HSV-2 & HIV: Consequences of an Endemic Opportunistic Infection
by Anna Wald, MD(1), Timothy Schacker, MD(2), Lawrence Corey, MD(3)
Infections with herpes simplex viruses (HSV) are very common among
persons with HIV infection. Despite the frequent co-infection with both
viruses, the interactions between HSV and HIV have been not fully
elucidated. However, evidence suggests that these interactions occur on
epidemiologic, clinical, and cellular levels:
HSV is a risk factor for acquisition and transmission of HIV;
HSV is a common opportunistic pathogen in the HIV infected person; and
HSV reactivation appears to up regulate HIV replication.
The clinical significance of these interactions
has not been well defined. In this article, we review the current
information about HSV-HIV interactions and suggest future directions for
this research.
Genital herpes and transmission and acquisition of HIV
Several studies have found that persons with HIV infection also have high
prevalence of HSV-2 infection. However, it remains unclear whether HSV-2 is
a marker for high risk sex behavior, or whether it truly facilitates
acquisition of HIV infection. Both epidemiologic studies of HIV acquisition
and the biology of HSV lesion suggest that the latter is true.
At least
five studies conducted in various populations suggest that those with HSV-2
infection are more likely to be HIV infected. The increase in risk of HIV
infection ranges from 2-fold to 7.5-fold. For example, in a longitudinal
study of heterosexual couples in Europe, those susceptible partners who had
a history of genital ulcers were 5.2 times as likely to acquire HIV than the
susceptible partners who did not have a history of genital ulcers.
Two biological aspects of genital herpes support the hypothesis that HSV-2 facilitates HIV acquisition. Genital ulcers cause a mucosal disruption, which may allow entry of HIV. Also, genital herpes lesions attract activated CD4 cells that act as target cells for HIV attachment.
Fewer data are available on the relationship between HSV-2 infection and HIV
transmission, as transmitters of disease are more difficult to study.
However, in an early description of a cluster of HIV infection among women,
a man who had HIV infection unknowingly infected 14 of 19 women with whom he
had sexual relations. He had a history of recurrent genital herpes.
Other
studies have also suggested that transmission of HIV is more likely to occur
from a person who has genital ulcers. This has been shown both for female
to male as well male to female transmission. In 1989, Kreiss and colleagues
detected HIV in 4 of 36 ulcers in women; subsequently, HIV has also been
detected in ulcers among men. These early studies were done in Kenya where
chancroid was the predominant cause of ulcerations. As genital herpes is
the most common cause of genital ulcers in the United States, we have
investigated whether we can recover HIV from genital herpes lesions in
persons with HIV infection.
Twelve men with a history of genital herpes were enrolled in this study.
The median CD4 count was 186 and the median plasma HIV RNA 41,000 (this
study was conducted prior to introduction of protease inhibitors). None of
the participants had a history of difficult to treat genital herpes. The
12 clients were followed for 26 episodes of genital herpes; 23 healed
without anti-herpes therapy, while 3 healed after administration of
acyclovir. Clients were seen within 24 hours of new recurrence and then
every other day, and swab samples were obtained from their genital lesions
for HIV polymerase chain reaction (PCR) assay. HIV RNA was detected in 25
out of 26 recurrences and in 116 of 170 lesion samples. Three-fourths (75%)
of the HIV RNA-positive samples contained 10,000 or more copies of HIV/ml.
In addition, the PCR signal was detected only when reverse transcriptase was
added to the reaction, suggesting that only virion RNA was present and not
proviral DNA. HIV was detected in lesions of people with high and low viral
loads, and regardless of concurrent antiretroviral therapy. In one person
in whom acyclovir was started on the fifth day of his genital herpes
recurrence, the levels of HIV RNA in lesions fell rapidly as the lesions healed.
This study supports the hypothesis that persons who have HIV and genital
herpes may transmit HIV infection to others more easily than those who are
not HSV-2 infected. In addition, it suggests that therapy of genital herpes
may curb transmission of HIV to susceptible sexual partners.
High rates of HSV shedding in the genital tract of the HIV infected persons
Large, chronic, persistent herpes ulcers were among the first opportunistic
infections described in homosexual men in 1981. Since that time, advanced
HIV infection has been associated with severe genital herpes and the
emergence of acyclovir resistance. Because of the unusual severity of
genital herpes in some HIV infected persons, persistent herpetic ulcerations
are an AIDS-defining diagnosis. Yet in spite of the anecdotal reports of
painful and difficult to treat genital herpes in some persons with HIV
infection, the natural history of HSV in HIV infected persons has not been
well defined. Clinical experience suggests the rate of clinical recurrences
(outbreaks) may be increased and that the response to antiviral therapy may
be delayed.
To assess the impact of HIV infection on the natural history of
genital herpes, we followed prospectively a cohort of 68 men with HIV and
HSV-2 infection. The men obtained daily swabs for viral culture from the
urethra, penile skin, and the perianal area, and maintained a diary of
recurrences. The median duration of study participation was 55 days. We
found that, overall, the rate of shedding was very high: HSV-2 was isolated
on 9.7% of days of cultures. In comparison, HIV seronegative men have a
significantly lower rate of shedding: 3.3% of days for men who have sex with
men (MSM), and 4.7% for heterosexual men in two separate studies. Shedding
was especially high in the perianal area, where virus was isolated on 8.6%
of the days. Of interest, the most common site of shedding among MSM men
who are HIV-negative is also the perianal area (2.9% of days), while among
heterosexual men the most common site is the penile skin (3.3% of days).
