In 1981, the Centres for Disease Control reported cases of Pneumocystis
carinii pneumonia and Kaposi's sarcoma in previously healthy
young male homosexuals. Before then, pneumocystis carinii was
mainly known to occur in immunodepressed patients following organ
transplantation or suffering from congenital immunodeficiencies.
Shortly afterwards, the same condition was seen in IV drug
abusers, haemophilliacs and babies of IV drug abusing mothers. It
was recognized that these patients had profound immunosuppression
due to the depletion of T4 helper lymphocytes. The name acquired
immunodeficiency was coined for this syndrome. Epidemiological
studies soon established that this disease was infectious,
transmitted by sexual intercourse, blood or blood products. There
were initial difficulties in isolating the virus due to the fact
that the lymphocytes of patients died early. Eventually the virus
was isolated by Montagnier and Gallo in 1984. In 1986, HIV-2 was
isolated from West Africa which did not cross-react serologically
with HIV-1 in screening tests.
Basic Properties
Belong to the lentivirus subfamily of the retroviridae
Enveloped RNA virus, 120nm in diameter, contains 2 copies of
the RNA genome
Replication depends on reverse transcriptase
cytopathic viruses, in contrast to the oncornaviruses
HIV-2 less cytopathic for in cell culture than HIV-1, and
shares 40% nucleotide homology with HIV-1
HIV-II is more related to SIV than to HIV-I
genome consists of 9200 nucleotides (HIV-1)
gag core proteins - p15, p17 and p24
pol - p16 (protease), p31 (integrase/endonuclease)
env - gp160 (gp120:outer membrane part, gp41:transmembrane
part)
other regulatory genes are present in addition to the above
ie. tat, rev, vif, nef, vpr and vpu
Electronmicrograph of HIV particles
Schematic representation of an HIV particle
The replication cycle is as follows; The first
step of infection is the binding of gp120 to the CD4 receptor of
the cell, which is followed by the fusion of the virus and cell
membrane and is mediated by the gp41 molecule. The virus then
penetrates into the cell and uncoating, reverse transcription,
provirus synthesis and integration takes place. This is followed
by the synthesis and maturation of virus progeny.
Source: Mims C, Playfair J, Roitt I, Wakelin D,
Williams R. 1993.
Medical Microbiology. p. 24.16
During 1996, members of the seven-transmembrane spanning
receptor family of chemokine receptors were proved to be the
necessary co-receptors for HIV-1 entry. These receptors
were CXCR4 (fusin) for T-cell line (T)-tropic strains and (principally)
CCR5 for macrophage (M)-tropic strains. It is important to note
that both M- and T-tropic viruses replicate in primary CD4-positive
T cells (Figure 1), despite the confusing nomenclature, which
will soon be revised.
HIV Genotypes
The strains of HIV-1 can be classified into four groups: M,
N, O and P. The most important group, M, is the ‘major’ group and is responsible
for the majority of the global HIV epidemic. The other three groups (N, O, and
P) are quite uncommon and have only been found in Gabon, Cameroon and Equatorial
Guinea. Within group M there are known to be at least nine genetically distinct
subtypes of HIV-1. These are subtypes A, B, C, D, F, G, H, J and K.
Additionally, different subtypes can recombine with each other to form hybrid
virus, known as a ‘circulating recombinant form’ (CRFs). Some studies suggest
that certain subtypes have a greater risk of transmission or faster disease
progression than others. On the other hand, antiretroviral drugs (ARVs),
although largely developed in relation to subtype B, have generally proven to be
effective against a wide range of subtypes. The most prevalent HIV-1 genetic
forms are subtypes A, B, and C, with subtype C accounting for almost 50% of all
HIV-1 infections worldwide (Fig. 3). Subtype A viruses are predominant in areas
of central and eastern Africa (Kenya, Uganda, Tanzania, and Rwanda) and in
eastern European countries. Subtype B is the main genetic form in western and
central Europe, the Americas, and Australia and is also common in several
countries of Southeast Asia, northern Africa, and the Middle East and among
South African and Russian homosexual men. Subtype C viruses are predominant in
those countries with >80% of all global HIV-1 infections, such as southern
Africa and India. The relevance of CRFs in the global HIV-1 pandemic is
increasingly recognized, accounting for 18% of infections.
Pathogenesis_of_AIDS
The profound immunosuppression seen in AIDS is due to the
depletion of T4 helper lymphocytes. In the immediate period
following exposure, HIV is present at a high level in the blood (as
detected by HIV Antigen and HIV-RNA assays). It then settles down
to a certain low level (set-point) during the incubation period.
