Single-dose nevirapine reduces transmission by 50%, which makes it the agent of choice in developing countries
We have known for the past six years that zidovudine monotherapy dramatically reduces the likelihood that HIV-positive women will infect their offspring in utero or during delivery. The efficacy of ZDV in interrupting vertical transmission was established by ACTG 076, a placebo-controlled trial in which ZDV was administered prepartum and during labor to seropositive women, and postpartum to their infants (1). The zidovudine doses used in that trial -- 100 mg orally five times daily prepartum; 2 mg/kg IV over one hour at the onset of labor, followed by 1 mg/kg IV per hour during labor; and 2 mg/kg orally every six hours for six weeks to the neonates -- reduced the risk of transmission by 67.5%.
ACTG 076 provided the first clear evidence that antiretroviral agents could reduce vertical transmission rates, and ZDV monotherapy, at the doses used in that trial, became the standard of care for pregnant, HIV-infected women in the United States and other developed countries.
Subsequently, less complex and costly regimens have also been shown to reduce vertical transmission of HIV. The Centers for Disease Control and Prevention sponsored a trial in Thailand that was designed to determine if a shorter course of ZDV, given from 36 weeks' gestation until delivery, would result in comparable reductions in transmission (2). A similar trial, known as PETRA, was conducted in sub-Saharan Africa using short courses of ZDV plus 3TC (3). Both of those trials were effective in reducing the rate of HIV transmission from mother to child.
The simplest regimen yet was used in a study undertaken in Uganda by a team of American and Ugandan researchers (3). These investigators enrolled 618 antiretroviral-naïve women, all in their ninth month of pregnancy, and randomized them to one of two drug regimens, single-dose nevirapine (n = 310) or ultra-short-course zidovudine (n = 308). Expectant mothers in the nevirapine arm received a single 200-mg oral dose at the start of labor, and their infants were given a single dose of nevirapine syrup within 72 hours of birth.
Mothers in the ZDV arm took two 300-mg tablets at the onset of labor and then one pill every three hours until delivery. The infants born to those mothers were given 300 mg of ZDV b.i.d. for the first week of life. Both of these regimens were initiated at the onset of delivery, and both provided antiretroviral therapy to neonates during the first week of life.
In sub-Saharan Africa, where seroprevalence rates among pregnant women range from 25% to 40% and where antiretroviral therapy is essentially nonexistent, the vertical HIV transmission rate is roughly 35%. In the Uganda trial, the transmission rate for ultra-short-course ZDV was 25%; for single-dose nevirapine it was 13%, a reduction of 50% compared with ZDV.
The American-Ugandan team plans to monitor this cohort for five years, to determine how many of the babies born HIV-negative are infected through breast-feeding in the first years of life. The investigators will also attempt to assess what adverse effects, if any, such brief exposure to antiretroviral agents may have had on the infants.
Would this regimen be cost-effective in developing countries with a high prevalence of HIV infection? When Marseille et al. performed an elaborate analysis in a hypothetical group of 20,000 pregnant women in sub-Saharan Africa, their data were emphatically affirmative (4). These investigators calculated the costs of treating all 20,000 women with this regimen, assuming HIV prevalence rates of 15% and 30%. They subjected the C.D.C. and PETRA regimens (ZDV monotherapy and ZDV plus 3TC) to the same analyses. Nevirapine as single doses for mother and infant was by far the cheapest intervention. Indeed, Marseille and coworkers deemed nevirapine to be cost-effective under almost all plausible scenarios. The greatest benefit -- and the cheapest program -- involved universal treatment of all 20,000 women, assuming a prevalence rate of 30%.
The authors point out that the feasibility of a universal treatment program is limited by a number of factors, foremost among them the fact that less than half of the women in sub-Saharan Africa have access to the types of clinics where this treatment could be given. Nevertheless, this intriguing analysis suggests that if such logistical impediments can be surmounted we may finally have a safe, effective, and inexpensive way of preventing a significant percentage of the hundreds of thousands of cases of vertical HIV transmission that occur in developed and developing countries every year.
Dr. Catherine M. Wilfert, the Scientific Director of the Elizabeth Glaser Pediatric AIDS Foundation, the author of "A Call to Action," the editorial on pages 3-6 of this issue, and a member of the editorial advisory board of HIV Newsline, comments:
Help is here at last for the tens of millions of seropositive women around the world who become pregnant and who desperately want to give birth to uninfected infants. Efforts to devise interventions that are effective in reducing vertical transmission, are simple enough that they can be administered in almost any setting, and are cheap enough that all but the most impoverished Third World countries can afford them have been under way since the early years of the epidemic.
In the past, clinical trials of these simplified treatment strategies have been criticized in some quarters for failing to offer state-of-the-art treatment to all participants. What these critics failed to appreciate is that in much of the developing world the standard of care for seropositive pregnant women is no HIV-specific care at all -- and in such settings short-course ZDV monotherapy, for example, is a potentially life-saving intervention, even if it is not the optimal First World regimen for interrupting vertical transmission.
