Clinical Queries: HIV-Treating Physicians in Houston Express Their Professional Opinions on the Public Health Implications of Antiretroviral Therapy
Scenario 1: Initiating Highly Active Antiretroviral Therapy (HAART) in an Uninfected Woman Attempting to Get Pregnant by Intentionally Having Unsafe Sex with Her HIV-Infected Husband
A 33-year-old HIV-infected male presents for routine follow-up. His regimen consists of nelfinavir (Viracept) and zidovudine/lamivudine (Combivir). His most recent viral load and CD4 T cell count were 1,311 copies/mL and 479 cells/mm3, respectively. He offers no complaint and his physical exam is unremarkable. The patient has been married for three years and his wife accompanies him on this visit. Throughout their marriage, the couple reports having consistently practiced safer sex. The wife has had six HIV antibody tests in the previous three years, including one last month, all of which were negative. After much discussion, the couple has decided to have a child of their own. They believe that antiretrovirals would reduce the risk of viral transmission and therefore ask you to prescribe a regimen for the wife while the couple attempts to conceive. Will you prescribe a regimen for her?
The question of initiating highly active antiretroviral therapy (HAART) in an uninfected woman attempting to get pregnant by intentionally having unsafe sex with her HIV-infected husband is a fascinating scenario. Since there are no scientific studies involving this situation and there are obvious risks of transmitting HIV, I as a physician cannot recommend to this couple that they attempt a pregnancy. But over the past 20 years state-of-the-art HIV medicine has involved carefully reviewing and interpreting published and unpublished experimental trials, trying new approaches and medications, and extrapolating ideas to new situations.
As an AIDS specialist I cannot recommend pregnancy, but I can educate this couple on the potential risks and possible problems. If their desire is to proceed, I can give suggestions and recommendations to decrease the risk to all persons involved, including the unborn child. There are general guidelines for antiretroviral drug use during pregnancy for HIV-infected women, but the potential impact of such therapy on the fetus and infant is unknown. There are guidelines for postexposure treatment for accidental HIV exposure and there are studies showing ways to decrease the risk of transmission to the uninfected. Using this information we can look at all parties involved: the husband, the wife, and the unborn child.
Sperm washing would be a safer but more expensive approach. Lowering viral load in the husband by changing to more effective HAART would decrease the infectivity. Carefully timing intercourse would decrease the number of exposures. The wife needs to consider side effects of HAART therapy such as nausea, vomiting, and diarrhea with any new medication; kidney stones and hyperbilirubinemia with indinavir (Crixivan); anemia induced by zidovudine (Retrovir); hypersensitivity induced by abacavir (Ziagen); protease inhibitor-induced diabetes and pancreatitis; and generalized allergic reactions with any medication.
There are very few studies on HAART in the mother and possible effects on the fetus but some observations have been made. Efavirenz (Sustiva) is not recommended because of birth defects in primates. Abacavir is associated with developmental toxicity in rats including decreased fetal body weight and skeletal malformations. The French have reported eight cases of mitochondrial toxicity in uninfected infants with neonatal exposure to nucleoside reverse transcriptase inhibitors (NRTIs) who developed neurological and developmental abnormalities leading to two deaths. The greatest risk of mitochondrial toxicity has been with zalcitabine (Hivid), didanosine (Videx) and stavudine (Zerit). Ritonavir (Norvir) has also shown birth defects in rats and rabbits but doesn't seem to cross the placental barrier in humans. Amprenavir (Agenerase) has caused bone malformations, low birth weights, and an increased risk of abortions.
If after fully discussing the potential risks (and with their full understanding) the patients are determined to proceed with a natural pregnancy, I would prescribe antiretroviral therapy for the uninfected wife with the following recommendations: 1) intercourse be carefully timed with her menstrual cycle; 2) two NRTIs be used, probably zidovudine and lamivudine (Epivir); 3) these drugs be started 10 days before attempting intercourse and continued for one month after intercourse; 4) the husband change HAART to achieve an undetectable status if possible; and 5) the husband, wife and child be followed by an HIV specialist and an HIV-experienced obstetrician.
-- Gordon Crofoot, M.D.
We also know that postexposure prophylaxis (PEP) can decrease transmission in occupational exposures by 81%. Despite the paucity of data, this has been generalized by many to provide postexposure prophylaxis in cases of sexual or other nonoccupational exposures. I also believe this is reasonable to do. However, what the couple is proposing is different than PEP for a single episode and carries much more risk.
What is going on in the semen is not necessarily reflected in the peripheral blood. Concentrations of antiretroviral drugs (ARVs) are different in those 2 compartments. For example, zidovudine is present in higher concentration in the semen than blood, lamivudine is similar in both, and nevirapine (Viramune) is much lower in semen. The penetration of protease inhibitors is variable. This may have implications on the resistance pattern of the seminal virus and complicate the decision on which prophylactic regimen to choose for the woman. I would have a difficult time deciding which regimen to prescribe her.
Finally, the effect the proposed prophylactic ARVs would have on a developing fetus is unknown. If the woman were prescribed an ARV regimen and became pregnant, she could be exposing the fetus to potential toxicity for a considerable amount of time during the critical first trimester. We do not know the risk that carries.
Therefore, taken on the whole, I would not recommend an ARV regimen for the woman. Instead, I would recommend another way to conceive their child. Several studies have now demonstrated the efficacy of "sperm washing" as a means of artificial insemination for HIV discordant couples. This relies on the fact that HIV is restricted to the seminal plasma and cells other than sperm in the semen. In this strategy, motile spermatozoa are isolated from other components of semen by a density gradient and "swim up" technique prior to insemination. This is a safer alternative to natural conception and is what I would recommend to the couple.