During the incubation period, there is a massive turnover of CD4
cells, whereby CD4 cells killed by HIV are replaced efficiently.
Eventually, the immune system succumbs and AIDS develop when
killed CD4 cells can no longer be replaced (witnessed by high HIV-RNA,
HIV-Antigen, and low CD4 counts).
HIV-1 Half-Lives. Activated cells that become infected with
HIV produce virus immediately and die within one to two days.
Production of virus by short-lived, activated cells accounts for
the vast majority of virus present in the plasma. The time
required to complete a single HIV life-cycle is approximately 1.5
days. Resting cells that become infected produce virus only after
immune stimulation; these cells have a half-life of at least 5-6
months. Some cells are infected with defective virus that cannot
complete the virus life-cycle. Such cells are very long lived,
and have an estimated half-life of approximately three to six
months. For a more detailed article on HIV pathogenesis, go to
the Medscape article "HIV
Pathogenesis and Viral Markers" Daniel R. Kuritzkes
The natural course of HIV infection is as follows;
1. Seroconversion illness - this is seen in 10% of
individuals a few weeks after inoculation and coincides with
seroconversion. These patients present with a mononucleosis like
illness which comprises of fever, sore throat, enlarged lymph
nodes, skin rash, joint aches and general malaise.
2. Incubation period - this is the period when the
patient is completely asymptomatic and may vary from a few months
to a more than 10 years. The median incubation period is 8-10
years. Children tend to have a shorter incubation period.
3. AIDS-related complex or persistent generalized
lymphadenopathy - at the end of the incubation period, a
number of signs and symptoms may appear which do not fulfill the
definition of AIDS or other HIV-associated syndromes. These
include slight immunological, dermatological, haematological and
neurological signs. Constitutional symptoms, such as fever,
weight loss, night sweats, and diarrhoea may develop. Generalized
lymphadenopathy may be seen. Laboratory findings may show a
decrease in the CD4 count, hyperimmunoglobulinaemia and
cytopenias.
The lymphadenopathy syndrome is defined as the enlargement of
lymph nodes to 1 cm or more at 2 or more body regions which
persists for more than 3 months without any other recognizable
cause other than HIV infection. AIDS-related complex is defined
as fever, weight loss, night sweats, or chronic diarrhoea of more
than 1 month's duration in the presence of disturbances of CMI
and in the absence of any other recognizable cause other than HIV
infection. These definitions may be in part overlapping and are
not mutually exclusive and they can be described generally as pre-AIDS.
4. AIDS - The first manifestation of HIV infection may
be noted at any disease stage and the different stages may not
occur consecutively. The transition to full-blown AIDS may occur
rapidly or slowly. The disease progression is probably influenced
by cofactors, such as other virus infections, stress, genetic
makeup of the individual etc. Poor prognostic factors include the
serial decrease in the number of CD4 lymphocytes, the
reappearance of HIV antigen in the blood, the decline or
disappearance of anti-core antibodies, and increased levels of B2-microglobulin
and neopterin. The diagnosis of AIDS is established with the
appearance of opportunistic infections, or of certain neoplasms,
such as Kaposi's sarcoma, primary lymphoma of the brain and other
non- Hodgkin's lymphomas. In the US, the diagnosis of AIDS is
also established by the finding of a CD4 count of less
than 200 cells/mm3.
a._Opportunistic_Infections
Protozoal
pneumocystis cariniI (now thought to be a fungi)
toxoplasmosis of the brain
crytosporidosis with diarrhoea
Opportunistic infections by protozoa, fungi, bacteria and
viruses are seen in patients with aids. Pneumonia caused by
Pneumocystis carinii is the most frequent opportunistic infection
in AIDS patients in N. America and Western Europe. The typical
symptoms are shortness of breath on exertion, dry cough and fever.
Diagnosis requires bronchoscopy and the demonstration of
Pneumocystis in the lavage fluid. Pentamidine and co-trimoxazol
are the treatment of choice. Toxoplasmosis is particularly
relevant because it causes CNS disease. It can be treated by a
combination of pyrimethamine and a sulfonamide. Cryptosporidium
frequently causes intractable diarrhoea for which no therapy is
available.
Candida Albicans is the second most frequent opportunistic
infection in AIDS patients. Thrush of the oral cavity is
frequently seen in patients with pre-AIDS. Candidiasis of the
oesophagus is a CDC criterion defining AIDS. Therapy is
relatively simple with amphomoronal solution or ketaconazol
tablets. Of further clinical importance is infection with the
fungus crptococcus neoformans which, if untreated, is fatal in
all cases. Early diagnosis may be made by the demonstration of
the fungus or fungal antigen in the CSF.
