Section by Judith A. Aberg, M.D., Kathleen Squires, MD, and Jules Levin

At this year’s Retrovirus Conference, there seemed more of an acknowledgement that both women and children have been devastated by the HIV/AIDS pandemic worldwide, and in the US, particularly African American and Hispanic women.

During the Opening Session, Dr. Kevin DeCock of the Centers for Disease Control and Prevention (CDC) and Dr. Jeffrey D. Sachs of Harvard University discussed the global HIV/AIDS pandemic and the impact it will have on the current and future generations. Despite our concerns, we seem to continue the adage of "all talk and little action". Even in the developed world, there continues to be reports depicting how women, African-Americans, and those in poverty are the least likely to get counseling, HIV testing, related laboratory tests and treatment (abstracts 494, 495, 496). The irony is that resource-poor countries are screaming for help with care and therapy, while even here in the United States we have patients that do have relative access to care, yet do not receive care.

A search of the official CD-ROM of the program and the abstracts presented at the conference utilizing the words "woman" or "gender" reveals approximately 100 abstracts. In reality, the number of abstracts that actually cover subjects specific to the manifestations of, course of disease, and efficacy and/or toxicity of antiretroviral therapy in HIV-infected women is a much more modest twenty-six. If one adds associated conditions such as cervical dysplasia and genital HPV infection, the total rises to thirty-one. This relative paucity (scarcity) of data needs to be considered in light of the fact that women comprise the majority of affected individuals in Sub-Saharan Africa and up to 40% of recent infections in some sections of the United States. Despite clear evidence that a number of medical conditions (perhaps the best studied is heart disease) differ significantly in male and female patients, the assumption is that there is no substantial difference in HIV infection between the sexes. A number of observations from clinical trials or cohort studies do however suggest gender-based differences in a number of areas ranging from viral load to toxicities and side effects to utilization of health care resources. Prospective hypothesis-driven studies are needed to determine the significance of these findings.

On the positive side, more studies are including larger percentages of enrolled women (abstracts 15, 330, many others). Some differences in treatment responses and adverse events among women have been reported elsewhere in this newsletter, see page 21.

Combination oral contraceptives ("birth control pills") might increase the risk of HIV transmission through the vagina, according to Dr. M. Prakash of Imperial College in London, UK (abstract 76). This is due to an increase in "CCR5" co-receptor expression on immune cells in the cervix of women taking combined oral contraceptives. CCR5 is a co-receptor that HIV uses to infect cells. Control women were not taking contraceptive medication. This was a small and preliminary study, and requires confirmation in larger studies. However, the findings were of concern.

Heterosexual transmission
Studies involving highly exposed but sero-negative women (Abstract 51) suggest that the major difference between them and women who do become infected through ongoing monogamous relationships is their ability to generate HIV-specific activity in immunologic assays. Review of factors that may affect heterosexual transmission in both discordant couple cohorts and mathematical models document that the level of viral load and history of or presence of an STD in the partner (Abstracts 221-223) are associated with an increased risk of transmission. These cohort studies have been instrumental in defining host genetic, virologic and immunologic correlates of transmission.

The identification of topical microbicides that allow women to control their contraceptive choices is an important area of research. Preliminary data was presented on PRO 2000, a gel antimicrobial compound that is active against HIV-1, HIV-2, herpes simplex viruses, chlamydia and gonococci. In a study utilizing female rhesus macaques, the majority of animals treated with 3 different concentrations of PRO 2000 remained infection free in contrast to all animals in the control group who were uniformly infected with SHIV within two weeks of challenge (Abstract 721).

In abstract 720, it was reported that ß- cyclodextrin (CD) is a cholesterol-removing compound that has effects on cell membranes, specifically on lipid rafts, the sites from which HIV-1 buds from infected cells. The study reported that CD (3%) is non-toxic to vaginal epithilium of theHuPBL-scid mice used in this test tube experiment and inhibits the vaginal transmission of cell-associated HIV-1 in this mouse model. Authors concluded CD warrants further evaluation as a vaginal microbicide to prevent HIV-1 transmission.

Disease Progression, Gender Differences in Viral Load & CD4
One recurring question is whether the variations in estrogen and progesterone that occur in pregnancy or menopause impact HIV disease progression. CD4 cell counts in 487 women participating in the European Women Study were analyzed in relation to the woman’s hormonal status. Postmenopausal and pregnant women had lower CD4 cell counts than pre-menopausal or non-pregnant women. These changes may reflect the changes in levels of reproductive hormones and may help to explain the gender difference in CD4 cell counts that has been reported (Abstract 205). Other studies, however, have documented that CD4 cell counts in pregnant women rapidly return to baseline after delivery; additional studies are needed to determine the implication of varying hormone levels on CD4 cell counts, viral load and long-term outcome. In the only session that offered oral presentations on HIV infection in women, Dr. Pitt reported on gender differences in immunologic and virologic markers in children born to HIV-infected women (Abstract 513). The import of this study lies in the finding that CD4 cells in HIV-infected and uninfected female babies were significantly higher than CD4 cells in both groups of male babies and HIV RNA levels were lower in infected female compared to the male babies (not statistically significant). These findings parallel those seen in HIV-infected adults and suggest that non-hormonal mechanisms need to be considered since children of this age have similar hormonal environments.