Most of the increase in the total shedding rate is accounted for by a
dramatic increase in the subclinical shedding rate, defined as the presence
of the virus on skin in the absence of herpes lesions. The subclinical
shedding rate was 7.3% of days among HIV-positive MSM, compared with 2.4% of
HIV-negative MSM and 2.2% of HIV-negative heterosexual men.
Thus it appears that the viral shedding rate is about three-fold higher in
HIV-positive versus HIV-negative men. The shedding rate was especially
increased among men who have CD4 counts below 200: the risk of shedding was
twice as high among men with CD4 counts less than 200 versus those with
higher CD4 counts. Therefore, the increase in the rate of viral shedding
appeared closely related to the degree of immunosuppression.
In a smaller group of people, we also examined viral shedding using the HSV
DNA polymerase chain reaction (PCR) test. This test was developed at the
University of Washington and detects minute amounts HSV DNA (1 to 10
copies/sample). Among 14 men who were studied with both viral culture and
HSV DNA PCR test, HSV was isolated in culture on 25% of days, but HSV DNA
was detected on 48% of the days. In fact, 5 of 14 men had HSV DNA detected
on more than 50% of the days. The high rate of positivity by both culture
and PCR was especially striking in men with CD4 counts under 200.
The HSV
DNA PCR assay is also able to estimate the number of viral copies present in
each sample. Using this semiquantitative measure, we found that people with
a CD4 count under 200 had 10 times the HSV DNA in the swab samples than
people with higher CD4 counts had. Therefore, it is clear that persons with
HIV-induced immunosuppression not only shed HSV more frequently, but also
that the shedding is associated with much more virus on the genital skin.
HSV reactivation upregulates HIV replication.
Several in-vitro laboratory studies have indicated that certain regulatory
HSV proteins (ICPO, ICP27, and VP16) can upregulate HIV replication. In
addition, both HSV-2 and HIV can co-infect CD4+ cells suggesting that these
viruses may interact frequently in vivo. At the same time, several clinical
studies have shown that opportunistic infections, or other means of immune
activation (such as Pneumocystis carinii pneumonia, bacterial pneumonia,
tuberculosis, or immunizations) can stimulate HIV replication and, at least
transiently, increase viral load. Recently, Mole and colleagues have shown
that the plasma HIV viral load increases in people with recurrences of
genital herpes. It is not known how these increases contribute to overall
progression of HIV disease.
Intriguing results have also been obtained from clinical trials that
suggested that administration of acyclovir is associated with increased
survival in HIV infected persons. While not all of the studies found that
effect, there is speculation that reactivation of HSV may accelerate
progression of HIV disease.
To examine this issue, we followed 12 people
(whose median CD4 count was 246) who were on stable antiretroviral therapy
(prior to introduction of protease inhibitors). Clients with serial plasma
HIV viral loads were evaluated, initially without acyclovir, and then while
being treated with acyclovir 800 mg tid (three times a day). The median
period of observation was 65 prior days prior to acyclovir and 62 days on
acyclovir therapy. Plasma HIV RNA was determined on average twice a week
during these observations. We found that the HIV RNA decreased from a mean
of 25,527 to 16,444 copies/ml, a 35% decrease. Also of interest, the
decrease was observed in all 12 people. This study supports the observation
that acyclovir may slow the progression of HIV disease by preventing
reactivation of HSV.
Summary
Currently available data suggest that several important interactions occur
between HSV and HIV. First, HIV shedding from genital herpes lesions is
frequent. Therefore, HSV is likely to facilitate transmission of HIV to
uninfected sexual partners. Second, HSV shedding in men with HIV infection
is chronic and mostly subclinical. Because men are not aware when they are
shedding HSV, they may engage in unsafe sex during HSV reactivation,
increasing the risk of transmission of both HSV and HIV. Third, acyclovir
therapy appears to decrease plasma HIV RNA. This supports the importance of
HSV as an endemic opportunistic infection and suggests that chronic
antiherpes therapy may provide benefit in some persons with HIV infection.
These studies leave several questions unanswered:
Is subclinical reactivation of HSV also associated with HIV shedding in the
genital tract? This would be important, as most episodes of HSV shedding
are not associated with recognized lesions.
Does treatment of genital HSV with antivirals decrease or prevent genital
shedding of HIV? Would such treatment prevent transmission of HIV to
susceptible sexual partners?
Can suppression of HSV with antiviral drugs reduce systemic and mucosal
levels of HIV RNA? Which people benefit more or less from such therapy?
Would this effect still be true in people who are treated with highly
active antiretroviral therapy (HAART), combination antiretroviral therapy
with protease inhibitors? No studies of natural history of HSV in persons
with HIV infection have been done since protease inhibitors were introduced
into clinical practice. Preliminary information regarding the effect of
protease inhibitors on the immune system is contradictory; some studies
suggest that immune reconstitution occurs, while others suggest that even
when the therapy is associated with an increase in CD4 cells, mature CD4
cells are not replaced.
Does HAART result in reconstitution of HSV-specific immune response?
The interest in opportunistic infections, including HSV, has abated somewhat
with the introduction of HAART. However, it is clear that many questions
remain regarding the relationship between HSV and HIV, both on clinical and
cellular levels.
Any person interested in participation in studies designed
to answer these important questions is invited to call the University of
Washington Virology Research Clinic at 206-720-4340 for more information.