An increasing problem are infections with mycobacteria. In N.
America and Western Europe infections with the atypical
mycobacteria, M. avium-intracellulare and M. Kansaii etc.
dominate. In the developing countries, particularly in Central
Africa, the classic M tuberculosis is more frequent. Although
classic TB is treatable, no therapy exists for atypical
mycobacteriosis.The most frequent viral infections are caused by
CMV, HSV and VZV. CMV causes retinitis, colitis, or less
frequently pneumonitis and hepatitis. Treatment is possible with
DHPG. HSV and VZV infections are best treated by acyclovir.
b. Opportunistic Tumours
The most frequent opportunistic tumour, Kaposi's sarcoma, is
observed in 20% of patients with AIDS. For unknown reasons, KS is
observed mostly in homosexuals and its relative incidence is
declining. KS is a vascular tumour is in its characteristic form
is readily identifiable. In 30 to 40% of patients, the mucosal
membrane, most frequently the oral cavity and the larynx, and the
internal organs, most frequently the oesophagus, the stomach and
the intestines are affected. In most case, no treatment is
required. Excision, local treatment with vincristine or laser
irradiation are the mainstay of palliative therapy.
Malignant lymphomas of HIV-infected patients differ from other
known lymphomas by their localization, degree of malignancy, and
response to therapy. HIV-associated lymphomas are frequently
found outside the lymphatic system, particularly in the brain,
bone marrow, GI tract, and skin. Their response to therapy is
much poorer than that of classical lymphomas. The pathogenesis of
KS and HIV-associated lymphomas are uncertain. In the case of
lymphomas, at least a certain proportion appears to be associated
with EBV.
c. Neurological manifestations
A high percentage of HIV-infected patients shows neurological
changes that are not explained by opportunistic infections or
tumors. The spectrum of symptoms ranges from slight
neuropsychological abnormalities (disturbances of memory, mood
and behavior) to organic psychosis and complete dementia. In
almost all cases a continuous deterioration is observed. The most
frequent neurological disorder is subacute encephalitis (AIDS
encephalopathy, AIDS dementia complex) which is seen in two
thirds of cases. Other clinical manifestations may be seen, such
as acute meningoencephalitis, aseptic meningitis and peripheral
neuropathy.
d. Dermatological Manifestations
In all stages of HIV infection, characteristic skin
manifestations may be observed which frequently may be the first
symptoms which lead the patient to seek medical attention. HIV
specific conditions include oral hairy leucoplakia and an itching
maculopapular eruption. Seborrhoeic eczema occur in 70% of AIDS
patients and allergic exanthemas and acne like eruptions are also
very common. Viral induced skin eruptions are also frequently
seen, such as herpes zoster, cobdylomata acuminatum, verruca
vulgaris, molluscum contagiosum.
e. Gastrointestinal Manifestations
Persistent diarrhoea which may be copious in volume, is a
frequent problem among these patients. Giardia lamblia, Entamoeba
histolytica, Shigella, Salmonella and Campylobacter all cause
symptomatic disease. However, appropriate treatment does not
always eliminate the watery diarrhoea. Cryptosporadium, CMV, M.
avium intracellulare or Kaposi's sarcoma may also be associated
with diarrhoea. It had also been suggested that HIV itself may be
enteropathic through infection of the mucosal cells and/or
through attacking the autonomic nervous supply to the gut.
f. Manifestations in children and during pregnancy
In children, the clinical spectrum of HIV infection differs
from that observed in adults. The typical opportunistic
infections of adults are less frequent and bacterial infections
predominate. In about 50% of children, a pneumonia is observed
which is called lymphoid interstitial pneumonia. It had been
suggested that this pneumonia is directly caused by HIV. In
addition, failure to thrive, weight loss and neurological
symptoms are seen.
HIV transmission to the fetus has been observed as early as
the 15th week of pregnancy. Prenatal infection may cause a HIV-
specific embryopathy in the majority of infected children. This
is characterized by a small forehead, short flat nose, pronounced
philtrum, microcephaly, thick lips and hypertelorism. The numbers
of newborns infected by their mothers have been rising steadily.
The transmission rate from mother to the newborn is estimated at
one-third. There is also evidence to suggest that pregnancy also
favours the progression of the HIV disease in the mother. The
maternal-fetal transmission rate varies geographically from
around 15% in Western Europe to up to 50% in Africa. It appears
the most important determinant is the virus load present in the
mother.