Would a pregnant, HIV-positive American with adequate health insurance and unrestricted access to care opt for single-dose nevirapine over other therapeutic strategies to prevent the infection of her infant? Probably not -- and in any case such a regimen would not be recommended to women identified as seropositive during the early stages of pregnancy. It might well be selected by women who are first identified as HIV-positive at the time they present to deliver their infants, however.
South of the Sahara -- where some 14 million adults and infants have died of AIDS in the past two decades, where in many places one adult in four is seropositive, where 5.6 million new cases of HIV infection appear every year, where an estimated 40 million children will be orphaned by HIV before the end of this decade -- there are usually no options.
But there is nevirapine -- safe, cheap, and remarkably effective even when given as a single dose to women in labor and to their babies. In this setting, the choice is easy: nevirapine provides a safe, feasible, and effective means of reducing the likelihood of mother-to-infant transmission.
CPCRA study suggests that daily dosing reduces incidence of PCP
Primary and secondary prophylaxis against Pneumocystis carinii pneumonia have achieved unqualified success in reducing the morbidity and mortality that were once associated with episodes of AIDS-related PCP infection. Data from numerous well-designed and well-controlled clinical trials show that, in those who tolerate the drugs, trimethoprim-sulfamethoxazole (Bactrim®) is superior to dapsone -- which in turn is superior to aerosolized pentamidine.
To assess whether thrice-weekly TMP-SMX prophylaxis is as effective as daily dosing in preventing pneumocystis, office-based clinicians affiliated with the Terry Beirn Community Program for Clinical Research on AIDS conducted a large prospective study of these two regimens. (CPCRA is a network of community physicians and researchers who conduct clinical studies in the context of private practices. Twenty "units" associated with CPCRA participated in this three-year, randomized, open-label study.)
A total of 2,625 patients were enrolled. The vast majority of the patients (84%) had no history of PCP and therefore received primary prophylaxis in this trial. The remainder, the secondary-prophylaxis arm, had experienced at least one episode of pneumocystis. Overall, 70% of the patients were already on TMP/SMX at the time they enrolled in the trial, while about 1% were on either dapsone or pentamidine. The only statistically significant difference between the two randomized groups was baseline CD4 count: the mean value for patients randomized to daily TMP/SMX was 128 cells/mm3, versus 136 cells/mm3 for the thrice-weekly group.
Over the course of the trial, adherence was generally excellent, although the data were self-reported, so the numbers may be inflated. At 12 months, 85% of the patients in the daily treatment arm and 86% of those in the thrice-weekly treatment group reported taking at least 80% of the prescribed doses. Ten percent of each group reported "fair" adherence (50% to 79% of doses) and 4% of each group reported "poor" adherence (less than 50%). Overall, 90 confirmed or probable cases of PCP occurred in the daily treatment group, while 105 such events were seen among those taking TMP/SMX three times a week.
The relative risk of PCP in the daily arm compared with the three-times-weekly arm was 0.86, indicating an advantage for daily treatment. The treatment advantage for daily dosing was more pronounced among recipients of secondary prophylaxis. A survival benefit was also noted among people with a prior history of PCP who were randomized to daily TMP/SMX. On the other hand, a larger percentage of patients receiving daily TMP/SMX (19%) needed to discontinue their assigned regimen and switch to thrice-weekly dosing because of adverse events, compared with those assigned to three-times-weekly dosing (9.6%).
El-Sadr, WM, Luskin-Hawk R, Yurik TM, et al. A randomized trial of daily and thrice-weekly trimethoprim-sulfamethoxazole for prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients. Clin Infect Dis 1999; 29: 775-83.
Dr. William G. Powderly, the author of "Prophylaxis of OIs in the Age of Protease Inhibitors -- An Update" (Vol. 4, No. 5, pages 89-92) and a member of the editorial advisory board of HIV Newsline, comments:
The authors conclude that daily treatment with TMP/SMX to prevent PCP is the regimen of choice, despite the higher rates of adverse events. For patients who cannot tolerate this regimen, thrice-weekly dosing may be an acceptable alternative. Additionally, greater use of desensitization protocols, although somewhat laborious, should increase the percentage of people who will be able to withstand daily dosing.
As all clinicians who treat HIV-positive patients are well aware, adverse reactions to TMP-SMX -- principally severe rash -- are seen in a significant percentage of the individuals assigned to this standard prophylaxis against P. carinii pneumonia. In some studies of PCP prophylaxis, up to 35% of the participants found that they were unable to tolerate therapy with TMP-SMX (see "Update: Pneumocystis carinii Pneumonia,".)