Anna Wald, M.D., Department of Medicine,
University of Washington, Seattle, Washington;
Timothy Schacker, M.D., Department of Medicine,
University of Washington, Seattle, Washington,
currently at University of Minnesota, Minneapolis, Minnesota;
Lawrence Corey, M.D., Departments of Laboratory and Medicine,
University of Washington, Program Infectious Diseases, Fred Hutchinson Cancer Research
Center, Seattle, Washington
Selected references:
Albrecht M, DeLuca N, Bryn R, Schaffer P, Hammer S. The herpes simplex
virus immediate-early protein, ICP4 is required to potentiate replication of
human immunodeficiency virus in CD4+ lymphocytes. J Virol 1989;63:1861-1868
Augenbraun M, Feldman J, Chirgwin K, Zenilman J, Clarke L, DeHovitz J,
Landesman S, Minkoff H. Increased genital shedding of herpes simplex virus
type 2 in HIV-seropositive women. Ann Intern Med 1995;123:845-847
Clumneck N, Taelman H, Hermans P, Piot P, Schoumacher M, DeWit S. A
cluster of HIV infection among heterosexual people without apparent risk
factors. N Engl J Med 1989;321:1460-1462
Cooper D, Pehrson P, Pedersen C, Moroni M, Oksenhendler E, Rozenbaum W,
Clumeck N, Faber V, Stille W, Hirschel B, Farthing C, Doherty R, Yeo J, and
a European-Australian Collaborative Group. The efficacy and safety of
zidovudine alone or as co therapy with acyclovir for the treatment of
patients with AIDS and AIDS-related complex: a double-blind, randomized
trial. AIDS 1993;7:197-207
de Vincenzi I. A longitudinal study of human immunodeficiency virus
transmission by heterosexual partners. N Eng J Med 1994;331:341-342
Kreiss J, Coombs R, Plummer F, Holmes K, Nikora B, Cameron W, Ngugi E,
Ndinya-Achola J, Corey L. Isolation of human immunodeficiency virus from
genital ulcers in Nairobi prostitutes. JID 1989;160:380-384
Siegal F, Lopez C, Hammer G, Brown A, Kornfeld S, Gold J, Hassett J,
Hirschman S, Cunningham-Rundles C, Adelsberg B, Parham D, Siegal M,
Cunningham-Rundles S, Armstrong D. Severe acquired immunodeficiency in male
homosexuals, manifested by chronic perianal ulcerative herpes simplex
lesions. N Engl J Med 1981;305:1439-44
Mole L, Ripich S, Margolis D, Holodniy M. The impact of active herpes
simplex virus infection on human immunodeficiency virus load. J Inf Dis
1997;176:766-770
HIV Drug Resistance and the Other Causes of Treatment Failure
by Jeffrey T. Schouten MD
The key point to emphasize is that HIV can only become resistant to a drug
if it is actively replicating (reproducing itself). When HIV viral loads
are reported to be "non-detectable," this is very misleading. What a
"non-detectable" result really means is that the amount of HIV present in
the blood is below the limits of the viral load test to detect HIV. Most
clinics in the country use tests which can detect 500 (or more) copies of
HIV, per ml of blood. Thus, "non-detectable" means that you have 499 (or
less) copies of HIV, per ml of blood. These tests are called "sensitive"
viral load tests. There are now several companies which have
"ultra-sensitive" viral load tests available, which can detect 20 (or more)
copies of HIV, per ml of blood. Thus, a "non-detectable" result from such a
test would mean that you have 19 (or less) copies of HIV, per ml of blood.
More accurately, the test result should be reported "below the limits of
quantification", not "non-detectable". This is not a trivial point, as will
be discussed in this article, the chance of HIV developing drug resistance
may be very different if your viral load is 490, versus 0 copies; yet, in
both situations the current, most widely-used viral load tests would report
the result to be "non-detectable."
"You'd better get that drug when it's new, because it won't work as well
once it's been around for a while." The factors leading to this truism of
medicine will explain many of the issues involved in the recent reports that
the new anti-HIV drugs control HIV replication for only about half of all
HIV-infected persons.
Reports by researchers from the University of
California at San Francisco presented at the ICAAC meeting in Toronto, in
September, 1997, showed that 53% of persons at their HIV clinic did not
achieve long-term suppression of HIV replication with combination therapy.
This contrasts to the controlled trials of highly active antiretroviral
therapy (HAART) which showed that triple drug combinations, including a
protease inhibitor (PI), completely suppressed HIV replication for 1-2 years
in up to 80-90% of persons studied. Why, then, do only half of persons
treated in the "real world" achieve a similar result?
Factors Contributing to Treatment Failure
Trial Participation Selection
Clinical trials are very selective in which people they enroll into the
trial. "Inclusion criteria" often exclude persons with significant liver,
kidney, of blood disorders.
A concrete example of the impact of this
selection process is that people with chronic liver disease, such as many
HIV-infected injection drug users with chronic hepatitis C infection, often
experience worsening of their liver disease when treated with protease
inhibitors (PI). Had these people been included in the initial PI trials,
the results would not have been so good. Additionally, controlled trials
usually enroll persons who are more compliant, more educated, and more
motivated to seek out the latest, best treatments. Some of these factors
are correlated with better treatment results, than those attained by the
broad spectrum of all persons seen in a clinic.
Some trials exclude persons
who have been treated with PI's or reverse transcriptase inhibitors in the
past. This may be done, for example, by a protocol which offers a new
protease inhibitor (PI) to people who have failed all other PI's, but also
requires that the person be on two reverse transcriptase inhibitors (RTI)
which they have never taken before. If a person has been on (and failed)
all the RTI's currently available, then they will not be able to participate
in that trial. The fact that a drug performs better in a controlled trial
than in the "real world" is not unique to anti-HIV drugs, but it has created
inflated expectations of the efficacy of the new anti-HIV drugs in the eye
of the public, many health care providers, and people living with HIV.