The earliest unambiguously identified HIV-antibody positive
serum stems from Kinhasa, Zaire dating back to 1959. It is evident that HIV
infection spread unrecognized in the 1960s and 1970s. As of 2015, 78 million
people had been infected with HIV since the beginning of the epidemic and 35
million had died from AIDS related illnesses. There were 2.1 million new HIV
infections in 2015. Of the 36.7 million people living with HIV, 18.2 million
were receiving antiretroviral therapy. It is still not completely clear to what
extent the mode of transmission, virus dose, cofactors, and genetic
predisposition influence the infection and the incubation period. It is now
thought that up to 95-99% of all untreated HIV-infected persons eventually
develop AIDS.
Seroconversion - the interval between infection and
seroconversion was generally assumed to last about 3 to 12 weeks.
Recently, serolatency of many months and up to several years have
been recognized in some patients.These observations may have far-
reaching implications.
Incubation period - the actual incubation period cannot
be predicted in individual cases. The available evidence so far
points to an median incubation period of 8 to 10 years (range: a
few months to more than 14 years)
Manifestation rate - the percentage of infected persons
who finally develop AIDS increases with the duration of the
infection by an average of 5 to 7% per year.
Modes of transmission - HIV is transmitted by sexual
contact, blood and blood products, or from the mother to the
newborn infant. Other theoretical ways of transmission such as by
saliva or insects do not play a role in the epidemiology of HIV
infection. Evidence is increasing that the infectivity of HIV-infected
individuals vary with the course of infection. It appears that
infectivity is correlated with viraemia and is greater very early
after infection before the appearance of antibodies and later in
the course after the development of symptomatic immunodeficiency.
Risk groups - male homosexuals and bisexuals constitute
the largest risk group in N. America and Western Europe. Anal
intercourse and the multiplicity of partners in the case of
homosexuals are the risk factors in the case of homosexuals.In
contrast, heterosexual spread is the largest category in
developing nations and may be associated with other sexually
transmitted disease, particularly those causing genital ulcers.
Prostitutes, particularly IV drug-abusing prostitutes are
important multiplicators of the epidemic. The infection rate of
prostitutes ranges from 0% in some European and American cities
to 90% in some African cities.
HIV is transmitted by blood transfusions, clotting factors,
and by contaminated needles and syringes. Blood transfusions as a
cause of infection have been virtually eliminated in Western
Europe and N. America since the introduction HIV antibody
screening in 1985 but it continue to be a important cause of HIV
transmission, particularly in Central Africa because of the high
degree of infection of the donors and the lack of resources to
implement the screening of the donor's blood. Infection
transmitted via clotting factor have been eliminated since HIV
inactivation steps have been included in their production process
since 1985. IV drug abusers represent the largest AIDS patient
groups in Italy (65%) and Spain (54%) and the second largest
group in the US and the majority of Western European countries.
The increase in HIV-infected mothers, mostly drug-dependent is
paralleled by an increase of HIV-infected newborns. The
transmission rate from infected mothers to their newborn infants
is about one-third. Medical personnel are not considered to be a
risk group. By April 1988, only 22 cases of medical personnel
infected via needle injuries and contact with the blood of HIV-infected
persons have been described worldwide.
Incidence and prevalence of HIV infection - no reliable
data exist on the incidence and prevalence of HIV infection in
the general population. The prevalence of HIV infections in
homosexuals in the US ranges from 20% to 70% in some urban
centres. On the basis of studies of samples from HIV risk groups
and from the general population, the total prevalence of HIV-infected
persons has been estimated in several countries. The prevalence
of HIV infected persons in the USA was estimated to be 1 to 1.5
million in June 1988.
The worldwide distribution of AIDS
Africa - HIV infection is not limited to certain risk
groups. The male:female ratio is 1:1 in contrast to Western
Europe and N. America where the ratio is approximately 13:1. The
extent of infection in the general population is considerable in
some regions, mainly in the large cities and in some rural areas.
In Kinshasa (Zaire) the prevalence of HIV infection was 7% in
pregnant women and blood donors in early 1988. The seropositivity
rate amongst blood donors in Kigali (Uganda) was 18% in 1984. The
highest infection rates were found in prostitutes and in patients
with sexually transmitted diseases.
Caribbean and South America - In these countries, the
transmission is homosexual and heterosexual. The male:female
ratio in Haiti is 4:1, suggesting that heterosexual transmission
is important.
Asia and Australia - the prevalence of HIV infection in
Asia is rising dramatically, especially in Thailand and India. It
is predicted that HIV infection in Asia will outstrip that in
Africa in due course. Most of the initial cases stem from Japan
and Israel. Transmission was primarily by students from Africa
and by contacts of Asian business people abroad. The epidemiology
of AIDS in Australia and New Zealand is similar to that of other
industrialized countries of N. America and Western Europe.
