HIV therapy in resource-limited settings can be a success in infants, with effective virological suppression and high adherence, report South African investigators in the July 11th edition of AIDS. With this evidence the expansion of treatment programmes to include the very young is now warranted, write the investigators, and they urge quick action so that HIV-positive infants around the globe can benefit from the same successes seen in the developed world.
In the developed world, effective HIV therapy has transformed paediatric HIV infection into a treatable chronic disease. However, in the developing world, it is still often a fatal infection. Over 2 million children are living with HIV in sub-Saharan Africa, and if untreated, 50% will die by the age of two. HIV progresses rapidly in the very young: by the age of six months, 85% of children will have immune damage so severe as to require treatment according to current guidelines.
While global programmes have expanded access to life-saving therapy in the developing world, infants and children are often missed. Of the estimated 600,000 HIV-positive children requiring treatment, less than 5% are being treated with anti-HIV drugs.
There are several obstacles to the provision of HIV treatment to infants. Diagnosis is difficult in newborns, the disease progresses rapidly, there are few infant drug formulations, and clinical expertise is often lacking. Furthermore, knowledge of optimal therapy for children lags behind that for adults, and most clinical studies are conducted with older children. The best way to use anti-HIV drugs in the very young remains unknown.
Infant treatment is also complicated by the fact that many children infected during pregnancy or delivery will acquire nevirapine-resistant virus, and that resistant virus may persist for at least one year after infection, reducing the effectiveness of nevirapine-based treatment for the infant.
There is an urgent need to understand how to best provide care to HIV-positive infants. To this end, an international team of South African, British and American investigators are studying approaches to antiretroviral treatment in newborns in resource-limited settings. Their three-year feasibility study is designed to look at clinical outcomes of three treatment strategies: deferred therapy, immediate continuous therapy and immediate therapy with structured interruptions. With data from the first year compiled, the investigators report combined data on virological response among all infants who received antiretroviral therapy. This study should not be confused with the CHER study, which also investigated immediate versus deferred treatment approaches in infants in South Africa.
From mid-2003 to late 2005, 740 babies were born to 719 HIV-positive mothers in two hospitals in KwaZulu Natal. Of the 75 babies confirmed to be infected with HIV, 63 were eligible for treatment: 43 were randomised to receive three-class therapy, 20 had treatment deferred until their CD4 percentage fell below 20%.
HIV treatment comprised the nucleoside reverse transcriptase inhibitors AZT (zidovudine, Retrovir) and 3TC (lamivudine, Epivir), with the protease inhibitor nelfinavir (Viracept) and the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine (Viramune). Three-class therapy was used due to the unknown effect on treatment response of nevirapine exposure during birth (39% of infants had baseline resistance to nevirapine), and because viral load suppression is more difficult to achieve due to the very high levels of viral load often seen in infants. Nevirapine was discontinued if the child achieved a viral load below 50 copies/ml.
Of those receiving immediate therapy, 36 completed one year of therapy. Of those in the deferred arm, 17 of 20 had their CD4 percentage fall below 20% (median 99 days), and 13 started therapy. Mean adherence to therapy was 99% when assessed verbally and 95% when measured by returned pill count.
At one year, 49 of 49 (100%) had a viral load below 400 copies/ml. Forty-six of 49 (94%) had a viral load below 50 copies/ml: 34 of 36 infants in the immediate treatment arm and 12 of 13 infants in the deferred arm. Ten infants required a second-line therapy due to virological failure or tuberculosis treatment, meaning 39 of 49 (80%) achieved a viral load below 400 copies/ml in an intent-to-treat analysis.
The median time to undetectable viral load (below 50 copies/ml) was not different between the two groups: 121 days in the immediate group and 115 days in the deferred group. The time to undetectable viral load was associated with maternal CD4 count and infant viral load.
NNRTI mutations showed no significant effect on the efficacy of HIV treatment, despite 39% of infants showing genotypic resistance to NNRTIs.
Death rates did not differ significantly between the immediate and deferred HIV treatment groups, five of 43 (12%) and one of 20 (5%), respectively. However, infants in the immediate group who started therapy by age two months had few illnesses (p = 0.003) and were less likely to be admitted to hospital (p = 0.09) than infants in the deferred group.
The apparent lack of difference in death rates between the groups contrasts with findings from the CHER trial, which stopped its deferred treatment arm early due to a four-fold higher rate of death compared with its immediate treatment arm (16% versus 4%, respectively). Whether the lack of difference is due to the small sample size or other factors is not clear and the investigators suggest that differences may appear later in the trial.
The investigators conclude, “Excellent adherence and virological suppression are achievable in infants, despite high-frequency NNRTI mutations and rapid disease progression.”
“This study,” they continue, “provides the much-needed evidence that early treatment is successful in resource-limited settings. Although the question of optimal regimens and timing of treatment needs to be clarified, this should not delay expansion of infant antiretroviral therapy provision so that the success achieved in resource-rich countries can be replicated in resource-limited countries globally.”
They also note that more research is needed to determine the optimal regimens for use after infant exposure to single dose nevirapine. Scored tablets that are crushable and dissoluble in water containing d4T, 3TC and nevirapine are available for infant treatment, but the protease inhibitors nelfinavir and lopinavir/ritonavir must be given as liquids to infants; paediatric lopinavir/ritonavir (Kaletra) tablets must not be broken and are unsuitable for use in children weighing less than 15kg (the weight generally achieved between two and three years of age in healthy infants). This means that triple class treatment that can overcome nevirapine resistance will remain complex for the foreseeable future.
Prendergast A, et al. Early virological suppression with three-class antiretroviral therapy in HIV-infected African infants. AIDS 22:1333 – 1343, 2008.