Compliance
Due to the unique ability of HIV to mutate, drug resistance can arise when a
person misses even a couple of doses of a drug (i.e. "is not compliant").
Thus, if a person is on a combination of drugs which is completely
suppressing all HIV replication in their body, resistance to the drug cannot
develop. However, if such a person were to miss a few doses of their
medication, then some HIV replication may occur, allowing the opportunity
for the virus to become resistant to the drugs that person is taking. It
has been estimated that the virus makes a mistake once every 10 times that
it copies itself. Many of these mistakes result in a defective virus which
is unable to infect other cells. However, every so often, one of these
random mutations results in the virus being resistant to a specific drug.
So, if the person is taking that drug to which HIV has become resistant,
then that particular mutant will grow unchecked and become the dominant
virus in the person's system. Because there may be up to a billion copies
of HIV in the body, many mutations occur everyday if there is high level of
HIV present (a high viral load). Thus, one of the major factors causing
treatment failure is mutation of HIV, resulting in HIV not suppressed by a
particular drug. This most often occurs due to lack of compliance, but also
may be due to cross-resistance from prior drug exposure or infection with a
resistant strain of HIV, as will be discussed below.
Drug Absorption
Another factor resulting in treatment failure is inability to absorb the
drug that a person is taking. In this situation, even though a drug is
being taken properly, it is not getting into the blood at adequate levels to
completely suppress HIV replication. Due to the many adverse impacts of HIV
and opportunistic infections on the gastrointestinal tract, drug absorption
can be a major problem for people with HIV infection. If almost no drug is
absorbed into the blood, then HIV replication will go on, but drug-resistant
HIV will not develop because there needs to be some drug present for a
significant drug-resistant population of HIV to develop. However, if some
drug is absorbed, then the HIV may become resistant due to suboptimal drug
level.
Thus, in the first case, treatment has failed, but not due to HIV
drug resistance, while in the latter scenario, HIV drug resistance has
resulted from the treatment failure. It is critical to differentiate these
two situations. As will be discussed later, resistance to one drug may
cause cross-resistance to other drugs in the same class (i.e. PI's).
Therefore, in choosing a second drug, it is critical to know whether or not
the reason for treatment failure was due to drug resistance.
Drug Activation
Some drugs are administered in a form which requires the body to change the
drug into an active form. This may be done, for example if the active form
is not absorbed well or is unstable. This is the case for zidovudine (AZT).
The body must convert zidovudine into the active form, before it can inhibit
the HIV reverse transcriptase enzyme. If the person's own metabolic
activation system is not functioning properly (or is genetically different)
for the required metabolic conversion, then the drug will not be effective.
As with poor drug absorption, a defect in the activation of the drug could
result in very low levels or in higher, but still sub-optimal levels. Thus,
you might have treatment failure due to very little active drug in the
system or due to drug resistance, resulting from sub-optimal levels of the
activated form of the drug.
Drug Metabolism
As with drug activation, there are differences in people's own metabolic
processes which remove drugs from the body. The rate of absorption and the
rate of drug removal determines how much drug is in a person's system and
for how long. This is critical for determining the amount and frequency of
a drug to take (in order to achieve optimal blood levels) so that HIV
suppression is maximized while toxicity is minimized. The most common
methods of drug removal from the body are metabolism and/or inactivation in
the liver, and excretion by the kidneys into the urine. For some anti-HIV
medications, these are very critical processes.
The long list of drug
interactions with ritonavir is due to the changes caused by that drug in
liver metabolism. The result is that some drugs are metabolized much slower
and thus reach much higher levels in the blood, while other drugs are
metabolized much faster and thus attain very low blood levels. For example,
saquinavir levels are raised by ritonavir. Thus, the usefulness of
combining these two drugs is that much higher and more effective blood
levels of saquinavir (which is poorly absorbed) can be attained if it is
administered with ritonavir.
Conversely, some drugs may be markedly reduced
due to the effect of ritonavir on the liver's metabolic processes. These
considerations are important to achieve the desired blood level of an
anti-HIV drug. Since the effect may vary from individual to individual,
ideally, blood levels of the drugs should be measured to determine if, in
fact, the drug is getting into the blood at the desired level. This is what
is done in early clinical trials (Phase 1 Trials), but it is not routinely
done in clinical practice.
Drug-Drug Interactions
Another reason for treatment failure may be due to the direct interaction of
two drugs against HIV. Whenever two drugs are used to attack the same
bacteria or virus, there may be one of three interactions. The two drugs
may work individually, they may augment each other (synergism), or they may
inhibit one another (antagonism). So, with synergism, the sum of the two is
greater than the individual effect of each added together, whereas with
antagonism, the sum of the two is less than the individual effect of each
added together. This is why it is important to test drug combinations in
clinical trials, because this interaction is not always predictable. A
problem today is that because there are so many FDA-approved anti-HIV drugs,
it will take many trials and a lot of time to test a new drug in all the
possible three, four or five-drug combinations with the currently
FDA-approved drugs. Care should be exercised when combining drugs which
have not been combined in prior clinical trails.
HIV Drug Resistance
The most common cause of HIV treatment failure is drug resistance, usually
due to a combination of the factors discussed above. However, it is also
possible that a person may have HIV which is resistant to a drug they have
never taken. This may be due to cross-resistance from another drug in the
same class (like another PI) that they have taken, or the strain of HIV that
the person was infected with was already resistant to the drug, or the HIV
developed resistance prior to any drug exposure by random, spontaneous
mutation after infection.