Several hypothesis regarding the origin of HIV have been
developed (1) mutation of older viruses (2) transmission of
animal viruses eg. SIV to man (3) transmission by an isolated
remote section of the population eg. by change of sexual behavior
and mobility. Available data at present favour the third
possibility.
1. Serology - the diagnosis of HIV infection is usually
based on serological tests.
(a) Antibody tests - ELISAs are the most frequently
used method for screening of blood samples for HIV antibody. The
sensitivity and specificity of the presently available commercial
systems approaches 100% but false positive and false negative
reactions occur. Other test systems available include passive
particle agglutination, immunofluorescence, Western blots and
RIPA bioassays. Western blots are regarded as the gold standard
and seropositivity is diagnosed when antibodies against both the
env and the gag proteins are detected. The sensitivity of the
test systems are currently being improved by the use of
recombinant antigens.
Interpretation of Western blot results for HIV antibody
(b) Antigen tests - HIV antigen can be detected early
in the course of HIV infection before the appearance of antibody.
It is undetectable during the latent period (antigen-antibody
complexes are present) but become detectable during the final
stages of the infection. It was argued that the routine use of
antigen screening tests in the blood transfusion service may
result in earlier cases of HIV infection being identified.
However a large scale study carried out in the US failed to show
any benefit.
2. Virus isolation - virus isolation is accomplished by
the cocultivation of the patient's lymphocytes with fresh
peripheral blood cells of healthy donors or with suitable culture
lines such as T-lymphomas. The presence of the virus can be
confirmed by reverse transcriptase assays, serological tests, or
by changes in growth pattern of the indicator cells. However
virus isolation is tedious and time consuming (weeks) and is
successful in only 70 to 90% of cases. Therefore virus isolation
is mainly used for the characterization of the virus.
3. Demonstration of viral NA - this can be accomplished
by probes or by PCR techniques. The latter may be useful because
of its extremely high sensitivity.
4. Prognostic Tests - the following may be useful as
prognostic tests; (1) HIV antigen (2) Serial CD4
counts (3) Neopterin (4) B2-microglobulin. (5) Viral
load. Of these tests, only serial CD4 counts and HIV viral load
are still routinely used.
a. HIV viral load - It appears that HIV viral load has
the greatest prognostic value. HIV viral load in serum may be
measured by assays which detect HIV-RNA e.g. RT-PCR, NASBA, or
bDNA. HIV viral load has now been established as having good
prognostic value, and in monitoring response to antiviral
chemotherapy. Patients with a low viral load during the
incubation period had a better prognosis than those with a high
viral load. Patients whose viral load decreased significantly
following the commencement of antiviral therapy had a better
prognosis than those who did not respond.Among patients who
responded to antiviral therapy, those who had a low pre-treatment
viral load had a better prognosis than those who had a high pre-treatment
viral load.
b. CD4 counts - despite the increasing use of HIV-RNA
assays, measurement of CD4 still has important value in
monitoring disease progression and response to antiviral
chemotherapy. whereas CD4 count gives an indication of the stage
of disease. “The measurement of HIV viral load tells
us where the disease is going, whereas CD4 count tells us where
the disease is at this moment”
Because of the increasing range of anti-HIV agents available,
there is increasing pressure on the provision of antiviral
susceptibility assays. There are two types of antiviral
susceptibility assays: phenotypic and genotypic assays
Phenotypic assays define whether a particular strain of virus
is sensitive or resistant to an antiviral agent by determining
the concentration of the drug needed to inhibit the growth of
virus in vitro. e.g. Plaque-reduction assay for HSV, plaque-reduction
assay for HIV. However, phenotypic assays can only be used for
viruses that can be cultivated. Moreover, in the case of HIV,
plaque reduction assays may not be that appropriate since not all
HIV strains produce plaques in cell culture.
In the case of genotypic assays, mutations that are associated
with resistance are assayed for by molecular biology methods such
as PCR and LCR. However, these assays are tedious and are
not suitable for a routine diagnostic laboratory. Moreover, he
results of genotypic assays may prove very difficult to interpret
since HIV mutates at a furious pace, and it is also
possible that resistant strains are present right at the
beginning of infection.
The huge resources that had gone into HIV research had
resulted in the development of a large number of anti-HIV agents. The speed of
advance in this area is unprecedented in the history of medicine and is one of
the greatest successes. To date with the correct therapy, there is no reason why
an HIV-infected person cannot have the same life expectancy as a non-infected
person. Therapy of HIV is complicated by the fact that the HIV genome is
incorporated into the host cell genome and can remain there in a
dormant state for prolonged periods until it is reactivated.
