HSV-2 & HIV:
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:
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.
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:
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.
Timothy Schacker, M.D., Department of Medicine,
University of Washington, Seattle, Washington,
Lawrence Corey, M.D., Departments of Laboratory and Medicine, University of Washington, Program Infectious Diseases, Fred Hutchinson Cancer Research Center, Seattle, Washington
HIV Drug Resistance and the Other Causes of Treatment Failureby 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.
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.
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.
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.
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.
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.
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.
ConclusionThere 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.
Virology Research Clinic
1001 Broadway, Suite 320
Seattle, Washington 98122
Primary Infection Clinic Enrolling for NIH Studiesby 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?
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.
You can also reach the clinic via e-mail at firstname.lastname@example.org.
Although we hope for the fewest possible seroconversions, it is our hope to have every case of early HIV identified and referred to us.