Drug resistant usually develops because HIV undergoes a mutation in its
genetic material which allows the virus to reproduce in the presence of
adequate levels of the drug. In the case of the nucleoside and
non-nucleoside reverse transcriptase inhibitors, the genetic mutation causes
a change in the structure of the HIV's reverse transcriptase enzyme, which
translates the HIV RNA into the host cell's DNA. The result of the mutation
is that transcription occurs, even in the presence of the drug, which had
previously prevented this process. Similarly, in the case of the protease
inhibitors, the genetic mutation results in a change in the HIV-produced
protease enzyme which is necessary for assembly of infectious viruses.
Testing for drug resistance may be performed by two methods: genotype and
phenotype testing.
Phenotype testing is a functional test whereby the HIV
is isolated from a person's blood, is placed into a test tube and grown in
the laboratory to test its ability to grow in the presence of a particular
antiretroviral drug. This test takes several weeks to conduct and is very
expensive.
Genotype testing analyzes the genetic sequence of the HIV when
isolated from a person's body. Then mutations in the genetic sequence are
looked for, which are known to be associated with HIV resistance to a
particular antiretroviral drug. This test costs about $300 and can be done
quickly.
Currently, neither test is approved by the FDA, and they are not
paid for by private or government insurance programs. There is debate among
HIV treatment experts about the usefulness of these tests in the clinical
treatment of HIV. Currently, many HIV research programs are studying
genotype testing.
Cross Resistance
There is now excellent data to show that when a person becomes resistant to
saquinavir, ritonavir or indinavir, they are probably resistant to all three
of these protease inhibitors. However, some of the data presented at the
ICAAC meeting in Toronto in September, 1997 suggested that resistance to
nelfinavir may not cause cross-resistance to the other PI's. Other data has
suggested that if a person develops a high level of nelfinavir resistance,
they will, in fact, also be resistant to the other three PI's. In theory, a
person should select a drug in a class (such as PI's) for front line use
which has the least possibility of causing cross resistance. Thus, if a
person becomes resistant to that first drug, there are some other options
available in that class of drugs. Because PI's, nucleoside reverse
transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors
all work at a different point to inhibit HIV replication, there is not
cross-resistance between the classes of drugs, but rather it is a problem
within a class of drugs.
One potentially beneficial use of genotype testing would be when a person
has failed a triple-drug combination, testing could provide useful
information in determining which of the three drugs the person has become
resistant to so that all three drugs would not necessarily have to be abandoned.
Mutations identified by genotype testing are reported by the location in the
genetic sequence of the virus where the change has occurred (the codon).
There are a series of known changes in the genetic sequence of HIV which are
associated with resistance in the clinical situation. So, a report might
note mutations at codons 41, 67, 70, and 215. These are all sites known to
result in resistance to zidovudine.
There are some serious limitations to genotype testing for drug resistance.
Drugs such as ddI and d4T do not show genetic mutations which correlate as
clearly with clinical resistance as does zidovudine. The genetic change
seen which confers resistance to 3TC may actually be beneficial in that the
particular genetic change in HIV associated with 3TC resistance confers
increased sensitivity to zidovudine (i.e. it makes HIV more likely to be
inhibited by zidovudine). With some drugs, only one or two mutations are
necessary to make HIV resistant, while other drugs (such as zidovudine and
saquinavir) may require several mutations in HIV to confer complete
resistance to these drugs (although one mutation at codon 215 will cause
complete resistance to zidovudine). Unfortunately, a report of genotype
testing does not give a simple answer to which drugs to use. If that were
the case, there would be a stronger call to make the test available to all
people living with HIV and for government and private insurers to pay for it.
A major limitation of genotype testing is that you need to get a sample of
HIV from the patient's blood, and if the viral load is very low this may be
difficult. Additionally, there exist in the blood several different
populations of HIV, so that some, but not all, of the HIV in your body may
be resistant to a drug, but the test may not accurately sample that
subpopulation of HIV. The test does not report the number of HIV which
contain a specific mutation; it is not a quantitative test. There is a
concern that drugs which may be beneficial to a person would be discontinued
prematurely (since the presence of a mutation does not mean that the drug is
100% ineffective); or, conversely, drugs which are not helping a person
might be continued based on a misleading genotype report showing no
mutations present.
Another use for genotype testing for resistance might be prior to initiating
any anti-HIV therapy, either in a person recently infected, or someone who
has been infected for a long time. One study, reported at the 4th Annual
Conference on Retroviruses and Opportunistic Infections, in January, 1997,
revealed that in a rural Iowa population, 26% of persons never treated with
a protease inhibitor had some genetic mutations associated with resistance
to all three of the protease inhibitors which were then approved, and 3% of
newly-infected persons had resistance to some reverse transcriptase inhibitors.
Other studies have shown that resistance occurs more frequently with lower
CD4 counts, and higher viral loads. It appears that the later therapy is
begun, the less likely you are to obtain complete viral suppress, allowing
for resistance to develop. Thus, the immune system may help in the
prevention of drug resistance. This is another observation in support of
the , "Hit hard, hit early" approach.