However although it may or not be possible to actually eradicate the virus
completely, it seems possible that the infection can be indefinitely contained
so that an infected will die with HIV infection rather than from it.
Zidovudine (AZT) was the first anti-viral agent used for the
treatment of HIV and was introduced in 1987. However, it became clear with
Concorde study in 1994 that monotherapy with AZT did not provide durable
efficiency and hardly made any dent in the mortality rate. In 1995, results of
the European DELTA and the American ACTG 175 studies became available and showed
that combination therapy with two nucleoside analogues were better than
monotherapy with one alone. A further breakthrough occurred with the
introduction of HIV protease inhibitors which were specifically designed against
HIV protease and were shown to be the most potent anti-HIV effect to date. An
early clinical trial reported that the use of oral ritonavir decreased HIV
mortality from 38% to 22%. Combination therapy, otherwise known as HAART (highly
active antiretroviral therapy) using two or three agents became available. The
rationale for this approach is that by combining drugs that are synergistic,
non-cross-resistant and no overlapping toxicity, it may be possible to reduce
toxicity, improve efficacy and prevent resistance from arising. The final
breakthrough occurred when David HO (Time Magazine Man of the Year 1996) finally
elucidated the pathogenesis of HIV infection. He showed that far from being
latent during the "latent phase" as previously thought, there is actually
massive replication during this period. David Ho had coined the slogan "hit hard
and early". The results of the new approach was seen quickly where within Within
four years, between 1994 and 1998, the incidence of AIDS in Europe sank from
30.7 to 2.5/100 patient years i.e. to less than a tenth.
What is less hopeful is the possibility of ever eradicating
HIV from the body i.e. complete cure. In the beginning, it is thought that
continuous treatment for 3 years would be sufficient to eradicate all the
remaining latently infected cells. However, the period of treatment required
kept on being revised upwards as new data became available. The most recent
estimate of eradication of all latently infected cells is 73.3 years. Therefore,
it is clear it will not be possible to achieve a complete cure in the short
term. Compliance is a major issue when therapy is expected to be life-long.
There is clearly a great need to have formulations whereby the number of tablets
to be taken per day is kept to a minimum. The development of side-effects with
long term use is another issue.
As knowledge builds up on the risks and efficacy on various
agents and regimens, recommendations on HIV are being continually revised. So
now, instead of "hit hard and early", there is a shift towards "hit hard, but
only when necessary". There is still a lot of debate on when to actually
commence therapy. Two measures are used for determining whether to start HIV
therapy: CD4 counts and viral loads. It is generally agreed that HIV therapy
should be given when the CD4 count is below 200. Some experts would recommend
treatment for any patient whose CD4 count is below 350. What is less clear are
patients with CD4 counts of 300-500 and a modest viral loads. A decision to
start therapy must be taken on an individual basis with the patient after
thorough discussion and counseling.
1. Anti-Retroviral Agents
A. Nucleoside Reverse Transcriptase Inhibitor
Zidovudine (Retrovir, AZT)
Didanosine (Videx, Videx EC, ddI)
Stavudine (Zerit, d4T)
Lamivudine (Epivir, 3TC)
Abacavir (Ziagen, ABC)
Tenofovir, a nucleotide analog (Viread, TDF)
Combivir (combination of zidovudine and lamivudine)
Trizivir (combination of zidovudine, lamivudine and abacavir)
Emtricitabine (Emtriva, FTC)
Truvada (combination of emtricitabine and tenofovir)
Epzicom (combination of abacavir and lamivudine)
B. Non-Nucleoside Reverse Transcriptase Inhibitor
Nevirapine (Viramune, NVP)
Delavirdine (Rescriptor, DLV)
Efavirenz (Sustiva or Stocrin, EFV, also part of Atripla)
Etravirine (Intelence, ETR)
Rilpivirine (Edurant, RPV, also part of Complera or Epivlera).
C. HIV Protease Inhibitors
Saquinavir (Invirase, SQV)
Indinavir (Crixivan, IDV)
Ritonavir (Norvir, RTV)
Nelfinavir (Viracept, NFV)
Amprenavir (Agenerase, APV)
Lopinavir/ritonavir (Kaletra or Aluvia, LPV/RTV)
Atazanavir (Reyataz, ATZ)
Fosamprenavir (Lexiva, Telzir, FPV)
Tipranavir (Aptivus, TPV)
Darunavir (Prezista, DRV)
D. HIV Entry Inhibitors
Enfuvirtide (Fuzeon, ENF, T-20)
Maraviroc (Selzentry or Celsentri, MVC)
E. HIV integrase inhibitors
Raltegravir (Isentress, RAL)
Elvitegravir (EVG, part of the combination Stribild)
Dolutegravir (Tivicay, DTG)
There are a number of combination preparations on the market
e.g. CBV (AZT+3TC), TZV (AZT+3TC+ABC), TVD (FTC+TDF), Kaletra (Lopinavir/ritonavir).
