Women and Children Get HIV Also!

     Judith A. Aberg, M.D., Medical Director, HIV Services, Washington University School of Medicine, AIDS Clinical Trials Unit

Finally this year there seemed more of an acknowledgement that both women and children have been devastated by this epidemic. African American women are the population most at risk of becoming positive yet little has been done studying this population. During the opening session, Kevin DeCock and Jeffrey Sachs discussed the global epidemic and the impact AIDS will have on this generation and the generation to follow. Despite our concerns, we seem to continue the adage of "all talk and no action". Even in the developed world, there continues to be abstracts (#494, #495 and #496) depicting how women, African-Americans, those in poverty are the least likely to get counseling, testing, laboratory tests and treatment. The irony of the whole thing is that the under-developed world is screaming for care and therapy while here in the United States we have patients that do have access to care yet do not receive care.

There were several anti-retroviral therapy trials discussed that did include a larger percentage of women in their cohort than in previous years. Kate Squires (Abstract 15) discussed the 24 and 48 week results of a protease inhibitor, BMS -232632, affectionately referred to as the "BMS compound". 38 % of this cohort was female. The BMS compound has several nice qualities including once daily dosing, fairly well tolerated and even if one develops resistance to the BMS compound, it does not share cross-resistance with other PI's currently on the market. Also, there was not a significant change in total cholesterol or lipids compared with nelfinavir. It is too early to determine if this compound will be associated with lipodystrophy. Kate Squires (Abstract 330) also presented the Women First Trial which compared twice daily vs three tmes daily combinations of nelfinavir (NFV) and saquinavir (SQV) in combination with 3TC and D4T. Although there was no significant difference between the two arms either virologically ( % of patients with undetectable viral load) or immunologically (increase in CD4 count), there was a trend toward improved virologic outcome and the drug levels of both NFV and SQV were higher among women taking the regimen twice daily.

Liver Toxicity & Rash in Women:

Women may experience drugs differently than men, we need trials just for women

The young John Bartlett from Duke (Abstract 19) discussed the disturbing news regarding severe liver toxicity associated with nevirapine. This was a double-blind, randomized study conducted in South Africa comparing FTC (emtricitabine), a nucleoside, with 3TC in a background of D4T and either nevirapine (NVP) if VL < 100,000 copies/ml or efavirenz (EFV) if VL > 100,000 copies/ml. 60% of this cohort was female and almost 90% black. Severe liver toxicity (Grade 3-4) occurred in 17% of those taking NVP compared with none in the EFV arm. 57% of the cases of severe liver toxicity were classified as Grade 4 (the worst). Of note 20% of females on NVP experienced severe liver toxicity compared with 12% of men on NVP. In addition, two females died! Both these women experienced Grade 4 liver complications around day 23-24. Data was not available regarding pregnancy (whether or not women in trial were pregnant). This brings to mind very critical questions that remain unanswered regarding the generalizability of previous trials done predominantly in gay white males from the USA. Fellay (Abstract 260) described marked variability in metabolism in drugs among patients due to genetic differences among Caucasians. One can only imagine that there may be strikingly more differences among the various ethnic groups as well as gender. We have not seen this extent of NVP associated liver toxicity in the USA and European studies. In fact, a recent article by Bersoff-Matcha, et al (Clin Infect Dis 2001;32:124-9) which retrospectively evaluated gender-related differences with NVP at 3 distinct geographically different centers in the USA noted an increase in severity of rash among women compared with men but failed to report any difference in liver toxicity. As NVP becomes the "drug of choice" for women in the developed world, this FTC-302 study discussed by Bartlett emphasizes the need to conduct more studies in other ethnic groups before we can make recommendations for all the world! Although HIV can infect anyone, it does not affect us all the same nor can it be treated the same for all.

So, what about Perinatal Transmission!

Treatment helps reduce transmission to newborns

A Tuesday afternoon symposia was devoted to discussing maternal-fetal transmission of HIV and its implications for care to women and children. Mary Glenn Fowler opened the session with incredible statistics showing that the transmission rate was down to 1% in infants whose mothers are on HAART. Dr. Fowler went on to discuss the increased rate of cesaerean sections among women in the developed world but it is unclear if all these women really needed c-section. (Abstract 702). Whether c-section offers any benefit to women on HAART with a low to undetectable viral load is unknown and the current recommendations are to offer c-section to all women who have a VL>1000 copies/ml at 36 weeks of gestation. Then you have real world (Abstract 703) in which Peters, et al described what was occurring in New York City. They retrospectively reviewed charts from 22 sites. Out of 1600 mothers in care, 80% had a prenatal HIV diagnosis and 76% of that group was prescribed HAART. 38% of the mothers had a c-sec (46 % of which were secondary to HIV status). They reported a transmission rate of 4% in the mothers who had received both prenatal (during pregnancy) and intrapartum ( during labor and delivery) antiretroviral therapy plus infants received therapy at birth. The mothers who did not take any antiretroviral therapy during pregnancy or delivery but allowed the infants to be treated had a transmission rate of 14% compared with 23% among mothers/infants who received no therapy. So, along with my social commentary above, we must ask ourselves why? Does HAART reduce the transmission of HIV from mother to infant? Absolutely. Does everyone have access to care? No, but the overwhelming population in the developed countries do. So, why aren't mothers in developed countries in care on HAART? Globally, we need to improve the infrastructure of healthcare which will allow all HIV infected individuals access to care but we must also address the reasons why those with access do not utilize the services that are available. Then there are women who are prescribed HAART, are adherent to their regimen and still have virologic failure, the so-called "unexplained failures".

