 274
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221 mechanism of action. Many of these drugs are now not being used in that all are cost-effective compared to the cost of the disease [36]. 275
222 clinical practice due to the availability of safer and more potent drugs.
223 The six drug families include nucleoside and nucleotide analog reverse 6.1. Behavioral change techniques 276
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224 transcriptase inhibitors (the most commonly used are abacavir,
225 emtricitabine, lamivudine, tenofovir, and recently the tenofovir pro- Individual behavioral change techniques, including the delivery of 277
226 drug tenofovir alafenamide or TAF), non-nucleoside reverse transcrip- preventative information and communication contents, have been
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227 tase inhibitors (efavirenz, rilpivirine, etravirine), protease inhibitors used since the identication of the transmission routes and proved to 279
228 (darunavir and atazanavir while lopinavir/ritonavir is the most used be effective [37,38]. The aim is to reduce the exposure to and acquisition 280
229 PI in low-to-middle income countries (LMICs)), fusion inhibitors of HIV in general terms, with some techniques including specic 281
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230 (enfuvirtide), integrase inhibitors (raltegravir, dolutegravir, and content, such as motivational interviewing [39], eroticization of safer 282
231 elvitegravir), and entry inhibitors (maraviroc). A booster needs to be sex [40], and promotion of sports [41]. Usually, most interventions are 283
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232 used with darunavir, atazanavir, and elvitegravir, namely, a low dose effective; therefore, the discussion is about whom to target, and for 284
233 of ritonavir or more recently cobicistat. A number of compounds are how long. Behavioral change intervention is usually recommended for 285
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234 in Phase II/III studies (doravirine, fostemsavir, BMS-955176, ibalizumab, specic populations at risk such as adolescents, MSM, CSW, intravenous 286
235 and cabotegravir, among others) [32]. Table 1 shows a list of the drug users (IVDU), and prisoners. Even single interventions may reduce 287
236 approved antiretroviral agents, their properties, and main associated the risk of acquiring HIV among high-risk populations up to 30% [42]. 288
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237 adverse effects.

238 Due to the current impossibility of eradicating HIV infection, the 6.2. HIV testing 289
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239 objectives of antiviral treatment remain the same as those dened at

240 the beginning of the epidemic: full suppression of viral load for improv- HIV serostatus knowledge via HIV testing is the gateway to HIV pre- 290
241 ing the immune function, the constant improvement of quality of care, vention and treatment. Technological advances have created the oppor- 291
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242 and the reduction of the morbidity and mortality [32]. Consistent viral tunity for expanding testing at a global level. Testing also provides 292
243 suppression results in both, fewer drug-resistant viral variants, and opportunities for preventative interventions, including behavioral 293
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244 prevents HIV transmission. Viral failure and resistance may occur sec- change interventions, risk reduction counseling, condom provision, 294
245 ondary to poor adherence, drug interactions, absorption problems, and linkage to care and treatment services for infected individuals. Test- 295
246 and selection of pre-existing mutations due to sub-optimal drug levels, ing also allows positive individuals to reduce onward transmission, as 296
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247 all reinforcing the need to focus on achieving high rates of retention, infected individuals use condoms more frequently and reduce their 297
248 adherence, and viral suppression at a population level [33]. number of sexual partners [43]. In the US, where 80% of HIV-infected in- 298
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dividuals are aware of their status, 49% of transmission comes from the 299
249 6. Prevention of HIV 20% of HIV-infected persons who are unaware of their infection. For 300
every 100 people newly diagnosed, 8 infections could be averted, and 301
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250 High local prevalence favors HIV transmission which is then condi- this number increases according to the level of viral suppression [44]. 302
251 tioned by individual behaviors and inuenced by structural factors In another mathematical model, annual screening of all adults 303
252 such as public policies and network and community characteristics combined with universal access to ART would virtually eliminate HIV 304
253 [34]. When planning for HIV prevention, a combined intervention transmission by 2050 [45]. This huge increase in the volume of HIV testing 305
t0:1 Notes to Table 1:

t0:2 Available combinations
t0:3 AZT/3TC (Combivir)
t0:4 ABC/3TC (Epzicom)
t0:5 AZT/ABC/3TC (Trizivir)
t0:6 TDF/FTC (Truvada)
t0:7 ABC/3TC/DTG (Triumeq)
t0:8 Emtricitabine/tenofovir/efavirenz (Atripla)
t0:9 Emtricitabine/tenofovir/rilpivirine (Complera)
t0:10 Emtricitabine/tenofovir/elvitegravir/cobicistat (Stribild)
306 could only be achieved by expanding testing through not mandatory improve the quality and accessibility of services, particularly for the 365
307 policies that promote universal screening by periodically targeting key most vulnerable populations. For example, in LMICs, nearly half of all 366
308 populations and paying careful consideration to the barriers to testing. HIV-positive PW may not be receiving any intervention and remain at 367
309 Barriers usually include cost, discrimination by health care workers, risk for disease progression and HIV transmission to their unborn 368
310 poor HIV testing accessibility, limited services availability (hours and children [1]. In 2013, the WHO made an unprecedented change by 369
311 days), and poor linkage to HIV care services [46]. Further approaches recommending: a) treat all PW, b) treat all with the same rst-line reg- 370
312 should include, among others, the discussion of rapid testing able to imen used for nonpregnant adults (once-daily tenofovir/efavirenz/ 371
313 detect acute HIV infection, the provision of partner notication services, emtracitabine), and c) do not stop ART after delivery, even in those 372
314 and the promotion of self-testing strategies with oral uid kits, etc. [47]. with high CD4 counts [61]. 373
315 6.3. Condom provision 7.2. Occupational and non-occupational post-exposure prophylaxis 374
316 The use of condoms is a pivotal strategy to reduce exposure to HIV. Post-exposure prophylaxis (PEP) to protect HIV-negative individ- 375
317 Condom programs increase their use and decreases rates of sexually uals is a recognized intervention although the evidence supporting its 376
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318 transmitted infections (STIs), unwanted pregnancies, and HIV acquisi- efcacy is limited. Traditionally, the term occupational was reserved 377
319 tion [48]. Evidence shows that interventions that increase accessibility for health care workers exposed during medical procedures while 378
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320 to condoms through structural, individual, and community interven- non-occupational pertained to sexual exposures. The clinical evidence 379
321 tions are efcacious in increasing condom use [49]. Communication is evaluating the efcacy of PEP in humans is scarce and future random- 380
322 important for the increased use of condoms. Effective communication ized research is limited due to ethical reasons. A retrospective case 381
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323 strategies should be more focused on the need and the benets of in- study among individuals exposed to HIV documented an 81% reduction 382
324 creased condom use instead of dealing with the sexual history of indi- in HIV acquisition associated with the use of zidovudine monotherapy 383
325 viduals or discussing about what safer sex means [50,51]. In Thailand, [62]. A meta-analysis of 18 studies in primates found the risk of HIV se- 384
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326 the 100% campaign, where condoms were provided along a compre- roconversion to be 89% lower in animals exposed to PEP compared with 385
327 hensive program including education, availability surveys, training on those that did not receive it. Based on these ndings, current recom- 386
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328 how to use condoms, STI tracing, and direct surveillance in brothels, mendations state that individuals reporting an exposure to blood or 387
329 was one of the most successful examples of how structural interven- body uids from a potentially HIV-infected source should receive a 388
330 tions that include condom provision can reduce HIV incidence [49,52]. 28-day course of ART as prophylaxis against HIV infection. Careful
D 389
331 An adaptation of this campaign was also very effective also among sex follow-up is recommended as occasional cases of seroconversion in 390
332 workers in the Dominican Republic [53]. However, condom acceptance spite of prophylaxis were reported for both occupational [63] and 391
333 and use can change in different contexts or populations such as bisexual non-occupational [64] HIV exposures. Tolerance and adherence are 392
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334 men and PUD [54], demonstrated by the low gure of only 16% consis- the most important limitations; therefore, developed countries are 393
335 tent condom use in MSM in the US. Therefore, continued and innovative recommending the use of new regimens such as raltegravir + tenofovir 394
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336 efforts need to be implemented to increase condoms use [55]. + emtricitabine or a single-pill regimen based on rilpivirine plus 395
tenofovir and emtricitabine to ameliorate those limitations [65]. A chal- 396
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337 6.4. Male circumcision lenge is that some health care providers feel uncomfortable providing 397
the full package of services recommended to individuals exposed to 398
338 Randomized clinical trials in Kenya, South Africa, and Uganda have HIV. In New York, according to local guidelines, doctors should docu- 399
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339 shown that medical male circumcision (MC) reduces the risk of ment follow-up and offer STI screening, risk reduction counseling, edu- 400
340 female-to-male HIV transmission by up to 60% and that this protection cation about the symptoms of acute HIV seroconversion, and effective 401
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341 persists for long periods [56,57]. Circumcision has the potential to also linkage to services. However, these practices were performed inconsis- 402
342 prevent other infections such as herpes, human papilloma virus tently and only 22% of doctors documented linkage to HIV services [66]. 403
343 (HPV), and Mycoplasma, alongside some types of cancer [58]. A growing
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344 number of countries in Africa have adopted large-scale MC campaigns 7.3. Pre-exposure prophylaxis and microbicides 404
345 with the support of the WHO other and international agencies. Adop-
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346 tion of MC requires educating millions of men and women about its pro- Pre-exposure prophylaxis (PrEP) refers to the use of ART in HIV-neg- 405
347 tective benets, delivering prevention information and preventing risk ative individuals to prevent HIV infection. In the absence of an effective 406
348 compensation. To maximize the benets of this prevention strategy, it vaccine, PrEP may play a signicant role in HIV prevention programs for 407
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349 should be recommended for high prevalence settings where men of HIV-negative people at high risk of infection [67]. Daily oral PrEP with 408
350 all ages are offered medical male circumcision. The benets of MC in set- emtricitabinetenofovir effectively prevented HIV transmission in sev- 409
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351 tings with concentrated epidemics and high ART coverage are unknown eral phase III large randomized clinical trials with varied efcacy [68]. 410
352 and controversial [59,60]. In the rst published study involving MSM, PrEP reduced HIV transmis- 411
sion by 44% overall, although protection increased to 92% in those who 412
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353 7. ART-based prevention took their medications regularly [69]. In the Partners in PrEP Study, in- 413
volving heterosexual serodiscordant couples, the administration of 414
354 7.1. Perinatal HIV transmission tenofovir or tenofovir + emtricitabine was associated with 67% and 415
75% risk reduction in male and female individuals, respectively [70]. 416
355 Since the identication of the benet of ART in preventing HIV Similarly, the TDF2 study [71] showed that tenofovir + emtricitabine 417
356 among infected pregnant women (PW), substantial success has been had a 62% efcacy in preventing HIV infection, although highlighted 418
357 achieved in ensuring access to ART among PW living with HIV. In the logistical difculties of sustaining enrolment and follow-up as well 419
358 2014, in 21 high-priority countries, 77% of HIV-positive PW received as the potential risk of adverse events. An alternative dosing schedule 420