In some instances it has proved possible to "treat through" adverse reactions to TMP-SMX by withdrawing the drug and then, after a washout period of several weeks, reintroducing the agent -- this time in liquid form and at a greatly reduced dose, which is then gradually titrated up to the standard dosage of one double-strength table daily.
ACTG 268 established that a gradual approach to initiation of therapy can avert a significant number of adverse reactions to TMP-SMX prophylaxis. In this clinical trial of patients with advanced disease (median baseline CD4 count: 169 cells/mm3), patients were randomly assigned to standard therapy or to ramped therapy at these daily dosages, which escalated at three-day intervals: 1, 2, 5, 10, and 20 mL.
After 14 weeks on their assigned regimen, 84% of the patients in the ramped therapy arm were still on therapy, versus 66% in the routine therapy arm (Figure). The investigators found that a number of characteristics -- among them serial CD4 counts below 100 cells/mm3 -- were predictive of therapeutic failure, but no single factor was as strongly predictive as mode of treatment: patients started on the full dose of TMP-SMX were 2.3 times more likely to discontinue therapy than those who received the ramped dose.
In ACTG 268, all subjects in the gradual-therapy arm were given a 4-oz. bottle of TMP-SMX in liquid form and were asked to take measured amounts once a day: 1/4 teaspoon on each of the first three days, 1/2 teaspoon on each of the next three days, and so forth. To help patients remember this stepped protocol, they were given a printed checklist for the dose-escalation period, and bottle checks were performed to ensure that patients were complying with the ramped-dosing schedule.
Why women may require therapeutic intervention at lower HIV RNA levels than men
Analyses of longitudinal cohort data have suggested that there may be differences in HIV RNA levels between men and women, with women tending to have lower HIV RNA levels than men who are at the same disease stage. If this is true, then HIV-positive women may require therapeutic intervention at lower HIV RNA levels than their male counterparts -- because they may, in fact, be sicker than their viral burdens suggest they are.
Increases in serum sildenafil levels can result in increased toxicity
Sildenafil (Viagra®) is indicated for the treatment of erectile dysfunction, but the phenomenal number of prescriptions being written for this new drug strongly suggests that it is being widely used by men who have normal libidos but who hope the drug will enhance their sexual performance. Men who frequent dance clubs routinely ingest controlled substances of dubious manufacture to alter their mood and amplify their sexual energy. It is reasonable to assume that they will experiment with Viagra in these venues. Indeed, anecdotal reports suggest that this experimentation is already well under way.
Sildenafil is metabolized via the cytochrome P450 pathway. The two oldest protease inhibitors, ritonavir and saquinavir, are both potent inhibitors of P450, and they are often prescribed in combination. When either or both are taken with Viagra the result can be increased blood levels of sildenafil -- and these elevated levels of sildenafil can lead to increased toxicity, including life-threatening hypotension.
Muirhead et al. conducted two randomized pharmacokinetic studies, each involving 28 healthy male volunteers, to assess the impact of ritonavir and saquinavir on sildenafil levels -- and the effect of sildenafil on levels of the two protease inhibitors. Ritonavir was shown to increase the area-under-the-curve concentration of sildenafil by 10.5-fold, and it increased the Cmax by 3.9-fold. Saquinavir increased the AUC and Cmax of sildenafil by 3.1-fold and 2.4-fold, respectively. Notably, sildenafil did not affect the pharmacokinetics of either ritonavir or saquinavir.
Muirhead GJ, Wulff, MB, Fielding A, et al. Pharmacokinetic (PK) interactions between the HIV protease inhibitors ritonavir (RTV) and saquinavir (SQV) and Viagra (sildenafil citrate). 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 26-29, 1999; San Francisco, CA. Abstract 659.
Dr. Judith A. Aberg, a member of the editorial advisory board of HIV Newsline, comments:
Diminished libido is a problem for many seropositive individuals, and erectile dysfunction and impotence are not uncommon in those with advanced disease. HIV-positive men who report reduced sexual drive or impaired function are often helped by testosterone injections -- which have the added benefit of reversing some of the symptoms of AIDS-related wasting. For these men, Viagra may also prove beneficial. Taken an hour before sex-play is initiated, Viagra helps men with a history of sexual dysfunction to attain and sustain an erection. My practice has been to recommend that HIV-positive patients with diminished libido take 25 mg of Viagra rather than 50 mg. At that dose patients report none of the vascular side effects of sildenafil, such as dizziness and/or headache -- complaints that are common at the standard dose of 50 mg.
The pharmacokinetic data gathered by Muirhead et al. indicate that when we prescribe Viagra to men who are taking ritonavir and/or saquinavir, the dose of sildenafil needs to be reduced. Because the optimal reduced dose has yet to be determined, we also need to caution patients that taking Viagra in combination with one or both of these protease inhibitors can potentially lead to a precipitous drop in blood pressure. (The same warning applies to the use of Viagra in combination with amyl or butyl nitrate, commonly known as "poppers." See "Something More You Need to Know About Viagra.")