The use of combination preparations will reduce the numbed of tablets that need
to be taken each time.
2. Monitoring anti-HIV therapy
a. Viral Load
Initiation - viral load is now the preferred
method of monitoring therapy. There should be >= 1 log
reduction in viral load, preferably to less than 10,000
copies/ml HIV-RNA within 2-4 weeks after the commencement
of treatment. If <0.5 log reduction in viral, or HIV-RNA
stays above 100,000, then the treatment should be
adjusted by either adding or switching drugs.
Monitoring - viral load measurement should be
repeated every 4-6 months if patient is clinically stable.
If viral load returns to 0.3-0.5 log of pre-treatment
levels, then the therapy is no longer working and should
be changed.
b. CD4 count
Initiation - within 2-4 weeks of starting
treatment, CD4 count should be increased by at least 30
cells/mm3. If this is not achieved, then the
therapy should be changed.
Monitoring - CD4 counts should be obtained every 3-6
months during periods of clinical stability, and more
frequently should symptomatic disease occurs. If CD4
count drops to baseline (or below 50% of increase from
pre-treatment), then the therapy should be changed.
c. Anti-HIV Drug Resistance Testing
Anti-retroviral drug resistance testing has become part
and parcel of patient management in N. America and W. Europe.
Many studies in treatment experienced patients have shown strong
associations between the presence of drug resistance and failure
of the antiretroviral treatment regimen to suppress HIV
replication.
Genotypic Assays - genotypic assays detect drug
resistance mutations that are present in the relevant
viral genes (i.e. RT and protease). Some genotyping
assays involve sequencing of the entire RT and protease
genes, while others utilize oligonucleotide probes to
detect selected mutations that are known to confer drug
resistance. Genotyping assays can be performed relatively
rapidly, such that results can be reported within 1-2
weeks of sample collection. Interpretation of test
results requires an appreciation of the range of
mutations that are selected for by various antiretroviral
drugs, as well as the potential for cross-resistance to
other drugs conferred by some of these mutations.
Phenotypic Assays - phenotypic assays measure the
ability of viruses to grow in various concentrations of
antiretroviral drugs. Automated, recombinant phenotyping
assays have recently become commercially available with
turn-around times of 2-3 weeks; however, phenotyping
assays are generally more costly to perform compared with
genotypic assays. Recombinant phenotyping assays involve
insertion of the RT and protease gene sequences derived
from patient plasma HIV RNA into a laboratory clone of
HIV. Replication of the recombinant virus at various drug
concentrations is monitored by expression of a reporter
gene and is compared with replication of a reference
strain of HIV. The concentrations of drugs that inhibit
50% and 90% of viral replication (i.e. the IC50 and IC90)
are calculated, and the ratio of the IC50s of the test
and reference viruses is reported as the fold increase in
IC50, or fold resistance. Interpretation of phenotyping
assay results is complicated by the paucity of data on
the specific level of resistance (fold increase in IC50)
that is associated with failure of different drugs.
Use in clinical setting - resistance assays may be
useful in the setting of virological failure on
antiretroviral therapy. Recent prospective data
supporting the use of resistance testing in clinical
practice come from trials in which the utility of
resistance tests were assessed in the setting of
virological failure. The VIRADAPT and GART studies
compared virological responses to antiretroviral
treatment regimens when genotyping resistance tests were
available to help guide therapy with those observed when
changes in therapy were guided solely by clinical
judgment. The results of both studies indicated that the
short-term virological response to therapy was
significantly greater when results of resistance testing
were available. Similarly, a recent prospective,
randomized, multicenter trial has shown that therapy
selected on the basis of phenotypic resistance testing
significantly improves the virological response to
antiretroviral therapy, compared with therapy selected
without the aid of phenotypic testing. Thus, resistance
testing appears to be a useful tool in selecting active
drugs when changing antiretroviral regimens in the
setting of virological failure.
The rapidity of developments in anti-HIV therapy makes it
virtually impossible for this site to keep up. For the latest
information on HIV and anti-retroviral therapy, I recommend the
HIV page at Medscape.com
The risk of contracting HIV increases with the number of
sexual partners. It is interesting to note that the first cases
of AIDS which were reported in homosexuals admitted to having
more than 100 sexual partners per year. A change in the lifestyle
would obviously reduce the risk. Paediatric AIDS generally occur
early in life although some children have survived congenital
infection for many years. Infected infants may serve as worldwide
reservoirs of AIDS if they survive infancy, as in the case of
hepatitis B.