Differences in access to care, prescription of HAART-based regimens, and HIV progression by sex and injection drug use persist (Abstracts 488 and 494). Although the use of HAART-based regimens has increased in all patient groups over the past several years, the gains have not been equally distributed over all the groups. A common theme is that certain populations of patients-women and/or African-Americans and/or IDUs-are less likely to benefit from the improvement in long-term outcome, in part due to more limited access. HIV-infected women are disproportionately represented in these patient populations.

Complications of Disease and Therapy

Pancreatitis
Dr. Moore and colleagues determined the incidence of pancreatitis in HIV-infected patients attending the Johns Hopkins HIV Clinic who were receiving NRTI’s (Abstract 620). Of note, female sex was an independent risk factor for pancreatitis in addition to the use of hydroxyurea and the "d" drugs-ddI and d4T (Moore did not analyze data to see if pregnancy was a risk factor).

Hepatoxicity
Boehringer-Ingelheim recently revised the management guidelines in the nevirapine package insert to indicate that liver function tests should be monitored closely, especially during the first eight weeks of therapy, to assess for drug-related hepatotoxicity. These guidelines were based, in part, on the reports of severe liver toxicity seen in FTC-302, a randomized study comparing FTC and 3TC with a background regimen of d4T and either nevirapine and efavirenz (Abstract 19). Ten percent of the patients receiving nevirapine experienced grade 4 elevations in liver enzymes; the incidence of grade 4 elevations in women was twice that of males. Two patients developed liver failure and died; both were women. Women were more impacted by hepatotoxicity in this study than men. This study was discussed in more detail on pages 20-21.

Genital Human Papilloma Virus Infection and Cervical Intraepithelial Neoplasia; consider routine biopsy
It is not clear if HAART can change the natural history of cervical intraepithelial neoplasia (CIN) in the same way that it has impacted most of the HIV-associated opportunistic infections. Dr. Heard and colleagues reported that biopsy-proven CIN either reverted to normal or regressed to a lower grade at a significantly higher rate in a group of HIV-infected women followed in France receiving HAART-based regimens (Abstract 518). The number of women who had high-grade CIN at baseline was much higher than has been reported in earlier studies. There are ongoing studies that should help delineate the impact of HAART on this commonly encountered infection. Data from the WIHS cohort indicate that the correlation between either cervical cytology or colposcopic impression and biopsy is poor and biopsy of visible lesions should be routinely considered for the optimal management of HIV-infected women with abnormal cervical smears (Abstract 722).

Mother-to-Infant HIV Transmission
An entire Symposium was devoted to discussing mother-to-child transmission of HIV and its implications for care to women and children (session 36). (The session’s entire audiovisual is available on the Internet at www.retroconference.org) Dr. Mary Glenn Fowler of the CDC opened the session with impressive statistics showing that the HIV transmission rate has decreased to 1% in infants whose mothers are taking HAART (abstract S12). She also discussed the increased rate of cesarean ("C") sections among HIV positive women in the developed world, but it is unclear whether all these women really needed cesareans (abstract 702). In the United States, the proportion of deliveries by caesarian section increased from 19% in 1994 to 44% in 2000 with the greatest increase in 1999. Whether "C-section" offers any benefit to the newborn whose mother is taking HAART and has a low to undetectable viral load is unknown. Current recommendations are to offer "c-section" to all HIV positive women who have an HIV viral load greater than 1000 copies per milliliter at 36 weeks of pregnancy.