359 ART and the rate of vertical transmission in these countries has halved was proposed and its efcacy was validated in a fully powered random- 421
360 from 28% in 2009 to 14% in 2014 [1]. Mother-to-child programs are a ized clinical trial: in MSM, PrEP taken before and after sexual encounters 422
361 quality marker for maternal and child health care services, and an op- (on demand) instead of daily showed an 86% efcacy in reducing HIV 423
362 portunity for expanding and combining with other public health strate- acquisition [72]. In IVDU, PrEP showed a 49% efcacy [73]. In contrast, 424
363 gies, such as syphilis or hepatitis B perinatal control programs. However, two studies looking at PrEP use in women showed no efcacy. In the 425
364 in spite of the above-mentioned achievements, there is still room to FEM-PrEP study in sub-Saharan Africa, the use of PrEP was ineffective 426
427 and had to be prematurely stopped. Less than 40% of the women were The initial development of the vaginal microbicides prompted the 493
428 actually taken medication according to the registries at the time of sero- development rectal microbicides which demonstrated to be challenging 494
429 conversion [74]. Similarly, in the VOICE study [75], which involved over due to the higher volume required to cover the rectal mucosa and 495
430 5000 women randomized to different treatment arms (oral placebo, provide protection [86]. The NIH in a phase II trial (MTN-017 trial) is cur- 496
431 oral tenofovir alone, oral tenofovir with emtricitabine, vaginal placebo rently exploring a tenofovir-based formulation but more options need to 497
432 gel and vaginal tenofovir gel), no efcacy could be found. This was at- be urgently developed, for the protection of both, men and women. 498
433 tributed to the fact that participants were not taking the drugs as indi-
434 cated, supported by evidence that only 30% of the blood samples had 8. Treatment update 499
435 detectable drug levels, although more than 80% of individuals reported
436 good adherence in computerized forms. Fear of adverse events, stigma, ART use started in 1987 when zidovudine showed a transitory im- 500
437 and being falsely labeled as HIV positive were factors that limited adher- provement in life expectancy and incidence of AIDS. Initial treatments 501
438 ence and thus need to be considered if implementing this program for based on mono or bi-therapy quickly showed emergence of resistance 502
439 women in the future [75]. Some of these limitations could be overcome due to the inability of effectively suppressing viral load. In 1996, the 503
440 by the use of topical microbicides. One study in Africa showed that 1% HIV eld was revolutionized with the introduction of highly activity an- 504
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441 tenofovir vaginal gel was associated with a 39% decrease in HIV tiretroviral therapy (HAART). For the rst time, three drug regimens, 505
442 incidence, which could increase to 54% in women with high adherence. based on 2 nucleoside analogues inhibitors of the reverse transcriptase 506
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443 Although several studies are underway, none are currently in the late enzyme plus a protease inhibitor or a non-nucleoside reverse transcrip- 507
444 phases of clinical development [76]. tase inhibitor, demonstrated a sustained efcacy, capability of achieving 508
445 Several factors, such as budget limitations, fear of resistance or risk a prolonged viral suppression, and drastically reduced both morbidity 509
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446 compensation, and programmatic challenges, including model of and mortality [87,88]. This prompted the recommendation for expand- 510
447 service provision have delayed the uptake of PrEP by National HIV ed treatment access based on the concept hit hard, hit early [89]. Over 511
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448 Programs. Resistance risk was a common topic [77], but studies have the next few years, the signicant challenges of inconvenient schedules, 512
449 demonstrated that although this is a possible phenomenon, it is not a high pill burden, low potency, pharmacokinetic interactions, and signif- 513
450 frequent situation [78]. Financial investment in PrEP is considered as icant early and long term toxicity were demonstrated. In 2001, a more 514
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451 cost-effective, although it is recognized that nal cost will depend on conservative approach was implemented, limiting treatment to those 515
452 local drug costs, the epidemic context, program coverage, prioritization with advanced disease and even exploring the option of stopping 516
453 strategies, and individual adherence [79]. PrEP is now a recommended therapy during variable periods of time called treatment holidays.
D 517
454 intervention by the International AIDS Society-USA (IAS-USA) guide- Contrary to its initial hypothesis, the SMART study demonstrated the 518
455 lines panel and is endorsed by the European AIDS Clinical Society negative effects of stopping ART which included a higher risk of 519
456 (EACS) guidelines. The Food and Drug Administration (FDA) approved developing AIDS-related conditions and other comorbidities [90]. 520
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457 its use in high-risk individuals in 2012, the WHO recommended its The most recent recommended combination regimens for 521
458 use for MSM in 2014 and recently broadened their recommendation treatment-naive patients vary according to the guideline used. The 522
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459 to include all population groups at substantial risk of HIV infection (inci- guideline from the US Department of Health and Human Services 523
460 dence 3 per 100 person-years) [80]. The WHO also states that PrEP (DHHS) recommends that two NRTIs (tenofovir + emtricitabine or 524
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461 should be an additional prevention strategy within a comprehensive abacavir + lamivudine) should be used with darunavir/ritonavir or 525
462 package of services that also includes HIV testing, counselling, male dolutegravir or elvitegravir or raltegravir [32]. European guidelines are 526
463 and female condoms, lubricants, ART for positive individuals, voluntary similar but include rilpivirine as an option for patients with a viral 527
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464 medical male circumcision, and risk reduction interventions for drug load less than 100,000 copies/mL [91]. Therefore, atazanavir/ritonavir 528
465 users [81]. and efavirenz were downgraded from preferred agent to alternative 529
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466 Microbicides are compounds intended to be applied inside the vagi- agents. The WHO continues recommending tenofovir + emtricitabine 530
467 na and/or rectum to protect against sexually transmitted infections plus efavirenz but is starting to consider dolutegravir as a conditional 531
468 (STIs), including HIV. They are usually formulated as gels, creams, agent [81]. 532
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469 lms, or suppositories and represent an alternative method of HIV pre- Lately, the three drugs paradigm as synonymous with HAART has 533
470 vention [76]. Most research is focused on vaginal microbicides, since been challenged. The GARDEL study is a full-powered study that dem- 534
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471 women account for over 50% of new HIV infections. Women suffer a onstrates the non-inferiority of dual therapy vs standard triple therapy 535
472 particular burden of HIV risk, especially young women. Pervasive social, [92], and other dual combinations are being explored for nave [93] as 536
473 legal, and economic barriers reduce the ability of women to protect well as for virologically suppressed individuals [9496]. A note of 537
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474 themselves from HIV infection and microbicides might help improve caution should be sounded about dual combinations that failed to dem- 538
475 this ability [82].The CAPRISA004 study assessed the efcacy of 1% onstrate non-inferiority, such as the use of darunavir/ritonavir and 539
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476 Tenofovir vaginal gel in a coitally dependent dosing scheme in raltegravir in patients with viral load of more than 100.000 copies/mL 540
477 preventing HIV in South Africa. After 18 months of use, a 39% overall re- or a CD4 count of less than 200 cells/mm3 [97,98]. 541
478 duction of HIV acquisition was demonstrated, increasing to 54% in high-