The most comprehensive discussion of HIV drug resistance can be found in the
report issued following the International Workshop on HIV Drug Resistance,
Treatment Strategies and Eradication, held in St., Petersburg, Florida, June
25-28, 1997. (The summary and other reports are available on the World Wide
Web at: http://www.healthcg.com/hiv/hivresistance/content.html.) The main
findings were: the realization of generalized resistance across the class of
protease inhibitors (cross-resistance), (although as noted above, whether
this applies to nelfinavir is not known at this time) highly active
antiretroviral therapy (HAART) can suppress viral load levels to very low
levels to minimize the chance of resistance developing, even in persons with
very low CD4 counts, as long as they were not treated with a lot of
antiretrovirals in the past; resistance assays need to be developed to tell
us which drugs to use, but at this time, we do not know how to interpret the
data; and, antiretroviral therapy needs to be individualized. This report
lists, in tabular form, all the known genetic mutations associated with
resistance for all the currently available antiretroviral drugs.
One other
point emphasized is that once you become resistant to a drug, even if you
are off of that drug for one year or longer, the resistant virus is still
present and repeat use of that drug will be unsuccessful.
Conclusion
There are many factors which can lead to HIV treatment failure. The most
important is the development of resistance to the antiretroviral drug (or
drugs). The two most important factors to consider are the amount and
nature of prior therapy and compliance with a difficult treatment schedule.
An inexpensive, accurate laboratory test which can tell which drug is going
to work in an individual person would be very helpful in designing treatment
plans. The current genotype and phenotype tests do not yet accomplish this
goal. However, for some people, a genotype test may be useful to select
antiretroviral drugs, particularly when that person has been treated with
many antiretroviral drugs in the past.
What's New in Kaposi's Sarcoma Research
Kaposi's sarcoma (KS) is a cancer of cells lining blood vessels and is
commonly seen as a complication of HIV infection. Prior to the HIV era, KS
was rarely seen, and when it was seen, it seemed to favor males over 50
years of age who were of Mediterranean or African origin. Otherwise healthy
women and children were rarely affected by KS. Since the beginning of the AIDS epidemic, KS has been seen primarily in gay men with HIV infection. KS
is also seen in people who have received organ transplants, due to the use
of drugs that suppress their immune response to the transplanted organ.
Recently, Chang and Moore found sequences of viral DNA in KS lesions (1).
This viral DNA was found to belong to new virus belonging to the herpesvirus
family. Several investigators have found human herpesvirus-8 (HHV-8) DNA in
almost all KS lesions examined (2-5). Other more common viral DNA has also
been found in KS lesions; however, no other virus appears as consistently as
HHV-8.
It is clear that HHV-8 DNA is consistently found in KS lesions and
recent studies report finding HHV-8 DNA in saliva, certain white blood cells
(B-lymphocytes), semen, prostate tissue, fecal material, and occasionally in
normal skin of people with KS (6-8). However, not all of these reports have
been confirmed by other investigators, so that controversy remains regarding
the prevalence of HHV-8 at various sites.
There are two reports from
investigators who have been able to grow infectious HHV-8 virus from KS
lesions (Foreman) and from white blood cells (Blackbourn) of a healthy blood
donor (9, 10). These findings suggest HHV-8 can be transmitted through
contact with infected secretions. However, the exact mode of transmission
and the efficacy of transmission of HHV-8 remain unknown.
HHV-8 is likely to be transmitted via sexual contact. While some
epidemiological studies suggest that oral-anal contact may be a risk factor
for development of KS (11), such contact would not be expected to be a
strong risk factor for transmission of a herpesvirus. Therefore, these
findings must be interpreted cautiously. Other risk factors for KS include
past history of having an sexually-transmitted disease (STD) other than HIV,
a high number of casual sex partners, and a high frequency of sex acts. A
report from McCarthy details the case of an HIV-positive mother and
vertically (at birth) HIV-infected child who both developed KS (12). This
is further support for transmission via infected secretions or blood.
There
are numerous reports of HHV-8 DNA recovery from circulating white blood
cells and one report of viable HHV-8 recovery from blood. There are no
reports of HHV-8 DNA recovery or of seroconversion (acquisition of HHV-8
antibody) after receiving blood products. And, it has been shown that those
people who become HIV-positive from blood product receipt (e.g.,
hemophiliacs) are very unlikely to show evidence of HHV-8 infection.
However, it remains unknown if blood and/or blood products can transmit HHV-8.
Blood tests for HHV-8 antibodies have been developed and are available in
some research laboratories. The sensitivity and specificity of these tests
are under study and newer methods to detect HHV-8 infection are also under
development.
The prevalence of HHV-8 seropositivity (presence of the
antibody that indicates infection) in different groups has been examined.
It appears that HHV-8 seropositivity is greatest (80%) in HIV-positive gay
men with KS. HHV-8 seropositivity is 18% in HIV-positive/KS-negative gay
males. In contrast, among HIV-positive hemophiliacs and HIV-negative
healthy blood donors, none had antibody to HHV-8 (13). Among people
presenting to the STD clinic with a positive serologic test for syphilis,
13% had antibody to HHV-8 (14).
The strongest evidence for causal role of
HHV-8 in the pathogenesis of KS is the temporal association between
seroconversion to HHV-8 and the development of KS. In a study of 40 men
with HIV and KS, 52% had seroconverted to HHV-8 a median of 33 months prior
to development of KS.
While the association between HHV-8 infection, immunosuppression, and
subsequent development of KS appears strong, much more work needs to be done
on HHV-8 epidemiology to gain a clear definition of risk transmission.
Thereafter, strategies can be recommended.
Laboratory studies suggest that HHV-8 is susceptible to ganciclovir,
foscarnet, and cidofovir, and resistant to acyclovir (14). It is unclear if
antiviral treatment of HHV-8 infection prior to KS onset can prevent KS or
eliminate HHV-8 carriage. The latter seems unlikely, as all other
herpesviruses establish life-long latency in the human host. In addition,
available effective antivirals can cause significant toxicity and their use
as KS prophylaxis may not be appropriate.