Indeed, in a Late Breaker presentation, Dr. A. Dorenbaum of Emeryville, California reported that 2 doses of nevirapine (NVP, Viramune, NNRTI drug) did not further reduce the HIV "perinatal" transmission rate from pregnant women already taking an anti-HIV drug regimen (abstract LB7). A total of 1,506 pregnant women (58% Black, 17% Hispanic) were enrolled in PACTG 316, a phase III study primarily in the US and France. Women were randomized to NVP or placebo, one dose during labor and one dose for the infant between ages 2-3 days. The treatment was AZT (zidovudine monotherapy, Retrovir, NRTI drug) monotherapy for 23%, AZT + 3TC (lamivudine, Epivir, NRTI drug) for 28%, and PI drug combination therapy for 41%. At the time of delivery, 49% had an undetectable viral load with a lower limit of 400 copies per milliliter. One-third had cesarean sections. The results showed an equal 1.5% transmission rate in both the ART + NVP and ART + placebo arms. An equal number were classified as infected at (prior to) birth in both arms. There was a non-significant increased risk of HIV newborn transmission from mothers who at delivery had lower CD4 counts, higher HIV RNA levels or whose infants were delivered vaginally by "forceps" (metal tool) or from women who were Black. Of concern is that 5 of 46 women with detectable viral loads developed NVP resistance after only a single dose. Interestingly, Dr. S. H. Eshleman of Johns Hopkins University in Baltimore, Maryland reported that in the HIVNET 012 study whereby pregnant HIV positive women from Uganda and their newborns each took only one dose of NVP (no other ART), 23% of the mothers who transmitted HIV to their infants developed NVP-resistance, as did 9 of 20 infected infants (abstract 516). Thus, short-course (1-2 doses) of NVP might have some limitations in the setting of preventing mother-to-newborn transmission and widespread resistance might limit its impact in resource-poor countries.

A "meta-analysis" (combined) of 7 prospective European and US studies evaluating mother-to-newborn HIV transmission was presented by Dr. J.P.A. Ioannidis from Greece (abstract 517). Among 1,202 women with HIV-1 RNA less than 1,000 copies per milliliter at or close to the time of delivery, only 44 cases of "vertical" transmission occurred (4%). However, the transmission rate was only 1% (8 of 834) for mothers receiving anti-HIV treatment during pregnancy and/or at delivery, compared to 10% (36 of 368) for untreated mothers. In "multivariate" statistical analysis, transmission was lower with anti-HIV treatment, cesarean ("C") section, higher birth weights and higher maternal CD4 cell counts.

Dr. Robert Janssen of the CDC reported that from 1992-99, mother-to-newborn HIV transmission in the US from 33 reporting sites declined by about 81% and AZT (zidovudine, Retrovir) use during pregnancy increased to approximately 90% (abstract S20). He reviewed results from Bangkok demonstrating an increasingly proportional "perinatal" HIV transmission risk with increasing maternal viral loads in blood at the time of delivery.

In New York City, much success has been achieved in decreasing HIV transmission to newborns, according to Dr. V. Peters from the Department of Public Health there (abstract 703). Dr. Peters retrospectively (after the fact) reviewed charts of HIV-exposed infants from 22 sites from 1996-1999. Out of 1,600 mothers in care, 80% had a prenatal HIV diagnosis and 76% of that group was prescribed HAART. A "C-section" occurred in 38% of the mothers, 46% of which were due to HIV. There was an overall HIV transmission rate of 4% from the mothers who had received both prenatal (during pregnancy) and intrapartum (during labor and delivery) anti-HIV therapy and whose infants received standard therapy after birth. Unfortunately, not all HIV positive women were identified before labor or had not taken anti-HIV medication during pregnancy.

Although HAART greatly reduces mother-to-newborn HIV transmission, there have been some related concerns about potential toxicity to HIV negative infants exposed to therapy. Dr. J.F. Delfraissy of Enquete Perinatale Francaise in Paris, France reported on symptoms of "mitochondrial" (energy producer of cells) abnormalities in children born to HIV-infected mothers (abstract 625B). The researchers are conducting an ongoing, prospective investigation for "symptoms consistent with mitochondrial abnormalities" in a French cohort of 4,083 HIV negative infants at least 6 months of age, including 1,874 who were not exposed to anti-HIV therapy and 2,209 infants with exposure to ART. Symptoms of mitochondrial dysfunction are determined by the medical record. The interim results showed that among children exposed to ART from 1986-1999, 101 files were selected and 9 had "mild suspicion of mitochondriopathy" (class I), 6 had strong suspicion of mitochondriopathy (class II), and 10 had confirmed mitochondriopathy (class III). Whereas, in the group of 1,874 children who were not exposed to ART, 23 files were selected and no cases of mitochondriopathy were found. The researchers qualified their findings by stating that the diversity of symptoms and difficulty in confirming or ruling out a mitochondrial origin (whether the problem was really due to mitochondrial dysfunction) makes their work difficult. Many attendees concurred, and this limits the significance of the findings somewhat. The conclusions were, "Symptoms consistent with persistent mitochondrial dysfunction are significantly more frequent in the children exposed to antiretroviral drugs." Similar analyses performed in the US have not revealed any evidence of mitochondrial problems in HIV negative infants exposed to anti-HIV therapy. The controversy continues.