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479 ly adherent women [83]. The VOICE trial was a ve-arm study 9. Treatment as prevention 542
480 comparing daily tenofovir gel or tablets with or without emtricitabine
481 that assessed efcacy of preventing HIV. The study was stopped due to The preventative benets of ART were rst documented in the ACTG 543
482 futility due to a low rate of adherence [75]. Recently, a vaginal ring load- 076 trial which showed that zidovudine given to HIV-positive PW re- 544
483 ed with dapivirine was tested in 2629 women between the ages of 18 duced vertical transmission from 22.6% to 7.6% [99]. Recently, several 545
484 and 45 years in Malawi, South Africa, Uganda, and Zimbabwe demon- studies have demonstrated the efcacy of HIV treatment in preventing 546
485 strating a modest reduction in HIV acquisition (27%), being this result HIV transmission, which is almost eliminated when patients achieve 547
486 attributable to low adherence [84]. Advantages of topical prophylaxis an undetectable viral load [100102]. At a community level, several 548
487 include avoiding the need of systemic administration, reduced cost, ad- studies in Canada [103], China [104], and South Africa [105] have 549
488 verse effect, and the potential of HIV resistance in individuals unaware shown that expansion of treatment programs are associated with a re- 550
489 of their HIV status. However, microbicides also have limitations, such duced incidence of new HIV infections. This evidence is the basis of 551
490 as unknown or limited protection to other routes of infection (i.e. anal the formulation of the treatment as prevention (TaSP) strategy, 552
491 sex in women using vaginal microbicides) and unpredictable pharma- where the expanded identication and treatment of infected individ- 553
492 cokinetics in different individuals [76,85]. uals reduces the community viral load hence the risk of HIV acquisition 554
555 to levels that might achieve epidemic elimination [106,107]. Achieving the histone deacetylation in silencing proviral gene expression and the 616
556 population-level control through TaSP is a feasible option, but one that availability of histone deacetylase Inhibitors (HDACi) reinvigorated 617
557 will require considerable investment of resources and changes in the research focused on additive interventions to ART for awaking the 618
558 service delivery models to allow for expansion of HIV testing, better virus from latently infected cells. The objective was to allow the im- 619
559 linkage to care systems, accessible ART, and adequate retention of care mune system to detect and kill infected replicative cells or triggering 620
560 [108]. Appropriate investment in monitoring systems will be required virus-induced apoptosis, a mechanism that was later named shock 621
561 to trace engagement, alongside specic support to improve ART adher- and kill [125]. Valproic acid was the rst HDACi tested. In the initial 622
562 ence, prevent virologic failure, and prevent of follow-up. Specic study, ART in HIV suppressed patients was intensied with enfuvirtide 623
563 vulnerable populations, such as drug users, homeless, unemployed, or and valproic acid was added during 3 months. Patients showed a mod- 624
564 mentally ill patients will require additional efforts to facilitate retention erate decrease in the resting CD4 T cells harboring proviruses, generat- 625
565 in care [109]. ing exciting discussions, and opening the road to other studies [126]. 626
Although vorinostat succeeded in increasing viral transcription, this 627
566 10. New challenges and opportunities strategy was unsuccessful in reducing integrated DNA [116], further 628
studies could not replicate the results and the search for more potent 629
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567 As there is no cure for HIV infection, lifelong ART is required to allow drugs continued [127,128]. Vorinostat is the most studied HDACi. A sin- 630
568 HIV-infected individuals to lead healthy lives. Currently available drugs gle dose of this agent induced cell-associated HIV-1 Gag RNA, a marker 631
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569 ensure safe long-term treatment for the majority of patients and new of reactivation without activating T cells but these effects were reduced 632
570 drugs are in the pipeline, many in the late stages of development with with multiple doses [129]. Subsequent studies involving more potent 633
571 potential for use in both treatment-experienced and treatment-naive HDACi were published, including romidepsin [130] and panobinostat 634
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572 populations. Current focus of research involves drugs with a higher safe- [131], which, while achieving more reactivation, failed to show elimina- 635
573 ty prole that can be used once daily and are easy to co-formulate. Drugs tion of infected cells, highlighting the need for combined approaches 636
574 that can be dosed on a less than daily basis are also being investigated. [132]. Other latency-reversing agents such as bryostatin derivatives 637
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575 Doravirine is a new non-nucleoside reverse transcriptase inhibitor, cur- [133] are also to be included in pilot studies, alone or combined with in- 638
576 rently in phase III trials as part of a two or three drug co-formulation. terventions targeted to improve cytotoxic responses [134,135], improve 639
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577 Long-acting dual-drug injectable regimens as maintenance therapy are innate immunity or neutralizing antibodies production [136,137] 640
578 also being investigated as potential additions to the HIV armamentarium, through vaccines [113], citoquines such as IL7 or IL15 [138,139] or 641
579 for example, cabotegravir (in oral and long-acting injection formula- immunomodulators such as anti PD-1 [140].
D 642
580 tions), and long-acting rilpivirine. Fostemsavir, an attachment inhibitor,
581 and BMS-955176, a maturation inhibitor, are drugs that have also 11.2. Gene-based therapy 643
582 shown encouraging preliminary results [110].
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The Berlin patient also heightened interest into gene therapy that 644
583 11. Cure prospects aims to disrupt the CCR5 coding sequence in T cells ex vivo, and expand 645
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and re-infuse into patients to reduce the pool of target cells susceptible 646
584 11.1. Eradication studies to infection. The feasibility of this strategy was demonstrated by a small 647
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study using zinc-nger nucleases that bind to a target site within the 648
585 The rst case of cure documented in 2009 named the Berlin pa- human chemokine (C-C motif) receptor5 gene (CCR5). Twelve patients 649
586 tient was an infected male that received an allogenic bone marrow participated showing acceptable tolerability and safety of this strategy. 650
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587 graft from a homozygousCCR5-32 alleles donor for the treatment of The cells engrafted and persisted after adoptive transfer and were asso- 651
588 acute leukemia. His ongoing spontaneous suppression of HIV viremia ciated with increased CD4 T cell levels. This resulted in a small and tran- 652
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589 in the absence of ART [111] has invigorated the research eld of HIV sitory decrease of the peak of viremia after treatment interruption [141]. 653
590 cure. Some important advances include the better characterization of This nding stimulated more studies involving stem cells and other ap- 654
591 the cells sustaining viral reservoirs [112], a better description of the rel- proaches such as the use of siRNAs to interfere with post-transcriptional 655
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592 evant immune responses [113], the mechanisms that eliminate infected gene silencing and specic steps of HIV replication, although extensive 656
593 CD4 T cells [114], the mechanisms that sustain latency [115], and strat- preclinical studies will be needed due to the high potential risk of 657
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594 egies that can be used to reservoir clearance [116]. Some individuals can toxicity [142]. 658
595 temporarily control HIV viremia. In patient cohorts treated during HIV
596 acute infection, up to 10% of individuals may maintain limited viral 11.3. Vaccines 659
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597 replication for several weeks after ART discontinuation [117,118].