Indeed, care providers would be wise to caution all of their sexually-active male patients who are taking ritonavir and/or saquinavir about the danger of hypotension when these protease inhibitors are combined with sildenafil. Viagra is widely available without prescription on the Internet, and providers should presume that these patients know about the drug's availability.
Thrice-weekly injections reduce infection rates and boost CD4 counts
GM-CSF (Neupogen®) is a cytokine currently used for the treatment of neutropenia. At the most recent ICAAC meeting, Angel and coworkers reported on a randomized placebo-controlled study of GM-CSF in 309 patients with advanced HIV disease (CD4 counts less than 50 cells/mm3) who had been clinically stable on antiretroviral therapy for at least 28 days. Participants received active drug or placebo (250 micrograms per dose, self-administered subcutaneously three times a week). Individuals with documented neutropenia were excluded from the study.
New data suggest that the transmission rate is higher than was previously thought
Oral sex has been classified as a low-risk mode of HIV transmission since the early days of the epidemic -- although no one has ever been able to quantify that risk or elucidate the mechanism of transmission. We still don't know exactly how infection occurs, but thanks to Dillon et al. we now have a better idea of how risky fellating an HIV-infected partner actually is. In a poster presented at the 7th Conference on Retroviruses and Opportunistic Infections, this group of investigators offered data indicating that 6.6% of the primary HIV infections seen in a cohort of gay and bisexual men and heterosexual men and women could be attributed to oral sex.
We know that the risk of transmitting HIV infection through oral sex is small -- small enough that risk-reduction counselors do not routinely discourage unprotected oral intercourse among sexually-active clients, particularly men who have casual sexual encounters with other men. The presumption has been that infection occurs only if semen is ingested (or comes into contact with a cut or open sore in the active partner's mouth).
The rationale behind this message is that prevention efforts should focus on reducing the overall risk of transmission -- and that the best way to do that is by not holding men who have sex with men to a "zero-risk" standard. As Dr. Thomas J. Coates, director of the Center for AIDS Prevention Studies, explains: "Sexual expression is a fundamental aspect of human nature, and when sexual activity is restricted to zero-risk activities, frustration is likely to build to the point of rebelliousness -- which can lead to distinctly unsafe sexual behaviors. Our hope is that by offering gay men some sexual leeway, a trade-off will be effected: more very-low-risk activity will occur, but as a result fewer breakouts of very-high-risk activity will occur."
Groups like CAPS recognize that sexual intimacy is as essential to well-being as proper nourishment, and their risk-reduction guidelines acknowledge that it is unreasonable to ask HIV-positive individuals to avoid having sex -- which is too primal, too pleasurable, and too central to human identity for most people to give up. Instead, they encourage their clients to give up those sexual activities that carry a high risk of infection.
Because unprotected receptive anal intercourse puts men who have sex with men at such high risk of infection, risk-reduction counselors have, in effect, accepted the trade-off that Dr. Coates speaks of -- and have not discouraged their clients from engaging in receptive oral sex. Unhappily, this enlightened approach to prevention has fostered the widespread misapprehension that oral sex is essentially risk-free. One of the most noteworthy findings of our study is that all of the men who reported oral sex as their only risk factor thought that this sexual activity was highly unlikely to lead to infection -- a dismaying level of ignorance among gay San Franciscans, who have access to the best community-based HIV education programs in the country.
The false assumption that it is virtually impossible to become infected with HIV through oral sex -- coupled with the equally false assumption that men with undetectable levels of HIV RNA cannot transmit the virus -- has led to incautious behavior on the part of many seronegative gay men. We know, thanks to half a dozen recent clinical studies, that transcription-competent virus can be found in the genitourinary tracts of men with undetectably low levels of HIV RNA in their serum (see "HIV in genital secretions: An important reservoir of transcription-competent virus.") And we now know, thanks to our study, that there is a modest but real risk of transmitting HIV infection through oral sex.
The data from our study must be interpreted with caution. Although we made every effort to elicit truthful responses from our subjects, the possibility exists that some of the men who claimed oral sex as their only risk factor did so because they did not want to admit to having engaged in more risky behaviors. Nonetheless, HIV counselors and care-providers alike need to stress that fellatio is not a risk-free activity. Virus is present in the pre-ejaculate and semen of seropositive men who have "undetectable" levels of HIV RNA, and seronegative men and women must be encouraged to remember this fact when they engage in sexual activity with HIV-positive partners. Partners must weigh the risks and benefits for themselves, but they should be told that oral sex is safer than some sexual activities, but it is not completely safe.
Back to the February 2000 HIV Newsline contents page.
This article was provided by San Francisco General Hospital. It is a part of the publication HIV Newsline.