Ermias DIRO

Thesis summary

The research included in this thesis aimed at investigating better management options for visceral leishmaniasis (VL) in people with HIV infection.

Leishmaniasis, a disease mainly found in remote and resource poor settings, is a neglected disease. As a result, our knowledge about the disease is limited. There are only a limited number of drugs available for treatment. The clinical management of VL in people with HIV infection is particularly challenging. Atypical clinical presentations occur that can delay the diagnosis. A rapid diagnostic test like the rK39 test that is ideal for field settings, performs poorly in people with HIV. The immune deficiency status of the patient makes it difficult to cure the patient. This is true for all available anti-leishmania drugs. Persistent parasitemia is common and cured patients may relapse within a few months. The two diseases reinforce each other and end up in profound immune deficiency that leads to the failure of both the HIV and the VL treatment. Eventually, patients with HIV/VL co-infection suffer from malnutrition and other opportunistic infections and die.

In this thesis, the different aspects of HIV/VL co-infection were studied. The research was done in northwest Ethiopia where the co-infection rate is high. First the available literature was reviewed. Only a few HIV/VL cohort studies were identified, with either a small sample size or with a high rate of lost to follow-up. The HIV prevalence among VL patients decreased from close to 50% in the early 1990th to 10-20% in the last few years. This is still more than 10 fold the national HIV prevalence. Thus, HIV/VL co-infection remains a major public health problem in the region. The treatment response to all anti-leishmania drugs was generally poor in patients with HIV co-infection. The best treatment outcome reported was a cure rate just above 80% with the use of AmBisome and miltefosine combination from a recent case series. There was no experience in the region with secondary prophylaxis for VL in people with HIV. In this review, we highlighted the knowledge gaps in the management of VL in people living with HIV.

Two major clinical challenges were addressed in this thesis. The first was the diagnostic challenge caused by the atypical clinical presentations of VL patients with HIV infection. These atypical manifestations include oral and rectal lesions, abdominal lymph node involvement and disseminated skin manifestations due to VL. The paper about these atypical manifestations aimed at alerting clinicians to take leishmaniasis into consideration in order not to delay the diagnosis.

The second challenge was the poor treatment response, i.e. low cure rate and high relapse risk. We assessed the treatment outcome of patients treated with sodium stibogluconate, the most commonly used drug for VL in Ethiopia. Although there were differences in the methods of diagnosis and assessment of cure compared with earlier studies (60-90% cure), our study showed a much lower cure rate than before – 43%. Serious toxicity was also high – 25% of the cases needed to discontinue the treatment. Treatment prolongation improved the success rate to 75%. The declining treatment response may be an early warning for the emergence of resistance. These findings call for the urgent need for safe and effective alternative drugs and for the establishment of a surveillance system for monitoring resistance against anti-leishmania drugs.

To decrease VL relapse rate a secondary prophylaxis clinical trial with monthly pentamidine was conducted for the first time in the region. In this study involving 74 patients, the probability of relapse free survival at the end of one year was 71%. A low CD4+ cell count was a risk factor for relapse. In a previous study from the same region, the annual risk of relapse in patients without secondary prophylaxis, was 56%, despite antiretroviral therapy. All other previous studies were small case series and case reports showing relapse rate of 50%-100% without prophylaxis. A meta-analysis of studies and reports on secondary prophylaxis from the Mediterranean region showed a reduction of recurrence from 67% to 31%. Thus, use of secondary prophylaxis reduces relapse rate. VL in people with HIV infection should be treated as early as possible before profound immune deficiency occurs. In our study patients were treated with anti-leishmania drugs until cure followed by secondary prophylaxis. They also received antiretroviral therapy. Despite this package of care the observed relapse speaks for the need for additional interventions for this group of patients. Other options such as new drugs, immune therapy, vaccine and nutritional interventions need to be investigated.

Some in vitro studies showed the anti-leishmania effect of HIV protease inhibitor drugs. The enhanced CD4 recovery with protease inhibitor containing ART regimens might also have clinical benefit on the treatment outcome of VL co-infection. The VL outbreak that occurred following the HIV pandemic in Europe was controlled after the introduction of antiretroviral therapy that often included a protease inhibitor drug. We reviewed the available evidence to see if there was enough evidence to consider a clinical trial with protease inhibitors. The anti-leishmania effect occurs only at high concentrations. With low doses given for patients with HIV, efficacy might be limited and emergence of resistant Leishmania parasites could pose a challenge. Thus, more research is needed before taking these drugs into a clinical trial.

A great deal was learned about the challenges of treating VL in people with HIV infection. However, there are still many research questions to be addressed to improve the clinical management of patients with HIV/VL co-infection. In the meantime, policy makers need to focus on the prevention and control of both diseases.