598 These patients that have a history of high viremia followed by viral con- The HIV vaccine is the holy grail of the HIV research. A preventative 660
trol after a period or ART are called post-treatment controllers in order
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599 HIV vaccine could save millions of lives and catalyze HIV global eradica- 661
600 to differentiate them from ECs [119], because of their differences in tion. However, signicant challenges exist, including HIV viral diversity 662
601 terms of immune responses or genetic background proles [120]. The secondary to the huge rate of errors during the transcription and the se- 663
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602 only characteristic that predicted viral control in these patients was a lection of escape mutants [143], the high variability of the exposed 664
603 low viral reservoir measured by proviral DNA at the time of stopping gp160 [144], the hiding of the conserved domains by the envelope 665
604 ART. This highlights the importance of starting treatment very early in [145] and the glycan shield [146], as well as the decit in production 666
605 the course of the infection for reducing reservoirs size [121], as patients of antibodies due to the affectation of B cells in the intestinal tissue 667
606 may be prioritized for eradication studies according to the size of the [147], among others. Broadly neutralizing antibodies can block a large 668
607 reservoir [122]. proportion of HIV strains by binding to Env epitopes; however, efforts 669
608 One of the rst trials designed to achieve virus eradication was the to elicit responses were limited by the weak serum-neutralizing 670
609 OKT3 trial published in 1999 [123]. HIV suppressed patients were of- response achieved with most immunogens [148]. Recently, passive 671
610 fered two courses of OKT3 and IL2 and were assessed for multiple out- transfer of monoclonal neutralizing antibodies demonstrated the ability 672
611 comes including changes in HIV-RNA, proviral DNA, viral outgrowth, to suppress viral load in animal and human studies [149,150] but the 673
612 and hybridization in situ of lymph node biopsies. Signicant toxicity cost and need for an intensive production of antibodies preclude their 674
613 prompted the termination of cycles prematurely and no changes in application as prophylactic therapy. 675
614 the reservoir could be detected, although this trial is important as it Among the vaccines evaluated in clinical trials, the RV144 vaccine 676
615 helped to inform subsequent trials [124]. The discovery of the role of based on ALVAC-HIV prime and AIDSVAX gp120 B/E boost showed 677
678 highest efcacy, although the protection was only 31% at 42 months schedule, be easily administrated, and be highly acceptable to both 742
679 [151]. This study, however, was pivotal in identifying the importance women and men [76]. 743
680 of the interaction between the V2 loop and the 47 integrin as target Nanotechnology have the potential to modulate the human immune 744
681 for new vaccines [152]. Plasma V1 V2 IgG antibodies conferred protec- system and generate controlled immune responses and therefore be 745
682 tion from infection, while Env plasma IgA correlated with higher rates incorporated in the search for an HIV vaccine [173]. Nanoparticles anti- 746
683 of infection. Further studies are needed to characterize cross-reactive gens provide an antigenic array with high density of antigen, allowing 747
684 ViV2-specic IgG that confers cross-clade protection. The use of potent multiple binding between the nanoparticle and the immune cells 748
685 adjuvants is usually needed in HIV vaccines, those proposed include resulting in the induction of a potent immune reaction. In addition, 749
686 viral vectors [153], adenosine deaminase [154], or nanoparticles loaded self-assembling protein nanoparticles can mimic viral particles, 750
687 with p24 antigen [155]. allowing using this technology for designing and testing new vaccines 751
688 Preventive and therapeutic dendritic cell-based vaccines [156] are [174]. Some preliminary attempts to create a subunit vaccine based on 752
689 gaining attention due to their capacity to restore function of natural kill- repetitive antigen display systems using this technology to induce 753
690 er cells [157] and improve immune-specic response, which is associat- HIV-neutralizing antibodies failed to elicit responses in vivo but provid- 754
691 ed with a moderate reduction of viral load [158] and avoids the increase ed tools for designing new vaccines that do not require adjuvants and 755
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692 of the reservoir size when stopping treatment [159]. intense research is being done in this area [175]. In addition, NP may 756
facilitate transdermal dosing. A recent study used a biocompatible NP 757
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693 12. The place of nanotechnologies in the HIV prevention and of a degradable polymer consisting of poly(propylene sulde conjugat- 758
694 treatment: A perspective from the clinical practice ed to a p24 peptide from the HIV-1 structural protein Gag to make 759
p24NP for inducing immunity against HIV-1. This vaccine induced po- 760
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695 According to UNAIDS, in order to eliminate HIV as a public health tent HIV-1-specic CD4 T-cell responses, as well as B-cell-mediated an- 761
696 problem by 2030, by 2020, the goals of 90% of people living with HIV di- tibody production supporting the potential of intradermal antigen 762
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697 agnosed, 90% of diagnosed cases treated and a 90% of treated patients delivery as an option in the developing of effective vaccines [176]. 763
698 achieving undetectable viral load should be achieved [33]. These ambi- Regarding HIV treatment, the landscape has evolved quickly, and 764
699 tious goals will require enormous efforts, investment, and programmat- this has been a major limitation for the development of nanodrugs. Sev- 765
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700 ic changes in how we prevent, diagnose, treat, and follow-up HIV eral of the initial developments (i.e. nanoformulations of zidovudine, 766
