Nucleic Acids Research Laboratory, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
a r t i c l e i n f o
Article history:
Received 6 September 2011
Accepted 5 February 2012
Available online 3 March 2012
Keywords:
HIV
Drug targets
FDCs
HAART
Viral reservoirs
Indian scenario
a b s t r a c t
As the menace of HIV/AIDS continues to rise, effective drug treatments are required to reach the infected
masses. HAART provides durable control of virus replication, however, it is not devoid of unwanted
side effects, especially in persons undergoing long-term treatment. The current therapy nds its lim-
itations in the emergence of multidrug resistance, transmission of drug-resistant HIV strains, and a
life-long treatment. Moreover, to improve patient adherence and to simplify the treatments, effective
xed dose combinations (FDCs) are needed. The picture of HIV/AIDS in India shows that HIV/AIDS is
declining through the country and perhaps through proper measures HIV can be eradicated. Thus, nd-
ing novel drug targets and new drugs is the need of the hour to treat the infected persons and to reach
HIV reservoirs in the body, like brain, lymph nodes, etc. to achieve the ultimate goal, i.e., the complete
eradication of the dreaded virus HIV, the causative agent for AIDS.
2012 Polish AIDS Research Society. Published by Elsevier Urban & Partner Sp. z.o.o. All rights reserved.
1. Introduction
HIV/AIDS continues tobe a dreadedkiller till date andmore than
33 million people worldwide are currently infected with Human
Immunodeciency Virus (HIV), discoveredabout three decades ago
[1,2] as the causative agent for Acquired Immunodeciency Syn-
drome (AIDS) an immunocompromised condition. Since its rst
disclosure in 1981 (Fig. 1), HIV/AIDS has killed more that 25 mil-
lion people all over the world and stands today as the major threat
to human health. However, as a result of sustained steps, which
also include the impact of HIV prevention efforts, a ray of hope has
emerged as HIVprevalence and incidence have gone down globally
over the decade as per UNAIDS 2010 report, except for, unfortu-
nately, Eastern Europe and Central Asia where a slight increase has
been noticed.
HIVis a retrovirus and possesses RNAas genetic material, which
is covered by a viral coat. Once this virus enters a host cell, it
removes its coat and produces another kind of genetic material
the dsDNA, known as the provirus. This provirus then gets incor-
porated into human DNA, hijacks the host cell apparatus and starts
producing hundreds and hundreds of new virion particles. Since
the whole life cycle of this virus passes inside the host cell, it
becomes really challenging to nd an appropriate treatment. The
This article is dedicated to Prof. David Shugar on his 96th Birth Day
(September 10, 2011).
Corresponding author. Tel.: +91 532 246 1005; fax: +91 532 246 1005.
E-mail address: rksinghsrk@gmail.com(R.K. Singh).
scientic community, however, has found some suitable drugs
against HIV, which target the different stages of its proliferation
and multiplication. Presently, seven groups of anti-HIV drugs tar-
geting different stages of its life cycle are being used: nucleoside
reverse transcriptase inhibitors (NRTIs), nucleotide reverse tran-
scriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase
inhibitors (NNRTIs), protease inhibitors (PIs), fusioninhibitors (FIs),
co-receptor inhibitors (CRIs) and integrase inhibitors (INIs), and
these drugs have proved their usefulness also in halting the HIV
from reproducing. However, a unique phenomenon was noticed
with HIV. Unlike other viruses, it was found capable of show-
ing different behavior not only from cell to cell but also from
person to person. This was because of mutation in its genetic mate-
rial and as a result, different strains of viruses were developed.
These mutated viruses developed resistance to the drugs being
used.
At this critical junction, a combinationtherapy knownas HAART
(Highly Active Antiretroviral Therapy) was introduced to stop HIV
from reproducing and it has greatly reduced the high morbid-
ity and mortality rate [35]. However, this therapy too cannot
cure AIDS and patients are destined to undergo life-long treat-
ment and use of this therapy has several limitations, like toxicity
[6], development of drug resistance [7] and poor tolerability [8].