Because of the use of HIV medicines and other strategies, the
risk of mother-to-child transmission can be lowered to 1% or less. The risk of
mother-to-child transmission of HIV is low when:
HIV is detected as early as possible during pregnancy (or
before a woman gets pregnant).
Women with HIV receive HIV medicine during pregnancy and
childbirth and, in certain situations, have a scheduled cesarean delivery
(sometimes called a C-section).
Babies born to women with HIV receive HIV medicines for 4
to 6 weeks after birth and are not breastfed.
The spread of HIV through blood transfusion had virtually been
eliminated since the introduction of blood donor screening in
many countries. It must be borne in mind that recently infected
donors who have yet to develop antibodies will escape detection.
There had also been recent reports of new virus isolates from
patients serologically negative for HIV, yet who may have AIDS-
related symptoms. Blood products such as factor VIII now undergo
routine treatment which appears to inactivate any HIV present
effectively.
Development_of_vaccines
An effective vaccine against HIV would have to elicit
protection against both free virus and virus-infected cells. HIV
neutralizing antibodies. Several examples of retroviral
infections eg. FeLV, suggest that neutralizing antibodies on its
own may be protective. The observation that HIV-neutralizing
antibodies do not prevent the progression of the disease and the
induction of neutralizing antibodies in chimpanzees by HIV gp160
do not prevent infection by HIV argues against the possibility
that neutralizing antibodies are sufficient for protection
against infection by HIV. Individuals with high neutralizing
antibody titres, however, seem to have a longer disease free
interval. Cellular immune response may be important for
protection and may take place through Tc cells, NK cells and ADCC
mechanisms. The role of these mechanisms in the protection
against HIV infection and their relevance for anti-HIV
vaccination are still unclear. Another obstacle to the development of an effective HIV
vaccine may be the high genetic variability of HIV, which resides
mainly in the env gene. In certain regions of the envelope gene,
the variability may be as high as 50%. However, conserved regions
exist in the gp120 and the gp41 region which can be recognized by
HIV sera and neutralizing antibodies can be induced with peptides
representing these regions. The main types of approaches to an
AIDS vaccine is as follows:
Live attenuated virus
Inactivated virus
Live recombinant viruses
Synthetic peptides
Recombinant DNA products (gp120, gp160)
Native envelope and/or core proteins
Anti-idiotypes antibodies
Passive immunization
Because of the serious nature of the disease and the ability
of retroviruses to induce latency, it is unlikely that live
attenuated or inactivated virus will ever be acceptable for human
use. Live recombinant viruses such as vaccinia or adenovirus
recombinant have been developed for HIV vaccination. They carry a
high immunogenicity since virus replication result in large
quantities of virus antigen. Both humoral and cellular immunity
can be induced. A disadvantage of this approach is possible
adverse effects observed after inoculation of vaccinia virus. Synthetic peptides can be designed such that
neutralizing and T cell epitopes can be included. The problems
with synthetic peptides are related to the tertiary structures
which may be different from those of native proteins. Another
promising approach is the production of recombinant viral
antigens, especially the gene products of the env region, and the
membrane associated p17 core protein. An alternative approach
would be the use of anti-idiotype antibodies whose usefulness had
been demonstrated against several infectious agents. Passive
immunization may eventually be available for postexposure protection.
As of 2007, despite 34 years of intense unprecedented
research, the development of an effective HIV vaccine appears to be as far off
as ever. There is a prevailing mood of pessimism that an HIV vaccine will not be
available for at least another 10 years or more, if ever. The reason for this
pessimism is the failure of the Phase IIb trial of the V520 vaccine in humans.
Although a large number of animal trials have been carried out with different
candidate vaccine. V520 was the first candidate to be tested in humans. V520
uses a recombinant adenovirus vector with 3 HIV genes and had shown great
promise in previous animal trials. It is thought that besides offering
protection against infection, it may offer therapeutic effects to those who had
been infected. However, it did not provide any protection against infection to
those who had been given the vaccine and those infected did not have a reduced
viral load. Why a candidate vaccine that had worked so well in an animal model
but failed in humans will be the subject of vigorous investigation. In February
2003, VaxGen announced that their AIDSVAX vaccine phase III trial was a failure
in North America as there was not a statistically significant reduction of HIV
infection within the study population. AIDSVAX was also a component of the prime
boost (ALVAC/AIDSVAX). RV 144 vaccine study in Thailand that showed marginal
successful results. In both cases the vaccines targeted gp120 and were specific
for the geographical regions. The Thai trial was the largest AIDS vaccine trial
to date when it started.