701 patients. Technological innovation is also needed, which is where nano- stavudine, didanosine or lopinavir) were dwarfed by the fast develop- 767
702 technologies could play a signicant role. ment of HIV drugs, with much more potent and safer alternatives
D 768
703 Regarding diagnosis, rapid HIV tests can identify infections exclu- being quickly available. Although novel HIV therapies have improved 769
704 sively based on HIV antibody detection and can thus miss acute HIV in- the landscape of the HIV therapeutics, the search for the ideal treatment 770
705 fections during the so-called window period. Acute HIV infection has a in the context of lifelong therapy continues due to many of currently 771
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706 signicant impact on the epidemic, with 2050% of new HIV cases relat- used drugs having limitations such as the potential for drug interactions 772
707 ed to acute HIV infection [160,161]. The identication of acute cases, and the need of high adherence in a daily dosing schedule. In addition, 773
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708 particularly in areas of high incidence, is needed to ensure HIV elimina- adverse effects, drug interactions, limited bioavailability, and lower ac- 774
709 tion [107]. Easier molecular techniques and/or viral detection tests will cess to compartments such as the central nervous system pose addition- 775
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710 also improve infant diagnosis and HIV treatment monitoring. Although al challenges. Drugs that can disseminate adequately in different organs 776
711 several molecular platforms are being developed [162], advances in and reservoirs, or in infected cells such as those harboring CD4 receptor 777
712 nanotechnology are providing alternative tools for identifying the HIV might improve efcacy and eventually allow for less frequent adminis- 778
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713 and eventually other co-infections from whole unprocessed blood tration with lower toxicity. 779
714 [163,164], that can provide rapid diagnosis with minimal equipment Nanoparticles have profound effects in the pharmacokinetics prop- 780
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715 and investment such as a smartphone [165]. erties of drugs. Small-sized particles loaded with drugs have large sur- 781
716 In order to prevent HIV, biomedical interventions must be offered in face-area-to-volume ratio, resulting in marked differences from the 782
717 combination within a comprehensive package of interventions. bulk forms of the drug regarding electromagnetic, thermal, optical, 783
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718 Microbicides based on ART that can be safe and stable at mucosal level and biochemical properties. Nanoformulated ARV drugs may readily 784
719 are being investigated and many examples of microbicides using nano- cross cell membranes and translocate around the body via blood and 785
O
720 technology are in preclinical development. Cellulose acetate phthalate lymph and might have a better ability to penetrate sanctuaries sites or 786
721 efavirenz combination nanoparticles showed a good in vitro activity specic cell populations and can evoke therapeutic effects at lower 787
722 [166]. Combined formulations were also developed using biodegradable doses for longer periods of time [177]. In order to improve the bioavail- 788
C
723 poly-lactide-co-glycolide (PLGA) nanoparticles (NP) loaded with ability of HIV drugs in children, a formulation of efavirenz-loaded mi- 789
724 efavirenz or saquinavir that had a 50-fold higher antiviral activity com- celles using surface aptamers to target CD4 T cells have been produced 790
N
725 pared to free drug formulations, and this activity was synergistic when in an oral solution that demonstrated improved oral bioavailability 791
726 the NP were co-formulated with tenofovir [167]. Complex systems and reduced inter-individual variability [178]. In a mouse model, the 792
727 using combined gene therapy (siRNA) targeting dendritic cells of the use of combined ART associated with a single PLGA-NP resulted in 793
U
728 vaginal epithelium were developed to prevent HIV [168]. Other particles, better and sustained suppression of HIV-1 [179]. Other formulations, 794
729 such as lysine dendrimers, showed anti-HIV and HSV activity and are in such as the colloidal gold-loaded, PLGA-NP could provide sustained 795
730 clinical phase II development although vaginal inammation associated release of drugs. Although stavudine (a drug that is currently not recom- 796
731 with its use is a concern for the future progress of this approach [169]. mended) was used in this study [180], this approach can be used 797
732 For HIV prevention, several drug formulations are being investigated for other drugs. Nanoformulations might allow the development of 798
733 for topical administration such as vaginal rings loaded with dapivirine, specic delivery systems to ensure adequate drug levels in specic 799
734 maraviroc, or tenofovir; tenofovir-based vaginal and rectal gels and sites such as the CNS, which could improve the management of menin- 800
735 tenofovir vaginal tablets that can be improved by nanothecnology geal tuberculosis, cryptococcosis, or HIV dementia through slow release 801
736 [170]. Current products under investigation include antiretroviral agents drugs [181,182] or by binding brain-specic apolipoprotein E receptors 802
737 formulated as dissolvable lm or nanobers to be applied topically, such [183]. Another example involves the specic delivery systems for the 803
738 as dapivirine, tenofovir, or acetatecarrageenan that might have also ac- lung, which might serve as the route for systemic treatment in patients 804
739 tivity against HSV and HPV [171,172]. The ideal microbicide would have that cannot tolerate or take oral drugs or improve treatment of pulmo- 805
740 adequate pharmacokineticpharmacodynamic relationship, high efca- nary diseases such as Pneumocystis jirovecii pneumonia or tuberculosis 806
741 cy and minimal toxicity, and would be affordable, have a exible [184]. 807
t2:1 Table 2
t2:2 Summary of antiretroviral drugs used in HIV-1 nanotherapeutics.
t2:3 Antiretroviral Nanoparticle type Comments References