Back to the Nevirapine (NVP) Issue

During the late-breaker session, Dr. Dorenbaum reported the results of PACTG 316, a phase III, randomized, double-blind controlled trial evaluating the safety and efficacy of intrapartum/postpartum NVP added to standard ART for the prevention of maternal-fetal HIV transmission. Women were randomized to receive either NVP or placebo during active labor and their infants received either NVP or placebo. The majority of the women were from the USA but several other countries were included. 58% of the women were black and 17% Hispanic. 41% of women were on combination therapy including a protease inhibitor. At the time of delivery, 49% of the women had undetectable viral loads. The transmission rate in the NVP treated infants was 1.5% compared with 1.4% in the placebo arm so there did not appear to be a benefit to adding a single dose of NVP at the time of delivery. Of concern is that 5/46 women with detectable viral loads developed NVP resistance after a single dose. No data on NVP resistance was available on the HIV-infected infants. In the HIVNET 012 study conducted in Uganda (Abstract 516) in which 23% of the women who transmitted HIV to their infants had a NVP resistant virus, 9/20 infected infants had NVP-resistant strains. Interestingly, the vast majority of the women with NVP resistance had the K103N mutation whereas the infant had the Y181C mutation. So, besides the concerns regarding liver toxicity, we must also consider the development of resistance. Further trials are in development comparing duration of infant prophylaxis on HAART especially during breast feeding.

So, what about Breastfeeding?

We know that HIV can be transmitted during breastfeeding. The big issue is that in the underdeveloped world the risk of infant non-HIV mortality from non-breast feeding is higher than in infants who are breastfed. Risk factors for breast feeding transmission include a younger maternal age, lower parity (number of pregnancies), maternal seroconversion (getting HIV) while breastfeeding, high maternal viral loads, duration of breastfeeding, lesions or abscesses of the breast and/or nipple. Breastfeeding poses a continuous risk yet it is interesting to note that perinatal HAART conferred some protection later on while breastfeeding. Dr. Fowler reported a breastfeeding transmission risk of 9-12% over 3-24 months. Future trials include giving NVP for various time courses to the infant during breastfeeding. As mentioned above, one of the concerns is the development of NVP resistance. I expect we will see more studies reported next year and at the International AIDS Conference. At the World AIDS Conference in Durban (Summer 2000), studies reported that women receiving ART to prevent perinatal transmission were generally successful initially. But after breastfeeding the rates of babies being positive significantly increased over time. You can read these reports on the NATAP web site in the Durban Reports in the Conference Reports section.

Rugrats to Adolescents:

Reservoirs, CD4 increases in children, the child's immune system is different than adults, should therapy be started earlier in infants?

Are children just little people? Should we treat them as adults? This was one of the hot questions during the conference as the new guidelines to wait until CD4 count <350 or symptomatic for adults was released. I won't even discuss whether children should be given pulsed therapy or structured treatment interruptions.