The stepping-stones towards the achievement of long-term virus
control are simplication of therapy, improvement of patient
adherence andminimizationof drug resistance. Thus, the challenge
still present before the scientic community all over the world is
to develop novel anti-HIV compounds with new mechanisms of
action, accepted toxicity and resistance prole.
1730-1270/$ see front matter 2012 Polish AIDS Research Society. Published by Elsevier Urban & Partner Sp. z.o.o. All rights reserved.
doi:10.1016/j.hivar.2012.02.003
6 G. Kumari, R.K. Singh / HIV & AIDS Review 11 (2012) 514
Fig. 1. Pictorial representation of landmarks in the treatment of HIV.
2. HIV infection: life cycle of HIV and drug targets
During HIV infection the immune system begins to fail, which
leads to various life-threatening opportunistic infections. HIV
infection occurs through transfer of blood, semen, vaginal uids,
pre-ejaculate or breast milk. HIV is present in these body uids
either as free virus particles or within infected immune cells. Thus,
the four major routes of HIV transmission are unsafe sex, con-
taminated needles, breast milk and from a mother to her baby
intrapartum.
2.1. Life cycle of HIV
The life cycle of HIV (Fig. 2) starts with the attachment of the
virus to the host cell membrane and ends with release of the new
virion particles fromthe host cell, which can be summarized in the
following steps:
(i) Binding and fusion: HIVbegins its life cycle by attaching its gly-
coprotein gp120 to CD4
+
T cells followed by CCR5 and CXCR4
co-receptors depending on its tropism. This leads to fusion of
the viral envelope, mediated by gp41, with the cell membrane
and the release of the HIV capsid into the cell. The virus is
now decapsidated releasing the viral RNA into the host cell
cytoplasm.
(ii) Reverse transcription: HIV reverse transcriptase converts its
ssRNA into dsDNA, known as the provirus.
(iii) Integration: The newly formed HIV provirus enters the host
cells nucleus, where an enzyme called HIV integrase, inte-
grates the provirus within the host cells DNA. The provirus
may remain inactive for several years.
(iv) Transcription: The provirus integrated into the host genome
uses a host enzyme called RNA polymerase to create copies of
the HIV genomic material, as well as shorter strands of RNA
called messenger RNA (mRNA).
(v) Translation: The mRNA is used as a blueprint to make long
chains of HIV proteins.
(vi) Assembly and budding: An HIV enzyme called protease cuts
the long chains of HIV proteins into smaller individual func-
tional proteins. The smaller HIV proteins come together with
copies of HIVs RNA genetic material and a new virus particle
is assembled.
(vii) Maturation and release: The newly assembled virus pushes out
from the host cell. During budding, the new virus steals part
of the cells outer envelope. This envelope is studded with
protein/sugar/lipid combinations and constitutes the HIV gly-
coproteins. The newcopies of HIV can nowmove on to infect
other cells.
G. Kumari, R.K. Singh / HIV & AIDS Review 11 (2012) 514 7
Fig. 2. Life cycle of HIV showing different stages fromits attachment to the cell membrane to the release of newvirion particles.
2.2. Drug targets
During its proliferation inside the host cell, the virus is exposed
to various types of interventions, which can prove detrimental to
its multiplication and, in turn, its existence. These possible targets
and agents for intervention have been summarized in Table 1.
3. Treatment: current status
3.1. Landmarks in the development of HAART
The major breakthroughs obtained in the treatment of HIV/AIDS
are shown in Table 2. After the identication of HIV as the etiolog-
ical agent for AIDS [9], collaboration between the National Cancer
Table 1
Possible HIV targets and potential interventions.
Stage of HIV life cycle Potential intervention
Binding to the host cell Antibodies to the virus or cell receptor
Entry to the host cell Drugs blocking fusion
Reverse transcription Reverse transcriptase inhibitors
Integration of DNA into the host
genome
Integrase inhibitors
Expression of viral genes Inhibitors of the tat protein
Production and assembly of viral
components
Myristoylation, glycosylation and
protease inhibitors
Budding of the virus Interferons
Institute, US and Burroughs-Wellcome Company led to the discov-
ery that AZT was able to suppress HIV-1 replication in vitro [10,11].