t2:4 drug
t2:5 Stavudine Methylmethacrylate-sulfopropylmethacrylate (MMA-SPM) Drug not currently used as rst-line treatment, with the exception of [196200]
t2:6 Delavirdine nanoparticles with grafted RMP-7 (RMP-7/MMA-SPM nanoparticles) lamivudine. Can improve delivery to CNS
t2:7 Saquinavir
t2:8 Zidovudine
t2:9 Lamivudine
t2:10 Ampenavir Transferrin (Tf)-conjugated quantum dots Amprenavir is a PI not currently in use. This formulation could improve [201]
delivery to CNS
t2:11 Dapivirine Poly(-caprolactone) nanoparticles To be used as microbicides. Saquinavir to be delivered to specic cells [202207]
t2:12 Efavirenz such as macrophages
t2:13 Saquinavir
t2:14 Ritonavir Tat-peptide-conjugates Target mononuclear cells [208]
t2:15 Stavudine Solid lipid nanoparticles (compritol 888 ATO, tripalmitin, and cacao Explored ARV drugs not used currently as treatment, with the exception [209211]
F
t2:16 Delavirdine butter stabilized by L--phospatidylcholine, cholesteryl of EFV.
t2:17 Saquinavir hemisuccinate, and taurocholate)
O
t2:18 Efavirenz
t2:19 Darunavir Lipid nanoparticles Used in combination with ritonavir and tenofovir [212]
t2:20 Atazanavir
t2:21 Saquinavir Nanoparticles with ternary components of polyethyleneimine, Use saquinavir that is not used currently. [213]
O
poly(-glutamic acid), and poly(lactide-co-glycolide acid) (PLGA)
t2:22 Stavudine Chitosan-based systems Stavudine was proven in vitro, Indinavir in dogs [214,215]
t2:23 Indinavir
R
t2:24 Saquinavir poly(lactide-co-glycolide acid) nanoparticles Were tested alone and in combination [167]
t2:25 Efavirenz
t2:26 Tenofovir Maraviroc, etravirine and raltegravir showed synergistic effects [216]
P
t2:27 Maraviroc,
t2:28 etravirine,
t2:29 raltegravir
t2:30 Rilpivirine Poloxamer formulations Were evaluated for oral, injectable and intranasal applications
D [217221]
t2:31 Atazanavir
t2:32 Nevirapine
t2:33 Maraviroc Dendrimers Used as microbicides. Dendrimers showed anti-HIV activity [222]
E
t2:34 Tenofovir
t2:35 Efavirenz
t2:36 Raltegravir Gold nanoparticles To be used in eradication [223]
T
C
808 The most advanced nanoformulation in clinical development is the Methionyl-Leucyl-Phenylalanine) nanocarriers have shown to improve 840
809 nanosuspension of a combination of cabotegravir (a new integrase in- HIV drug delivery to tissue macrophages, one of the HIV reservoirs 841
810 hibitor) and rilpivirine (an approved NNRTI). A phase I study involving [190]. New formulations targeting CD4 T memory cells (the most im- 842
E
811 40 HIV-negative patients demonstrated that injection of this combina- portant cell sustaining HIV viral reservoir) could be crucial in ART deliv- 843
812 tion was safe and able to maintain adequate drug levels for a long period ery or to combine them with gene therapy to activate apoptosis or 844
R
813 of time. A lead dose of cabotegravir IM 800 mg with rilpivirine 1200 mg activation systems [191,192]. Various polymeric systems can be used 845
814 was able to maintain drug levels at 30 days that controlled the virus to immune modulate DCs or to deliver small molecules, proteins, or 846
815 IC90 [185]. These results justify further investigation development DNAs as potential immunotherapies [193,194]. However, a better un- 847
R
816 into the use of this combination as a maintenance strategy after a course derstanding of HIV latency and the immune mechanisms that support 848
817 of oral treatment [186] or, as a preventive therapy [187]. More long- the formation and maintenance of reservoirs is needed to inform better 849
O
818 acting agents that can be delivered via injections, subcutaneous implant, interventions. Nanotechnology can also facilitate our understanding of 850
819 or transdermal patches that co-formulate safe drugs in dual combina- the biological processes that govern the host immune response and for- 851
820 tion (including lamivudine with other drugs such as integrase or prote- mation of the synaptic junctions between dendritic cells and CD4 T cells, 852
C
821 ase inhibitors) could offer further options for maintenance regimens. It recapitulating the trafcking of dendritic cells using live cell optical 853
822 is urgent to develop new options and to design clinical trials aimed at tracking [195]. Nanotechnology is expected to have a growing impor- 854
N
823 demonstrating the safety, stability, and clinical efcacy of these formu- tance on the HIV research agenda, particularly in the search for a cure. 855
824 lations [188]. Table 2 presents some of the drugs that have been or are
825 being tested using nanoparticles as drug delivery systems. 13. Conclusions 856
U
826 One of the major limitations when evaluating drugs for therapeutics
827 is that the ART eld is very dynamic and preferred drugs regimen iden- Major scientic advances of the last decades have dramatically 857
828 tied for treatment change quickly according the results of clinical trials, changed the face of HIV epidemic, allowing infected individuals to 858
829 highlighting the intense research activity in this area. Change to pre- enjoy long and productive lives. However, many individuals are not 859
830 ferred drug regimens will slow as long as the new drugs can meet the beneting from these medical advances due to delayed diagnosis, toxic- 860
831 criteria for ideal therapy: safe, potent, ability to be used throughout ity, or treatment-related complications. Cure remains an elusive goal, 861
832 the population, low pill burden, low milligram dose that could allow the presence of reservoirs being the main challenge for eradication, 862
833 for co-formulation in once pill daily, and no need for specic monitor- and it is expected that lifelong adherence to therapy will be required 863
834 ing. Although new drugs that demonstrate many of these characteristics for many more years. 864
835 have been added to the formulary, in particular integrase inhibitors, One of the latest innovations on the HIV drug development agenda is 865
836 there is still room for improvement. the nanoformulation of drugs. Nanoparticles could reduce the amount 866
837 For eradication, nanocarriers exhibit the capability to deliver drugs of drug delivered, toxicity, or could target where to deliver specic 867
838 to specic sites or cells that might be important adjuvants in eradication drugs, genes, or immunotherapies. Sustained release injectable formu- 868
839 studies [189]. The Macrophage-Targeted PEG-fMLF (N-Formyl- lations have entered Phase IIb and we expect results soon. However, 869
870 many questions need to be answered before we can see a wider [28] D. Nolan, S. Mallal, Complications associated with NRTI therapy: update on clinical 951
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872 als involving nanoparticles are needed to investigate both the benets [29] M. del M. Gutierrez, M.G. Mateo, F. Vidal, P. Domingo, The toxicogenetics of antire- 954
873 and drawbacks of this technology. troviral therapy: the evil inside, Curr. Med. Chem. 18 (2011) 209219 (http:// 955
www.ncbi.nlm.nih.gov/pubmed/21110805, accessed March 6, 2016). 956
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Clinical Challenges in HIVAIDS