During the Tuesday symposium, Debbie Persaud discussed whether the latent reservoirs seen in adults are the same in children. As noted in adults, children do have this latent reservoir of virus and this persistance of viral replication makes it unlikely that we will ever be able to eradicate the virus. Katherine Luzuriaga focused her talk on the need to control HIV replication to allow long term survival, to delay and prevent clinical symptoms and to preserve the normal development of the immune system. She then discussed 2 PACTG trials. PACTG 345 evaluated AZT/3TC and RTV. PACTG 356 compared AZT/3TC/NVP vs AZT/3TC/NVP/ABC vs D4T/3TC/NVP/NFV. In both trials, the response was similar to those reported in adults with 60% children achieving an undetectable viral load, but unlike adults it took slightly longer for the children to become undetectable (median 20 weeks). Initiation of therapy prior to three months was associated with preservation of the immune system. As reported in adults, lymphoproliferative responses to p24 were not recovered although non-HIV immunity was restored. Further studies evaluating using a recombinant HIV/MVA vaccine to restore HIV specific immunity are planned. . Bill Borkowsky discussed immune reconstitution in children. Children have greater thymic activity and it has previously been reported that children have increased numbers of naïve cells compared with adults. CD4 cells in children increase on average 320-650 cells compared with 100-250 cells in adults. Dr. Borkowsky stated that the CD4 increase correlates inversely with age meaning that the younger you are, the greater the increase in CD4 cell count is which in turn correlates with thymic size. He also suggested that the CD4 count may not correlate with viral replication and in fact, children may have discordant CD4 counts and viral loads similar to those reported in adults. Dr. Borkowsky gave a strong argument for aggressive early treatment in infants given the consequences of HIV on both growth and development of the nervous system. It was less clear what the therapeutic approach in older children should be. There were subtle differences in immune reconstitution between children and adults. A report by Weinberg, et al (Abstract 688), examined the lymphoporliferative responses to Candida and Tetanus in children on a 4 drug HAART regimen. It has previously been reported that adults will mount a response to candida but not tetanus. Undetectable viral load at 24 weeks was significantly associated with the recovery of immune responses to both tetanus and candida. At week 40, children with higher CD4 and lower CD8 counts were more likely to have positive responses to both candida and tetanus.

Treatment: Kaletra, T-20, switch from PI to Efavirenz

Abstracts 677 and 685 were devoted to antiretroviral therapy in children. For the most part, the response rates to antiretroviral therapy was similar to adults. Saez-Llorens ,et al (Abstract 680) conducted a trail evaluating the use of lopinavir/ritonavir (LPV/r) in both naïve and ART-experienced children. 77% of the ART-naïve and 70% ART-experienced achieved HIV VL< 400 copies/ml at week 60. They reported few adverse advents. Church , et al (Abstract 681) reported the first study evaluating the safety and tolerability of T-20 in children. Three out of four in the 30mg/m2 and six out of eight in the 60 mg/m2 achieved a > 0.7 log decrease in HIV VL at day 7. Nine out of twelve children had achieved > 1 log decrease in HIV VL at week 8. McComsey, et al (Abstract 679) reported on the first switch study (Protease inhibitor changed to efavirenz). 15 children who had undetectable HIV VL for 4 months and had been on a PI for 6 months were followed for a mean of 32 weeks. All children remained undetectable and of note, their trigylceride levels decreased. Similarly, Machado, et al (Abtsract 682) evaluated EFV containing regimen on 38 Brazilian children who were either ART-naïve or experienced. 42% of the children were female and interestingly, female sex as well as baseline viral load were predictors of a better virologic response. As seen in the adult population, 56% children reported mild to moderate CNS side effects.

Speaking of side effects:

Lipodystrophy, bone disorders

Just as adults seem to be developing a whole host of metabolic consequences on ART, so do children. (Abstracts 649 and 653). Although in abstract 653, the group from Washington University did not report the metabolic disturbances described in the other posters, they only reported on 13 children, 11 of whom were on PI's. A careful look over the actual metabolic descriptions did show that there was a trend toward an increase in c-peptide as well as a trend for other metabolic disorders in the older children. I suspect over time and with a larger cohort, this group will develop metabolic disorders similar to those reported elsewhere. Of great concern, is the potential for bone disorders in children. Gaughan, et al (Abstract 638) reported avascular necrosis of the hip in children at a prevalence of 86/100,000 person years in HIV infected children compared with 6/100,000 in the HIV negative population. Typically this disorder in children occurs almost exclusively in males whereas in this study, 2/5 affected children were female

In summary, this year's meeting did address more issues regarding therapeutic options for women and children. Nevertheless, we end with similar questions as before. As we move ahead with future studies, we must take into account genetic variation, cultural differences, gender and age differences in metabolism. Studies should be stratified by gender to accurately depict the adverse events occurring with antiretroviral therapy whether it be hepatotoxicity or metabolic. We need to better define the reconstitution of the immune system. Is it the same for men and women? There are obvious differences between adults and children. Is there a difference by gender at any age? We need to understand the factors involved with adherence or even a much simpler question, why do people not seek care? And , why do those in care not want to take therapy? But then one could respond, why should I take therapy when the largest group of HIV experts cannot even tell me when the best time to take therapy is. One of the frustrations we all share is that we still do not know enough. It is difficult to advise people to follow recommendations when they are constantly changing and more adverse effects are being reported. We ask everyone to trust us because we believe we are doing the best we can with the information we have. Our patients learn from us and we learn from our patients. Overall, we have made a tremendous impact on HIV morbidity and mortality in the developed world. We need further efforts in prevention and transmission. Although some individuals displayed anger at our prevention efforts, prevention plays a large role. It is only with prevention and getting those infected into care and on treatment globally that we will continue to make this impact last.

Judith A. Aberg, M.D.
Director of HIV Services
Washington University, St Louis