The approval of rst PI, sanquinavir followed by the rst NNRTI,
nevirapine, brought a revolution in the treatment of HIV/AIDS.
The introduction of HAART resulted in marked decrease in plasma
viremia in most patients [12]. Combivir was the rst xed dose reg-
imen consisting of AZT and FTC and it was developed primarily to
improve adherence to treatment, which is a major cause of failure
and emergence of drug resistance. Since then xed-dose combina-
tions (FDCs) have playedanessential role insimplifying some of the
Table 2
Landmarks in the treatment of HIV.
1981 Mortality and Morbidity Weekly Report reports of men treated for
biopsy showed signs of severe immunodeciency.
1983 A newhuman lymphotropic retrovirus (HTLV-III/HIV-1) was
isolated fromthe T-cells of patients
1984 Etiological link of HIV to AIDS was demonstrated
1985 Zidovudine (AZT) was identied as a NRTI
1987 AZT approved for antiretroviral therapy
1995 Sanquinavir (protease inhibitor) approved by FDA
1996 Nevirapine (NNRTI) approved by FDA
1997 Combivir (AZT+3TC) approved as rst xed-dose combination pills
2003 Enfuvirtide (fusion inhibitor) approved by FDA
2006 The rst single pill Atripla (TDF +FTC+EFV) approved by FDA
2007 Maraviroc (CCR5 antaagonist) and raltegravir (integrase inhibitor)
approved by FDA
2009 Long termcontrol of HIV by CCR%-32 stem-cell transplantation
is reported
8 G. Kumari, R.K. Singh / HIV & AIDS Review 11 (2012) 514
N
NH
2
O
S
O
HO
N
NH
2
O
S
O
HO
F
N
NH
2
O
S
O
HO
F
Racivir (50:50 mixture of the -enantiomer of emtricitabine)
N
N
N
N
NH
2
NH
2
O
O
HO
N
N
NH
2
O
S
HO
Amdoxovir Elvucitabine
Apricitabine
Fig. 3. NRTIs undergoing phase II or phase III clinical trials.
most frequently used regimens. After the development of AZT, the
Food and Drug Administration (FDA), USA has played an important
role in approving antiretrovirals and in streamlining the regulatory
processes.
The present day combination therapy HAART utilizes seven
classes of drugs that target various stages in the life cycle of HIV.
These drugs are discussed as follows:
3.1.1. Nucleoside reverse transcriptase inhibitors (NRTIs)
The rst approvedanti-HIVdrugfor the treatment of AIDS AZT,
anucleosideanalog, actedbyinhibitingthefunctionof reversetran-
scriptase. Since then, several NRTIs have been approved. In total,
there are seven NRTIs approved for clinical use, viz. zidovudine
(AZT), 1,3-didanosine (ddI), lamivudine (3TC), zalcitabine (ddC),
stavudine (d4T), abacavir (ABC) and emtricitabine (FTC) [1316].
All NRTIs lack 3
-uoro-2
,3
-didehydro-2
,3
-
dideoxyadenosine) and its derivatives (Fig. 4) are being developed
as NtRTIs as these have shown less renal and mitochondrial toxic-
ities [30].
3.1.3. Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
The NNRTIs bind non-competitively at the allosteric site located
about 10
A away from the active site of reverse transcriptase
[3135]. Currently, four NNRTIs [36,37] are approved for treat-
ment of HIV, viz. nevirapine, efavirenz, delaviridine and etravirine.
The use of rst generation NNRTIs led to the rapid development of
resistance [38]. Thus, second generation NNRTIs were developed.