The treatment of established KS varies from no treatment to systemic
multi-drug chemotherapy. Liquid nitrogen has been used on small isolated
lesions and local radiation therapy has been used to treat diffuse lesions
of the lower extremities. Topical retinoids (vitamin A compounds) are
showing promise and are likely to be approved for use soon. In non-HIV
immunosuppressed people, withdrawal of some or all of the immunosuppressive
drugs sometimes results in clearance of KS. More often, systemic
chemotherapy is required and many times response to therapy is incomplete
(15).
Even when complete clearance is achieved, later recurrence is not
uncommon in all forms of KS. It is unknown if long-term clearance of KS
could be achieved by antiviral treatment and suppression of HHV-8 infection.
Co-treatment of HHV-8 infection and KS is likely to be studied in the
future. There is little information on the relationship between the
quantity of HHV-8 DNA in blood (and perhaps tumor) and response to
treatment.
The relationship, if any, between HHV-8, DNA quantity, and
treatment response needs further study. Intra-lesional human chorionic
gonadotropin (hCG) has been shown to induce KS regression in ten of 12 human
KS lesions; HHV-8 DNA levels were not reported. Interferon alpha-2a has
also shown promise in treating KS.
Much progress has been made in understanding the etiology and
pathophysiology of KS. As our research progresses and our understanding of
HHV-8-KS increases, better treatment will evolve. The University of
Washington has an active research program investigating the basic science,
clinical and epidemiological aspects of HHV-8 infection. An antibody test
for HHV-8 has been developed for research purposes.
The Virology Research Clinic can be contacted at (206)720-4340.
University of Washington
Virology Research Clinic
1001 Broadway, Suite 320
Seattle, Washington 98122
(206)720-4340
(206)720-4371 fax
References cited:
Said, J. Kaposi's sarcoma-associated herpesvirus (KSHV): a new viral
pathogen associated with Kaposi's sarcoma, primary effusion lymphoma, and
multicentric Cattlemans disease. WJM. 1997;167:37-38.
Moore PS, Kingsley LA, Holmberg SD, Spira T, Gupta P, Hoover DR, Parry JP,
Conley LJ, Jaffe HW, Chang Y. Kaposi's sarcoma associated herpesvirus
infection prior to onset of Kaposi's sarcoma. AIDS.
1996;10:175-180.
Ziegler JL, Katongole-Mbidde E. Kaposi's sarcoma in childhood: an
analysis of 100 cases from Uganda and relationship to HIV infection. Int J
Cancer. 1996;65:200-203.
Schalling M, Ekman M, Kaaya EE, Linde A, Biberfeld P. A role for a new
herpes virus (KSHV) in different forms of Kaposi's sarcoma. Nat Med.
1995;1:707-708.
Schatz O, Bogner JR, Goebel FD. Kaposi's sarcoma: is the hunt for the
culprit over now? J Mol Med. 1997;75:28-34.
Koelle DM, Huang ML, Chandran B, Vieira J, Piepkorn M, Corey L. Frequent
detection of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8)
DNA in saliva of human immunodeficiency virus-infected men: clinical and
immunologic correlates. J Inf Dis. 1997;176:94-102.
Howard MR, Whitby D, Bahadur G, Suggett F, Boshoff C, Tenant-Flowers M,
Schulz TF, Kirk S, Matthews S, Weller IV, Tedder RS, Weiss RA. Detection of
human herpesvirus 8 DNA in semen from HIV-infected individuals but not
healthy semen donors. AIDS. 1997;11:F15-9.
Purvis SF, Katongole-Mbidde E, Johnson JL, Leonard DG, Byabazaire N,
Luckey C, Schick HE, Wallis R, Elmets CA, Giam CZ. High incidence of
Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus in tumor
lesions and peripheral blood mononuclear cells from people with Kaposi's
sarcoma in Uganda.
Foreman KE, Friborg J Jr, Kong WP, Woffendin C, Polverini PJ, Nickoloff
BJ, Nabel GJ. Propagation of a human herpesvirus from AIDS-associated
Kaposi's sarcoma. N Eng J Med. 1997;363:163-171.
Blackbourn DJ, Ambroziak J, Lennette E, Adams M, Ramachandran B, Levy JA.
Infectious human herpesvirus 8 in a healthy North American blood donor.
Primary Infection Clinic Enrolling for NIH Studies
by Michelle Berrey
The Primary Infection Clinic began in September of 1992 with the goal of
following the natural history of early/acute HIV, an area about which very
little was known at the time.
In the past 5 years, partly as a result of
our work, knowledge surrounding acute or primary HIV has grown from a
suspicion about a viral conversion syndrome to a well-described clinical
symptom complex of pharyngitis, fever, and fatigue (1).
The variation of
symptoms and severity of illness among individuals is marked, and may range
from a mild sore throat that lasts only a couple of days, to high fevers,
rash, and headache that require hospitalization. The most common symptoms
reported in our natural history study at the University of Washington are
fever and/or night sweats, sore throat, headaches, muscle aches (similar to
those experienced with the flu), fatigue, and rash.
Dr. Phillipe Vanhems of
France recently compared our data to two primary infection clinics in
Geneva, Switzerland and Sydney, Australia. He found reassuring evidence
that the same symptoms we see here in individuals seroconverting were seen
in both Australia and Switzerland. Other symptoms seen less frequently in
all three clinics were oral and genital ulcers, swollen lymph nodes,
diarrhea, and anorexia (loss of appetite).