-- Ben J. Barnett, M.D.
Scenario 2: A Patient Asks that You Prescribe a Regimen for Him in an Effort to Reduce the Risk of Viral Transmission to His Partner. Will You Prescribe a Regimen for Him?
A 37-year-old HIV-infected male presents for routine follow-up. He is not taking any antiretroviral therapy. His most recent viral load and CD4 T cell count were 559 copies/mL and 842 cells/mm3, respectively. He offers no complaint and his physical exam is unremarkable. The patient is well known to you and reports having been in a monogamous relationship with his male partner for the last seven years. His partner, who most recently tested HIV seronegative last month, accompanies him on this visit. The two tell you that they have consistently practiced safer sex during most of their relationship, but have "slipped" recently on several occasions. Although you and the patient have previously agreed that he did not need antiretroviral therapy, he asks that you prescribe a regimen for him in an effort to reduce the risk of viral transmission to his partner. Will you prescribe a regimen for him?
A recent study (N Engl J Med, 342:13, p. 921, 2000) followed 415 serodiscordant couples for up to 30 months in rural Uganda. Despite the provision of counseling and condoms as part of the study, 90 of the initially HIV-1-uninfected partners (21.7%) seroconverted. HIV-1-infected subjects with the highest serum HIV-1 RNA levels were the most likely to infect their sexual partners. Conversely, none of the 51 HIV-1-infected subjects with viral load less than 1,500 copies/mL transmitted the virus to their sexual partner. So, let's treat everybody now to lower viral loads and stop the HIV pandemic! Unfortunately it is not that simple. Although HIV viral load is considered a very important factor influencing transmission, it is not the only one.
Regarding the sexual transmission of HIV, several studies have demonstrated a marked effect of antiretroviral treatment on the shedding of the virus in the male and female genital tract, indicating a potential role of antiretroviral treatment for the prevention of HIV infection. Seminal HIV RNA levels have been strongly associated with culturable virus in the semen. However, the HIV RNA level in semen has not been a reliable reflection of the HIV RNA level in serum, meaning that even with a very low level of replicating virus in serum, the risk of HIV transmission might still be present. Furthermore, other factors can increase HIV seminal shedding (and with it the risk of transmission) such as systemic illnesses, male genital tract inflammation, reactivation of genital herpes virus infections, or the shedding of other viruses including cytomegalovirus.
Based on this information, the patient is still considered contagious -- even with a low plasma HIV viral load (only 559 copies/mL). If we decide to start antiretroviral therapy, there is no full certainty that we will be able to reduce the risk of HIV transmission to zero. Also, a dangerous false atmosphere of security could be created. The advances in HIV treatment can trigger or be used as a justification for sexual risk-taking behaviors.
On the other hand, starting HAART today requires a life-long commitment. We all know that it is far from being completely effective, and that it is associated with a growing list of potential side effects. There is also the risk of compromising future treatment options if HAART is begun now. Although potent antiretroviral therapy is beneficial on a public health basis, patients with no detectable virus in their blood under treatment should not be considered noninfectious and patients should continue with safer sex practices.
In summary, I would discuss these data with the patient and his partner to be sure that they understand the risks of HIV transmission, and I would discourage any unsafe sex practices. I would also discourage beginning antiretroviral therapy now in this patient.
-- Esteban C. Nannini, M.D.
Having an undetectable viral load gives the appearance that the disease is under control. However, the difficulties in taking the medications (either because of side effects and toxicity or trouble adhering to the dosing schedule) and the rates of failure and development of viral resistance to drugs are much worse than initially anticipated. Still, there is no doubt that therapy can delay AIDS if employed at the right time. In fact, growing evidence supports delaying therapy until just before the risk of developing AIDS. If therapy is initiated prior to that time, it is more likely that a patient will develop serious long-term therapy complications before experiencing any clinical disease progression. Studies are needed to show how and when to use antiretroviral therapy for the best long-term advantage to the patient.
But getting back to the original question, would I prescribe a regimen for the 37-year-old HIV-infected male in question? Clearly, treatment should begin before the patient is in danger of getting a life-threatening opportunistic infection. This would mean starting therapy while the patient has a CD4 T cell count greater than 200 cells/mm3. However, this patient has a count well above that number. Also, a very high viral load (above 100,000 copies/mL) would indicate that the patient is in greater danger of a sudden drop in CD4 T cell count and a subsequent risk of clinical progression. But this patient's viral load is 559 copies/mL, which is very low. Early signs of disease, such as shingles or thrush, may influence a decision to begin therapy sooner; however, this patient has no such complaints and his physical exam is unremarkable.
This patient does not have the clinical indications I use to begin antiretroviral therapy. There is no evidence, in my mind, that he is progressing. I think the fact that the patient and his partner "slipped" recently on several occasions sexually does not warrant the risk of exposing this patient to the toxicity of therapy started too early. It is my opinion that prescribing a regimen for a patient in an effort to reduce the risk of viral transmission to his partner is not warranted. The best way to prevent transmission is to consistently practice safe sex. Both the partner and the patient should respect each other enough to do this. This patient in particular has been in a monogamous relationship with his male partner for the last seven years and his risk of transmission is low.
-- Patricia D. Salvato, M.D.
This article was provided by The Center for AIDS. It is a part of the publication Research Initiative/Treatment Action!. Visit CFA's website to find out more about their activities and publications.