Six more NNRTIs, rilpivirine [39], calanolide A[40], (R,E)-methyl(2-
carbomyl-5-chloro-1H-indol-3-yl)(3-(2-cyanovinyl-5-methylphe-
nyl)phosphinate) (IDX-899) [41], 1-(5-cyanopyridin-2-yl)-3-
((1S,2S)-2-(6-uoro-2-hydroxy-3-propionyl-phenyl) cyclopropyl)
urea (MIV-150) [42], potassium 4-(2-((5-bromo-4-)(4-cyclo-
propylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl))-acetamido-3-chl-
orobenzoate (RDEA806) [43] and 4-(2-(11-ethyl-5methyl-6-oxo-
6,11-dihydro-5H-dipyrido[3,2-b:2
,3
-e][1,4]diazepin-8-yl)etho-
xy)-quinoline-1-oxide (BILR 355 BS) [44,45] (Fig. 5) are undergoing
phase II or phase III clinical trials. Besides being more potent and
effective against mutants, these have shown good oral bioavail-
ability. The only anti-HIV natural product undergoing clinical trials
is calanolide A, isolated fromtropical rain forest plant, Calophyllum
lanigerum[46].
3.1.4. Protease inhibitors (PIs)
The protease enzyme is responsible for cleavage of the gag and
gag-pol precursor polyproteins to the structural proteins (p17, p24,
p7, p6, p2 and p1) and (p66/p51) and integrase (p32), thereby
causing maturation of the progeny virions [47]. The HIV protease
is a homodimer that acts catalytically as an asparatic acid pro-
tease, and the active site is located at the interface of the dimer.
Ten protease inhibitors, viz. darunavir (TMC-114) [48], tipranavir
[49], sanquinavir [50], ritonavir [51], indinavir [52], nelnavir [53],
amprenavir [54], lopinavir (ABT-378) [55], fosamprenavir [56] and
atazanavir (ATV) [57] are currently approved by FDA. Except for
tipranavir, all the approved PIs are of peptide nature and have
poor bioavailability. The other side effects are the development of
resistance and toxicity.
3.1.5. Fusion inhibitors (FIs)
The infection of the host cell with HIV involves the interaction
between the virion glycoprotein gp120 on the outer membrane
and the CD4+ receptor on the host cell surface resulting in certain
conformational changes, which lead to the unmasking of a second
gp120-binding site for target chemokines co-receptors CXCR4 and
CCR5. Binding of gp120 to either or both co-receptors leads to the
fusion-active conformation of the viral trans-membrane protein
gp41. A hairpin like structure is formed, which contains a thermo-
dynamicallystablesix-helixbundlethat draws theviral andcellular
membranes closer for fusion [58]. The fusion inhibitor, enfuvirtide
is the only approved fusion inhibitor used for treatment of AIDS
[59].
Studies are going on to nd effective mimics of the transient
gp41intermediate. Tri-functionalized3,2
,2
-terphenyl derivatives
(Fig. 6) are being used and have been found to inhibit HIV-1 medi-
ated cell-to-cell fusion [60].
3.1.6. Co-receptor inhibitors (CRIs)
The chemokine receptors, viz. CCR5 andCXCR4 eventually allow
virus-cell fusion [61]. A large number of CCR5 and CXCR4 antago-
nists have been identied. At present, only maraviroc is approved
for the treatment of HIV infection [62]. Besides this, vicriviroc [63],
TAK-220 [64] and PF-232798 [65] are undergoing phase II and
phase II clinical trials andappear tobe promisingcandidates for fur-
ther development (Fig. 7). The main concern is that these inhibitors
lead to the emergence of resistant HIV-1 strains [66].
G. Kumari, R.K. Singh / HIV & AIDS Review 11 (2012) 514 9
N
N
N
N
NH
2
F
O
P
O
HO
HO
N
N
N
N
NH
2
F
O
P
O
O
N
H
O
O
N
N
N
N
NH
2
O P
O
O
O
O
O
O
O
O
O
.
HO
OH
O
O
Fig. 4. Structures of NtRTIs under clinical trials.
O O
OH
O
O N
N N
Br S
N
H
O
Cl
O
-
K
+
O
O
F
N
H
N
H
O
N
CN
MIV-150 Calanolide A RDEA-806
N
H
Cl
O
NH
2
P
O
O
CN
N
N
N
N
O
O
N
+
O
-
NC
N
H
N
N
N
H
CN
IDX899 BILR 355 BS Rilpivirine
Fig. 5. Structures of NNRTIs undergoing clinical trials.
