The rollout of ART has substantially reduced the risk for opportunistic infections among HIV patients in low- and middle-income countries, especially during the first year of treatment, according to a recently published meta-analysis of nearly 500,000 patients.
“In low- and middle-income countries (LMIC), the global rollout of ART has led to more than 15 million patients on ART, and a decline in HIV-related deaths by 40% since 2004,” Philippa J. Easterbrook, DTM&H, MPH, senior scientist in WHO’s HIV department, and colleagues wrote. “The profound effect of ART on the incidence of most HIV-related [opportunistic infections (OIs)] is the key reason for the observed global decline in HIV-related mortality, and highlights the continued priority of expanding ART access.”
Oral candidiasis, TB most frequent OIs
Although OIs are responsible for many morbidities and mortalities among people living with HIV, the impact of ART on OIs is not well-documented in LMICs due to a lack of routine country-level monitoring, Easterbrook and colleagues wrote.
To address this, the researchers reviewed study data on the incidence of 16 OIs among adults with HIV published from January 1990 to Nov. 21, 2013. Eligible data included incidence reports from prospective and retrospective observational cohort studies, as well as incidence rates observed within the placebo arm of randomized controlled trials. Studies including children or pregnant women, participants primarily infected with HIV-2, pre-selected populations or any others with nonreliable denominators were excluded. The researchers calculated incident risks for participants who were ART naive, undergoing their first year of ART or had been receiving ART for more than 1 year. The researchers also estimated the treatment costs and number of OI cases averted in LMIC due to early ART initiation (CD4 ≥ 200 cells/μL) in 2013.
Of the 952 journal citations and conference abstracts screened by the researchers, 126 studies met the analysis’ inclusion criteria. These comprised data from 89 cohorts or trials, and reported outcomes of 491,608 HIV patients living in 38 sub-Saharan African (n = 432,469), Asian (n = 42,243) and Latin American (n = 16,896) LMICs.
Among patients unexposed to ART, oral candidiasis (19.1%; 95% CI, 13-27.3), unspecified tuberculosis (10%; 95% CI, 8.7-11.5) and herpes zoster (9.4%; 95% CI, 6.7-13.2) were the most frequently observed OIs. With the exception of genital ulcer disease and bacterial pneumonia, all incidences were lowest among LMICs in sub-Saharan Africa.
Patients in their first year of ART demonstrated incidence reductions ranging from 57% to 91%, with the greatest declines seen in oral candidiasis, cerebral toxoplasmosis and Pneumocystis carinii pneumonia. The risk for OI during this time period was greatest for unspecified TB (4.2%; 95% CI, 3.5-4.9), pulmonary TB (3.5%; 95% CI, 2.9-4.3), herpes zoster (2.3%; 95% CI, 1.6-3.3) and oral candidiasis (2.3%; 95% CI, 1.6-3.4), with the risk for all other OIs decreasing to less than 2%.
In 2013, early ART was estimated to have prevented 857,828 OI cases (95% CI, 828,032-874,853) among LMICs, with an estimated cost savings of $46.7 million (95% CI, $43.6 million to $49.4 million).
Easterbrook and colleagues wrote that these findings demonstrate the importance of continued ART availability, but also the need for other interventions against OIs in this population.
“A significant proportion of HIV-infected persons continue to present with advanced disease, and so other measures to reduce mortality remain important,” they wrote. “This includes prompt initiation of [co-trimoxazole] prophylaxis, screening for TB and cryptococcal disease, and the use of isoniazid and fluconazole chemoprophylaxis in those with advanced disease.”
Resistance threatens ART efficacy
Despite these benefits, the increase in Viread (tenofovir disoproxil fumarate, Gilead Sciences)-resistant HIV strains within LMICs noted in another recently published study could jeopardize the treatment’s efficacy.
Ravindra K. Gupta, MRCP, honorary infectious diseases consultant at the University College London NHS Foundation Trust, and colleagues identified 44 clinical trials measuring tenofovir resistance in various world regions since January 1999. To be eligible for inclusion, patients were required to have documented virologic failure after first-line combination ART with tenofovir, resistance testing after virologic failure, use of a tenofovir-based ART for at least 4 months before failure, and no observed thymidine analogue mutations at testing. The study’s primary outcome was tenofovir resistance after virologic failure, with secondary outcomes including first-generation, non-nucleoside reverse-transcriptase inhibitors (NNRTIs) and cytosine analog resistance.
Gupta and colleagues’ final cohort included 1,926 individuals from 36 countries. On average, patients were aged 37 years and taking tenofovir for 14 months before failure.
The prevalence of tenofovir resistance ranged by region, with lower resistance rates seen in high-income areas such as Western Europe (20%) and North America (22%) and higher rates in low- or middle-income areas including Asia (39%) Southern Africa (56%), Eastern Africa (57%) and West/Central Africa (60%). Among the 700 patients who developed tenofovir resistance, many also demonstrated resistance to cytosine analogs (83%), NNRTIs (78%) or both (65%). Viral loads recorded upon treatment failure among patients with and without tenofovir resistance were similar, the researchers wrote, hinting that these resistant strains may be just as infectious as nonresistant strains.
“Tenofovir is a critical part of our armamentarium against HIV, so it is extremely concerning to see such a high level of resistance to this drug,” Gupta said in a press release. “It is [a] very potent drug with few side effects, and there aren’t any good alternatives that can be deployed using a public health approach. Tenofovir is used not only to treat HIV, but also to prevent it in high-risk groups, so we urgently need to do more to combat the problem of emerging resistance.” – by Dave Muoio
Disclosures: Easterbrook and colleagues report no relevant financial disclosures. Gupta reports receiving unrelated personal fees from Bristol-Myers Squibb and Janssen-Cilag. Please see the full study for a list of all other authors’ relevant financial disclosures.