Our recent data suggest that individuals with more severe syndromes, i.e.,
those who present to medical attention, may have a more rapid progression to
clinical AIDS (2), suggesting a strong need to identify all such cases early
and to offer early treatment. Local HIV/AIDS epidemiologists in the State
Department of Health and the Seattle-King County Department of Public Health
estimate that we continue to have 600 to 900 seroconversions per year in
this state, possibly half of which have a symptomatic seroconversion
syndrome (3).
We know from our data that only about half of persons with
HIV who present to their medical provider with symptoms will be screened for
HIV antibody. We hope that reminding the public and providers about primary
HIV will increase the number of infections caught early on.
Symptoms are not required for enrollment in the Primary Infection Clinic,
however. I have outlined our criteria below, but we are happy to perform all
screening bloodwork.
After an initial behavioral-risk-factor interview,
consent forms are signed to allow blood to be studied for antibody, viral
load testing (plasma RNA), proviral HIV detection (DNA PCR), CD4+ cell
count, and cellular response to the potential HIV infection (cytotoxic
T-lymphocytes). During very early HIV infection, the anti-HIV antibody (the
antibody that is detected on the standard screening test) may remain
negative for 6 weeks after the infecting exposure, so it is important to
test for HIV RNA in the plasma, which may be detectable within 10 days after
exposure. It takes a week to get the viral load (RNA) back from the lab; at
that time we review the results and discuss potential studies for
enrollment, which I discuss below.
Our contribution to the current understanding of early HIV infection has
recently been recognized with a 4-year, multi-site, $6.7 million/year grant
from the National Institute of Allergy and Infectious Diseases for the
continuation of our studies. The Aaron Diamond AIDS Research Center, the
University of California at San Francisco, Johns Hopkins University School
of Medicine, the University of Colorado Health Sciences Center, and the
University of Alabama at Birmingham will be collaborating with us on the
Acute Infection and Early Disease Research Program. We have established a
cooperative network with clinics in Minnesota (Tim Schacker); Cincinnati
(Judith Feinberg); National Institute of Health (Anthony Fauci); Sydney,
Australia (David Cooper); and Geneva, Switzerland (Luc Perrin) to better
understand the evolution of the infecting virus, the cellular immune
response of the host (particularly the early defect in immune response),
emergence of the neutralizing antibodies, and how pharmaceutical
intervention may impact all of these.
Who can be enrolled?
Acute seroconvertor. An individual with an acute seroconversion syndrome with corresponding labs
bDNA-positive and EIA- negative, or
EIA-positive, with indeterminate western blot converting to positive
Asymptomatic seroconvertor; An individual with a negative antibody test
within the last 6 months, who has a positive test now (no seroconversion
symptoms)
Symptomatic seroconvertor; An individual with a negative antibody test
within the last 12 months, a positive EIA now, and with a seroconversion
syndrome within the last 3 months.
What studies are being offered?
The Primary Infection Clinic's natural history study enrolls individuals who
meet the above-listed criteria to better define the clinical, virologic, and
immunologic characteristics of primary HIV. The study provides free
laboratory tests including viral load testing and CD4 counts, and offers
optional testing of semen viral load and lymph node biopsies. The study is
ongoing and is not limited to a maximum number of participants.
We are currently enrolling in a trial of "triple" drugs: AZT (zidovudine),
3TC (lamivudine), and indinavir (Crixivan) to study the effects of early
intervention on the mutations of the virus, the viral replication rates,
CD4+ cell counts, and other measures of immune system integrity. The study
provides free medication for 12 months, as well as free lab tests during the
study. The study is limited to persons infected within the last 3 months
(with a recent negative EIA or with symptoms suggestive of recent
infection), and will include a maximum of 10 enrollees.
The International Acute Infection and Early Research Network grant funded by
the NIH will also include a pharmaceutical intervention with multiple
antiretrovirals. This trial will begin enrollment around the first of 1998.
Medications will be provided, as will frequent lab monitoring.
Drug treatment during primary HIV has the theoretical benefit of attacking
HIV when the virus has perhaps not established a foothold in the body, when
the immune system is strongest, and while a relatively homogeneous strain of
virus still predominates. However, there is also real concern that we may
be using up our "magic bullet" too soon -- that over the long haul early
therapy will not always be optimal. And, of course, there are toxicities
with all these drugs.
The trials performed in our clinic are designed to
observe clinical as well as viral and immunologic parameters in early
intervention, and will, we hope, reveal some of the predictors that may help
us be able to decide very early whether someone would benefit from very
early intervention, or whether his or her own immune system will be able to
control the virus.
To answer questions means we need to see people and enter them into clinical
trials. Our approach is to allow individuals to select their therapeutic
approach with their primary care providers, although we are certainly
available at any time to help with therapeutic decision-making. Through the
new Madison Clinic at Harborview we can also provide primary care for those
people who do not have a regular provider.
Please feel free to contact us at any time with questions at 206-667-5300,
or toll-free within the state of Washington
at 800-968-1437.
Although we hope for
the fewest possible seroconversions, it is our hope to have every case of
early HIV identified and referred to us.
Michelle Berrey is the clinic physician at the Primary Infection Clinic.
She has been doing clinical research in primary HIV infection since 1996.
Notes:
Schacker T, Collier AC, Hughes J, Shea Y, Corey L. Clinical and
epidemiologic features of primary HIV infection. Annals of Internal Medicine
1996;125:257-264.
Schacker TW, Hughes JP, Shea T, Coombs RW, Corey L. The natural history
of primary HIV infection (in press)
Personal communication, Bob Wood, MD. Seattle-King County Department of
Public Health, January 1997.