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Clinical Challenges in HIVAIDS

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ADR-12973; No of Pages 15

Advanced Drug Delivery Reviews xxx (2016) xxxxxx

Contents lists available at ScienceDirect

Advanced Drug Delivery Reviews

journal homepage: www.elsevier.com/locate/addr

1Q1 Clinical challenges in HIV/AIDS: Hints for advancing prevention and

43 4. HIV and viral cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

48 6.3. Condom provision . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

51 7.1. Perinatal HIV transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

57 11. Cure prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

58 11.1. Eradication studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

87 the HIV cure agenda.

91 broad epidemiological patterns have been identied. The rst are

101 consequent underestimation of the need for targeted interventions in

t1:3 Drug Mechanisms of action Characteristics Side effects

t1:4 NRTIs/NtRTIs: (nucleotide reverse transcriptase inhibitor)

t1:42 ATZ: atazanavir ritonavir 100 mg.

t1:45 adverse effects. headache

237 adverse effects.

239 objectives of antiviral treatment remain the same as those dened at

t0:1 Notes to Table 1:

597 replication for several weeks after ART discontinuation [117,118].

t2:3 Antiretroviral Nanoparticle type Comments References

913 http://dx.doi.org/10.1016/j.virol.2005.06.001. 14651858.CD001224.pub4. 999

916 (2006) 566571, http://dx.doi.org/10.1016/j.patbio.2006.07.035. 893896, http://dx.doi.org/10.1097/QAD.0b013e328351f73f. 1002

replication, Blood 119 (2012) 46454655, http://dx.doi.org/10.1182/blood-2011-

NEJMoa1011205. ment with lopinavir-ritonavir plus lamivudine or emtricitabine and a second

[167] T. Chaowanachan, E. Krogstad, C. Ball, K. a Woodrow, Drug synergy of tenofovir 007-9402-5.

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