HO
O
O
OH
O
Fig. 6. Structure of terphenyl derivative.
3.1.7. Integrase inhibitors (INIs)
The enzyme, HIV integrase, catalyzes the integration of the
proviral DNA into the host cell chromosomal DNA. It is a 32kDa
protein comprising of three domains [67]. The key functions of this
enzyme are 3
-end
processing takes place after reverse transcription as the cDNA
(or dsDNA) formed, is primed for integration in the cytoplasm
by the trimming of the 3
-ends of the DNA. It requires both the integrase and the integrity
of the last 1020 base pairs at both the ends of the viral DNA.
Only one FDA approved HIV-integrase inhibitor, raltegravir is
present and another one, elvitegravir, is under phase III clinical
trials (Fig. 8).
N
O
N
O
Cl
N NH
2
O
N
N
N
O
N
N
O
CF
3
F
H
N
O
N
N
N
N
O
PF-232798 Vicriviroc TAK-220
Fig. 7. Structures of CRIs undergoing clinical trials.
10 G. Kumari, R.K. Singh / HIV & AIDS Review 11 (2012) 514
Table 3
Anti-HIV drugs currently undergoing clinical trials.
Drug Manufacturer Class Phase
Elvitegravir Gilead Sciences INIs III
AK-602 Kumamoto University CRIs III
AMD070 AnorMed CRIs II
PF-232798 Pzer CRIs II
Vicriviroc Schering Plough CRIs III
Apricitabine Avexa NRTIs III
Amdoxovir RFS Pharma NRTIs II
Elvucitabine Achillion Pharmaceuticals NRTIs II
Racivir Pharmasset NRTIs II
(+)-Calanolide A Sarawak MediChemPharmaceutics NNRTIs II
IDX899 Idenix Pharma NNRTIs II
RDEA806 Ardea NNRTIs II
Rilpivirine Tibotec NNRTIs II
BILR 355 BS Boehringer Ingelheim NNRTIs II
MIV-150 Medivir, Chiron NNRTIs II
It is doubtless that new anti-HIV drugs are needed with novel
mechanisms of action as these would contribute towards the
broadening of the combinations used in HAART. A number of such
drugs undergoing clinical trials have been summarized in Table 3.
3.2. Combinations of anti-HIV drugs
HAART, the combination therapy, has signicantly decreased
the morbidity and mortality rates in HIV patients [7072]. Cur-
rently, more focus is given on including two or three or even more
drugs targeting the life cycle of HIV. The introduction of HAART in
mid-1990s resulted in increase in the number of tablets to be taken
by the patients, which required an increased drug compliance and
adherence. So efforts are being made to design single formulations
containing more than one drug. Combivir, the rst to be approved,
consists of two NRTIs and is taken as one tablet twice daily. Five
anti-HIV drug combinations are currently being used as shown in
Table4. Theavailabilityof thesedrugcombinations has changedthe
face of anti-HIV drug treatment as a single pill has replaced more
than 10 pills a day. As a result, improvement in adherence to med-
ication is achieved and drug resistance has been lowered, which
has, in turn, improved the quality of life of HIV-positive people.
4. Challenges on the way to successful HAART
The introduction of HAART has achieved tremendous success,
however, still many challenges lay ahead. The main problems faced
currently are the development of resistant strains, toxicity of the
drugs, side effects and lowadherence because of complicated drug
schedule. The challenges before the present treatment can be sum-
marized as:
4.1. Minimizing drug resistance
Suboptimal treatment efcacy and lack of adherence lead to
treatment failure due to the emergence of drug resistance [73].
Thus, the use of potent antiretroviral regimens together with NNR-
TIs and PIs active against drug resistant HIV strains, reduces the
emergence of resistant viral strains. New agents with improved
resistance proles should be explored, for example, the FDCs. The
availabilityof FDCs canhelpimprove the treatment complianceand
reduce further resistance selection.
4.2. Simplication of regimens
To avoid the emergence of resistant strains and suppress viral
replication, it is necessary to achieve a high adherence to HAART
[74]. As soon as the treatment starts, it is necessary to take it for
life but it is quiet a difcult task to maintain [75]. Side effects and
daily life interferences affect adherence to HAART [76,77].
Various strategies are being used to improve adherence, for
example, simplication of drug regimens and newonce-daily xed
dose regimens (FDRs) consisting of tenofovir, FTC, elvitegravir or
GS-9350 or another one consisting of tenofovir DF, FTC and NNRTI
rilpivirine.
4.3. Reduction of side effects
The use of anti-HIV drugs can lead to various toxicities, which,
though not life threatening, can eventually affect the quality of life
and the willingness of the patients to adhere to their regimens. In
some cases, patients may needtochange their initial drugcombina-
tion because of adverse affects. Besides, long-termtoxicities occur
as a result of treatment discontinuation or regimen switching due
to adverse effects. Hence new alternatives with better tolerance
and convenient dose schemes are needed.
Newoptions are nowbeing searched that can alleviate the side
effects and reduce compliance. The growth hormone releasing fac-
tor analogtesamorelinhas shownreductionof adiposetissueinHIV
patients being treated with HAART [78]. Clinical trials are going on
tostudythe effect of uridine, pravastatine andtheir combinationon
the recovery of HAART-associated lipoatrophy. However, minimal
benet has been found in this approach [79].
4.4. Viral reservoirs
These are anatomical sanctuaries of HIV, most often in the brain.
These pose obstacles in the eradication of HIV because most of
anti-HIV drugs fail to cross the BloodBrain-Barrier (BBB). Also the
development of resistant antiretroviral strains canserve as a source
of HIV. In the case of NRTIs, the best drug able to cross the BBB is
AZT and in the case of NNRTIs, nevirapine is the most capable of
crossing the BBB. PIs are not very capable to cross the BBB.
Virtually, almost all anti-HIV drugs are not able to cross the BBB
due to active efux transport [64]. Thus, there is a need for devel-
opment of newanti-HIV drugs, which can effectively cross the BBB
and penetrate the CSF.
5. Future prospects: emerging approaches in the treatment
of HIV infection
Identication and testing of newpotent antiretroviral regimens
are important targets for drug development. The uncertain effects
Table 4
Fixed dose combination pills as approved by FDA.
FDC Components Manufacturer and approval date
Two drug combinations
Combivir AZT (300mg) +3TC (150mg) GlaxoSmithKline; September 27, 1997
Kivexa/Epzicom ABC (600mg) +3TC (300mg) GlaxoSmithKline; August 2, 2004
Truvada TDF (300mg) +FTC (200mg) Gilead Sciences, August 2, 2004
Three drug combinations
Trizivir AZT (300mg) +3TC (150mg) +ABC (300mg) GlaxoSmithKline; November 14, 2000
Atripla TDF (300mg) +RTV (200mg) +efavirenz (600mg) Bristol-Myers Squibb, Gilead Sciences; July 12, 2006
G. Kumari, R.K. Singh / HIV & AIDS Review 11 (2012) 514 11
of life-long therapy, requirement of strict adherence and the high
costs of treatment stimulate the exploration of novel approaches
that can potentially be used. Prevention strategies involving
microbicides and antiretroviral prophylaxis, which reduce HIV
transmission rates are being explored extensively [80]. But the best
alternative still would be an efcacious vaccine, the ultimate but
elusive objective for combating the deadly pandemic of AIDS.
5.1. Antiretroviral treatment
The main objective for exploring antiretroviral drugs with new
combinations is to simplify the existing treatment regimens or
to achieve efcacy. NRTIs are the key components of HAART but
these have specic limitations different from other classes of
anti-HIV drugs, like more frequent resistance development and
adverse metabolic effects [81,82]. Probably, with the availability of
new drugs more NRTI-sparing regimen would be explored. It has
been found that NRTI-sparing regimens consisting of novel potent
drugs (for example, raltegravir +etravirine +darunavir/ritonavir)
are attractive options for patients with drug resistance.
One of the newer strategies that have been tested over the years
is maintenance monotherapy. Patients with stable undetectable
viral load while on a combination regimen, may be considered for a
simplied maintenance treatment. Studies have shown that PIs are
more effective for maintenance therapy than NRTIs and NNRTIs.
Moreover, dual combinations of PIs and INIs may be more suit-
able for this therapy [83]. Data fromstudies initially indicated that
delaying the start of therapy, due to adverse effects, resulted in
higher costs and development of resistance. But now it has been
recommended to initiate the treatment at a CD4
+
T cell count of
350 per L or nearby [84]. Recent studies have also shown that
initiating the treatment earlier may prevent or reduce potentially
irreversible immune-systemand end-organ damage.
Novel viral and host targets are being searched, which include
vif-APOBEC3G, integrase-LEDGF andfactors involvedinHIVassem-
bly and maturation [85]. In persistently lymphopenic patients,
normal T-cell counts can be restored by adjuvant therapies. Simi-
larly, agents like interleukin-T have shown to improve the survival
of T-cells, increasing peripheral CD4
+
T lymphocytes in HIV-
infected patients [86].
Use of more advanced diagnostic technologies will help bring
improvements in the use of antiretrovirals. Interpretation of
genotypic data with new phenotypic assays by using improved
algorithms can streamline drug resistance analyses and make them
more affordable. Also, use of new approaches, such as ultra-deep
sequencing for detection of populations of drug-resistant viruses
andultra-sensitiveviral loadassays for monitoringvirus replication
may achieve more widespread use.
5.2. Prevention and prophylaxis
It is probably the only approach for effectively controlling HIV,
which can ultimately lead to the eradication of this deadly virus.
Main focus is now given on the development of preventive vac-
cines. Efforts are going on for development of vaccines for creating
immunity. Besides this, topical microbicides and oral antiretroviral
prophylaxis are also being explored. Additional ways to reduce HIV
transmission include behavioral changes, medical control of STDs
and male circumcision.
Microbicides can be used to avoid infection through sexual
contact. A large number of topical microbicides have been tested
in clinical trials. Partial protection was achieved by PRO2000, a
non-specic entry/fusion inhibitor. But cellulose sulfate gel, 1%
C31G(SAVVY), carraguardandbuffer-gel products failedtoprevent
HIV transmission. A large number of trials with topically applied
antiretroviral agents, such as tenofovir are going on [87,88].
An effective vaccine that can prevent or cure HIV infection
remains the top priority. Several candidates in this aspect have
been developed but none has qualied so far. The main difcul-
ties for an effective vaccine is that HIV inoculum consists of a
geneticallydiversepopulationof quasispecies andthegenerationof
further diversity over the course of infection, which allows effec-
tive immune escape. Both mucosal and systemic immunity must
be elicited by a vaccine to give protection against transmission of
virus into the bloodstream. Besides, an effective HIV vaccine must
elicit robust humoral and cellular responses. The elite controllers, a
small subset of HIV-positive individuals, have an immune system,
which is able to mount potent antibody and cellular responses. The
capacity of HIV to mutate, allows it to develop new mechanisms
of evading the humoral immune system and shielding the major-
ity of the surface envelop glycoproteins, rapidly mutating exposed
epitopes without signicantly affecting the viral replication.
Several trials with combination treatment are being carried
out to reduce MTCT (Mother-to-Child Transmission) during intra-
partum period. Caesarean can further reduce HIV-1 transmission
during intrapartum period. Replacement feeding is often recom-
mended because HIV can be transmitted through breast-feeding.
Use of antiretrovirals during breast-feeding canalso reduce the risk
of transmission. Focus should be given on initiation of antiretrovi-
ral therapy in pregnant mothers with lowCD4
+
T cell counts at the
time of pregnancy and thereafter. The most effective MTCT therapy
involves a combination of three antiretroviral drugs taken during
pregnancy.
The successful HIV prevention strategies include:
-Azido-3
-deoxythymidine (BWA509U):
an antiviral agent that inhibits the infectivity and cytopathic effect of human
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